OTOTOXICITY

OTOTOXICITY
Peter S. Roland, MD
Professor and Chairman
Department of OtolaryngologyHead and Neck Surgery
The University of Texas Southwestern Medical Center at Dallas
Dallas, Texas

John A. Rutka, MD, FRCSC

Associate Professor
Department of Otolaryngology
University of Toronto
Staff Neurotologist
University Health Network
Co-Director
Multidisciplinary Neurotology Clinic
and University Health Network Centre for Advanced Hearing and Balance Testing
Toronto, Ontario

2004
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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including
choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However,
since research and regulation constantly change clinical standards, the reader is urged to check the product information
sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is
particularly important with new or infrequently used drugs. Any treatment regimen, particularly one involving medication,
involves inherent risk that must be weighed on a case-by-case basis against the benefits anticipated. The reader is cautioned
that the purpose of this book is to inform and enlighten; the information contained herein is not intended as, and should
not be employed as, a substitute for individual diagnosis and treatment.
 This book is dedicated to our families:

Marilena, Jake, Fiona Lauren, and Rory

Melissa, Melinda, Evelyn, Jason, Britney, Kenzey and Thomas

 Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 10. Macrolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Andrew R. Scott, BM, BS, MPhil, FRCS(ORL-HNS),
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
and John A. Rutka, MD, FRCSC
Section I Anatomy and Physiology
1. Anatomy and Physiology of the Cochlea . . . . . . . . 1 Section III Topical Toxicity
Karen S. Pawlowski, PhD 11. Middle Ear Effects of Ototopical Agents . . . . . . 107
2. Physiology of the Vestibular System . . . . . . . . . . . 20 Charles G. Wright, PhD, and Peter S. Roland, MD
John A. Rutka, MD, FRCSC 12. Topical Aminoglycoside Cochlear Toxicity . . . . 114
Peter S. Roland, MD, and Charles G. Wright, PhD
Section II Systemic Toxicity
13. Topical Aminoglycoside Vestibular Toxicity . . . 121
3. Salicylates, Nonsteroidal Anti-inflammatory Narayanan Prepageran, MBBS, FRCS(Ed),
Drugs, Quinine, and Heavy Metals. . . . . . . . . . . . 28 FRCS(Glas), MS(ORL), Vitaly E. Kisilevsky, MD,
Narayanan Prepageran, MBBS, FRCS(Ed), and John A. Rutka, MD, FRCSC
FRCS(Glas), MS(ORL), and John A. Rutka, MD,
FRCSC 14. Chloramphenicol, Colymycin, and Polymyxin . 128
Leonard P. Rybak, MD, PhD, and
4. Ototoxicity of Loop Diuretics . . . . . . . . . . . . . . . . 42 Srinivasan Krishna, MD, MPH
Narayanan Prepageran, MBBS, FRCS(Ed),
FRCS(Glas), MS(ORL), Andrew R.Scott, BM, 15. Topical Antifungals . . . . . . . . . . . . . . . . . . . . . . . 134
BS, MPhil, FRCS (ORL-HNS), and Lawrence W. C. Tom, MD, Lisa M. Elden, MS, MD,
John A. Rutka, MD, FRCSC and Roger R. Marsh, PhD

5. Cinical Uses of Cisplatin . . . . . . . . . . . . . . . . . . . . 50 16. Surgical Disinfectants and Antiseptics . . . . . . . . 140

Jeremy Sturgeon, MD, FRCPC Andrew R. Scott, BM, BS, MPhil, FRCS(ORL-HNS),
Narayanan Prepageran, MBBS, FRCS(Ed),
6. Ototoxicity of Platinum Compounds . . . . . . . . . 60 FRCS(Glas), MS(ORL), and John A. Rutka, MD,
Michael Anne Gratton, PhD, and FRCSC
Brendan J. Smyth, PhD, MD
7. Iron Chelating and Other Chemotherapeutic
Section IV Interventions
Agents: The Vinca Alkaloids . . . . . . . . . . . . . . . . . 76
Andrew R.Scott, BM, BS, MPhil, FRCS(ORL-HNS), 17. Genetic Factors in Aminoglycoside
Narayanan Prepageran, MBBS, FRCS(Ed), Ototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
FRCS(Glas), MS(ORL), and John A. Rutka, MD, Nathan Fischel-Ghodsian, MD
FRCSC
18. Audiologic Monitoring for Ototoxicity . . . . . . . 153
8. Clinical Aminoglycoside Ototoxicity . . . . . . . . . . 82 Kathleen C. M. Campbell, PhD
Coleman Rotstein, MD, FRCPC, and
19. Monitoring Vestibular Ototoxicity . . . . . . . . . . . 161
Lionel A. Mandell, MD, FRCPC, FRCP(Lond)
Vitaly E. Kisilevsky, MD, R. David Tomlinson,
9. Mechanisms for Aminoglycoside Ototoxicity: PhD, Paul Ranalli, MD, FRCPC, and
Basic Science Research . . . . . . . . . . . . . . . . . . . . . . 93 Narayanan Prepageran, MBBS, FRCS(Ed),
Jochen Schacht, PhD FRCS(Glas), MS(ORL)
viii Contents

20. Ototoxic Damage to Hearing: Section VI Medicolegal Concerns

Otoprotective Therapies . . . . . . . . . . . . . . . . . . . 170
23. Medicolegal Aspects of Ototoxicity . . . . . . . . . . 198
Thomas R. Van De Water, PhD, and
Peter E. Rhatican, JD, Sloan H. Mandel, LLB, and
Leonard P. Rybak, MD, PhD
John A. Rutka, MD, FRCSC
Appendix 1: Information Provided to Lawyers. . . . . 207
Section V Therapeutic Uses of Ototoxic Effects
Appendix 2: Summary of the 2004 AAO-HNS
21. Systemic Treatment of Bilateral Menieres
Consensus Panel Recommendations . . . . . . . . . . . . . 213
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Sumit K. Agrawal, MD, and Appendix 3: Major Groups of Agents Recognized
Lorne S. Parnes, MD, FRCSC to be Ototoxic in Humans . . . . . . . . . . . . . . . . . . . . . 214
22. Intratympanic Gentamicin in the Treatment of Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Menieres Disease . . . . . . . . . . . . . . . . . . . . . . . . . 191
Brian W. Blakley, MD, PhD, FRCSC
 Preface


Ototoxicity can be broadly defined as the tendency of
certain substances, either systemic or topical, to cause
functional impairment and cellular damage to the
tissues of the inner ear and especially to the end organs
of the cochlear and vestibular divisions of the eight
cranial nerves. Much less frequent would be the find-
ing of impairment or injury at the level of the central
nervous system.
In relative terms, ototoxicity is not common. It
nevertheless generates much interest amid controversy
for those physicians who treat often life-threatening
medical conditions with potentially ototoxic medica-
tions (primum non nocere) and for basic science
researchers who try to determine at a genetic and cel-
lular level the underlying pathophysiology of injury in
the hopes of one day being able to prevent damage or
perhaps even to regenerate damaged end-organ hair
cells (fiat lux). However, we should never forget that
when ototoxicity occurs it is not victimless and it places
a truly considerable burden of disability on the affected
individual. To lose ones hearing profoundly limits
ones abilities to communicate and socialize in a hear-
ing world; to lose ones balance literally robs one of the
ability to perform physical activities and ultimately
limits independence.
The book is divided into several sections according
to broad topics. We approach ototoxicity with a basic
review of the anatomy and physiology of the cochlea and
the vestibular system. This is followed by chapters pri-
marily concentrating on those agents that under certain
circumstances have proven to be ototoxic, both histori-
cal agents (eg, acetylsalicylic acid, quinine, and the
aminoglycoside class of antimicrobial therapy) and some
recently introduced (eg, azithromycin, deferoxamine).
Many of the books clinical chapters focus on the
phenomenon of systemic aminoglycoside and plat-
inum-based chemotherapeutic ototoxicity. In this
regard there is no doubt that if we could eliminate all
aminoglycosides, for example, we would certainly wit-
ness a significant decline in ototoxicity in most of the
industrialized world and in those populations (specif-
ically in China) where certain genetic predispositions
serve to make an individual extraordinarily sensitive to
their ototoxic effects. Unfortunately, the above scenario
is unlikely to occur in the foreseeable future, as clinical
indications for aminoglycoside therapy (often life-
threatening sepsis), their convenience for use in outpa-
tient treatment (single daily dosing), their overall lack
of bacterial resistance, and the pharmacoeconomics
(low per-unit cost) suggest they will be with us for
some time. Until basic science research into the mech-
anisms of aminoglycoside and platinum-based ototox-
icity might provide us with new clinically applicable
treatment stratagems for its prevention (and even hair
cell regeneration), clinicians still need to monitor
patients appropriately for early changes indicative of
cochleovestibular dysfunction and to act accordingly
on those findings.
One of the great controversies addressed in this
book deals with the occurrence of topical aminoglyco-
side ototoxicity arising from the treatment of middle ear
sepsis in the presence of a tympanic membrane defect.
As recently as the 1980s most clinicians would have felt
this to be a rare and mostly theoretical concern in
humans, despite animal experimental data to the con-
trary. The efficacy of concentrated topical gentamicin in
the treatment of incapacitating unilateral Menieres dis-
ease drew attention to this agents primary vestibulo-
toxic nature. This ultimately led to the recognition in
certain patient cohorts and later its demonstration in a
series of patients with Menieres disease that commonly
used commercially available gentamicin ear drops could
also be ototoxic in humans if used long enough in the
presence of a dry middle ear. The development of non-
ototoxic fluoroquinolone antibiotic drops, for example,
represents a major advance in the treatment of open
middle ear sepsis and was in part expedited by major
concerns regarding topical aminoglycoside ototoxicity.
Recognizing that topical ototoxicity exists introduces
the possibility that whatever gets into the middle ear
x Preface
may eventually make its way into the inner earthis
should give us pause when using other ototopical agents
and even the disinfectants and antiseptics routinely
used in ear surgery.
The final chapter looks at the medicolegal aspects
of ototoxicity through the eyes of two distinguished
trial lawyers, Sloan Mandel (Canada) and Peter Rhati-
can (United States). Although the laws between these
two countries differ, the concepts behind them regard-
ing the standard of care, harm, and what constitutes
appropriate informed consent are remarkably similar.
A learned discussion follows each presented case his-
tory involving ototoxicity, which the clinician is urged
to read carefully (it might help prevent a medicolegal
action from occurring in future).
The inclusion of three appendices at the end
brings our book to a close. Appendix 1 provides the
reader with full disclosure and the expert information
our trial lawyers would have used to formulate their
opinions. Appendix 2 contains a summary of the 2004
American Academy of OtolaryngologyHead and
Neck Surgery (AAO-HNS) Consensus Panel Recom-
mendations regarding the use of potentially ototoxic
topical antibiotics for middle ear use. This landmark
report founded on evidence-based medicine (EBM)
sets a new standard for patient care and should be
carefully read by all physicians who use topical therapy
for the treatment of middle ear disease. In Appendix 3
we have provided a handy reference list for those
agents currently recognized to be ototoxic in humans
should there ever be any doubt.
We are indebted to several individuals whose help
made this book possible. We acknowledge the vision of
Chuck Inman, who challenged us while providing us
with the necessary encouragement to write this book.
We thank our publisher and those individuals at
BC Decker Inc, namely Rochelle Decker, Paula Presutti,
and Monika Holden, for their help with the organiza-
tion, editing, typesetting, and the usual things publish-
ers do. Many of the illustrations in the book and on its
cover were made possible by permission from Solvay
Pharma; with thanks to Meena Bhogal for her assistance
in this matter. We would be remiss to not specifically
thank the many authors who wrote their chapters with-
out complaint and in a timely fashion. To them we are
eternally grateful. Finally, we would like to formally
acknowledge the respective roles of our families, who
understood our need to complete this work, which has
constituted the better part of our academic life over the
past decade, and provided us the latitude to do so.
PETER ROLAND
JOHN RUTKA
July 2004
 List of Contributors


Sumit K. Agrawal, MD Roger R. Marsh, PhD
Department of Otolaryngology Department of OtorhinolaryngologyHead and Neck Surgery
University of Western Ontario University of Pennsylvania
London, Ontario Philadelphia, Pennsylvania

Brian W. Blakley, MD, PhD, FRCSC Lorne S. Parnes, MD, FRCSC

Department of Otolarygology Department of Otolaryngology and Clinical
University of Manitoba Neurological Sciences
Winnipeg, Manitoba University of Western Ontario
London, Ontario
Kathleen C. M. Campbell, PhD
Karen S. Pawlowski, PhD
Department of Surgery
Department of OtolaryngologyHead and Neck Surgery
Southern Illinois University School of Medicine
University of Texas Southwestern Medical Center
Springfield, Illinois
Dallas, Texas
Lisa M. Elden, MS, MD Narayanan Prepageran, MBBS, FRCS(Ed), FRCS(Glas),
Department of OtorhinolaryngologyHead and Neck Surgery MS(ORL)
University of Pennsylvania Department of Otorhinolaryngology
Philadelphia, Pennsylvania University Health Network
University of Toronto
Nathan Fischel-Ghodsian, MD
Toronto, Ontario
Department of Pediatrics
Cedars-Sinai Medical Center Paul J. Ranalli, MD, FRCPC
Los Angeles, California Department of Medicine
University of Toronto
Michael Anne Gratton, PhD Toronto, Ontario
Department of OtorhinolaryngologyHead and Neck Surgery
University of Pennsylvania School of Medicine Peter E. Rhatican, JD
Philadelphia, Pennsylvania Mendham, New Jersey

Vitaly E. Kisilevsky, MD Peter S. Roland, MD

University Health Network Department of OtolaryngologyHead and Neck Surgery
University of Toronto The University of Texas Southwestern Medical Center at Dallas
Toronto, Ontario Dallas, Texas

Coleman Rotstein, MD, FRCPC

Srinivasan Krishna, MD, MPH
Department of Medicine (Infectious Diseases)
Department of Surgery
McMaster University
Southern Illinois University School of Medicine
Hamilton, Ontario
Springfield, Illinois
John A. Rutka, MD, FRCSC
Sloan H. Mandel, LLB Department of Otolaryngology
Thompson Rogers University of Toronto
Toronto, Ontario Toronto, Ontario

Lionel A. Mandell, MD, FRCPC, FRCP(Lond) Leonard P. Rybak, MD, PhD

Department of Medicine (Infectious Diseases) Department of Surgery
McMaster University Southern Illinois University School of Medicine
Hamilton, Ontario Springfield, Illinois
xii List of Contributors

Jochen Schacht, PhD Lawrence W. C. Tom, MD

Department of Otolaryngology
University of Michigan Medical School
Andrew R. Scott, BM, BS, MPhil, FRCS(ORL-HNS)
Department of Otolaryngology
University Health Network
Toronto, Ontario
Department of OtorhinolaryngologyHead and Neck Surgery
University of Pennsylvania
Philadelphia, Pennsylvania
R. David Tomlinson, PhD
Department of Otolaryngology
University of Toronto
Toronto, Ontario

Brendan J. Smyth, PhD, MD Thomas R. Van De Water, PhD

Department of Clinical Pharmacology Department of Otolaryngology
Georgetown University School of Medicine University of Miami School of Medicine
Washington, District of Columbia Miami, Florida

Jeremy Sturgeon, MB, BS, DIBIM(Med Oncol), FRCPC Charles G. Wright, PhD
Department of Medicine Department of OtolaryngologyHead and Neck Surgery
University of Toronto University of Texas Southwestern Medical Center
Toronto, Ontario Dallas, Texas
 Anatomy and Physiology

CHAPTER 1

Anatomy and Physiology of the Cochlea

Karen S. Pawlowski, PhD

This overview of the anatomy and physiology of the A C

various components of the cochlea includes informa- TM
tion about (1) the position of the cochlea within the
temporal bone; (2) the anatomy and physiology of the
cochlear fluid spaces, the vascular system, the support-
ing tissues, and the neuroepithelia that are responsible
for the sensorineural transduction of sound; and
(3) the electrophysiology associated with sensorineural
transduction.

COCHLEAR ANATOMY
The inner ear includes the osseous labyrinth, a series of
interconnected chambers within the temporal bone, EAC IAC
and the membranous labyrinth, which occupies the V
osseous labyrinth. The membranous labyrinth houses
the neuroepithelia responsible for auditory and
vestibular sensation. The osseous labyrinth lies within B ES
the petrous portion of the temporal bone and forms
part of the skull base (Figure 1-1A). IAC
The auditory component of the inner ear is the V
cochlea. The cochlea of mammals has a coiled, snail-
shell shape. Its main axis runs anterior to posterior. The TM CA
narrow, apical end lies anterior in the head, and the
wide, basal end of the spiral lies posterior and slightly
more medial and dorsal to the apex (Figure 1-1B). The
number of turns in the cochlear spiral varies among
species; humans have 2.5 to 3 turns.1 The sensory cells C
of the auditory system lie along the turns of the cochlea
EAC
on a flexible membrane, called the basilar membrane E
(see Basilar Membrane). The two types of sensory cells
that lie on the basilar membrane, inner hair cells Figure 1-1 Diagrams showing the position of the cochlea
(IHCs) and outer hair cells (OHCs), have different roles within the human head. A, Horizontal view of the skull base
in hearing (see Organ of Corti). The IHCs are respon- with a close-up of the left temporal bone. B, Coronal view of
the head with a close-up of the external, middle, and inner
sible for transferring the fluid motion at their surface
ear. The inner ear is composed of the cochlea and the vestibu-
into a neural signal that can be passed to the brain to
lar apparatus. The vestibular nerve, cochlear nerve, and a
be perceived as hearing. The OHCs lie on the flexible portion of the facial nerve all enter the brain cavity via the
portion of the basilar membrane. They have the capac- internal auditory canal. C = cochlea; CA = cochlear aqueduct;
ity to contract and elongate as the basilar membrane E = eustachian tube; EAC = external auditory canal; ES =
moves. Their role in hearing is to modify the incoming endolymphatic sac; IAC = internal auditory canal; TM = tym-
signal by altering the fluid motion at the top of the panic membrane; V = vestibular apparatus.
2 Anatomy and Physiology

H
SL SV

St

RM
SM

OS IS
SV
SM

B O of C SG
ST SG ST OSL

Figure 1-3 The constituents of the scala media (SM) show-

RWM
Figure 1-2 A right cochlea cut in half along the modiolar axis
showing the three cochlear scalae. The scala vestibuli (SV)
and scala tympani (ST) are continuous with one another at
the helicotrema (H). Arrows in the scala tympani indicate
direction of spiral of the scalae. RWM = round window
membrane; SG = spiral ganglion within the modiolus; SM =
scala media.
IHC. Details of the roles of these cells are covered in
this chapter.
Fluid Spaces
The cochlea is subdivided into three fluid-filled com-
partments. The scala tympani and scala vestibuli com-
partments are continuous with one another at the
helicotrema, in the apex of the cochlea (Figure 1-2).
ing the adjacent areas of the scala vestibuli (SV) and scala
tympani (ST). The stria vascularis (St) is responsible for pro-
duction of the endocochlear potential and the high potassium
concentration in the endolymph. The organ of Corti (O of C)
houses the sensory receptor cells, the inner and outer hair
cells. B = Bttcher cells; BM = basilar membrane; IS = inner
sulcus cells; OS = outer sulcus cells; OSL = osseous spiral
lamina; RM = Reissners membrane; SG = spiral ganglion
inside the OSL; SL = spiral ligament.
The scala media is sandwiched between the scala tym-
pani and scala vestibuli as they spiral up the cochlea
from base to apex. These three compartments spiral
along the cochlear turns and around a nerve-filled bony
central axis, the modiolus. The fluid that occupies the
scala tympani and scala vestibuli is perilymph.2 The ion
composition of perilymph is similar to that of cere-
brospinal fluid (CSF) and many extracellular fluids
(Table 1-1), with a low sodium (Na+) concentration
and a high potassium (K+) concentration.38
The scala media lies between scala tympani and
scala vestibuli and contains endolymph (Figure 1-3).
The endolymph is high in K+ and low in Na+, in inverse

Table 1-1 Composition of Fluids (mMol)

Component Scala Media Scala Vestibuli Scala Tympani Endolymphatic Sac CSF Plasma

Na+ 11.3 141145 138148 103 149 145

K + 157 6 4.2 15 3.1 5

Ca2+ 0.023 0.62 12 0.5 1.2 2.6

Cl 131132 121 119 129 106

HCO3 31 18 21 19 18

pH 7.4 7.3 7.3 7.3 7.3

Composition of the various fluids found within the cochlea. Other low-concentration components, such as proteoglycans and glycosaminogly-
cans, are not included. Sodium and calcium ion concentrations are low in the endolymphatic compartment (scala media) and high in the peri-
lymphatic compartments (scala tympani and scala vestibuli), whereas potassium ion concentration is the reverse. These ions, with their relative
concentrations within the compartments of the inner ear, are important in the activation of hair cells. Values derived from several sources.3,58
CSF = cerebrospinal fluid.

SMA
CMV
LA
VCA
AICA
RWM
SMV
BA
Figure 1-4 The vasculature in a human cochlea. The darker
vessels illustrate arterial flow. The lighter vessels illustrate
venous flow. Oxygenated blood enters via the basilar artery
(BA); the anterior inferior cerebellar artery (AICA) branches
off the BA and extends to the labyrinthine artery (LA), which
extends into the cochlea and vestibular apparatus. The spiral
modiolar artery (SMA) extends from the cochlear portion of
the LA to supply the modiolus, lateral wall, and organ of
Corti. The venous drain starts from the spiral modiolar vein
(SMV), which drains into the cochleomodiolar vein (CMV),
which joins up with the venous system of the vestibular appa-
ratus at the vein of the cochlear aqueduct (VCA). RWM =
round window membrane. Adapted from Axelsson A, Ryan
AF. Circulation of the inner ear. I. Comparative study of vas-
cular anatomy in the mammalian cochlea. In: Jahn AF, San-
tos-Sacchi J, editors. Physiology of the ear. New York: Raven;
1988. p. 295315.
ratio relative to the perilymph, and this difference is
critical for hearing.2,3
The perilymph of the scala tympani communicates
with CSF via the cochlear aqueduct (see Figure 1-1B).
There is also some communication between perilymph
and CSF via the internal auditory meatus.5,9 These
communication routes are not completely open, as the
cochlear aqueduct in humans is filled with loose con-
nective tissue and the internal auditory meatus is filled
with the auditory, vestibular, and facial nerves and their
associated tissues. Scala tympani is separated from the
middle ear space by the round window membrane (see
Figure 1-2). The stapes footplate separates the vestibule
from the middle ear space. Scala vestibuli is continuous
with the vestibule at the basal end of the cochlea. Scala
tympani and scala vestibuli are also in contact with the
vascular system. Radiating arterioles extend out along
the bony wall of scala vestibuli from the spiral modio-
lar artery. A network of collecting venules lines the
bony wall of scala tympani before the venules connect
with the spiral modiolar vein (Figure 1-4; see Blood
Supply and Vasculature).10
Communication routes into the endolymphatic
space of the scala media are limited to a vascular route,
via the stria vascularis, or a perilymphatic route, via
scala tympani and scala vestibuli. Scala media is part of
the membranous labyrinth. The endolymphatic space
Anatomy and Physiology of the Cochlea 3
ES
ED
Cr
DR
CD
*
SM
UM
Figure 1-5 The membranous labyrinth. Endolymph is
formed in the pars superior portion (dark shaded area) of the
membranous labyrinth (utricle and semicircular canals) and
in the pars inferior portion (light shaded area) of the mem-
branous labyrinth (cochlear duct and saccule). Endolymph
from the cochlear duct (CD) drains into the saccule via the
ductus reuniens (DR); from there it enters the endolymphatic
duct (ED). Endolymph drains from the pars superior via the
utriculoendolymphatic valve of Bast (*) into the ED. From
the ED, endolymph drains into the endolymphatic sac (ES),
where it is broken down and resorbed into the vascular
system. Cr = cristae ampularis of the superior, posterior, and
lateral semicircular ducts; SM = sacular macula; UM =
utricular macula.
of the scala media is a fluid-filled compartment that
extends from the apex through the base of the cochlea,
continuing into the saccule and the rest of the vestibu-
lar apparatus via the ductus reuniens (Figure 1-5). The
endolymphatic space of the utricle and semicircular
canals is somewhat isolated from the endolymphatic
space of the cochlea and saccule by a small valve, called
the utriculoendolymphatic valve of Bast. This valve lies
at the opening of the utricle into the endolymphatic
duct system, which connects the endolymph of the
utricle and semicircular canals to the endolymph of the
cochlea, saccule, and endolymphatic duct. The
membranous labyrinth continues from the vestibular
space through the endolymphatic duct to terminate in
the endolymphatic sac. The endolymphatic sac lies
within the dura on the medial aspect of the temporal
bone (see Figure 1-1B). Both the perilymphatic fluid
space and the membranous labyrinth can be affected by
fluid pressure changes within the brain cavity due to
fluid communication via the cochlear aqueduct, the
endolymphatic duct and sac, and the internal auditory
meatus. This relationship is important for fluid pres-
sure regulation within the inner ear.913 The fluid pres-
sure ratio between endolymphatic and perilymphatic
compartments of the cochlea need to be stable in order
to allow proper fluid motion at the tip of the sensory
4 Anatomy and Physiology
cells. A shift of the endolymphperilymph fluid ratio
has been implicated in several conditions involving
tinnitus and hearing loss.4
Blood Supply and Vasculature
The cochlear blood supply is one route of entry for
cochleotoxic agents. Blood is supplied to the inner ear
via the labyrinthine artery, which branches from the
anterior inferior cerebellar artery branch of the basilar
artery (see Figure 1-4). From the labyrinthine artery,
blood to the cochlea is circulated via the spiral modio-
lar artery and vein.11,15,16 Arterioles branch off the large
spiral modiolar artery to form capillary beds in the
tissues of the modiolus, osseous spiral lamina, and
tympanic lip along the outside lip of the spiral lamina.
Branches from the modiolus also radiate out toward
the lateral wall along the bony wall of scala vestibuli.
The stria vascularis, spiral ligament, and spiral
prominence comprise the lateral wall of the scala media
(see Figure 1-3). Arterioles branching from the modi-
olus form distinct capillary beds in the lateral wall: one
each for the spiral ligament, stria vascularis, and spiral
prominence.
Separate capillary networks supply the various tis-
sues in the lateral wall. The three capillary beds in the
lateral wall serve distinct purposes, and their walls are
constructed to reflect their purpose. The vessel walls of
these lateral wall networks are specialized to filter sub-
stances from the blood supply to the cochlear tis-
sues. 16,17 In general, the structure of the vessel
endothelial cells prevents free diffusion of solutes from
the blood into cochlear tissues. Under normal condi-
tions, solutes must first cross the endothelial cells, via
active transport, before they can enter the cochlear tis-
sues. Tight junctions between adjacent endothelial cells
prevent passive diffusion of substances from the blood
to the perilymphatic tissues and the perilymph or to the
stria vascularis and the endolymph.
The tightness of this capillary system varies within
the cochlea depending on location.17,18 In the spiral lig-
ament, capillaries that lie near Reissners membrane
(suprastrial region) have endothelial cells that contain
stress fibers that may be able to regulate the flow of
blood to the rest of the lateral wall vasculature.18 The
portion of the spiral ligament that lies adjacent to the
stria vascularis has vascular walls that are composed of
continuous layers of endothelial cells connected by
tight junctions, with a prominent basement membrane
surrounded by pericytes. This arrangement creates a
fairly tight bloodperilymph barrier.
The vessels in the spiral prominence, near the basi-
lar membrane, appear to be more permeable than those
of the adjacent spiral ligament and stria vascularis
because they have less basal lamina. This region is near-
est the collecting venules of the lateral wall; therefore,
these vessels may serve as the entry point for substances
coming from the endolymph and surrounding tissues
to the vasculature.
The densest capillary network of the lateral wall is
in the stria vascularis. Strial capillaries are surrounded
by a continuous layer of endothelial cells, a thickened
basal lamina, and pericytes that are similar in appear-
ance to those of the adjacent spiral ligament.15,16 How-
ever, the basal lamina of stria vascularis vessels is twice
as thick as that of the vessels that lie in the adjacent
spiral ligament. The basement membrane of the stria
vascularis runs between closely packed marginal, inter-
mediate, and basal cells, whereas the spiral ligament
basal lamina runs through loosely packed connective
tissue. The arrangement of the basal lamina within the
stria vascularis is thought to efficiently supply nutrients
to the strial cells and can serve as a pathway for other
substances to the strial cells, once they pass from the
vasculature to the intracellular space.17
Capillaries in the central portion of the modiolus
are fenestrated, allowing quick passage of fluids and
solutes. Capillaries that are found in the tympanic lip
portion of the spiral limbus, near the basilar membrane,
are thought to supply the organ of Corti with oxygen.
These capillaries are not fenestrated but have endo-
thelial cells connected by tight junctions, similar to the
vessels of the lateral wall.11,19
Because of the bloodperilymph and bloodstrial
barriers, entry of solutes into the inner ear is mediated
by their interaction with the vascular endothelial cells,
vascular pericytes, and tissues along the pathway to the
fluids. This is true not only of oxygen and nutrients, but
also drugs that have accumulated in the vasculature.
The lag time for substance accumulation or equili-
bration between endolymph, perilymph, and blood
concentrations of an intravascularly administered sub-
stance indicates that there is a moderate barrier
between blood and perilymph and a high barrier
between blood and endolymph and between
endolymph and perilymph.17,18
The cochlear vasculature is also important for the
maintenance of the endocochlear potential (see Lateral
Wall ). The active system that maintains endocochlear
potential is strongly dependent on oxygen availability,
which is supplied by the cochlear artery and the vascu-
lature of the stria vascularis.
Lateral Wall
The lateral wall of scala media houses structures
important in the production of the endocochlear
potential. The endocochlear potential is a standing
potential that exists between the endolymphatic space
and the perilymphatic space.20,21 The lateral wall is also
responsible for active accumulation of potassium ions
(K+) in the endolymphatic space.20 The endocochlear
potential and high endolymphatic K+ are important

for K+ entry and triggering of an action potential in
hair cells when ion channels in these cells are opened.20
The spiral ligament consists of fibrous tissue, vas-
culature, epithelial cells, and extracellular matrix. The
stria vascularis is situated between the spiral ligament
and the endolymphatic space. It consists of three types
of cells: marginal, intermediate, and basal. The strial
vessels occupy the central portion of the stria vascularis
adjacent to all three cell types (Figure 1-6). The strial
cells are isolated from their surroundings by a series of
tight junctions.22,23 The marginal cells are adjacent to
the endolymphatic space and are joined to one another
by tight junctional complexes near the endolymphatic
surface. Marginal cells interdigitate with strial vessels,
intermediate cells, and basal cells. Intermediate cells lay
within the middle layer of the stria vascularis, adjacent
to the strial vessels. They are in direct communication
with basal cells via gap junctions.24 The basal cells are
flat, overlapping cells on the lateral side of the stria vas-
cularis. A series of tight junctional complexes between
basal cells separates this side of the stria vascularis from
the perilymphatic fluid spaces adjacent to it. The basal
cells are in direct communication with some of the
fibrocytes in the spiral ligament via gap junctions.25,26
Basilar Membrane
The basilar membrane is a multilayered fibrous struc-
ture that extends from the osseous spiral lamina later-
ally to the spiral ligament. It separates scala media from
scala tympani (see Figure 1-3). Epithelial cells cover the
basilar membrane on the scala tympani side. The organ
of Corti, the inner and outer sulcus cells, and Bttcher
cells line the scala media side of the basilar membrane.
Mechanical properties of the basilar membrane
dictate the vibratory pattern of the membrane in
response to a sound stimulus.27,28 The mechanics of the
basilar membrane are complex and frequency specific.
The basilar membrane is narrow and stiff at the basal
end, gradually becoming wide and flexible, with an
increased mass at the apical end. This causes the peak
amplitude of vibration in response to high-frequency
stimuli to occur at the basal end. The higher the fre-
quency, the more basal the location of peak amplitude
of vibration, and the lower the frequency, the more
apical the peak vibration point. These mechanical
properties, along with the action of the OHCs and the
refractive properties of the individual nerve cells (see
below), dictate the location at which the various fre-
quency components of a sound stimulus are encoded
along the basilar membrane.20 This description is an
oversimplification, as the position of maximum vibra-
tion to a certain frequency is also dependent on the
intensity of the sound carrying that frequency. An
increase in intensity of a simple tone will cause the
point of maximum vibration amplitude to shift toward
the apex. Complex sounds also affect frequency coding
Anatomy and Physiology of the Cochlea 5
EL
MC
IC
V
IC
BC
BC
F
Figure 1-6 The stria vascularis. Medium dark cells adjacent
to the endolymphatic space (EL) illustrate marginal cells
(MC). Light cells in the middle of the tissue, adjacent to the
vessel (V), are intermediate cells (IC); the darkest cells
beneath the IC and above the fibrocytes (F) are basal cells
(BC). Tight junctions at the endolymphatic surface of the
marginal cells, between the basal cells and between the vas-
cular endothelia cells, isolate the intercellular fluid of the stria
vascularis from its surroundings. Gap junctions allow direct
communication between BC and F of the spiral ligament as
well as between BC and IC.
at the basilar membrane (for more information see
Pickles 20 ). The coding of complex sounds is very
involved and is not discussed in this chapter.
Tectorial Membrane
The tectorial membrane is a gel-like structure, consist-
ing of highly hydrated layers of collagen, related pro-
teins, and glycosaminoglycans. 2931 It lies near the
surface of the reticular lamina of the organ of Corti
(Figure 1-7). In mammals the tectorial membrane has
several distinct zones. Some function as structural
elements for the tectorial membrane, whereas others
serve as an interface between the tectorial membrane
and the organ of Corti. The tectorial membrane is in
contact with the OHCs. The stereocilia of the IHCs are
close to the tectorial membrane, but they do not make
direct contact with it.31,32 Although the tectorial mem-
brane is not part of the organ of Corti, it plays a key role
in organ of Corti function.
Organ of Corti
The organ of Corti houses the auditory sensory epithe-
lia (see Figure 1-7). It is a long ribbon of cells that
6 Anatomy and Physiology
HS
IB
TM
3 Mi
2 1 IP
HC I
OP
DC MSO IPh
HP SG OSL
Figure 1-7 Cross section of the organ of Corti and its associ-
ation with the tectorial membrane (TM) and Hensens stripe
(HS). 1, 2, 3 = first, second, third row outer hair cells, respec-
tively; DC = Deiters cells; HC = Hensens cells; HP = habenula
perforata; I = inner hair cell; IB = inner border cell; IP = inner
pillar cells; IPh = inner phalangeal cell; MSO = efferent fiber
from the medial superior olivary bundle; OP = outer pillar
cells; OSL = osseous spiral lamina; SG = spiral ganglion.
spirals along the basilar membrane from base to
apex.3235 This tissue modifies and transduces the wave
motion of the basilar membrane into the neurochemi-
cal signal. The cells of the organ of Corti include the
sensory cells (IHCs and OHCs); their supporting cells
(the inner border and inner phalangeal and Deiters
cells, respectively); afferent (type I and type II spiral
ganglion) and efferent nerve endings (the medial and
lateral olivocochlear bundles); the inner and outer
pillar cells; and Hensens cells.32,34 The configuration of
the cells of the organ of Corti changes as it spirals api-
cally. For example, OHCs at the apex of the cochlea in
humans are longer than those at the base.3538 Also, in
humans, the Bttcher cells that line the basilar
membrane just lateral to the Hensens cells at the base
slowly disappear by midcochlea. These gradations in
structure of the organ of Corti, along with associated
structures, such as the basilar membrane and lateral
wall, are important for tuning the frequencies to which
an individual hair cell responds.
Outer Hair Cells and Supporting Cells
Of the two types of sensory cells in the cochlea, the
OHCs are more abundant than IHCs (approximately
12,000 OHCs compared with 3,500 IHCs in
humans35,36), yet the IHCs are responsible for coding of
sound waves into neural signals. The OHCs are respon-
sible for fine-tuning the wave action of the basilar
membrane and reticular lamina.38
In mammals, the OHCs are arranged in three or
four rows that lie more lateral to the modiolus than do
B S
HB
CP
SC
N
DC
AF
EF
Figure 1-8 An outer hair cell, associated Deiters cell (DC),
and afferent (AF) and efferent (EF) nerve endings. All hair
cells have an eccentric nucleus (N), numerous mitochondria
(Mi), and a basal body (B), and their cuticular plates (CP) are
connected to the adjacent cells via tight junction complexes.
Stereocilia (S) of varying heights project from the surface of
the cuticular plate. They are connected to each other via tip
and side links, and they possess a dense core that runs down
into or through the cuticular plate. The denseness of the
subsurface cisternae (SC) and the Hensens body (HB) are
unique to the outer hair cells, as is the fact that the tallest row
of stereocilia is attached to the underside of the tectorial
membrane.
the IHCs. The endolymphatic surfaces of the IHCs and
OHCs consist of the cuticular plate with stereocilia. The
cuticular plate is a hard cuticle-like component of the
endolymphatic portion of the cell. Cytoplasmic gaps are
interspersed within the cuticular plate near the complex
cellular junctions between the hair cells and supporting
cells.3941 These gaps in the cuticle are thought to be
important for intercellular communication between the
endolymphatic surface of the cell and the rest of the
cytoplasm. The OHC is connected to the surrounding
supporting cells, Deiters cells, by tight junction com-
plexes at the level of the cuticular plate (Figure 1-8).42
The stereocilia are long projections extending from
the cuticular plate on the surface of the hair cells
(Figures 1-8 to 1-10). Stereocilia of OHCs are shaped
like a W and progress in height from a short row
toward the modiolar side of the cell to a tall row that is
embedded in the tectorial membrane on the lateral side
of the cell (see Figure 1-8).32,33,41 All of these stereocilia
are connected together by a network of side links. Their
tips are connected with tip links that are part of a

Figure 1-9 Scanning electron micrograph of a mouse organ
of Corti. A row of inner hair cells shows the flat U shape of
the stereocilia. Rows of outer hair cells show the W shape
of the stereocilia. The bar represents 10 microns.
1, 2, 3 = first, second, third row outer hair cells, respectively;
I = inner hair cells. Courtesy of Dr. Charles G. Wright,
UT Southwestern Medical Center.
spring-loaded gate system that opens a nonselective
cation gate when the stereocilia are displaced toward the
apex and laterally, toward the tallest row of stereocilia.
The influx of K+ ions then sets off a cycle, which ends in
changes in cell shape and the release of synaptic vesicles
into the synaptic cleft at the base of the hair cell.44
The center of the stereocilia is mainly organized
actin fibers, with a dense core, called the stereocilia
rootlet, running from close to midway on the portion
of the stereocilia that is above the cuticular plate to the
bottom or beneath the cuticular plate (see Figures 1-8
and 1-10). This portion of the stereocilia is important
in communicating the inflow of K+ at the tip of the
stereocilia to the rest of the cell.39,40
The supporting cells that surround the OHCs are
Deiters cells and pillar cells. Pillar cell projections con-
tact the modiolar side of the first (most modiolar) and
second row of OHCs.40 The first-row OHCs make con-
tact with pillar cells on the modiolar and lateral side of
the OHCs. Deiters cell processes only contact the first-
row OHCs on either side of the lateral pillar processes.
The pillar cells contact the second row of OHCs only at
the modiolar side. The remaining sides of the second-
row OHCs plus third-row OHCs are all contacted by
Deiters cell processes. Junctional complexes that con-
nect OHCs, Deiters cells, and outer pillar cells create a
tight barrier between endolymph and perilymph. These
junctions are arranged in a complex manner so that
they do not open even during scar formation, suggest-
ing that maintenance of this barrier is very important
in the continued health of the organ of Corti sur-
rounding the traumatized area.
The outer and inner pillar cells form the tunnel of
Corti, separating the IHC region of the organ of Corti
from the OHC region (see Figures 1-7 and 1-9).45 The
Anatomy and Physiology of the Cochlea 7
S
B
CP
SC
IB
RER
Ve
N
Mi
IPh
AF
EF
Figure 1-10 An inner hair cell, with its associated supporting
cells and nerve endings. Like the outer hair cells these cells
have an eccentric nucleus (N), mitochondria (Mi), and a
basal body (B), with a cuticular plate (CP) that is connected
to the adjacent cells via tight junction complexes. The inner
hair cell is goblet-shaped with numerous vesicles (Ve) and
rough endoplasmic reticulum (RER) in the neck of the gob-
let. Like the outer hair cells, the stereocilia (S) of the inner
hair cell vary in height, are linked together via tip and side
links, and contain rootlets that project to and through the
cuticular plate. The stereocilia, however, are not attached to
the underside of the tectorial membrane, and there are fewer
rows of them than on the outer hair cell. AF = afferent nerve
fiber; EF = efferent nerve fiber; IB = inner border cell; IPh =
inner phalangeal cell; SC = subsurface cisterna.
inner and outer pillar cells are major structural cells of
the organ of Corti that are filled with microfilaments
and microtubules for strength.
The Deiters cell is a highly evolved epithelial cell
whose purpose is to support the OHC and buffer its
environment (see Figure 1-7). 45 The architectural
arrangement of the OHC and Deiters cell is such that
the Deiters cell acts as a cable to the rigid beam struc-
ture of the OHC, allowing contraction but limited
expansion of the OHC.
8 Anatomy and Physiology
Inner Hair Cells and Supporting Cells
The IHCs are responsible for the signal that is sent to
the brain via the primary afferent nerve for hearing, the
auditory nerve.46 The IHCs are goblet-shaped cells that
lie in a single row on the modiolar side of the organ of
Corti and basilar membrane (see Figure 1-10). Situated
at the lip of the osseous spiral limbus, on the modiolar
side of the pillar cells and tunnel of Corti, beneath and
slightly lateral to Hensens stripe, the stereocilia of the
IHCs are positioned to receive the most refined fluid
wave action during sound stimulation. Unlike the
OHCs, the IHC is not in direct contact with the tecto-
rial membrane.4749 Therefore all of the input to the cell
through the stereocilia occurs via fluid mechanics.
The IHC stereocilia differ from OHC stereocilia in
that they are arranged in more of a U or collapsed
W shape on the surface of the cell, which correlates
with a smaller, more ovoid shape to the cuticular plate
within which they are embedded (see Figure 1-9).50 Like
the OHC, the cuticular plate of the IHC has a fonticu-
lus, occupied by a basal body, and cytoplasmic gaps that
run through the cuticular plate (see Figure 1-10).39 The
body of the IHC is shaped like a flask, with the apical
neck portion filled with mitochondria, Golgi apparatus,
endoplasmic reticulum, lysosomes, and multivesicular
bodies.51 A cytoplasmic cistern lines the sides of the cell
apically, to midcell region. The synaptic region basal to
the cell nucleus is filled with synaptic specializations, as
one IHC is in contact with an average of 20 type I affer-
ent nerve fibers.52 Adult IHCs are rarely directly con-
tacted by efferent nerve fibers. This contact when it
occurs is more common in the apical region of the
cochlea. Typically, efferent nerves associated with IHCs
synapse on the afferent nerve endings.
The cuticular plates of the IHCs and OHCs, along
with their supporting cells, comprise the reticular lam-
ina. A thick coat of proteoglycans covers the structures
at the endolymphatic surface and protects the cell bod-
ies of the organ of Corti from the otherwise toxic com-
ponents of the endolymph.53
Neural Structure
Cochlear innervation includes afferent and efferent
innervation to the organ of Corti plus a sympathetic
innervation system.5457 Organ of Corti innervation is
composed of four types: type I and type II afferent
nerves and the efferent nerves, the medial and lateral
olivocochlear bundles.
The type I afferents predominantly innervate the
IHCs. In humans, each IHC synapses with an average
of 20 afferent nerve fibers.52 The exact numbers vary,
but not in any base-to-apex gradient. Often the highest
concentration of afferent fibers is in a region of the
basilar membrane that represents the most sensitive
frequency for a given species. 57 The type I spiral
ganglion cells are the most numerous, representing 90
to 95% of the total ganglion within the modiolus. The
IHC afferent specializations are characterized by synap-
tic bars or ribbons surrounded by clear, irregularly
shaped vesicles (see Figure 1-10).52 The presence of
synaptic ribbons indicates that a high number of
synaptic vesicles are released onto the nerve ending
during activation of the hair cell.
Type I spiral ganglion are bipolar cells with periph-
eral endings that radiate from the modiolus to the
IHCs, which lie close to the nerve cell soma. The cen-
tral endings of type I fibers bifurcate twice before enter-
ing three different areas of the ipsilateral cochlear
nucleus in the brainstem.58 The type I fibers are myeli-
nated from the central projection to the periphery up
to the point where they leave the modiolus to cross the
basilar membrane and enter the organ of Corti. The
first node of Ranvier occurs near the organ of Corti.
These nerve cells differ in their firing characteristics
depending, in part, on their spontaneous activity.59,60
Each IHC is connected to nerve cells that represent all
levels of spontaneous activity. The spontaneous activ-
ity of a nerve cell is dictated by the nerves refractory
property (the time it takes for a nerve cell to reset
itself after firing). Low, intermediate, or high sponta-
neous rate neurons lie within specific areas beneath the
IHC. High spontaneous rate fibers tend to synapse on
the lateral side of the IHC and low spontaneous rate
fibers synapse on the medial side, closest to the habe-
nulae perforatae.
The major neurotransmitter released by the IHC is
glutamate (Table 1-2).61,62 Two major types of nonN-
methyl-D-aspartate (non-NMDA) glutamate receptors
have been found on the postsynaptic nerve ending,
kainate and -amino-3-hydroxy-5-methylisoxazole-4-
propionic acid (AMPA), AMPA being the more abun-
dant of the two. Non-NMDA glutamate receptors are
ion channels that are thought to be responsible for
rapid afferent transmission. Several non-NMDA gluta-
mate receptors have been found in the organ of Corti.
They include glutamate receptor 3 (GR3), GR4, GR5,
GR6, and kainate receptor KA1.63 Receptors for AMPA,
quisqualate, and domoic acid have also been indicated
via changes in neural output after application of these
neurochemicals.64 NMDA receptors have also been
found.65 The role of NMDA receptors is typically mod-
ulation of the ionic glutamate receptors.
P2X2 receptors for adenosine triphosphate (ATP)
have been found on postsynaptic nerve endings, indi-
cating a potential modulator role for ATP in these
cells.66 There is also some evidence that the type I affer-
ents contain metabotropic glutamate receptors. These
types of receptors initiate a metabolic change within a
cell that ultimately changes the cells firing character-
istics. Their purpose within the auditory system is not
yet clear.
Table 1-2 Neurotransmitters and Receptors within the Organ of Corti

Afferent Nerves Efferent Nerves

IHC OHC IHC OHC

Type I SG/IHC Synapse Type II SG/OHC Synapse LOC/IHC Synapse MOC/OHC Synapse
Neurotransmitters Neurotransmitters Neurotransmitters Neurotransmitters

Glutamate Glutamate Acetylcholine Acetylcholine

CGRP CGRP
GABA GABA
Opioid peptides:
Enkephalins
Dynorphins
Dopamine

IHC Receptors OHC Receptors IHC Receptors OHC Receptors

GluR ? AChr (-7 nicotinic) AChr (-9 and -10 nicotinic)

NPR NPR
GABAR GABAR

Type I Dendrite Receptors Type II Dendrite Receptors LOC Efferent Receptors MOC Efferent Receptors

Non-NMDA glutamate receptors GluR ? ?

AMPA

Kainic acid
Quisqualic acid
Domoic acid

NMDA receptors

ATP receptors
P2X2
Metabotropic receptors

The complete list of neurotransmitters and receptors is still being compiled, but the main excitatory afferent neurotransmitter for both type I and type II spiral ganglion (SG) is most likely glutamate. The
major neurotransmitters for the efferent system are acetylcholine, calcitonin gene-related peptide (CGRP), and -aminobutyric acid (GABA). AChr = acetylcholine receptor; AMPA = -amino-3-hydroxy-
Anatomy and Physiology of the Cochlea

5-methylisoxazole-4-propianic acid; ATP = adenosine triphosphate; GluR = glutamate receptor; IHC = inner hair cell; LOC = lateral olivocochlear efferent; MOC = medial olivocochlear efferent;
9

NMDA = N-methyl-D-aspartate; NPR = neuropeptide receptors; OHC = outer hair cell. Information for this table was derived from several sources.61,62
10 Anatomy and Physiology
Approximately 5% of the spiral ganglion popula-
tion is composed of type II afferent fibers.55 These cells
are bipolar or pseudobipolar in character with little or
no myelination and are covered by a simple sheath of
Schwanns cells, surrounded by a basement membrane.
Their peripheral targets are the OHCs. The type II spi-
ral ganglion fibers, called outer spiral fibers, cross the
floor of the tunnel of Corti to extend out under the
three rows of OHCs. From there they make contact
with the base of several of the OHCs as they extend up
to 0.6 mm apically.67 The central target of these neurons
is the shell region of the cochlear nucleus, which pro-
jects to the superior olivary complex.68 One function of
the type II spiral ganglion is believed to be a feedback
loop to the OHCs. The neurotransmitters at the type II
synapse are still being elucidated, but glutamate is a
probable candidate (see Table 1-2).63,69
The cochlear efferent system is composed of two
separate fiber tracts, the medial olivocochlear bundle
(MOC) and the lateral olivocochlear bundle (LOC)
fibers.70 The MOC efferents originate predominantly
from the contralateral medial superior olivary nucleus
in the brainstem, with some ipsilateral contribution.71
The MOC fibers are myelinated fibers that become
unmyelinated at the habenulae perforatae, where they
cross the tunnel of Corti at midlevel (see Figure 1-7)
and run parallel to the three rows of OHCs to form the
outer spiral bundle.71,72 They synapse with a multitude
of OHCs along the way. The uncrossed (ipsilateral)
MOC efferents synapse almost equally with OHCs
from the apex of the cochlea to the base, with a slight
increase in synapse count in the midregion of the
cochlea. The crossed (contralateral) MOC efferents
preferentially synapse with the more basal, high-
frequency components of the cochlea. In fact, the fibers
typically enter the OHC area basally and branch out
toward the apex.72 How the MOC efferents function in
hearing is still being elucidated, but it has been shown
that activation of the crossed MOC efferents can
change the response to evoked otoacoustic emissions
(OAEs) and can decrease the size of compound action
potentials.73
The LOC efferents are unmyelinated and originate
in the lateral superior olivary nucleus in the brain-
stem.70 From there they can run either ipsilateral or
contralateral to the nucleus. All LOC efferent axons ter-
minate, without much branching, on afferent nerve
endings in the vicinity of the IHCs. The ipsilateral pro-
jections synapse in essentially equal numbers from base
to apex. The crossed projections synapse predomi-
nantly in the apical, lower-frequency regions of the
cochlea.72
The IHC synaptic ultrastructure for efferent and
afferent nerve endings closely resembles that of stan-
dard configurations. This is not the case for OHC
synaptic ultrastructure. Many large efferent endings
synapse directly onto the OHCs (see Figure 1-8). Also,
evidence of reciprocal synapses has been found in
human OHCs. 74 At nerve endings with reciprocal
synapses, both afferent and efferent configurations can
be found on the same nerve ending. The roles of the
efferent and afferent innervations to the OHC are not
completely clear. However, there is evidence that acti-
vation of the efferent innervation changes the activity
of the OHCs, as recorded by distortion product OAEs
and compound action potentials.73
Sympathetic nerve fibers in the cochlea are pre-
dominantly noradrenergic and enter the cochlea along
the cochlear artery in the internal auditory meatus.56
Many of the fibers stay associated with the vasculature,
but some branch out into the cochlear nerve, spiral
ganglion, and Rosenthals canal. Some radiate out into
the osseous spiral lamina as far as the habenulae perfo-
ratae. There is some disagreement whether fibers that
are not associated with vessels reach into the organ of
Corti itself, but the diffusion properties of nor-
epinephrine allow it to influence nearby neural activity
without direct contact. Therefore, the organ of Corti
activity may be directly affected by sympathetic nerve
activity.
COCHLEAR PHYSIOLOGY
The anatomic arrangement of structures within the
cochlea is essential for the transformation of acoustic
signals into neurochemical signals that can be inter-
preted by the brain as sound. Equally important is the
physiology of the system. Cochlear physiology is usu-
ally divided into two types: the cellular physiology of
the cochlear tissues, involving biochemistry and mole-
cular biology of the cells, and the electrophysiology of
neural transduction, involving measurement of neural
activity of the neuroepithelial cells. The cellular physi-
ology, molecular biology, and biochemistry of tissues
are directly affected by ototoxic agents, with conse-
quences to the anatomy and electrophysiology of the
system. These aspects vary by cell and by tissue. There-
fore, ototoxic agents affect different tissues, depending
on the agents effect on the biology of the cell and access
to the vulnerable tissue.
The cochlear duct houses the tissue structures that
are responsible for sensorineural transduction. Two
major structures of the cochlear duct are the organ of
Corti and the lateral wall (see Figure 1-3). The lateral wall
consists of the spiral ligament and the stria vascularis.
The stria vascularis and spiral ligament are responsible
for maintaining the high potassium levels in the
endolymph as well as the endocochlear potential
required for the sensorineural transduction.75 The spiral
ligament contains four different types of fibrous tissue
that are important for ion transport activity.76 The type II
fibrocytes near the basilar membrane and the type I
fibrocytes adjacent to the stria vascularis are important

for the recycling of K+ from the area of the organ of Corti
back to the stria. Fibrocytes that are in the region of the
spiral ligament that is adjacent to the basilar membrane
contain stress fibers that can supply tension to the basi-
lar membrane. These fibrocytes are thought to play an
active role in basilar membrane mechanics.77
There are three major cell types in the stria vascu-
laris: marginal, intermediate, and basal cells (see Fig-
ure 1-6). Strial marginal cells are polar cells with a flat
hexagonal surface adjacent to the endolymphatic space
and long interdigitating projections that extend deep
into the strial tissue. Tight junctional complexes on the
endolymphatic side of the cells isolate the strial intra-
cellular space from the endolymphatic space. 17,23,78
Marginal cells contain a high concentration of Na+K+
adenosine triphosphase (ATPase) and numerous mito-
chondria, which are required for pumping K+ into the
endolymph. Strial basal cells line the spiral ligament
side of the stria vascularis. They are in direct commu-
nication with spiral ligament cells and strial intermedi-
ate cells via gap junctions. Tight junctions between the
basal cells isolate the strial intracellular space from the
spiral ligament, which is key for endocochlear potential
production. 78 Strial intermediate cells are neural
crestderived cells that are situated between the mar-
ginal and basal cells, nearest the vasculature. These cells
function as a buffering system as they typically react
first to insults, and they are essential for endocochlear
potential generation.79,80
The stria vascularis is important in secreting K+
into the endolymph and in creating a large potential
across the epithelia that lines the scala media (Figure 1-
11). A standing current flows through the cochlear tis-
sues, between the current source (the stria vascularis)
and the two current sinks (the perilymphatic fluids of
the scala vestibuli and the scala tympani). This current
is required for sensorineural transduction by hair
cells.78,81 The composition of the endolymphatic and
perilymphatic fluids is crucial in this process as they
provide the charge-carrying molecules and the ionic
milieu for current to flow and transduction to occur.
The endolymphatic fluid space is physically separated
from the perilymphatic spaces of scala tympani and
scala vestibuli by a series of tight junction complexes
that rim the endolymphatic fluid space, along with the
series of tight junction complexes that isolate the stria
vascularis from its surroundings (see Figure 1-11, bold
lines).23,46 The composition of the endolymph is poiso-
nous to most cells external surfaces, and isolation of
the endolymph from the rest of the tissues is needed to
protect the tissue from endolymphatic poisoning.53 Iso-
lation of endolymph from surrounding tissues is very
important to the homeostasis of the cochlea. Therefore,
physiologic mechanisms are in place to minimize inter-
mixing of fluids even during scar formation in the
organ of Corti.42
Anatomy and Physiology of the Cochlea 11
P
RM
EL
St
SL
O of C
P
Figure 1-11 The generation of the standing current in
the cochlea. K+ is pumped into the endolymph (EL) via
Na+Ka+ ATPase in the marginal cells of the stria vascularis
(St). A barrier exists between the EL and perilymphatic (P)
spaces created by tight junctional complexes between the cells
lining the endolymphatic space and stria vascularis (bold
lines). Some K+ can leak across Reissners membrane (RM),
and it crosses the organ of Corti (O of C) during hair cell
transduction. K+ is then taken up by cells lining the perilym-
phatic space and travels intracellularly to fibrocytes of the spi-
ral ligament (SL, long arrows). K+ then passes into the stria
vascularis through gap junctions between the fibrocytes, the
strial basal cells, and the strial intermediate cells to supply the
K+ for uptake by the strial marginal cells (small arrow).
The osseous spiral lamina and organ of Corti
house the auditory nerves and neuroepithelia (see Fig-
ure 1-3). The two types of neuroepithelial cells within
the organ of Corti, the IHCs and OHCs, have their
apices exposed to endolymph and their bases exposed
to perilymph-like fluids (cortilymph).45 The OHC has
a unique ultrastructure of cisterns along its sidewalls
that are continuous with the Hensens body in the api-
cal region and with the synaptic cistern at the base. This
cistern is involved with mechanical cell changes that
modify the wave action of the basilar membrane. The
walls of these cells are also responsible for maintaining
the high hydrostatic pressure within the cell. Deiters
cells are the main supporting cells of the OHCs (see
Figure 1-8). Deiters cells have been shown to undergo
conformational changes after injection of current in
vitro similar to what has been shown for OHCs. This
indicates a strong interaction between the two cell
types. Thus, OHCs are cradled by the Deiters cell in
12 Anatomy and Physiology
the synaptic region of the cell, which indicates a buffer-
ing role for this type of cell. Even with this buffering
system in place, OHCs tend to exhibit the first sign of
degeneration after noise or other ototoxic insults to the
organ of Corti.23
Similar to the OHC supporting cells, the cells
surrounding the IHC are thought to buffer the IHC
environment.46 They have also been suggested to be
essential for maintenance of the afferent nerves. The
loss of afferent nerve endings after an insult to the
organ of Corti is often accompanied by the loss of these
supporting cells, as well as the IHCs.57
As stated earlier, movement of OHC stereocilia
results in conformational changes in the cell and, sec-
ondarily, release of neurotransmitters at the synapse.
This differs from IHC activation, which results in a
much larger release of neurotransmitters into the
synaptic gap between the sensory cell and the sur-
rounding nerves. Unlike OHCtype II afferent nerve
interactions, much more is known about IHCtype I
afferent nerve interactions. The predominant neuro-
transmitter at the IHC afferent synapse is glutamate.
Glutaminergic neurons are subject to excitotoxicity,
which occurs when too much glutamate is released into
the synaptic gap at one time, causing swelling in the
postsynaptic cell.58 Like glutaminergic central nervous
system (CNS) neurons, overstimulation of the IHC can
cause excitotoxicity in the postsynaptic nerve ending.
Unlike CNS neurons, where excitotoxicity affects the
soma, the portion of the type I neuron that is affected
in cochlear excitotoxicity is the unmyelinated part of
the fiber, peripheral to the habenula perforata and rel-
atively distant from the cell soma. In many cases of
cochlear excitotoxicity the peripheral process will
recover as long as the IHC is intact. If the IHC and sup-
porting cells are lost during the insult, recovery is lost.
However, animal experiments have shown that it is pos-
sible to stimulate regrowth of the dendrites by apply-
ing neurotrophic factors, such as glial cell linederived
neurotrophic factor (GDNF) and brain-derived neu-
rotrophic factor (BDNF), in animals.58
Although not considered part of the organ of
Corti, the tectorial membrane plays an important role
in the transduction that takes place there. Fluid dynam-
ics at the IHC stereocilia are important in the sen-
sorineural transduction of an acoustic stimulus.46 The
movement of the reticular lamina in relation to the tec-
torial membrane dictates fluid dynamics. The move-
ment of the basilar membrane and OHC activity alters
the association of the reticular lamina with the tector-
ial membrane. The molecular components of the
tectorial membrane are key to this association. The
type II and type IX collagen fibers contribute to its ten-
sile strength and resist stretch.82 They are aligned in the
membrane in an apicalradial direction, consistent
with the movement of the membrane in response to
sound stimulation. Because the glycosaminoglycans
and proteoglycans in the membrane have a high
negative-charge density, they create a highly hydrated,
loose gel matrix that resists the forces of compression
and radial expansion that are endured by the mem-
brane during sound stimulation.46 Alterations in tecto-
rial membrane hydration or proteoglycan content can
alter its shape and mechanical properties, which could
alter the membranes relationship with the reticular
lamina during sound stimulation, thus altering sound
transduction.47
ELECTROPHYSIOLOGY
Sensation in the auditory system, as well as every other
sensory system, relies on neural conduction of chemo-
electric potentials, resulting from a flow of ions through
channels in the membranes of either neurons or the
receptor cells.83,84 These electrical events create electric
fields with varying electric potentials that can be tracked
through the use of electrodes, placed either locally (con-
nected to the cell in patch clamp procedures or next to
the cell in near field recordings) or remotely (placed on
the surface of the head). Only the more clinically rele-
vant remote fields will be discussed here.
Electric events occur in the auditory system on an
ongoing basis. The electrical potentials can be divided
into two types: spontaneous responses (activity that
occurs in absence of an external stimulus) and stimu-
lus-evoked responses (which occur in response to
acoustic stimulation). Here we focus on stimulus-
evoked responses that occur in the cochlea and primary
auditory nerve (the eighth nerve). This neural activity
is measured using electrodes sensitive to changes in
electrical currents that occur when a hair cell or neu-
ron is activated. Electrophysiology can be used to study
cochlear responses to sound stimulation.
Cochlear Potentials
There are several steps involved in the auditory signal
transduction that generates electrochemical potentials
within the organ of Corti. These potentials can be
recorded and used to observe various components of
electrophysiology within the cochlea. The potentials
included in this chapter are cochlear microphonics
(CM), the summating potential (SP), the compound
action potential (CAP), and the auditory brainstem
response (ABR).
Cochlear Microphonics
CM is an evoked response that follows the spectral
components of the stimulus, similar to how a micro-
phone transduces sound into analog changes in electric
current. This potential is alternating current (AC) in
nature and follows the frequency and amplitude fluc-
tuations of the acoustic stimulation of moderate ampli-
tude. Weaver and Brey, who originally recorded CM,

thought that the source of the current fluctuations was
the auditory nerve.84 Later work done by Tasaki and
colleagues using recording electrodes within the
cochlea demonstrated that the source of CM is the hair
cells, within the organ of Corti.81 As there are three
times as many OHCs as IHCs, the OHCs are the major
contributor to CM.85 CM represents the vector sum of
activity from a large number of hair cells. CM ampli-
tude varies with the intensity of the input stimulus and
does not appear to adapt over the length of the stimu-
lus signal, unlike some of the other potentials.21 CM is
initiated by displacement of the basilar membrane, and
therefore the spatial distribution of CM activation
coincides with area of peak vibration of the membrane,
which changes according to frequency and intensity of
the input signal.
Summating Potential
SP also arises from activity in the organ of Corti.86 SP
is recorded as a direct current (DC), unidirectional
shift in potential in response to a stimulus that lasts as
long as the stimulus. This shift can be either positive or
negative, depending on the parameters of the stimulus
and recording techniques. This potential is also a con-
sequence of hair cell activation and is thought to arise
from the hair cell transduction process. Studies have
shown that both IHCs and OHCs contribute to this
potential, but IHCs are the major contributors. 20
Abnormal SPs occur when there is loss of IHCs and
OHCs or when there is a bias in the position of the
basilar membrane, such as in endolymphatic hydrops.87
Compound Action Potential
CAP is a measure of the synchrony of firing for fibers
of the auditory nerve. Each nerve fiber is connected to
an auditory nerve cell that fires or creates an action
potential when the cell reaches the threshold of firing.88
These cells fire even in an unstimulated, or resting,
state, but the activity is more or less random and asyn-
chronous. They fire in synchrony when they are driven
by an external stimulus. This pattern of activity is what
the CAP measures. A normal CAP occurs at a specific
time after presentation of a stimulus (latency) and with
a large negative-going voltage peak (measured in
microvolts), followed shortly by a second negative
peak.89 The latency and the amplitude of the first peak
vary with intensity of the stimulus. The minimum
intensity sound to create the CAP is called the CAP
threshold for that sound. The CAP threshold for pure-
tone, short-duration sounds varies according to the fre-
quency of the sound. The inner ear sensitivity to sound
varies with frequency, and different species demon-
strate different sensitivities. Loss of sensitivity of the
CAP could be because of an attenuation of the sound
stimulus reaching the inner ear, a problem with the hair
Anatomy and Physiology of the Cochlea 13
+ V V +
I III I
AI .25uV
L 80dB III R 80dB
.25uV
- -
LATENCY 4.00 ms / div
Figure 1-12 A normal human auditory brainstem response
(ABR) recorded on a standard clinical evoked potential
recorder at 80 dB nHL stimulus intensity. Results from the left
ear are presented on the left and the right ear presented on the
right. Positive potential (+) is up and measured in
0.25 microvolt units. Latencies are indicated at the abscissa in
4 millisecond divisions. I, III, and V denote the first, third,
and fifth peak in the wave form. Courtesy of Judy DeMorest,
AuD, University of Texas at Dallas Callier Center for
Communication Disorders.
cells in the organ of Corti, or a problem with the nerve
cells themselves.
Brainstem Potentials
Brainstem potentials can also be recorded using elec-
trode placements similar to those used for recording
remote cochlear potentials. The main protocol for
studying brainstem potentials that are associated with
cochlear function is the auditory-evoked brainstem
potential, also called the ABR.90
Measurement of the ABR is used to observe the
activity of the lateral and medial aspects of the auditory
nerve and the auditory brainstem, up to about the
inferior colliculus.90 The ABR is preferred clinically
over measurement of the CAP because it is more robust
and gives more information about nerve function. The
graph of a normal human ABR displays both positive
and negative voltage peaks occurring at different times
after the stimulus (Figure 1-12). The first positive peak
of the ABR is similar in latency and intensity to the first
negative peak of the CAP. In humans, this first positive
peak is thought to arise from the synchronous activity
of the peripheral part of the auditory nerve, with the
second peak arising from the central component of the
auditory nerve as it synapses with the cochlear nucleus.
These two peaks merge in smaller animals because of
the proximity of the peripheral and central compo-
nents of the nerve, which reduces the latencies between
the two peaks and is harder to separate spatially on the
smaller heads of the animals. The third peak of an ABR
graph comes from the upper brainstem in humans, and
the latency between the first and fifth peaks is used clin-
ically to identify lower brainstem pathology.
OTOACOUSTIC EMISSIONS AND BASILAR
MEMBRANE MECHANICS
Basilar Membrane Mechanics
Sensorineural transduction of acoustic waves into
neural signals occurs in the cochlea. The structure of
14 Anatomy and Physiology
the basilar membrane and its resonant properties are
key to the physical separation of an acoustic wave into
its component frequencies. In 1952, George von Bksy
was the first to observe the wave motion of the basilar
membrane in human and animal cadaver cochleae in
response to an acoustic stimulus.21
The inner ear is essentially closed fluid-filled com-
partments with a piston-like stapes footplate associated
with one fluid compartment (scala vestibuli) and an
elastic membrane (round window membrane)
stretched across the communication route between the
fluids of another fluid compartment (scala tympani)
and the middle ear space. At the stapes footplate,
acoustic waves transmitted by the ossicles of the mid-
dle ear are transferred from a wave traveling in air to
one traveling in fluid. The in-and-out piston action of
the stapes (initiated by the transfer of an acoustic wave
through the tympanic membrane and ossicular chain
to the stapes) and the elasticity of the round window
membrane act on the essentially incompressible fluids
of the inner ear to create a wave of pressure fluctuations
through the cochlea. As a result of the acoustic wave
traveling through fluid, the basilar membrane is set in
motion. This is the motion von Bksy observed.21
The organ of Corti lies on the basilar membrane,
and the hair cells are situated so that they are stimu-
lated when the basilar membrane is forced to vibrate as
the wave arrives.91 The basilar membrane is shaped so
that the low-frequency components of the acoustic
wave set the more apical areas into motion, with pro-
gressively higher frequency components setting pro-
gressively more basal components of the basilar
membrane into motion.21,92 The representation of fre-
quencies is laid out along the basilar membrane in a
continuous manner, similar to that of a piano key-
board.
Factors affecting basilar membrane motion other
than the properties of the basilar membrane itself are
the inertia of the fluid mass within the cochlea, the fric-
tional resistance created by the fluid motion and stiff-
ness of the associated tissues (the round window
membrane, the ligaments of the stapes, Reissners
membrane, the organ of Corti, and the spiral
ligament), and an active component associated with the
action of the OHCs.92 The extents to which these prop-
erties affect the traveling wave motion are still under
investigation.
The motion that von Bksy observed was a broad-
tipped, wave-like motion with a peak activity corre-
sponding to the frequency of the stimulus.21 The wave
appeared to travel from the base of the cochlea toward
the apex. The more basal portions of the basilar mem-
brane are lighter and stiffer than the apex. However, the
basal portions are set into motion with relative ease
compared with the apex because of the increase in mass
toward the apex.92,93 As the factor of mass is overcome,
the wave of vibration travels toward the apex. High-
frequency sounds do not travel far toward the apex, as
their place of maximum vibration is at the base.
Correspondingly, the lower the frequency of the stim-
ulus, the farther toward the apex the wave travels, until
it reaches a point of maximum vibration. The wave is
quickly dampened apical to this point.
The envelope of maximum vibration observed by
von Bksy was extremely broad, which did not corre-
spond with what had been learned by physiologic mea-
sures, that frequency tuning at the basilar membrane is
sharp and the internal filters are narrow. Since von
Bksys work, this discrepancy has been attributed to
an active tuning system at the level of the basilar mem-
brane that is responsible for sharpening the tuning.92
The OHCs have been shown to be the major compo-
nent of this active tuning system, along with the effer-
ent system that supplies the OHCs.94,95 The action of
the OHCs alters the input to the IHCs, thus changing
the output of the auditory nerve. This system is respon-
sible not only for the sharpness of the tuning, but also
for an increase in sensitivity of 30 to 40 dB sound pres-
sure level over a damaged system that lacks OHC
input.96,97
Otoacoustic Emissions
Active events other than electric potentials occur
within the cochlea and can be useful in examining the
condition of the cochlea. OAEs are acoustic waves of
various frequencies generated at the basilar membrane
that can be measured with a microphone in the exter-
nal auditory canal.98 The waves arise from the action of
the basilar membrane as a consequence of an active,
electromotile response occurring in the organ of Corti
after OHC activation (active tuning system). The waves
propagate through the middle ear in the opposite direc-
tion to that of sounds from the environment.99 OAEs
are a reflection of the activity of the basilar membrane,
basilar membrane mechanics, and the overall health of
the organ of Corti. They can be measured with acoustic
measurement equipment placed in the external audi-
tory canal.
OAEs can occur spontaneously, without inten-
tional stimulation, or as a response to intentional stim-
ulation (evoked).100 Non-audible spontaneous OAEs
(SOAEs ) are typical in humans and are thought to arise
from nonlinearities in the activity of the basilar mem-
brane.101,102 SOAEs occur more often in right ears ver-
sus left and in women more often than men.102
Evoked forms of OAEs have proven useful clini-
cally, as the nonlinearity of basilar membrane motion
is linked to the active tuning process in the organ of
Corti, thus the OHCs. Damage to the OHCs results in
a loss or decreased amplitude of evoked OAEs.97,103 As
OHCs are typically the most vulnerable cells in the
organ of Corti to toxic insults, OAE tests can give

Patient: JAD Ear: Left
Birthdate: ID:
Comment: Result: PASS
dB
TE Signal
NF Noise
0
-10
0 1 2 3 4 5 kHz
Figure 1-13 Transient evoked otoacoustic emissions
(TOAEs) recorded from the external ear canal from a normal
adult human. abscissa = frequency of emission;
NF = noise floor (black area), ordinate = level of emission in
dB, relative to stimulus; TE = evoked emission (gray area).
Courtesy of Judy DeMorest, AuD, University of Texas at Dal-
las Callier Center for Communication Disorders.
valuable, noninvasive information about the condition
of the organ of Corti.
There are two types of OAEs that are typically used
clinically to test the health of the organ of Corti: tran-
sient evoked OAEs (TEOAEs) and distortion product
OAEs (DPOAEs) (Figures 1-13 and 1-14). TEOAEs are
typically produced using click stimuli, which represent
a pan-frequency stimulus. This stimulus produces a
robust response spectrum that represents the spectrum
of the stimulus in a nonspecific manner.104 DPOAEs, on
the other hand, are a product of a two-tone stimulus,
which represent the basilar membrane activity a specific
distance away from the two eliciting tones. The position
along the basilar membrane that is represented is deter-
mined by the difference in frequency and amplitude of
the two tones. DPOAEs allow the tester to examine the
condition of the active tuning system (the OHCs) at
specific points along the basilar membrane.104,105
CONCLUSION
The better our understanding of the anatomy and gen-
eral physiology of the cochlea, the more we can learn
about the mechanisms involved in ototoxicity. The
anatomy of the cochlea is fairly well understood. How-
ever, work in understanding the cellular and electro-
physiology of the peripheral hearing organ is ongoing.
Less yet is known about the complex physiology of the
central auditory system. As more is understood about
the normal functioning of these systems in the percep-
tion of simple and complex sounds, the better our
understanding of the affects of ototoxic drugs will be.
Anatomy and Physiology of the Cochlea 15
On the basis of our present understanding of
cochlear anatomy and physiology we have been able to
demonstrate that
1. Ototoxic substances affect the anatomy and
physiology of the auditory system.
2. The ability of ototoxic substances to affect
specific tissues of the cochlea is dependent on
the entry of the substance into the cochlear
compartment that harbors that tissue and by
its ability to interact with the physiology of
that tissue.
3. Ototoxic substances enter the cochlear tissues
via the vascular system, the CSF (via either the
cochlear aqueduct or the internal auditory
meatus), or via the middle ear, across the
round window membrane.
4. Ototoxic substances can directly affect the tis-
sues that comprise the neurosensory epithelia
(organ of Corti).
5. Ototoxic substances can also affect the tissues
that support the normal physiologic function-
ing of the organ of Corti (such as stria vascu-
laris), thereby affecting the organ of Corti
function in an indirect manner.
6. The most common anatomical change within
the organ of Corti resulting from ototoxic
damage occurs in the OHCs. The degree of
change ranges from altered stereocilia
anatomy or complete loss of the cell.
7. The preferred method for detection of OHC
damage is the measurement of OAEs.
Lastname Firstname Ear Date Result
JAD Left 30-Sep-03 Pass
JAD Right 30-Sep-03 Pass
dB
60
40
20
0
-20
2 2 kHz
DP-Gram DP-Gram F2 Frequency
Figure 1-14 Distortion product otoacoustic emissions
(DPOAEs) recorded from the external canals from a normal
adult human. Results from the left and right ears are on the
left and the right side of the graph, respectively. The two top
lines represent the input levels of the two test frequencies, the
middle line represents the output level of the emission, and
the bottom line represents the output level of the noise floor.
Courtesy of Judy DeMorest, AuD, University of Texas at
Dallas Callier Center for Communication Disorders.
16 Anatomy and Physiology
8. The sensory receptor for the auditory nerve is
the IHC, which synapses with type I spiral
ganglion. Type I spiral ganglia are responsible
for conveying the auditory signal to the CNS.
9. Loss of function of the type I spiral ganglion
or the IHC results in loss of acoustic informa-
tion from that portion on the basilar mem-
brane. However, OHC loss will only reduce
the sensitivity of that portion. The OHCs
main function is to modify the acoustic infor-
mation that reaches the IHCs.
10. Preferred methods of detection of auditory
nerve activity are measurement of the CAP or
measurement of the ABR.
SUMMARY
The effects of substances on the peripheral audi-
tory system are caused either by a whole body
reaction causing secondary affects on the inner
ear or by the entry of substances into the inner
ear where they affect specific cellular targets.
Substances entering into the inner ear can cause
toxicity by their interaction with the biochem-
istry of the tissues and physiology of individual
cell types. In either case, the administration of an
ototoxic agent ultimately results in observable,
pathologic changes in the anatomy and electro-
physiology of the auditory system. To under-
stand the pathologic changes to peripheral
auditory system, it is necessary to understand
the systems normal anatomy and physiology.
The inner ear is a fluid-filled, neurosensory
structure within the skull base that converts the
mechanical, acoustic waves of sounds into
chemoelectric signals that are transported to the
brain via the auditory nerve. The health of this
system can be directly observed in postmortem,
histological preparations or by premortem
observation of chemoelectric signals via electro-
physiologic testing.
There are several fluid compartments in the
cochlea: the endolymph of the scala media; the
perilymph of the scala vestibuli, which is con-
tinuous with the perilymph of the scala tympani;
the cortilymph; and the vascular system. Routes
of entry into the cochlear tissues for ototoxic
substances are through one or more of these
fluids. Substances that enter the fluids either can
affect the health of the cells that are directly
involved in sensorineural transduction (the hair
cells and nerve endings) or can affect other tis-
sues within the cochlea that play supporting
roles (such as stria vascularis).
The unique architecture of the inner ear struc-
ture allows for tuning of the sensory epithelium
(basilar membrane and organ of Corti) to the
frequency and temporal components of sound.
The specificity and sensitivity of tuning of the
basilar membrane and organ of Corti in a nor-
mal ear involve an active mechanism, a major
component of which is the mechanical action of
the OHCs. The OHCs are especially susceptible
to a variety of ototoxic insults, and the health of
these cells can be monitored using otoacoustic
testing or electrophysiologic testing.
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 CHAPTER 2

Physiology of the Vestibular System

John A. Rutka, MD, FRCSC

Within the inner ear are specialized sensory receptors
responsible for the perception of the forces associated
with head movement and gravity. Control centers
within the brainstem integrate this information along
with other biologic signals derived from vision and
proprioceptive sensors in the final determination of an
individuals orientation in three-dimensional space.1
Although anatomically developed and responsive at
birth, the vestibular system matures along with other
senses in the first 7 to 10 years of life.2
Recognition of the heads movement relative to the
body is provided by the linear (otolithic macula) and
angular (semicircular canals) acceleration receptors of
the inner ear. Electrical activity generated within the
inner ear travels along the vestibular nerve (primary
afferent neuronal pathway) to the central vestibular
nuclei of the brainstem, forming second-order neu-
ronal pathways that become the vestibulo-ocular reflex
(VOR), the vestibulospinal tracts, and the vestibulo-
cerebellar tracts. Pathways derived from vestibular
information also travel to the brainstem emetic centers,
which serves to explain vegetative symptoms such as
nausea, vomiting, and perspiration that a patient typi-
Of all the human vestibular pathways, the VOR
remains the most important and most studied. At its
simplest level the VOR is required to maintain a stable
retinal image with active head movement. When an
active head movement is not accompanied by an equal
but opposite conjugate movement of the eyes, retinal
slip occurs. When the VOR is affected bilaterally (as
could occur from systemic aminoglycoside poisoning)
patients characteristically complain of visual blurring
with head movement, better known as oscillopsia, in
addition to having significant complaints of imbalance
and ataxia.3 True vertigo is typically not a feature of a
bilateral peripheral vestibular loss.
Oculomotor
Vestibulo-ocular
nuclei
Pathways
Medial
longitudinal
fasciculus

cally experiences following an acute unilateral vestibu- Reticular

formation
lar loss (Figure 2-1). S S
Disruption of peripheral (inner ear and the vestibu-
lar nerve) or central vestibular pathways as a result of, for L L
D Utricle
example , trauma, ototoxicity, or surgical deafferentation D
M
leads to the patient experiencing a distortion in orienta- Vestibulospinal M
tion. The patient often uses the term dizziness, which Pathways Vestibular
nucleus
is an all-encompassing yet relatively nonspecific term Medial
longitudinal
that can include symptoms such as giddiness, light- fasciculus
headedness, and floating sensation. Clinically, the term Other Pathways
(not demonstrated)
vertigo is best suited to describe a precise type of
To Emetic Centers
dizzinessa hallucination of movement involving one- To Vestibulocerebellum
self (subjective vertigo) or the surrounding environment
(objective vertigo) that is apt to occur when there is an Figure 2-1 Schematic representation of the vestibular system
acute interruption of vestibular pathways.1 and its pathways.

Vestibule
Figure 2-2 Anatomic organization of the peripheral vestibular system (vestibular end-organs and the vestibular nerve).
Reproduced with permission from Solvay Pharma, Canada.
ANATOMY OF THE VESTIBULAR SYSTEM
Peripheral Vestibular System
The peripheral vestibular system includes the paired
vestibular sensory end-organs of the semicircular
canals (SCCs) and the otolithic organs. These receptors
are found within the fluid-filled bony channels of the
otic capsule (the dense endochondral-derived bone
that surrounds the labyrinth and cochlea) and are
responsible for perception of both the sense of position
and motion. The vestibular nerve (both superior and
inferior divisions of the VIIIth nerve) is the afferent
connection to the brainstem nuclei for the peripheral
vestibular system (Figure 2-2).
Perception of angular accelerations is chiefly the
responsibility of the three paired SCCs (superior,
posterior, and lateral). Within the ampullated portion
of the membranous labyrinth are the end-organs of the
cristae, containing specialized hair cells that transduce
mechanical shearing forces into neural impulses.
Histologically the hair cells of the ampulla are
located on its surface. Their cilia extend into a gelati-
nous matrix better known as the cupula, which acts like
a hinged gate between the vestibule and the canal itself
(Figure 2-3).
The otolithic organs of the utricle and the saccule
are found within the vestibule. Chiefly responsible for
the perception of linear accelerations (eg, gravity,
deceleration in a car), their end-organs consist of a flat-
tened, hair cellrich macular area whose cilia project
into a similar gelatinous matrix. The matrix, however,
differs from the matrix associated with the SCCs in its
support of a blanket of calcium carbonate crystals bet-
ter known as otoliths, which have a mean thickness of
approximately 50 m (Figure 2-4).4
Physiology of the Vestibular System 21
Superior
Posterior Semicircular
Canals
Lateral
Superior Vestibular
Nerve
Inferior Vestibular
Nerve
Utricle
Saccule
Information from the vestibular end-organs is
transmitted along the superior (which receives infor-
mation from the superior, horizontal SCCs and utricle)
and inferior (which receives information from the pos-
terior SCC and saccule) divisions of the vestibular
nerve. Although its role is primarily afferent in the
transmission of electrical activity to the central vestibu-
lar nuclei of the brainstem, an efferent system does
exist that probably serves to modify end-organ activ-
ity.5 Each vestibular nerve consists of approximately
25,000 bipolar neurons whose cell bodies are located in
a structure known as Scarpas ganglion, which is typi-
cally found within the internal auditory canal (IAC).6
Type I neurons of the vestibular nerve derive informa-
tion from corresponding type 1 hair cells, whereas
type II neurons derive information from corresponding
type 2 hair cells at its simplest.
Cupula
Type 1 and 2
Hair Cells
Supporting Cells
Ampullary Nerve
Figure 2-3 Stylized representation of the crista: angular
acceleration receptor. Reproduced with permission from
Solvay Pharma, Canada.
22 Systemic Toxicity
At Rest
Figure 2-4 Stylized representation of macular end-organ: linear acceleration receptor. Reproduced with permission from Solvay
Pharma, Canada.
Central Vestibular System
Primary vestibular afferents enter the brainstem divid-
ing into ascending and descending branches. Within
the brainstem there appears to exist a nuclear region
with four distinct anatomic types of second-order
neurons that have been traditionally considered to con-
stitute the vestibular nuclei. It appears, however, that
not all these neurons receive input from the peripheral
vestibular system.4,7 The main nuclei are generally
recognized as the superior (Bechterews nucleus),
lateral (Deiters nucleus), medial (Schwalbes nucleus ),
and descending (spinal vestibular nucleus).
Functionally, in primate models, the superior
vestibular nucleus appears to be a major relay station
for conjugate ocular reflexes mediated by the SCCs.
The lateral vestibular nucleus appears to be important
for control of ipsilateral vestibulospinal (the so-called
righting) reflexes. The medial vestibular nucleus,
because of its other connections with the medial longi-
tudinal fasciculus, appears to be responsible for coordi-
nating eye, head, and neck movements. The descending
vestibular nucleus appears to have an integrative func-
tion with respect to signals from both vestibular nuclei,
the cerebellum, and an amorphous area in the reticular
formation postulated to be a region of neural integra-
tion. Commonly referred to as the neural integrator
among neurophysiologists, it is responsible for the
ultimate velocity and position command for the final
common pathway for conjugate versional eye move-
ments and position.8
The vestibular nerve in part also projects directly
to the phylogenetically oldest parts of the cerebellum
namely, the flocculus, nodulus, ventral uvula, and the
ventral paraflocculuson its way directly through the
vestibular nucleus. Better known as the vestibulocere-
bellum, this area also receives input from other
Blanket of Calcium
Carbonate Crystals
Gelatinous Matrix
Type 1 and 2
Hair Cells
Macula
Afferent Neuron
neuronal pathways in the central nervous system (CNS)
responsible for conjugate eye movements, especially
smooth-pursuit eye movements, which, in addition to
the VOR, are responsible for holding the image of a
moving target within a certain velocity range on the
fovea of the retina. The Purkinjes cells of the flocculus
are the main recipients of this information, of which
some appears to be directed back toward the ipsilateral
vestibular nucleus for the purposes of modulating eye
movements in relation to gaze (eye in space) velocity
with the head still or during combined eyehead
(vestibular signal-derived) tracking.9,10 Important for
cancelling the effects of the VOR on eye movement
when it is not in the best interest of the individual
(think of twirling ballet dancers or figure skaters and
how they can spin without getting dizzy), the vestibu-
locerebellum is also important in the compensation
process for a unilateral vestibular loss.7,9,10
The Hair Cells
The fundamental unit for vestibular activity on a
microscopic basis inside the inner ear consists of
broadly classified type 1 and 2 hair cells (Figure 2-5).
Type 1 hair cells are flask-shaped and surrounded
by the afferent nerve terminal at its base in a chalice-
like fashion. One unique characteristic of the afferent
nerve fibers that envelop type 1 hair cells is that they are
among the largest in the nervous system (up to 20 m
in diameter). The high amount of both tonic (sponta-
neous) and dynamic (kinetic) electrical activity at any
time arising from type 1 hair cells has probably neces-
sitated this feature for the neurons that transfer this
information to the CNS. Type 2 hair cells are more
cylindrical and at their base are typically surrounded by
multiple nerve terminals in contradistinction.11
 Physiology of the Vestibular System 23

Type 1 Type 2

KC KC
H H

Ct Ct

M
Nu M Nu

NC With Otolithic Displacement

NE 1
NE 2 NE 2
N Figure 2-6 Physiology of macular stimulation and inhibition
Figure 2-5 Schematic representation of type 1 and type 2 hair
cells. Ct = cuticular plate; H = hairs; KC = kinocillum;
M = mitochondria; NC = nerve chalice; NE = nerve ending;
Nu = nucleus.
Each hair cell contains on its top a bundle of 50 to
100 stereocilia and one long kinocilium that project
into the gelatinous matrix of the cupula or macula. It
is thought that the location of the kinocilium relative
to the stereocilia gives each hair cell an intrinsic polar-
ity that can be influenced by angular or linear acceler-
ations. It is important to realize that an individual is
born with a maximum number of type 1 and 2 hair
cells that cannot be replaced or regenerated if lost as a
result of the effects of pathology (eg, ototoxicity or sur-
gical trauma) or aging (the postulated presbyvestibular
dropout from cellular apoptosis). Presumably the same
process holds for the type I and II neurons that com-
prise the vestibular nerve.
from otolithic shift and its shearing effect on stereocilia and
kinocilium of the hair cells.
The SCCs largely appear to be responsible for the
equal but opposite corresponding eye-to-head move-
ments better known as the VOR. The otolithic organs
are primarily responsible for ocular counter-rolling
with tilts of the head and for vestibulospinal reflexes
that help in the maintenance of body posture and
muscle tone.
In order to ultimately produce conjugate versional
VOR-mediated movements of the eyes, each vestibular
nucleus receives electrical information from both sides
that is exchanged via the vestibular commissure in the
brainstem. The organization is generally believed to be
specific across the commissure. Neurons in the right
vestibular nucleus, for example, that receive type I
input from the right horizontal SCC project across the
commissure to the neurons found in the left vestibular
nucleus that are driven by the left horizontal SCC
receiving contralateral type II input and vice versa.7

APPLIED PHYSIOLOGY Displacement of Sensory Hairs

At the microscopic level, movements of the head or Resting Rate Toward Kinocilium Away from Kinocilium
changes in linear accelerations deflect the cupula or
shift the gelatinous matrix of the otolithic organs with
its load of otolithic crystals that will either stimulate
(depolarize) or inhibit (hyperpolarize) electrical activ-
ity from type 1 and 2 hair cells. Displacement of the
stereocilia either toward or away from the kinocilium
influences calcium influx mechanisms at the apex of
the cell that causes either the release or reduction of
neurotransmitters from the cell to the surrounding Discharge Rate Vestibular Nerve
afferent neurons (Figures 2-6 and 2-7 ).12 The electri-
cal activity generated is then transferred along the Tonic Resting Activity Stimulation Inhibition
(depolarization) (hyperpolarization)
vestibular nerve to the vestibular nuclei in the brain-
stem. Information above the tonic (spontaneous) firing Figure 2-7 The physiology of motion and position sense.
rate of the type 1 hair cells transmitted along type I Concept of hair cell signal (electrical activity generation) at
neurons is largely thought to have a stimulatory effect rest (resting discharge rate) and with respect to effects of
in contrast to a more inhibitory effect attributable to movement resulting in depolarization (stimulation) and
type 2 hair cells and type II neurons. hyperpolarization (inhibition).
24 Systemic Toxicity
KEY CONCEPTS
According to Leigh and Zees seminal text, the key con-
cepts of vestibular physiology can be best appreciated
in the context that the pushpull pairings of the
canals, the resting vestibular tone and exchange of
neural input through the vestibular commissure maxi-
mize vestibular sensitivity in health and provide a sub-
strate for compensation and adaptation.7
VOR Gain
In order to maintain a stable retinal image during head
movement, the eyes should move in an equal but oppo-
site direction to head movement. Anything less than
unity (corresponding eye movement/head movement)
may result in the perception of visual blurring with
head movementoscillopsia being the classic sympto-
matic complaint of an individual with a bilateral
peripheral vestibular loss as might result from genta-
micin vestibulotoxicity.
Nystagmus
Defined as a rhythmic to-and-fro, back-and-forth
movement of the eyes, nystagmus represents the cardi-
nal sign of unilateral peripheral vestibular or central
vestibular dysfunction.
In an acute unilateral loss of peripheral vestibular
activity that might occur from topical aminoglycoside
drops or certain disinfectant surgical preparation solu-
tions used in the presence of a tympanic membrane
defect, injury to the end-organ causes a difference in
neural activity between the left and right vestibular
nuclei. Should the pushpull pairings of the canals be
affected as a result of pathology, the eyes are typically
driven with a slow movement toward the affected side
only to be corrected by a fast corrective saccade gen-
erated within the CNS away from the side of the lesion
in a repetitive fashion. Although somewhat misguided,
the direction of the nystagmus by convention refers to
the fast phase, typically away from the side of the
lesion under circumstances of an acute unilateral
peripheral vestibular loss.
Habituation and Adaptation
In humans the CNS may habituate (show a reduced
response) the VOR depending on the environmental
circumstances. This may happen in individuals who
are blind or in those exposed to constant velocity rota-
tions or continuous low-frequency oscillations (such as
on a ship). The mechanisms for adaptation or the adap-
tive plasticity of the VOR are usually visually driven and
have been experimentally studied by subjects wearing
reversing prisms.13 This phenomenon is frequently
experienced by those wearing new prescriptive glasses
with the explanation that they take some time to get
used to. Eventually one adapts to the new lenses as the
gain of the VOR changes accordingly. The same holds
true to some extent for those with a unilateral periph-
eral vestibular loss, where the gain can be somewhat
influenced, though not perfectly.
Compensation
Clinical improvement following acute unilateral
peripheral vestibular deafferentation requires the pres-
ence of intact central vestibular connections primarily
at the level of the vestibulocerebellum.4,7 The loss of
tonic or spontaneous vestibular activity from the end-
organ is ultimately replaced by the development of
spontaneous electrical activity arising within the
vestibular nuclei of the affected side.14 At rest the asym-
metries that would be expected from the pushpull
effects from the canals are kept in check, and as a result
there is the gradual resolution of the once-present spon-
taneous nystagmus. Quick head movements producing
changes in the dynamic electrical activity, however, can
never be completely compensated through this mecha-
nism on the affected side, and a bilateral loss of inner ear
function never does despite the insertion of midrota-
tion corrective saccades. For a more detailed explana-
tion of the phenomenon of compensation and why it
often fails in the setting of a bilateral vestibular loss see
Chapter 19, Monitoring Vestibular Toxicity.
CLINICAL MANIFESTATIONS OF VESTIBULAR
DYSFUNCTION
Loss of vestibular function is associated with several
signs and symptoms.
Unilateral Peripheral Vestibular Loss
With a loss of unilateral vestibular function the patient
acutely experiences the sensation of true vertigo from
interruptions of VOR pathways and tends to lie per-
fectly still, as any movement aggravates vegetative
symptoms such as nausea and vomiting that arise from
the emetic centers. Nystagmus beating away from the
side of lesion is the cardinal physical sign that obeys
Alexanders law (the quick phase of the nystagmus
induced by the imbalance in activity at the level of the
vestibular nuclei is greatest in amplitude and frequency
when the eyes are turned away from the side of the
lesion).15 Interruption in vestibulospinal tract pathways
causes the patient to fall or list toward the affected side.
Findings of ipsilateral hemispheric cerebellar dysfunc-
tion presenting with behaviors such as past-pointing,
an inability to perform rapid alternating movements
(dysdiadochokinesis), and gait ataxia reflect acute
vestibulocerebellar tract involvement. Features distin-
guishing peripheral from central mediated nystagmus
can be found in Table 2-1.
With compensation (implying the existence of a
normal functioning CNS and contralateral peripheral
vestibular system) there may be minimal symptoma-
 Physiology of the Vestibular System 25

Table 2-1 Characteristics of Nystagmus/Oculomotor Abnormalities in Peripheral Vestibular vs Central Pathology

Feature Acute Unilateral Peripheral Loss Bilateral Peripheral Loss Central

Direction of nystagmus Mixed horizontal torsional None expected Mixed or pure torsional
(arching) or vertical

Fixation/suppression Yes Yes No

Slow phase of nystagmus Constant No nystagmus Constant or increasing/

expected decreasing exponentially

Smooth pursuit Normal Normal Usually saccadic

Saccades Normal Normal Often dysmetric

Caloric tests Unilateral loss Bilateral loss Intact/direction of

nystagmus often perverted
(reverse direction)

CNS symptoms Absent Absent Often present

Symptoms Severe motion aggravated Oscillopsia/imbalance/gait Vertigo not as severe as in

vertigo/vegetative symptoms ataxia, vertigo not a complaint acute unilateral loss

CNS = central nervous system.

tology that is only brought out by very rapid head
movements. The spontaneous nystagmus disappears,
vegetative symptoms resolve, gait improves, and in the
case of a chronic condition the patient may experience
only a slight imbalance when turning quickly.
the patient requires assistive devices for ambulation or
is relegated to a wheelchair. Compensation is generally
unlikely to occur despite the best efforts of vestibular
rehabilitation therapy and a greater reliance on infor-
mation from visual and proprioceptive receptors.

Bilateral Peripheral Vestibular Loss SPECIAL CLINICAL TESTS OF

Vertigo is not a feature of a bilateral vestibular loss even
when it occurs in an acute fashion. Injury to the end-
organs as might occur in systemic aminoglycoside
vestibulotoxicity causes a bilateral loss of function that
tends to be electrically symmetric at the level of the
vestibular nuclei in the brainstem. Instead the patient
tends to complain of oscillopsia and imbalance. The gait
is typically broad-based and ataxic, especially with eyes
closed. Falls are not infrequent and in many instances
VESTIBULAR FUNCTION
The following clinical tests are used at the bedside in
the assessment of vestibular function and are specific
for the VOR. A summary can be found in Table 2-2.
High-Frequency Head Thrust or Halmagyi
Maneuver
Perhaps the most specific test for horizontal VOR
function, the high-frequency head thrust, shares the

Table 2-2 Special Clinical Tests of Vestibular Function

Clinical Vestibular Test Purpose

High-frequency head thrust (Halmagyi maneuver) High-frequency test of VOR function usually performed in the horizontal
plane. Presence of refixation saccades to stabilize eyes on a target follow-
ing fast head movement suggests a defect in the horizontal VOR

Head shake test for 1520 seconds High-frequency vestibular test. Presence of post-headshake nystagmus
correlates well with increasing right/left excitability difference on caloric
testing. Fast phase of nystagmus usually directed away from side of lesion.

Oscillopsia test Visual loss of more than 5 lines with rapid horizontal head shaking while
looking at a standard Snellens chart suggests a bilateral vestibular loss.

VOR suppression test Inability to visually suppress nystagmus during head rotations suggests a
defect at the level of the vestibulocerebellum. Pursuit eye movements are
invariably saccadic

VOR = vestibulo-ocular reflex.

26 Systemic Toxicity
same physiologic basis as the dolls eye maneuver in
neurology. During a quick head movement to the nor-
mal side with the patient focusing on a target, there
should be almost perfect compensatory conjugate ver-
sional movement of the eyes in an equal but opposite
direction to head movement. When a defect occurs in
the VOR, quick movements of the head are usually
associated with incomplete compensatory conjugate
eye movements often requiring refixation saccades to
stabilize gaze.16,17 Not surprisingly patients with a uni-
lateral vestibular loss often volunteer subjective blur-
ring of vision when they move their head to the
affected side.
Although a positive head thrust maneuver is always
indicative of pathology somewhere along the course of
VOR, false-negative findings can arise. This can occur
when an individual throws in corrective midrotation
saccades that are imperceptible to the human eye. Iden-
tification with advanced eye-movement recording sys-
tems such as magnetic scleral coil search studies would
typically be required.18
Head Shake Test
Rapid horizontal head shaking for 15 to 20 seconds
occasionally results in horizontal post-headshake
nystagmus usually (but not always) directed away from
the side of a unilateral vestibular loss.19 Frenzels glasses
are generally worn to prevent ocular fixation and sup-
pression of nystagmus by vision. Headshake nystagmus
is generally thought to occur when asymmetries in rest-
ing vestibular tone are exaggerated at the level of the
postulated central velocity storage mechanism in
the brainstem.20
Dynamic Visual Acuity (Oscillopsia Testing)
Complaints of oscillopsia are best assessed by asking
the patient to read the lowest line possible on a stan-
dard Snellens chart. While repetitively shaking the
head in the horizontal plane (at a frequency > 2 Hz) the
patient is asked to read the lowest line possible for com-
parison purposes. A loss of more than five lines during
active head-shaking is considered definitely clinically
significant for a bilateral vestibular loss.21 The test can
also be performed using an optotype such as the letter
E (the so-called dynamic illegible E, or DIE, test)
presented in random orientations and different sizes on
a chart or monitor. Comparison between the static and
dynamic optotypes correctly identified has been used
to determine if a bilateral vestibular loss exists.22,23
VOR Suppression Testing (Fixation of Vestibular-
Induced Nystagmus)
This test assesses the ability of the CNS to suppress a
vestibular signal. It can be assessed by asking patients
to follow with the head in the same direction an object
that rotates (eg, patients look at their outstretched
hands held together while seated in a chair that rotates).
If the vestibulocerebellum is intact then the eyes should
remain stable in the orbit from visual fixation and sup-
pression of the VOR. In central vestibular pathology,
oculomotor testing typically reveals pursuit eye move-
ments that are saccadic associated with the presence of
a breakthrough nystagmus during head rotations as
fixation is incomplete.24 VOR suppression testing is
somewhat analogous to the parallel phenomenon of
failure of fixation suppression during caloric testing
when visual fixation does not suppress caloric-induced
nystagmus.
SUMMARY
The vestibular system is responsible for the per-
ception of both the sense of position and
motion. Angular accelerations are perceived by
the SCCs, linear accelerations by the otolithic
macula of the utricle and saccule.
Vestibular pathways include the VOR, vestibu-
lospinal tracts, and vestibulocerebellar tracts.
Overall the VOR remains the most important
and most clinically studied vestibular pathways,
being responsible for the maintenance of a sta-
ble retinal image with active head movement.
Defects in these pathways arising from pathol-
ogy demonstrate several well-recognized physi-
cal signs, the cardinal sign of a unilateral
peripheral vestibular loss being nystagmus.
The concepts of VOR gain, nystagmus, habitua-
tion or adaptive plasticity, and compensation all
have their substrates in the pushpull pairings of
the canals, resting vestibular tone, and exchange
of neural input through the vestibular commis-
sure from peripheral and central vestibular path-
ways that maximize vestibular sensitivity in
health and demonstrate pathologic features
when diseased. (For detailed information
regarding oculomotor and vestibular physiology,
see Leigh and Zee7 and Baloh and Honrubia.4)
True vertigo is usually present in an acute uni-
lateral peripheral vestibular loss. A bilateral
peripheral vestibular loss typically results in
oscillopsia (visual blurring with head move-
ment) and imbalance that worsens in the
absence of visual clues. True vertigo is rarely ever
a feature of bilateral peripheral vestibular loss.
Clinical bedside tests apply the concepts of
vestibular physiology and are important in rec-
ognizing disease pathology involving the
vestibular system. The high-frequency head
thrust (Halmagyi maneuver) is probably the
most specific clinical test of vestibular function.
Other tests include the headshake test, oscillop-
sia testing, and VOR suppression and fixation.

ACKNOWLEDGMENTS
The author thanks Mr David Mazierski (medical illus-
trator), Ms Elise Walmsley (medical illustrator, TriFocal
Communications), and Solvay Pharma Canada (illus-
trations and permissions).
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1. Rutka JA. Evaluation of vertigo. In: Blitzer A, Pills-
bury HC, Jahn AF, Binder WJ, editors. Office based
surgery in otolaryngology. New York: Thieme;
1998. p. 718.
2. Westcott SL, Lowes LP, Richardson PK. Evaluation
of postural stability in children. Current therapies
and assessment tools. Phys Ther 1997;77:62945.
3. Brickner R. Oscillopsia: a new symptom com-
monly occurring in multiple sclerosis. Arch Neurol
Psych 1936;36:58690.
4. Baloh RW, Honrubia V. Contemporary neurology
series: clinical neurophysiology of the vestibular
system. Philadelphia (PA): FA Davis Company;
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5. Goldberg JM, Fernandez C. Efferent vestibular
system in the squirrel monkey: anatomical location
and influence on afferent activity. J Neurophysiol
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6. Park JJ, Tang Y, Lopez I, Ishiyama A. Age related
change in the number of neurons in the human
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43743.
7. Leigh RJ, Zee DS. Contemporary neurology series:
the neurology of eye movements. Philadelphia
(PA): FA Davis Company; 1983.
8. Robinson DA. Ocular motor control signals. In:
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9. Zee D, Yamazaki A, Butler PH, et al. Effects of abla-
tion of the flocculus and paraflocculus on eye
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10. Nedzelski JM. Cerebellopontine angle tumors:
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ated oculomotor abnormalities. Laryngoscope
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11. Ades HW, Engstrom H. Form and innervation of
the vestibular epithelia. Symposium on the role of
the vestibular organs in the exploration of space.
US Naval School Aviat Med, Pensacola, Florida,
Physiology of the Vestibular System 27
1965. NASA SP-77. Washington (DC): National
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12. Ersall J, Lundquist PG. In: Graybiel A, editor. Sec-
ond symposium on the role of vestibular organs in
space exploration. NASA SP-115. Washington
(DC): National Aeronautics and Space Adminis-
tration; 1966.
13. Gonshor A, Melvill Jones G. Extreme vestibular-
ocular adaptation induced by prolonged optical
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14. Precht W. Vestibular mechanisms. Annu Rev
Neurosci 1979;2:26578.
15. Doslak MJ, DellOsso L, Daroff RB. A model for
Alexanders law of vestibular nystagmus. Biol
Cybern 1979; 34:18190.
16. Halmagyi M, Curthoys IS, Ae ST, et al. The human
vestibular-ocular reflex after unilateral vestibular
deafferentation. The results of high frequency
acceleration impulsive testing. In: Sharpe J, Barber
HO, editors. The vestibulo-ocular reflex and
vertigo. New York: Raven Press; 1993. p. 4555.
17. Halmagyi GM, Curthoys IS. A clinical sign of canal
paresis. Arch Neurol 1988;45:7379.
18. Prepageran N, Kisilevsky V, Tomilinson D, et al.
Symptomatic high frequency vestibular loss:
consideration for a new clinical syndrome of
vestibular dysfunction. Acta Otolaryngol 2004;
124:17.
19. Asawavichianginda S, Fujimoto M, Mai M, et al.
Significance of head shaking nystagmus in the
evaluation of the dizzy patient. Acta Otolaryngol
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20. Hain TC, Sindler J. Head-shaking nystagmus. In:
Sharpe J, Barber HO, editors. The vestibulo-ocular
reflex and vertigo. New York: Raven Press; 1993.
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21. Chambers BR, Mai M, Barber HO. Bilateral
vestibular loss, oscillopsia and the cervico-ocular
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4037.
22. Longridge NS, Mallinson AI. The dynamic illegible
E (DIE) test: a simple technique for assessing the
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laryngol 1982;11:1417.
 Systemic Toxicity
CHAPTER 3
Salicylates, Nonsteroidal Anti-inflammatory Drugs,
Quinine, and Heavy Metals
Narayanan Prepageran, MBBS, FRCS(Ed), FRCS(Glas), MS(ORL), and John A. Rutka, MD, FRCSC


Salicylates are one of the most widely used drugs.
Acetylsalicylic acid (ASA), commonly known as
Aspirin, is widely used for its anti-inflammatory,
antipyretic, and analgesic properties. ASA inhibits
platelet aggregation and is used in the treatment of
patients with a history of transient ischemic attacks
(TIAs), stroke, unstable angina, and myocardial
infarcts. Up to 20,000 tons of salicylates are consumed
annually in the United States.1 ASA is rapidly absorbed
after oral administration and is hydrolyzed in the liver
into its active form, salicylic acid. Therapeutic levels
range from 25 to 50 g/mL for analgesic and antipyretic
effects to 150 to 300 g/mL for treatment of acute
rheumatic fever. 2 Nonsteroidal anti-inflammatory
drugs (NSAIDs) constitute a heterogeneous group of
compounds that have therapeutic actions and side
effects similar to those of salicylates. Since these drugs
can be obtained without prescription, they are poten-
tially available for long-term use and abuse.3 Quinine
is another compound with therapeutic actions and
clinical side effects similar to those of salicylates.
One of the side effects of salicylates and many
NSAIDs is ototoxicity manifesting as mild to moderate
usually reversible hearing loss and tinnitus. ASA oto-
toxicity has been reported to occur in 11 per 1,000
patients, with a much higher incidence reported for
long-acting salicylates.3,4 Elderly patients have been
reported to be at a significantly higher risk for salicy-
late toxicity, even at lower doses.5 Although the use of
quinine as an antimalarial drug has been decreasing in
favor of less toxic semisynthetic derivatives, it is com-
monly used as a treatment for nocturnal leg cramps.
For this reason, quinine ototoxicity is still occasionally
seen in clinical practice.1
SALICYLATE OTOTOXICITY
History
The use of naturally occurring salicylates, such as the
bark of the willow tree, for their medicinal properties
dates to at least the fourth century BCE. Hippocrates
recommended their use to relieve the pain of child-
birth.2 The active ingredient of willow bark, called
salicin, was first isolated by Leroux in 1829. The
antipyretic properties of salicylate, in the form of
sodium salicylate, were used in 1875 for the treatment
of rheumatic fever.1 In 1899, Hoffman, a chemist with
Bayer, prepared the ASA compound that was called
Aspirin.6 Muller first identified the ototoxic effects of
high doses of salicylate in 1877; reports of deafness
from Aspirin surfaced in 1884.1,7,8
Pharmacokinetics of Salicylate
ASA is rapidly absorbed in the upper small intestines
and stomach. Appreciable serum levels of ASA have
been noted within 30 minutes of oral ingestion, with
peak levels occurring at 2 hours.1,6 The passive diffusion
of salicylic acid through the mucosa is determined by
various factors: tablet dissolution rate, mucosal pH
value, and the gastric emptying rate. Subsequently, sali-
cylate is widely distributed, undergoes biotransforma-
tion in the liver, and is excreted by the kidneys. The
main metabolic products are salicyluric acid, phenolic
glucuronide (the ether), and acyl glucuronide (the
ester). Salicylate metabolites excreted by the kidney in
the urine include free salicylic acid (10%), salicyluric
acid (75%), salicylate phenolic (10%), acyl glu-
curonides (5%), and gentisic acid (< 1%). The plasma
half-life of ASA is about 15 minutes, whereas the
plasma half-life of salicylate is 2 to 3 hours for low
doses and 12 hours or longer for higher doses.1,6
Ishii and colleagues in 1967 documented the rapid
entry of salicylate into the cochlea after systemic
administration of tritium-labeled salicylate. Autoradi-
ography detected the tritium-labeled salicylate in the
stria vascularis and spiral ligament. Within 1 hour, sal-
icylate was detected around the outer hair cells (OHCs)
and near the spiral ganglion cells. There was no accu-
mulation in any specific structures.9 Evidently, salicylate
undergoes rapid absorption and promptly reaches the
 Salicylates, Nonsteroidal Anti-inflammatory Drugs, Quinine, and Heavy Metals
cochlea via the arteries, where it readily diffuses to all
parts of the cochlea.1 Salicylic acid, transported in the
undissociated or un-ionized form, is highly permeable
across lipid layers10 and human red blood cell mem-
branes.11 When salicylic acid enters a cell, dissociation
to salicylate occurs. The final concentration of the dis-
sociated form appears dependent on intracellular pH.12
Serum salicylate levels and perilymph levels have
been extensively studied in animals and humans.
Woodruff and colleagues reported serum salicylate
levels of 51 to 78 mg/dL, with a median of 65.3 mg/dL,
3 hours after intramuscular injection of sodium salicy-
late (400 mg/kg) in chinchillas.1,13 Salicylate concentra-
tion has also been documented in serum, cerebrospinal
fluid (CSF), and perilymph after intraperitoneal injec-
tion of ASA (300 mg/kg).14 Peak levels appeared within
0.5 to 1 hour in serum and 1 hour in CSF, whereas per-
ilymph levels peaked at 2 hours. The concentration of
salicylate in perilymph was the lowest (10 mg/dL),
approximately 20% of the serum concentration
(65 mg/dL), but only slightly lower than CSF levels
(14 mg/dL).1 Silverstein and colleagues reported peri-
lymph levels of 25 to 40 mg/dL and serum concentra-
tions of 51 to 86 mg/dL, 5 to 7 hours after injecting
salicylate (350 mg/kg) into cat peritoneum.1,15 Jastre-
boff and colleagues in 1986 documented a peak serum
level of 70 mg/dL 3 to 4 hours after an intraperitoneal
dose of sodium salicylate in guinea pigs and 60 to
70 mg/dL in rats. They also documented that the sali-
cylate levels in perilymph were closely related to both
drug levels in serum and CSF. Higher levels were sys-
tematically observed in perilymph than in CSF. The
conclusion drawn was that salicylate is not passively
transported into perilymph across CSF but, rather,
appears to be transported from blood directly into peri-
lymph.16 Day and colleagues studied the concentration
response relationships for salicylate-induced ototoxic-
ity in normal volunteers and reported that total and
unbound plasma salicylate concentration increased dis-
proportionately with increasing daily doses of ASA. The
increase in unbound salicylate in plasma was relatively
greater since the percentage of unbound salicylate
increased over the dose range investigated from a mean
of 3.9 to 10.4%.17
Studies have correlated serum salicylate levels to
hearing loss. Myers and Bernstein18 and Bernstein and
Weiss19 reported a correlation (r = .84) between hear-
ing loss and increasing serum levels up to 40 mg/dL.
Levels above this did not produce a significantly greater
degree of hearing loss.1 Bonding and McFadden and
colleagues21 found strong correlations (r = .73 and
r = .6 respectively) between hearing loss and serum
salicylate levels.1,20,21 Various salicylate serum concen-
trations (ranging from 19.9 to concentrations
> 67 mg/dL) have been reported to correlate with
documented ototoxicity.22 Levy reported that the time
29
courses of various pharmacologic effects of single doses
of ASA are not coincident with the plasma concentra-
tion of either ASA or salicylic acid. There was reason-
ably good evidence, however, that the pharmacologic
effects were related to the concentration of ASA, sali-
cylic acid, or both.23 He concluded that the pharmaco-
logic activity of salicylate is produced by free
(unbound) drugs. The plasma protein that binds sali-
cylic acid is concentration dependent and subject to
pronounced individual variations, making it preferable
to monitor unbound rather than total concentrations
of salicylate in plasma.23
Halla and colleagues identified that most reports of
salicylate toxicity have been based on total serum lev-
els, whereas unbound serum salicylate concentrations
appear to reflect more closely the risk of ototoxicity.22
Day and colleagues reported that in a study of volun-
teers hearing loss and tinnitus intensity increased
progressively with ASA dosage and increasing con-
centration of both total and unbound plasma salicylate
concentrations. Hearing loss and unbound salicylate
concentration appear to have a linear relationship.17
Conversely, Halla and colleagues concluded that tinni-
tus and subjective hearing loss were too nonspecific
and not sensitive enough to be used as a useful indica-
tor of serum salicylate concentration.22,24
Mechanisms of Salicylate Ototoxicity
The dominant ototoxic effects of salicylates are tinni-
tus and a reversible sensorineural hearing loss (SNHL).
The hearing loss is typically mild to moderate and
bilaterally symmetric. Recovery usually occurs 24 to
72 hours after cessation of the drug. As such, the mech-
anism of salicylate ototoxicity is probably more related
in humans to reversible biochemical or metabolic
changes in the cochlea rather than to morphologic
abnormalities.1
Pathology
The pathology of salicylate ototoxicity has been docu-
mented from human and animal temporal bone
histopathology and ultrastructural examinations of the
organ of Corti, especially the cochlear hair cells. In
many instances, there have been conflicting and vari-
able interspecies differences. For example, Kirchner in
1881 identified areas of hemorrhage in the organ of
Corti and the cochlear labyrinth in a human temporal
bone following salicylate ototoxicity.1 Similar findings
were noted in guinea pigs in 1938.1 Bernstein and Weiss
in 1967 reported histopathologic findings in temporal
bones from two patients who had received large doses
of ASA (more than 5 g/d) before death.19 They docu-
mented that the organ of Corti was essentially unin-
volved. Most hair cells were normal, with the exception
of the hair cells in the basal turn, which were consis-
tent with change as a result of aging.1 DeMoura and
30 Systemic Toxicity
Hayden in 1968 also reported the organ of Corti to be
normal with no significant hair cell loss in a patient
who apparently had a 40 to 50 dB hearing loss from
taking ASA of up to 5.2 g/d for 7 months.25 The patient
recovered 20 dB of hearing 3 days after she stopped
taking ASA.1
Histopathologic examinations of temporal bones
have revealed minor and presumably reversible micro-
scopic changes in the cochlea. In 1938, Covell noted
evidence of mitochondrial change and dilatation of
stria vascularis in the strial and OHCs of the guinea
pigs.26 The spiral ganglia, however, appeared to be nor-
mal. Other investigators have noted different micro-
scopic changes. Gotlib, in 1957, reported some changes
in the spiral ganglion with normal strial tissues. 27
Although Falbe-Hansen (1941) noted some loss of hair
cells, Myers and Bernstein (1965) did not find any sig-
nificant abnormalities in the cochlea microstructure in
subjects when compared with a control group.1,18 In an
animal study using chinchilla exposed to 400 mg/kg of
salicylate, Woodford and colleagues noted scattered
OHC loss.1 Conversely, again using the chinchilla as the
animal model, Deer and Hunter-Duvar found no sig-
nificant abnormalities.1,28 There was no evidence of cell
destruction in the stria vascularis or organ of Corti.
The cochlea vessels and stereocilia of inner and outer
hair cells were normal. Transmission electron
microscopy showed no difference in the inner hair cells,
supporting cells, or stria vascularis between the study
and the control group.1,28 The OHCs of the experimen-
tal animals, however, revealed an accumulation of
organelles, namely membrane bound vacuoles, dark
staining spheres near the Golgi apparatus, swollen
mitochondria, lysosomes, and whorls of fenestrated
smooth cisternae surrounding degraded mitochon-
dria.1 A similar ultrastructural study of longitudinal
and transverse sections of guinea pig temporal bones
after exposure to a high dose of sodium salicylate
revealed no abnormalities. Falk found no abnormalities
in the cell membrane, nuclear membrane, mitochon-
dria, Golgi bodies, endoplasmic reticulum, myelin
sheath of spiral ganglia, axoplasm, Schwanns nucleus,
or auditory nerve cytoplasm.1,29
Morphologic changes secondary to salicylate oto-
toxicity have been documented with the aid of electron
microscopy in the last few decades. In 1983, Douek and
colleagues reported cochlea morphologic findings in
guinea pigs after administering 375 mg/kg of sodium
salicylate daily for 1 week. Although no significant
changes were noted on light microscopy in the stria vas-
cularis and the number of hair cells between the study
and control groups, electron microscopy revealed
extensive vacuolization of the endoplasmic reticulum
underlying the cell membrane of the OHCs in the study
group. In addition, long-term salicylate administration
caused bending of the OHC stereocilia.1,30 Dieler and
colleagues reported certain ultrastructural morpho-
logic changes on the OHCs of guinea pigs after salicyl-
ate infusion. They noted subsurface cisternae dilatation
and vesiculation. These changes appeared to be time
and dose dependent and were reversible over 30 min-
utes.31 They speculated that intact, unfenestrated sub-
surface cisternae were required for optimal generation
of electrically induced motility in mammalian OHCs.
The OHC changes may therefore form the morphologic
basis by which salicylate ototoxicity reduces sponta-
neous and evoked emissions.1
Physiology
Physiologic studies of salicylate ototoxicity have pre-
dominantly focused on the evaluations of cochlear
potentials, acoustic emissions, and cochlear blood flow.1
Effects on Cochlear and Auditory Potentials
Early animal studies have identified some electrophys-
iologic changes after exposure to salicylate. In 1973,
Mitchell and colleagues noted that a single subcuta-
neous dose of sodium salicylate reversibly interfered
with the generation of cochlear nerve action potentials
(APs) in guinea pigs.32 This process was more pro-
nounced in the higher frequencies of hearing. The
cochlear microphonics (CM) remained normal. Silver-
stein and colleagues, however, noted decreases in the
amplitudes of both CM and APs in cats after intraperi-
toneal injections of salicylate.15 McPherson and Miller
noted similar results in guinea pigs in 1974.33 Sty-
pulkowski in 1990 reported his findings of increased
CM and reduced summating potentials.34 No signifi-
cant change was identified in endocochlear potentials.
Other researchers have reported varying increases
in the spontaneous activity of auditory neurons after
salicylate administration.35 Evans and Borerwe noted
an increase in the spontaneous activity of auditory neu-
rons.36 This finding was further supported by the works
of Kumagai in 199237 and Stypulkowski in 1990.34 Chen
and Jastreboff in 1995 identified increased central
activity in the inferior colliculus.38 A similar pattern
was noted by Jastreboff and Sasaki 39 in 1986 and
Manabe and colleagues40 in 1997. Ochi and Eggermont,
however, identified increased spontaneous activity in
the auditory cortex after salicylate administration.41
Most physiologic observations from animal studies
were obtained after a single high dose of salicylate in an
acute setting. This differs from most human studies
where high doses of salicylate were repeatedly admin-
istered over days.35
Effects on Otoacoustic Emissions
The discovery and application of otoacoustic emission
(OAE) testing have helped to further our understanding
of salicylate ototoxicity. OAEs are presumed to reflect an
active mechanical process in the cochlea, especially at
 Salicylates, Nonsteroidal Anti-inflammatory Drugs, Quinine, and Heavy Metals
the level of the OHCs.1 Johnson and Eberling reported
decreased OAEs after the ingestion of 10 g of ASA.42
McFadden and Plattsmier measured spontaneous OAEs
prior to, during, and following administration of ASA.43
They noted that all spontaneous OAEs gradually dimin-
ished and disappeared during the treatment protocol.
Small emissions were noted to disappear early, within 14
to 20 hours of drug ingestion, whereas larger emissions
took 40 to 70 hours to disappear completely. There was
complete recovery once the drug administration ceased;
the length of recovery lasted from 24 hours to a few days.
Long and Tubis noted decreased spontaneous emissions,
delayed OAEs, and synchronous emissions after inges-
tion of high-dose ASA.44 Reduction of OAE induced by
salicylates suggested abnormalities in the OHCs.1
Brownell and Winston reported a decrease in the turgor
of the OHCs, which reduced their ability to contract.45
Alterations in cell membrane permeability are believed
to be the result of salicylate increasing the potassium ion
conductance of the OHCs, which in turn has been pos-
tulated to cause the decrease in the OHC turgor.34,45
Decrease in OHC turgidity and interference with elec-
tromotility has been demonstrated by Shehata and col-
leagues to be dose dependent and reversible.46 More
recently, Tunstall and colleagues. showed that salicylates
reduce OHC-membrane capacitance.47 This was later
confirmed by Kakehata and Santos-Sacchi in 1996.12
Effects on Cochlear Blood Flow
A vascular basis for salicylate ototoxicity has also been
recently highlighted. Reduction of blood flow to the
cochlea has been suggested as a possible mechanism for
salicylate toxicity.1,48 Hawkins noted that acute ASA
ingestion produced vasoconstriction of the capillaries of
the spiral ligament and stria vascularis.48 The localized
drug accumulation and vasoconstriction in the auditory
microvasculature may have been mediated by anti-
prostaglandin activity in these agents.49 Using a laser
Doppler flowmeter, Didier and colleagues demonstrated
decreased cochlear blood flow by 25% that was associated
with significant elevated compound AP thresholds with
high doses of ASA (300 mg/kg).50,51 Jung and colleagues
found a similar significant reduction of cochlear blood
flow both by systemic (300 mg/kg) and round window
membrane (RWM) application of sodium salicylate.1
Biochemistry
Transient biochemical abnormalities have long been
believed to be responsible for the reversible nature of
salicylate ototoxicity. Biochemical investigations of sal-
icylate ototoxicity include abnormalities in inner ear
enzymes, catecholamines, and cations such as zinc and
arachidonic metabolism.1
Silverstein and colleagues in 1967 demonstrated
reduced malic dehydrogenase activity in the perilymph
and endolymph and decreased electrical activity in the
31
cochlea, possibly reflecting an inhibition in the stria
vascularis and organ of Corti.15 Ishii and colleagues
noted that salicylate interfered with cholinesterase
activity in the organ of Corti. 9 Krzanowski and
Matschinsky in 1971 reported that salicylate interferes
with phosphate metabolism in phosphocreatine reserve
at the basal turn of the organ of Corti and in the adeno-
sine triphosphate (ATP) of Reissners membrane.52
Jung and colleagues in 1990 found elevated levels
of catecholamines, in particular, norepinephrine in the
perilymph of chinchillas after intraperitoneal injection
of salicylate.53 Other researchers have discovered that
antagonists of norepinephrine prevent salicylate oto-
toxicity.54,55 These findings further strengthen the pos-
sibility of abnormal catecholamine metabolism in
salicylate ototoxicity.
Gunther and colleagues in 1989 noted that simul-
taneous administration of zinc prevented salicylate-
induced hearing loss. They proposed that a relative zinc
and magnesium deficiency could conceivably play a
role in salicylate ototoxicity.56,57
In 1971 Vane discovered that salicylates and
NSAIDs inhibited cyclooxygenase pathways in the
arachidonic acid cascade from producing prostaglandin
(PG).58 This led to speculation that inhibition of PG
might play a role in salicylate ototoxicity.59 In the mid-
1980s Jung and colleagues reported that perilymph
contained relatively higher levels of 6-keto-
prostaglandin F1 than did CSF and that indomethacin
and salicylate markedly reduced these levels. 1,60,61
Decreased PG levels and synthesis in the guinea pig
cochlea were noted after exposure to salicylate.60 Kawata
and colleagues in 1988 reported in vitro PG synthesis in
the cochlea.61 These findings further verified the possi-
ble role of PG metabolism in salicylate ototoxicity.
Altered arachidonic acid metabolisms after salicy-
late administration has also been postulated to play an
important role in ototoxicity. This was first noted by
Jung and colleagues when decreased PG levels (cyclo-
oxygenase products) and increased leukotriene (LT) or
lipooxygenase products were noted in the perilymph of
chinchillas after systemic or RWM application of sali-
cylates.62,63 Applying exogenous LT on the RWM in ani-
mal studies caused hearing loss and changes in the
eicosanoid levels similar to those found in salicylate
ototoxicity.1,64 The role of PG and LT in salicylate oto-
toxicity was further validated when salicylate ototoxic-
ity was prevented by the use of LT blockers and steroids
before salicylate treatment.6567 Pretreatment with an
LT blocker prevented the reduction of cochlear blood
flow.68 This series of studies underlines the probable
importance of increased LT levels in the inner ear in the
pathogenesis of salicylate ototoxicity.1
To summarize, it appears that the mechanisms for
salicylate ototoxicity are both multifactorial and multi-
locational. Minimal morphologic abnormalities have
32 Systemic Toxicity
been reported. Acoustic emission studies suggest OHC
abnormalities in salicylate ototoxicity. Decreased
cochlear blood flow also plays a role. This may be medi-
ated by catecholamines or arachidonic acid metabo-
lites. Biochemical changes with increased levels of
norepinephrine, decreased PGs, and increased LTs have
also been demonstrated. Abnormal levels of arachi-
donic metabolites appear to reduce cochlear blood flow
and abnormal permeability of the OHC.1
MANIFESTATIONS OF SALICYLATE OTOTOXICITY
Manifestations of salicylate toxicity in humans are well
documented. Nausea, vomiting, tinnitus, hearing loss,
headache, mental confusion, quickened pulse, and
increased respiration have all been reported.6
Hearing Loss
The classic description of salicylate-induced SNHL is of
a mild to moderate bilaterally symmetric loss, which
may be flat or only in the higher frequencies. The hear-
ing loss is typically reversible, and recovery usually
occurs 24 to 72 hours after cessation of the drug.69
In the 1960s, Myers and Bernstein and Bernstein
and Weiss reported salicylate ototoxicity in patients with
rheumatoid arthritis after large daily doses of ASA, 6 to
8 g/d. The SNHL was noted to be flat bilaterally in the
order of 20 to 40 dB. Hearing apparently recovered
within hours after drug cessation.18,19 In 1965 McCabe
and Dey noted temporary high-frequency hearing loss
with tinnitus in five healthy volunteers after high doses
of ASA. The hearing loss progressed from 4 dB after
1 day to 28 dB after 5 days (at 6 kHz). Increased dura-
tion and dosage caused greater hearing loss. All five vol-
unteers had their hearing return to normal within
72 hours upon termination of treatment.69 McFadden
and Plattsmeir in 1983 demonstrated that both dosage
and duration of ASA ingestion affected the degree of
hearing loss. They reported that 3.9 g/d of ASA for
nearly 3 days resulted in a hearing loss of 2 to 19 dB at
between 2.5 and 8 kHz. A dose of 4.9 g/d for 4 days
resulted in threshold shifts of 18 dB at 4 kHz and 25 dB
at 8 kHz. They also reported hearing loss of 8.4 to
21.6 dB at 3.5 kHz in three of five subjects receiving 3.9 g
of ASA per day for 5 days.70 Some studies have demon-
strated an additive effect of salicylate administration
and noise exposure on the threshold shift. Most studies,
however, demonstrate that salicylate does not aggravate
noise-induced hearing loss or cause cochlear damage.1,71
The recovery periods for hearing loss after salicyl-
ate ototoxicity appear to range from a few days to
2 weeks and show large individual variability with no
apparent relation to the duration of treatment, serum
salicylate levels, or amount of hearing loss.18,35,44 Most
cases of hearing loss after salicylate toxicity appear to
be reversible, although a few cases of permanent hear-
ing loss have been reported.7274 One patient has also
been reported to have developed symptoms of cochlear
hydrops with fluctuating hearing loss, unsteadiness,
tinnitus, and aural fullness after taking 2 g/d of ASA.
The patient suffered a 40 to 70 dB hearing loss, which
recovered to 20 dB after 3 weeks.1,75 Ototoxicity has
also been reported after topical application of salicy-
lates for psoriasis.76
Salicylate ototoxicity appears to be associated
with changes in suprathreshold characteristics of
hearing, such as a decrease in temporal integration,
poorer temporal resolution, and impaired frequency
selectivity.1
Animal studies have documented changes in hear-
ing threshold levels following administration of salicyl-
ates. The hearing loss in animals varies with the species
of the animal tested. This variability may relate to the
differences in physiology and serum and perilymph
metabolism of salicylate.
Myers and Bernstein measured the hearing thresh-
old in monkeys following subcutaneous injection of
500 to 600 mg/kg of salicylate. Hearing loss was noted
to be flat, ranging from 17 to 36 dB with an average of
30 dB.18 A similar study with monkeys after an intra-
muscular injection of 250 mg/kg of sodium salicylate
revealed a 22 dB loss at 4 kHz within 1 hour of injec-
tion and complete recovery within hours. Higher doses
of salicylates caused higher threshold shifts with com-
plete recovery within 24 hours.1,77
Other studies involving guinea pigs, chinchillas, and
cats with hearing losses measured by various methods
(such as auditory brainstem response [ABR], evoked
responses from electrodes permanently placed in infe-
rior colliculus, and AP-threshold shifts) have revealed
reversible hearing losses of varying degrees.13,62,7881
Some studies have demonstrated an additive effect
of salicylate administration and noise exposure on the
threshold shift. Most studies, however, demonstrate
that salicylate does not aggravate noise-induced hear-
ing loss or cause cochlear damage.1,70
Overall, it appears that high-dose salicylate admin-
istration causes a reversible, bilaterally symmetric, mild
to moderate hearing loss, which may be flat or present
in the high frequencies. The threshold shifts typically
recover after cessation of salicylate. The duration of
recovery varies from individual to individual.
Tinnitus
Tinnitus also occurs with salicylate toxicity. Salicylate-
induced tinnitus has been characterized as tonal, and
pitch matching has identified the tinnitus frequencies
to be usually around 7 to 9 kHz.70 Clinically the onset
of tinnitus has been used as the earliest sign of salicyl-
ate toxicity.
Several studies had been carried out to correlate
serum salicylate levels with the onset of tinnitus. In
1973, Mongan and colleagues reported that tinnitus
 Salicylates, Nonsteroidal Anti-inflammatory Drugs, Quinine, and Heavy Metals
may be a useful indicator of salicylate ototoxicity in
patients with normal hearing.82 This was based on their
study where patients with normal hearing and
impaired hearing were given ASA in an increasing
dosage as an analgesic. They noted that all patients with
normal hearing eventually developed tinnitus, com-
pared with 31% of patients with a preexisting hearing
impairment. Most patients developed tinnitus with a
minimum serum salicylate level of 19.6 mg/dL.
Day and colleagues in 1989 reported a study
involving volunteers whereby hearing loss and tinnitus
intensity increased progressively with both the ASA
dosage and increasing concentration of total and
unbound plasma salicylate concentrations. There
appeared to be a linear relationship between hearing
loss and the unbound salicylate concentration.17 Oto-
toxic symptoms were noted at lower concentrations of
total salicylate than previously observed. There appears
to be no minimal serum salicylate concentration for
threshold shift.1 Conversely, Halla and colleagues con-
cluded that tinnitus or subjective hearing loss was too
nonspecific and not sensitive to be used as a useful indi-
cator of serum salicylate concentration.22,24 They noted
that in patients with rheumatoid arthritis, mean salicyl-
ate levels were not higher in those with tinnitus than in
those without. The presence of tinnitus correlated with
serum salicylate levels in only 30% of patients.
Clinical reports indicate that during long-term
salicylate treatment in humans, tinnitus occurs after
several days, becomes louder as treatment is continued,
and is characterized as a high-pitched noise.17,70,83 The
loudness of salicylate-induced tinnitus from long-term
salicylate treatment has been matched in humans to
pure-tone levels ranging from 20 to 60 dB sound pres-
sure level.17
Studies on the spontaneous neural activity of the
auditory system in animal models have contributed to
our understanding of salicylate-induced tinnitus. Vari-
ous degrees of increase in the spontaneous activity of
auditory neurons after salicylate administration have
been reported at the level of the auditory nerve,36,37 infe-
rior colliculus,3840 and auditory cortex.40
An ensemble measure of auditory nerve sponta-
neous firing rate can be obtained in animals from the
average spectrum of recordings in silent conditions
from a gross electrode on the nerve or on the RWM.8385
This spectrum measure changed after a single dose of
salicylate.85,86 Similar measures carried out in humans
during eighth cranial nerve surgery indicated that in
several patients with tinnitus, the average spectrum of
activity of the auditory nerve was altered.35,86,87 Cazals
and colleagues measured the average spectrum of elec-
trophysiologic cochleoneural activity (ASECA) and
auditory nerve compound action potentials (CAPs) in
guinea pigs after salicylate administration. They noted
ASECA alterations without changes in CAP. This find-
33
ing provides evidence that tinnitus is the first subjective
sign of salicylate ototoxicity, before hearing loss.35
Although tinnitus appears to be the initial sign of
impending ototoxicity, serum salicylate levels appar-
ently do not correlate well with tinnitus in patients
with salicylate ototoxicity.
OTOTOXICITY OF NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS
The ototoxicity of NSAIDs is in general similar to that
of salicylates. NSAIDs are a heterogeneous group of
compounds that share similar therapeutic actions and
side effects with salicylates.1,6 Most NSAIDs act as anal-
gesics and anti-inflammatories by inhibiting cyclooxy-
genase pathways.
Chapman in 1982 reported a series of five patients
who sustained hearing loss with naproxen; two recov-
ered their hearing after discontinuing the drug.88 Rarely
does a significant and permanent loss of hearing occur
shortly after the start of NSAIDs.
Few animal studies have been carried out to assess
the ototoxicity of NSAIDs. Koopman and colleagues
found no alterations in the ABR of guinea pigs after
long-term ibuprofen treatment.89 Morrison and Blakely
noted no ultrastructural abnormalities in guinea pigs
treated with indomethacin except for a questionable
distention of Reissners membrane.1,90 Jung and col-
leagues in 1992 noted that RWM application of
indomethacin in chinchillas resulted in hearing loss,
decreased PGs, increased LTs, and reduced cochlear
flow, similar to the effects of salicylate.1,63,91
QUININE OTOTOXICITY
Research into the mechanisms of quinine and salicylate
ototoxicity has historically been closely linked because
of their similar clinical manifestations. Quinine is an
effective drug in suppressing an acute attack of malaria.
Intravenous quinine continues to be the initial treat-
ment for severe Plasmodium falciparum malaria
following the occurrence of widespread chloroquine-
resistant strains92 Although the use of quinine as an
antimalarial agent has been decreasing in favor of less
toxic semisynthetic derivatives, its use for nocturnal leg
cramps continues to rise.
Research into quinine ototoxicity has been com-
paratively minimal. As a result, the exact mechanism of
quinine ototoxicity is still largely unknown, except that
it has a distinctly different mechanism from salicylate.1
History
Quinine has been used in the treatment of malaria
since the early 1600s. Derived from the cinchona bark,
indigenous to parts of South America, it was initially
also used as an antipyretic. The tree apparently was
named after the wife of a viceroy to Peru, Countess
Anna del Chinchon, whose cure from its bark led to the
34 Systemic Toxicity
trees importation to Spain in 1639.1,93 It was popularly
known as Jesuits bark as the Jesuit fathers were the
main distributors in Europe at that time.1
The first side effect from the treatment of malaria
with quinine was reported by Richard Morton in 1692.
He described the treatment as rather safe: I have never
known anyone suffer a misfortune as a result of using
Cinchona bark (quinine) other than a distressing type
of hearing loss. 92 Today, quinine is largely used in tonic
beverages or converted to its stereoisomer, quinidine,
which has many of quinines side effects, including, on
rare occasion, ototoxicity.1
Pharmacokinetics of Quinine
The metabolism of quinine begins with its absorption in
the upper small intestine and is over 80% complete, with
peak levels occurring 1 to 3 hours after a single oral dose.
Plasma concentration falls with a half-life of 11 hours.
Around 90% of plasma quinine is protein bound, with
CSF levels ranging between 2 and 5% of that of plasma.
It is metabolized extensively in the liver, with only 10%
eliminated by the kidneys unaltered.1,93 Among the
plasma proteins, 1-acid glycoprotein appears to be the
main plasma-binding protein for quinine.92
Intravenous quinine is in many instances the
mainstay of treatment for severe P. falciparum infec-
tion. For therapeutic effect, a plasma concentration of
10 mg/L is advised.94,95 However, plasma quinine con-
centrations above 5 mg/L in malaria patients can
become ototoxic, selectively affecting high-frequency
hearing.94,96,97 Reports of serious side effects of quinine
are relatively rare, which could be because of the slow
infusion rates and extensive binding of quinine to
plasma proteins in the acute phase of falciparum
malaria.94,98 The pharmacokinetic properties of quinine
in malaria patients have been noted to be different from
those in healthy patients.94,99,100
MECHANISMS OF QUININE OTOTOXICITY
Morphology
Large doses of quinine are known to produce reversible
hearing loss and tinnitus, similar to salicylates. Cochlear
OHCs seems to be the common site for the ototoxic
effect of both drugs. Studies have shown that prolonged
administration of high-dose quinine in guinea pigs
resulted in loss of OHCs, which would explain the hear-
ing loss.6,101 This finding probably represents the end
point of prolonged exposure. Reversible hearing loss is
unlikely to be associated with such permanent morpho-
logic changes.1 Karlsson and Flock have reported ultra-
structural changes in the OHCs in the cochlea of guinea
pigs after exposure to quinine.92,102
Recently, Dieler and colleagues studied the mor-
phologic changes of the isolated OHCs of guinea pigs
exposed to large doses of quinine. Ototoxic doses of
quinine did not induce any morphologic changes. No
changes in turgor, shape, or fine structure of OHCs
were noted. As a result they concluded that the under-
lying mechanisms of quinine toxicity are considerably
different from those of salicylates, although both sub-
stances lead to identical symptoms.103
Physiology
High doses of quinine have demonstrated a selective
effect on the CAP in response to both high- and low-
frequency responses.1,104 Intermediate frequencies were
normal. CMs were suppressed in most animals.
Researchers additionally have noted other physiologic
changes. Dieler and colleagues reported that quinine
exposure led to a hyperpolarization followed by a
depolarization of the hair cells membrane potential.
It also caused a diminution of evoked rapid motile
responses that was more apparent in response to
hyperpolarizing pulses than depolarizing pulses.
Responses were largely dose dependent and
reversible. 103 Exposure of quinine to OHCs and
Hensens cells revealed alterations of the microme-
chanical tuning of the organ of Corti.105 Kenmochi and
Eggermont recently measured local field potentials in
cats primary cortex before and after application of
salicylates and quinine. They found a significant
decrease with both drugs, suggesting a central effect of
both drugs in addition to a peripheral one.106
Reduction of cochlear blood flow has been postu-
lated as another explanation for quinine ototoxicity.
Gradenigo in 1893 and Wittmaack in 1903 suggested
the possibility of vasoconstriction for ototoxicity.48
Vasoconstriction had been noted in guinea pigs
following quinine in the capillaries of the suprastrial
spiral ligament, stria vascularis, and basilar mem-
brane.48 Smith and colleagues additionally noted a
significant reduction in erythrocytes in all turns of the
cochlea and localized vessel narrowing as a result of
endothelial cell swelling.104 There is speculation that
quinine induces osmotic changes in endothelial cells as
it does in red blood cells and hepatocytes, by blocking
calcium-dependent potassium channels. Motion
photographic studies of cochlear microcirculations
after quinine demonstrate a temporary cessation of
blood flow through the terminal capillaries in the basi-
lar membrane.1,107 Lee and colleagues noted a signifi-
cant decrease in cochlear blood flow, measured by laser
Doppler flowmeter, that corresponds to hearing loss.108
Quinine, in susceptible individuals, binds to
plasma protein and acts as a hapten, triggering the
complement cascade, leading to thrombocytopenic
purpura, disseminated intravascular coagulation, and
hemolytic anemia.109,110 This mechanism has been sug-
gested by some researchers to be responsible for the
microvascular changes in the cochlea after quinine
ingestion.111
 Salicylates, Nonsteroidal Anti-inflammatory Drugs, Quinine, and Heavy Metals
Biochemistry
Reduction in endogenous PGs has been noted in rats
after exposure to high doses of quinine. This has been
postulated to interfere with the generation of APs in
nerves and vascular smooth muscle. Others propose
that quinines antiprostaglandin effects arise from the
inhibition of the phospholipase A 2 enzyme. 1,112,113
Quinine has also been noted to block calcium-depen-
dent potassium channels, which are found in a wide
variety of cells.103,114
MANIFESTATIONS OF QUININE OTOTOXICITY
Quinine ototoxicity, or cinchonism, presents as hearing
loss, tinnitus, vertigo, headache, nausea, and visual loss.
Hearing Loss
Transient hearing loss appears to be the first manifes-
tation of quinine ototoxicity. It occurs a few hours after
initiating high-dose therapy (up to 2 g in the treatment
of malaria).
After prolonged daily dose courses of 200 to
300 mg, up to 20% of patients might have some degree
of hearing loss. 1,115 The hearing loss is typically
reversible and a bilateral symmetric SNHL that affects
the higher frequencies initially (at 4, 6, and 8 kHz) with
a characteristic 4 kHz notch. Discrimination scores
have been noted to drop below 30%.1,75
Although the hearing loss after quinine adminis-
tration is typically reversible, permanent hearing loss
has been reported, affecting the conversational fre-
quencies.115 In addition, to prevent irreversible hearing
loss, ultrahigh-frequency audiometry (10 to 20 kHz)
has been advocated for accurate monitoring of
impending ototoxicity.97
Tange and colleagues administered high doses of
quinine-dihydrochloride intravenously to 12 healthy
volunteers and 10 patients with falciparum malaria. In
healthy subjects, hearing loss was documented at 2 to
4 hours after quinine infusion at a mean maximal
plasma quinine concentration of only 2 mg/L. Both
high-frequency audiometry (HFA) at 10, 12, 14, and
16 kHz and conventional audiometry (CA) were per-
formed. A unilateral hearing loss was initially noted in
five healthy volunteers during infusion itself (four in
HFA and one in CA). Maximal hearing loss was mea-
sured 2 to 4 hours after infusion unilaterally in nine
subjects (seven in HFA and two in CA). Hearing loss
did not exceed 25 dB, except in one ear, which showed
35 dB loss at 10 and 13 kHz with a persistent loss of
20 dB at 14 kHz after 14 months. All others recovered
completely within 1 week.92 This study underscores the
importance of HFA in the early detection of quinine
ototoxicity. All patients with malaria experienced oto-
toxicity initially; 9 had hearing loss, 10 had tinnitus,
8 had aural pressure, and 4 felt giddy. The hearing loss
35
was maximal on the third day of infusion. Final audio-
grams were normal, indicating reversibility in hearing
loss.92 Similar findings were noted by Claessen and col-
leagues in 1998.94
In cases of quinine self-poisoning, clinical hearing
loss is common only at plasma concentrations over
10 mg/L94 Hearing loss secondary to quinine ototoxicity
in patients with plasma levels above 10 mg/L has been
found to be largely, if not completely, reversible.94,96,97
Clinical auditory toxicity from quinine has been
reported sparingly in malaria patients, despite quinine
concentrations almost invariably exceeding 10 mg/L.
This is probably explained by the differences in protein
binding, the free fraction of quinine being reduced by
25% in patients with uncomplicated malaria and up to
40% for severe malaria.94,100 Healthy volunteers were
noted to have only one-third of the concentration of
1-acid glycoprotein (the main plasma binding protein
for quinine) found in malaria patients.92
Tinnitus and Vertigo
Tinnitus is a known symptom of quinine ototoxicity.
Quinine-induced tinnitus has been reported to be sim-
ilar to salicylate-induced tinnitus, which typically pro-
duces a high-pitched narrow-band tone.116,117 Some
studies indicate that quinine-induced tinnitus can be
blocked with nimodipine, a calcium channel blocker, in
a dose-dependent manner.116 The calcium channel
blocker verapamil, however, did not prevent hearing
loss after quinine administration to guinea pigs.118
The vestibular effects of quinine are also well rec-
ognized. Minimal amounts of quinine are found in
tonic beverages, which may lead to low-serum quinine
concentrations adequate for producing clinically sig-
nificant vestibular changes.1 Blood quinine levels of
0.2 mg/L have been found in pilots who died in avia-
tion accidents, suggesting that quinine toxicity may
have played a causative role.1,119 Transient positional
abnormalities have also been noted during electronys-
tagmography in volunteers who drank 1.6 L of tonic
water (105 mg) daily for 2 weeks.111
HEAVY METALS (MERCURY AND LEAD)
Mercury
Mercury (Hg) is a toxic heavy metal; its different chem-
ical forms account for various degrees of toxicity. In Asia,
cinnabar (a naturally occurring mercuric sulfide [HgS]
compound) has been used in combination with Chinese
herbal medicine as a sedative for more than 200 years.
Abuse of cinnabar as a sedative for infants has resulted
in cases of Hg toxicity.120 HgS is almost insoluble in
water. Orally administered HgS is absorbed and has been
reported to accumulate in the kidney and liver.120
Impaired hearing and deafness have been reported
to result from developmental and adult exposure to
36 Systemic Toxicity
methyl mercury, a chemical form of Hg.120,121 Mercury
toxicity may be subclinical, and ABR has been reported
to be a sensitive tool in detecting early subclinical Hg
toxicity before clinical manifestations. Discalzi and col-
leagues in 1993 recorded ABRs from patients exposed
to industrial Hg or lead, comparing them with age- and
sex-matched control subjects who were never exposed
to either heavy metal. They noted a significant prolon-
gation of wave IV time compared with control sub-
jects.122 Counter and colleagues in 1997 found similar
prolongation in mercury- and lead-exposed workers.123
Chang and colleagues in 1995 noted prolonged neural
conduction times in auditory-evoked AP studies of
patients exposed to Hg vapor.124 Animal studies have
revealed similar results.120 Monkeys exposed to methyl
mercury from birth displayed selective high-frequency
deficits.125 Analysis of ABRs in mice treated with mer-
curial compounds revealed significant elevation of
physiologic hearing threshold, as well as prolongation
of interwave latency of IV that increased with mean
blood Hg level.120
Animal studies have aided our understanding of
the pathophysiology of Hg toxicity.
Inhibition of Na+K+ adenosine triphosphatase
activity and overproduction of nitric oxide in the
brainstem subsequently alter neuronal activity in the
auditory brainstem.120 This has been one of the postu-
lated mechanisms for Hg ototoxicity.
Lead
Lead toxicity is a well-documented phenomenon with
multisystemic toxic effects, particularly involving the
peripheral and central nervous systems. A review of
studies in humans suggests that lead toxicity affects the
auditory system.126 Auditory thresholds of adults and
children exposed to lead were noted to be elevated.127,128
ABRs were noted to be abnormal in lead-exposed chil-
dren and adults.129,130 Discalzi and colleagues studied
49 lead-exposed workers (mean exposure was 7.4 years)
and compared their ABRs with those of age- and sex-
matched control subjects. They noted marked prolon-
gation of interpeak differences in the study group.131
Animal studies suggest that the auditory pathways,
especially the higher auditory centers, may be unusually
sensitive to the toxic effects of lead.126 Yamamura and
colleagues in 1989 reported that lead toxicity affected
the VIIIth nerve CAP of adult guinea pigs but not the
CM or the endocochlear potential.132 They noted that
the cochlea was spared from lead toxicity. Lasky and
colleagues conversely noted abnormal OAE in lead-
exposed monkeys, implicating cochlear pathology. They
also noted similar ABR-prolonged latencies in experi-
mental animals.126 These experimental results suggest
that lead toxicity affects neural transmission primarily
in auditory pathways.
SUMMARY
High-dose salicylate administration usually
causes a reversible, bilaterally symmetric, mild to
moderate hearing loss that may be flat or present
in the higher frequencies. Threshold shifts typi-
cally recover after cessation of salicylate.
The duration of recovery varies from individual
to individual.
High-pitched tinnitus is usually the first sign of
impending salicylate ototoxicity and typically
resolves when salicylates are discontinued.
Serum salicylate levels do not correlate well with
tinnitus in patients with salicylate ototoxicity.
Mechanisms for salicylate ototoxicity are multi-
factorial and multilocational.
Large doses of quinine have been associated with
reversible hearing loss and tinnitus similar to
those seen in salicylate ototoxicity.
Toxic levels of mercury and lead can result in
auditory toxicity. Studies have suggested that
the toxicity is primarily neural, affecting elec-
trical transmission along the VIIIth nerve and
brainstem.
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127. Repko JD, Corum CR. Critical review and evalua-
tion of the neurological and behavioral sequalae
of inorganic lead absorption. CRC Crit Rev
Toxicol 1979;6:13587.
128. Schwartz J, Otto D. Blood lead, hearing thresholds
and neuro-behavioral development in children
and youth. Arch Environ Health 1987;42:15360.
129. Holdstein Y, Pratt H, Goldsher M, et al. Auditory
brainstem evoked potentials in asymptomatic lead-
exposed subjects. J Laryngol Otol 1986;100:10316.
130. Otto D, Robinson G, Bauman S, et al. Five year fol-
low-up study of children with low to moderate
lead absorption: electrophysiological evaluation.
Environ Res 1985;38:16886.
 Salicylates, Nonsteroidal Anti-inflammatory Drugs, Quinine, and Heavy Metals 41

131. Discalzi GL, Capellaro F, Bottalo L, et al. Audi- 132. Yamamura K, Terayama K, Yamamoto N, et al.
tory brainstem evoked potential (BAEPs) in Effects of acute lead acetate exposure on adult
lead-exposed workers. Neurotoxicology 1992;13: guinea pigs: electrophysiological study of the
2079. inner ear. Fundam Appl Toxicol 1989;13:50915.
 CHAPTER 4

Ototoxicity of Loop Diuretics

Narayanan Prepageran, MBBS, FRCS(Ed), FRCS(Glas), MS(ORL),
Andrew R. Scott, BM, BS, MPhil, FRCS(ORL-HNS), and John A. Rutka, MD, FRCSC

Loop diuretics are a class of diuretics widely used and because of impaired secretion of the drug, enhancing
occasionally implicated in ototoxicity. They are organic its toxic effects.
compounds that exert potent saliuretic effects by block-
ing the reabsorption of sodium and chloride from the Clinical Manifestations
epithelial cells in the loop of Henle and the proximal
The ototoxicity of ethacrynic acid has been well docu-
renal tubule.1,2 Loop diuretics comprise several groups
mented by case reports of sensorineural hearing loss
of compounds with diverse chemical structures
(SNHL) in humans and experimental animals. Ototox-
sulfonamides, phenoxyacetic acid derivatives, and het-
icity in humans was first reported by Maher and
erocyclic compounds.1 Furosemide, bumetanide, and
Schreiner in 1965.5 They noted temporary hearing loss
ethacrynic acid are the most commonly used loop
in patients treated with ethacrynic acid for refractory
diuretics. Ethacrynic acid is usually reserved for those
edema. The hearing recovered to its pretreatment level
cases allergic or refractory to furosemide.1 Other mem-
after 6 to 24 hours. This historical report was soon
bers of this group include piretanide, azosemide, tri-
followed by additional case reports of temporary hear-
flocin, and indapamide.2
ing loss noted by various authors.69 Subsequent publi-
Loop diuretics are generally used in the treatment
cations have documented permanent hearing loss in
of congestive cardiac failure, renal failure, cirrhosis,
several patients.1013 However, most, if not all, of these
and hypertension. These diuretics, especially furo-
reports involved patients with impaired renal function.14
semide, are also widely used in the neonatal intensive
David and Hitzig in 1971 reported a case of an
care unit in the treatment of bronchopulmonary dys-
oliguric patient who, soon after intravenous (IV)
plasias.3 Patients at greatest risk for loop diuretic oto-
administration of 100 mg of ethacrynic acid, devel-
toxicity include those with renal impairment,
oped a severe hearing loss that persisted for 1 hour.15,16
premature infants, and possibly those receiving amino-
Homer in 1971 reported a transient hearing loss of
glycoside antibiotics.2 As loop diuretics are eliminated
4 hours in a patient who received 50 mg of IV etha-
by glomerular filtration, renal impairment will prolong
crynic acid for ascites.17 Meriwether and colleagues
their half-life. This increase in serum half-life may per-
later documented seven cases of permanent SNHL
mit accumulation of these drugs in the inner ear,
related to ethacrynic acid, most of which occurred in
thereby increasing the risk for ototoxicity.2
patients with renal failure.1,5
ETHACRYNIC ACID Rybak, in 1988, reported a renal transplant recipi-
ent who sustained a permanent profound SNHL of
Ethacrynic acid is a highly potent saliuretic diuretic.
middlehigh frequency in both ears after receiving a
Chemically, it is composed of an unsaturated ketone
total of 200 mg of ethacrynic acid intravenously.18 A
derivative of an aryloxyacetic acid [2,3-dichloro-4-(2-
cooperative study reported the incidence of hearing loss
methylenebutyryl)-phenoxyacetic acid]. Ethacrynic
with ethacrynic acid therapy to be 7 patients per 1,000
acid is rarely used, except where subjects are allergic or
treated.1,19 Reversible tinnitus and vertigo have also
refractory to furosemide.
been reported after administration of loop diuretics.20
Ethacrynic acid inhibits active sodium reabsorp-
tion in the ascending limb of the loop of Henle.4 The
recommended dose of intravenous ethacrynic acid for Mechanisms of Toxicity
adults is about 1.0 mg/kg body weight. In patients with Experimental animal studies have aided our under-
impaired renal function, serum levels rise quickly standing of the mechanisms involved in the toxicity of

loop diuretics. Studies looking at ethacrynic acid have
suggested the following mechanisms for ototoxicity:
Reduction in Endocochlear Potential
Both ethacrynic acid and furosemide produce a dose-
related, reversible reduction in endocochlear potential
in animal experiments.20,21 Prazma and colleagues have
demonstrated depression of the endocochlear potential
following IV administration of ethacrynic acid in
guinea pigs. They speculated that this was secondary to
the inhibition of sodiumpotassium (Na + Ka + )-
activated adenosine triphosphatase (ATPase) of the
stria vascularis, thought to be the origin of endo-
cochlear potentials. 4,14 Silverstein and colleagues
reported consistent and marked depressions in
cochlear potentials after administration of ethacrynic
acid with recovery of electrical potentials within
24 hours.16 They concluded that the cochlear potential
changes were reversible and transient. Other studies
have revealed reductions in cochlear microphonics
(CM), summating potentials (SPs), and eighth nerve
compound action potentials (APs) for variable periods
following ethacrynic acid administration.2225
Perilymph or Endolymph Electrolyte Alterations
Several investigators have noted alterations in the Na+
and K+ and potassium concentrations of the laby-
rinthine fluids following the administration of
ethacrynic acid. A marked increase in K+ in perilymph
with a corresponding increase in the Na+ concentration,
from 5.9 to 145 mEq/L, has been noted, as has a
decrease in K+ concentration from 154 to 25 mEq/L in
endolymph.26 It has also been suggested that ethacrynic
acid inhibits active ion transport in the ductus
cochlearis, reversing the K+ and Na+ concentration,
thereby producing a reduction in cochlear poten-
tials.26,27 This attractive theory, however, has been dis-
puted by subsequent studies, where alterations of the
cochlear potential were noted without intralabyrin-
thine electrolyte changes.28
Alterations in Hair Cell Glycogen Metabolism
High concentrations of glycogen have been noted in the
hair cells of the inner ear, and several researchers have
reported that ethacrynic acid appears to have a direct
inhibiting effect on glycolysis. 29 Duggan and Noll
reported the ability of ethacrynic acid, similar to cer-
tain cardiac glycosides, to inhibit the Na+K+-activated
ATPase, an enzyme associated with active ion trans-
port.30 Other researchers have found similar results.31,32
Morphologic and Histologic Changes
Morphologic changes have been documented in
ethacrynic acid ototoxicity both in animal models and
human temporal bones. Degenerative changes have
been noted in the stria vascularis in both guinea pigs
Ototoxicity of Loop Diuretics 43
and cats after ethacrynic acid administration.28 Atrophy
of the intermediate layer of the stria vascularis was par-
ticularly prominent.33 Characteristic edema and cystic
changes in stria vascularis, especially in the intercellu-
lar spaces, have also been noted. Thickening of the stria
and irregularities of the marginal cell borders facing the
endolymph were also identified. The membranous
labyrinth, hair cells, and spiral ganglia appeared nor-
mal. Examination of animal temporal bones 1 month
after initial administration revealed a normal-looking
organ of Corti and a marked decrease in intercellular
strial edema. These morphologic changes were noted to
recover more slowly when compared with inner ear
electrical potentials.16 Freeze-fracture studies of guinea
pigs cochlea after ethacrynic acid administration also
revealed alterations in the gap junction morphology in
the stria vascularis. These changes suggest that a phys-
iologic uncoupling of stria cells could have occurred in
response to ethacrynic acid.1,34
Martz and colleagues and Martz and Hinojosa
reported histologic changes in humans after exposure
to ethacrynic acid.10,35 They noted edema of the stria
vascularis, loss of outer hair cells (OHCs) in the basal
turn of the cochlea, and cystic degeneration of hair
cells in the ampulla of the posterior semicircular canal
and macula of saccule.
FUROSEMIDE
Furosemide represents the most widely used loop
diuretic, especially in the treatment of congestive car-
diac failure, renal failure, cirrhosis, and hypertension.
It is also widely used in bronchopulmonary dysplasia,
a common sequela among premature infants with low
birth weight treated for respiratory distress syndrome
with oxygen and ventilator therapy. 3 Furosemide
appears to improve pulmonary function by promoting
the clearance of excess pulmonary interstitial edema.
Adverse effects, such as volume loss and chloride deple-
tion, nephrocalcinosis, and ototoxicity, can occur.36
Metabolic alkalosis, hypokalemia, and cholelithiasis
appear related to the long-term administration of furo-
semide. 37 This is more pronounced in premature
infants in whom reduced renal tubular secretion of
furosemide into the urine causes an accumulation of
furosemide in plasma to potentially ototoxic levels.38
Furosemides serum half-life is normally 47 to 53 min-
utes but has been found to be significantly higher in
neonates and patients with renal failure.2
Clinical Manifestations
Clinical experience with furosemide indicates that it
may produce transient or permanent hearing loss in a
fashion similar to ethacrynic acid following either oral
or IV administration.2 Reports of ototoxicity surfaced
soon after furosemide was introduced into clinical use.39
Schwartz and colleagues in 1970 reported temporary
44 Systemic Toxicity
hearing loss in five patients who received high doses of
furosemide intravenously. Two of the patients also
developed vertigo, suggesting possible vestibular toxic-
ity as well.39 Similar reports surfaced in 1971 and 1973,
documenting furosemide ototoxicity.40,41
Administrative Effects Associated with Ototoxicity
Rate of Infusion
The rate of infusion of furosemide has been noted to
influence ototoxicity. Clinical studies have suggested
that rapid infusion of furosemide increases the inci-
dence of ototoxicity. Heiland and Wigand reported that
the infusion of furosemide at a constant rate of 25 mg
per minute caused noticeable hearing loss in two-thirds
of patients. However, when the infusion rate was
reduced to 15 mg per minute in patients with severe
renal impairment, only minor hearing losses were
noted. They suggested that furosemide not be given at a
rate of more than 4 mg per minute.42 Bosher in 1977
reported patients who had received furosemide at a rate
of 25 mg per minute developing symptoms of ototoxi-
city, whereas those whose dosage rate was 5.6 mg per
minute or less developed no symptoms of ototoxicity.43
Bolus Dosing
Large bolus dosings of furosemide appear in general to
be more toxic to the inner ear. Venkateswaran reported
transient severe hearing loss in a patient with chronic
renal failure and edema who was given 500 mg of
furosemide as an IV bolus injection over 3 minutes.
The hearing loss, however, was recovered after 4 hours.
A later infusion of 240 mg over 5 minutes apparently
did not cause subjective hearing loss.44
Large bolus dosings have been reported to cause
tinnitus without hearing loss. In one study, a large IV
dose of 3,200 mg of furosemide given over less than
4 hours caused severe tinnitus that spontaneously dis-
appeared after the drug was stopped or the rate of
infusion was reduced. No subjective hearing loss was
reported by the patients, and normal audiograms were
obtained on testing.45
Route of Administration
In a study of patients with renal failure, those receiving
only oral furosemide demonstrated no hearing loss.
One patient, however, who received furosemide
480 mg/d orally and 60 mg/d intravenously for 10 days,
had an average hearing loss of 25 dB in the right ear and
30 dB in the left ear.46
Notwithstanding, a critical review of the world lit-
erature reveals that the incidence of furosemide ototox-
icity is not entirely dependent on dose or route of
administration. Freis and colleagues, for example, stud-
ied a group of patients with renal failure who received
500 to 1,000 mg of furosemide by infusion over 6 hours.
They found no evidence of hearing impairment in this
study group. 47 Similarly, Rastogi and colleagues
reported no hearing loss in patients receiving large oral
doses of furosemide, up to 2 g/d.48 Conversely, other
authors have reported permanent hearing loss from
much smaller oral doses of furosemide.4951 Permanent
hearing loss with furosemide after IV administration
has also been reported, although most cases of furo-
semide ototoxicity have been reversible.5254
Other Considerations
Audiometric studies in patients receiving high doses of
furosemide have demonstrated some unexpected find-
ings. Wigand and colleagues identified acute reversible
hearing loss, greatest in the middle frequencies, after
rapid infusion of 1,000 mg of furosemide over 40 min-
utes in patients with renal impairment.55 Tuzel com-
pared the ototoxic effects of bumetanide (another loop
diuretic) and furosemide. He reviewed audiometric
changes in patients receiving either bumetanide or
furosemide and found that only 1.1% of patients receiv-
ing bumetanide had a minimum 15 dB elevation of pure
tone audiometry thresholds, compared with 6.4% of
patients receiving furosemide.56
Several studies in neonates have also confirmed the
ototoxicity of furosemide in this age group. Salamy and
colleagues studied 224 low-birth-weight infants with
repeated auditory brainstem response (ABR) testing,
first in the newborn nursery, then at 6-month intervals
for the first 2 years of follow-up, and annually until the
age of 4 years. SNHL was statistically associated with
greater amounts of furosemide administered for longer
periods and in combination with aminoglycoside
antibiotics. 3,57 Brown and colleagues studied
35 neonates with SNHL and in 70 age-matched control
subjects with normal ABRs. Several factors, including
seizures and exposure to anticonvulsant drugs,
kanamycin, and furosemide, were associated with
SNHL. After multivariate analysis, however, only the
exposure to furosemide remained a consistent risk fac-
tor for hearing loss.3,58
Mechanisms of Toxicity
The mechanisms of furosemide ototoxicity are
probably similar to those of ethacrynic acid. Further
experimental studies with furosemide in animal
models, however, have revealed some new findings for
consideration.
Reductions in Endocochlear Potentials and Auditory
Electrical Pathway Activity
Chodynicki and Kostrzewska first demonstrated that
systemic furosemide administrations reduced endo-
cochlear potentials in guinea pigs.59 Subsequent studies
have demonstrated a dose-related reduction of endo-
cochlear potentials in animal experiments following

furosemide administration.6064 In addition, furosemide
has been reported to reduce CM potentials and reduce
the amplitude of the cochlear-vestibular nerve APs in
animal studies.25,65,66
Studies involving animal auditory nerves have
revealed that furosemide causes a temporary loss of
sharpness of tuning in the cochlear nerve fibers that
have characteristic frequencies of 7 to 30 kHz.67 The
spontaneous firing rate of the auditory nerve was noted
to be reduced in proportion to the amount of reduction
of the endocochlear potential.68 Furosemide has also
been reported to depress evoked cortical potentials in
cats and brainstem-evoked responses in guinea pigs.69,70
Relationship to Hypoalbuminemia
Animal studies have revealed that rats deficient in albu-
min are more susceptible to furosemide ototoxicity
than those with a normal serum albumin. Dose-
response curves of both endocochlear potentials and
compound APs revealed that the dose of furosemide
required to produce half-maximal changes in albumin-
deficient rats was about one-half of the dose required
in normal rats. This supports the hypothesis that the
ability of furosemide to reach its site of ototoxic action
in the cochlea depends on the amount of unbound
furosemide in the serum.71
Morphologic and Histologic Changes
Morphologic changes following furosemide ototoxicity
have been extensively reported. However, no perma-
nent damage to the hair cells has been identified in
temporal bone studies involving microscopic examina-
tion of the cochlea in both guinea pigs and dogs.72,73
Nevertheless, strial edema and degeneration of inter-
mediate cells in guinea pigs treated with 200 mg/kg of
IV furosemide have been noted.54 Strial edema corre-
lated well with alterations in endocochlear potentials in
this model.74
Other changes have been noted. The endolymph
perilymph barrier, for example, appears to be altered by
the administration of furosemide. Rarey and Ross
found a lower number of apical ridges and greater than
normal depths of the strands in the tight junctions of
the marginal cells of the stria vascularis. 75 Greater
cross-linking of the more basal strands was also noted.
Endolymphatic sac morphology appeared altered after
the administration of furosemide. Increased cytoplas-
mic contents of endoplasmic reticulum and more
prominent Golgi structures of the light cells have been
noted immediately after administration. After 10 days
of administration, the epithelial cytoarchitecture of the
endoplasmic sac was altered, with pronounced veiling
of the light cells by the dark cells in one study.76
OHCs and their stereocilia can be affected by
furosemide. Histochemical studies in animals by
Tamura and by Comis and colleagues have suggested
Ototoxicity of Loop Diuretics 45
that the oxidative metabolism of OHCs is impaired.77,78
Splaying of OHCs, stretching or breakage of tip links,
and erosion and fracture of cross-links between stereo-
cilia of furosemide-treated guinea pigs have been
documented.79,80
Human temporal bone studies of a patient with
suspected ototoxicity from a loop diuretic revealed
granular and densely staining hair cells in the vestibu-
lar neuroepithelium and organ of Corti, particularly in
the basal turn. The endoplasmic reticulum of some spi-
ral cells appeared dilated. The major cytologic changes,
however, were found in the stria vascularis of the
cochlea and dark cell areas of the vestibular neuro-
epithelium.20
Biochemical Changes
Biochemical alterations have also been noted in exper-
imental animal studies. In animal studies, the adenylate
cyclase complex of the stria vascularis can be inhibited
by both furosemide and ethacrynic acid. Further obser-
vation revealed that the G-protein complex that regu-
lates adenylate cyclase is affected by furosemide. 81
Brusilow reported increased endolymph Na+ concen-
tration and reduced K+ activity in endolymph with
furosemide, in conjunction with decreased endo-
cochlear potential.60
Interestingly, some compounds have been noted to
reduce the ototoxic effect of furosemide on the endo-
cochlear potential in animal studies. These include
quinine, iodinated benzoic acid derivatives, and
probenecid.8284
BUMETANIDE
Bumetanide, introduced in the 1970s, inhibits Na+
transport in the thick ascending limb of the loop of
Henle. It is structurally and pharmacologically similar
to furosemide, but it is approximately 40 times more
potent by mass. After oral administration, it is rapidly
absorbed, with peak serum concentrations attained at
approximately 30 minutes. Its pharmacokinetic prop-
erties are similar to those of furosemide.
Bumetanide has demonstrated efficacy in the
management of edema associated with congestive car-
diac failure, liver cirrhosis, and renal impairment. Its
adverse effects profile is similar to that of furosemide,
although the incidence of hypochloremia and hypo-
kalemia appears to be greater. The incidence of
hyperglycemia and ototoxicity, however, seems to be
greater with furosemide. As a result, the principal
indication for bumetanide may be in patients with an
increased risk for ototoxicity. Unfortunately, cost con-
siderations have relegated bumetanide to a secondary
role for the treatment of Na+ and fluid retention in
most clinical settings.85
Reports of ototoxicity first surfaced shortly after
bumetanides introduction to the marketplace. Asano
46 Systemic Toxicity
and colleagues in 1974 reported hearing loss in a
patient who received 1 mg of bumetanide for
2 weeks.1,86 Nevertheless, Bourke reported hearing loss
in a patient after furosemide administration that was
completely recovered when bumetanide was substitute
for furosemide.1,87 Evans and colleagues carried out a
prospective study of patients receiving bumetanide by
performing high-frequency audiograms (820 kHz).
They could not detect any significant changes in pure
tone threshold of those frequencies.1,88
Brown compared IV bumetanide and furosemide
in beagle dogs to study the effects of these agents on
CM and primary auditory afferent activity. He noted
that the acute ototoxic potency of bumetanide in beagle
dogs was 6.5 times that of furosemide, whereas its
diuretic potency was 40 to 60 times that of furosemide.
When the clinical dosages of the two drugs were con-
sidered, the relative acute ototoxic potency of
bumetanide in the dogs was approximately 0.11 to
0.16 times that of furosemide. A similar range has been
obtained in cats. Histologic examination of the cochlea
did not reveal any significant pathology.89
In summary, bumetanide is probably a more
potent diuretic with less ototoxic potential than
furosemide has. Relative cost appears to be the rate-
limiting factor in its clinical use. Nevertheless, it would
be appropriate to consider this medication as an alter-
native to furosemide, especially when patients exhibit
symptoms suggestive of ototoxicity from furosemide.
OTHER LOOP DIURETICS
Other class agents include torsemide, piretanide,
azosemide, ozolinone, and indacrinone. They are rarely
used clinically.
Torsemide, for example, produces a more pro-
longed water and electrolyte excretion than equipotent
doses of furosemide, but it does not cause kaliuresis to
the same extent. Studies have confirmed the efficacy of
low-dose torsemide (2.55 mg/d) in the treatment of
hypertension and shown it to be effective when admin-
istered orally at a dosage of 5 to 20 mg/d in the man-
agement of congestive cardiac failure. Dosage of
torsemide of 20 mg/d has been noted to increase
plasma renin levels, angiotensin II activity, and urinary
dopamine and prostaglandin E secretion. Adverse
effects are usually mild and transient in nature. No evi-
dence of ototoxicity has been demonstrated to date,
and torsemide does not appear to affect blood glucose
levels, serum uric concentrations, or serum potassium
levels at dosages below 5 mg/d.90 Animal studies have
shown no permanent hearing impairment, even at very
high doses of torsemide.91
Piretanide, however, has been shown in animal
studies to reduce endocochlear potentials and com-
pound APs.1,92,93 Azosemide, ozolinone, and indacri-
none have been shown to affect compound APs in
animal studies as well. 93,94 Both ozolinone and
indacrinone have relatively less ototoxic potential than
do other loop diuretics.
SUMMARY
Both reversible SNHL and permanent SNHL
have been reported in patients receiving loop
diuretics.
Patients at greatest risk for loop diuretic-
induced ototoxicity include those with renal
impairment, premature infants, and those
receiving aminoglycoside antibiotics.
Furosemide ototoxicity clinically has been pri-
marily identified in those who have received
furosemide intravenously or a large bolus dose
over a short period, or with a rapid rate of infu-
sion (typically > 5 mg/min).
Bumetanide appears more potent and less oto-
toxic when compared with furosemide and as
such would represent a reasonable alternative in
patients who exhibit symptoms suggestive of
ototoxicity from furosemide.
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37. Guignard JP, Dubourg L, Gouyon JB. Diuretics in
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38. Chemtob S, Papageorgiou A, DuSouich P, Aranda
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40. Morrison JC, Fort AJ, Fish SA. Diuretic induced
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41. Cooperman LG, Rubin IL. Toxicity of ethacrynic
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43. Bosher SK. Ethacrynic ototoxicity as a general
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44. Venkateswaran PS. Transient deafness from high
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45. Cantarovich F, Locatelli A, Fernandez JC, et al.
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46. Muth RG. Furosemide in severe renal insufficiency.
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47. Fries D, Pozet N, Dubois N, et al. The use of large
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48. Rastogi SP, Volans G, Elliott RW, et al. High dose
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49. Gallagher KL, Jones JK. Furosemide-induced oto-
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50. Keefe RE. Otoxicity from oral furosemide. Drug
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51. Rifkin SI, DeQuesada AM, Pickering MJ, et al.
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54. Quick CA, Hoppe W. Permanent deafness associ-
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55. Wigand ME, Heidland A. Ototoxic side effects of
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56. Tuzel IH. Comparison of adverse reactions to
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63. Ng PSY, Conley CE, Ing TS. Deafness after
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65. Comis SD, Pratt SR, Hayward TL. The effect of sulfa-
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67. Klinke R, Evans EF. The effects of drugs on the
sharpness of the tuning of single cochlear nerve
fibres. Pflugers Arch 1974;347 Suppl:R53.
68. Sewell WF. The relation between the endocochlear
potential and spontaneous activity in the auditory
nerve fibres in the cat. J Physiol 1984;347:68596.
69. Jung W, Rosskopf K. Evoked response audiometry
(ERA) am Meerschweinchen vor und nach Lasix-
Induriertem Horstorz. Laryngol Rhinol Otol
(Stuttg) 1975;54:4118.
70. Mathog RH, Matz GJ. Ototoxic effects of etha-
crynic acid. Ann Otol 1972;81:8716.
71. Whitworth C, Morris C, Scott V, Rybak LP. Dose-
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in rat. Hear Res 1993;71:2027.
72. Brown RD, Manno JE, Daigneault EA, et al. Com-
parative acute ototoxicity of intravenous
bumetanide and furosemide in the pure bred
beagle. Toxicol Appl Pharmacol 1979;48:15769.
73. Federspil P, Mausen H. Experimentelle unter-
suchungen zur Ototoxicatat des Furosemids. Res
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changes produced by intravenous furosemide.
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lymph-endolymph barrier by freeze fracture. Acta
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Andersen H. Effects of ototoxic diuretics (loop
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77. Tamura H. Histochemical study on pathogenesis of
the inner ear damage caused by ethacrynic acid
and furosemide. Audiology Jpn 1978;21:66887.
78. Comis SD, Pratt SR, Hayward TL. The effect of
furosemide, piretanide and bumetanide on
cochlear succinic dehydrogenase. Neuropharma-
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79. Comis SD, Osborne MP, Jeffries D Jr. The effect of
furosemide upon the morphology of hair bundles
in the guinea pigs cochlear hair cells. Acta Oto-
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coupled G protein complex by ototoxic diuretics
and cis-platinum in the inner ear of the guinea pig.
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82. Rybak LP, Whitworth C. Quinine reduces noxious
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Am J Otolaryngol 1988;9:23843.
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tion of furosemide in chinchilla. J Pharmacol Exp
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89. Brown RD. Comparative acute cochlear toxicity of
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Ototoxicity of Loop Diuretics 49
pure bred beagle. J Clin Pharmacol 1981;21(1112 Pt
2):6207.
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91. Klinke R, Mertens M. Quantitative assessment of
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1988;38:1535.
92. Rybak LP, Whitworth C. Comparative ototoxicity
of furosemide and piretanide. Acta Otolaryngol
1986;101:5965.
93. Gottl KH, Roesch A, Klinke R. Quantitative evalu-
ation of ototoxic side effects of furosemide, pire-
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 CHAPTER 5
Clinical Uses of Cisplatin
Jeremy Sturgeon, MD, FRCPC
Of all the drugs used in the modern chemotherapy of
cancer, cisplatin occupies a unique role in causing signif-
icant ototoxicity in a large percentage of patients treated.
In 1965, Rosenberg and his coworkers observed that
an electric current delivered between platinum elec-
trodes inhibited the proliferation of Escherichia coli.1,2
This inhibition was related to the formation of inor-
ganic platinum-containing moieties, in the presence of
ammonium and chloride ions. Cisplatin, or cis-diam-
minedichloroplatinum (II), was noted to be the most
active platinum complex in experimental tumor sys-
tems, and it was soon introduced into clinical oncology
in the early and mid-1970s. As an oncologic drug, it has
been extensively tested against most human tumors.
RELEVANT CLINICAL PHARMACOLOGY
Mechanism of Action and Resistance
The toxicity of cisplatin is believed to be related to the
development of platinum deoxyribonucleic acid
(DNA) interstrand cross-links and also to the forma-
tion of intrastrand bifunctional N7 adducts at d(GpG)
and d(ApG).3 Other effects of cisplatin may be related
to the inhibition of sodiumpotassium adenosine
triphosphatase, transport of essential amino acids, cal-
cium channel function, and mitochondrial function.46
The mechanisms of resistance are believed to include
reduced cellular drug accumulation, cytosolic inactiva-
tion of drug, and the enhancement of DNA repair. Cer-
tain genes and proteins may be important in
determining the sensitivity of cells to cisplatin (see
Chapter 6, Ototoxicity of Platinum Compounds).79
Pharmacokinetics
After an intravenous injection of cisplatin, peak plasma
levels are reached almost immediately, and these
decrease by over 50% within 2 hours. The clearance of
cisplatin is triphasic, with a distribution half-life (t 1/2 )
of 13 minutes, an elimination half-life (t 1/2 ) of
43 minutes, and a terminal half-life (t 1/2 ) of 5.4 days.10
About 25% of a dose of cisplatin is eliminated from the
body during the first 24 hours, with renal clearance
accounting for more than 90%.
Toxicity
The use of cisplatin is associated with severe nausea
and vomiting in almost all patients.11 The introduction
of 5-hydroxytryptamine (5-HT3) receptor antagonists
into clinical use has dramatically reduced the amount
and severity of nausea and vomiting with this drug.12
The effects on vomiting have been shown to be signif-
icantly better with this class of drugs than the effects on
nausea, which remains a problem in patient manage-
ment. The regular use of these agents permits treat-
ment with cisplatin to be administered in an
ambulatory care setting.
Neurotoxicity (Including Ototoxicity)
The neurotoxicity associated with the use of cisplatin
includes peripheral sensory neuropathy, high-frequency
hearing loss, and autonomic neuropathy, most com-
monly producing constipation. Much more rarely,
seizures and encephalopathy have been reported. Neuro-
pathy has been shown to be dose dependent and can
occur in over 80% of patients who have a cumulative
dose greater than 300 mg/m 2. In up to 50% of patients,
the neuropathy is not reversible.13 High-frequency hear-
ing loss is believed to be caused by damage to the outer
hair cells in the organ of Corti and is permanent.14
Although several types of drugs are being evaluated to
protect patients from neurotoxicity, these are largely
experimental and include free oxygen radical scavengers
and nucleophilic sulfur thiols.15 Today neurotoxicity has
become the major dose-limiting toxicity of this drug
(see Chapter 6,Ototoxicity of Platinum Compounds).
Nephrotoxicity
The nephrotoxicity of cisplatin can be severe but can be
moderated with appropriate therapy. 16,17 Proximal
tubular damage leads to a decreased reabsorption of
 Clinical Uses of Cisplatin 51

sodium and water and, subsequently, impairment of

Table 5-1 Chemotherapy Regimens in Testicular Cancer
distal tubular re-absorption, renal blood flow, and
glomerular filtration lead to an enhanced excretion of Treatment
enzymes, proteins, and other electrolytes, particularly Regimen Dose Frequency
potassium and magnesium. In early clinical trials, it BEP*
was shown clearly that aggressive hydration with nor-
Bleomycin 30 U IV weekly on days 2, 9, and 16
mal saline, together with infusion of hypertonic saline
and with mannitol-induced diuresis, could significantly Etoposide 100 mg/m2 IV daily 5
reduce the renal toxicity of cisplatin. It is important to Cisplatin 20 mg/m2 IV daily 5
note that in patients who have preexisting renal impair-
ment, cisplatin should be used with caution and should EP
not be used if the glomerular filtration rate (GFR) is Etoposide 100 mg/m2 IV daily 5
less than 30 mL/min. Full doses are usually employed if Cisplatin 20 mg/m2 IV daily 5
the GFR is more than 50 mL/min.18
Drugs such as amifostine, a thiol-containing com- VP-I-P
pound, have been shown to reduce renal toxicity from
Etoposide 75 mg/m2 IV daily 5
cisplatin.19 Amifostine is preferentially taken up and
metabolized by normal cells. The active thiol moiety Ifosfamide 1.2 g/m2 IV daily 5
acts as a nucleophile, which can inactivate carbonium Cisplatin 20 mg/m 2 IV daily 5
ions generated by alkylating agents and prevent DNA IV = intravenous.
damage. Clinical trials have shown that treatment with * Cycles repeated every 21 days for 3 or 4 cycles.
amifostine can protect against cisplatin-induced Cycles repeated every 21 days.

nephrotoxicity without compromising the antitumor Cycles repeated every 2128 days.

effects of this drug.

Currently, the most widely used regimen for man-

CLINICAL USES OF CISPLATIN
When cisplatin was combined with other drugs, includ-
ing bleomycin and vinblastine, it had significant cura-
tive potential in treating metastatic germ cell tumors,
which were hitherto almost always fatal. When it was
first tested in epithelial ovarian cancers, it produced sig-
nificantly higher response rates than had previously
been seen with alkylating agents and antimetabolites.
Cisplatin in combination with cyclophosphamide, with
or without the addition of doxorubicin, rapidly became
the standard treatment for ovarian cancer. Cisplatin has
been widely used in the treatment of lung cancer, head
and neck cancer, and carcinoma of the cervix. In some
of these diseases, it has been combined with external
beam irradiation therapy and has significantly
improved treatment outcomes. More recently, cisplatin
has been employed in salvage regimens for patients with
lymphoma whose disease has failed to respond or has
progressed after initial chemotherapy and who are being
considered for autologous stem cell transplant.
Germ Cell Tumors of the Testis
Testicular cancer represents the primary example of a
disease in which cisplatin has been proven to cure large
numbers of patients when combined with other effec-
tive agents. Further, in this disease site the substitution
of carboplatin for cisplatin produces inferior results,
and cisplatin-containing combination chemotherapy
remains the standard of care after more than 25 years
in clinical use.
aging nonseminomatous testicular cancer in North
America and Europe is the BEP regimen, using for its
name the initials of its components: bleomycin, etopo-
side, and platinum (cisplatin) (Table 5-1).20 These
drugs are used for three or four cycles of treatment,
depending on the risk category of the individual
patient. Although short-term toxicity is moderately
severe, patients with this condition are generally young
and tolerate treatment well. Long-term studies have
shown that, with the use of cisplatin, high-frequency
hearing is permanently impaired and GFR is perma-
nently reduced as demonstrated by serial measure-
ments of creatinine clearance before and after
treatment. Normal fertility is recovered in at least 50%
of patients treated with this regimen.
A randomized trial at Memorial Hospital com-
pared four cycles of etoposide and cisplatin with four
cycles of etoposide and carboplatin (EP) in 270 patients
who were considered to have good-risk testicular can-
cer. Although the complete response rates were compa-
rable in both arms, the event-free and relapse-free
survivals were less favorable in the arm containing
carboplatin, such that the authors recommended
restricting carboplatin to the category of investigational
status in patients with germ cell tumors.21 Because of
the risk of serious lung toxicity from bleomycin, studies
have been undertaken to see whether this drug can be
safely removed from the treatment regimen.
Comparisons of treatment with and without
bleomycin have led to a good deal of controversy.22 At
52 Systemic Toxicity
Table 5-2 Randomized Trials of Chemotherapy with Cisplatin in Ovarian Cancer
Study Number of Patients Regimen
Kaye et al 25 159 CP
CP
McGuire et al 26 485 CP
CP
Erlich et al 27 56 CAP
Conte et al 28 133 CEP
CAP = cyclophosphamide, doxorubicin, and cisplatin; CEP = cyclophosphamide, epidoxorubicin, and cisplatin; CP = cyclophosphamide, and
cisplatin.
the present time, for good-risk patients, it is proposed
that standard treatment include three cycles of BEP,
equivalent to four cycles of EP. For patients with poor-
risk testicular cancer, the standard of care at this time
is the use of four cycles of BEP.
Although the cure rate is high in this disease,
approximately 30% of patients who have poor-risk tes-
ticular cancer will fail to achieve a complete remission
with four courses of BEP or will undergo a relapse,
which occurs usually within 1 to 2 years of completing
initial therapy. Such patients receive salvage regimens
that include vinblastine, ifosfamide, cisplatin, and
paclitaxel. 23 At least 25% of patients treated with
second-line chemotherapy will achieve stable complete
remission. The use of high-dose chemotherapy and
stem cell transplant for patients who relapse after pri-
mary therapy remains controversial, although it is clear
that a subset of patients may be cured with this aggres-
sive approach.24
Despite these drugs being used to treat testicular
cancer for over 25 years, it has not been possible to
decrease the doses of chemotherapy in a way that
would reduce ototoxicity or nephrotoxicity. Because of
the high curability of this disease, most patients are
aggressively managed and most are willing to accept the
predicted toxicities when they are offered the chance of
cure of their disease. Although undesirable, most of
these toxicities are not life threatening.
For metastatic seminomas of the testis, the stan-
dard of care today usually includes the use of etoposide
and cisplatin without bleomycin. Some studies in the
literature suggest that for certain patients with metasta-
tic seminoma, complete remission and long-term cure
may be achieved with the use of cisplatin alone. Despite
this, most patients are currently treated with the two-
drug combination. Toxicity is moderately severe but of
short duration, and the complete response and long-
term survival rates are high.
Platinum Dose (mg/m 2) Median Survival (mo)
50 q3 wk 6 17
100 q3 wk 6 29
50 q3 wk 8 20
100 q3 wk 4 21
50 q3 wk 6 23
100 q4 wk 3 27
50 q4 wk 6 24
100 q4 wk 6 29
Epithelial Ovarian Cancer
When cisplatin was first introduced into clinical prac-
tice, it was rapidly found to be an active agent in the
treatment of advanced epithelial ovarian cancer. Prior
to this time, patients were treated with single alkylating
agent chemotherapy, and clinical remissions were of
short duration. When cisplatin was first used, it was
rapidly introduced into combination chemotherapy.
This happened in the 1970s, when superiority had been
demonstrated for combination chemotherapy com-
pared with single-agent treatment for the management
of patients with advanced Hodgkins disease and also in
the treatment of men with advanced testicular cancer.
The assumption was therefore made that combination
chemotherapy would probably prove superior in the
management of other malignant diseases. However, 20
years later there is still uncertainty as to the superiority
of single-agent versus combination chemotherapy in
the management of epithelial ovarian cancer.
Throughout the 1980s, the standard management
of patients with advanced ovarian cancer reflected in
most reviews and textbooks included either the combi-
nation of cyclophosphamide and cisplatin or the com-
bination of cyclophosphamide, doxorubicin, and
cisplatin.2528 Unfortunately, although this treatment
produced a high response rate, 70 to 75% in most tri-
als of advanced ovarian cancer, the vast majority of
patients relapsed from treatment and died from their
disease despite subsequent chemotherapy. The median
survival was 22 to 26 months (Table 5-2). Once this
became clearly recognized, more attention was paid to
the toxicity of treatment when weighed against the
probable outcome of therapy.
In order to answer some of the questions concern-
ing the most appropriate therapy for advanced ovarian
cancer, the Advanced Ovarian Cancer Trialists Group
undertook a meta-analysis of all of the randomized
trials in the literature. The most recent update from this

Table 5-3 Randomized Trials of Paclitaxel-Cisplatin* versus Paclitaxel-Carboplatin in Advanced Ovarian Cancer
Number of
Study Patients Arms
Ozols et al33 798 Paclitaxel (135 mg/m 2/24 h)
+ cisplatin
Paclitaxel (175/3 h)
+ carboplatin AUC 7.5
Sandercock 798 Paclitaxel (185 mg/m 2/3 h)
et al34 + cisplatin
Paclitaxel (185 mg/m 2/3 h)
+ carboplatin AUC 6
Neijt et al35 258 Paclitaxel (175 mg/m 2/3 h)
+ cisplatin
Paclitaxel (175 mg/m 2/3 h)
+ carboplatin AUC 5
AUC = area under curve; NA = not available; NS = not significant; PFS = progression-free survival.
*Dose of cisplatin 75 mg/m2.
group in 2002 suggested the following: (1) platinum-
containing combination regimens are superior to
similar regimens without cisplatin; (2) platinum-com-
bination chemotherapy is superior to single-agent plat-
inum therapy; and (3) there is no difference in efficacy
between cisplatin and carboplatin. 29 Many studies
address the question of dose intensity of the drugs
employed, and the conclusion that can be drawn is that
intensifying the dose beyond the accepted standard
leads to unacceptable toxicity. Until the late 1980s,
therefore, standard treatment for advanced ovarian
cancer was 500 mg/m 2 to 1,000 mg/m2 cyclophos-
phamide with 50 mg/m2 to 100 mg/m2 cisplatin. Con-
troversy continues as to the efficacy of adding
doxorubicin to this regimen.30
In the late 1980s, the Gynecologic Oncology Group
(GOG) presented evidence from a randomized trial
comparing cisplatin and cyclophosphamide with cis-
platin plus a new taxane compound, paclitaxel. The
results of this study showed an improvement in overall
survival of more than 12 months in the patient arm
treated with paclitaxel.31 A subsequent intergroup trial
followed from the European Organization for Research
and Treatment of Cancer (EORTC) and from the
National Cancer Institute of Canada (NCIC) and the
Nordic Gynecological Study Group (NOCOVA).32 This
large trial confirmed a survival advantage to paclitaxel
plus cisplatin as compared with the previous standard
of cyclophosphamide plus cisplatin. These studies used
different doses of each drug and different time sched-
ules for the administration of paclitaxel. From these
studies, it was widely concluded that the new standard
of care for patients with advanced ovarian cancer was
the use of paclitaxel plus cisplatin.
Clinical Uses of Cisplatin 53
Median PFS Median Overall
(mo) Survival (mo) p
19.4 49 NA
20.7 57
17.2 43.3 NS
19.1 44.1
16 30 NS
16 32
Because carboplatin had come into clinical use by
this time and was recognized as producing less nephro-
toxicity and ototoxicity, although with greater myelo-
suppression than with cisplatin, several clinical trial
groups explored the use of carboplatin together with
paclitaxel in ovarian cancer. The goal of these studies
was to determine whether the use of carboplatin would
lead to reduced toxicity without impairing the high
response rate seen in patients treated with combination
chemotherapy. Table 5-3 presents information from
randomized trials comparing combination regimens
with either cisplatin or carboplatin. The conclusion has
been drawn that there is no disadvantage to the use of
paclitaxel and carboplatin; therefore, in North America,
this regimen is now widely accepted as the standard of
care.3335
One additional result from a clinical trial has
added to the controversy over the most appropriate
initial management of advanced ovarian cancer.
A large European study, ICON3, compared the combi-
nation regimen of cyclophosphamide, doxorubicin,
and cisplatin with single-agent carboplatin in over
1,500 patients with ovarian cancer who required
chemotherapy. No survival difference was seen in
either group.36 The median survival was 33 months in
both groups. This result questioned the assumption
that combination chemotherapy was superior to
single-agent treatment, as well as the assumption that
an anthracycline-containing treatment was better than
a nonanthracycline-containing treatment. Therefore,
either no regimen has demonstrated superiority to
single-agent carboplatin or no regimen has demon-
strated superiority to the combination of paclitaxel
plus carboplatin.
54 Systemic Toxicity
In summary, most patients with advanced ovarian
cancer are probably being treated with the combination
of paclitaxel and carboplatin unless additional features
such as advanced age and poor performance status sug-
gest a more conservative approach, in which case sin-
gle-agent carboplatin or, less often, cisplatin is
employed. This treatment provides a high clinical com-
plete remission rate of 75%; long-term survival is seen
in only a small minority (< 5%) of patients.
Intraperitoneal Chemotherapy in Ovarian Cancer
For over 20 years, investigators have studied the use of
intraperitoneal chemotherapy with cisplatin for
patients with ovarian cancer. Such treatment has
attracted interest because this disease is largely confined
to the peritoneal cavity and because higher doses of
treatment can be administered intraperitoneally with
increased pharmacokinetic advantages. To date, no firm
conclusions have been reached about the efficacy of
intraperitoneal treatment or of the advantages of this
route of treatment as compared with standard systemic
intravenous chemotherapy. Patients with small
amounts of residual disease in the peritoneal cavity
would be most likely to respond to treatment by the
intraperitoneal route. Cisplatin is one of the drugs
shown to provide maximal penetration of tumors. Sev-
eral clinical trials have been carried out on patients
with modest amounts of residual tumor comparing
intraperitoneal with intravenous chemotherapy. These
trials suggest that progression-free survival improves by
approximately 25% in the intraperitoneal therapy arm.
Moreover, overall survival may be improved in patients
treated by this route by approximately 8 months.37,38
Further clinical trials of large numbers of patients
would be necessary before a major shift in current clin-
ical practice occurs favoring the use of intravenous
chemotherapy for all stages of epithelial ovarian cancer.
Cancer of the Cervix
When megavoltage irradiation was developed in the
1950s, it became the mainstay of treatment for patients
with invasive cervical cancer. Approximately 50% of
patients with this disease have locally advanced disease
at the time of diagnosis. With pelvic irradiation, 5-year
survival rates of 65% overall have been achieved for
patients with carcinoma of the cervix. Recently, strate-
gies use concurrent chemotherapy with radiation in
the treatment of this disease. Cisplatin remains the sin-
gle agent most likely to produce clinical responses in
patients with metastatic cancer of the cervix, although
such responses are mostly of short duration. It has been
proposed that combining chemotherapy with cisplatin
and radiation may increase the killing of tumor cells.
Chemotherapy may act synergistically with radiation to
inhibit the repair of radiation-induced damage, and it
may also act independently to increase the rate of death
of tumor cells. Several recent trials comparing radio-
therapy alone with radiation and concurrent cisplatin
chemotherapy have shown a significant improvement
in the control of pelvic disease and also in overall sur-
vival.3941 Because of these studies, the National Cancer
Institute issued a recommendation that strong consid-
eration be given to incorporating concurrent cisplatin-
based chemotherapy with radiation therapy in women
who require radiation therapy for the treatment of cer-
vical cancer. Many centers employ weekly doses of cis-
platin of 40 mg/m2, to a maximum individual dose of
70 mg IV. Although the systemic toxicity from the cis-
platin is not usually severe, local reactions may be more
marked at the site of radiation, and patients need care-
ful monitoring of their renal function and of their
levels of magnesium and potassium, which may require
supplementation.
Squamous Cell Cancer of the Head and Neck
Until recently, chemotherapy was largely employed only
in the palliative management of patients with metasta-
tic head and neck cancer, but more recently it has been
added to the early treatment of this disease with surgery
and radiation. A more aggressive approach has been
developed in recognition of the fact that patients who
present with locally advanced disease have expected
cure rates of approximately 50% with the standard
approach to treatment of surgery and radiation therapy.
Treatment failure with these methods is usually
ascribed to an inability to control local and regional dis-
ease because of inadequate margins at surgery and
because of the presence of lymph node metastases
within the neck. The addition of chemotherapy at the
onset of treatment is based on the supposition that
improved drug delivery to tumors with intact vascular
beds may lead to an improvement in local control. The-
oretically, systemic micrometastases can be treated at
an early stage in their development. Most of the induc-
tion regimens presently used employ cisplatin or 5-
fluorouracil (5-FU). Complete clinical remission rates
of 20 to 50% are seen in patients who have locally
advanced disease, but as yet this has not been shown to
lead to an improvement in patient survival.42,43
Two randomized trials have shown that in laryn-
geal cancer, laryngeal preservation could be achieved
with induction chemotherapy followed by radiation
therapy and that survival rates were similar to those
achieved with surgical resection followed by post-
operative radiation therapy for laryngeal cancer.44
At the present time, concurrent chemotherapy and
radiotherapy are being increasingly explored. A meta-
analysis of chemotherapy in the Head and Neck Cancer
Collaborative Group review of 65 randomized trials
conducted between 1965 and 1993 compared local
treatment in locoregionally advanced disease with or
without chemotherapy. A significant absolute survival

Table 5-4 Randomized Trials of Chemotherapy with Cisplatin in Metastatic Transitional Cell Carcinoma of the Bladder
Number of
Study Patients Chemotherapy
46
NBCCG 109 Cisplatin
CP
ECOG 47
135 Cisplatin
CAP
SCSG 48 91 Cisplatin
CAP
Intergroup 49 244 Cisplatin
MVAC
CAP = cyclophosphamide, doxorubicin, and cisplatin; CP = cyclophosphamide and cisplatin; ECOG = Eastern Cooperative Oncology Group;
MVAC = methotrexate, vincristine, doxorubicin, and cisplatin; NBCCG = National Bladder Cancer Collaborative Group; SCSG = Southeastern
Cancer Study Group.
advantage of 4% at 5 years was found for patients
receiving concurrent chemotherapy and radiation.45
Most studies have demonstrated that platinum-based
chemotherapy and concurrent radiotherapy lead to
better local control as well as to increased survival when
they are compared with radiation alone.
Several chemotherapeutic agents have activity
when combined with radiation in the treatment of
advanced head and neck cancer. These include cisplatin,
5-FU, carboplatin, methotrexate, and mitomycin-C. Of
these, cisplatin has been studied most extensively
because of its properties as a radiation sensitizer.
It is not clear whether combination chemotherapy
is superior to single-agent chemotherapy when given
concurrently with radiation for head and neck cancer.
Chemotherapy-induced mucositis remains a very
severe problem in this treatment group. The optimum
radiation fractionation schedules are not clear. The
optional use of chemotherapy and radiation remains
to be defined by further clinical trials in head and
neck cancer.
Bladder Cancer
Transitional cell carcinomas of the bladder are sensitive
to several chemotherapeutic drugs, including cisplatin,
methotrexate, doxorubicin, ifosfamide, gemcitabine,
and paclitaxel. The most active single agent is cisplatin,
and response rates of between 15 and 30% have been
reported from phase II and III trials in patients with
metastatic disease. Whereas some studies comparing
cisplatin alone with cisplatin-containing combinations
have shown no difference in overall survival, the MVAC
regimen (methotrexate, vincristine, doxorubicin, and
cisplatin) has been shown to improve survival when
compared with cisplatin alone (Table 5-4).4649 With the
MVAC regimen, long-term survival is about 4%, but
Clinical Uses of Cisplatin 55
Response Median Survival
Rate (%) (mo) Survival
20 Not stated No difference
11.9
17 6 No difference
33 7.3
15 5.2 No difference
21 7.2
12 8.2 MVAC superior
39 12.5
there is significant toxicity and treatment-related mor-
tality for this population, which is generally of advanced
age with concurrent medical problems. More recent
studies have identified promising results from phase II
studies of gemcitabine and cisplatin and one random-
ized phase III clinical trial comparing MVAC with gem-
citabine and cisplatin, showed that the gemcitabine and
cisplatin regimen led to similar response rates and sur-
vival with a lower treatment-related mortality.
In carcinoma of the bladder, preexisting renal
impairment may present difficulties with the adminis-
tration of cisplatin-based chemotherapy. Where appro-
priate, obstruction can be managed with stents or
nephrostomies, thereby permitting the use of this
agent.
Lung Cancer
Small Cell Lung Cancer
Small cell lung cancer tends to disseminate early in the
course of its natural history and to display aggressive
clinical behavior. Death is usually a result of dissemi-
nated systemic disease, and, as a result, much attention
has been paid to the use of chemotherapy in the primary
treatment of this disease. Small cell carcinoma is sensi-
tive to a wide variety of chemotherapy agents. Among
the more active agents are nitrogen mustard, doxoru-
bicin, methotrexate, ifosfamide, etoposide, vincristine,
vindesine, nitrosoureas, cisplatin, and carboplatin.50,51
Randomized trials conducted in the 1970s showed that
combination chemotherapy produced superior survival
compared with single-agent treatment. For the last
20 years, therefore, combination chemotherapy has
been the primary method of managing this disease.52,53
The earliest combinations, from the late 1970s and early
1980s, tended to employ cyclophosphamide-based
regimens, often including doxorubicin and vincristine.
56 Systemic Toxicity
Slightly later, regimens containing cisplatin and etopo-
side became widely used. When the combination of
cyclophosphamide, doxorubicin, and vincristine was
compared in trials with cisplatin and etoposide, there
was no clear survival advantage for either regimen for
patients with advanced-stage disease. The treatment
choice is often based on a patients other medical
problems. Patients with preexisting renal disease or pre-
existing neuropathy may not be offered a cisplatin-
containing regimen. Similarly, patients with preexisting
heart disease may not be appropriate candidates to
receive cisplatin because of the requirement for aggres-
sive intravenous hydration.
With most of the active regimens, objective
response rates in the range of 80 to 90% are seen, with
complete remissions occurring in up to one-half of
patients, depending on their clinical stage at presenta-
tion. The best results are seen in patients with good per-
formance status and limited-stage disease. Such
patients may enjoy median survivals up to 20 months.54
NonSmall Cell Lung Cancer
Nonsmall cell lung cancer accounts for about 80% of
patients with a diagnosis of lung cancer. The major his-
tologic subtypes of nonsmall cell lung cancer are ade-
nocarcinoma and squamous cell carcinoma. A smaller
number of patients present with large cell carcinoma or
bronchioalveolar carcinoma. In contradistinction to
small cell lung cancer, which is highly responsive to
chemotherapy, until recently, the role of chemotherapy
in nonsmall cell lung cancer was less clear. Clinical
data show that patients with advanced-stage nonsmall
cell lung cancer who receive combination chemother-
apy have an improved median survival of 3 to 4 months
and also 1-year survival (3540%). Studies have also
shown that the quality of life of patients receiving such
combination chemotherapy is improved when thoracic
radiation is given as well.55
The regimens chosen to treat nonsmall cell lung
cancer are many and varied, but most of them contain
cisplatin or carboplatin.56 Paclitaxel with carboplatin or
cisplatin is used frequently in the United States,
whereas in Canada combined vinorelbine and cisplatin
is usually used as the first line of treatment. A combi-
nation of gemcitabine with cisplatin is also considered
to be effective. Many new classes of chemotherapy
agents are undergoing clinical evaluation in nonsmall
cell lung cancer. Patients with this disease should be
entered into clinical trials of new agents whenever pos-
sible. In early-stage nonsmall cell lung cancer, adju-
vant chemotherapy must be considered experimental.
Lymphoma
Cisplatin does not play a significant role in the primary
treatment of Hodgkins disease or the non-Hodgkins
lymphomas. For patients with Hodgkins disease and for
patients with intermediate-grade non-Hodgkins lym-
phomas, induction chemotherapy regimens have
become established over the last 25 years, and they lead
to a high proportion of patients achieving complete
remission. When patients relapse, they may be consid-
ered for high-dose chemotherapy and autologous stem
cell transplant. Before being accepted into such a pro-
gram, such patients must be shown to have chemo-
therapy-sensitive disease. In this setting they are treated
with a variety of regimens, some of which include
cisplatin, such as the ESHAP 57 regimen (etoposide,
methylprednisolone, cytarabine, and cisplatin) and the
DHAP58 regimen (dexamethasone, cytarabine, and cis-
platin). A more recent regimen includes the use of cis-
platin with gemcitabine. With such regimens, more than
60% of patients will achieve remissions, and of these a
proportion may go on to high-dose chemotherapy and
receive an autologous stem cell transplant. There are
occasions when cisplatin-containing protocols such as
these are used in patients who will not be proceeding to
transplant. For various reasons, such as age, the mortal-
ity risk from transplant may be considered excessive, but
if such patients have a good performance status and no
serious concurrent medical problems, a further attempt
at intensive chemotherapy may be justified.
SUMMARY
The curative role of cisplatin in the treatment of
germ cell tumors has been established for more
than 20 years, and this drug has maintained its
place in first-line therapy.
In other diseases such as ovarian cancer, despite
the initial success with cisplatin in achieving
remissions, it has gradually been supplanted by
carboplatin because of a reduction in nephro-
toxicity and neurotoxicity, without jeopardizing
response rates or survival time. In other disease
settings the development of other drugs has led
to the replacement of cisplatin in many first-line
chemotherapy regimens. Cisplatin, however,
retains its place as one of the most important
drugs used in combination therapy for the man-
agement of malignant disease.
The toxicity profile of cisplatin is well recog-
nized. To this end, nephrotoxicity may be largely
prevented by aggressive hydration and correc-
tion of electrolyte imbalance. The use of drugs to
reduce the severity of peripheral neuropathy has
been described. Unfortunately, there is no
known way to prevent dose-related ototoxicity
despite its predictability. Future developments
in chemoprotective agents might help minimize
and possibly prevent this complication.
The decision to use cisplatin in any clinical situ-
ation must always be based upon the balance
between the expected outcome of treatment and

the toxicity, as well as on the identification of
other medical problems that may increase the
likelihood of developing side effects, such as pre-
existing renal disease or neuropathy.
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 CHAPTER 6
Ototoxicity of Platinum Compounds
Michael Anne Gratton, PhD, and Brendan J. Smyth, PhD, MD
Cisplatin may be likened to a medical pearl: following
a serendipitous discovery, its simple inorganic structure
fascinates, its fundamental mechanism of action capti-
vates, and its marvelous chemotherapeutics across
tumor types equates it to one of the most powerful
anti-neoplastic agents ever introduced. Yet its toxicity
continues to elude and evade, with the result that
carboplatin, third-generation oxaliplatin, and now
fourth-generation platinum agents are in the process of
proving their chemotherapeutic salt. The impetus to
review the ototoxicity of platinum compounds stems
from the issue of quality of life for cancer survivors.
The platinum compounds are widely used in gyne-
cologic, testicular, lung, central nervous system, and
head and neck cancers. They are noncell-cycle-specific
agents that insert into the deoxyribonucleic acid
(DNA) helix, disrupting replication. The dose and effi-
cacy of platinum chemotherapy is limited largely by
adverse effects. Cisplatin is the most ototoxic of the
platinum compounds even with the inclusion of hyper-
tonic saline, prehydration, or mannitol diuresis in
chemotherapeutic regimens.
HISTORY OF CHEMOTHERAPEUTIC DISCOVERY
The chemotherapeutic potential of platinum complexes
was first recognized by Rosenberg and Cavalieri in 1964
while they were investigating the effects of electric fields
on Escherichia coli growth. 1 Clinical trials in 1971
demonstrated cisplatins potent antineoplastic activity.2
Cisplatin ototoxicity initially appeared inconsequen-
tial. Kovach and colleagues described the ototoxicity of
cisplatin as resulting in a mild threshold elevation
above 4 kHz in eight patients, whereas DeConti and col-
leagues reported only two cases of tinnitus persisting
for several hours to 1 week.3,4 Cisplatins cumulative
ototoxic potential was repeatedly obscured by inconsis-
tencies in case reports.5 Elucidation of cisplatins oto-
toxic pathogenesis was delayed when promising
chemotherapy phase I clinical trials were abandoned
secondary to cisplatin nephrotoxicity. Following the
Table 6-1 Clinical Presentation of Cisplatin Ototoxicity
Tinnitus
High-frequency sensorineural hearing loss
Progression toward lower frequencies
Bilateral and usually symmetrical hearing loss
Permanent and usually irreversible hearing loss
Total cumulative dose generally > 200 mg
discovery that forced saline diuresis is renoprotective,
cisplatin was finally approved for use in human malig-
nancies in 1978.6 Unfortunately, renoprotective proto-
cols do not reduce the ototoxic potential of cisplatin.7
By the 1980s, cisplatin ototoxicity was characterized
and risk factors established (Tables 6-1 and 6-2).
During the past two decades, cisplatin became the
foundation for the development of curative regimens
against solid epithelial tumors. The drug remains unri-
valed in efficacy against germ cell, ovarian, endo-
metrial, cervical, urothelial, head and neck, lung, and
brain cancers (see Chapter 5, Clinical Uses of
Cisplatin).8 Unfortunately, cisplatin is systemically
toxic and predictably ototoxic.7,9 It is the standard for
the 5/5 rating of the Hesketh Classification of Potential
Scale.10 These factors, plus a narrow tumor indication
and the occurrence of tumor resistance, continue to
spur development of newer generations of platinum-
based agents.11,12
Table 6-2 Cisplatin Ototoxicity Predisposing Factors
Dose, duration, and mode of administration
Age extremes
Previous or concurrent cranial irradiation
Previous history of hearing loss
Renal disease
Concomitant use of other ototoxic agents
Volume status

To date, more than 1,000 cisplatin analogues have
been synthesized. More than 20 have entered clinical
trials.12 Rosenbergs team was first with the synthesis of
carboplatin. This less toxic, second-generation plat-
inum compound gained approval of the US Food and
Drug Administration (FDA) in 1989. 13,14 Third-
generation oxaliplatin is currently in active clinical
trials.15 Although third- and fourth-generation agents
have the purported benefit of decreased ototoxic
potential, their clinical utility and long-term post-
exposure toxic sequelae remain to be established. Thus,
cisplatin is expected to remain in the chemotherapeu-
tic armamentarium indefinitely, prompting develop-
ment of effective strategies to protect or rescue the
cancer patient from its ototoxicity.1619
CISPLATIN
Chemistry
The platinum compound standard is cisplatin, a square-
planar inorganic platinum (Pt) molecule consisting of
a divalent Pt(II) central atom accommodating ligands
of cis positioned pairs of chlorine atoms or amine
groups (Table 6-3).12 Cisplatins cis geometry is crucial
for cytotoxic activity and optimal Pt(II) binding to sul-
fur-donating cytosolic platinophiles (such as gluta-
thione and methionine) or DNAs purine N7 atom.20
Cisplatins systemic toxicity may be related to the ease
with which Pt-N or Pt-S reactions occur following
nonenzymatic displacement of the chlorine atoms by
hydrolysis.21,22 In contrast, the reduced systemic toxicity
of the new Pt(IV) agents is attributed to ligand inertness
to deactivation reactions.12 In addition, many Pt(IV)
agents being developed are Pt(II) prodrugs in which
chemical substitutions in the cisplatin amino groups
result in altered lipophilia and tissue distribution.23,24
Mechanism of Action
The initial intracellular action of cisplatin is similar to
that of the alkylating agents. Both agents preferentially
form covalent bonds with N7 of the purine guanine by
hydrolytic displacement of chlorine atoms. The
extremely reactive intrastrand and interstrand cross-
linked Pt-DNA adducts formed by the covalent bonds
inhibit template function and DNA replication.20 Bind-
ing to non-DNA targets follows, with subsequent
induction of cell death through apoptosis, necrosis, or
a combination of both mechanisms of cytolysis.25
Clinical Pharmacology
Following intravenous administration, cisplatin has an
initial plasma half-life (t1/2) of 20 to 30 minutes. The
variability of the terminal t1/2 of 6 to 47 days is related to
the extensive (> 90%) plasma protein binding displayed
by cisplatin. Cisplatin undergoes incomplete urinary
excretion (only 3550% after 5 days) via renal tubule
Ototoxicity of Platinum Compounds 61
secretion and glomerular filtration, with detectability in
tissue samples for as long as 4 months post administra-
tion. Cisplatin preferentially concentrates in the liver,
kidneys, and large and small intestines, with low pene-
tration of the central nervous system.26
Indications and Clinical Use
Cisplatin is employed as palliative therapy in estab-
lished combination treatment regimens for metastatic
testicular tumors in patients who have already received
surgical, radiotherapeutic, or chemotherapeutic pro-
cedures. It is used as a secondary therapy for metasta-
tic ovarian tumors that are refractory to standard
chemotherapy. Other indications include advanced-
stage and refractory bladder carcinomas as well as in
head and neck squamous cell carcinoma (see Table 6-3).
A complete listing of cisplatin-based chemotherapy
regimens, acronyms, and links to their clinical trial
results can be found in a concept report on the Web
site of the National Cancer Institute (NCI) at
<http://ncimeta.nci.nih.gov/MetaServlet/servlet/Result
Servlet2?conceptID=C0008838>.
Nonotological Manifestations of Cisplatin Toxicity
The primary nonotological toxicities of cisplatin are
listed in Table 6-4. Peripheral neuropathy is currently
the main dose-limiting toxicity of cisplatin. Permanent
neuropathy occurs in 30 to 50% of patients receiving a
high cumulative cisplatin dose.27
Although the precise mechanism for the renopro-
tection is unknown, cisplatin-induced nephrotoxicity is
minimized by saline diuresis protocols and volume
repletion. 28 Nevertheless, high cumulative doses
(> 120 mg/m2) of cisplatin produce renal failure despite
diuresis.29
Unrelenting acute and delayed nausea with vomiting
remains a patients most feared side effect of cisplatin.30
Emesis does not appear to be related to vestibular toxic-
ity. Premedication with 5-hydroxytryptamine-3 (5-HT3)
receptor antagonists and corticosteroids is the standard
of care for the emetogenicity associated with cisplatin.
Cisplatin-induced myelosuppression is dose-
related and characterized as anemia, leukopenia, and
thrombocytopenia. Severe thrombocytopenia or leuko-
penia occurs in about 5% of cases.31 Myelosuppression
is generally reversible.
Cisplatin Ototoxicity
The incidence for irreversible ototoxicity varies,
depending upon the dose regimen and the criteria used
to define ototoxicity.3235 Patients with cisplatin oto-
toxicity generally present with high-frequency hearing
loss. The principal characteristics of the ototoxicity are
summarized in Table 6-1.36,37 Cisplatin ototoxicity is
considered to be exclusively confined to the cochlea.
Risk factors (see Table 6-2) for ototoxicity include age
 62

Table 6-3 Platinum Compounds in Clinical Use or in Active Clinical Trials

Year Clinical FDA-Approved

Platinum Compound Approved Status Indications Cancer Indications (In Clinical Trial)

H 3N NH3 1978 Worldwide Bladder, testicular, and Astrocytoma, breast, carcinoid, cervical, desmoid, esophageal, gastric
ovarian cancers head and neck, hepatocellular, malignant glioma, malignant melanoma,
Systemic Toxicity

Pt neuroblastoma, NSCLC, NHL, osteogenic sarcoma, penile

Cl Cl
Cisplatin

H 3N OCO 1985 Worldwide Ovarian cancer ALL, AML, bladder, bone marrow ablation, breast, cervical, germ cell,
head and neck, lung, malignant glioma, neuroblastoma, osteogenic
Pt
sarcoma, soft tissue sarcoma, stem cell transplant preparation, testicular,
H 3N OCO Wilms tumor
Carboplatin
O 1996 Worldwide Colorectal cancer Breast, head and neck, mesothelioma, NHL, ovarian, pancreatic,
NH2 O C
testicular
Pt
NH2 O C
O
Oxaliplatin

O 1995 Japan NSCLC, SCLC, bladder, cervical, esophageal, head and neck,
H 3N O
Phase III ovarian, testicular
Pt clinical trials
H 3N O
Nedaplatin (254-S)
H 3N CI 2002 FDA fast track Hormone-resistant Bladder, breast, cervical, mesothelioma, ovarian
Pt phase IIIII prostate cancer
N CI clinical trials

CH3
AMD-473 (ZD0473)
O
O 2004 FDA fast track Hormone-resistant Breast, cervical, colon, gastric, ovarian, NSCLC, SCLC
H 3N CI
Pt phase IIIII prostate cancer
CI
NH2 O clinical trials
O
Satraplatin (JM-216)

ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; NHL = non-Hodgkins lymphoma; NSCLC = nonsmall cell lung cancer; SCLC = small cell lung cancer.

Table 6-4 Toxicity Profiles of Platinum Compounds
Toxicity Cisplatin Carboplatin
Myelosuppression XX
Nephrotoxicity XX X
Neurotoxicity X XX
Ototoxicity X X
Nausea/vomiting X X
X = significant; XX = main dose-limiting toxicity.
extremes, renal insufficiency, intravenous bolus admin-
istration or high cumulative dosage of cisplatin, co-
administration with aminoglycoside antibiotics or
loop-inhibiting diuretics, and excessive noise exposure
with concomitant cisplatin administration.3841
Cisplatin-based regimens commonly contain other
potentially ototoxic chemotherapeutic agents. Exam-
ples of these agents include cytarabine, bleomycin,
nitrogen mustard, vincristine, and vinorelbine.40,4247 It
is imperative to assess auditory acuity at the onset of
therapy and prior to each successive treatment given
the variability of occurrence and individual suscepti-
bility to cisplatin ototoxicity.
Epidemiology of Cisplatin Ototoxicity
Cisplatin has the highest ototoxic potential of all plat-
inum compounds.48 Differences in chemotherapy regi-
mens, in the definition of ototoxicity, and in methods
used to assess auditory ability contribute to the variance
in the epidemiology of cisplatin. Thus, Moroso and
Blair, in a review of early clinical studies, found a 9 to
91% range in the incidence of ototoxicity, although more
recent studies reported a 50 to 60% incidence of ototox-
icity.7,34,4953 Approximately 50% of head and neck can-
cer patients treated with cisplatin develop ototoxicity.41
Cisplatin ototoxicity is related to dose. In a large ret-
rospective study covering the period of 1990 to 2001, de
Jongh and colleagues found that 42% of 400 patients
receiving high-dose cisplatin (7085 mg/m2; median
cumulative dose of 420 mg) incurred symptomatic oto-
toxicity (Common Toxicity Criteria [CTC] grade 34; see
Table 6-5).39 In contrast, cisplatin ototoxicity was
incurred by only 20% of patients receiving a low-dose
Table 6-5 Common Toxicity Criteria for Hearing
Adverse Event 0 1
Inner ear/hearing Normal Hearing loss on
audiometry only
Adapted from Cancer Therapy Evaluation Program, Common Toxicity Criteria, Version 2 72 DCTD, NCI, NIH, DHHS, March 1998.
Ototoxicity of Platinum Compounds 63
Oxaliplatin Nedaplatin AMD-473 Satraplatin
XX XX XX
X
X X X X
cisplatin therapy but 75 to 100% of patients receiving a
very high-dose regimen.35,40,54 Although these studies
seem to link cisplatin ototoxicity to dosage, the first-
order predictor of cisplatin ototoxicity is cumulative dose
in both clinical and animal studies.55 Bokemeyer and col-
leagues, as well as others, have found that the incidence
of ototoxicity increased dramatically when the total
cumulative dose exceeds 400 mg, although McKeague
states that the critical total dosage is 600 mg.40,5660
The method used to determine the presence of
ototoxicity influences epidemiological reports. The
most commonly employed measure of auditory status
is conventional audiometry (0.58 kHz). The use of
high-frequency audiometry (920 kHz), however, is the
optimal method for early detection of cisplatin sensi-
tivity (see Chapter 18, Audiologic Monitoring for
Ototoxicity).34,56,6164 In a comparative study, increased
thresholds were noted with high-frequency audiometry
when the cumulative dose approximated 200 mg. How-
ever, with use of conventional audiometry, hearing loss
was not detected until the cumulative dose approxi-
mated 400 mg.56 The greater cumulative dose associ-
ated with hearing loss in the frequency range of
conventional audiometry reflects the progressive
nature of cisplatin ototoxicity. A five-frequency
sequence (8, 9, 10, 11.2, and 12.5 kHz) was recently pro-
posed by Fausti and colleagues for rapid and sensitive
detection of early-onset ototoxicity.64
The auditory brainstem response (ABR) is often
employed to assess hearing status and determine the
presence of cisplatin ototoxicity in pediatric cancer
patients.6567 Significant increases in wave V latency for
click stimuli were found to precede threshold elevations
2 3 4
Tinnitus or hearing Tinnitus or hearing Severe unilateral or
loss, not requiring loss, correctable bilateral hearing loss
hearing aid or with hearing aid (deafness), not
treatment or treatment correctable
64 Systemic Toxicity
for conventional audiometry by several cycles of chemo-
therapy.67 Use of the ABR technique with high-fre-
quency specific stimuli (ie, tone bursts) has been
proposed as a screening device for ototoxicity.65 Evoked
otoacoustic emissions (OAEs) can also be used as a
screening tool for cisplatin ototoxicity, although con-
troversy exists regarding whether transient OAEs or
distortion-product OAEs are more sensitive in detection
of cisplatin ototoxicity.68,69 Reduced amplitude of the
distortion-product OAEs has been noted to precede the
threshold changes noted by conventional audio-
metry.70,71 The final methods of evaluating cisplatin
ototoxicity are the CTC (Table 6-5) and World Health
Organization Grades of Hearing Impairment.72,73 These
criteria can be used for subjective rather than audio-
metric assessment of auditory status.39,72,73 However,
subjective assessment underestimates the incidence of
ototoxicity since a slight increase in threshold or hear-
ing loss confined to high frequencies will not
be detected.
Characteristics of Cisplatin Ototoxicity
Cisplatin ototoxicity is characterized as a sensorineural
hearing loss that is initially detected in the very high
frequencies. The hearing loss is bilateral and usually
symmetric. The high-frequency (> 2 kHz) character of
the hearing loss causes difficulty in speech discrimina-
tion, especially in the presence of background noise.
Higher cumulative dosing results in further increase in
the severity of the high-frequency hearing loss as well
as a progression to lower frequencies. However, a bolus
administration of cisplatin to a susceptible patient may
result in rapid-onset severe hearing loss. Only one case
of complete recovery and several cases of partial recov-
ery have been reported following cessation of cisplatin
chemotherapy.34,51 Most investigators have reported
virtually no recovery in the ototoxic hearing loss fol-
lowing cessation of cisplatin treatment. Thus, cisplatin
ototoxicity is regarded as permanent. A larger threshold
shift may exist for a few days immediately following the
cisplatin administration compared with the hearing
threshold 1 week after drug administration (Gratton,
unpublished data, 1988).
Pathophysiology of Cisplatin Ototoxicity
The pathogenesis of cisplatin ototoxicity is multifacto-
rial. Animal research indicates that reduced auditory
acuity is partially mediated by free radical generation
and antioxidant inhibition.74,75 The presence of super-
oxide radicals leads to changes in the stria vascularis,
organ of Corti, and spiral ganglion cells. The perma-
nent hearing loss associated with cisplatin is linked to
the degeneration of cochlear outer hair cells. However,
cisplatin is toxic to the stria vascularis as well as the
organ of Corti.
Several animal studies report that following low-
dose cisplatin, alterations to the stria vascularis precede
changes to the organ of Corti. The strial damage occurs
primarily in the marginal cells, with some changes
noted in the intermediate cells.7682 Decreases in cell size,
which lead to overall thinning of the stria, occur fol-
lowing low-dose cisplatin.76 Histopathology from single
high-dose injections or prolonged treatment of cisplatin
show bulging or ruptured marginal cells as well as strial
atrophy. Overall, in the same cochlear region, the strial
changes are minor compared with the cisplatin-induced
damage observed in the organ of Corti.
In the organ of Corti, low-dose cisplatin causes
damage primarily to the hair cell stereocilia.83,84 Wright
and Schaefer, as well as Comis and colleagues, observed
stereocilia abnormalities including a rough surface
coat, disruption of the stereocilia cross-links, fusion,
splaying or drooping of the stereocilia, and formation
of giant stereocilia.85,86 Larger doses of cisplatin cause
hair cell degeneration through sequelae that involve
softening of the cuticular plate, aggregation of lyso-
somes in the supranuclear portion of the hair cell body,
and cytoplasmic extrusion from the hair cell.
The loss of outer hair cells follows a pattern simi-
lar to that seen with aminoglycoside antibiotics.
Initially, outer hair cells in the most basal region of the
cochlea degenerate.87 As the ototoxic reaction increases,
outer hair cells located more apically degenerate.84 Hair
cell destruction is most pronounced in the first row and
least in the third row of outer hair cells. Inner hair cells
show damage and degeneration only after all three rows
of outer hair cells in the same region have degener-
ated.88,89 High doses of cisplatin cause focal damage to
pillar cells and other supporting cells.87,90
The cisplatin-induced pathology noted in animal
studies has been verified by examination of human
temporal bones.83,85,91,92 In addition to noting the hall-
mark of outer hair cell degeneration, atrophy of the
stria vascularis and degeneration of the fibers of the
eighth nerve and spiral ganglion cells were observed.
Moreover, Hoistad and colleagues reported that the
otopathology from cisplatin could be aggravated by
combination therapy. They noted that temporal bones
removed from patients who had received cranial irra-
diation as well as cisplatin therapy included altered
cochlear vasculature with serum effusion and fibrosis
in addition to damage to the organ of Corti and stria
vascularis histopathology detailed above.92
Assessment of cochlear function using the ABR and
OAE techniques after cisplatin administration to ani-
mals agrees with human data showing variable, but
reduced, threshold sensitivity and OAE amplitude.
These data, in conjunction with decreased cochlear
microphonics, are consistent with outer hair cell pathol-
ogy.78,87,88,90 Pathology in the stria vascularis is associated
with a lowered endocochlear potential. Interestingly,

endolymphatic ionic concentrations are not altered, nor
is strial sodium, potassium adenosine triphosphatase
(Na+, K+-ATPase) activity decreased.88
Other Manifestations of Cisplatin Ototoxicity
Tinnitus as a sequela to cisplatin therapy occurs in as
many as 60% of patients.40,93,94 However, tinnitus is not
predictive of hearing loss.95 The occurrence of tinnitus
can be transient, disappearing after the cessation of
chemotherapy.
Although cisplatin vestibulotoxicity has been the
subject of several studies, no clear and consistent
evidence of toxicity is reported.96100 Vestibulotoxic
effects have been found only in those cancer patients
whose vestibular system was previously exposed to a
damaging agent (eg, aging or aminoglycoside antibiotic
therapy) unrelated to the cisplatin chemotherapy.101
Risk Factors
There is substantial variability in susceptibility to
cisplatin-induced ototoxicity. Factors affecting the
severity of the ototoxic reaction to cisplatin are a
high cumulative dose, age extremes, preexisting hearing
loss, anemia, coadministration of other ototraumatic
agents or high-dose vinca alkaloids, and prior cranial
irradiation (see Table 6-2).32,37,3941,86,102112
Cisplatin-mediated ototoxicity is age dependent.50,51
Studies involving older adults or young children report
a greater degree of hearing loss in these age groups.
Helson and colleagues report that patients aged 8 to 20
years or older than 46 years of age who received a high
cumulative dose of cisplatin (> 400 mg) incurred a
more severe hearing loss than that incurred by 21- to
45-year-old patients receiving a high cumulative cis-
platin dose.50 In summary, a greater sensitivity to cis-
platin ototoxicity exists for both older and pediatric
patients once a critical cumulative dose of cisplatin has
been reached.
However, in the study by Helson and colleagues,
the average preexposure threshold at 4 to 8 kHz for
patients 47 years of age or older ranged from 30 to
40 dB (American National Standards Institute [ANSI],
1969), whereas that of the younger patients was within
the normal range ( 25 dB HL). The study concluded
that cisplatin ototoxicity increased with age, but it is
not possible to differentiate the effect of age from that
of a preexisting hearing loss.50 Two clinical studies
reported that the degree of the cisplatin ototoxicity in
patients with a preexisting hearing loss was the same as
that of patients with normal baseline hearing.93 In con-
trast, Aguilar-Markulis and colleagues reported that
preexisting cochlear hearing loss sensitized the audi-
tory system, resulting in greater hearing loss from the
cisplatin than was incurred by those with normal base-
line hearing ability.51 Fleming and colleagues agreed,
finding that a greater than average baseline threshold
Ototoxicity of Platinum Compounds 65
resulted in a greater degree of ototoxicity.113 In a study
that compared different schedules and rates of cisplatin
infusion, Vermorken and colleagues found that patients
with baseline thresholds > 15 dB HL developed oto-
toxicity from a lower cumulative dose of cisplatin than
did patients who had normal baseline hearing. How-
ever, since the degree of ototoxicity was the same
regardless of baseline hearing status, Vermorken and
colleagues concluded that the presence of a preexisting
hearing loss did not increase susceptibility to cisplatin
ototoxicity.7 In summary, the results of studies address-
ing the issue of preexisting hearing loss are equivocal in
their results, requiring further study of this topic.
Several clinical studies observed that concurrent or
prior cranial irradiation increased susceptibility to the
ototoxic potential of cisplatin.37,41,103,112 Brock and col-
leagues reported that 64% of their pediatric patients
displayed severe cisplatin ototoxicity at a cumulative
dose of only 200 mg, half that of the critical cumula-
tive dose of cisplatin as a sole agent.73 Cranial irradia-
tion as a risk factor for cisplatin ototoxicity was
evaluated in an animal study. 114 The bulla, which
received cranial radiation prior to administration of
cisplatin, displayed greater ototoxicity than did the
control ear exposed solely to cisplatin. Thus, animal
research supports the clinical observation that cranial
irradiation predisposes the chemotherapy patient to
cisplatin ototoxicity.
Interaction between Cisplatin and Other
Ototraumatic Agents
The interaction of cisplatin with other potentially oto-
toxic drugs, such as the aminoglycoside antibiotics and
the loop-inhibiting diuretics, has been explored in ani-
mal studies, as has the relationship between noise and
cisplatin.86,104108 In each instance, the degree of ototox-
icity from the cisplatin was enhanced by exposure to
another ototraumatic agent.
Based upon ABR and cochleogram data, Schweitzer
and colleagues reported that administration of both
cisplatin and kanamycin caused greater ototoxicity than
occurred from either of the two control agents.84 The
kanamycin was administered at a dosage that produced
little or no ototoxicity. The cisplatin alone showed a
50% loss of basal turn outer hair cells. Administration
of both agents produced a complete or near-complete
loss of outer hair cells in the basal turn of the cochlea.
The decrease in hearing status as assessed by ABR cor-
related with histologic data. However, the combination-
treated group sustained substantial nephrotoxicity that
may have contributed to the loss of auditory sensitivity.
Nevertheless, an additive interaction was noted in this
study between cisplatin and the aminoglycoside antibi-
otic.86 A second study examining the potentiation of
cisplatin ototoxicity by gentamicin varied the time dur-
ing which cisplatin was administered during the 14-day
66 Systemic Toxicity
course of gentamicin injections in guinea pigs.104 A
time-dependency for the potentiation of the ototoxic-
ity was found. Exposure to cisplatin during the begin-
ning of the course of gentamicin administration
resulted in greater ototoxicity than did the presence of
cisplatin late in the gentamicin treatment or with the
administration of each agent alone.
The possibility that hearing loss from cisplatin
might be augmented by administration of a loop-
inhibiting diuretic was explored in two studies.107,108
Komune and Snow found that the combination of cis-
platin and ethacrynic acid affected the amplitude of
the cochlear microphonic and resulted in a greater loss
of outer and inner hair cells than did administration
of either agent alone.107 Brummett and colleagues mea-
sured the change in the stimulus intensity necessary to
elicit the cochlear microphonic after administration of
cisplatin or a loop-inhibiting diuretic (ethacrynic acid,
furosemide, bumetanide, or piretanide).108 The results
indicated that administration of cisplatin with a loop-
inhibiting diuretic caused a decrease in hearing sensi-
tivity greater than that expected from administration
of either agent alone. The severity of the ototoxicity
was the greatest for the combination of ethacrynic acid
and cisplatin. This is reasonable since ethacrynic acid
is the most potent of the loop-inhibiting diuretics.
However, the augmentation of cisplatin ototoxicity by
the administration of a loop-inhibiting diuretic has
clinical implications. The technique of forced diuresis
to minimize cisplatin nephrotoxicity requires using a
nonloop-inhibiting diuretic, such as mannitol.
A history of noise exposure has been reported to
increase the risk of cisplatin ototoxicity threefold.40
Several animal studies have investigated the potential
for noise exposure to interact with cisplatin ther-
apy.105,106 Laurell demonstrated that noise exposure that
preceded cisplatin administration resulted in a poten-
tiation of the toxic effects of both ototraumatic agents,
whereas noise exposure that followed the cisplatin
administration did not result in a potentiation of the
cisplatin ototoxicity.105 The threshold of noise intensity
was investigated by Gratton and colleagues in a study
that concomitantly exposed cisplatin-treated chin-
chillas to noise. A synergistic interaction was found
between low-dose cisplatin and noise of 85 dB SPL.106
CARBOPLATIN
Chemistry
Carboplatin is a second-generation analog of cisplatin
consisting of a central platinum atom in the same plane
as the two ammonia groups and chloride or 1,1-cyclo-
butanedicarboxylate ligands in the cis position. The lig-
and-leaving groups are present in a ring structure
versus the two chloride arms of cisplatin. This differ-
ence confers stability to the carboplatin molecule with
a resulting decrease in nephrotoxicity, neurotoxicity,
ototoxicity, and emetogenicity.27
Mechanism of Action
The exact mechanism of carboplatin cytotoxicity is
not known. Carboplatin, like cisplatin, induces
platinumDNA adducts, although requiring a 10-fold
higher drug concentration and a 7.5-fold longer
incubation time.115 Carboplatin becomes hydrolyzed,
similar to cisplatin, but at a hundredfold slower
rate.116 Carboplatin is a noncell-cycle-specific agent as
well as a radiation sensitizer.117,118
Clinical Pharmacology
Following intravenous administration of carboplatin,
the initial t1/2 = 24 hours. Carboplatin binds plasma
proteins with greater than > 85% efficiency. A wide
tissue distribution has been noted including kidney,
liver, skin, and tumor tissue in addition to erythro-
cytes. As much as 70% of carboplatin is excreted
unchanged in the urine within 24 hours of adminis-
tration. Carboplatin is not secreted by the proximal
renal tubules, thus permitting calculation of total
glomerular filtration rate by creatinine clearance.119
Indications and Clinical Use
Carboplatin is used primarily in combination with
other chemotherapy agents (see Table 6-3). Carbo-
platin constitutes the first successful application of
pharmacokinetic-directed therapy in oncology. The
carboplatinetoposide combination, with or without
cyclophosphamide or ifosfamide, has become the back-
bone of high-dose chemotherapy for germ cell tumors
with stem cell support.120 In addition, carboplatin-
based high-dose chemotherapy combinations have
been extensively employed for treatment of pediatric
brain tumors.121,122 Moreover, carboplatin is equally
effective as cisplatin for testicular (with bleomycin and
vinblastine), bladder, head and neck (with bleomycin
and fluorouracil), ovarian (with cyclophosphamide or
doxorubicin), and advanced-stage small cell or
nonsmall cell lung cancers (with etoposide). 27,123
Carboplatin-based chemotherapy regimens, acronyms,
and links to clinical trial results can be found in a con-
cept report on the Web site of the National Cancer
Institute at <http://ncimeta.nci.nih.gov/MetaServlet/
servlet/ResultServlet2?conceptID=C0008838>.
Nonotological Manifestations of Carboplatin
Toxicity
The primary nonotological toxicities of carboplatin are
delineated in Table 6-4. Prior exposure to carboplatin
substantially increases the risk and severity of toxicities
such as myelosuppression, emetogenesis, peripheral
neuropathy, and ototoxicity.124 Thrombocytopenia is
the primary dose-limiting toxicity of carboplatin. The

incidence of severe thrombocytopenia and neutropenia
is 25 and 18%, respectively. Myelotoxicity is minimized
by use of the Calvert AUC formula, which estimates car-
boplatin dose from the area under the concentration
(AUC) time curve based on creatinine clearance, plus a
constant for nonrenal clearance in opposition to a fixed
dosing based on the body surface area.124126 Myelosup-
pression less commonly presents as leukopenia or ane-
mia. Risk factors for myelotoxicity include advanced
age, impaired renal function, and concurrent myelo-
suppressive therapy.124 Anemia is more common with
increased carboplatin exposure and has been linked to
ototoxicity.40 Blood transfusions with growth factors
may be needed during prolonged (> 6 cycles) carbo-
platin therapy.
Peripheral neuropathy occurs in 3% of patients.124
Nephrotoxicity occurs after high-dose carboplatin.119
Carboplatin, although less emetogenic than cisplatin,
still requires aggressive antiemetic therapy.
Carboplatin Ototoxicity
Carboplatin ototoxicity following conventional dose
regimens is generally reported in only 1% of patients.
However, the incidence following high-dose or com-
bined carboplatin chemotherapy is approximately
33%.127129 A direct relationship between AUC and
auditory toxicity exists with high-dose chemother-
apy. 130 Parsons and colleagues reported significant
hearing loss in 82% of children with advanced-stage
neuroblastoma who received high-dose carboplatin as
part of their conditioning regimen for autologous bone
marrow transplant.131 Wandt and colleagues reported a
dose-limiting CTC grade 2 to 3 ototoxicity (Table 6-5)
during a phase I/II study in advanced ovarian cancer,
which involved sequential cycles of high-dose
chemotherapy with dose escalation of carboplatin with
or without paclitaxel supported by granulocyte colony-
stimulating factor (G-CSF) mobilized peripheral blood
progenitor cells.132 In this study, the maximum cumu-
lative tolerated dose of sequential carboplatin that
avoided ototoxicity was 1,600 mg.
Pathophysiology of Carboplatin Ototoxicity
The pathogenesis of carboplatin ototoxicity has not
been elucidated. Like cisplatin, carboplatin is toxic to
the organ of Corti. Surprisingly however, the preferred
target of carboplatin is the inner hair cells rather the
outer hair cells that are targeted by cisplatin. Addi-
tional damage to outer hair cells has been observed
only at higher doses of carboplatin. The preference of
carboplatin ototoxicity for the inner hair cells has
proven an advantage to research investigating the spe-
cific role in audition of inner hair cells versus outer
hair cells.
Ototoxicity of Platinum Compounds 67
NEDAPLATIN
Chemistry
Nedaplatin (254-S, cis-diammineglycolatoplatinum) is
a second-generation cisplatin analogue. The central
Pt(II) atom accommodates two cis positioned ammo-
nia groups and a glycolate ring.
Mechanism of Action
The exact mechanism(s) of action of nedaplatin
is unknown. Nedaplatin induces the same
platinumDNA adducts as cisplatin and is cell cycle
phase nonspecific. The fact that it displays the same
cross-resistance to cisplatin tumor types as carboplatin
suggests that these drugs are affected by the same resis-
tance mechanisms.
Clinical Pharmacology
The dose range for nedaplatin is 60 to 100 mg/m2.133
Similar to other second-generation platinum com-
pounds, nedaplatin can be given without hydration.
Indications and Clinical Use
Nedaplatin, which is similar to carboplatin in many
ways, has been approved for clinical use in Japan since
1995. Nedaplatin has shown promising response rates
in phase II trials for treatment of squamous cell
carcinoma of the head and neck, lung, esophagus, and
uterine cervix (see Table 6-3).134137 A recently pub-
lished phase I study combined nedaplatin with pacli-
taxel to successfully treat unresectable lung, thymic,
and head and neck squamous cell carcinoma.133 In
Japan, nedaplatin has also been approved for the treat-
ment of ovarian cancer.138
Nonotological Nedaplatin Toxicity
Similar to carboplatin, the dose-limiting toxicity of
nedaplatin is myelosuppression in the form of throm-
bocytopenia (see Table 6-4).138
Nedaplatin Ototoxicity
Horiuchi and colleagues evaluated the use of
nedaplatin in phase II studies. 139 In addition to
nedaplatin as a single agent, nedaplatin plus vindesine
and cisplatin plus vindesine were included in the study.
The incidence of hearing loss was 25.8% (16/62) for the
nedaplatin group, 17.6% for the nedaplatinvindesine
group, and 20.0% for the cisplatinvindesine group.
Each combination group consisted of fewer than
20 patients. These results indicate that the ototoxicity
of nedaplatin occurs more frequently than does carbo-
platin ototoxicity but is less prevalent than with cis-
platin. Conversely, Nishida and colleagues reported that
five or six patients incurred a slight hearing loss.140
68 Systemic Toxicity
OXALIPLATIN
Chemistry
Oxaliplatin is a third-generation analogue of cisplatin
in which the amine and chlorine groups are replaced
by a 1,2-diaminocyclohexane (DACH) carrier group
and an oxalate-leaving group, respectively (see Table 6-
3). The DACH group provides unique antitumor activ-
ity, whereas the oxalate group improves water
solubility and greatly accelerates DNA adduct forma-
tion to 50 times that of cisplatin. The DACH group
also affects cellular uptake beyond that of cisplatin.141
Aroplatin, a novel liposomal formulation of oxali-
platin, is currently under clinical trial.142
Mechanism of Action
The cellular and molecular details of the mechanisms
of action for oxaliplatin have yet to be elucidated.
Similar to the other platinum compounds, oxaliplatin
undergoes nonenzymatic hydrolysis in physiologic
solutions to several active derivatives via displacement
of its labile oxalate ligand. Oxaliplatin inhibits DNA
replication and transcription through the formation of
N7 intra- and interstrand DNA adducts, which are
bulkier and more hydrophobic than are those of cis-
platin or carboplatin. These properties contribute to
the enhanced activity in DNA inhibition and synthesis
as well as the lack of cross-resistance displayed by oxali-
platin. Like other platinum compounds, oxaliplatin is
a noncell-cycle-specific agent. Synergistic activity has
been demonstrated between oxaliplatin and 5-fluoro-
uracil (5-FU) and leucovorin (LV), all components of
the FOLFOX4 regimen, in both in vitro and in vivo
tumor models.141
Clinical Pharmacology
Following a single 2-hour intravenous infusion of
85 mg/m2 of oxaliplatin, platinum levels are triphasic:
initial t1/2 = 0.43 hours, second t1/2 =16.8 hours, and ter-
minal t1/2 = 391 hours. Oxaliplatin displays an irre-
versible plasma protein binding greater than 90%. It is
rapidly incorporated into a wide distribution of tissues.
Renal clearance for oxaliplatin accounts for approxi-
mately 50% of the total plasma clearance. However,
because tissue distribution is a major factor in oxali-
platin clearance, renal clearance alone is not a useful
predictor of platinum exposure and toxicity after oxali-
platin administration.141
Indications and Clinical Use
Oxaliplatin in combination with 5-FU and LV was
approved as first-line treatment for metastatic colorec-
tal cancer in Europe (1999) and recently in the United
States by the FDA (January 2004). Clinical trials are
ongoing for relapsed and refractory non-Hodgkins lym-
phoma (eg, DHAOx regimen, consisting of dexametha-
sone, high-dose cytarabine, and oxaliplatin).143 Other
earlier clinical trials investigated oxaliplatin in the treat-
ment of ovarian, gastric, pancreatic, head and neck,
nonsmall cell lung, and breast cancers (see Table 6-3).144
Oxaliplatin clinical trial updates are available at <http://
cancer.gov/search/clinical_trials/results_clinicaltrials
advanced.aspx?protocolsearchid=167647>.
Oxaliplatin Toxicity
Unlike cisplatin or carboplatin, oxaliplatin is not asso-
ciated with significant nephrotoxicity or ototoxicity,
whereas hematologic toxicity is usually mild.141 The
main dose-limiting toxicity of oxaliplatin is an unusual
peripheral sensory neuropathy that can occur in 85 to
95% of patients and is often aggravated by exposure to
cold temperatures (see Table 6-4).141 It is this side effect,
which has two formsacute and chronicthat is of
interest to the otolaryngologist. The toxicity can pre-
sent as an acute dysesthesia affecting the extremities
either during or shortly after the infusion and more
rarely as a pharyngolaryngeal dysesthesia, which
resolves in hours.147 The chronic form of peripheral
neuropathy usually resolves a few months following
cessation of treatment.141
NEW PLATINUM COMPOUNDS IN
CLINICAL TRIAL
The latest platinum compounds are designed for out-
patient oral administration. They display efficient
solid-tumor cytotoxicity, as well as reduced systemic
toxicity and tumor resistance.
AMD473 (M473 or ZD473) is a sterically hindered
Pt(II) compound, which overcomes cisplatin resistance
by forming different DNA adducts than previous plat-
inum compounds.148 AMD473 is in active clinical trials
for hormone-refractory prostate cancer (HRPC),
ovarian cancer, small and nonsmall cell lung cancers,
and mesothelioma. AMD473 has a toxicity profile sim-
ilar to carboplatin for nephrotoxicity, neurotoxicity,
and ototoxicity.149
Satraplatin (JM-216) is a Pt(IV) complex that is
metabolized to active Pt(II) compounds. Satraplatin
may hold promise against prostate, ovarian, and
nonsmall cell lung cancers.150 It is currently under-
going phase III clinical trials to evaluate its activity as
second-line treatment of docetaxel-refractory HRPC.
Satraplatin is reported to lack cisplatin cross-resistance
and has reduced nephrotoxicity and neurotoxicity.150
Ototoxicity has not yet been reported.
TUMOR RESISTANCE
The leading cause of chemotherapeutic failure is the
development of tumor multidrug resistance. No clear-
cut dominant mechanism of resistance to cisplatin has
been identified. Nucleotide excision repair appears to
be the most important pathway for cisplatinDNA

damage. The critical gene appears to be excision repair
cross-complementing 1 (ERCC1). High levels of the
ERCC1-relative messenger ribonucleic acid (mRNA)
are associated with response and survival after cisplatin
treatment. 151 Another possible cisplatin resistance
mechanism is a genetic abnormality affecting TP53, a
gene associated with apoptosis. Mutations in TP53 are
found in 60% of nonsmall cell lung cancer patients.151
Overall, studies have revealed that a combination of
reduced platinum transport, increased cellular toler-
ance to PtDNA adducts, increased cytoplasmic detox-
ification via elevated glutathione or metallothionein
levels, and enhanced DNA repair may underlie resis-
tance to platinum compounds.152 In the development
of new platinum compounds, alterations in rate of
hydrolysis, transport to and within the cell, and DNA
binding are being used to deter tumor resistance.12,153
OTOPROTECTION
The future success of platinum chemotherapeutic
regimens depends not only on their clinical efficacy but
also on strategies that directly improve quality of life by
reducing ototoxic risk. The principal cause for hair cell
death implicates signaling in the apoptotic pathway via
(1) reactive oxygen species and free radicals formed as
by-products that elicit damage by reacting with cellu-
lar proteins, (2) caspase activation, and (3) calpain
activation.154,155 Several laboratories have been investi-
gating not only the mechanisms of ototoxicity but also
the pharmacodynamics of potential chemoprotective
agents in animal models. Strategies for prevention of
free radical formation have included the temporal or
anatomic separation of the platinum compounds with
agents such as vitamin E (-tocopherol), sodium thio-
sulfate, D-methionine, or N-acetylcysteine (see Chapter
20, Ototoxic Damage to Hearing: Otoprotective
Strategies).8,17,74,156159
Superoxide radicals can cause cell death via iron-
and calcium-dependent pathways.160 The combination
of a calcium chelator (Quin 2-AM) and the iron chela-
tor (2,2-DPD) provided protection from hair cell
degeneration in cochlear explants, indicating the pres-
ence of both iron- and calcium-dependent components
in cisplatin ototoxicity. These findings suggest that use
of iron chelators may prevent cisplatin ototoxicity.75,160
The protection from platinum ototoxicity provided
by salicylates may involve the scavenging of platinum-
generated reactive oxygen species (ROS), inhibition of
NFB translocation to the nucleus, or inhibition of
tumor necrosis factor (TNF-) via IB stabilization.
Regardless, the final action of the salicylates is to inhibit
cisplatin activation of apoptotic pathways.161,162
Manipulation of the signal transduction pathways
to increase survival and decrease apoptosis pathways
may ameliorate cisplatin ototoxicity. For example, inor-
ganic thiophosphates, such as WR2721 (amifostine),
Ototoxicity of Platinum Compounds 69
may protect against nephrotoxicity and ototoxic-
ity.129,163 This mechanism of protection may involve
enhanced DNA repair and synthesis or the release of
free thiols after dephosphorylation with alkaline phos-
phatase acting as free radical scavengers and metal-
binding centers.164,165
Sodium thiosulfate is a well-studied cytoprotective
agent. Use of this agent in a clinical trial of patients
with brain tumors has been found to decrease the
degree of ototoxicity when there is a delay of 4 hours
between administration of carboplatin and the sodium
thiosulfate.171 Anatomic separation with this agent
using a two-compartment model has also been shown
to have some success in protecting against ototoxicity.8
This model uses the relative impermeability of the
blood-brain barrier to allow only the intra-arterially
administered chemotherapeutic agent access to the
tumor while the intravenously administered protective
agent acts on other parts of the body. There is a need
for additional clinical trials to evaluate the efficacy of
the chemotherapy in relation to dose and timing of
sodium thiosulfate. The other chemoprotective agents
mentioned above have been evaluated only in animal or
in vitro tumor models. Their effectiveness in reducing
platinum ototoxicity while maintaining the needed
antitumor effects of the platinum compounds has yet
to be evaluated in clinical trials.
SUMMARY
Platinum based chemotherapy is used widely for
the treatment of gynecologic, testicular, lung,
central nervous system, and head and neck can-
cers. Platinum compounds are noncell-cycle-
specific agents that inhibit DNA replication.
Binding to non-DNA targets induces cell death
through mechanisms of apoptosis, necrosis, or a
combination of both mechanisms. Cisplatin is
the still the most widely used and ototoxic plat-
inum based agent. Non-otologic toxicities of
cisplatin include peripheral neuropathy (in
3050%), nephrotoxicity (which can be largely
minimized by saline diuresis protocols and vol-
ume repletion) and myelosuppression (dose
dependent and severe in approximately 5%).
Cisplatin ototoxicity is related to dose and in
particular total cumulative dosage (especially
when > 400 mg). It is primarily cochleotoxic
causing a permanent, usually symmetric sensor-
ineural hearing loss that begins in the higher fre-
quencies and progresses toward the lower
frequencies. Other predisposing factors include
age extremes (the very young or old), previous
or concurrent cranial irradiation, renal disease,
concomitant use of other ototoxic agents (ie
aminoglycosides), and a previous history of
70 Systemic Toxicity
hearing loss. Tinnitus may occur in up to 60% of
patients receiving cisplatin.
The pathogenesis of cisplatin ototoxicity is
multifactorial with changes noted in the stria
vascularis, spiral ganglion cells, and the outer
hair cells (OHCs) especially. Carboplatin, a
second generation analog conversely appears to
be preferentially toxic for the inner hair cells
(IHCs) and is also a radiation sensitizer.
Inhibition of cisplatin activated cellular apopto-
sis has formed the basis for current investigative
otoprotective strategies. Strategies that prevent
free radical formation have included the tempo-
ral and anatomic separation of platinum
compounds with agents such as inorganic thio-
phosphates (WR2721), sodium thiosulfate, or
iron chelating agents.
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 CHAPTER 7
Iron-Chelating and Other Chemotherapeutic Agents:
The Vinca Alkaloids
Andrew R. Scott, BM, BS, MPhil, FRCS(ORL-HNS),
Narayanan Prepageran, MBBS, FRCS(Ed), FRCS(Glas), MS(ORL),
and John A. Rutka, MD, FRCSC


IRON-CHELATING AGENTS
Deferoxamine
Deferoxamine (DFO), also known as desferrioxamine,
is an iron-chelating agent available for intramuscular,
subcutaneous, and intravenous administration. It
obtained approval from the US Food and Drug Admin-
istration (FDA) for this use in 1968.1 It is indicated for
the treatment of acute iron intoxication and of chronic
iron overload secondary to multiple transfusions (as
may occur in the treatment of chronic anemias, includ-
ing thalassemia, thalassemia intermedia, and Dia-
mond-Blackfan anemia).1,2 DFO also has antimalarial
properties, antioxidant effects, antiproliferative effects,
and the ability to chelate aluminum. These are areas of
research and not licensed clinical indications for
DFO use at this time.1
Reports of ototoxicity attributed to DFO emerged
in the 1980s.2 Somewhat paradoxically, DFO has been
used more recently in animal studies, for its iron-
chelating and antioxidant effects, to try to better
understand the ototoxic mechanisms of other agents,
including excessive noise, aminoglycosides, to cis-
platin, and to try to protect the inner ear from these
agents.314
De Virgillis and colleagues reported sensorineural
hearing loss (SNHL) in thalassemia major patients
receiving DFO in 1979.15 However, the authors did not
initially consider DFO to be responsible.2 It should also
be noted that thalassemic patients appeared more
prone to conductive hearing loss, possibly related to
adenoidal hypertrophy causing eustachian tube dys-
function, than were normal subjects.2 Marsh and col-
leagues described a case of reversible tinnitus associated
with DFO in 1981.16 The patient, a woman with thal-
assemia intermedia, developed tinnitus while receiving
DFO that resolved upon discontinuation of DFO. Of
interest, the tinnitus returned on further DFO therapy,
suggesting a drug effect. No hearing loss was detected
on audiometry, however. A further case of suspected
DFO ototoxicity was reported by Guerin and colleagues
in 1985.17 They described a 26-year-old woman on
hemodialysis who had acquired iron overload sec-
ondary to multiple transfusions for severe anemia.
After 7 months of treatment with DFO the patient
noticed a hearing loss. Audiometry demonstrated a
mid- to high-frequency SNHL. Hearing reportedly
returned to normal within 5 weeks following cessation
of DFO. The authors commented that the toxicity had
occurred once the iron levels had fallen to normal and
cautioned that DFO should be discontinued once signs
of metal overload disappeared. Further isolated case
reports have continued.1820
Heightened awareness of the potential for ototoxi-
city from DFO has led to several published case series
from the mid-1980s to the present day. These are sum-
marized in Table 7-1 according to underlying pathology,
number of patients affected, size of series, hearing loss
described, and whether hearing loss was supported
audiometrically.2135 A wide range in incidence of SNHL
in these populations has been identified (3.856%).
This may be partly explained by the different popula-
tions examined, with some series focusing on a pedi-
atric setting with varying pathologies. Reporting may
also vary, with some authors including only those
patients in whom they felt the SNHL was definitely
attributable to DFO, whereas others included all SNHL
in the populations studied. Nevertheless, only 3 of the
15 studies concluded that the risk of DFO ototoxicity
was exaggerated or negligible when compared with the
general population.24,27,34 The pattern of SNHL encoun-
tered was predominantly high frequency, although
some series also reported other patterns, including
notched hearing at 3 or 6 kHz or pan-frequency
losses.22,25,33
Reversibility of the hearing loss is variable in the
published reports. Although some patients recovered
their hearing completely, others experienced no
improvement, and a proportion required amplification
with hearing aids.2 Although cause and effect remains
 Iron-Chelating and Other Chemotherapeutic Agents 77

Table 7-1 Published Case Series of SNHL with DFO

Study Pathology Patients (%) Audiogram SNHL Pattern Reversibility

Olivieri et al, 1986 21 Hemoglobinopathy 22/89 (25) Yes High frequency 4 complete,
1 partial

Barratt and Toogood, 1987 22 Hemoglobinopathy 9/27 (33) Yes 6 high frequency, NP
2 flat line,
1 midfrequency

Albera et al, 1988 23 Hemoglobinopathy 58/153 (38) Yes High frequency NP

Masala et al, 1988 24 Hemoglobinopathy 12/100 (12) Yes High frequency NP

Wonke et al, 1989 25 Hemoglobinopathy 13/54 (26) Yes 6 high-frequency notch, 1 complete,
2 low frequency, 4 partial
5 high frequency

Porter et al, 1989 26 Hemoglobinopathy 9/47 (19) Yes NP 2 partial

27
Cohen et al, 1990 Hemoglobinopathy 2/52 (3.8) Yes High frequency 1 partial

Cases et al, 1990 28 Hemodialysis 6/41 (15) Yes Mid- to high frequency 3 complete,
3 partial

Triantafyllou et al, 1992 29 Hemoglobinopathy 26/120 (22) Yes NP NP

De Espana et al, 1992 30 Hemodialysis 3/20 (15) NP NP NP

Styles and Vichinsky, 1996 31 Hemoglobinopathy 8/28 (29) Yes High frequency 8 complete

Kontzoglou et al, 1996 32 Hemoglobinopathy 24/88 (27) Yes High frequency 12 partial

Chiodo et al, 1997 33 Hemoglobinopathy 22/75 (29) Yes High frequency, NP

High frequency notch

Ambrosetti et al, 200034 Hemoglobinopathy 15/57 (26) Yes Mild to moderate high- No change
frequency loss

Karimi et al, 2002 35 Hemoglobinopathy 72/128 (56) Yes High frequency NP

Adapted and updated from Kanno et al.2

DFO = deferoxamine; NP = data not provided; SNHL = sensorineural hearing loss.

unproven in the case series studies, an association
between DFO therapy and SNHL in these groups of
patients seems likely at this time.
Risk Factors and Minimizing DFO Ototoxicity
In their earlier review of the subject, Kanno and col-
leagues identified five risk factors for DFO ototoxicity:
(1) younger age, (2) higher dose of DFO, (3) lower
serum ferritin level, (4) monthly DFO amount, and
(5) better compliance with chelation therapy.2 The total
cumulative dose of DFO, however, did not appear to be
a risk factor.
The observation that hearing loss often became
apparent when serum ferritin levels had fallen to nor-
mal led Porter and colleagues to recommend the use of
a therapeutic index to adjust the dosage of DFO to
minimize the risk of ototoxicity.26,36,37 The therapeutic
index is calculated by dividing the mean daily dose of
DFO by the serum ferritin level. If the therapeutic
index is less than 0.025, then the risk of developing oto-
toxicity is said to be reduced. Porter also recommended
the mean daily dose not exceed 40 mg/kg and that rou-
tine audiologic monitoring be performed.37 Treatment
if toxicity develops, largely consists of discontinuing
DFO (depending on the riskbenefit assessment for
that individual patient). Pinna and colleagues
described a case in which oral zinc supplemented the
cessation of DFO. 38 The patient was a 25-year-old
woman with thalassemia major who developed pre-
sumed DFO-induced optic neuropathy and SNHL
(confirmed audiometrically). The visual disturbance
and audiogram returned to normal after 2 days of with-
holding DFO and of treatment with oral zinc sulfate
(100 mg twice daily). This was a much quicker recov-
ery than would normally be anticipated by withholding
DFO alone. They concluded that oral zinc sulfate might
accelerate neurotoxicity reversal.
78 Systemic Toxicity
Mechanism of DFO Ototoxicity
Neurologic disturbances with DFO treatment include
peripheral sensory, motor, or mixed neuropathy. 1
Where DFO exerts its main effect on the auditory path-
way is unclear. Positive recruitment tests and normal
auditory brainstem responses (ABRs) measured in sev-
eral of the case series have suggested a cochlear
effect.15,23,25,26,28 Conversely, abnormal ABRs in another
series would point to a retrocochlear process.30
Animal studies are also conflicting. Shirane and
Harrison administered DFO to chinchillas using a
chronic regimen of 100 mg/kg/d for 5 days per week for
3 months.39,40 Functionally, no significant difference in
auditory thresholds compared with control animals
was found. Morphologically, no evidence of cochlea
damage was seen on scanning electron microscopy
(SEM). Ryals and colleagues, however, did find mor-
phological evidence of cochlea damage on light
microscopy when they examined adult quails that had
received 300 or 750 mg/kg DFO for 30 days.41 At the
lower dosage, supporting cells only were damaged,
whereas the higher dose also affected the sensory hair
cells. Yamanobe and Kanno were also able to demon-
strate DFO ototoxicity in an animal model.42 A regimen
of 600 mg/kg DFO per day administered to guinea pigs
produced an increase in thresholds of compound
action potential (CAP) from the auditory nerve. SEM
studies on these animals showed damage predomi-
nantly to the outer hair cells of the cochlea. Thus, DFO
appears to have a direct effect on the cochlea, at least at
an animal level. However, the possibility remains that
higher pathways could also be involved by the neuro-
pathic effects of DFO.
VINCA ALKALOIDS
The vinca alkaloids are a class of antitumor drugs that
include vincristine, vinblastine, and vinorelbine.1 They
are structurally similar compounds that are made up of
two multiringed units, vindoline and catharanthine.
Vincristine and vinblastine are derived from an alka-
loid obtained from the periwinkle plant (Vinca rosea,
Linn.). Vinorelbine is semisynthetic. Vinca alkaloids
are predominantly metabolized by the liver.1 Their pre-
cise mechanism of cytotoxicity continues to be under
investigation. Vinorelbine and vincristine appear to
mainly affect microtubule formation during mitosis.1
Vinblastine differs in that it seems to interfere with the
metabolic pathways of amino acids leading from
glutamic acid to the citric acid cycle and to urea.1
Although there are many reports of ototoxicity
with combination chemotherapy, isolating the respon-
sible agent is often not possible. This is particularly true
of the vinca alkaloids, which are not infrequently used
along with cisplatin, for example, in the treatment of
testicular tumors. Cisplatin is known to be ototoxic, so
it is often impossible to separate the relative effects of
the combination agents.
Vincristine
Vincristine obtained FDA approval in 1984, and its
current indications include acute leukemia, selected
lymphomas, rhabdomyosarcoma, and Wilms tumor.1
Mahajan and colleagues described one case of oto-
toxicity attributed to vincristine.43 They documented a
73-year-old woman with non-Hodgkins lymphoma
who had two episodes of bilateral SNHL (60 dB aver-
ages) after the sixth and seventh 2 mg doses of vin-
cristine. Her hearing gradually returned over 2 to
3 months following discontinuation of the vincristine.
Yousif and colleagues described a further case, in a
woman, also in her eighth decade of life, also with non-
Hodgkins lymphoma and running a similar course.44
Deafness after the first course of chemotherapy (vin-
cristine, chlorambucil, and prednisolone) was reported
as being attributed partly to a concomitant upper res-
piratory tract infection. The patient was described as
becoming profoundly deaf in both ears after the second
course of chemotherapy with tuning fork tests indicat-
ing a SNHL. No audiologic data were provided. The
hearing reportedly returned to near pretreatment levels
over a few weeks.
Lugassy and Shapira also described a case of SNHL
associated with vincristine treatment in a 64-year-old
patient with multiple myeloma.45 They went on to con-
duct a prospective cohort study to further assess this
possible association.46 Twenty-three patients were fol-
lowed audiometrically before and during treatment.
No adverse effects on hearing, including pure tone
audiometry and speech audiometry, were reported at
moderate doses of vincristine (616 mg total dose).
However, in the patient who received high-dose vin-
cristine (24 mg total dose), a mild SNHL was observed.
In an earlier study, Engstrom and colleagues looked
at the ototoxic effects of combination chemotherapy in
26 patients with small cell carcinoma of the lung.47 Each
patient received combination treatment with doxoru-
bicin, vincristine, cyclophosphamide, and methotrex-
ate. Hearing was monitored with repeated audiometry
during treatment. No significant impairment of hearing
was observed. In addition, postmortem examination of
the temporal bones was performed in seven patients,
and no alterations in cochlear morphology were
reported. As mentioned previously, identifying the inju-
rious agent in combination therapy is often not pos-
sible. However, in a multivariant analysis of the risk
factors for cisplatin ototoxicity in a group of 86 patients
with testicular cancer, high-dose vincristine was identi-
fied as an independent risk factor, and greater vigilance
was called for in this subset of patients.48 In summary,
the clinical evidence suggests a potential for ototoxicity
with vincristine, particularly at higher doses.

The mechanism for vincristine ototoxicity is
unclear. Vincristine is known to have neuropathic effects
on peripheral, autonomic, and cranial nerves.1,49,50 Some
evidence from animal work suggests that it may also be
directly toxic to the cochlea. Using light microscopy, Ser-
afy and Hashash examined the cochleas of six rabbits
exposed to vincristine via intraperitoneal injections
compared with six animals that received control injec-
tions.49 One-half of the animals were sacrificed and
examined after three injections and the rest after five.
Atrophy of the organ of Corti was reported in the ani-
mals that received vincristine. There was also degenera-
tion of the nerve fibers in the bony spiral lamina, spiral
ganglion, and cochlear nerve. Moreover, the neural
degeneration was greater in the animals that received the
longer course of vincristine. The authors postulated that
the changes seen in the organ of Corti were the direct
effect of the drug or secondary to the degeneration of spi-
ral ganglion cells. The direct effect hypothesis was
favored given that damage to the organ of Corti appeared
relatively greater than that to the neural structures in the
animals that had received the shorter course of vin-
cristine. Either explanation, however, remains possible.
Vinblastine
Vinblastine obtained FDA approval in 1964, and its cur-
rent indications include breast carcinoma, embryonal
cell carcinoma, testicular carcinoma, choriocarcinoma,
histiocytosis X, selected lymphomas, mycosis fungoides,
Kaposis sarcoma, and teratocarcinoma.1
Again, identifying the toxic agent in multidrug
treatment regimens is difficult. A case report by Moss
and colleagues, however, suggests that vinblastine may
cause ototoxicity.51 They described a 29-year-old man
with recurrent Hodgkins disease who received doxoru-
bicin, bleomycin, vinblastine, and dacarbazine (ABVD)
chemotherapy, every 2 weeks for 12 cycles. The patient
reported tinnitus after each treatment cycle, and when
audiology was performed a mild high-frequency SNHL
was noted. Vinblastine was implicated because of its
temporal association with the auditory symptoms and
its similarities with vincristine.
Serafy and colleagues examined the ototoxicity of
vinblastine in an animal model, similar to their work on
vincristine.52 They noted progressive damage to the
organ of Corti with increasing doses of vinblastine. The
nerve cells of the spiral ganglion appeared preserved
(contrary to the findings with vincristine), and therefore
a direct toxic effect on the end organ was concluded.
In summary, vinblastine appears to be potentially
ototoxic, but clinical evidence remains sparse for the
doses and regimens being used in current practice.
Vinorelbine
Vinorelbine is a relatively newer agent, obtaining FDA
approval in 1994 for the treatment of lung carcinoma.1
Iron-Chelating and Other Chemotherapeutic Agents 79
A case of ototoxicity in a patient treated with vinorel-
bine and paclitaxel for metastatic breast carcinoma
has been reported.53 Vinorelbine is known to cause
peripheral neuropathy, and ototoxicity has been
observed in combination with cisplatin previously.1
Again, it is not possible to determine which agent was
responsible for the ototoxicity or indeed if both may
have had an effect.
SUMMARY
Iron-chelating agents, namely deferoxamine
(DFO), also known as desferrioxamine, have
been associated with a predominantly high-
frequency SNHL is some series.
Risk factors for DFO toxicity include younger
age, higher dose of DFO, lower serum ferritin
levels, monthly DFO amount, and, somewhat
paradoxically, better compliance with DFO
therapy. A therapeutic index for DFO (mean
daily dose of DFO [mg/kg] divided by serum
ferritin level) of less than 0.025 appears to be
associated with a reduced risk for ototoxicity.
Vinca alkaloids (vincristine, vinblastine, and
vinorelbine) have all been associated with risk
for ototoxicity at higher doses. Determining
whether a vinca alkaloid in itself is responsible
for ototoxicity is often not possible as these
agents are typically used in combination with
other potentially ototoxic chemotherapeutic
agents (eg, cisplatin).
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3. Clerici WJ, DiMartino DL, Prasad MR. Direct
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5. Clerici WJ, Yang L. Direct effects of intraperilym-
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8. Song BB, Sha SH, Schacht J. Iron chelators protect
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9. Wantanabe H, Kanno H. Experimental studies of
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13. Tabuchi K, Okubo H, Fujihira K, et al. Protection of
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14. Tabuchi K, Tsuji S, Asaka Y, et al. Ischemia-reper-
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17. Guerin A, London G, Marchais S, et al. Acute deaf-
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19. Cases A, Campistol JM, Sabater M, et al. Desfer-
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20. Cases A, Kelly J, Sabater J, et al. Acute visual and
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21. Olivieri NF, Buncic JR, Chew E, et al. Visual and
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22. Barratt PS, Toogood IRG. Hearing loss attributed to
desferrioxamine in patients with beta-thalassaemia
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ferrioxamine in homozygous beta-thallasaemia.
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24. Masala W, Meloni F, Gallisai D, et al. Can deferox-
amine be considered an ototoxic drug? Scand
Audiol Suppl 1988;30:2378.
25. Wonke B, Hoffbrand AV, Aldouri M, et al. Reversal
of desferrioxamine induced auditory neurotoxicity
during treatment with G-DTPA. Arch Dis Child
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26. Porter JB, Jawson MS, Huehns ER, et al. Desfer-
rioxamine ototoxicity: evaluation of risk factors in
thalassaemic patients and guidelines for safe
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27. Cohen A, Martin M, Mizanin J, et al. Vision and
hearing during deferoxamine therapy. J Pediatr
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28. Cases A, Kelly J, Sabater F, et al. Ocular and audi-
tory toxicity in haemodialyzed patients receiving
desferrioxamine. Nephron 1990;56:1923.
29. Triantafyllou N, Fisfis M, Sideris G, et al. Neuro-
physiological and neuto-otological study of
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city of deferoxamine. An Otorrinolaringol Ibero
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31. Styles LA, Vichinsky EP. Ototoxicity in hemo-
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415.
32. Kontzoglou G, Koussi A, Tsatra J, et al. Sensori-
neural hearing loss in children with thalassemia
major in Northern Greece. Int J Pediatr Otorhino-
laryngol 1996;35:22330.
33. Chiodo AA, Alberti PW, Sher GD, et al. Desfer-
rioxamine ototoxicity in an adult transfusion-
dependent population. J Otolaryngol 1997;
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34. Ambrosetti U, Donde E, Piatti G, Cappellini MD.
Audiological evaluation in adult beta-thalassemia
major patients under regular chelation treatment.
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35. Karimi M, Asadi-Pooya AA, Khademi B, et al. Eval-
uation of the incidence of sensorineural hearing
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regular chelation therapy with desferrioxamine.
Acta Haematol 2002;108:7983.
36. Porter JB, Faherty A, Stallibrass L, et al. A trial to
investigate the relationship between DFO phasma-
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37. Porter JB. A risk-benefit assessment of iron-
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38. Antonio P, Corda L, Carta F. Rapid recovery with oral
zinc sulphate in deferoxamine-induced presumed
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39. Shirane M, Harrison RV. A study of the ototoxicity
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40. Shirane M, Harrison RV. The effects of deferox-
amine mesylate and hypoxia on the cochlea. Acta
Otolaryngol 1987;104:99107.
41. Ryals B, Westbrook E, Schacht J. Morphological
evidence of ototoxicity of the iron chelator
deferoxamine. Hear Res 1997;112:448.
42. Yamanobe S, Kanno H. An experimental study of
ototoxicity induced by deferoxamine mesilate. J
Otorhinolaryngol Soc Jpn 1998;101:97987.
43. Mahajan SL, Ikeda Y, Myers TJ, Baldini MG. Acute
acoustic nerve palsy associated with vincristine
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44. Yousif H, Richardson SG, Saunders WA. Partially
reversible nerve deafness due to vincristine. Post-
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45. Lugassy G, Shapira A. Sensorineural hearing loss
associated with vincristine treatment. Blut 1990;
61:3201.
46. Lugassy G, Shapira A. A prospective cohort study
of the effect of vincristine on audition. Anticancer
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47. Engstrom B, Hillerdal M, Hillerdal G, Nou E. Hear-
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48. Bokemeyer C, Berger CC, Hartmann JT, et al.
Analysis of risk factors for cisplatin-induced oto-
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49. Serafy A, Hashash M. The effect of vincristine on
the neurological elements of the rabbit cochlea.
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50. Schweitzer VG. Ototoxicity of chemotherapeutic
agents. Otolaryngol Clin North Am 1993;26:
75989.
51. Moss PE, Hickman S, Harrison BR. Ototoxicity
associated with vinblastine. Ann Pharmacother
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52. Serafy A, Hashash M. The effect of vinblastine on
the neurological elements of the rabbit cochlea.
J Laryngol Otol 1982;96:9759.
53. Tibaldi C, Pazzagli I, Berrettini S, De Vito A. A case
of ototoxicity in a patient with metastatic carci-
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vinorelbine. Eur J Cancer 1997;34:1133.
 CHAPTER 8
Clinical Aminoglycoside Ototoxicity
Coleman Rotstein, MD, FRCPC, and Lionel Mandell, MD, FRCPC, FRCP(Lond)
Aminoglycoside antibiotics have been an important and
integral part of our antibacterial drug armamentarium
since their discovery in the 1940s. They possess potent
in vitro activity against Pseudomonas aeruginosa and
most other aerobic gram-negative bacilli while also
exhibiting some activity against Staphylococcus aureus.1
They also demonstrate a synergistic activity when used
in combination with certain -lactam antibiotics.2 Their
toxicity, however, has led to comparatively restrained
use in the past two decades, particularly since the broad-
spectrum cephalosporins, carbapenems, and fluoro-
quinolones were introduced. Indeed, it is fair to say that
their narrow therapeutic window has limited their use.3
The major toxicities of note shared by all aminoglyco-
sides are nephrotoxicity, which occurs in approximately
15% of patients receiving divided-dose regimens, and
ototoxicity, which is manifested by hearing loss (5%)
and vestibular toxicity (3%).410
Aminoglycosides are fermentation products or
semisynthetic derivatives from soil actinomycetes. They
are produced or derived from Streptomyces or Micro-
monospora species,1 and the suffix of the drug name
indicates its origin. Thus, aminoglycosides ending in
mycin are derived directly or indirectly from Strepto-
myces. Similarly, the aminoglycosides ending in micin
are products of Micromonospora. Currently, eight
aminoglycosides (gentamicin, tobramycin, amikacin,
streptomycin, neomycin, kanamycin, paromomycin,
and spectinomycin) are approved by the Food and
Drug Administration and marketed in the United
States. In Canada, only six products are presently avail-
able (gentamicin, tobramycin, amikacin, streptomycin,
netilmicin, and paromomycin) (Table 8-1). Only cer-
tain aminoglycoside products are available for par-
enteral, oral, or topical use (otic or ophthalmologic
solutions) (see Table 8-1).11,12
All aminoglycosides have a six-member ring
(aminocyclitol) with amino-group substituents and
glycosidic bonds between the aminocyclitol ring and
two or more sugars, thereby accounting for the name
aminoglycoside. The compounds are highly soluble in
water. Their insolubility in organic solvents limits their
ability to cross lipid-containing cellular membranes.1
At an alkaline pH, aminoglycosides have a very high
positive charge (ie, cationic), which enhances their
antibacterial activity. In contrast, acidic environments
(eg, the stomach) reduce their activity. Compared with
other drugs, such as the fluoroquinolones, the amino-
glycosides do not have well understood structure-activ-
ity relationships.
CLINICAL INDICATIONS FOR
AMINOGLYCOSIDE THERAPY
Aminoglycosides are considered first and foremost to
be bactericidal antimicrobial agents. They act at various
sites of the bacterial cell. As a first step, cationic amino-
glycosides bind to the anionic outer membrane of the
gram-negative organisms, thereby disrupting the
integrity of the cell walls normal permeability func-
tion. Their uptake into the bacterial cell is increased in
an alkaline environment producing greater intracellu-
lar concentrations, thus enhancing the antibacterial
effect of the drug. Second and most important, amino-
glycosides impair bacterial protein synthesis by binding
to the 30S ribosomal subunit leading to misreading of
the genetic code and inhibition of translocation.13,14
Elongation of the amino acid chain fails to occur,
resulting in bacterial death.
Two important pharmacodynamic properties
related to the activity of aminoglycosides are their
postantibiotic effect and concentration-dependent
killing. The postantibiotic effect can be simply
described as persistent suppression of bacterial growth
that occurs after the drug has been removed in vitro or
cleared by metabolism and eliminated in vivo.15 In
addition, aminoglycosides kill bacteria more rapidly
and efficiently when higher drug concentrations are
achieved. High drug concentrations may be easily
achieved with once-daily dosing compared with twice-
 Clinical Aminoglycoside Ototoxicity 83

Table 8-1 Origin and Availability of Parenteral, Oral, and Topical (Otic/Ophthalmic Solutions) Aminoglycosides

Year of Parenteral Availability or Otic/Ophthalmic*

Drug Origin Discovery Oral Preparation Solution Availability

Amikacin Streptomyces 1972 Canada, United States (IM, IV) NA

kanamyceticus

Gentamicin Micromonospora 1963 Canada, United States (IM, IV) Canada, alone or in combination
purpurea and with betamethasone; United
M. echinospora States

Kanamycin S. kanamyceticus 1957 United States (IM, IV) NA

Neomycin S. fradiae 1949 United States (oral powder, United States, in combination with
solution, or tablets) polymyxin B and hydrocortisone;
Canada, gramicidin, neomycin, and
polymyxin B combination, framy-
cetin (neomycin II), gramicidin
and dexamethasone combination

Netilmicin M. inyoensis 1975 Canada (IM, IV) NA

Paromomycin S. fradiae 1959 United States, Canada NA

(oral capsules only)

Spectinomycin S. spectabilis 1962 United States (IM) NA

Streptomycin S. griseus 1944 United States, Canada (IM) NA

Tobramycin S. tenebrarius 1968 United States, Canada (IM, IV) United States/Canada, tobramycin
alone and with dexamethasone
combination*

IM = intramuscular; IV = intravenous; NA = not available.

*Ophthalmic solutions containing aminoglycosides are not infrequently used in an off-label fashion for otic disease.

or thrice-daily dosing while avoiding elevated trough
concentrations that are linked to nephrotoxicity.16
In Vitro Activity
The aminoglycosides exhibit in vitro activity against a
wide range of aerobic gram-negative pathogens,
including Enterobacteriaceae (Escherichia coli, Kleb-
siella spp, Enterobacter spp, Proteus spp, Serratia spp,
and Citrobacter spp) and Pseudomonas spp. In vitro
activity against Burkholderia cepacia, Stenotrophomonas
maltophilia, the anaerobic bacteria such as Bacteroides
spp and Clostridium spp, and Streptococcus pneumoniae
is absent or poor. In addition, aminoglycosides have
activity against methicillin-susceptible but not -resis-
tant S. aureus. Streptomycin remains the most active
aminoglycoside against Mycobacterium tuberculosis,
whereas amikacin is more active against M. avium-
intracellulare and other nontuberculous mycobacteria.
Streptomycin is also considered the drug of choice for
Yersinia pestis infection.
Gentamicin, tobramycin, netilmicin, and amikacin
possess virtually identical spectrums of activity,
although gentamicin and tobramycin are consistently
more active than the other drugs against Serratia and
P. aeruginosa, respectively. 1 Spectinomycin is used
clinically for Neisseria gonorrhoeae, whereas paro-
momycin can by used for the treatment of Entamoeba
histolytica.
Therapeutic Indications
Because of their spectrum of activity and bactericidal
properties, the aminoglycosides are clinically useful
agents for documented serious infections such as sep-
ticemia, complicated urinary tract infections, intra-
abdominal infections, respiratory tract infections, and
osteomyelitis caused by susceptible aerobic gram-
negative bacilli (Enterobacteriaceae). Aminoglycosides
are also often employed in combination with other
antibiotics (usually extended spectrum penicillins with
or without a -lactamase inhibitor, cephalosporins, or
carbapenems) for serious infections resulting from
Pseudomonas spp.1
Combination therapy with gentamicin is fre-
quently used for the treatment of enterococcal infec-
tions, particularly endocarditis when the enterococci
do not exhibit high-level aminoglycoside resistance.
Gentamicin may also be used for 2 weeks initially in
combination with antistaphylococcal penicillins or
vancomycin for serious staphylococcal infections to
enhance bacterial eradication. Gentamicin specifically
84 Systemic Toxicity
demonstrates synergistic activity with ampicillin for
the treatment of Listeria monocytogenes infections.
Aminoglycosides are also routinely used in combi-
nation with broad-spectrum -lactam agents with
activity against aerobic gram-negative bacilli as empiric
antibacterial therapy for febrile neutropenic cancer
patients. Aminoglycoside monotherapy, however, even
for susceptible organisms, in neutropenic cancer
patients is suboptimal and often results in unacceptable
failure rates.17 Finally, gentamicin in combination with
ampicillin or vancomycin remains a mainstay as pro-
phylaxis to diminish the risk of developing infective
endocarditis related to procedures involving the gas-
trointestinal or genitourinary tracts.
As mentioned previously, aminoglycosides play a
role in the treatment of mycobacterial diseases. Strep-
tomycin is the most active of the aminoglycosides
against M. tuberculosis, whereas amikacin is the one
employed in nontuberculous mycobacterial infections.1
Compared with the cephalosporins and fluoro-
quinolones, the aminoglycosides have demonstrated
relative stability against the development of resistance
despite many years of use. Resistance is infrequently
encountered during treatment of gram-negative bacil-
lary infections. The main mechanisms of resistance to
aminoglycosides are (1) the bacterial production of
enzymes that modify the antibiotics and inactivate them
and (2) the decreased uptake of the antibiotics.14 The
latter mechanism is mainly seen in Pseudomonas spp
and is likely caused by membrane impermeability.14 The
former mechanism, however, is of greater importance.
Aminoglycosides are inactivated by phosphoryla-
tion, adenylation, or acetylation by means of enzymes
encoded in plasmids, but they are also associated with
transposable elements.14 Alteration of the ribosomal
binding site can occur from enzymatic activity or
mutational modification, as seen in M. tuberculosis.1
Low-concentration aminoglycoside resistance is
observed in enterococci because of their anaerobic
metabolism. This may be overcome through synergism
when a cell wall active agent such as penicillin is com-
bined with the aminoglycoside. This synergism is elim-
inated, however, when high-level resistance to the
aminoglycoside (minimum inhibitory concentrations
> 2,000 mg/L) exists in enterococci.1
CLINICAL TOXICITIES ASSOCIATED WITH
AMINOGLYCOSIDE THERAPY
All aminoglycosides, except for spectinomycin, share
the potential to be nephrotoxic, to damage the cochlea
or vestibular apparatus, and to produce neuromuscu-
lar blockade.
Nephrotoxicity
The reported incidence of nephrotoxicity varies widely,
from 0 to 34%, with most reports claiming between
5 and 25% incidence.1,4,1821 This range of nephrotoxi-
city is a result of variations in study design, toxicity
definitions, patient populations, frequency of measure-
ments, and concomitant risk factors. In general, gen-
tamicin and tobramycin appear to be equally
nephrotoxic and only slightly more so than amikacin
and netilmicin.18
The pathogenesis of the acute renal insufficiency
resulting from aminoglycosides stems from the devel-
opment of acute tubular necrosis. This adverse event is
relatively common, with a rise in plasma creatinine of
0.5 to 1.0 mg/dL (44 to 88 mol/L), occurring in 10 to
20% of patients.22,23 As the aminoglycosides are freely
filtered in the kidney, almost all of these drugs are then
excreted. Only a small portion of the drug is taken up
by and stored in the renal tubular cells, particularly the
lysosomes of proximal tubule cells. It is this subsequent
concentration that damages the cells. As aminoglyco-
sides accumulate within the proximal tubular epithelial
cells in lysosomal phospholipid complexes, these com-
plexes eventually rupture and initiate cell death. As a
consequence, the local reninangiotensin system is acti-
vated, producing local vasoconstriction and diminished
glomerular filtration rate, thereby increasing plasma
creatinine values.22 Acute renal failure may occur even
if drug serum concentrations are closely monitored,
but it tends to occur more frequently in patients with
higher serum concentrations.2325 The propensity to
accumulate aminoglycosides in the tubular cells may be
overcome by administering the drugs once a day rather
than in divided doses because the uptake mechanism in
the proximal tubule is saturable. A large single dose will
therefore not increase drug uptake once the resorptive
capacity is exceeded.26,27 It should be noted that tubu-
lar injury is typically reversible, and recovery of renal
function may occur despite continued therapy if
decreased cellular exposure occurs, as may be accom-
plished by prolonging the dosage interval.28
The molecular charge on the aminoglycoside mol-
ecule interestingly may be a determinant of nephro-
toxicity. The number of cationic amino groups (NH3+)
per module appears to be a contributing factor for the
development of nephrotoxicity. Since neomycin pos-
sesses the largest number of amino groups (six
groups), it has the greatest predilection for renal com-
promise, compared with streptomycin (three groups),
which has the least. 23,29 Gentamicin, tobramycin,
netilmicin, and amikacin (four or five groups) have
intermediate potential for nephrotoxicity.24 Cationi-
cally charged aminoglycosides bind to megalin, an
anionic protein in the luminal membrane, which facil-
itates the movement of the complex to the lysosome
and thereafter fusion with lysosome membranes. Lyso-
some localization of aminoglycosides is observed about
an hour after exposure. The megalin dissociates and
returns to the cell membrane. The subsequent rupture

of lysosomal complexes culminates in cell death, local
vasoconstriction, and decreased glomerular filtration
(ie, renal insufficiency). Investigators have experimen-
tally attempted to ameliorate these effects in animals to
prevent aminoglycoside-induced nephrotoxicity.30
Ototoxicity
Ototoxicity is an adverse effect of aminoglycoside use
affecting both the auditory and vestibular functions of
the ear. The pathophysiology involves the destruction
of the sensory hair cells in the cochlea and vestibular
labyrinth.8
Although ototoxicity is the second most common
form of toxicity encountered with aminoglycosides, its
precise incidence is controversial. Some investigators
have reported auditory ototoxicity in up to 41% of sub-
jects,31 whereas others have reported a much lower inci-
dence of about 7%.32 Pooled data from meta-analyses
have demonstrated an approximate 5% incidence of
auditory toxicity (as measured by at least a 15 dB change
in hearing by audiometry) with multiple daily dosing
(MDD) of aminoglycosides, compared with a slightly
higher 5.8% incidence when single daily dosing (SDD)
of aminoglycosides was employed.33,34 A similar situa-
tion is reflected in the relatively sparse vestibular toxic-
ity data. Vestibular toxicity has been reported in 0 to 7%
of those patients receiving aminoglycosides.18,3537 What
defines a vestibulotoxic event, however, remains some-
what unclear. For example, a decrement in vestibular
function as evidenced by a 5 to 8% reduction in caloric
test scores, though clinically insignificant, may occur
even in healthy volunteers receiving tobramycin.38
Discordant results in the incidence of auditory and
vestibular aminoglycoside-induced toxicity have arisen
because of the discrepancies between clinical observa-
tions demonstrating that very few patients receiving
these drugs actually complain of diminished hearing or
vertigo and the results of systematic objective testing for
these toxicities. With respect to hearing loss, aminogly-
coside toxicity primarily affects high-frequency hearing
earlier than low-frequency hearing.8 Hearing loss at
higher frequencies (> 4,000 Hz) is often detectable
audiometrically well before it becomes severe enough to
involve the speech frequency range and thereby be per-
ceived by patients. The subliminal nature of a vestibular
loss also makes vestibular toxicity difficult to detect at
times. As aminoglycoside vestibular toxicity typically
occurs without an accompanying injury to the auditory
system,35 a vestibular injury can often be compensated by
visual and proprioception cues, which probably helps
mask the true incidence of this form of aminoglycoside
toxicity. Unfortunately, when auditory or vestibular
toxicity occurs, it is often irreversible, in contrast to
nephrotoxicity.
At one time only parentally administered amino-
glycosides were thought to cause both forms of
Clinical Aminoglycoside Ototoxicity 85
ototoxicity. In recent years topical aminoglycoside
eardrops have also been implicated as a cause for oto-
toxicity (see Chapter 12, Topical Aminoglycoside
Cochlear Toxicity and Chapter 13, Topical Amino-
glycoside Vestibular Toxicity,).39 Otic solutions con-
taining gentamicin instilled into the ear canal in the
presence of a tympanic membrane defect have pro-
duced both hearing loss and vestibular damage.39,40
The round window membrane (RWM) is thought to
play a key role in the absorption of topical aminogly-
cosides into the inner ear. The degree of ototoxicity
appears to be directly related to the duration and dose
of the preparation in contact with the RWM. Toxic lev-
els of aminoglycosides may therefore occur in the
inner ear with repeated exposures to the eardrops.41,42
Aminoglycoside-induced ototoxicity is a complex
process (see Chapter 9, Mechanisms for Aminoglyco-
side Ototoxicity: Basic Science Research) involving the
effect of the drugs on the sensory hair cells in the
cochlea and vestibular labyrinth as well as a super-
imposed genetic predisposition of these cells (see
Chapter 17, Genetic Factors of Aminoglycoside Oto-
toxicity) for this adverse event.8,43 Following parenteral
administration aminoglycosides enter the inner ear
rapidly but do not apparently accumulate in the peri-
lymph and endolymph as the concentrations never
exceed those of serum.43,44 Once again, there appears to
be an initial interaction between the cationic amino-
glycosides and the anionic membranes of the hair cells,
which leads to their rapid transport into the cells.45 The
exact intracellular target is unknown. One postulate is
that aminoglycosides, such as gentamicin, form com-
plexes with iron.46 This activates molecular oxygen-pro-
ducing superoxides that progress to free hydroxyl
radicals, which in turn damage the cell. Another
hypothesis of aminoglycoside ototoxicity has been
based on the overactivation of glutamate receptors on
cochlear synapses.47 The proposed mechanism is related
to receptors for N-methyl-D-aspartate (NMDA), which
are present at the synapse between cochlear hair cells
and neural afferents. Aminoglycosides mimic the
positive modulation of polyamines at these receptors,
possibly producing excitotoxic damage. The adminis-
tration of NMDA antagonists such as dizocilpine and
ifenprodil can markedly attenuate hearing loss in ani-
mals.48 This effect may have been confounded by the
fact that dimethyl sulfoxide (DMSO), a potent hydroxyl
radical scavenger, was the vehicle for the administration
of the antagonists and may have enhanced the protec-
tion provided by the antagonists.47
Genetic factors may also contribute to susceptibil-
ity for ototoxicity. There appears to be a genetic predis-
position linked to two (possibly more) mutations in the
mitochondrial chromosome. The first mutation discov-
ered is in location 1555 of the mitochondrial ribosomal
ribonucleic acid (RNA) where A-to-G substitution
86 Systemic Toxicity
Table 8-2 Risk Factors for Aminoglycoside
Auditory Toxicity
Risk Factor Reference
Duration of therapy Moore et al51
Bacteremia Moore et al51
Renal dysfunction Forge and Schacht,47 Moore
et al,51 Neu and Beadush52
Peak temperature Moore et al51
Liver dysfunction Moore et al51
Advanced age Forge and Schact,47
Gatell et al53
Concomitant ototoxic drugs Govaerts et al54
Higher serum concentrations Black et al55
Preexisting hearing disorders Forge and Schacht47
occurred.49 This mutation has been identified in several
Chinese and Japanese families and correlated with a
maternally inherited hypersensitivity to aminoglyco-
side-induced hair cell death.43 It is noteworthy that
patients with this mutation have exhibited only cochlear
toxicity with no involvement of the vestibular system.47
A second point mutation in the small 12S ribo-
somal RNA gene has also been described.50 The mutant
human RNA binds aminoglycosides with high affinity;
in contrast, the wild-type human RNA does not bind
aminoglycosides. The binding was also tighter for the
clinically more toxic drugs such as neomycin than for
others such as gentamicin and tobramycin.50
Several other risk factors have been implicated in
the development of aminoglycoside-induced ototoxic-
ity (Table 8-2). These studies have predominantly
assessed the association of these factors with auditory
ototoxicity. Auditory toxicity may be unilateral or bilat-
eral.56 In contrast, vestibular toxicity is more likely to
occur in patients with prior disorders of balance57 and
renal dysfunction.47
One must also be cognizant of the varying poten-
tial for cochlear and vestibular ototoxicity among the
aminoglycosides. It is somewhat uncommon to have
both vestibular and cochlear symptoms in the same
patient,1 but either form of ototoxicity may occur with
any of the aminoglycosides. A hierarchy of auditory
toxic potential has been established among the amino-
glycosides: neomycin is the most toxic, followed in
order of decreasing toxicity by gentamicin, tobramycin,
amikacin, and netilmicin.1,35,45,54,58 Vestibular symptoms
of dizziness, imbalance, nausea, and oscillopsia are
comparable with gentamicin and tobramycin, less
frequent with amikacin, and least frequent with
netilmicin.45,57
An additional issue to be considered whenever dis-
cussing both auditory and vestibular toxicity resulting
from aminoglycosides is the methods employed to
detect these toxicities. Auditory toxicity is typically
verified by a decrease in hearing acuity. The common
standard used in the literature is a 15 dB reduction in
the hearing threshold at two or more frequencies.59
Nevertheless, other definitions such as 10 dB or 20 dB
reductions have also been used.32,60 Testing for vestibu-
lar toxicity is far less standardized. Diagnostic testing
for vestibular toxicity covers a spectrum from clinical
symptom documentation to caloric testing with
electronystagmography (ENG) and other advanced
tests of vestibular function. Variability in the reporting
of vestibular toxicity in the literature might have been
avoided by standardized testing. Nevertheless, stan-
dardization has usually been hampered in practice by
the lack of availability of tests such as an ENG.61,62
Neuromuscular Blockade
Neuromuscular blockade is a rarely reported adverse
effect of aminoglycoside use, although it may be more
common than previously believed.63 It is more likely to
occur when aminoglycosides are given intravenously
and coadministered with neuromuscular blocking
drugs or anesthetic agents.63 It has been noted with all
of the parenterally administered aminoglycosides. The
risk of blockade is magnified by hypomagnesemia,
hypocalcemia, and perhaps calcium channel-blocking
agents.64 The blockade results from inhibition of the
presynaptic release of acetylcholine and blockage of
postsynaptic receptor sites of acetylcholine. Calcium
internalization must occur before acetylcholine release,
which aminoglycosides prevent. In addition, the
aminoglycosides blunt the response of postsynaptic
receptors to acetylcholine.65 Neomycin is more apt to
inhibit presynaptic release, whereas streptomycin and
netilmicin act at the postsynaptic site.1
AMINOGLYCOSIDE ADMINISTRATION: MULTIPLE-
DAILY VERSUS ONCE-DAILY DOSING
All parenterally administered aminoglycosides possess
similar pharmacokinetics. The drugs distribution and
elimination occur in three phases.66 The first or distrib-
utive phase is the result of drug distribution from the
vascular to the extravascular compartment. This phase
typically occurs over 15 to 30 minutes. This is the reason
peak drug concentrations are usually checked 30 min-
utes after the completion of a 15- to 30-minute infusion.
The second or phase of elimination encompasses
excretion of the drug from the plasma and extravascu-
lar space. This phase is determined by the glomerular fil-
tration rate. With poor renal function the elimination
rate is more prolonged. In general, the half-life of
aminoglycosides with normal renal function is 1.5 to

3.5 hours.1,67,68 The third or phase represents the slow
elimination of drug that has accumulated in the kidney.
As a result of these pharmacokinetic properties,
aminoglycosides were traditionally administered in
MDD regimens either every 8 or 12 hours commenc-
ing with a loading dose to rapidly achieve therapeutic
plasma concentrations and followed by a maintenance
dose to maintain the drug in a steady state of thera-
peutic peak concentrations. With this approach, the
desired therapeutic concentrations would achieve clin-
ical success. Similarly, by measuring peak and trough
serum concentrations of the drug, one ensured that
sufficient drug was being administered for clinical effi-
cacy while obviating the development of tissue uptake
that might prove to be toxic to the kidney or inner ear.69
In contrast, based on the above-mentioned phar-
macodynamic properties of concentration-dependent
killing and their postantibiotic effect, aminoglycosides
may be administered once daily. As previously
described, aminoglycosides kill microorganisms more
efficiently and rapidly when higher drug concentra-
tions are present.15 This fact, coupled with the concept
that aminoglycoside uptake into the renal proximal
tubule cell is saturable, led to the introduction of once-
daily dosing in the hopes that it might reduce the inci-
dence of nephrotoxicity. Drug administration costs
were also expected to be somewhat curtailed with this
strategy. As a result, numerous trials have attempted to
compare MDD with SDD treatment regimens.
Published data on once-daily dosing have recently
been reviewed by Turnidge.61 He reported that SDD
was compared with MDD in 45 clinical trials involving
over 6,500 patients where identical or similar total daily
aminoglycoside doses were administered. Another
900 patients have also been studied in whom SDD was
employed in an uncontrolled fashion or with unequal
drug dosages compared with MDD. Data have been
compiled in meta-analytic fashion.10,33,34,7076 The meta-
analyses demonstrate superiority for SDD or favor
SDD for bacteriologic eradication and a decreased inci-
dence of nephrotoxicity, although the results were not
always consistently statistically significant. For ototox-
icity predominantly assessed by auditory toxicity, no
trend emerged. 10,33,34,70,71,73,75 Some reports favored
SDD, 10,33,34,73 whereas others favored MDD. 70,71,75
Vestibular toxicity summary data were inconsistent and
demonstrated no statistically significant differences
between the SDD and MDD regimens.10,70,71,76
The inconsistencies in the meta-analyses described
above with regard to ototoxicity are understandable.
This variation is two-pronged. First, there has been
tremendous variability in the clinical studies evaluating
auditory toxicity as far as testing is concerned, both in
performing the test at baseline and end of therapy and
in adhering to a standardized definition of toxicity. The
variability is even more pronounced regarding the data
Clinical Aminoglycoside Ototoxicity 87
on vestibular toxicity, where the interpretation and
deficiencies in testing vestibular function have ham-
pered meaningful comparisons. Second, the pathogen-
esis of ototoxicity as previously discussed does not
provide a sound rationale for SDD. In contrast to the
kidney, where the uptake mechanism of aminoglyco-
sides into the proximal tubule cells is saturable and
favors the SDD regimen, hair cell uptake of aminogly-
cosides in the inner ear does not emulate the afore-
mentioned saturable process, making SDD a bane.
Although SDD of aminoglycosides has emerged as
the standard of care when employing these agents
because of its efficacy, lower drug-induced nephrotox-
icity, simplicity (especially in the outpatient setting),
and cost reductions, some caveats remain as to its
acceptance in all clinical situations. MDD of aminogly-
cosides, is still preferred for enterococcal endocarditis,
severe renal compromise, cystic fibrosis, burns, preg-
nancy, and meningitis.1,77
RENAL AND CONCENTRATION
SERUM MONITORING
Rapid attainment of therapeutic concentrations of
aminoglycosides has been correlated with clinically
successful therapy. When using MDD of aminoglyco-
sides in patients with normal renal function, genta-
micin, tobramycin, and netilmicin are administered
three times daily according to the manufacturers rec-
ommendations, whereas amikacin is administered
twice daily. The treatment regimens are divided into an
initial loading dose (2 mg/kg for gentamicin,
tobramycin, and netilmicin but 7.5 mg/kg for ami-
kacin) and subsequent maintenance doses (1.7 mg/kg
every 8 hours for gentamicin and tobramycin, 2 mg/kg
every 8 hours for netilmicin, and 7.5 mg/kg every
12 hours for amikacin).1 The loading and maintenance
aminoglycoside doses are based on ideal body weight,
with a modification for obese individuals.1,34,61 Appro-
priate dosage adjustments are required in the presence
of renal insufficiency.61
The dosing regimen is somewhat different when
administering aminoglycosides in the SDD format.
With this approach, gentamicin and tobramycin are
administered at a single daily dose of 5 mg/kg in
patients with normal renal function. In patients with an
anticipated increased volume of distribution, the
dosage is 7 mg/kg/day.78 For netilmicin and amikacin
the doses are 6 mg/kg and 15 mg/kg, respectively. The
doses are based on ideal body weight, and there is an
adjustment in the dosage interval should renal insuffi-
ciency be a factor.1,34,61
Monitoring of serum aminoglycoside concentra-
tions is essential for both efficacy and the avoidance of
toxicity during MDD therapy. Serum aminoglycoside
peak and trough levels are measured after the first or sec-
ond maintenance dose, and then the maintenance dose
88 Systemic Toxicity
is adjusted accordingly.1 Peak serum concentrations of 4
to 10 mg/L and trough concentrations < 2 mg/L are
desired goals for gentamicin, tobramycin, and netil-
micin. The corresponding values for amikacin are 15 to
30 mg/L and < 10 mg/L, respectively.1 An accurate record
of aminoglycoside administration times and the time
the serum concentrations were obtained is essential for
interpreting the results. Moreover, serum creatinine
should be monitored every 2 to 3 days.
If the creatinine level is stable, it is usually not
necessary to repeat the serum aminoglycoside concen-
trations. However, if renal function changes, the dosage
must be adjusted, and thereafter the peak and trough
serum concentrations require sampling again.
SDD of aminoglycosides targets much higher peak
concentrations and permits trough concentrations
< 1 mg/L. Elevated peak serum concentrations for gen-
tamicin and tobramycin of 20 mg/L, netilmicin of
26 mg/L, and amikacin of 60 mg/L are to be expected
in patients with normal renal function.1 As with MDD,
peak serum levels are measured to ensure efficacy, and
trough levels are performed to monitor for the occur-
rence of toxicity. However, rather than measuring peak
serum levels 30 minutes after the completion of a 30-
minute infusion and trough levels within 30 minutes of
the ensuing infusion as is the routine for the MDD of
an aminoglycoside, it may be preferable to obtain a
level between 6 and 14 hours after the dose. This serum
level is subsequently applied to a nomogram to deter-
mine the dosage interval.34,78,79 Alternatively, the more
familiar practice of obtaining peak and trough serum
concentrations may be employed. As previously men-
tioned serum creatinine determinations are monitored
every 2 to 3 days to provide information about renal
function. Dosage interval adjustments are predicated
from renal function.
The question remains whether serum concentra-
tion monitoring is at all necessary if in the final analy-
sis dosage adjustments are carried out solely based on
determinations of renal function. Development of ele-
vated serum concentrations ensues secondary to the
reduction in renal clearance of the aminoglycoside.
Accordingly one may anticipate elevations in peak or
trough serum concentrations as a consequence of
elevations in serum creatinine and diminished renal
clearance of the drug. Following this logic, serum
aminoglycoside determinations may be deemed super-
fluous. On the other hand, a rational approach may be
to determine peak and trough serum concentrations at
the commencement of therapy to ensure that one is in
the therapeutic range while precluding potential
accumulation of the aminoglycoside in tissues and
thereby reducing toxicity. Prevention of renal dysfunc-
tion may in turn reduce the possibility of ototoxicity.
Monitoring of serum creatinine every 2 to 3 days may
be sufficient while reducing the unnecessary costs of
measuring peak and trough serum aminoglycoside
concentrations.
To date there is no convincing evidence in the liter-
ature to substantiate a causal relationship between peak
or trough serum concentrations for aminoglycosides
administered in MDD and treatment outcome.19 Moore
and colleagues reported on the outcome of 37 cases of
gram-negative pneumonia treated with MDD of
aminoglycosides.80 Successfully treated patients had
higher mean and maximal peak serum concentrations,
with a mean peak serum concentration of 6 mg/L cor-
relating with an improvement in outcome. Neverthe-
less, these data are of little import in an era of SDD for
aminoglycosides where peak serum levels approach
20 mg/L for gentamicin and tobramycin, 26 mg/L for
netilmicin, and 60 mg/L for amikacin.1 Similarly, treat-
ment outcomes are not enhanced via the use of indi-
vidualized dosing of aminoglycosides with concomitant
serum concentration monitoring.19 Although elevated
serum concentrations of aminoglycosides have been
demonstrated to be a risk factor for ototoxicity, partic-
ularly auditory toxicity,55,81 no specific threshold serum
level has been identified as the precipitating factor for
this toxicity.19 Although a higher incidence of nephro-
toxicity has been observed with trough aminoglycoside
levels > 2 mg/L,4,82 it is unclear whether this elevation
actually preceded serum creatinine increases. Some
clinicians have suggested that changes in trough serum
concentrations occur more rapidly than do serum cre-
atinine determinations. 19 As previously noted, the
mechanism of renal insufficiency (ie, decreased creati-
nine clearance) prompts elevations in serum aminogly-
coside concentrations.
In summary, serum creatinine measurements
remain the most accessible and economical means of
monitoring renal function, thereby preventing the
development of significant nephrotoxicity and debili-
tating ototoxicity. As previously recommended, creati-
nine levels should be determined every 2 or 3 days
while on therapy.
RECOMMENDATIONS FOR AMINOGLYCOSIDE
THERAPY
Although aminoglycosides are potent and clinically
effective antimicrobial agents for treating infections
resulting from susceptible bacteria, their use has been
largely supplanted with the introduction of fluoro-
quinolones and broad-spectrum cephalosporins that
possess comparable spectrums of activity. Despite their
inherent and perceived nephrotoxicity and ototoxicity,
aminoglycosides remain indispensable agents for
patients allergic to fluoroquinolones and cephalosporins
and in combination therapy for staphylococcal, entero-
coccal, L. monocytogenes, and mycobacterial infections.
They may also be considered to be salvage drugs in the
face of higher antibiotic resistance rates to the fluoro-

quinolones and cephalosporins in aerobic gram-nega-
tive bacillary infections. They remain a mainstay of pro-
phylactic therapy in combination with ampicillin or
vancomycin to diminish the risk of endocarditis related
to gastrointestinal or genitourinary procedures.
When considering aminoglycoside therapy, risk
factors that impair renal function, such as the
concomitant use of nephrotoxins (vancomycin,1,4,83
amphotericin B,1 and furosemide1), should be noted.
Efforts to avoid or minimize risk factors that predispose
patients to ototoxicity, such as older age, concomitant
ototoxic drugs, preexisting hearing or balance disor-
ders, and renal dysfunction, should be undertaken.
As the clinical indications for aminoglycoside use
have diminished, the usual precautionary considera-
tions are often not exercised as frequently. When
aminoglycoside use is necessary in patients at risk, it is
prudent to employ once-daily dosing unless this
method of administration is inappropriate based on the
clinical infection. The use of an aminoglycoside should
be restricted to the shortest time interval possible.
Serum concentrations should be obtained at the outset
of therapy to ensure therapeutic efficacy. Renal function
should be monitored every 2 to 3 days. For patients
requiring a more protracted treatment course of amino-
glycosides of more than 14 days, baseline and weekly
auditory (see Chapter 18, Audiologic Monitoring for
Ototoxicity) and vestibular function should be moni-
tored to detect ototoxicity.19 Others have advocated
daily bedside testing of vestibular function, such as the
head thrust test, dynamic visual acuity evaluation, and
Romberg test, and an assessment of gait while on ther-
apy and after the completion of therapy if patients
develop symptoms of vestibular hypofunction (see
Chapter 19, Monitoring Vestibular Ototoxicity).62 At
the first sign of auditory or vestibular dysfunction, the
aminoglycoside should be discontinued immediately to
allow for reversibility of the condition. No outcome
studies, however, have demonstrated whether monitor-
ing for ototoxicity will actually reduce morbidity.
CONCLUSION
Aminoglycosides have potent antimicrobial
activity against P. aeruginosa and most other
gram-negative bacilli, as well as S. aureus. Their
spectrum of activity and bactericidal properties
have made them clinically useful agents for the
treatment of septicemia; complicated urinary
tract, respiratory tract, and intra-abdominal
infections; and osteomyelitis caused by suscepti-
ble aerobic gram-negative bacilli. Their major
toxicities include nephrotoxicity, ototoxicity, and
neuromuscular blockade. Since the 1980s their
use has waned and been supplanted by the broad-
spectrum cephalosporins and fluoroquinolones
with impressive gram-negative coverage.
Clinical Aminoglycoside Ototoxicity 89
Despite reservations concerning their toxicities,
bacterial resistance to aminoglycosides continues
to be low. They remain indispensable agents in
patients allergic to fluoroquinolones and
cephalosporins and in combination therapy for
staphylococcal, enterococcal, L. monocytogenes,
and mycobacterial infections. They may also be
considered salvage drugs in the face of height-
ened antibiotic resistance rates and have
remained a mainstay for prophylactic therapy in
combination with other antibiotics for bacterial
endocarditis prophylactic therapy.
Auditory and vestibular ototoxicity has been
well documented with both parenteral (MDD
and SDD therapy) and topical use. Unlike
nephrotoxicity, the full extent of ototoxicity
problem is not well appreciated because of lim-
itations in testing for these toxicities as well as
inadequate reporting of symptoms.
SDD for aminoglycosides has pharmacodynamic
advantages over MDD based on heightened con-
centration-dependent killing and the postan-
tibiotic effect. Pharmacoeconomic advantages
for SDD include relative ease of delivery in the
outpatient setting and reduced monitoring
costs. Meta-analyses overall suggest that SDD
delivery of aminoglycosides results in less
nephrotoxicity. The same claim cannot be made
with regard to ototoxicity as the mechanisms for
toxicity, including their entry into the sensory
hair cells of the inner ear, are different. Nephro-
toxicity is typically reversible. The same cannot
be said for ototoxicity.
There are no a priori surrogate markers available
to clinicians designating which patients will
develop ototoxicity. Serum creatinine determina-
tions should be measured every 2 to 3 days. Peak
aminoglycoside levels in SDD and MDD regi-
mens are measured to ensure efficacy and trough
levels measured to monitor toxicity. Prevention of
renal dysfunction may reduce the possibility of
ototoxicity but does not eliminate it completely.
Prudent medical practice dictates that clinicians
must apprise their patients of the potential for
ototoxicity and vigilantly monitor patients for
this important adverse event. Clinicians should
at all times carefully weigh the risk-to-benefit
ratio when contemplating the use of aminogly-
cosides in their patients, especially in the case of
prolonged treatment.
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neomycin and its penetration through the round
window membrane into the perilymph. Ann Otol
Rhinolaryngol 1986;95:4047.
43. Hutchin T, Cortopassi G. Proposed molecular and
cellular mechanism for aminoglycoside ototoxicity.
Antimicrob Agents Chemother 1994;38:251720.
44. Henley CM, Schacht J. Pharmacokinetics of
aminoglycoside antibiotics in blood, inner ear flu-
ids and tissues and their relationship to ototoxic-
ity. Audiology 1988;27;13746.
45. Hakashima T, Teranishi M, Hibi T, Kobayashi M.
Vestibular and cochlear toxicity of aminoglyco-
sidesa review. Acta Otolaryngol 2000;120:90411.
46. Song B-B, Schacht J. Variable efficacy of radical
scavengers and iron chelators to attenuate genta-
micin ototoxicity in guinea pig in vivo. Hear Res
1996;94:98793.
47. Forge A, Schacht J. Aminoglycosidic antibiotics.
Audiol Neurootol 2000;5:322.
48. Basile AS, Huang J-M, Zie C, et al. N-Methyl-D-
aspartate antagonists limit aminoglycoside anti-
biotic-induced hearing loss. Nat Med 1996;2:
133843.
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49. Fischel-Ghodsian N, Prezant TR, Chaltraw WE, et
al. Mitochondrial gene mutation is a significant
predisposing factor in aminoglycoside ototoxicity.
Am J Otolaryngol 1997;18:1738.
50. Hamasaki K, Rando RR. Specific binding of
aminoglycoside to a human RNA construct based
on a DNA polymophism which causes aminogly-
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123238.
51. Moore RD, Smith CR, Lietman PS. Risk factors for
the development of auditory toxicity in patients
receiving aminoglycosides. J Infect Dis 1984;
149:2330.
52. Neu HC, Bendush CL. Ototoxicity of tobramycin:
a clinical overview. J Infect Dis 1976;134:
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53. Gatell JM, Ferran F, Araujo V, et al. Univariate and
multivariate analyses of risk factors predisposing
to auditory toxicity in patients receiving amino-
glycosides. Antimicrob Agents Chemother 1987;
31:13837.
54. Govaerts P, Van De Heyning PH, Jorens G, et al.
Aminoglycoside induced ototoxicity. Toxicol Lett
1990;53:22751.
55. Black RE, Lau WK, Weinstein RJ, et al. Ototoxicity
of amikacin. Antimicrob Agents Chemother
1976;9:95661.
56. Manian FA, Stone WJ, Alford R. Adverse antibiotic
effects associated with renal insufficiency. Rev
Infect Dis 1990;12:23649.
57. Black FO, Pesznecker SC. Vestibular ototoxicity:
clinical considerations. Otolaryngol Clin North
Am 1993;26:71336.
58. Tange RA. Ototoxicity. Adverse Drug React Toxicol
Rev 1998;17:7589.
59. Rybak MJ, Abate BJ, Kang SL, et al. Prospective
evaluation of the effect of an aminoglycoside dos-
ing regimen on rates of observed nephrotoxicity
and ototoxicity. Antimicrob Agents Chemother
1999;43:154955.
60. Nordstrom L, Rinberg H, Cronberg S, et al. Does
administration of an aminoglycoside in a single
daily dose affect its efficacy and toxicity? J Anti-
microb Chemother 1990;25:15973.
61. Turnidge J. Pharmacodynamics and dosing of
aminoglycosides. Infect Dis Clin North Am
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62. Minor LB. Gentamicin-induced bilateral vestibular
hypofunction. JAMA 1998;279:5414.
63. Snavely SR, Hodges GR. The neurotoxicity of
antibacterial agents. Ann Intern Med 1984;101:
92104.
64. Del-Pozo E, Baezem JM. Effects of calcium chan-
nel blockers on neuromuscular blockade induced
by aminoglycoside antibiotics. Eur J Pharmacol
1986;128:4954.
92 Systemic Toxicity
65. Wright JM, Collier B. The effects of neomycin
upon transmitter release and action. J Pharmacol
Exp Ther 1977;200:57687.
66. Laskin OL, Longstreth JA, Smith CR, et al.
Netilmicin and gentamicin multidose kinetics in
normal subjects. Clin Pharmacol Ther 1983;34:
64450.
67. Barza M, Brown RB, Shen D, et al. Predictability of
blood levels of gentamicin in man. J Infect Dis
1975;132:16574.
68. Neu HC. Pharmacology of aminoglycosides. In:
Whelton A, Neu HC, editors. The aminoglycosides:
microbiology, clinical use and toxicology. New
York: Marcel Dekker Inc.; 1982. p. 12542.
69. Schentag JJ. Aminoglycoside pharmacokinetics as
a guide to therapy and toxicology. In: Whelton A,
Neu HC, editors. The aminoglycosides: microbiol-
ogy, clinical use and toxicology. New York: Marcel
Dekker Inc.; 1982. p. 14367.
70. Ali MZ, Goetz MB. A meta-analysis of the relative
efficacy and toxicity of single daily dosing versus
multiple daily dosing of aminoglycosides. Clin
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multiple daily doses of aminoglycosides. Br Med J
1996;312:33845.
72. Hatala R, Dinh TT, Cook DJ. Single daily dosing of
aminoglycosides in immunocompromised adults:
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73. Ferriolos-Lisart R, Alos-Alminana M. Effectiveness
and safety of once-daily aminoglycosides: a meta-
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114150.
74. Freeman CD, Strayer AH. Mega-analysis of meta-
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JP. Aminoglycoside single or multiple dosing? A
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adults. J Pharm Technol 1998;14:229.
77. Gerberding JL. Aminoglycoside dosing: timing is
of the essence. Am J Med 1998;105:2568.
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ommendations for clinical practice. J Antimicrob
Chemother 1997;39:67786.
79. Nicolau DP, Freeman CD, Belliveau PP, et al. Expe-
rience with once-daily aminoglycoside program
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Agents Chemother 1995;39:6505.
80. Moore RD, Smith CR, Lietman PS. Association of
aminoglycoside plasma levels with therapeutic
outcome in gram-negative pneumonia. Am J Med
1984;77:65762.
81. Lerner SA, Schmitt BA, Seligsohn R, Matz GJ.
Comparative study of ototoxicity and nephrotoxi-
city in patients randomly assigned to treatment
with amikacin or gentamicin. Am J Med 1986;
80:98104.
82. Matzke GR, Lucarotti RL, Shapiro HS. Controlled
comparison of gentamicin and tobramycin
nephrotoxicity. Am J Nephrol 1983;3:117.
83. Rybak MJ, Albrecht LM, Boike SC, et al. Nephro-
toxicity of vancomycin alone and with an amino-
glycoside. J Antimicrob Chemother 1990;25:
67987.
 CHAPTER 9
Mechanisms for Aminoglycoside Ototoxicity:
Basic Science Research
Jochen Schacht, PhD


The toxic side effects of aminoglycoside antibiotics
against the kidney (nephrotoxicity) and the inner ear
(ototoxicity) became evident in the first clinical trial,1
just a year after the discovery of the first compound in
this class, streptomycin, by Selman Waksman.2 It then
took almost 50 years for the mechanisms of this toxic-
ity to be unraveled. The last decade has brought signif-
icant advances in our understanding of aminoglycoside
action, to the point that we can now suggest a rational
hypothesis explaining the death of hair cells induced by
this class of antibiotics. Based on the basic research
into these mechanisms, successful protective therapies
against the ototoxic side effects have already been
formulated.
This review covers pertinent studies elucidating
the biochemical and molecular steps leading to cell
death. Although protection from drug-induced hearing
loss is covered later (see Chapter 20, Ototoxic Damage
to Hearing: Otoprotective Therapies), some of the
same literature is drawn upon here because much of
what is known about the mechanisms of cell death
comes from attempts to prevent it.
STRUCTURE AND ACTIVITY OF
AMINOGLYCOSIDES
Aminoglycoside antibiotics are valued for their
bactericidal properties, which are the result of a com-
plex series of events starting at the cell membrane and
culminating in the inhibition of bacterial protein syn-
thesis. They are produced by different strains of soil
actinomycetes: Streptomyces, which produce aminogly-
cosides classified by the suffix -mycin, and by Micro-
monospora, which produce aminoglycosides identified
by the suffix -micin. Various other drugs carry the
same suffixes, although they are structurally and phar-
macologically unrelated to aminoglycoside antibiotics,
for example, the antineoplastic drug bleomycin or the
macrolide antibiotic erythromycin. Within the amino-
glycoside group, however, the individual drugs, from
the first-discovered streptomycin to dihydrostrepto-
mycin, neomycin, tobramycin, kanamycin, gentamicin,
and their semisynthetic derivatives, such as netilmicin
and amikacin, all share common properties. They have
a molecular weight of approximately 300 to 600 daltons
and are composed of ring structures, primarily six-
membered saturated cyclitol rings and five- or six-
membered sugar rings that are linked via glycosidic
bonds. All aminoglycosides carry hydroxyl and amino
groups, giving them their basic character and water
solubility. Because of the similarity in their chemical
structures and behaviors, results obtained for one
aminoglycoside can often be extrapolated to the entire
class of these drugs. Although there are exceptions to
this rule, evidence suggests that the mechanisms of oto-
toxicity discussed here are shared by all aminoglycoside
antibiotics.
DEFINITION OF OTOTOXICITY
When considering molecular mechanisms of ototoxic-
ity, bear in mind that aminoglycoside antibiotics have
a multitude of effects on cells of the auditory (and
vestibular) system as well as on cells in other tissues of
the body. Some of these actions lead to only a tempo-
rary impairment of auditory function (at least in exper-
imental animals) and therefore should not be strictly
considered ototoxic. In particular, the propensity of
aminoglycoside antibiotics to displace calcium from its
binding sites and to block calcium channels renders any
physiological event relying on calcium susceptible to
these drugs. Examples are depression of the micro-
phonic output of the lateral line by streptomycin3 or
depression of the cochlear microphonics,4 both of
which are transient and easily reversed by applying
solutions of high K+ or high Ca++ concentrations. Like-
wise, aminoglycosides can block transduction channels
of stereocilia, although this action does not directly
lead to hair cell death.5 An acute phase of aminoglyco-
side intoxication is also seen in the dendrites beneath
the inner hair cells (IHCs), which swell in response to
aminoglycoside treatment.6 The strict definition of
94 Systemic Toxicity
ototoxicity is that of a permanent auditory threshold
shift as a result of the irrevocable loss of outer hair cells
(OHCs) and, to some degree, IHCs as well.
Regardless of the specific aminoglycoside used or
the species of animal studied, ototoxicity progresses
from the high frequencies to the low frequencies, cor-
responding to a loss of hair cells from the base of the
cochlea to the apex. Within this base-to-apex gradient,
the OHCs seem to be most vulnerable to an amino-
glycoside attack, whereas IHCs succumb much later in
treatment or at higher doses of the drug.
PHARMACOKINETICS OF
AMINOGLYCOSIDE ANTIBIOTICS
An obvious prerequisite to death from aminoglycoside
toxicity is the uptake of the drug into the cells. Amino-
glycoside antibiotics enter the inner ear rapidly follow-
ing parenteral administration. The drugs can be found
in the inner ear within minutes and may reach a plateau
as soon as 30 minutes to 3 hours following administra-
tion.7 Much has been said about an accumulation of
aminoglycosides in inner ear fluids being responsible
for the selective death of auditory structures. This,
however, is not the case since aminoglycoside antibi-
otics are present in the fluids (perilymph and
endolymph) and the tissues of the inner ear at signifi-
cantly lower levels than are reached in the serum.
Aminoglycosides, however, persist in inner ear tissues
long after the drug has essentially been cleared from the
bloodstream. Although the half-life of most amino-
glycosides in serum is around 3 to 5 hours, the drugs
may persist in inner ear fluids for months after treat-
ment, which may account for the delayed hair cell death
that can occur after cessation of treatment.7,8
Following systemic application, aminoglycosides
can be detected mostly in hair cells and to a lesser extent
in supporting cells of the basilar membrane and the tis-
sues of the lateral wall.912 In hair cells, the aminoglyco-
sides appear to be initially transported into lysosomal
structures near the apical surface, compatible with a
receptor-mediated endocytotic internalization.13,14 The
precise nature of the aminoglycoside transporter in the
inner ear is unresolved. In the kidney, the glycoprotein
and mediator of endocytotic uptake, megalin, is
strongly supported as an aminoglycoside transporter in
proximal tubules. 15 Megalin is also present in the
epithelia of the cochlear duct, including lateral wall tis-
sues, but has been claimed to be absent from OHCs, the
primary targets of aminoglycoside toxicity.16,17
An alternative component of the cell membrane
that may be involved in aminoglycoside uptake is the
unconventional myosin-VII-A. Explants from the inner
ear of mutant mice lacking this myosin do not take up
aminoglycosides and are protected from their toxic-
ity.18 A polyamine-like uptake mechanism has also been
discussed.19
More precise information on uptake mechanisms
would be valuable in designing therapeutic protection,
assuming that exclusion from the cell interior would
prevent the toxic actions. However, considering the cel-
lular mechanisms of cell death, uptake is a necessary, but
not sufficient, factor for aminoglycoside ototoxicity.
Several lines of evidence argue against the correla-
tion of uptake (presence in cells) and toxicity. First, the
uptake is widespread in the cochlea, whereas the
destruction of hair cells by aminoglycoside antibiotics
is rather selective. Second, the concentrations reached
in the inner ear by different aminoglycosides do not
correlate with the magnitude of their ototoxic poten-
tial.20 Third, primarily vestibulotoxic or cochleotoxic
drugs do not show a preferential uptake into the struc-
tures that they are targeting for destruction.21 Interest-
ingly, even in OHCs, the presence of the drug alone will
not lead to an immediate functional impairment or to
morphological changes. Although the drugs reach the
inner ear within minutes of their systemic application,
there is a profound time lag of several days before the
death of hair cells.14,22 This time lag points to a complex
series of intracellular reactions that slowly reach and
surpass a toxic threshold.
CELL DEATH
Apoptosis and necrosis are two classically accepted
pathways of cell death. More recent literature, however,
includes subtle distinctions from these paradigms, such
as apoptosis-like cell death and necrosis-like cell death,
which can be distinguished by morphological features
and the associated biochemical reactions. 23 These
subtleties have not yet been addressed in aminoglyco-
side ototoxicity. Apoptosis is most often mentioned as
the prevailing (or even only) form of cell death. It is the
irreversible end stage of programmed cell death that
removes damaged cells without producing inflamma-
tion. Consistent with such a way of death, the affected
hair cells are removed from the organ of Corti and
replaced by expansion of their supporting cells, which
form a scar-like closure of the reticula lamina.24 How-
ever, some caution is necessary in interpreting these
results. Most of the studies on mechanisms of cell death
have been carried out in model systems such as vestibu-
lar or organ of Corti explants. It remains an open ques-
tion whether the acute exposure of cells in tissue or
organ culture to the drugs is indeed a precise reflection
of the slow cell death that occurs in chronic systemic
application of aminoglycosides. Apoptosis indeed
seems to be a major pathway of cell death in tissue cul-
ture, reported for both cochlear and vestibular hair
cells and based on morphological features of apoptosis,
such as condensed and marginated chromatin.2527
Necrotic events are mentioned not nearly as much in
the context of aminoglycoside toxicity. However, in
vivo studies that report apoptosis also concede an
 Mechanisms for Aminoglycoside Ototoxicity: Basic Science Research
undetermined amount of necrotic events taking place
in the cochlea.28,29 It seems most likely that different
conditions of intoxication (eg, in vitro vs in vivo, low
vs high dose of drugs) will have a different balance of
apoptotic and necrotic pathways.
Since apoptosis is a controlled event of cell disin-
tegration, it proceeds via defined pathways. These path-
ways are triggered by an initial noxious stimulus that
activates signaling cascades of sequential activation of
protein kinases, which ultimately activate transcription
factors that then will translocate into the nucleus.
When attached to their binding regions on deoxy-
ribonucleic acid (DNA), these transcription factors will
initiate the expression of specific genes. In apoptotic
pathways, the resulting proteins and enzymes will con-
tribute to the demise of the cell. Conversely, signaling
pathways exist for restitution of homeostasis and rescue
of cells from such noxious stimuli.
A well-characterized pathway of apoptosis proceeds
via the activation of c-Jun N-terminal protein kinase
(JNK), a member of the mitogen-activated protein
kinase family that is involved in the phosphorylation of
precursors to transcription factors. The activation of
JNK can be strongly inferred from studies that show that
inhibitors of this pathway will rescue hair cells from the
toxic effects of aminoglycoside antibiotics.30 Although
apoptotic pathways are well defined, there are complex
overlapping and interconnected pathways that eventu-
ally determine cell fate. One of the committing steps in
another sequence to cell death is the activation of cas-
pases, specific proteases. Caspases are involved in amino-
glycoside-induced cell death since inhibitors of caspase
activation protect from the toxic effects of the drugs.31
Although events such as the activation of JNK or
caspases are essential to apoptotic cell death, these
events are in turn regulated by upstream pathways that
respond to the initial noxious stimulus (Figure 9-1).
So-called small guanosine triphosphatases (GTPases)
are common activators of JNK, and it appears that the
subfamily of Rho-GTPases plays a role in aminoglyco-
side toxicity signaling. When inhibitors of Rho-family
GTPases are added to tissue cultures treated with gen-
tamicin, these cultures are protected from ototoxicity,
implying this family of GTPases as an upstream activa-
tor consistent with the existence of JNK signaling path-
ways.32 Likewise, permeability changes in mitochondria
precede the activation of caspases, and such perme-
ability transitions have been shown in response to
aminoglycosides in cultured cells.33
Consideration of signaling pathways leads to the
question: what are the initial noxious events that trig-
ger these apoptotic pathways? Compelling evidence
leads us to believe that free radicalsreactive oxygen
species (ROS) and possibly reactive nitrogen species
(RNS)are the ultimate triggers of aminoglycoside-
induced cell death.
95
ROS
Change in redox status
GSH depletion
Activation of signaling pathways
Mitochondria JNK
Caspases Gene transcription
APOPTOSIS
[ NECROSIS ]
Figure 9-1 Putative cell death pathways in aminoglycoside
ototoxicity. The noxious formation of reactive oxygen species
(ROS; free radicals) exhausts the cellular antioxidant defenses
and changes the redox status of the cell, most notably the
glutathione (GSH) balance. This triggers the activation of
signaling pathways (eg, Rho guanosine triphosphatases) that
set an apoptotic machinery in motion. Represented are the
pathways involving mitochondria and caspase activation and
c-Jun N-terminal protein kinase (JNK) leading to gene tran-
scription. The stippled arrow is a reminder that additional
pathways (for example, to necrosis) exist and that pathways
frequently cross-talk and influence each others activity.
FREE RADICAL FORMATION AS THE CAUSE OF
CELL DEATH
Free radicals such as superoxide, hydroxyl, and nitric
oxide are naturally produced compounds that distin-
guish themselves from other cell metabolites by the
presence of an unpaired electron in their structure.
This unpaired electron renders them chemically reac-
tive, and in the worst-case scenario, free radicals can
attack cell constituents ranging from cell membranes to
proteins to DNA, thereby causing irreparable damage
and, ultimately, cell death. Conversely, ROS and RNS
serve distinct and important roles in the physiologic
control of cell function.34 They function as intermedi-
ates in synthetic reactions (eg, for prostaglandins),
signaling molecules in homeostatic reactions to balance
cellular metabolism, or as second messengers like nitric
oxide. Their toxic effects are held in check by naturally
occurring antioxidants in the cell, notably by glu-
tathione, and by enzymes that inactivate free radicals
(or their proradicals) such as superoxide dismutase,
catalase, and glutathione peroxidase. If enhanced pro-
duction of free radicals by cellular overstimulation or
by drugs exceeds the capacity of the antioxidant system,
96 Systemic Toxicity
free radical damage can ensue. Oxidative stress as a
result of an excess of free radicals has been associated
with a variety of pathologic conditions, including
artheriosclerosis, inflammation, ultraviolet ray dam-
age, certain cancers, and even aging.
The suggestion that aminoglycoside antibiotics
produce free radicals was made relatively early based on
studies in renal mitochondria35 and in the inner ear.36
However, subsequent failure to link free radicals to
nephrotoxicity 37or to ototoxicity 38 laid this hypothesis
initially to rest. Only in recent years has evidence accu-
mulated both from in vivo and in vitro experiments to
clearly establish a causal relationship between free
radicals and ototoxicity. Discussions have centered on
ROS derived from superoxide and RNS derived from
nitric oxide.
NITRIC OXIDE IN AMINOGLYCOSIDE
OTOTOXICITY
Nitric oxide is a physiologically important second mes-
senger and neuromodulator but also the potential pre-
cursor of the highly destructive peroxynitrite radical.
The enzyme responsible for its synthesis, nitric oxide
synthase, can be activated by calcium influx through
N-methyl-D-aspartate (NMDA) receptors. Such recep-
tors are associated with the afferent system in the
cochlea, as they respond to glutamate, the neurotrans-
mitter at the IHC synapse. NMDA receptors, specifi-
cally those of the NR1A/NR2B type, are sensitive to
modulation and stimulation by polyamines such as
spermine. Aminoglycosides share some basic features
with polyamines, and polyamineaminoglycoside
interactions are well documented in many systems,
including the inner ear, where polyamines interfere
with aminoglycoside uptake and inhibit cochlear
ornithine decarboxylase. 19,39 Overstimulation of
NMDA receptors and the resulting excitotoxicity has
been postulated as a mechanism of aminoglycoside
ototoxicity.40 Although this is an interesting concept,
the original study is difficult to interpret because of
confounding factors. The hypothesis of a polyamine-
like action responsible for aminoglycoside ototoxicity
was supported by the observation that NMDA receptor
antagonists prevented aminoglycoside ototoxicity in
vivo. The design of the study, however, did not control
for the vehicle used for the drugs, dimethyl sulfoxide,
which itself is a radical scavenger. The vehicle alone
subsequently was shown to convey protection against
aminoglycoside-induced auditory damage.41 Another
difficulty in interpreting this hypothesis is the fact that
excitotoxicity manifests itself as a transient swelling of
afferent nerve endings but does not affect OHCs.42
Swollen afferent dendrites beneath the IHCs were
indeed observed following administration of the
aminoglycoside amikacin,6 but the authors considered
this pathology to be an acute phase of insult whereas
the chronic phase resulted in complete loss of OHCs.
The NMDA receptor antagonists MK-801 gave only
inefficient protection. Further, when the effects of a
series of aminoglycosides on NR1A/NR2B receptors
were probed, no direct relationship emerged between
the potency of an aminoglycoside and its ototoxicity.43
Thus, although nitric oxide production and swelling of
dendrites may be part of the overall pattern of amino-
glycoside ototoxicity, they probably cannot be consid-
ered a direct cause of hair cell loss.
ROS IN OTOTOXICITY
Following the standoff in the early 1980s on the ques-
tion of free radicals and ototoxicity,36,38 evidence from
studies in vitro, in cell culture, and in vivo began to con-
verge to the notion that ROS are causally related to
aminoglycoside-induced damage. Manipulations of the
endogenous cochlear antioxidant system were able to
change the extent of aminoglycoside-induced damage.
Depletion of glutathione in inner ear tissues enhanced,
and restoration of glutathione levels attenuated amino-
glycoside-induced ototoxicity in vivo.4446 Complement-
ing these indirect approaches were demonstrations that
free radicals emerged in inner ear explants following
the addition of aminoglycosides in explants of the
inner ear.47,48
One of the difficulties in accepting the involve-
ment of free radicals in the toxic actions of aminogly-
cosides was the absence of a rational explanation of
how these drugs can catalyze the formation of ROS.
However, in vitro experiments soon showed that
aminoglycosides can form complexes with transition
metals (with iron and copper in particular). These com-
plexes are redox active (ie, can form free radicals49,50) in
a reaction in which molecular oxygen is reduced to the
superoxide radical at the expense of an electron donor
such as arachidonic acid.51 Following the generation of
superoxide, iron-catalyzed Fenton-type reactions can
then promote the formation of other, more aggressive
free radicals such as hydroxyls. The ability to catalyze
free radical generation in this manner is shared by a
variety of aminoglycoside antibiotics.52
Products of lipid peroxidation can be found in the
inner ear following aminoglycoside treatment,53 which
is compatible with the idea that arachidonic acid or a
homologous polyunsaturated fatty acid participates in
the reduction of oxygen to superoxide. Arachidonic
acid, as an electron donor, also links these new observa-
tions to earlier findings that aminoglycoside antibiotics
have a high binding affinity for polyphosphoinositide
lipids, which correlates extremely well with their oto-
toxic potential. 54,55 Polyphosphoinositides contain
arachidonic acid as the esterified lipid in their 2-posi-
tion. The ability of aminoglycosides to bind both a tran-
sition metal and a lipid would bring the redox catalyst
iron and the electron donor arachidonate in close
 Mechanisms for Aminoglycoside Ototoxicity: Basic Science Research
O2
PUFA e- Aminoglycoside
[Fe 2+/3+]
lipid peroxides
NO
superoxide O2
SOD
ONOO -
H2O + 1/2 O2 H2 O2 peroxynitrite
Fenton reaction
[Fe2+]
hydroxyl radical OH
Figure 9-2 Formation of free radicals by aminoglycoside
antibiotics. The reduction of molecular oxygen to the super-
oxide radical is catalyzed by aminoglycosides and iron. The
reducing electrons are derived from polyunsaturated fatty
acids (PUFA; eg, arachidonic acid) yielding lipid peroxides,
which can engage in a separate branch of free radical reac-
tions. The slowly reacting superoxide radical is effectively dis-
mutated to hydrogen peroxide by superoxide dismutase
(SOD). Hydrogen peroxide, a proradical, can be inactivated
by catalase to water and oxygen. However, nonenzymatic,
iron-catalyzed Fenton reactions compete with catalase and
can generate the aggressive hydroxyl radicals. If nitric oxide
(NO) were produced by aminoglycosides it could react with
excess superoxide to the very destructive peroxynitrite radi-
cal. Note that reactions are not written with all steps or in full
stoichiometry.
proximity in a ternary complex, enabling an efficient
electron transfer to oxygen and formation of super-
oxide (Figure 9-2).
These or very similar mechanisms must also oper-
ate in vivo. Transgenic mice overexpressing superoxide
dismutase (SOD), the enzyme that inactivates super-
oxide, show significantly lower threshold shifts after
kanamycin treatment than do their nontransgenic lit-
termates with normal levels of SOD.56 Likewise, in
organotypic cultures from neonatal mice, the SOD
mimetic M40403 significantly protected against damage
induced by gentamicin.57 Conversely, in normal animals
the levels of antioxidant enzymes such as superoxide dis-
mutase, catalase, and glutathione peroxidase inversely
correlated with their hearing loss after amikacin treat-
ment.53 Adding persuasive evidence is the success of
antioxidant therapy, which has been a highly successful
interventional strategy against aminoglycoside ototoxi-
97
city. Antioxidants, when coadministered with amino-
glycoside antibiotics, will significantly attenuate the
expected functional and morphologic damage.58 This
protective effect is shared by a wide variety of iron chela-
tors, such as deferoxamine or dihydroxybenzoic acid, or
radical scavengers such as mannitol, methionine, or
lipoic acid.5962 The only common denominator of these
protective agents is their iron-chelating or antioxidant
capacity, strongly suggesting free radical formation as a
causative action in aminoglycoside ototoxicity. Most
intriguing, from a therapeutic point of view, is the find-
ing that salicylic acid is an effective protectant. Salicylate
is the active ingredient of aspirin.63
In line with apoptotic and necrotic cell death in
aminoglycoside ototoxicity is the fact that free radicals
are powerful triggers of cell death. Further, a free radi-
calbased mechanism could even explain the preferen-
tial destruction of OHCs and the base-to-apex gradient
in the progression of hair cell damage. OHCs are
intrinsically more sensitive to damage by free radicals
than are IHCs and supporting cells, and along the
cochlear spiral, basal outer hair cells are more sensitive
than apical cells.64
Finally, we need to consider that aminoglycosides
are both potentially cochleotoxic and vestibulotoxic,
mostly against type 1 vestibular hair cells. Less atten-
tion has been paid to the potential underlying mecha-
nisms in the vestibular system than in the cochlea. We
can, however, safely assume that similar mechanisms of
toxicity are operating in both parts of the inner ear.
First, the mechanism of free radical formation by
aminoglycosides has been established in vitro and is
therefore independent of a specific tissue. Second, the
protective antioxidant therapies that prevent destruc-
tion of cochlear hair cells also prevent the destruction
of vestibular hair cells.65
SUMMARY
Despite the discovery of aminoglycosides as a distinct
antimicrobial class over 60 years ago, basic science
research in aminoglycoside toxicity has only recently
allowed us to formulate a rational hypothesis that can
explain hair cell death induced by an ototoxic agent.
Because of similarities in their chemical struc-
tures and behaviors, results obtained from one
aminoglycoside can usually be extrapolated to
the entire group of these drugs. Overall, the
phenomenon of aminoglycoside cochleotoxicity
has been better studied than aminoglycoside
vestibulotoxicity.
Aminoglycosides can cause both temporary and
permanent impairment of cellular function.
Temporary impairment is thought to occur from
the competitive blockade of calcium channels
required for the generation of receptor or action
98 Systemic Toxicity
potentials. Permanent impairment occurs when
their uptake into the hair cells ultimately results
in cell death from apoptosis and possibly cellular
necrosis mechanisms.
The uptake of aminoglycosides into the hair cell
is a necessary but not in itself a sufficient cause
for ototoxicity. Recent basic science research has
supported the formation of free radicals
ROSderived from iron-aminoglycoside com-
plexes in the cell as the ultimate triggers of
aminoglycoside-induced cellular death. Free
radical formation has been used convincingly to
explain the preferential toxicity for OHCs versus
IHCs and the base-to-apex gradient progression
of hair cell damage in cochlear toxicity.
Future treatments using antioxidants may have
a role in preventing cellular injury and death
from aminoglycoside toxicity.
ACKNOWLEDGMENTS
This research is supported by grant DC03685 from the
National Institute of Health. The author thanks
Ms Andra Talaska for valuable comments on the
manuscript.
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 CHAPTER 10
Macrolides
Andrew R. Scott, BM, BS, MPhil, FRCS(ORL-HNS), and John A. Rutka, MD, FRCSC
Erythromycin is a macrolide antibiotic discovered in
1952 and used widely to treat a variety of bacterial
infections, including upper and lower respiratory tract
infections. 1 Ototoxicity has been reported with
erythromycin and more recently with some of the
newer macrolide antibiotics, including azithromycin
and clarithromycin.
ERYTHROMYCIN
Erythromycin obtained approval from the US Food
and Drug Administration (FDA) in June 1964. Its
mechanism of action is to inhibit protein synthesis in
sensitive bacteria by reversibly binding to 50S ribo-
somal subunits. Nucleic acid synthesis is not affected.2
The first cases of erythromycin ototoxicity were
reported in the literature by Mintz and colleagues in
1973.3 They described two women treated for pneu-
monia with intravenous erythromycin who developed
a noticeable hearing loss. Audiometry revealed a 50 to
55 dB sensorineural hearing loss (SNHL). Erythro-
mycin was discontinued, and the patients were
switched to a cephalosporin antibiotic. In both cases
the hearing returned to normal. A further case of
reversible hearing loss in a woman treated with
erythromycin was reported by Eckman and colleagues
in 1975.4 In their case the erythromycin had been
administered orally; again a normal audiogram was
obtained on cessation of treatment. No audiogram was
obtained during the period of perceived hearing loss.
Further reports of reversible hearing loss soon fol-
lowed. Karmody and Weinstein reported three cases.5
However, in one patient, the recovery was probably
incomplete.6 Quinan and McCabe reported two cases,
one of whom also complained of vertigo in addition to
tinnitus and hearing loss.7 This report appears to be the
first to document a possible vestibulotoxic as well as a
cochleotoxic effect. Van Marion and colleagues
reported two further cases of reversible hearing loss,
and Lornoy and Steyaert reported one patient who also
experienced vestibular symptoms.8,9 Although it had
been pointed out that the ototoxic effects of erythro-
mycin could not necessarily be assumed to be reversible
on cessation of therapy, this was the general impression
that emerged from these early case reports.7
Findings of irreversible ototoxicity were first docu-
mented by Levin and Behrenth in 1986.10 Their patient
was a 54-year-old woman who had experienced hearing
loss and tinnitus after four doses of intravenous eryth-
romycin (1 g every 6 hours). An audiogram taken
24 hours later demonstrated a sloping SNHL, worse in
the high frequencies down to 65 dB at 8 kHz. After
1 year the audiogram had slightly improved to 45 dB at
8 kHz. Her tinnitus persisted. There was, however, as
with many of these case reports, no pretreatment audio-
gram available for comparison, making it truly difficult
to document any degree of reversibility from eryth-
romycin toxicity. Dylewski also reported a case of irre-
versible hearing loss attributed to erythromycin. 11
Audiograms were performed at 5 and 23 weeks with no
improvement. Further case reports of erythromycin
ototoxicity without other obvious contributory factors
have continued to be reported.1225
PREDISPOSING FACTORS FOR ERYTHROMYCIN
OTOTOXICITY
Reports of erythromycin ototoxicity with associated or
possible predisposing factors have also emerged. In
1979 Mery and Kanfer described ototoxicity in three
patients with renal impairment.26 Audiograms were not
provided, but a symmetrical high-frequency SNHL was
described. Thompson and colleagues reported a case of
reversible SNHL in an 18-year-old woman with severe
renal failure.27 Taylor and colleagues reported on two
patients who received erythromycin while on peri-
toneal dialysis. 28 In addition to hearing loss, one
patient developed diplopia, and the other slurred
speech and confusion. These symptoms recovered on
cessation of erythromycin therapy and raised the ques-
tion of a central nervous system effect of eryth-
romycin.6 Further cases of erythromycin ototoxicity in
102 Systemic Toxicity
renal failure have been reported.2931 Kanfer and col-
leagues carried out a study on the pharmacokinetics of
erythromycin in renal failure.32 They compared chronic
renal failure patients with normal subjects receiving a
single dose of 1 g of erythromycin daily. Although the
number of study participants was small, there was a
trend toward higher maximum serum concentrations
and increased overall bioavailability of erythromycin in
the renal failure patients, which might predispose them
to the toxic effects.
Hepatic impairment and concomitant use of other
ototoxic drugs have also been suggested to increase the
potential for erythromycin ototoxicity. Umstead and
Neuman reported two cases of reversible hearing loss in
cancer patients with hepatic impairment who received
erythromycin.33 Both were receiving other potentially
ototoxic agents and both also had acute psychotic reac-
tions. Although there are clearly several confounding
factors, the hearing loss and psychoses appeared tem-
porally related to the erythromycin treatment. Wallach
and colleagues reported a case of erythromycin-
induced reversible ototoxicity in a patient who had suf-
fered cisplatin-induced high-frequency hearing loss
9 months previously.34
Another group of patients who may have increased
susceptibility to erythromycin toxicity are transplant
recipients. Vasquez and colleagues performed a retro-
spective case note review of renal transplant patients
treated with erythromycin for pneumonia. 35 They
found hearing loss in 11 (32%) of 34 treatment courses
of erythromycin. They also demonstrated a dose-related
toxic effect. Hearing loss occurred more frequently in
patients who received the higher dose of 4 g daily com-
pared with those who received 2 g daily (53% vs 16%).
Hearing loss was also significantly more common in
those patients receiving longer courses (9.6 4.7 days)
of erythromycin compared with those treated with a
shorter course (5.7 3.6 days). Three cases of ery-
thromycin ototoxicity have also been reported in liver
transplant recipients.36
RISK FACTORS FOR ERYTHROMYCIN
OTOTOXICITY
Several papers have attempted to analyze risk factors for
erythromycin ototoxicity. Hugues and colleagues
reported on 30 patients who received erythromycin and
in whom audiograms had been performed before and
after treatment.37 Age and concurrent medical prob-
lems were recorded. Of interest, no hearing loss was
found in any patient, including those with renal or
hepatic problems. Swanson and colleagues performed a
prospective case-control study in patients treated for
community-acquired pneumonia.38 Thirty patients
receiving erythromycin were compared with 15 patients
receiving other antibiotics as the control group.
Sequential audiograms were recorded by an audiologist
blinded to the treatment received. Serum erythromycin
concentrations were measured for patients receiving
erythromycin. They found evidence of ototoxicity in 5
of the 30 patients in the erythromycin group compared
with none in the control group. Ototoxicity occurred
only in patients receiving 4 g of erythromycin daily and
not in those receiving 2 g daily. Ototoxicity was
reversible and related to serum erythromycin concen-
tration. The available evidence suggests that erythro-
mycin ototoxicity is dose dependent and that patients
with renal impairment or who have had a transplant are
at increased risk. Hepatic dysfunction, advanced age,
and female sex may also be risk factors (see also case
reviews by Haydon and colleagues, Brummett, and
Sacristan and colleagues).6,16,25
Azithromycin
Azithromycin is a new-generation macrolide antibiotic
that is often used for treating infections related to
human immunodeficiency virus (HIV), including
those caused by Mycobacterium avium complex
(MAC). Azithromycin obtained FDA approval in
November 1991. It has a similar mode of action to
erythromycin, namely to bind to the bacterial 50S ribo-
somal subunit and inhibit protein synthesis.2
Wallace and colleagues reported three cases of oto-
toxicity in 21 HIV patients with MAC infections receiv-
ing prolonged courses of 500 mg of azithromycin
daily.39 Symptoms occurred at 4 to 12 weeks into treat-
ment and resolved within 2 to 4 weeks after cessation
of therapy. Tseng and colleagues identified eight cases
of potential azithromycin ototoxicity in a retrospective
review of 46 patients from their HIV clinic who had
received azithromycin (600 mg daily for a mean of
7.6 weeks). 40 Onset of ototoxicity followed 2 to
20 weeks of treatment and recovery occurred 2 to
11 weeks after discontinuing the azithromycin. Lo and
colleagues reported a further case of hearing loss in a
35-year-old man with HIV and Mycobacterium infec-
tion treated with azithromycin.41 There were many pos-
sible confounding or contributory factors in these
reports, including renal disease, hepatic disease, and
concurrent drug therapy, and audiograms were not
performed on all patients. However, these papers sug-
gest a potential for ototoxicity when azithromycin is
used at these higher doses for prolonged periods in this
population of patients.
There have also been reports of hearing loss in
patients without HIV infection following azithro-
mycin. Brown and colleagues studied adverse events in
39 elderly patients treated with 600 mg of azithromycin
daily for mycobacterial lung disease.42 Among other
effects, 10 (26%) of the patients developed hearing loss
that was confirmed on baseline and repeat audiology.
When the daily dose was halved to 300 mg in these
patients, the adverse effects were reported to resolve.

Bizjak and colleagues described a case of complete
deafness in a 47-year-old woman following an 8-day
course of intravenous azithromycin for community-
acquired pneumonia.43 They cautioned that intra-
venous dosing regimens can result in much higher
serum concentrations of azithromycin and untoward
toxic effects.
Ress and Gross reported a case of irreversible SNHL
in a 39-year-old woman.44 She was prescribed a 5-day
course of azithromycin (500 mg orally for 1 day fol-
lowed by 250 mg orally for 4 days) for a urinary tract
infection. Her medical history was otherwise unre-
markable, and she was not taking other medications.
She experienced bilateral tinnitus after the first dose,
which worsened after the second dose and was accom-
panied at that stage by a subjective hearing loss. The
azithromycin was subsequently stopped. Audiometry
demonstrated an asymmetrical high-frequency SNHL
that had not improved on retesting 12 months later. No
pretreatment audiogram was available. Magnetic reso-
nance imaging (MRI) was normal. Mamikoglu and
Mamikoglu replied to this paper with a letter to the edi-
tor in which they described two further cases of possible
azithromycin ototoxicity occurring after short-term
low-dose therapy in nonHIV-infected patients.45 The
first patient developed a 70 dB loss in one ear after 3 days
of 500 mg (once daily) of azithromycin. Hearing
improved to 30 dB after 5 days in conjunction with
steroid and antiviral therapy. Their second patient
received treatment for an acute otitis media with a 5-day
course of azithromycin (500 mg on day 1 followed by
250 mg daily for 4 days) when she developed tinnitus in
the affected ear. Audiometry reportedly demonstrated a
mixed (conductive and sensorineural) hearing loss with
a mild to moderate sensorineural component as well as
a 10 dB air-bone gap.
Clearly it is difficult to demonstrate cause and
effect in all of these cases, especially when there are con-
founding factors including local pathology in the
affected ear and no pretreatment audiometry. These
cases raise concerns of azithromycin ototoxicity at lower
doses and after shorter treatment durations in other-
wise healthy individuals.
Clarithromycin
Clarithromycin has a broad spectrum of activity against
aerobic and anaerobic gram-positive and gram-
negative bacteria and in particular most MAC microor-
ganisms. It obtained FDA approval in October 1991 and
has a similar mode of action to the other macrolides.
Kolkman and colleagues in 2002 published the first
case report to demonstrate ototoxicity as a result of cla-
rithromycin.46 They described a 76-year-old man who
developed hearing loss after 4 days of high-dose clarith-
romycin therapy for atypical pulmonary tuberculosis.
The hearing loss improved subjectively on cessation of
Macrolides 103
clarithromycin but worsened again on reexposure. The
dose was halved, and the hearing improved.
There were also earlier studies suggesting a possible
link between clarithromycin and hearing loss. In a study
by Fernandez-Martin examining the treatment of
Toxoplasma-associated encephalitis in patients with
acquired immune deficiency syndrome (AIDS), they
reported hearing loss in 2 of 13 patients. 47 Their
patients were treated with a combination of clarithro-
mycin (2 g daily) and pyrimethamine (75 mg daily) for
6 weeks. The two patients developed hearing loss
2 weeks into treatment, which was confirmed audio-
metrically. Another study looked at the efficacy of
clarithromycin, either alone or in combination, for
treating Mycobacterium-associated lung disease in 45
HIV-negative patients.48 This study identified 12
patients with hearing abnormalities pretreatment
(although not all of the 45 patients were tested). Four
of these described worsening hearing loss during treat-
ment. The losses were not detailed further. None of the
patients reported losses severe enough to require their
treatment to be stopped. In a further study looking at
the treatment of Mycobacterium lung disease in HIV-
negative patients, three cases of ototoxicity were
reported in 30 patients receiving a combination of cla-
rithromycin (0.752 g daily), minocycline (200 mg
daily), and clofazimine (100 mg daily).49 Although there
are obviously confounding factors, such as concurrent
drug therapy and illness, these studies nevertheless alert
to the possibility of clarithromycin ototoxicity.
Ketolides
Ketolides represent a new class of macrolide antibiotic.
They include telithromycin, which has been approved
for clinical use, and ABT-773, which is currently in
development. They share the same macrolactone ring
structure as erythromycin, from which they are derived
and to which they have a similar mode of action on the
50S ribosomal subunit, although they act in different
ways on the nucleotides. Although the main site of
ketolide and macrolide interaction is located at
nucleotides A2058 and A2059 in domain V, the
ketolides have an additional interaction at A752 in
domain II. This additional binding site means that the
ketolides have a higher affinity than do the macrolides
for forming interactions with the ribosomes and there-
fore should delay emergence of drug resistance.50 To
date, no cases of ototoxicity have been reported, includ-
ing the eight double-blind, randomized comparative
phase III trials (n = 2,045).50 Postmarketing surveil-
lance studies will ultimately determine if ototoxicity
occurs with this class of macrolide.
MECHANISMS OF ERYTHROMYCIN OTOTOXICITY
The mechanisms of erythromycin ototoxicity are not
fully understood. There is evidence for both central
104 Systemic Toxicity
and peripheral effects on the auditory pathways. In the
first animal study to look into this phenomenon Stupp
and colleagues in 1973 instilled a 0.1 mg solution of
erythromycin into the middle ear space of guinea pigs
three times in 1 day.51 The cochleas from the animals
were harvested, then examined. Sensory hair cell loss
was reported, especially in the lower turns. This finding
suggests a peripheral toxic effect, although the route of
administration is currently not applicable to humans.
Brummett and colleagues reported on their findings of
auditory brainstem response (ABR) changes with
erythromycin.6 In their first report, anesthetized guinea
pigs were administered erythromycin (125 mg/kg/h)
and ABR was recorded to an 8 kHz tone pulse stimulus.
The first effect was an increase in latency of the fourth
wave, followed in sequence by the other waves. When
the erythromycin infusion was stopped, the ABR
returned to baseline in the reverse order. In their sec-
ond report ABRs were recorded in patients receiving
erythromycin. An increased latency in wave V was
noted, which caused the authors to speculate that
erythromycin ototoxicity may be caused by a central
effect on the brainstem auditory pathways. Evidence for
central nervous system effects of erythromycin is also
supported by reports of acute psychiatric reactions to
the drug, as mentioned previously.33,52 Conversely, in
another report two patients who experienced eryth-
romycin-induced hearing loss had abnormalities of
waves I to III recorded on the ABR. The ABR returned
to normal after erythromycin was stopped. Nonetheless
these wave abnormalities would suggest a more periph-
eral effect.24
Further evidence for a direct toxic effect on inner
ear structures has come from other animal studies. Liu
and colleagues employed electrophysiological tech-
niques in vitro to study the effects of erythromycin per-
fusion on each side of cells from the stria vascularis and
also on each side of the homologous vestibular dark
cells.53 They found reversible changes when the solution
was applied to the basolateral cell surface in both mod-
els. They concluded that erythromycin has an inhibitory
effect on ion transport by the stria vascularis and
vestibular dark cells. Kobayashi and colleagues studied
the effects of intravenous administration of erythro-
mycin (100 and 150 mg/kg) on guinea pigs cochlear
potentials.54 They recorded a transient reduction in
endocochlear potential and cochlear microphonics at
the first turn of the cochlea. Uzun and colleagues mea-
sured transiently evoked otoacoustic emissions from
guinea pigs in their study.55 The effects of erythromycin
(125 mg/kg intravenously), azithromycin (45 mg/kg
orally,) and clarithromycin (75 mg/kg intravenously)
were recorded. Azithromycin and clarithromycin caused
a reversible reduction in the emission response,
although, interestingly erythromycin did not.
The mechanism of macrolide ototoxicity is not
determined, but certainly there is evidence from ani-
mal models that macrolides have direct effects on the
inner ear as well as effects on higher central auditory
pathways.
SUMMARY
Ototoxicity from erythromycin and class-related
macrolides has usually been associated with
reversible SNHL. Nevertheless, cases of irre-
versible SNHL have been reported.
Predisposing factors for ototoxicity appear to
include having renal failure or hepatic impair-
ment, being a transplant recipient, and using
concomitant ototoxic agents. Risk factors
include high-dose prolonged macrolide therapy.
Little is known about the effects of macrolides
on the vestibular system.
Animal models of erythromycin ototoxicity have
suggested that erythromycin impairs ion trans-
portation at the level of the stria vascularis and
may also affect higher central auditory pathways.
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tycin, a new antibiotic. Antibiot Chemother 1952;
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3. Mintz U, Amir J, Pinkhas J, deVries A. Transient
perceptive deafness due to erythromycin lacto-
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4. Eckman MR, Johnson T, Riess R. Partial deafness
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6. Karmody CS, Weinstein L. Reversible sensori-
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7. Quinnan GV Jr, McCabe WR. Ototoxicity of
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8. van Marion WF, van der Meer JW, Kalff MW,
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12. Meyer RD, Edelstein PH, Kirby BD, et al. Legion-
naires disease: unusual clinical and laboratory
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14. Miller SM. Erythromycin ototoxicity. Med J Aust
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17. Rydberg J. Reversible hearing loss and eryth-
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25860.
19. Koegel L. Ototoxicity: a contemporary review of
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26. Mery JP, Kanfer A. Ototoxicity of erythromycin in
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32. Kanfer A, Stamatakis G, Torlotin JC, et al. Changes
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33. Umstead GS, Neumann KH. Erythromycin oto-
toxicity and acute psychotic reaction in cancer
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34. Wallach PM, Love SR, Fiorica JV, et al. Eryth-
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Assoc 1992;79:8212.
35. Vasquez EM, Maddux MS, Sanchez J, Pollak R.
Clinically significant hearing loss in renal allograft
recipients treated with intravenous erythromycin.
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36. Moral A, Navasa M, Rimola A, et al. Erythromycin
ototoxicity in liver transplant patients. Transpl Int
1994;7:624.
37. Hugues FC, Laccourreye A, Lasserre MH, Toupet
M. Cochlear toxicity of erythromycin in elderly
patients. Therapie 1984;39:5914.
38. Swanson DJ, Sung RJ, Fine MJ, et al. Erythromycin
ototoxicity: prospective assessment with serum
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618.
39. Wallace MR, Miller LK, Nguyen MT, et al. Ototox-
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40. Tseng AL, Dolovich L, Salit IE. Azithromycin-
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41. Lo SH, Kotabe S, Mitsunaga L. Azithromycin-
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42. Brown BA, Griffith DE, Girard W, et al. Relation-
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43. Bizjak ED, Haug MT III, Schilz RJ, et al. Intra-
venous azithromycin-induced ototoxicity. Phar-
macotherapy 1999;19:2458.
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45. Mamikoglu B, Mamikoglu O. Irreversible sensori-
neural hearing loss as a result of azithromycin oto-
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Laryngol 2001;110:102.
106 Systemic Toxicity
46. Kolkman W, Grooneveld JH, Baur HJ, Verschuur
HP. Ototoxicity induced by clarithromycin. Ned
Tijdschr Geneeskd 2002;146:17435.
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with AIDS. Antimicrob Agents Chemother 1991;
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49. Roussel G, Iqual J. Clarithromycin with minocy-
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50. Zhanel GG, Walters M, Noreddin A, et al. The
ketolides: a critical review. Drugs 2002;62:1771804.
51. Stupp H, Kupper K, Lagler F, et al. Inner ear con-
centrations and ototoxicity of different antibiotics
in local and systemic application. Audiology
1973;12:35063.
52. Cohen IJ, Weitz R. Psychiatric complications with
erythromycin. Drug Intell Clin Pharm 1981;
15:3898.
53. Liu J, Marcus DC, Kobayashi T. Inhibitory effect of
erythromycin on ion transport by stria vascularis
and vestibular dark cells. Acta Otolaryngol 1996;
116:5725.
54. Kobayashi T, Rong Y, Chiba T, et al. Ototoxic effect
of erythromycin on cochlear potentials in the
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106(7 Pt 1):599603.
55. Uzun C, Koten M, Adali MK, et al. Reversible oto-
toxic effect of azithromycin and clarithromycin on
transiently evoked otoacoustic emissions in guinea
pigs. J Laryngol Otol 2001;115:6228.
 Topical Toxicity
CHAPTER 11
Middle Ear Effects of Ototopical Agents
Charles G. Wright, PhD, and Peter S. Roland, MD
Topical preparations containing antibiotics and anti-
inflammatory agents continue to be widely used for
prophylaxis and treatment of external and middle ear
infections. In addition to their primary ingredients,
these preparations typically contain various solvents,
penetrance enhancers, and preservatives that may have
undesirable side effects. When placed in the external ear
canal, topical preparations may enter the middle ear via
tympanostomy tubes or tympanic membrane (TM)
perforations, or they may be intentionally applied to
the middle ear during surgery. Under those conditions,
the constituents of otic drops can potentially cross the
round window membrane of the cochlea and adversely
affect the inner ear.
Although inner ear toxicity from agents used in
ototopical preparations has been the focus of many
studies in laboratory animals, the effects of those mate-
rials on tissues of the middle ear have received much
less attention. However, the work that has been com-
pleted to date indicates that some constituents of top-
ical ear drops may produce middle ear injury, especially
in cases in which the tympanic cavity is relatively free
of effusion or active infection. This chapter briefly
summarizes findings relating to antibiotics, steroids,
and various other ingredients of topical preparations
that have been investigated with specific regard to their
effects on the middle ear.
ANTIBIOTICS
One of the first publications to focus on the issue of
middle ear toxicity caused by constituents of topical
preparations was published in 1978 by Parker and
James.1 These investigators assessed the effects of vari-
ous antibiotics, antifungal compounds, anti-inflamma-
tory agents, and solvents on the middle and inner ears
of guinea pigs. The animals included in that study
received 0.1 mL intratympanic injections of the test
substances once daily for 5 days. Temporal bones were
taken for anatomical study 10 days after the last injec-
tion. Of the nine antibiotics that were tested, only three
(penicillin G, carbenicillin, and colimycin) were found
to be without significant inflammatory effects on the
guinea pig middle ear. The other antibiotics assessed in
the Parker and James study included gentamicin sul-
fate, chloramphenicol, bacitracin, and three tetracy-
cline compounds, all of which produced middle ear
inflammation, with chloramphenicol being the worst
offender. The only aminoglycoside in the group, gen-
tamicin, was reported to result in moderate mucosal
inflammation and a thick mucoid secretion in all ani-
mals that were tested. In a more recent study by Barlow
and colleagues, 0.3% gentamicin ophthalmic solution
produced mild mucosal thickening as well as inflam-
matory cell infiltration and thickening of the guinea pig
TM following middle ear instillation for 7 days.2
As noted above, Parker and James found penicillin
G and carbenicillin to be free of inflammatory effects
in the guinea pig middle ear.1 That feature, however, is
apparently not shared by other penicillin derivatives.
In a 1995 study by Jakob and colleagues it was found
that ticarcillin, either alone or in combination with the
-lactamase inhibitor clavulanic acid, resulted in dam-
age to cochlear tissues and provoked severe inflamma-
tory changes in the chinchilla middle ear after
administration of a single dose. 3 Those changes
included hemorrhage within the TM and middle ear
mucosa, fibrous adhesion formation, and the develop-
ment of serous effusion. Dramatic thickening (on the
order of 40) of the TM was observed, including
disruption of the integrity of the middle fibrous layer.
In several animals sacrificed 4 weeks after drug admin-
istration, hyperplastic epidermis on the lateral side of
the TM was found to penetrate the disrupted fibrous
layer and reach the medial surface to produce middle
ear cholesteatoma. As discussed below, propylene gly-
col is also capable of producing the rather specific
structural alterations of the TM necessary to permit
migration of epidermis through the intact TM. To our
knowledge, ticarcillin is the only antibiotic studied to
date that appears to affect the TM in such a way as to
108 Topical Toxicity
Figure 11-1 Histologic cross sections showing alterations of
the chinchilla tympanic membrane and middle ear mucosa
1 week after application of a topical preparation containing
10% sulfacetamide. A, Thickening of the tympanic mem-
brane with hyperplasia of its epidermal (Ep) and mucosal
(Mc) layers. The highly active epidermis is producing large
amounts of keratin (Kr) on the lateral surface. FL = fibrous
layer. (Toluidine blue stain; 400 original magnification.)
B, Inflamed middle ear mucosa. Several widely dilated blood
vessels are present in the thickened subepithelial tissue; one
of these vessels is indicated by V. Acute inflammatory cells
(IC) are seen lying immediately over the mucosa. Bn = bony
wall of middle ear; MC = middle ear cavity. (Hematoxylin
and eosin stain; 100 original magnification.) Adapted from
Brown OE et al.4
stimulate cholesteatoma formation in experimental
animals.
Over the last two decades, various broad-spectrum
antibiotics have been tested in laboratory animals in an
effort to identify antimicrobials that might be free of
ototoxicity and also be effective in the management of
middle ear infection. Sulfacetamide and ceftazidime are
two such agents that appear to produce little or no inner
ear toxicity in the highly sensitive chinchilla model. Sul-
facetamide is a sulfonamide antibiotic effective against
both gram-positive and gram-negative organisms,
whereas ceftazidime is a third-generation cephalo-
sporin with a broad antibacterial spectrum. Despite the
absence of significant inner ear effects, studies by Brown
and colleagues demonstrated that preparations con-
taining either sulfacetamide sodium or ceftazidime
resulted in mucosal inflammation, hemorrhage, and
TM thickening in animals killed 1 week after single-
dose middle ear application (Figures 11-1 and 11-2).4,5
These effects, however, were largely resolved in animals
kept for 1 month after instillation of either drug,
suggesting that these agents may not have long-term
deleterious effects on the middle ear.
The fluoroquinolone antibiotics are highly effective
against most pathogens associated with otitis media,
and these drugs show considerable promise for use in
the formulation of topical preparations that might be
used to treat both acute and chronic middle ear infec-
tions. An important representative of this class of com-
pounds, ciprofloxacin, has been well documented to be
free of inner ear toxicity. To date, however, little pub-
lished information is available regarding its effects on
the middle ear. Ofloxacin is another fluoroquinolone
antibiotic that appears to be without toxic effects on the
inner ear but has been found to produce mild to mod-
erate middle ear inflammation in animal studies. Bar-
low and colleagues described mild mucosal and TM
thickening with some inflammatory cell infiltration in
guinea pigs sacrificed 1 week after a series of seven daily
middle ear instillations of 1% ofloxacin.2 In an unpub-
lished study from the authors laboratory, mucosal
inflammation and hyperplasia of the TM epidermis
were seen 1 week after a single middle ear application of
a commercially available otic solution containing 0.3%
ofloxacin (Figure 11-3A). Moderate mucosal changes
together with some osteoneogenesis were still evident in
these animals 4 weeks after the ofloxacin applications
(Figure 11-3B).
Cortisporin Otic Suspension (Burroughs Well-
come, Research Triangle Park, NC) is a topical prepa-
ration containing the antibiotics neomycin and
polymyxin B, which is intended for use in the external
ear canal but has been used in patients with tympa-
nostomy tubes or TM perforations where it may enter
the middle ear. In animal studies this preparation has
been shown to result in severe middle and inner ear
toxicity.2,68 There is some evidence that polymyxin B
is capable of bonding to and inactivating bacterial
endotoxin, thereby potentially reducing endotoxin-
mediated inflammation in otitis media.9 However, as is
true for neomycin, polymyxin B is quite toxic to the
inner ear, and readily crosses the round window
membrane. In fact, when applied to the middle ears of
chinchillas and primates at the same concentrations
used in Cortisporin, polymyxin B has been found to be
significantly more ototoxic than neomycin. 10 The
major middle ear effects of combination preparations
such as Cortisporin appear to be caused by their non-
antibiotic constituents.
STEROIDAL ANTI-INFLAMMATORY AGENTS
Several of the topical preparations that have been used
in clinical management of ear disease contain one or
more antibiotics in combination with a steroidal anti-
inflammatory agent, usually hydrocortisone or dexa-
methasone. The effects of steroids on middle ear tissues
are complex, and their use in the treatment of otitis

Figure 11-2 Mucosal hemorrhage associated with topical
administration of ceftazidime. A, Dissection of chinchilla
middle ear showing mucosal hemorrhage (H) in the hypo-
tympanum 7 days after application of 10% ceftazidime.
C = apex of cochlea; TM = medial surface of tympanic mem-
brane. (Unstained preparation; 7 original magnification.)
Adapted from Brown OE et al.5 B, Histologic cross section of
middle ear mucosa in an area of hemorrhage 7 days after
application of ceftazidime. The mucosa contains dilated blood
vessels (one of which is indicated by V), and an accumula-
tion of extravasated blood (RBCs) lies against the mucosal
surface. (Toluidine blue stain; 400 original magnification.)
media remains somewhat controversial. Steroids have
been shown to up-regulate transepithelial sodium
transport in the middle ear mucosa, which may result
in improved fluid clearance from the middle ear.11 In
addition to their ability to block the production of
inflammatory mediators produced via the arachidonic
acid cycle, corticosteroids appear to directly counteract
the vasoactive effects of histamine on the mucosal vas-
culature, thereby reducing inflammation.12
Dexamethasone was one of the agents included in
the Parker and James study, and they reported that it
had no deleterious effects on the guinea pig middle ear
when applied either in suspension form or in solution
(as dexamethasone sodium phosphate).1 Conversely, it
is well known that steroids can produce atrophic
changes in human skin and may significantly inhibit
wound healing, including the healing of TM perfora-
tions. Delayed healing of experimental TM perfora-
tions was demonstrated by Spandow and colleagues,
who also found that hydrocortisone application was
Middle Ear Effects of Ototopical Agents 109
associated with inflammatory cell infiltration of the
lamina propria of the TM and hypertrophy of epider-
mal cells on the lateral aspect of the drum.13 In another
study published in 1990, Spandow and colleagues con-
firmed the somewhat surprising finding that hydrocor-
tisone may have proinflammatory effects when applied
to the middle ears of experimental animals.14 They
reported that application of hydrocortisone to the nor-
mal rat middle ear resulted in thickening of the
mucosal epithelium and polymorphonuclear leukocyte
infiltration of the subepithelial connective tissue.14 In
this study, 20 L of a 2% hydrocortisone solution was
instilled into the middle ear once daily for 5 days, and
animals were sacrificed at 5, 10, and 21 days after the
last hydrocortisone application. Evidence of mucosal
inflammation was still present, even after 21 days, and
secondary infection was ruled out by middle ear cul-
ture. These findings have been supported by recent
work from Nordang and colleagues, who also reported
inflammation of the round window membrane and
middle ear mucosa after hydrocortisone administration
in the rat.15 Interestingly, they observed no inflamma-
tory changes in the middle ears of animals given dex-
amethasone, a finding that parallels the older report
from Parker and James. 1 It therefore appears that
steroids may differ in their potential for producing
inflammatory changes in the middle ear.
SOLVENTS AND PRESERVATIVES USED IN
TOPICAL PREPARATIONS
As noted above, topical otic preparations containing
combinations of antibiotics such as neomycin and
polymyxin B together with steroids and various other
constituents have been found to injure the middle and
inner ear in experimental studies. One of the first inves-
tigations to address this issue was that of Meyerhoff and
colleagues in 1983.16 In that research, chinchillas were
fitted with tympanostomy tubes, and Cortisporin Otic
Suspension was placed in the external ear canals once
per day for 5 days. Subsequent evaluation demonstrated
that the otic drops entered the middle ear via the tym-
panostomy tubes, and the animals showed elevated
auditory thresholds as well as sensory cell loss in the
basal cochlear turn. In later work, it was shown that
Cortisporin placed in the ear canals of animals with
tympanostomy tubes also resulted in middle ear inflam-
mation, including formation of effusion and granula-
tion tissue as well as focal mucosal hemorrhage.17 When
Cortisporin is placed directly in the chinchilla middle
ear, it consistently produces severe cochlear hair cell
loss; middle ear inflammation with extensive granula-
tion tissue formation, fibrosis, bone erosion, and osteo-
neogenesis; and dramatic alterations of the TM (Figures
11-4, 11-5, and 11-6).6,7 After a single middle ear instil-
lation of the otic drops, approximately 50% of animals
110 Topical Toxicity
Figure 11-3 Cross sections of tympanic membrane and
middle ear mucosa illustrating the effects of a topical prepa-
ration containing 0.3% ofloxacin applied to the chinchilla
middle ear. A, Hyperplasia of tympanic membrane epidermis
(Ep) 1 week after ofloxacin application. FL = fibrous layer of
TM. (Toluidine blue stain; 100 original magnification.) B,
Middle ear mucosa and underlying bone (Bn) 4 weeks after
ofloxacin application. There is thickening and fibrosis of the
subepithelial connective tissue (CT), and a layer of new bone
(asterisk) has been deposited by osteoblasts at the interface
between the bone and connective tissue (arrows). (Toluidine
blue stain; 50 original magnification.)
kept for 4 to 6 weeks before sacrifice have also been
found to develop middle ear cholesteatoma.7
Subsequent work has shown that the middle ear
inflammatory effects of Cortisporin are in large part a
result of propylene glycol, which is included in the for-
mulation as a solvent and penetrance enhancer. Propy-
lene glycol is not severely toxic to the inner ear in
concentrations that are present in topical preparations,
but it has significant inflammatory effects in the middle
ear.1820 Its effects on the TM are of particular interest
since it produces structural changes that lead to
cholesteatoma formation in laboratory animals, such as
chinchillas and rats.2022 When propylene glycol solu-
tions are placed in the middle ear, the epidermal and
mucosal layers of the TM are quickly destroyed, leaving
the middle fibrous layer denuded.23 As the epithelial
layers regrow over the fibrous layer, they become hyper-
Figure 11-4 Abnormalities typical of chronic inflammatory
disease associated with application of Cortisporin Otic
Suspension and subsequent cholesteatoma development in
the chinchilla middle ear. This specimen was taken 6 weeks
after Cortisporin was applied to the tympanic cavity.
The mucosal epithelium (ME) consists largely of ciliated
columnar and goblet cells, and the subepithelial connective
tissue (CT) is dramatically thickened. Inflammatory cells
(IC) overlie the altered mucosa. Bn = bony wall of middle
ear; MC = middle ear cavity. (Hematoxylin and eosin stain;
66 original magnification.)
plastic and markedly thicker than normal (see Figure
11-6). Connective tissue surrounding the fibrous layer
also becomes dramatically thickened, resulting in dis-
tortion and disruption of the fibrous layer so that
hyperplastic epidermis on the lateral side of the drum
can migrate entirely through the TM to reach the medial
surface and continue to grow, leading to cholesteatoma
development (see Figures 11-6 and 11-7). The process of
epidermal migration may also produce TM perfora-
tions, but when it begins, the TM is usually intact.24
Once cholesteatoma is established in the middle ear it
provokes additional inflammation as well as bone ero-
sion just as is seen in human cholesteatoma.7,20 Taken
together, these findings from laboratory animals suggest
that considerable caution should be exercised in the
clinical use of preparations containing propylene glycol
in situations in which they may enter the middle ear.
Various preservative and bacteriostatic agents have
also been used in the formulations of topical medica-
tions for the ear and eye, and these may be an addi-
tional source of undesirable middle ear effects. One of
these agents is benzalkonium chloride, which is some-
times included as a preservative. In their guinea pig
study, Barlow and colleagues tested benzalkonium
chloride at concentrations of 0.026 and 0.05%.2 At the
0.026% concentration, mild mucosal thickening was
noted, whereas at the 0.05% level moderate to severe
mucosal inflammation was found after a series of
seven daily middle ear instillations. A dose-dependent
effect was also observed for the TM, with specimens in

Figure 11-5 Middle ear cholesteatoma following Cortisporin
application in the chinchilla. A, Low-power view of a peri-
annular air cell in the middle ear showing cholesteatoma
matrix (Ch) overlying granulation tissue (Gn) in an area
where multinucleated osteoclasts are eroding bone (arrows).
The cholesteatoma matrix consists of keratinizing (Kr) strat-
ified squamous epithelium, which has invaded the middle ear
cavity (MC). This cross section is from a specimen taken
6 weeks after Cortisporin Otic Suspension was applied to the
middle ear. (Hematoxylin and eosin stain; 25 original
magnification.) Adapted from Wright CG et al.7 B, Higher
power view of multinucleated osteoclasts (arrows) eroding
bone (Bn) in an adjacent area of the same specimen. Ch =
cholesteatoma matrix epithelium. (Hematoxylin and eosin
stain; 400 original magnification.)
the 0.05% group showing approximately twice the
thickening seen in the 0.026% group of animals.
Parker and James reported severe mucosal inflamma-
tion in guinea pig middle ears that received a series of
five doses of an unspecified concentration of benzal-
konium chloride.1 After application of 0.1% benzalko-
nium chloride to the guinea pig external ear canal,
Monkhouse and colleagues noted severe inflammation
and a marked increase in thickness of the epidermis of
the medial portion of the ear canal.25 However, at the
concentrations typically employed in commercially
available topical preparations (0.00250.02%), it seems
reasonable to expect that benzalkonium chloride
would not have serious inflammatory effects on the
middle ear mucosa.
Middle Ear Effects of Ototopical Agents 111
Figure 11-6 Tympanic membrane changes resulting from
middle ear application of propylene glycol. A, Cross section
of normal chinchilla tympanic membrane. At this relatively
low magnification, it is difficult to discern the very thin
epidermal and mucosal layers covering the fibrous layer,
which is the most prominent structural feature of the
tympanic membrane. (Toluidine blue stain; 66 original
magnification.) B, Greatly thickened tympanic membrane
from an animal sacrificed 2 weeks after middle ear applica-
tion of propylene glycol. The epidermal (Ep) and mucosal
(Mc) layers are markedly hyperplastic, and the fibrous layer
(FL) is distorted and broken (arrow) by rapid proliferation
of surrounding connective tissue. (Toluidine blue stain;
approximately 66 original magnification.) Adapted from
Masaki M et al.22 C, Similar specimen from an animal sacri-
ficed 3 weeks after propylene glycol administration. At the
arrow, hyperplastic epidermis (Ep) is penetrating a break in
the fibrous layer (FL) to reach the medial portion of the tym-
panic membrane. Mc = mucosal layer. (Toluidine blue stain;
approximately 66 original magnification.) Adapted from
Wright CG et al.23
ANTISEPTICS AND ANTIMYCOTICS
Antiseptic agents employed during myringotomy and
other surgical procedures may enter the middle ear
and contact the mucosal epithelium, medial surface of
the TM, and round window membrane. Of the many
antiseptics that have been used in ear surgery, only a
few have been specifically tested for possible middle
ear toxicity. Parker and James included chlorhexidine
acetate in their study and found that it caused cochlear
112 Topical Toxicity
Figure 11-7 Dissection of chinchilla middle ear showing the
medial surface of the tympanic membrane (TM) with a
cholesteatoma (Ch) in contact with the promontory (Prm) of
the cochlea. This specimen was taken 3 weeks after propylene
glycol was applied to the middle ear. An = bony annulus of
tympanic membrane. (Unstained preparation; approximately
10 original magnification.) Adapted from Masaki M et al.22
hair cell loss as well as moderate middle ear inflam-
mation in guinea pigs.1 More recently, Igarashi and
Oka investigated the effects of 0.05% chlorhexidine
gluconate on the cat middle ear and found evidence of
fairly minor mucosal damage, primarily involving the
ciliated cells of the tympanic cavity.26
Gentian violet has occasionally been used as a dis-
infectant or antimycotic in the ear. This agent appears
to be severely ototoxic if it reaches the tympanic cavity.
In a recent study by L.W. Tom, in which gentian violet
was administered to the guinea pig middle ear, animals
were found to develop signs of vestibular dysfunction,
indicating significant inner ear toxicity.27 Also, severe
inflammation and new bone growth were observed in
the middle ears of animals receiving gentian violet.
Other antimycotics tested in this study included clotri-
mazole, miconazole, tolnaftate, and nystatin. All
appeared to be free of deleterious effects, except that
nystatin was noted to leave a persistent residue in the
middle ear. Nystatin was reported to be without signif-
icant middle ear inflammatory effects in the Parker and
James study, although two other antifungal agents,
amphotericin B and griseofulvin, produced severe mid-
dle ear inflammation.1
CONCLUSION
As is clear from the laboratory findings reviewed above,
our knowledge of undesirable side effects from topical
medications used in the ear is based almost entirely on
studies of animals. Given the quite considerable varia-
tions in response between different species, it is often
difficult to meaningfully extrapolate findings from the
research laboratory to the clinical setting. This is espe-
cially true in view of the fact that these medications are
generally used in patients with active ear disease in
whom middle ear inflammation and effusion are
already present, and those factors will certainly alter the
ears response to topical drug treatment.
Nonetheless, the animal studies do serve as a guide
for identifying agents that are likely to be problematic,
and they are useful in designing new and improved for-
mulations for topical preparations. Until new medica-
tions are available that are entirely free of possible
deleterious effects, currently available topical drugs
should be used with appropriate attention to possible
toxicity associated with their use.
SUMMARY
Topical pharmaceutical preparations used in
management of ear disease contain a variety of
ingredients that may have undesirable side effects
on the middle ear and inner ear.
Laboratory animal studies have shown that anti-
biotics, steroids, preservatives, and penetrance
enhancers used in ototopical preparations are
potentially injurious to middle ear tissues.
Although it is difficult to extrapolate the exper-
imental findings to human patients, these prepa-
rations should be used with caution in the
clinical setting.
Since currently available ototopical agents show
significant potential for toxicity, there is a need to
develop new formulations that remain effective
but are less likely to adversely affect the middle
and inner ear.
REFERENCES
1. Parker FL, James GWL. The effect of various
topical antibiotic and antibacterial agents on the
middle and inner ear of the guinea pig. J Pharm
Pharmacol 1978;30:2369.
2. Barlow DW, Duckert LG, Kreig CS, Gates GA.
Ototoxicity of topical otomicrobial agents. Acta
Otolaryngol 1994;115:2315.
3. Jakob T, Wright CG, Robinson K, Meyerhoff WL.
Ototoxicity of topical ticarcillin and clavulanic
acid in the chinchilla. Arch Otolaryngol Head Neck
Surg 1995;121:3943.
4. Brown OE, Wright CG, Masaki M, Meyerhoff WL.
Ototoxicity of vasocidin drops applied to the chin-
chilla middle ear. Arch Otolaryngol Head Neck
Surg 1988;114:569.
5. Brown OE, Wright CG, Edwards LB, Meyerhoff WL.
The ototoxicity of ceftazidime in the chinchilla

middle ear. Arch Otolaryngol Head Neck Surg
1989;115:9402.
6. Wright CG, Meyerhoff WL. Ototoxicity of otic
drops applied to the middle ear in the chinchilla.
Am J Otolaryngol 1984;5:16676.
7. Wright CG, Meyerhoff WL, Burns DK. Middle ear
cholesteatoma: an animal model. Am J Otolaryn-
gol 1985;6:32741.
8. Vassalli L, Harris DM, Gradini R, Applebaum EL.
Inflammatory effects of topical antibiotic suspen-
sions containing propylene glycol in chinchilla
middle ears. Am J Otolaryngol 1988;8:15.
9. Darrow DH, Keithley EM. Reduction of endo-
toxin-induced inflammation of the middle ear by
polymyxin B. Laryngoscope 1996;106:102833.
10. Wright CG, Meyerhoff WL, Halama AR. Ototoxic-
ity of neomycin and polymyxin B following middle
ear application in the chinchilla and baboon. Am J
Otol 1987;8:4959.
11. Tan CT, Escoubet B, Van den Abbeele T, et al. Mod-
ulation of middle ear epithelial function by ste-
roids: clinical relevance. Acta Otolaryngol 1997;
117:2848.
12. Chan KH, Swarts JD, Tan L. Middle ear mucosal
inflammation: an in vivo model. Laryngoscope
1994;104:97080.
13. Spandow OD, Hellstrom S, Schmidt S-H. Hydro-
cortisone delay of tissue repair of experimental
tympanic membrane perforations. Ann Otol
Rhinol Laryngol 1990;99:64753.
14. Spandow O, Hellstrom S, Anniko M. Structural
changes in the round window membrane following
exposure to Escherichia coli lipopolysaccharide and
hydrocortisone. Laryngoscope 1990;100:9951000.
15. Nordang L, Linder B, Anniko M. Morphologic
changes in round window membrane after topical
hydrocortisone and dexamethasone treatment.
Otol Neurotol 2003;24:33943.
16. Meyerhoff WL, Morizono T, Wright CG, et al.
Tympanostomy tubes and otic drops. Laryngo-
scope 1983;93:10227.
Middle Ear Effects of Ototopical Agents 113
17. Anderson RG, Wright CG, Meyerhoff WL. Inflam-
matory effects of otic drops on the middle ear. Int
J Pediatr Otorhinolaryngol 1984;7:915.
18. Vernon J, Brummett R, Walsh T. The ototoxic
potential of propylene glycol in guinea pigs. Arch
Otolaryngol 1978;104:7269.
19. Morizono T, Paparella MM, Juhn SK. Ototoxicity
of propylene glycol in experimental animals. Am J
Otolaryngol 1980;1:3939.
20. Vassalli L, Harris DM, Gradini R, Applebaum EL.
Propylene glycol-induced cholesteatoma in
chinchilla middle ears. Am J Otolaryngol 1988;
4:1808.
21. Huang CC, Shi GS, Yi ZX. Eperimental induction
of middle ear cholesteatoma in rats. Am J Oto-
laryngol 1988;9:16572.
22. Masaki M, Wright CG, Lee DH, Meyerhoff WL.
Experimental cholesteatoma. Acta Otolaryngol
1989;108:11321.
23. Wright CG, Bird LL, Meyerhoff WL. Tympanic
membrane microstructure in experimental
cholesteatoma. Acta Otolaryngol 1991;111:
10111.
24. Wright CG, Bird LL, Meyerhoff WL. Development
of tympanic membrane perforations associated
with experimental cholesteatoma. In: Lim DJ,
Bluestone CD, Klein JO, et al, editors. Recent
advances in otitis media. Proceedings of the Fifth
International Symposium. Hamilton (ON): Decker
Periodicals; 1993. p. 4579.
25. Monkhouse WS, Moran P, Freedman A. The
histological effects on the guinea pig external
ear of several constituents of commonly used
aural preparations. Clin Otolaryngol 1988;13:
12131.
26. Igarashi Y, Oka Y. Mucosal injuries following
intratympanic applications of chlorhexidine glu-
conate in the cat. Arch Otorhinolaryngol 1988;
245:2738.
27. Tom LW. Ototoxicity of common topical antimy-
cotic preparations. Laryngoscope 2000;110:50916.
 CHAPTER 12
Topical Aminoglycoside Cochlear Ototoxicity
Peter S. Roland, MD, and Charles G. Wright, PhD
The ototoxic and nephrotoxic effects of systemically
administered aminoglycoside antibiotics have been rec-
ognized since the introduction of streptomycin for the
treatment of tuberculosis in the 1940s.1 As other amino-
glycoside drugs came into use they too were found to be
associated with inner ear toxicity. It was subsequently
discovered that these drugs may also damage the
cochlea when topically applied in situations where they
have access to the middle ear cavity. Much of the evi-
dence for cochleotoxicity from topically administered
aminoglycosides has come from experimental animal
studies in which the drugs have been applied directly to
the middle ear. As discussed below, such studies have
consistently shown that these antibiotics are capable of
producing severe inner ear damage, including large-
scale sensory cell loss, neural degeneration, and dra-
matically compromised auditory function. To what
extent topically applied aminoglycosides may injure the
human inner ear in the clinical setting has been a mat-
ter of considerable discussion and debate.26 This chap-
ter reviews both laboratory and clinical findings
regarding cochlear ototoxicity associated with topical
application of aminoglycoside antibiotics.
Topical antibiotic preparations have often been
used to treat otorrhea after tympanostomy tube inser-
tion and for management of acute or chronic otitis
media in the presence of tympanic membrane perfora-
tions. Antibiotic preparations have also been adminis-
tered prophylactically following tympanostomy tube
placement to reduce the probability of postoperative
otorrhea and to help prevent tube occlusion. Under any
of these conditions, antibiotics applied to the external
ear canal may enter the middle ear and contact the
round window membrane, thereby gaining access to
the inner ear. This has been a matter of concern since
studies conducted in laboratory animals have demon-
strated that aminoglycoside antibiotics used in topical
otic preparations are potentially ototoxic.
Animal studies relating to topical aminoglycoside
ototoxicity have a long history. During the 1950s
Schucknecht reported that concentrated solutions of
streptomycin applied to the middle ears of cats pro-
duced degeneration of cochlear as well as vestibular
sensory cells.7 This research was part of an effort to
develop an effective vestibular ablation procedure for
relief of Menieres disease and was done within the con-
text of the recognized vestibulotoxic properties of
streptomycin. In addition to his experimental trials
with cats, Schuknecht treated a group of Menieres dis-
ease patients with topical streptomycin and obtained
clear evidence that the antibiotic made its way into the
inner ear and damaged both the cochlea and the
vestibular apparatus.7 To our knowledge, this was the
first published study demonstrating topical aminogly-
coside ototoxicity in human subjects. Schuknecht also
observed severe ototoxicity in cats after a single middle
ear application of streptomycin, whereas multiple doses
were required to produce a comparable effect in human
patients. He attributed this difference to greater expo-
sure of the round window membrane in the cat middle
ear relative to humans.
Reports from animal studies appearing in the late
1960s and early 1970s began to focus on the ototoxic
potential of other aminoglycosides, which were then
being used for topical treatment of otitis externa and
otitis media. In a 1969 study, Kohonen and Tarkkanen
applied neomycin to the middle ears of guinea pigs in
concentrations of 5, 10, 20, 50, and 100 mg/mL and
found histologic evidence of cochlear hair cell injury at
all concentrations above 10 mg/mL, with increasing
amounts of sensory cell loss at the higher antibiotic
concentrations.8 In a subsequent study that included
several aminoglycoside antibiotics, Stupp and col-
leagues applied isomolar concentrations (0.1 M) of
streptomycin, kanamycin, gentamicin, and neomycin
to the middle ears of guinea pigs once daily for 3 days.9
The animals were terminated 2 days after the last drug
application for anatomic assessment of cochlear hair
cell damage and measurements of antibiotic concentra-
tion in perilymph. It was found that neomycin and

gentamicin produced complete destruction of sensory
cells, and these drugs were also found to reach the peri-
lymph in higher concentrations than did the other
antibiotics tested. Similar results were later reported by
Harada and colleagues, who placed 5 mg of neomycin
directly on the round window membrane in guinea pigs
and assessed perilymph concentrations of the drug and
cochlear hair cell loss after various time intervals.10
These investigators found high concentrations of
neomycin in the perilymph after 30 minutes of applica-
tion, indicating that the antibiotic easily penetrated the
round window membrane. Loss of hair cells was
observed after neomycin application for 4 hours with
increasing damage following longer periods of drug
placement on the round window membrane. In an
effort to approximate dosage schedules used in treat-
ment of chronic otitis media, Brummett and colleagues
applied 0.1 mL doses of neomycin at a concentration of
either 5, 15, or 45 mg/mL to the middle ears of guinea
pigs three times per day for 4 weeks.11 At the end of the
drug administration period, the animals were kept for
30 days before they were evaluated electrophysiologi-
cally and cochlear tissues were taken for histologic
study. These workers found dose-dependent effects on
cochlear microphonics, and at the two higher neomycin
concentrations, there was extensive loss of sensory cells
in all cochlear turns. In an even longer-term study,
which included evaluation of spiral ganglion cells,
Zappia and Altschuler administered a single intra-
tympanic dose of neomycin to guinea pigs and assessed
cochlear histology at 10 weeks posttreatment.12 Exten-
sive destruction of outer hair cells (OHCs) and inner
hair cells (IHCs) was observed, together with spiral gan-
glion cell loss in all cochlear turns. The loss of ganglion
cells was probably secondary to IHC loss. However, the
possibility of a direct effect of the antibiotic on the
spiral ganglion was not ruled out. In a study designed to
compare the effects of single-dose, middle ear adminis-
tration of neomycin and the nonaminoglycoside anti-
biotic polymyxin B in both chinchillas and baboons,
Wright and colleagues found that although neomycin
did damage cochlear sensory cells, it was significantly
less toxic than polymyxin B when each antibiotic was
administered at concentrations equal to those used in a
commercially available ototopical preparation.13 Both
antibiotics were found to be dramatically less ototoxic
in the primate than in the rodent model.
The studies summarized above are representative
of a sizable body of laboratory work demonstrating that
single aminoglycoside antibiotics applied to the middle
ears of experimental animals are capable of crossing the
round window membrane to reach the inner ear, where
they adversely affect auditory function and cause struc-
tural damage of sensory cells and neural elements
within the cochlea. In order to broaden the spectrum of
antimicrobial activity for clinical management of ear
Topical Aminoglycoside Cochlear Ototoxicity 115
infections, aminoglycosides are often used together
with other antibiotics and with anti-inflammatory
agents in combination ototopical preparations such as
Cortisporin Otic Suspension (containing neomycin,
polymyxin B, and hydrocortisone) and Coly-Mycin S
Otic Suspension (neomycin, polymyxin E, and hydro-
cortisone).
According to manufacturers recommendations,
otic preparations such as Cortisporin are to be used
only in the external ear canal in patients with intact
tympanic membranes. In actual practice, however, they
are often administered to patients with patent tympa-
nostomy tubes or with tympanic membrane perfora-
tions and are also used in intraoperative packing
materials placed in the middle ear during surgery. Otic
drops have also been recommended for prophylactic
use in patients with tympanostomy tubes following
water contamination of the ear canal.14 Since these
preparations contain ingredients (including aminogly-
coside antibiotics) with proven ototoxic potential, their
clinical use in situations in which they can enter the
middle ear has been questioned.
As outlined above, several individual antibiotics
such as neomycin, gentamicin, and the polymyxins
have been shown to be ototoxic in experimental stud-
ies. It is therefore not particularly surprising that
combination otic drops such as Cortisporin Otic Sus-
pension are also injurious to the cochlea when topically
applied to the middle ears of laboratory animals, as has
been demonstrated in species ranging from guinea pigs
to primates. One of the first such studies was done by
Meyerhoff and colleagues, who placed Cortisporin
Otic Suspension in the external ear canals of chin-
chillas that had been previously implanted with tym-
panostomy tubes.15 These investigators observed that
the antibiotic preparation readily entered the middle
ear and contacted the round window membrane
within 30 minutes after placement in the ear canal.
Following application of Cortisporin for 5 consecutive
days in this animal model, there was elevation of audi-
tory evoked potential thresholds and histologic evi-
dence of OHC loss in the basal turn of the cochlea as
illustrated in Figure 12-1. It was subsequently shown
that a single application of 0.5 mL of Cortisporin
directly to the chinchilla middle ear invariably results
in complete destruction of all inner and OHCs
throughout the cochlea (Figure 12-2), together with
severe damage of the sensory epithelia of the vestibu-
lar apparatus.16
Electrophysiologic evidence for the ototoxic effects
of combination otic drops in the chinchilla has also
been reported by Morizono.17 Morizono applied 50 mL
of Cortisporin Otic Suspension and Coly-Mycin S Otic
Suspension directly to the round window membrane
for 10 minutes and then rinsed it away. Over the next
24 hours compound action potential thresholds
116 Topical Toxicity
Figure 12-1 Scanning electron micrographs illustrating
outer hair cell (OHC) loss in the basal cochlear turn of a chin-
chilla following application of Cortisporin Otic Suspension
to the external ear canal in the presence of a patent tympa-
nostomy tube. A, Scattered OHC loss in the upper portion of
the basal turn. B, More severe OHC loss in the lower basal
turn of the same animal. Reproduced with permission from
Meyerhoff WL et al.15
became elevated in association with application of both
preparations, but the deleterious effects were found to
be greater for the Coly-Mycin preparation, which, in
addition to neomycin, contains polymyxin E rather
than polymyxin B.
Barlow and colleagues compared the morphologi-
cal effects of Cortisporin Otic Suspension and 0.3%
gentamicin ophthalmic solution on the middle and
inner ears of guinea pigs following a series of seven
daily middle ear instillations of the test agents.18 Exten-
sive IHC and OHC loss was observed following the
Cortisporin applications, whereas only minor sensory
cell loss, which was not significantly different from
saline controls, was seen with the gentamicin solution.
In addition to laboratory findings obtained from
work with rodent species, combination otic drops have
also been shown to be ototoxic following topical
middle ear administration in a primate model. After a
single middle ear instillation of Cortisporin Otic Sus-
pension in baboons, Wright and colleagues found
IHC and OHC loss in all six animals included in their
study (Figures 12-3 and 12-4)19; however, the sensory
Figure 12-2 Scanning electron micrograph showing total loss
of cochlear sensory cells in the third cochlear turn following
direct middle ear application of Cortisporin Otic Suspen-
sion in a chinchilla. Only phalangeal scars remain on the
reticular lamina in the inner (IHC) and outer hair cell (OHC)
areas. PL = pillar cell headplates. The scale bar at lower left
indicates 10 m.
cell loss was confined to the basal turn of the cochlea.
The cochlear damage was therefore less severe than had
been previously observed following Cortisporin
administration in the chinchilla. The lesser degree of
cochlear injury seen in the baboon was attributed to the
thicker and more densely structured round window
membrane in the primate, which probably affords a
more effective barrier to penetration of ototoxic agents.
Tobramycin is another aminoglycoside antibiotic
found in topical ophthalmic solutions that have
occasionally been used for treatment of ear infections.
With regard to possible ototoxicity, tobramycin has
received much less attention in animal studies than
antibiotics such as neomycin. However, in a study in
which the ototoxic properties of tobramycin were
compared with those of gentamicin following systemic
administration in guinea pigs, it was observed to be
significantly less cochleotoxic than gentamicin.20 Also,
Jinn and colleagues included Tobradex (containing
0.3% tobramycin and 0.1% dexamethasone) in an in
vitro study of isolated OHC toxicity from otic drops
and found it to be largely free of adverse effects in their
cell culture model.21
Although most of the aminoglycosides are unequiv-
ocally ototoxic in laboratory animals, reports of hearing
loss associated with their topical use in human patients
have been rather scattered and, for the most part, lim-
ited to single case reports. This is true despite the fact
that ototopical antibiotics have been in widespread clin-
ical use for many years. It is generally believed, therefore,
that the human inner ear is less vulnerable to injury
from these medications. Several factors are likely to con-
tribute to this apparent difference between species. One
of the more important of these is the fact that the human
cochlea is relatively well protected from toxic agents

Figure 12-3 Light micrographs showing surface preparations
of the organ of Corti from a baboon following middle ear
application of Cortisporin Otic Suspension. A, Upper basal
turn illustrating a normal sensory cell population. 1, 2, and 3
indicate the first, second, and third rows of outer hair cells
(OHC). IHC = inner hair cell area. B, Midbasal turn showing
scattered loss of OHCs. C, Lower basal cochlear turn; all
OHCs destroyed. Only phalangeal scars remain in the OHC
area. (All three micrographs, osmium tetroxide stain; 400
original magnification.) Reproduced with permission from
Wright CG et al.19
placed in the middle ear cavity. Most investigators agree
that the round window membrane is the most signifi-
cant soft tissue barrier between the middle ear and the
inner ear and is the most important site of entry for oto-
topical agents. In the human temporal bone, the round
window is positioned within a relatively deep niche,
which, in more than 50% of cases, is partially or com-
pletely covered by a fold of mucous membrane (Figure
12-5).22 In the chinchilla and guinea pig, on the other
hand, the round window membrane is fully and directly
exposed to the middle ear space. In the animal species,
therefore, materials in the middle ear can more easily
come into direct contact with the round window mem-
brane. The membrane itself is also a considerably more
substantial barrier in the human ear than in animals. In
rodents the round window membrane is quite thin, on
the order of 12 to 16 microns in its central portion.19,23
Even in nonhuman primates, such as the baboon, the
Topical Aminoglycoside Cochlear Ototoxicity 117
Figure 12-4 Dissection of the basal cochlear turn from a
baboon 5 months after application of Cortisporin Otic
Suspension to the middle ear. The arrows indicate three of
the several areas in which there is focal degeneration of the
organ of Corti (OC) and of myelinated nerve fibers in the
osseous spiral lamina (OSL). (Osmium tetroxide stain; 12
original magnification.) Adapted from Wright CG et al.19
membrane is only about 20 microns in thickness.19 In
contrast, the human round window membrane averages
65 to 70 microns in thickness, and its middle, fibrous
layer is quite substantial and densely structured.22,24
These differences in round window membrane mor-
phology are illustrated in the histologic cross sections
shown in Figure 12-6, and they probably play a role in
the decreasing vulnerability to topical ototoxicity seen
from rodents to nonhuman primates to man. In the
presence of middle ear inflammation or infection, the
round window membrane tends to undergo a series of
changes leading to decreased permeability.25 In the acute
phases of inflammation, the surface epithelial layer fac-
ing the middle ear cavity can be damaged, and perme-
ability of the membrane may increase for a period of
time. However, as the middle ear disease process
becomes more chronic the membrane thickens and
becomes increasingly fibrotic, making it a more effective
physical barrier to drug penetration.24 Also, mucosal
inflammation and edema, together with the presence of
middle ear effusion, tend to reduce drug contact with
the round window membrane surface. Thus, it might be
expected that the risk of ototoxicity would be reduced in
the presence of chronic middle ear disease, and that
appears to be the case.
Several authors have expressed views consistent
with the idea that patients without active middle ear
disease may be at greater risk for ototoxicity associated
with use of topical antibiotics. Dumas and colleagues
reported sensorineural hearing loss in a group of eight
patients with tympanic membrane perforations who
received aminoglycoside otic drops, and they stated
that individuals who did not have middle ear inflam-
mation or effusion were more likely to suffer adverse
effects from topical drug treatment. 26 Lind and
118 Topical Toxicity
Figure 12-5 Human temporal bone cross section through the
round window niche area. The two arrows pointing toward the
right indicate a sheet of mucous membrane that partially cov-
ers the opening of the niche. The round window membrane
(RWM) lies in a protected position within the niche, which is
relatively deep compared with that of laboratory animals.
(Hematoxylin and eosin stain; original magnification 25.)
Kristiansen also reported a patient who had a patent
tympanostomy tube and an uninflamed middle ear and
who was treated over a 10-day period for otitis externa
with topical drops containing neomycin, gramicidin,
and dexamethasone.27 This individual developed per-
manent, severe sensorineural hearing loss that
appeared, with high probability, to be a result of the
antibiotic medication.
Figure 12-6 Histologic cross sections showing increasing
thickness and density of the normal round window mem-
brane from chinchilla (A) to baboon (B) to human infant
(C). (All three micrographs, toluidine blue stain; original
magnification 400.) Reproduced with permission from
Wright CG et al.19
Nonetheless, if otic drops are used for extended
periods of time, patients with active middle ear disease
may also be at risk. Nomura, for example, described a
patient with chronic suppurative otitis media who
developed severe hearing loss during 7 months of
treatment with otic drops containing neomycin.22 In
that individual, the hearing loss progressed to total
deafness after the antibiotic preparation was discontin-
ued. A similar case was reported by Tommerup and
Moller involving a patient with chronic otitis media
who used otic drops containing framycetin (an amino-
glycoside available in Europe) over an 11-month period
and developed a severe-to-profound sensorineural
hearing loss in the treated ear.28 In one of the only
prospective studies that included multiple subjects,
Podoshin and colleagues evaluated 150 patients with
chronic otitis media, 124 of whom received a topical
preparation containing neomycin, polymyxin B, and
dexamethasone, whereas the remaining 26 patients
were given dexamethasone alone.29 Evidence for minor
sensorineural hearing loss (6 dB on average) was
obtained in the antibiotic group following prolonged
treatment (greater than 1 year). The average loss in the
26 patients given dexamethasone alone was 0.9 dB, and
the difference between the groups proved to be signif-
icant at the p .025 level.
In general, the available literature suggests that
topical aminoglycosides are relatively safe for use in
patients with chronic ear disease if treatment is of
reasonably limited duration. For example, in a study of
44 pediatric patients with chronic suppurative otitis
media and patent tympanostomy tubes, Merifield and
colleagues found no audiometric changes after treat-
ment with aminoglycoside drops for periods of 2 days
to 2 weeks.30 (Their investigation included a total of
70 ears from the 44 patients, and bone-conduction
thresholds were measured at 3, 4, and 6 kHz before and
after treatment.) In another, larger study of 300
patients with otorrhea who received 0.3% gentamicin
drops for up to 3 weeks, Gyde reported clinical success
of the treatment in 271 of the patients with no evidence
of ototoxic injury based on audiograms performed
before, during, and after treatment.31
Although there have been occasional reports of
human ototoxicity in connection with administration
of topical antibiotics, many otologists are of the opin-
ion that these drugs are highly effective and are safe if
they are used with appropriate caution. Nearly 94% of
the 2,235 otolaryngologists who participated in the
1993 survey by Lundy and Graham reported using top-
ical antibiotic drops to treat otorrhea through ventila-
tion tubes, and 84% used ototopical antibiotics in
patients with draining tympanic membrane perfora-
tions.32 However, only 3.4% of the respondents believed
they had ever observed irreversible sensorineural hear-
ing loss caused by the medications. In a 1995 opinion

paper on topical antibiotic ototoxicity, Roland reviewed
the relevant literature and expressed strong support for
the safety of ototopical medications, particularly when
used in patients with active middle ear disease.5 Other
clinicians have continued to recommend prophylactic
use of otic drops to reduce the risk of postoperative
otorrhea and contend that the likelihood of ototoxicity
is very small, even in patients with patent tympanos-
tomy tubes and dry middle ears, provided that the
duration of topical antibiotic treatment is kept short.
For prophylaxis after tympanostomy tube placement,
Baker and Chole specifically recommended the use of
gentamicin drops rather than preparations containing
multiple antibiotics and propylene glycol, which may
carry a greater risk of ototoxicity.33
However, some otologists continue to stress the
need for caution. Even though previous studies have
indicated that topical drops containing gentamicin are
relatively safe for clinical use, recent reports have
emphasized that gentamicin preparations are not with-
out significant ototoxic potential, especially when used
in patients who do not have active middle ear disease
(see Chapter 13, Topical Aminoglycoside Vestibular
Toxicity). In a series of carefully conducted clinical
studies,3436 these investigators clearly demonstrated
vestibulotoxicity associated with administration of
gentamicin-containing drops, particularly when the
topical preparations were applied for periods longer
than 7 days. Although the toxicity does appear to be
primarily vestibular rather than cochlear, some patients
who received gentamicin drops did develop hearing
loss, indicating that cochlear injury may also occur. On
the basis of these findings, Bath and colleagues have
stated that preparations containing aminoglycoside
antibiotics should not be used in patients with healthy
middle ears, and, if they are employed to treat otorrhea,
the topical drops should be discontinued promptly
after middle ear discharge has stopped.35
Other investigators have also suggested that the
extent of cochlear injury produced by topical antibi-
otics may have been underestimated, and there are at
least two reasons why that may be true.6,11,37 First, the
earliest and most severe changes in auditory function
are likely to occur at frequencies above those usually
tested by conventional audiometry. Damage to the
basal region of the organ of Corti, near the round
window membrane, would therefore not be apparent
during clinical evaluation. Second, it should be remem-
bered that sensorineural hearing loss has been
described as a possible sequela of chronic otitis media.
In some patients the hearing loss might actually be
caused by the antibiotics used to treat the otitis media
rather than by the disease itself.
Thus, there are numerous issues to be considered
with regard to the possible role of topical aminoglyco-
sides in human sensorineural hearing loss. Although
Topical Aminoglycoside Cochlear Ototoxicity 119
topical antibiotic preparations continue to be an
important asset in clinical management of external
and middle ear infections they do have some potential
for inner ear injury. In their informative review on
topical ototoxicity, Pickett and colleagues listed several
strategies helpful in minimizing the risk of toxic effects
during topical antibiotic therapy.6 Among these are the
following: (1) use wicks to apply medications when
treating otitis externa in the presence of tympanic
membrane perforations, (2) keep the duration of treat-
ment as short as possible, (3) monitor patients hear-
ing function, especially when longer-term treatment is
necessary, (4) choose topical medications that are less
likely to affect the inner ear whenever possible. Until
treatment methods are developed that are entirely free
of possible toxicity, topical antibiotics should be
administered with appropriate caution in order to
avoid the possibility of hearing loss associated with
their use.
SUMMARY
Laboratory studies have demonstrated that
aminoglycoside antibiotics are capable of
producing severe inner ear damage when topi-
cally applied to the middle ears of experimental
animals.
The available evidence indicates that topical
aminoglycosides are less likely to have ototoxic
effects in human patients.
Although these drugs appear to be relatively safe
for clinical application, they should be adminis-
tered judiciously, with appropriate attention to
the fact that under some conditions they are
capable of damaging the inner ear.
REFERENCES
1. Hinshaw HC, Feldman WH. Streptomycin in the
treatment of clinical tuberculosis: a preliminary
report. Proc Mayo Clin 1945;20:3138.
2. Mittelman H. Ototoxicity of ototopical antibi-
otics: past, present, and future. Trans Am Acad
Ophthalmol Otolaryngol 1972;76:143243.
3. Wright CG, Meyerhoff WL. Ototopical agents: effi-
cacy or toxicity in humans. Ann Otol Rhinol
Laryngol 1988;97 Suppl 131:302.
4. Brummett RE, Morrison RB. The incidence of
aminoglycoside antibiotic-induced hearing loss.
Arch Otolaryngol Head Neck Surg 1990;116:
40610.
5. Roland PS. Clinical ototoxicity of topical antibiotic
drops. Otolaryngol Head Neck Surg 1994;110:
598602.
6. Pickett BP, Shinn JB, Smith MFW. Ear drop oto-
toxicity: reality or myth? Am J Otol 1997;18:
78291.
120 Topical Toxicity
7. Schuknecht HF. Ablation therapy in the manage-
ment of Menieres disease. Acta Otolaryngol Suppl
1957;132:142.
8. Kohonen A, Tarkkanen J. Cochlear damage from
ototoxic antibiotics by intratympanic application.
Acta Otolaryngol 1969;68:907.
9. Stupp H, Kupper K, Lagler F, et al. Inner ear con-
centrations and ototoxicity of different antibiotics
in local and systemic application. Audiology 1973;
12:35063.
10. Harada T, Iwamori M, Nagai Y, Nomura Y. Oto-
toxicity of neomycin and its penetration through
the round window membrane into the perilymph.
Ann Otol Rhinol Laryngol 1986;95:4047.
11. Brummett RE, Harris RF, Lindgren JA. Detection
of ototoxicity from drugs applied topically to the
middle ear space. Laryngoscope 1976;86:117787.
12. Zappia JJ, Altschuler RA. Evaluation of the effect of
ototopical neomycin on spiral ganglion cell density
in the guinea pig. Hear Res 1989;40:2937.
13. Wright CG, Meyerhoff WL, Halama AR. Ototoxic-
ity of neomycin and polymyxin B following mid-
dle ear application in the chinchilla and baboon.
Am J Otolaryngol 1987;8:4959.
14. Jaffe BF. Are water and tympanostomy tubes com-
patible? Laryngoscope 1981;91:5634.
15. Meyerhoff WL, Morizono T, Wright CG, et al.
Tympanostomy tubes and otic drops. Laryngo-
scope 1983;93:10227.
16. Wright CG, Meyerhoff WL. Ototoxicity of otic
drops applied to the middle ear in the chinchilla.
Am J Otolaryngol 1984;5:16676.
17. Morizono T. Toxicity of ototopical drugs: animal
modeling. Ann Otol Rhinol Laryngol 1990;99:425.
18. Barlow DW, Duckert LG, Kreig CS, Gates GA.
Ototoxicity of topical otomicrobial agents. Acta
Otolaryngol 1994;115:2315.
19. Wright CG, Halama AR, Meyerhoff WL. Oto-
toxicity of an ototopical preparation in a primate.
Am J Otolaryngol 1987;8:5660.
20. Brummett RE, Himes D, Saine B, Vernon J. A com-
parative study of the ototoxicity of tobramycin and
gentamicin. Arch Otolaryngol 1972;96:50512.
21. Jinn TH, Kim PD, Russell PT, et al. Determination
of ototoxicity of common otic drops using isolated
cochlear outer hair cells. Laryngoscope 2001;111:
21058.
22. Nomura Y. Otological significance of the round
window. Adv Otorhinolaryngol 1984;33:1162.
23. Schachern PA, Paparella MM, Duvall AJ. The
normal chinchilla round window membrane. Arch
Otolaryngol 1982;108:5504.
24. Sahni RS, Paparella MM, Schachern PA, et al.
Thickness of the human round window membrane
in different forms of otitis media. Arch Otolaryn-
gol Head Neck Surg 1987;113:6304.
25. Goycoolea MV, Munchow D, Schachern P. Experi-
mental studies on round window structure: func-
tion and permeability. Laryngoscope 1988;
44 Suppl:120.
26. Dumas G, Bessard G, Gavend M, et al. Risque de
surdite par instillations de gouttes auricularies
contenant aminosides. Therapie 1980;35:35763.
27. Lind O, Kristiansen B. Deafness after treatment
with ear drops containing neomycin, gramicidin
and dexamethasone. ORL J Otorhinolaryngol
Relat Spec 1986;48:524.
28. Tommerup B, Moller K. A case of profound hear-
ing impairment following the prolonged use of
framycetin ear drops. J Laryngol Otol 1984;
98:11357.
29. Podoshin L, Fradis M, Ben David J. Ototoxicity of
ear drops in patients suffering from chronic otitis
media. J Laryngol Otol 1989;103:4650.
30. Merifield DO, Parker NJ, Nicholson NC. Thera-
peutic management of chronic suppurative otitis
media with otic drops. Otolaryngol Head Neck
Surg 1993;109:7782.
31. Gyde MC. When the weeping stopped. An otologist
views otorrhea and gentamicin. Arch Otolaryngol
1976;102:5426.
32. Lundy LB, Graham MD. Ototoxicity and ototopi-
cal medications: a survey of otolaryngologists.
Am J Otol 1993;14:1416.
33. Baker RS, Chole RA. A randomized clinical trial of
topical gentamicin after tympanostomy tube
placement. Arch Otolaryngol Head Neck Surg
1988;114:7557.
34. Marais J, Rutka JA. Ototoxicity and topical ear-
drops. Clin Otolaryngol 1998;23:3607.
35. Bath AP, Walsh RM, Bance ML, Rutka JA. Ototoxi-
city of topical gentamicin preparations. Laryngo-
scope 1999;109:108893.
36. Kaplan DM, Hehar SS, Bance ML, Rutka JA. Inten-
tional ablation of vestibular function using
commercially available topical gentamicin-
betamethasone eardrops in patients with Menieres
disease: further evidence for topical eardrop oto-
toxicity. Laryngoscope 2002;112:68995.
37. Stringer SP, Meyerhoff WL, Wright CG. Ototoxic-
ity. In: Paparalla MM, Shumrick DA, Gluckman JL,
Meyerhoff WL, editors. Otolaryngology. Vol II.
3rd ed. Philadelphia (PA): WB Saunders; 1991.
p. 165369.
 CHAPTER 13
Topical Aminoglycoside Vestibular Toxicity
Narayanan Prepageran, MBBS, FRCS(Ed), FRCS(Glas), MS(ORL), Vitaly Kisilevsky, MD,
and John A. Rutka MD, FRCSC


Topical preparations containing aminoglycoside (eg,
neomycin, framycetin, tobramycin, and gentamicin) are
widely used by both otolaryngologists and primary care
physicians for treatment of external otitis, acute otitis
media (AOM) with perforation, chronic suppurative
otitis media (CSOM), and posttympanostomy tube
otorrhea (PTTO). Their frequency of use is primarily
related to their broad spectrum of antibacterial activity,
in particular against Pseudomonas aeruginosa, which is
the most commonly cultured organism in external oti-
tis and CSOM,13 and their low per unit cost. Topical
administration is also a favored route because it is con-
venient to use, it is effective, and other routes are either
impractical or inappropriate because of poor gastro-
intestinal absorption.1
According to Browning and colleagues in 1988,
approximately 5% of adults in the United Kingdom
have CSOM, of whom at any given time approximately
2% will have an associated mucopurulent discharge
indicative of an active infection.4,5 This in turn provides
a rough estimate of the large number of patients pos-
sibly receiving topical antibiotic therapy for CSOM and
the proportionate time and resources involved in the
management of these patients.
THE CONTROVERSY: DOES CLINICAL TOPICAL
OTOTOXICITY REALLY EXIST?
Most product monographs and package inserts of
aminoglycoside ototopical preparations caution that
ototoxicity may occur if used in the presence of a tym-
panic membrane (TM) perforation, but this may be
overstated.6 There is little doubt that topical antibiotics
are effective and indicated in the treatment of CSOM.7,8
Acuin and colleagues in a meta-analysis of treatment for
CSOM from 1966 to 1996 concluded that topical treat-
ment with antibiotics or antiseptics was more effective
than systemic antibiotics (six trials, odds ratio 0.46,
95% CI 0.300.69).8 They also concluded that combin-
ing topical and systemic antibiotics was not more effec-
tive than topical antibiotics alone. In addition, topical
quinolones were found to be more effective than non-
quinolones (five trials, odds ratio 0.26, 95% CI 0.16
0.41).
Although practice patterns vary, they will continue
to evolve as safer topical antibiotic alternatives are
introduced and as a result of medicolegal actions
should topical ototoxicity occur.
To demonstrate how practices have varied, a 1988
survey of UK general practitioners revealed that 66%
would not prescribe topical aminoglycoside antibiotic
ear drops in the presence of a TM perforation and that
85% would not give topical treatment in patients with
discharging grommets (ventilation tubes).9 The pri-
mary reason for this reluctance was the perceived risk
for ototoxicity and other complications. This concern,
however, was apparently not shared by otolaryngolo-
gists in the United States. Lundy and Graham in 1992,
for example, carried out a nationwide survey and
reported that 84.1% of otolaryngologists felt comfort-
able prescribing ototopical aminoglycoside prepara-
tions in the presence of a discharging perforation and
that 93.7% would use this treatment for PTTO. Eighty
percent felt that the inherent risk of ototoxicity from
CSOM was as great as, if not greater than, the risk
involved from using aminoglycoside drops. A more
recent questionnaire in 1999 carried out by Lancaster
and colleagues among the consultant members of the
British Association of OtorhinolaryngologistsHead
and Neck Surgeons (BAO-HNS) revealed that 93%
routinely used topical aminoglycoside-containing
drops as part of their management of active mucosal
safe CSOM. Only 48% believed there was a definite
risk for ototoxicity when using these drops in ears with
a known TM perforation. Of the 48% who acknowl-
edged there was a risk, most of them justified their
rationale for using these drops, feeling that the risk of
ototoxicity is small and no greater than the risk
imposed by active infection upon the inner ear.4
In 1994, Roland analyzed the reported incidence of
ototopical ototoxicity and concluded that amino-
122 Topical Toxicity
glycoside-containing drops were exceedingly safe.10 This
frequently cited report, however, appeared to have pri-
marily focused on reported cochlear, not vestibular, tox-
icity. Considering that only one patient in this review
had any form of vestibular assessment, and acknowl-
edging that, for example, gentamicins toxicity is pri-
marily vestibular, many cases of vestibulotoxicity might
have been overlooked.6
Against this backdrop, guidelines and warnings
from national regulatory committees regarding the
potential toxic effects of topical aminoglycoside ear
drops have been previously issued and continue to be
updated as evidence mounts for topical ototoxicity. In
1981, the Committee on Safety of Medicines (CSM)
and the Medicines Control Agency in the United King-
dom issued a warning of an increased risk of deafness
associated with topical aminoglycosides for the treat-
ment of otitis externa complicated by a perforated TM.
In 1997, a further review by the CSM warned of similar
risks of ototoxicity from aminoglycoside topical drops
in any ear with a perforated TM.4,11 Similar precautions
have been issued in Canada.12 In 1999, the National
Formulary passed by an act of the British parliament
formally limited the duration of topical aminoglycoside
therapy to 7 days because of mounting evidence of oto-
toxicity.7 In 2002, Health and Welfare Canada advised
against using all topical aminoglycoside agents in the
presence of a TM defect or perforation because of
increasing evidence for topical ototoxicity from surveil-
lance and adverse drug reports.12 In the United States
increasing concerns regarding ototoxicity, especially
from topical aminoglycoside-containing preparations,
led the American Academy of OtolaryngologyHead
and Neck Surgery (AAO-HNS) to revisit, in March
2004, its previously endorsed position statement. A
summary of the consensus panels recommendations is
found in Appendix 2.
PORTAL OF ENTRY AND MECHANISM
FOR OTOTOXICITY
There is ample evidence that topical preparations of
aminoglycosides, and gentamicin in particular, applied
to the middle ear may enter the inner ear, especially in
animal models. 13 The round window membrane
(RWM) is the most likely portal of entry. Other pro-
posed sites include the annular ligament of the stapes
footplate and the otic capsule if congenital dehiscences
or microfractures are present. Anatomical studies have
shown that the RWM membrane in humans has an
average thickness of 70 m and is composed of three
layers: outer cuboidal, middle fibrous-connective tis-
sue, and inner mesothelial. All three layers contain
micropinocytic vesicles for active substance transfer
across the membrane.6 In addition, the RWM has been
documented to be permeable to a wide variety of sub-
stances, including horseradish peroxidase, labeled elec-
trolyte ions, I131, and radiolabeled albumin.14
In animal studies, several important principles
regarding topical aminoglycoside absorption into the
inner ear have been established. Harada and colleagues
demonstrated that when neomycin was applied to the
RWM the degree of cochlear damage appeared to be
related to the duration of contact between neomycin
and the RWM.15 In another study, Ikeda and Morizono
demonstrated that the permeability of the RWM was
increased in the presence of otitis media, making it
more likely for ototoxic agents to gain entry into the
inner ear.16 Moreover, when gentamicin was applied
topically to the RWM, it appeared to enter the peri-
lymph, albeit relatively slowly. Its clearance from the
inner ear, however, appeared to be slower than its entry
rate, suggesting that it may concentrate in the inner ear
over time, allowing toxic levels to occur with pro-
longed use.6,17 Studies by Aran and coworkers from
Bordeaux additionally identified the persistence of
radiolabeled gentamicin in the inner ear 11 months
after the initial treatment, suggesting a possible
mechanism for increased toxicity from repeated treat-
ment courses.18
There is also evidence for the systemic absorption
of gentamicin when used topically in the management
of CSOM. Lancaster and colleagues measured plasma
gentamicin levels in 27 patients with active CSOM
treated with the topical gentamicin-containing prepa-
ration Gentisone HC (Roche, Welwyn Garden City,
Hertfordshire, UK). They noted that 7 (26%) of the
patients studied had detectable plasma gentamicin lev-
els and thereby concluded that systemic absorption of
gentamicin from topical application could eventually
be absorbed into the perilymph via the blood-
labyrinthine barrier.1 This observation provides an
alternative route for the entry of a topical aminoglyco-
side into the perilymph, thus possibly potentiating any
topical toxicity.
EXPERIMENTAL STUDIES IN ANIMALS
There is little debate that topical aminoglycosides cause
ototoxicity in animal models. Although all aminoglyco-
sides may cause both cochleotoxicity and vestibulotox-
icity, some (eg, gentamicin) appear more vestibulotoxic
whereas others (eg, amikacin) appear more cochle-
otoxic.6 Middle ear placement of gentamicin in certain
animal models has been shown to result in both histo-
logical and functional cochlear damage by primarily
destroying outer hair cells (OHCs) in the basal turn,
which corresponds to a high-frequency loss demon-
strated by auditory brainstem response recordings and
cochlear microphonics. 19,20 The effects of topical
aminoglycosides on the vestibular system, however,

have not been as well investigated, despite the fact that
gentamicin clinically is primarily vestibulotoxic.6
Regarding topical vestibular ototoxicity, Rudnick
and colleagues demonstrated that maximum morpho-
logic injury occurred in vestibular structures approxi-
mately 1 week after middle ear injections. This finding
of delay correlates well with the delayed dizziness
usually seen in humans following intentional topical
aminoglycoside ototoxicity and after prolonged thera-
peutic use. 21 Omura and colleagues additionally
demonstrated that intralabyrinthine injections of
gentamicin markedly reduced posterior canal nerve
ampullary potentials in a progressive fashion.6,22 Wana-
maker and colleagues reported dose-related damage to
the sensory hair cells in posterior crista and cochlea of
Mongolian gerbils with transtympanic gentamicin
injections.23
Although gentamicin is predominantly vestibulo-
toxic, the earliest detectable inner ear changes occur in
the OHCs of the basal turn of the cochlea.24 This find-
ing supports the theory that aminoglycosides gain
access into the inner ear via the RWM; they would
come into contact with hair cells in the basal turn
before ascending through the cochlea to the labyrinth,
where concentration may occur gradually because of
slower clearing abilities.6,16 This would also explain the
delayed presentation of vestibular toxicity that occurs
usually after prolonged treatment.
Extrapolating to humans from animal models that
demonstrate ototoxicity with topical drops is less than
ideal, given cross-species anatomical differences. The
anatomical relationship between the TM and RWM, for
example, differs significantly between humans and
research animals such as guinea pigs and chinchillas.4
In humans, the RWM is deeper, thicker, and frequently
covered by another mucous membrane or web forma-
tion.4 In addition, when the infected human ear is
receiving treatment, pus or mucosal edema may cover
the RWM and provide additional protection.
THE CASE FOR TOPICAL VESTIBULOTOXICITY:
CLINICAL STUDIES IN MAN
Case Reports and Series
Although hearing loss and cochlear toxicity from topi-
cal aminoglycosides have been demonstrated sparingly
in the English literature, 2527 only recently has the
vestibulotoxicity from these commercially available
proprietary medications been documented.6,28,29
Perhaps the earliest association of vestibular
dysfunction following topical gentamicin drop appli-
cation was noted by LeLiever in 1985.30 In 1994 Long-
ridge and colleagues reported two cases of acute
vestibular deafferentation temporally related to
Garasone (Schering Canada Inc, Pointe Claire, Quebec,
Topical Aminoglycoside Vestibular Toxicity 123
Canada) ear drops (1 mL contains 3 mg gentamicin
sulfate and 1 mg betamethasone sodium phosphate).
Both patients experienced oscillopsia, ataxia, and
imbalance shortly after administration of the drops in
the presence of a TM defect. Vestibular deafferentation
was confirmed by ethyl chloride air caloric electro-
nystagmography (ENG).31
In a slightly larger retrospective clinical series,
Wong and Rutka in 1997 reported on five patients with
TM perforations or defects who developed primary
vestibulotoxicity after topical Garasone administration.
The cases were instructional in that one patient devel-
oped acute vertigo after 3 weeks of treatment where the
middle ear was dry. In another patient, unilateral high-
frequency sensorineural hearing loss and vestibular loss
were noted after prolonged treatment. The other three
cases in the series each developed a bilateral vestibular
loss confirmed by ENG following instillation of these
drops over a prolonged treatment course of weeks
to months.29
Topical vestibulotoxicity from another ototopical
preparation, this time containing gentamicin and dexa-
methasone, was also reported by Abello and colleagues.32
All six reported cases presented with acute vertigo. Most
had received topical treatment without medical super-
vision in the presence of a TM perforation. Treatment
was prolonged and continued after their suppuration
from the middle ear had cleared. Audiometric and
vestibular examination revealed only vestibular involve-
ment. Clinical recovery was spontaneous.
Since the late 1990s much of the clinical incidence
data linking topical aminoglycoside drops to vestibulo-
toxicity has arisen from the University of Toronto.33 In
1998, Marais and Rutka reported 9 (12 ears) well-
documented, incontrovertible cases of iatrogenic
vestibulotoxicity in patients with TM perforations
using topical Garasone ear drops. Six of the nine
patients presented with an acute unilateral deafferenta-
tion, whereas three presented with a bilateral peripheral
vestibular loss following treatment for bilateral middle
ear pathology. This study underscored prolonged treat-
ment in the presence of a dry middle ear as the major
risk factor for the development of vestibulotoxicity. At
the time of onset of vestibular symptoms, the mean
duration of use of drops was 5.4 weeks, and affected
patients had continued the drops on average for 18.4
days from cessation of otorrhea.6
A further update by Bath and colleagues docu-
mented topical ototoxicity from Garasone in 16
patients. All affected patients had either TM perfora-
tions or a tympanostomy (ventilation) tube in place.
The earliest toxicity occurred around day 7 of drop use
in an individual with a dry middle ear. This study
included the case report of the intentional ablation of
vestibular function in one patient with unilateral
124 Topical Toxicity
incapacitating Menieres disease using the same com-
mercially available drops. The patient had a quantifi-
able normal pre-ablation caloric test response and had
an absent response on caloric testing after treatment.28
Topical Gentamicin in the Treatment of
Menieres Disease
Vestibulotoxicity associated with systemic gentamicin
administration has been a well-recognized phenome-
non since its introduction in the 1960s. Paradoxically,
because of this very property gentamicin has been used
for the intentional topical ablation of vestibular func-
tion. Following initial reports by Beck and Schmidt,34
numerous authors have reported on the therapeutic
use of intratympanic gentamicin in the treatment of
unilateral Menieres disease.3546 Both titration and
fixed-schedule protocols evolved throughout this
period in the hopes that undesirable side effects, pri-
marily the worsening of sensorineural hearing, could
be minimized.
One of the initial fixed-schedule protocols for
chemical ablation popularized by Nedzelski and col-
leagues applied topical concentrations of intratym-
panic gentamicin of approximately 25 mg/mL several
times a day for 3 to 5 days. 47 Under this protocol
patients invariably developed acute vertigo indicative of
a vestibular deafferentation in a delayed fashion, some-
times as late as 1 to 2 weeks after treatment, suggesting
a progressive concentration in the vestibular labyrinth.
Because of concerns regarding the variability in dose
response, however, treatment modalities appear to have
become more conservative, with low-dose intra-
tympanic gentamicin becoming more favored.48
Over the years the effects of topical gentamicin
ablation therapy in the treatment of incapacitating
Menieres disease have become well established, and
consistent objective reductions in caloric activity have
been demonstrated in the serial ENG testing of patients
treated with this modality.47 Patients typically display a
delayed onset of acute vertigo that parallels what is
seen in cases of inadvertent topical vestibular toxicity.
High-frequency hearing loss has also been identified in
many as a common finding after gentamicin ablation
therapy. 6 Although much higher concentrations of
intratympanic gentamicin are employed for chemical
ablation in Menieres disease than are found in com-
mercially available drops (ie, around 25 mg/mL vs
3 mg/mL), the duration of treatment is shorter than the
average duration of topical use identified in cases of
inadvertent ototoxicity.6
Vestibular Ablation with Commercially Available
Topical Gentamicin Drops in Menieres Disease
Skepticism regarding the occurrence of topical vestibu-
lar toxicity was largely put to rest with the publication
of reports of intentional vestibular ablation in patients
with Menieres disease using commercially available
gentamicin ear drops. This provided irrefutable
evidence for the potential vestibulotoxicity of topical
gentamicin-containing preparations.
As previously mentioned, Bath and colleagues in
1999 had reported the first case in the world literature
of deliberate ablation of vestibular function in unilat-
eral Menieres disease with gentamicin-containing ear
drops (Garasone).8 Their initial report identified that
Garasone ear drops, and by implication all topical
aminoglycoside ear drops, could be vestibulotoxic in
the presence of a TM defect. The patient had incapaci-
tating unilateral Menieres disease with a normal pre-
treatment ENG caloric test and became symptom free
after instilling Garasone (2 drops bid) into her ear
using subsequent tragal pressure to pump the drops
into the middle ear for 3 weeks. A ventilation tube had
been previously inserted. During treatment, the patient
experienced continued attacks of intermittent vertigo
associated with decreased hearing from her Menieres
disease. After finishing the prescribed course of ear
drops, her attacks of vertigo stopped. Repeat ENG with
air caloric stimulation at 10C using the Dundas Grant
method revealed absent vestibular function on the
affected side.
Kaplan and colleagues provided further evidence
of topical ear drop ototoxicity in a prospective study of
20 patients who underwent intentional vestibular abla-
tion for unilateral Menieres disease using Garasone ear
drops.33 Tympanostomy tubes were inserted under
local anesthesia, and patients were instructed to instill
the same gentamicin-containing ear drops tid until
they became acutely vertiginous for longer than
24 hours and then for an additional 2 days, or for
1 month if they did not become vertiginous, whichever
came first. Although the methodology was slightly
inconsistent (ENG with caloric testing was measured
before treatment using bithermal water calorics and
after treatment using air caloric tests owing to the tym-
panostomy tubes), most patients developed symptoms
in the first 2 weeks after starting treatment (range 9 28
days; mean 15 days). On repeat ENG testing, 15 (75%)
patients were identified to have had a significant reduc-
tion in caloric excitability difference (ED) compared
with pretreatment values. Ten (50%) patients had
absent air caloric test responses on the treated side.
These findings were almost identical to the ED results
when a more concentrated solution of intratympanic
gentamicin (25 mg/mL) was used initially for a shorter
period. They concluded that the use of a less concen-
trated form of topical gentamicin for a longer period of
time would yield the same results (Figure 13-1).7,33
Kaplan and colleagues, in their study of ototoxic
events related to topical gentamicin therapy, which
included a clinical history of prolonged vertigo lasting

Figure 13-1 Pre- and posttreatment caloric responses in 20
Menieres disease patients treated with Garasone ablation
protocol through a tympanostomy tube. Caloric excitability
difference (ED) along x-axis. Adapted from Kaplan DM et al.33
days during the treatment, also found posttreatment
signs of vestibular deafferentation (eg, the presence of
posthead-shake nystagmus or a positive head-thrust, or
Halmagyi, maneuver [see Chapter 2, Physiology of the
Vestibular System]), in conjunction with changes in the
pre- versus posttreatment audiometry and ENG caloric
testing.33 Although falling short of a definitive double-
blind randomized control trial (RCT), this prospective
cohort study provided conclusive evidence that com-
mercially available gentamicin ototopical preparations
penetrate the middle ear via a tympanostomy tube, where
they can be absorbed into the inner ear and subsequently
result in ototoxicity if used for a prolonged time.
TOPICAL OTOTOXICITY: INDIVIDUAL
VARIABILITY?
There is little doubt that when topical gentamicin is
applied to the middle ear it can not only be absorbed
into the inner ear, it can also result in severe vestibular
and cochlear damage. Topical gentamicin (and by
extension all other topical aminoglycosides) ototoxic-
ity from ear drops probably occurs relatively infre-
quently, considering the number of prescriptions per
year. Nevertheless it is not negligible. Many factors
probably play a role in the development of ototoxicity
and whether it will be clinically manifest in a given
Topical Aminoglycoside Vestibular Toxicity 125
individual. 6 Labyrinthine penetration by topical
aminoglycosides is dependent on both the concentra-
tion placed in the middle ear and the duration of con-
tact.17 Local factors that may prevent or influence the
duration of contact of a topical aminoglycoside with
the RWM include the following6,7:
1. The site and size of TM perforation
2. Presence of edematous mucosa, granulation
tissue, pus, and debris, for example, that pro-
tect the RWM from drops
3. A patent eustachian tube that allows drainage
of drops into nasopharynx
4. Barriers around the RWM, such as pseudo-
membranes, webs, and adhesions
5. Varying degrees of RWM thickness
6. The presence of exotoxins within the middle
ear, which may accelerate diffusion and active
transport by pinocytosis across the RWM
7. Inherent susceptibility or resistance to amino-
glycosides
Many patients, especially those with a unilateral
peripheral vestibular loss, probably do not seek further
investigation or treatment for ototoxicity because the
condition reverses itself or the central nervous system
compensates for it. Patients may also accept some
dizziness as the inevitable consequence of an ear infec-
tion and do not report it.6 Despite seeking treatment,
cases of bilateral topical vestibulotoxicity may not be
readily recognized by physicians, as it is not widely
appreciated that the features of a bilateral peripheral
vestibular loss are those of ataxia, oscillopsia, and
imbalance, not vertigo. Unfortunately, many physicians
equate ototoxicity solely with hearing loss, not vestibu-
lar loss per se, and therefore tend not to ascribe much
importance to complaints of imbalance.6
SUMMARY
Vestibular ototoxicity as a result of topical
aminoglycoside use is relatively rare. It is not
negligible, however, and it is documented in the
world literature and warned against by regula-
tory bodies such as Health and Welfare Canada,
the Committee for Safety of Medicines (United
Kingdom), and the Medicine Control Agency
(United Kingdom).
Although infrequent, topical vestibulotoxicity
probably occurs far more commonly than is
realized, given the widespread use of aminogly-
coside-containing ear drops.
A bilateral peripheral vestibular loss presents
with features of ataxia, oscillopsia, and imbal-
ance, not vertigo.
Topical aminoglycoside ear drops should be used
for as short a duration as possible. Patients should
126 Topical Toxicity
clearly understand that they should stop treat-
ment as soon as the otorrhea has cleared. Dosage
and method of administration should be clearly
explained to patients, and they should be advised
to stop treatment immediately if any dizziness,
tinnitus, or hearing loss occurs. Patients with
open middle ear spaces should be reviewed after
1 week to assess the need for further drops.
Nonototoxic topical preparations (eg, fluoro-
quinolones) are now widely available and have
efficacy shown to be comparable with topical
aminoglycosides. Increased use of these agents
in the management of active CSOM is
anticipated.4951
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4. Lancaster JL, Makura ZGG, Porter G, McCormick
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5. Browning GG, Gatehouse S, Calder IT. Medical
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9. Bickerton RC, Roberts C, Little JT. Survey of
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16. Ikeda K, Morizono T. Changes in the permeability
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17. Tran BA, Huy P, Meulemans A, et al. Gentamicin
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18. Aran JM, Erre JP, Lima da Costa D, et al. Acute and
chronic effects of aminoglycosides on cochlear hair
cells. Ann N Y Acad Sci 1999;884:608.
19. Kohonen A, Tarkannen J. Cochlear damage from
ototoxic antibiotics by intratympanic application.
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20. Morozino T, Johnstone BM. Ototoxicity of topic-
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physiological measurement. Acta Otolaryngol
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21. Rudnick MD, Ginsberg IA, Huber PS. Aminoglyco-
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22. Omura R, Harada Y, Suzuki M. Structural and
physiological change in the bullfrog semicircular
canals due to gentamicin intoxication. Acta Oto-
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23. Wanamaker HH, Gruenwald L, Damm KJ, et al.
Dose-related vestibular and cochlear effects of
transtympanic gentamicin. Am J Otol 1998;
19:1709.
24. Wright CG, Halama AR, Meyerhof WL. Ototoxic-
ity of an ototopical preparation in a primate. Am J
Otol 1987;8:5660.
25. Lind O, Kristiansen B. Deafness after treatment
with ear drops containing neomycin, geramicidin
and germathasone. A case report. ORL J Otorhino-
laryngol Relat Spec 1986;48:524.
26. Murphy KW. Deafness after topical neomycin.
Br Med J 1970;2:114.
27. Tommerkup B, Moller K. A case of profound hear-
ing impairment following the primary use of
framycetin ear drops. J Laryngol Otol 1984;
98:11357.

28. Bath AP, Walsh RM, Bance ML, Rutka JA. Ototox-
icity of topical gentamicin preparations. Laryngo-
scope 1999;109(7 Pt 1):108893.
29. Wong DLH, Rutka JA. Do aminoglycoside otic
preparations cause ototoxicity in the presence of
tympanic membrane perforations? Otolaryngol
Head Neck Surg 1997;116:40410.
30. Leliever WC. Topical gentamicin induced posi-
tional vertigo. Otolaryngol Head Neck Surg
1985;93:5535.
31. Longridge NS. Topical gentamicin vestibular toxi-
city. J Otolaryngol 1994;23:4446.
32. Abello P, Vinas JB, Vega J. Topical ototoxicity:
review over a 6-year period. Acta Otorrinolaringol
Esp 1998;49:3536.
33. Kaplan DM, Hehar SS, Bance ML, Rutka JA.
Intentional ablation of vestibular function using
commercially available topical gentamicin-
betamethasone eardrops in patients with Menieres
disease: further evidence for topical eardrop
ototoxicity. Laryngoscope 2002;112:68995.
34. Beck C, Schmidt CL. Ten year experience with
intratympanically applied streptomycin (genta-
micin) in the therapy of morbus Menieres. Arch
Otorhinolaryngol 1978;221:14952.
35. Schmidt CL, Beck C. Treatment of morbus
Menieres with intratympanically applied genta-
micin. Laryngorhinootologie 1980;59:8047.
36. Odkvist LM. Middle ear ototoxic treatment for
inner ear disease. Acta Otolaryngol Suppl 1988;
457:836.
37. Youssef, Poe Ds. Intratympanic gentamicin injec-
tion for the treatment of Menieres disease. Am J
Otol 1998;19:43542.
38. Kaasinen S, Pryykko I, Ishizaki H. et al. Intra-
tympanic gentamicin in Menieres disease. Acta
Otolaryngol 1998;118:2948.
39. McFeely WJ, Singleton GT, Rodriguezet FJ, Antonelli
PJ. Intratympanic gentamicin in Menieres disease.
Otolaryngol Head Neck Surg 1998;118:58996.
40. Minor LM. Intratympanic gentamicin for control
of vertigo in Menieres disease: vestibular signs that
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specify completion of therapy. Am J Otol 1999;
20:20919.
41. Silverstein H, Arruda J, Rosenberg SI, et al. Direct
round window membrane application of genta-
micin in the treatment of Menieres disease. Oto-
laryngol Head Neck Surg 1999;120:64955.
42. Atlas JT, Parnes LS. Intratympanic gentamicin
titration therapy for intractable Menieres disease.
Am J Otol 1999;20:35763.
43. Kaplan DM, Chen JM, Nedzelski JM, Shipp DB.
Intratympanic gentamicin for the treatment of
unilateral Menieres disease: a ten year experience
using a predetermined treatment regimen. Laryn-
goscope 2000;110:1298305.
44. Murofishi T, Halmagyi GM, Yavor RA. Intratym-
panic gentamicin in Menieres disease: result of
therapy. Am J Otol 1997:18:527.
45. Harner SG, Kasperbauer JL, Facer GW, Beatty CW.
Transtympanic gentamicin for Menieres syn-
drome. Laryngoscope 1998;108:14469.
46. Blakely BW. Update on intratympanic gentamicin
for Menieres disease. Laryngoscope 2000;
100:23640.
47. Nedzelski JN, Bryce GE, Pfleiderer AG. Treatment
of Menieres disease with topical gentamicin: a
preliminary report. J Otolaryngol 1992;21:95101.
48. Bath AP, Walsh RM, Bance ML. Presumed reduc-
tion of vestibular function in unilateral Menieres
disease with aminoglycoside eardrops. J Laryngol
Otol 1999;113:9168.
49. Gehanno P, Cohen B. Effectiveness and safety of
ofloxacin in chronic otitis media and chronic
sinusitis in adult outpatients. Eur Arch Otorhino-
laryngol 1993;250:134.
50. Sumitsawan Y, Tharavichikul P, Prawatmuang W, et
al. Ofloxacin otic solution as treatment of chronic
suppurative otitis media and diffuse bacterial otitis
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51. Jones RN, Milazzo J, Seidlin M. Ofloxacin otic solu-
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adults. Arch Otolaryngol Head Neck Surg 1997;
123:1193200.
 CHAPTER 14
Chloramphenicol, Colymycin, and Polymyxin
Leonard P. Rybak, MD, PhD, and Srinivasan Krishna, MD, MPH
Polymyxins, colymycin, and chloramphenicol (alone or
in combination with other antibiotic agents, steroids,
antifungals, and antiseptics) were historically among
the first topical antibiotic agents to be used in the treat-
ment of various ear diseases, ranging from external
otitis and chronic suppurative otitis media to post
tympanostomy tube otorrhea.
POLYMYXINS
History
The polymyxins were discovered in 1947. They form a
group of closely related antibiotic substances produced
by strains of Bacillus polymyxa, an aerobic spore-form-
ing rod found in soil. Colistin, also known as
polymyxin E, is produced by Bacillus colistinus, a
microorganism found in soil samples from Fukushima
Prefecture in Japan.1
Mechanism of Action
The polymyxins are cationic surface-active compounds
(detergents) at physiologic pH. They are relatively sim-
ple, basic peptides with molecular weights of about
1,000. They produce their antibacterial effect by inter-
acting with phospholipid components of the cytoplas-
mic membrane of susceptible bacteria, disrupting
membrane integrity, causing osmotic imbalance and
death of the bacterial organism.2 The antimicrobial
activity of polymyxins is directed toward gram-nega-
tive bacteria, including Enterobacter sp, Escherichia coli,
Klebsiella sp, Salmonella sp, Shigella sp, Pasteurella sp,
Bordetella sp, Vibrio sp, Haemophilus sp, and Pseudo-
monas aeruginosa. Proteus sp, Providencia sp, and Ser-
ratia marcescens are usually resistant.2 Sensitivity to
polymyxin B appears to be related to the content of
phospholipid in the cell wallmembrane complex. The
cell wall of certain resistant bacteria may prevent access
of the drug to the cell membrane.1 Polymyxins are not
active against Neisseria, gram-positive bacteria, most
obligate anaerobes, or fungi.2
Polymyxin B binds to the endotoxin in the outer
membrane of gram-negative bacteria and inactivates
this molecule. 2 Polymyxins are poorly absorbed
through the gastrointestinal tract, through mucous
membranes, or through burns.
Therapeutic Uses
Parenteral forms of polymyxin B or colistimethate
sodium are extremely limited in their indications. They
are not considered drugs of choice for systemic infec-
tions. These drugs are primarily used for infections of
the skin, mucous membranes, eye, and ear caused by
organisms sensitive to polymyxin B. The drug is usually
applied as an ointment, solution, or suspension. It may
be curative for external otitis or corneal ulcers caused
by P. aeruginosa.
Because resistance to antibiotics can develop
rapidly in P. aeruginosa, a prospective study of the sus-
ceptibilities of aural isolates in 231 consecutive children
seen in the outpatient Pediatric Otolaryngology
Department at Childrens Hospital of Pittsburgh dur-
ing the years 1992 to 1993 was carried out. Only 18% of
isolates were sensitive to neomycin. Conversely, 99.6%
were sensitive to polymyxin B, 97.4% were sensitive to
colistin, and 98.3% were sensitive to norfloxacin.3
Proprietary Agents Containing Polymyxins
The American Medical Association drug evaluations2
list several otic preparations containing polymyxin B as
one of the antimicrobial ingredients. These include
the following:
1. Coly-Mycin S Otic with neomycin and hydro-
cortisone suspension contains colistin sulfate,
neomycin sulfate, acetic acid, hydrocortisone
acetate, thonzonium bromide, trimerosal, and
polysorbate 80.
2. Cortisporin Otic Solution contains neomycin
sulfate, polymyxin B, hydrocortisone, cupric

sulfate, glycerin, propylene glycol, and potas-
sium metabisulfate.
3. Cortisporin Otic Suspension contains neo-
mycin sulfate, polymyxin B, hydrocortisone,
cetyl alcohol, propylene glycol, polysorbate 80,
and thimerosal.
4. Pedi-Otic Suspension contains the same
ingredients as Cortisporin Otic Suspension
with the exception of polysorbate 80, which is
not present in Pedi-Otic Suspension.
5. Otobiotic Solution contains polymyxin B,
hydrocortisone, and propylene glycol.
6. Otocort Solution contains neomycin sulfate,
polymyxin B, hydrocortisone, propylene gly-
col, glycerin, and potassium metabisulfate.
7. Otocort Suspension contains neomycin sul-
fate, polymyxin B, hydrocortisone, propylene
glycol, cetyl alcohol, polysorbate 80, and
thimerosal. (Several other proprietary ear
drops contain neomycin, polymyxin B, and
hydrocortisone.)
8. Pyocidin-Otic Solution contains polymyxin B,
hydrocortisone, and propylene glycol.
Toxicities
Parenteral polymyxins may cause serious nephrotoxic-
ity and neurotoxicity. These toxic side effects and the
availability of effective and less toxic alternative antimi-
crobial agents have resulted in the limited usefulness of
polymyxins for systemic use.
Animal Studies
Guinea pigs have been used to study the ototoxicity of
neomycin, polymyxin B, and colymycin (colistin).4
Concentrations of 1 to 25 mg/mL of polymyxin B and
2 to 10 mg/mL of colistin were instilled into the mid-
dle ear. Polymyxin B at concentrations greater than
1 mg/mL resulted in hair cell degeneration. Higher
concentrations caused total degeneration of the organ
of Corti. The application of 5 mg/mL or greater
concentrations of colistin resulted in slight to nearly
complete destruction of hair cells in the majority of
cochleas. A 0.1 M solution of polymyxin B was
applied intratympanically in guinea pigs daily for
3 days. The cochlea was examined by light microscopy
of surface preparations harvested 2 days following the
last dose. A 50% hair cell loss was observed following
this treatment.
Polymyxin B has been shown to cause cochlear
damage and loss of cochlear function in guinea pigs
following application to the middle ear space. Solutions
containing polymyxin B in concentrations similar to
those found in commercially available otic drops were
found to cause ototoxicity, as revealed by changes in the
ability of the cochlea to generate the alternating current
(AC) cochlear potential, and morphologic changes, as
Chloramphenicol, Colymycin, and Polymyxin 129
demonstrated by the loss of inner and outer hair cells
on surface preparations of the cochlea examined
microscopically. These changes were observed only in
the treated ears. The contralateral control ears were
found to have normal morphology.5
Polymyxin B in combination with neomycin
(Cortisporin Otic Suspension) was found to be highly
ototoxic in the chinchilla. Following the application of
0.5 mL of Cortisporin Otic Suspension to the middle
ear of these experimental animals, degeneration of all
inner and outer hair cells throughout the cochlea, severe
damage to the stria vascularis, and moderate to severe
degeneration of the vestibular receptor organs were
observed.6 Unfortunately, this study was performed
with a mixture of at least two ototoxic drugs (neomycin
and polymyxin B), and the solvent, propylene glycol,
may also be ototoxic. Therefore, it is not clear whether
the ototoxicity observed was primarily caused by
polymyxin B, neomycin, or their combination with
propylene glycol. Subsequent studies of the individual
components, neomycin and polymyxin B, applied as
solutions in the middle ear of the chinchilla and the
baboon, were carried out. In both the rodent and the
primate, the extent of hair cell loss and injury to the stria
vascularis following application of polymyxin B alone
was comparable to that previously reported after appli-
cation of Cortisporin Otic Suspension.7 Although both
species suffered hair cell loss after polymyxin B, the
extent of the hair cell loss was much greater in the chin-
chilla than in the baboon.8
Polymyxin B was also perfused at a concentration
of 1 mM through the scala tympani of the guinea pig
cochlea, and cochlear potentials were monitored. Both
cochlear microphonics (CM) and the endocochlear
potential were altered, but in an independent manner.
These data suggested that both the organ of Corti and
the stria vascularis are involved in ototoxicity caused by
polymyxin B.7
Colymycin applied to the middle ear of the chin-
chilla resulted in a dose-related elevation of compound
action potential (CAP) thresholds that affected the
higher frequencies more than the lower frequencies and
progressed over time, resulting in hearing loss at all
frequencies by 24 hours.9
A comparative study of various otic preparations
has been carried out in the guinea pig.10 These prepa-
rations were instilled daily for 7 days into the bulla of
juvenile guinea pigs. Fourteen days after treatment the
animals were sacrificed, and the organ of Corti was
examined using light and scanning electron micro-
scopy. The average hair cell loss was 66% following the
application of Cortisporin Otic Solution.
Fosfomycin has previously been studied as a pos-
sible protective agent against polymyxin B ototoxicity.11
The former is an antibiotic that had been previously
shown to reduce the ototoxicity of aminoglycoside
130 Topical Toxicity
antibiotics in animals. Two groups of chinchillas were
tested. One group received polymyxin B solution alone
in the middle ear cavity, whereas the second group was
administered polymyxin B in combination with fos-
fomycin. Cochlear damage was dramatically reduced in
the animals receiving the combination of fosfomycin
with polymyxin B.
Human Studies
Only a few case reports document clinical evidence for
ototoxicity attributable to topical otic preparations.
Gyde performed a double-blind randomized study to
compare the efficacy and safety of trimethoprim-
polymyxin B (TP) and trimethoprim-sulfacetamide-
polymyxin B (TSP) drops in the treatment of
otorrhea.12 Sixty-eight patients were treated with vary-
ing pathologies and conditions such as external otitis,
recurrent otitis media with tympanic membrane (TM)
perforation, infected mastoid cavities, and postopera-
tive tympanoplasty. The TP ototopical solution was
successful clinically in 61% of cases, compared with
89% of cases treated with TSP, a statistically significant
difference using the chi-square with Yates correction
statistical method. There were no signs of ototoxicity in
either group.12 In addition, Rakover and colleagues
reported no change in auditory thresholds in children
with tympanostomy tubes who were treated with
neomycin or polymyxin B ear drops for 2 weeks.13
Merrifield and colleagues studied 44 pediatric patients
with tympanostomy tubes who were treated with
potentially ototoxic ear drops.14 Pre- and posttreatment
bone-conduction audiometry was carried out. The ear
drops used included Cortisporin Otic Suspension,
a gentamicin ophthalmic solution, Cortisporin
Ophthalmic Solution, Pedi-Otic Suspension, and Coly-
Mycin S Otic. The duration of treatment ranged from
2 days to 2 weeks. No significant bone-conduction
threshold shifts were detected in 70 ears tested. The
authors concluded that no significant sensorineural
hearing loss occurred as a result of otic drop treatment
in the presence of ventilation tubes with purulent oti-
tis media.14 Welling and colleagues treated 446 patients
with neomycin, polymyxin B, or gentamicin drops after
ventilation tube insertion.15 Only a single dose of ear
drops was administered, but no auditory toxicity was
detected.
To date, 10 cases of ototoxicity have been attrib-
uted to the topical use of neomycin/polymyxin B drops
in the presence of a TM perforation. Dumas and
colleagues reported eight cases.16 Lindner and col-
leagues reviewed the charts of 134 patients with pos-
sible antibiotic-related ototoxicity.17 They found that
two patients had bilateral profound sensorineural hear-
ing loss attributable to excessive administration of ear
drops containing framycetin (neomycin B) and
polymyxin in the presence of a TM perforation. The
authors concluded that although ototopical prepara-
tions have been widely used in the presence of TM per-
forations, they appear to rarely induce sensorineural
hearing loss.17
Recommendations for Safe Use
When it is possible clinically, the physician should use
topical antibiotic preparations that do not have the
potential for ototoxicity when treating on open middle
ear space or mastoid cavity. If it is necessary to use a
potentially ototoxic preparation in an infected ear, its
use should be discontinued promptly after resolution
of the infection. In the latter instance, the patient
should be forewarned of the potential risk of ototoxic-
ity. If any symptoms of ototoxicity appear, such as hear-
ing loss, new-onset tinnitus, or dizziness, the patient
should promptly notify the physician so that appropri-
ate measures can be instituted.
CHLORAMPHENICOL
History
Chloramphenicol was first isolated in 1947, from
Streptomyces venezuelae, an organism isolated from a
soil sample in Venezuela.18 It was synthesized in 1949,
becoming one of the first completely synthetic anti-
biotics of importance to be produced commercially.
Mechanism of Action
Chloramphenicol inhibits the peptidyl transferase step
of protein synthesis by binding reversibly to the 50S
ribosomal subunit of bacterial cells.18 It can also inhibit
mitochondrial protein synthesis in mammalian cells,
with erythropoietic cells being particularly sensitive.
Chloramphenicol has a wide antibacterial spec-
trum against aerobic and anaerobic gram-positive and
gram-negative organisms. It is primarily bacteriostatic
but may be bactericidal to certain species, such as
Haemophilus influenzae, Neisseria meningitidis, Strepto-
coccus pneumoniae, and Bacteroides fragilis. 18 Most
strains of E. coli, Proteus sp, and Klebsiella pneumoniae
are susceptible. P. aeruginosa is very resistant, whereas
most Rickettsia spp, Mycoplasma spp, and Chlamydia
spp are sensitive to chloramphenicol.19
The drug is rapidly absorbed from the gastroin-
testinal tract and is metabolized by the liver. It is well
distributed in body fluids with concentrations in the
cerebrospinal fluid reaching 60% of plasma concentra-
tions in the presence of meningitis. Resistance to
chloramphenicol is caused by a plasmid-encoded
acetyltransferase that inactivates the drug.19
Therapeutic Uses
Systemic indications for chloramphenicol are
extremely limited because of its toxicities. It is generally
reserved for patients refractory to less toxic anti-

bacterial agents. In the past, it has been used in the
treatment of typhoid fever, bacterial meningitis,
anaerobic infections (brain abscesses, abdominal infec-
tions, etc), rickettsial diseases, and brucellosis.
Topical chloramphenicol is still used, either as a
powder or as drops, in therapy of refractory ophthalmic
and otologic infections, such as mastoid bowl infec-
tions, chronic refractory otitis media, and chronic
refractory otitis externa, particularly in developing
countries.20 It is particularly effective against B. fragilis.21
Proprietary Agents Containing Chloramphenicol
Chloromycetin Otic contains 0.5% chloramphenicol
and propylene glycol.21
Toxicities
The most significant systemic adverse reaction is bone
marrow suppression. This can be a dose-dependent
toxicity resulting in anemia, leukopenia, or thrombo-
cytopenia or an idiosyncratic response resulting in fatal
pancytopenia.18
Animal Studies
The toxicity of topical chloramphenicol has been stud-
ied extensively in animal experiments. In 1963, Patter-
son and Gulick found progressive loss of the CM
responses in guinea pigs after topical application of a
relatively low dose of chloramphenicol to the round
window membrane for 30 minutes.22 The losses ranged
from 20 to 30 dB and were irreversible.
Gulick and Patterson in 1964 again reported that
the decrease in CM potentials did not return to predrug
levels for up to 60 hours after topical application of
chloramphenicol to the round window membrane of
cats.23 Thus the effects seem to be long lasting.
Proud and colleagues in 1968 studied the effects of
two different concentrations of chloramphenicol succi-
nate (1.44 M vs 0.72 M) in a single application to the
round window niche for 30 minutes in 22 guinea pigs.19
These were compared with eight control animals that
had round window applications of sodium succinate
solutions at the same concentrations and pH. All ani-
mals were euthanized at 3, 6, 9, and 24 hours after the
application. Histopathology of the temporal bones was
performed. In the experimental animals, the cochlea
showed marked destruction of the outer and inner hair
cells, as well as the supporting cells (Deiters cells,
Claudius cells, Hensens cells, and a few inner sulcus
cells) of the basal turn of the cochlea only, and not in the
other turns.19,24,25 Additionally, the stria vascularis of the
basal turn showed variable but consistent damage in the
experimental animals but not in the control animals.
The results were similar regardless of the concentration
of the drug used or the time of sacrifice after application.
The dosages of the drug used were reportedly much
Chloramphenicol, Colymycin, and Polymyxin 131
lower than comparable human doses, and the time of
exposure was much less than in clinical situations, and
yet the toxicity was significant. Hence, the authors con-
cluded that chloramphenicol succinate is not well suited
for topical application to the middle ear.19
DAngelo and colleagues applied chloramphenicol
powder to the round window membrane of guinea pigs
and measured the cochlear responses to various tonal
stimuli. They found that the responses were markedly
reduced in all frequencies.26
In 1966, Koide and colleagues published a study
wherein they injected chloramphenicol solution into
the middle ear of guinea pigs. After several days, the
cochleas were harvested and studied. They found that
the activity of oxidizing enzymes such as succinic dehy-
drogenase and diphosphopyridine nucleotide dia-
phorase was much reduced in the outer hair cells of the
basal turn of the cochlea. The inner hair cells, support-
ing cells, and nerve fibers were not affected.24
In 1975, Morizono and colleagues observed that
chloramphenicol dissolved in propylene glycol to attain
final concentrations of 1% or greater and instilled in
the tympanic bulla of guinea pigs for more than 1 day
caused a decrease in CM potentials in both higher and
lower frequencies.27 However, chloramphenicol sodium
succinate dissolved in Ringers solution was not toxic
until the 5% concentration was reached. They con-
cluded that propylene glycol used as a solvent for
chloramphenicol is ototoxic by itself and worsens the
ototoxicity of chloramphenicol.
Systemic chloramphenicol has also been shown to
potentiate noise-induced hearing loss in rats.28,29
Human Studies
Ototoxicity from systemic administration of chloram-
phenicol was first reported by Gargye and Dutta in
1959.30 They reported a case of irreversible sudden-
onset nerve deafness following high doses of intra-
venous chloramphenicol. Subsequently, Svenungsson
and colleagues, in 1976, described eight cases of unilat-
eral hearing loss following chloramphenicol therapy
for meningitis.31 Iqbal and Srivatsav, in 1984, reported
a case of a 20-year-old woman with bilateral profound
sensorineural hearing loss following the systemic
administration of chloramphenicol.32 Initially, unilat-
eral hearing loss and tinnitus were noted about
2 months after completion of systemic therapy with
chloramphenicol for typhoid. The hearing loss was
gradually progressive. Subsequently, after a repeat
course of the drug 2 months later, the other ear was also
affected, and the patient finally developed profound
bilateral sensorineural hearing loss.
Joy and colleagues in 1960 reported optic and
peripheral neuritis as a probable effect of prolonged
chloramphenicol therapy,33 whereas Mortimer reported
bilateral optic atrophy from its use.34
132 Topical Toxicity
The first clinical case report of hearing loss
following topical application of chloramphenicol ear
drops was from Matsumaru in 1964.35 He reported on
a 45-year-old man who experienced a severe case of
deafness, tinnitus, and dizziness immediately after
application of a few drops of Chloromycetin ear drops
(0.5% chloramphenicol, 1% solution of ethylamino-
benzoate in 100% propylene glycol) for chronic sup-
purative otitis media. However, this report could not
conclude that the ototoxicity was specifically from the
chloramphenicol and not from the additives, such as
the propylene glycol.
Supiyaphun and colleagues in 2000 published a
study comparing the safety and efficacy of 0.3%
ofloxacin drops twice daily and that of oral amoxicillin
thrice daily plus 1% chloramphenicol otic drops thrice
daily, in a 2-week course for acute exacerbation of
chronic suppurative otitis media.36 This was a prospec-
tive, randomized, single-blinded study of 80 adult
patients at the Chulanglongkorn University Hospital in
Thailand. All patients were 15 years of age or older and
had otorrhea with a central TM perforation for at least
21 days. Pure tone and speech audiometry was per-
formed in all patients before treatment and at day 14
posttreatment. Ototoxicity was defined as an elevation
in bone-conduction threshold or speech reception
threshold of greater than 5 dB or the presence of a
high-frequency hearing loss following treatments.
There was a significant deterioration in mean bone-
conduction threshold, from 22.8 10.4 dB to 24.8
10.4 dB (p = .007), in the amoxicillin plus chloram-
phenicol ears.39 The change in speech reception thresh-
old was not statistically significant, however. There was
a significantly higher rate of ototoxicity in the amoxi-
cillin plus chloramphenicol group than in the ofloxacin
group. Since systemic amoxicillin has not been shown
to have any ototoxicity, the change in hearing may be
attributable to the chloramphenicol otic drops. In addi-
tion, the chloramphenicol drops appeared to cause
mild to moderate soreness in up to 37% of the patients
in this study.
Overall, topical chloramphenicol appears to have
significant risk of ototoxicity, particularly if applied to
the middle ear near the round window niche or mem-
brane. This would preclude its use as a first-line
ototopical agent in the treatment of chronic otitis
media with a perforated TM. Safer alternatives are
available. Topical chloramphenicol, however, may have
a role in treating select situations of recalcitrant mas-
toid bowl infections, particularly after other agents
have not been successful.
Of cautionary note, two cases of fatal aplastic ane-
mia and two cases of reversible bone marrow suppres-
sion following the use of topical chloramphenicol in
the eye have been reported.37 This point merits consid-
eration when using topical choramphenicol prepara-
tions in the ear. Skin reactions including erythema
multiforme-like eruptions, have also been identified to
result from topical chloramphenicol.38
SUMMARY
Polymxins, colymycin, and chloramphenicol
(alone or in combination with other antibiotics,
solvents, antifungals, and steroids) are com-
monly found in many commercially available
ototopical medications.
Polymyxins have a broad spectrum of antibacte-
rial activity that especially targets gram-negative
organisms such as P. aeruginosa, E. coli, and
Klebsiella sp. Chloromycetin appears to have
limited activity against P. aeruginosa but is
bactericidal toward H. influenzae, N. meningi-
tidis, S. pneumoniae, and B. fragilis.
Animal studies have consistently demonstrated
their potential for causing topical ototoxicity
upon reaching the inner ear. Human studies and
clinical series have demonstrated that topical oto-
toxicity occurs but is relatively infrequent unless
used in a prolonged fashion (more than 7 days).
When clinically possible, topical preparations
that do not have the potential for ototoxicity
should be used to treat ear disease in the pres-
ence of a TM defect or perforation.
To date there have been no reports of bone mar-
row depression or aplastic anemia in patients
receiving topical chloramphenicol for treatment
of their ear disease. There have, however, been
two reported cases of fatal aplastic anemia and
two cases of reversible bone marrow suppression
following the use of topical chloramphenicol in
the eye.
REFERENCES
1. Sande MA, Mandell GL. Antimicrobial agents:
tetracyclines, chloramphenical, erythromycin and
miscellaneous antibacterial agents. In: Gilman AG,
Rall TW, Nies AS, Taylor P, editors. Goodman and
Gilmans the pharmacological basis of therapeutics.
8th ed. New York: Pergamon Press; 1990. p. 1138.
2. American Medical Association. Drug evaluations
annual. Chicago: American Medical Association;
1993. p. 154952.
3. Dohar JE, Kenna MA, Wadowsky RM. In vitro sus-
ceptibility of aural isolates of Pseudomonas aerug-
inosa to commonly used ototopical antibiotics. Am
J Otol 1996;17:2079.
4. Kohonen A, Tarkannen J. Cochlear damage from
ototoxic antibiotics by intratympanic application.
Acta Otolaryngol 1969;68:907.
5. Brummett RE, Harris RF, Lindgren JA. Detection of
ototoxicity from drugs applied topically to the
middle ear space. Laryngoscope 1976;86:117787.

6. Wright CG, Meyerhoff WL. Ototoxicity of otic
drops applied to the middle ear in the chinchilla.
Am J Otolaryngol 1984;5:16676.
7. Halama AR, Wright CG, Meyerhoff WL. Ototoxic-
ity of an ototopic preparationexperimental
results and clinical facts. Acta Otorhinolaryngol
Belg 1991;45:27982.
8. Wright CG, Meyerhoff WL, Halama AR. Ototoxic-
ity of neomycin and polymyxin B following mid-
dle ear application in the chinchilla and baboon.
Am J Otol 1987;8:4959.
9. Morizono T. Toxicity of ototopical drugs: animal
models. Ann Otol Rhinol Laryngol Suppl 1990;
148:425.
10. Barlow DW, Duckert LG, Kreig CS, Gates GA. Oto-
toxicity of topical otomicrobial agents. Acta Oto-
laryngol 1995;115:2315.
11. Leach JL, Wright CG, Edwards LB, Meyerhoff WL.
Effect of topical fosfomycin on polymyxin B oto-
toxicity. Arch Otolaryngol Head Neck Surg
1990;116:4953.
12. Gyde MC. A double-blind comparative study of
trimethoprim-polymyxin B versus trimethoprim-
sulfacetamide-polymyxin B otic solutions in the
treatment of otorrhea. J Laryngol Otol 1981;
95:2519.
13. Rakover Y, Keywan K, Rosen G. Safety of topical
ear drops containing ototoxic antibiotics. J Oto-
laryngol 1997;26:1946.
14. Merrifield DO, Parker NJ, Nicholson NC. Thera-
peutic management of chronic suppurative otitis
media with otic drops. Otolaryngol Head Neck
Surg 1993;109:7782.
15. Welling DB, Forrest LA, Goll F III. Safety of oto-
topical antibiotics. Laryngoscope 1995;105:4724.
16. Dumas G, Bessard G, Gavend M, Charachon R.
Risk of deafness following ototopical administra-
tion of aminoglycoside antibiotic. Therapie 1980;
35:35763.
17. Lindner TE, Zwicky S, Brandle P. Ototoxicity of
ear drops: a clinical perspective. Am J Otol 1995;
16:6537.
18. Chambers HF. Antimicrobial agents: protein syn-
thesis inhibitors and miscellaneous antibacterial
agents. In: Goodman and Gilmans the pharmaco-
logical basis of therapeutics. 10th ed. New York:
Pergamon Press; 2001. p. 124650.
19. Proud GO, Mittelman H, Seiden GD. Ototoxicity
of topically applied chloramphenicol. Arch Oto-
laryngol 1968;87:3441.
20. Fairbanks DNF. Otic topical agents. Otolaryngol
Head Neck Surg 1980;88:32731.
21. American Medical Association. Drug evaluations
annual. Chicago: American Medical Association;
1994. p 1574.
Chloramphenicol, Colymycin, and Polymyxin 133
22. Patterson WC, Gulick WL. The effects of chloram-
phenicol upon the electrical activity of the ear. Ann
Otol Rhinol Laryngol 1963;72:505.
23. Gulick WL, Patterson WC. The effects of chloram-
phenicol upon the electrical activity of the ear.
Long term data. Ann Otol Rhinol Laryngol
1964;73:2049.
24. Koide T, Hata A, Hando R. Vulnerability of the
organ of Corti in poisoning. Acta Otolaryngol
1966;61:332.
25. Mittelman H. Ototoxicity of ototopical antibi-
otics: past, present, and future. Trans Am Acad
Ophthalmol Otolaryngol 1972;76:143243.
26. DAngelo EP, Patterson WC, Morrow RC. Chlo-
ramphenicol. Topical application in the middle ear.
Arch Otolaryngol 1967;85:6824.
27. Morizono T, Johnstone BM. Ototoxicity of chlo-
ramphenicol ear drops with propylene glycol as
solvent. Med J Aust 1975;2:6348.
28. Brown RD, Penny JE, Henley CM, et al. Ototoxic
drugs and noise. Ciba Found Symp 1981;
85:15171.
29. Henley CM, Brown RD, Penny JE, et al. Impairment
in cochlear function produced by chloramphenicol
and noise. Neuropharmacology 1984;23:197202.
30. Gargye AK, Dutta DV. Nerve deafness following
chloromycetin therapy. Indian J Pediatr 1959;26:
265.
31. Svenungsson B, Bengtsson E, Fluur E, Siegborn J.
Hearing loss as a sequel to chloramphenicol and
ampicillin treatment of Haemophilus influenzae
meningitis. Scand J Infect Dis 1976;8:17580.
32. Iqbal SM, Srivatsav CPB. Chloramphenicol ototox-
icity. A case report. J Laryngol Otol 1984;98:5235.
33. Joy JT, Scalettar R, Sodee DB. Optic and peripheral
neuritis: probable effect of a prolonged chloram-
phenicol therapy. JAMA 1960;173:17314.
34. Mortimer AC. Bilateral optic atrophy following
chloramphenicol therapy. JAMA 1953;151:1403.
35. Matsumuru H. A case report of anaphylaxis caused
by application of 0.5% chloromycetin otic solu-
tion. Otologica Fukuoka 1964;10:48.
36. Supiyaphum P, Kerekhanjanarong V, Koranaso-
phonepun J, Sastarasadhit V. Comparison of
ofloxacin otic solution with oral amoxicillin plus
chloramphenicol ear drops in the treatment of
chronic suppurative otitis media with acute exac-
erbation. J Med Assoc Thai 2000;83:638.
37. Fraunfelder FT, Bagby GC Jr, Kelly DJ. Fatal aplas-
tic anemia following topical administration of
ophthalmic chloramphenicol. Am J Ophthalmol
1982;93:35660.
38. Fisher AA. Erythema multiforme-like eruptions
due to topical medications: Part II. Cutis 1986;
37:158, 1601.
 CHAPTER 15
Topical Antifungals
Lawrence W. C. Tom, MD, Lisa M. Elden, MS, MD, and Roger R. Marsh, PhD
Andral and Gavarret in 1843 and Mayer in 1844 first
described fungal infections of the external auditory
canal. Virchow suggested the term otomycosis be used
to describe this condition. Although otomycosis has
been classically described as a fungal infection of the
external auditory canal, it has been suggested that the
term be expanded and redefined to include fungal
infections of the middle ear and open mastoid cavities.1
Otomycosis occurs throughout the world, and its
prevalence changes with location and climate. This
condition is more common in tropical and subtropical
environments and occurs more frequently when the
weather is warm and humid. In temperate climates, it
accounts for less than 10% of cases of external otitis.1,2
Many genera of fungi have been known to cause
otomycosis. Aspergillus and Candida, well-known
human pathogens, are the most common offending
genera, with A. niger and C. albicans being the most
common offending species. The exact prevalence of
these pathogens varies by climatic region. Overall,
Aspergillus spp are responsible for most cases of
otomycosis.3,4
The difficulty in treating this annoying and stub-
born condition has been well recognized. Multiple oral,
topical, and intravenous agents and even radiation have
been recommended to manage otomycosis.57 Many of
these treatments have proven to be ineffective, unsafe,
or both. For example, thimerosal (Merthiolate) has
been reported to be an effective agent but contains
mercury. 8 The US Food and Drug Administration
(FDA) has banned the use of mercury compounds as
topical antiseptics because of their potential for sys-
temic toxicity.9
The goals of management of otomycosis are to
relieve symptoms, eliminate disease, and prevent recur-
rence. This is accomplished by identifying the infecting
organisms, identifying and treating any predisposing
factors, cleansing and drying the ear, and applying
topical antifungal medications. Systemic antifungals
may be necessary as a last resort in refractory cases.
Several well-recognized factors increase a patients
susceptibility to fungal infections and their complica-
tions. Alterations in the immune state (primarily cellu-
lar immunity), systemic steroids, prolonged use of
antibiotics, and diabetes can all increase the chance of
developing fungal ear infections. Other factors that pre-
dispose the patient to otomycosis include the warmth,
humidity, and configuration of the ear canal, the pres-
ence of open mastoid cavities, hearing aids with occlu-
sive molds, trauma, and bacterial infections. The use of
topical antibiotics or steroids, loss of cerumen, and
water exposure have been previously implicated as pre-
disposing factors, but it is not clearly established if they
play a role in the development of otomycosis.
Meticulous dbridement is the mainstay of treat-
ment of otomycosis. Cleansing removes the offending
fungi, along with secretions and debris that provide
nutrition for the organism, and allows topical medica-
tion to reach the affected area. Cleansing should be per-
formed with the operating microscope. If irrigation is
employed, microscopic examination should be per-
formed after its completion. Dbridement should be
repeated frequently. The entire ear must be meticulously
cleaned, with special attention directed to the pretym-
panic sulcus. The sulcus is the site of many early infec-
tions, and failure to clean this area may be responsible for
recurrences.10 After the ear is cleaned, it should be dried
with gentle mopping using a cotton-tip applicator or air.
At the time of the initial cleaning, specimens may
be sent for cultures in order to identify the fungal
species. Although not necessary in all cases, the use of
cultures will help direct therapy and is especially
important for recurrent or resistant infections.
Despite the need for a topical medication for oto-
mycosis, there is no FDA-approved otic preparation that
is specific for the treatment of otomycosis.1114 Con-
sequently, many agents with antimycotic properties have
been used to treat otomycosis, but there are limited data
available as to which agents are the most effective in
treating this condition. Since manufacturers have not

pursued approval for ototopical application, the ototoxic
properties of these preparations have not been well stud-
ied. In many instances, patients with otomycosis also
have communications between the external ear and the
middle ear space, including those with pressure equal-
ization (PE) tubes, tympanic membrane perforations,
and open mastoid cavities. Wright and Meyerhoff have
shown that antibiotic otic drops readily pass through a
patent PE tube into the middle ear and onto the round
window in chinchillas.15 Any topical antibacterial or
antifungal medication can reach the cochlea by diffusion
through the round window membrane (RWM). If the
agent has ototoxic properties, temporary or permanent
electrophysiologic changes within the inner ear or mor-
phologic injury to the stria vascularis, hair cells, and
supporting cells of the organ of Corti may occur.
In general, studies designed to assess the ototoxic-
ity of antifungal agents in humans have been flawed
because they have been based on clinical impressions
such as the lack of side effects and not on objective
measurements of ototoxicity.1,14 Alternatively, electro-
physiologic and histologic investigations of potential
ototoxic effects of some topical antimycotic medica-
tions have been performed in animals.1619 Although
differences in the anatomy, methods of testing, and
assessment make comparisons of ototoxicity between
animals and humans difficult, the animal studies do
have clinical relevance. If a preparation has been shown
not to be ototoxic in animals, it is not likely to be oto-
toxic in humans. Knowledge of the presence or absence
of potential ototoxicity of specific agents offers the clin-
ician guidance regarding the choice of a particular top-
ical antifungal medication when there is potential of
exposure to the RWM.
The choice as to which topical medication to use
should be based on the susceptibility of the infecting
species, the efficacy of the topical agent, and the poten-
tial ototoxic side effects. Antiseptics are not specific
antifungal agents but achieve their therapeutic effects
through secondary actions. Specific antifungal med-
ications have been developed, but none is available as
an otic preparation. Alcohol, acetic acid, boric acid,
M-cresyl acetate, and gentian violet have been used to
treat otomycosis for over 50 years.20 Clotrimazole,
miconazole, econazole, nystatin, tolnaftate, potassium
sorbate, and polysorbate are newer agents that have
also been reported to be effective in the management
of otomycosis.1,11,12,2025
ANTISEPTICS
Alcohol is a solvent and antiseptic that works by dry-
ing out the ear canal and may prevent the recurrence of
otomycosis. Alcohol has been frequently combined
with other substances to supplement their antimycotic
actions. When it is applied to the middle ear, alcohol
causes inflammation and pain and may be ototoxic.
Topical Antifungals 135
Evaluating cochlear microphonics and endocochlear
direct current potential, Morizono and Sikora have
demonstrated that ethanol is ototoxic when applied to
the middle ears of guinea pigs.26
Manning has suggested that most cases of otomy-
cosis can be treated with topical therapy of mild acidic
drops27 because fungal cells die when the pH is less
than 4.28 Acidifying agents, such as acetic acid and boric
acid, have long been used to treat this condition. Boric
acid relieves pain, decreases inflammation, and
destroys spores. It is available as a solution or powder,
which also has a drying effect. In regions where specific
antifungals are too expensive or unavailable, boric acid
powder has been recommended as the treatment for
otomycosis.29 It is not known whether boric acid causes
ototoxicity. Acetic acid, however, has produced small
auditory brainstem threshold shifts in guinea pigs, sug-
gesting the potential for ototoxicity, and when acetic
acid is combined with the solvent propylene glycol
(VoSol), the ototoxic effects have been shown to
increase substantially.23
M-cresyl acetate solution (Cresylate) is an anti-
septic with antibacterial, antifungal, and anesthetic
properties. In the ear canal it causes exfoliation of
epithelium, reduction of pain, prevention of sporula-
tion, and inhibition of secondary bacterial infection.5
In the past it has been widely used to manage otomy-
cosis.13,28 Cresylate is often applied to the affected ear
via a wick, which is then saturated with the solution. It
is approved for use in the external ear but has some
disadvantages. It has a bad odor, may burn, and is dif-
ficult to obtain. Cresylate is not recommended for use
in the presence of a tympanic membrane perforation.30
Cresylate has been shown to be ototoxic in guinea pigs.
In one study, auditory brainstem responses became sig-
nificantly reduced 1 hour after it has been injected into
the auditory bulla.17
Gentian violet, an aniline dye, is an antiseptic,
which has anti-inflammatory, antibacterial, and anti-
fungal properties, and has been used to treat otomyco-
sis for over 60 years. Although it appears to be effective,
it stains skin and clothing, which can result in non-
compliance. Gentian violet has been shown to inhibit
the growth of several species of Aspergillus, and in one
study 81% of patients with otomycosis improved after
treatment with gentian violet.1 Gentian violet, how-
ever, is ototoxic. Spandow and colleagues reported that
when it is applied to the round window niche of rats,
the latencies of auditory evoked potentials increase.16 In
another study that was designed to evaluate
histopathology of the cochlea following instillation of
several antifungal agents, gentian violet was found to be
significantly ototoxic if it enters the middle ear.19 This
study was intended to dose 10 animals with gentian
violet, but only 4 were dosed because the dye produced
such dramatic, adverse changes. Three of the four
136 Topical Toxicity
guinea pigs developed torticollis, a behavioral response
typical of severe vestibular injury. After the animals
were sacrificed, three of the four had new bone growth
that affected all surfaces of the middle ear; in two ani-
mals, the middle ear space was virtually obliterated by
granular bone deposits. The cochlea was opened in one
specimen, and the basal turn was filled with scar tissue.
The intended histologic studies could not be performed
because of the extreme new bone growth and cochlear
fibrosis. Gentian violet should be used with great cau-
tion if there is a chance of its reaching the middle ear.
SOLVENTS
Propylene glycol is a common ingredient of many otic
preparations and serves as solvent carrier and pene-
trance enhancer. Glasgold and Boyd reported that a
solution containing 99.9% propylene glycol and 0.1%
dexamethasone effectively treated otomycosis and sur-
mised that the hydrophilic and hydroscopic properties
of the propylene glycol were responsible for the anti-
fungal effects.31
Propylene glycol, however, has been shown to cause
severe middle ear inflammation and cochlear toxicity in
animals. Two studies by Morizono and colleagues
demonstrated that there was a reduction in the cochlear
microphonics of guinea pigs and chinchillas after weak
concentrations of propylene glycol were instilled into the
animals auditory middle ears.32,33 Further, in comparing
chinchillas that had been treated with similar topical
medications differing only in their concentrations of
propylene glycol, Vassalli and colleagues found signifi-
cant middle ear inflammatory changes, including fibrous
adhesions and serous effusions and the development of
cholesteatomas in ears treated with a 10.5% concentra-
tion of propylene glycol compared with those treated
with a 2% concentration, which developed no lesions.34
They concluded that propylene glycol was the agent most
likely responsible for these changes. To limit the risk of
sensorineural hearing loss during ototopical therapy,
Pickett and colleagues suggested that agents containing
propylene glycol should be avoided unless there is clear
clinical advantage.35 Preparations containing high con-
centrations of propylene glycol probably should not be
used when there is potential access to the middle ear.
ANTIFUNGALS
Although systemic and topical antifungal medications
are readily available, the FDA has not approved these
compounds for use in the ear. Despite this lack of
approval, many antifungal medications are commonly
used topically in the ear to treat otomycosis. Since the
efficacy of these newer preparations has varied and has
not been well studied, there is no consensus regarding
which topical agent is most useful in eradicating this
condition. In addition, several recommended drugs
have limited availability or are no longer available.
The newer agents can be grouped into three general
categories: polyenes, azoles, and miscellaneous.1,36 The
polyenes are macrolides, which inhibit sterol synthesis
in the cell membrane, leading to increased membrane
permeability and death. They include amphotericin B,
natamycin, and nystatin. The azoles are synthetic agents
that reduce the concentration of ergosterol, an essential
sterol in the normal fungal cytoplasmic membrane, and
include clotrimazole, fluconazole, ketoconazole, bifon-
azole, and econazole. In the miscellaneous category are
tolnaftate, polysorbate, and potassium sorbate, which
have different mechanisms of action.
Nystatin is the only commercially available topical
polyene presently used to treat otomycosis. Ampho-
tericin B is no longer available as a commercial, topical
medication but is administered intravenously for seri-
ous fungal infections. Amphotericin B powder is used
for the preparation of intravenous solutions. This med-
ication can be obtained through a pharmacy either as
powder or prepared into solution for instillation into
the ear. It is not known whether amphotericin B is oto-
toxic. Natamycin is no longer available. Nystatin can be
administered as a cream, ointment, or powder or can be
made into a solution. Insufflation of nystatin powder
into affected ears also helps to eliminate moisture. Oral
nystatin may also supplement topical therapy.37 Ny-
statin is one of the most effective topical antifungal
agents because it has a wide spectrum of activity.
Although nystatin has not been reported to be oto-
toxic, it may be prudent to avoid its use when there may
be access to the middle ear. In one study to determine
cochlear hair cell toxicity, nystatin-treated animals were
free of any hair cell damage, but a persistent residue of
the medication or vehicle remained in the round win-
dow niche weeks after application.19 The significance of
this finding is unknown but raises a concern for poten-
tial middle ear toxicity.
Several azoles have been instilled into the ear to
treat otomycosis. Bifonazole and econazole are no
longer available. Miconazole is available as a cream that
can be instilled into the ear. Stern and colleagues found
that miconazole is effective in vitro, but it does not
appear to be as potent as some other azoles.11 It does
not appear to cause middle ear or cochlear injury.19
Clotrimazole is the most widely used topical azole,
and it appears to be one of the most effective agents for
the management of otomycosis. 1,11,12,14,23 It has an
antibacterial effect, and this is an added advantage
when treating mixed bacterial-fungal infections. Clotri-
mazole comes in a solution, lotion, and powder. Kwok
and Hawke have reported that a single application of
powder is superior to repeated applications of lotion.38
The powder coats the entire canal, delivers a higher
concentration of medication, and decreases the humid-
ity within the canal. In addition, the carrier vehicle for
the liquid preparations of clotrimazole frequently

irritates the underlying inflamed skin and exposed
middle ear mucosa, causing pain. Pain is a common
reason for noncompliance when clotrimazole liquid is
applied in the presence of a tympanic membrane per-
foration or patent PE tube. Clotrimazole is relatively
free of ototoxic effects. Marsh and Tom reported that
after it was applied to the middle ear of guinea pigs
there was a small shift in the auditory brainstem thresh-
olds, suggesting a slight hearing loss.17 There has been
no clinical evidence of clotrimazole ototoxicity, and
histologic examinations have demonstrated that clotri-
mazole does not cause any cochlear hair cell loss.1,14,19
The systemic azoles, ketoconazole and fluconazole,
have a limited but useful role in the management of oto-
mycosis. Although they have a broad spectrum of activ-
ity, these agents are effective in treating Candida and not
Aspergillus. Lucente has recommended that these drugs
be used as adjuvants to topical therapy in refractory
cases.28 Cohen and Thompson reported that they
successfully managed 8 of 10 children with Candida
infection of the middle ear or mastoid with oral ketacon-
azole.39 However, fluconazole has a more favorable phar-
mocologic profile and may be superior to ketaconazole in
the management of Candida infections. Hepatotoxicity is
a rare but potentially fatal side effect of both these med-
ications, and they should be prescribed only after con-
sultation with a physician who is familiar with their use.28
Tolnaftate is one of the most popular antifungal
agents. It is available as a solution, cream, or powder
and can easily be instilled into the ear. Tolnaftate acts
by distorting hyphae and inhibiting the mycelial
growth of susceptible fungi. It is a potent antifungal
agent with a broad spectrum of activity. It has been
recommended as an excellent choice for refractory
cases of otomycosis and is well tolerated, with virtually
no side effects. Its only disadvantage is that it may be
ineffective against Candida sp.1 Tolnaftate is not oto-
toxic. Virtually no changes in auditory brainstem
responses were found after instillation of tolnaftate
solution into the middle ears of guinea pigs.17 When
compared with untreated control animals, tolnaftate
did not cause any middle ear injury, and there was no
evidence of hair cell toxicity.19
Potassium sorbate and polysorbate are mold and
yeast inhibitors. Fairbanks has reported that potassium
sorbate is an effective topical agent for otomycosis.40
Although they are not available as primary active
ingredients in any topical medication, potassium
sorbate and polysorbate have been added to several
well-known ototopical preparations such as Corti-
sporin TC Otic Suspension and Cipro HC Otic Sus-
pension because of their antifungal properties.
Studies do not exist that report on the ototoxic poten-
tial of either agent. However, polysorbate is presumed
to be safe to use in the ear because Cipro HC Otic
Suspension lacks ototoxicity.
Topical Antifungals 137
APPLICATION
There is no consensus regarding the best way to apply
these topical agents. Application of ointment, insuffla-
tion of powder, and instillation of drops have all been
recommended.2,28,38 Instillation of drops is the easiest
method of application, but powder has advantages over
drops because it can coat the surface, deliver a higher
concentration of medication, and reduce humidity.
The status of the ear should be considered when
choosing the vehicle. Powder is preferred when the ear
is wet and macerated and when there is an open
mastoid cavity.4,21 Drops may be easier for the patient
to apply but are more likely to enter the middle ear if
there is a defect in the tympanic membrane. Drops may
be beneficial if the infection involves the middle ear, but
the medication may produce inflammatory changes,
causing pain, discomfort, and local injury. Entrance
into the middle ear also increases the chance that the
drug may diffuse through the RWM into the inner ear
causing cochlear ototoxicity. Insertion of gauze or a
polyvinyl acetal wick into the ear canal or mastoid
cavity and impregnating it with the medication is an
excellent way to maintain continuous tissue contact
and therapeutic levels while minimizing the potential
for cochlear ototoxicity.
CONCLUSION
Cleansing and drying of the ear and application of top-
ical antifungal medications are important in the man-
agement of otomycosis. Although no FDA-approved
otic preparation exists that is specific for the treatment
of otomycosis, several antiseptics and antifungal agents
are effective in managing this condition (Table 15-1).
Table 15-1 Available Topical Agents Used to Treat
Otomycosis
Agent Ototoxicity
Antiseptics
Alcohol Yes
Acetic acid Yes
Boric acid Unknown
Gentian violet Yes
M-cresyl acetate (Cresylate) Yes
Antifungals
Amphotericin B Unknown
Clotrimazole No
Miconazole No
Nystatin Probably not
Tolnaftate No
138 Topical Toxicity
The decision as to which medication to use should be
based on the susceptibility of the infecting species, effi-
cacy of the agent, and, when a communication with the
middle ear is present, the potential ototoxicity.
Electrophysiologic and histologic studies in ani-
mals suggest that the antiseptics used to treat otomy-
cosis are ototoxic, whereas the antifungals are nontoxic
to the inner ear. Clotrimazole and tolnaftate are the
most effective antifungal agents, and if the middle ear
space communicates with the external ear, they are
potentially the safest choices.
SUMMARY
Otomycosis commonly occurs in humid, tropi-
cal, and subtropical environments. Aspergillus
and Candida spp appear to be most responsible.
Risk factors when normal external and middle
ear anatomy exists include defects in cellular
immunity, systemic steroids, diabetes, and the
prolonged use of topical antibiotic drops. The
presence of an open mastoid cavity or the wear-
ing of an occlusive hearing aid also appear to be
predisposing factors.
Removal of infected debris, drying of the ear,
and application of topical antifungals remain
important in the management of otomycosis.
Special attention should be focused on meticu-
lous cleansing of the pretympanic sulcus, which
is the site of many early infections and the area
responsible for recurrences.
No FDA-approved otic solution for treatment of
otomycosis exits at the present time. Antiseptics,
solvents, and antifungals have all proven effec-
tive. Most animal studies, however, demonstrate
significant inner ear toxicity from commonly
used antiseptics should they reach the middle ear
through a tympanic membrane defect, a point
not to be overlooked in humans. Topical anti-
fungals such as nystatin, tolnaftate, and those of
the azole class (eg, clotrimazole or miconazole)
appear to be safe without the risk for ototoxicity.
The decision to use a specific topical treatment
for otomycosis should be based on the infective
pathogen, its susceptibility, the efficacy of a
known treatment, and whether a defect exists in
the tympanic membrane.
REFERENCES
1. Paulose KO, Al Khalifa S, Shenoy P, Sharma RK.
Mycotic infection of the ear (otomycosis): a
prospective study. J Laryngol Otol 1989;103:305.
2. Mugliston T, ODonoghue G. Otomycosisa con-
tinuing problem. J Laryngol Otol 1985;99:32733.
3. Hirsch BE. Disease of the external ear. Am J Oto-
laryngol 1992;13:14555.
4. Selesnick SH. Otitis externa: management of a
recalcitrant case. Am J Otol 1994;15:40812.
5. Gill K. Otitis externa mycotica: comments con-
cerning the prevalence, diagnosis and treatment of
otomycosis. Arch Otolaryngol 1932;16:7682.
6. Conley JJ. Evaluation of fungous disease of the
external auditory canal. Arch Otolaryngol 1948;
47:72145.
7. Ismail HK. Otomycosis. J Laryngol Otol 1962;
76:7139.
8. Schneider ML. Merthiolate in treatment of otomy-
cosis. Laryngoscope 1981;91:11945.
9. Status of certain additional over-the-counter Drug
Category II and III active ingredients. Federal
Register. April 22, 1998. 19799802.
10. Beaney GPE, Broughton A. Tropical otomycosis. J
Laryngol Otol 1967;81:98797.
11. Stern JC, Shah MK, Lucente FE. In vitro effective-
ness of 13 agents in otomycosis and review of the
literature. Laryngoscope 1988;98:11737.
12. Lawrence TL, Ayers LW, Saunders WH. Drug ther-
apy in otomycosis: an in vitro study. Laryngoscope
1978;88:175560.
13. Saunders WH. Otomycosis. In: Gates GA, editor.
Current therapy in otolaryngology-head and neck
surgery 19841985. Toronto: BC Decker; 1984.
p. 12.
14. Bassiouny A, Kamel T, Moawad MK, et al. Broad
spectrum antifungal agents in otomycosis. J Laryn-
gol Otol 1986;100:86773.
15. Wright CG, Meyerhoff WL. Ototoxicity of otic
drops applied to the middle ear in the chinchilla.
Am J Otolaryngol 1984;5:16676.
16. Spandow O, Anniko M, Mller AR. The round
window as access route for agents injurious to the
inner ear. Am J Otolaryngol 1988;9:32735.
17. Marsh RR, Tom LWC. Ototoxicity of antimycotics.
Otolaryngol Head Neck Surg 1989;100:1346.
18. Parker FL, James GWL. The effect of various
topical antibiotic and antibacterial agents on the
middle and inner ear of the guinea-pig. J Pharm
Pharmacol 1978;30:2369.
19. Tom LWC. The ototoxicity of common topical
antimycotic preparations. Laryngoscope 2000;
110:50916.
20. McBurney R, Searcy HB. Otomycosis: investiga-
tion of effective fungicidal agents in treatment.
Ann Otol Rhinol Laryngol 1936;45:9881008.
21. Smyth GDL. Fungal infections in the post-operative
mastoid cavity. J Laryngol Otol 1962;76:797821.
22. Damato PJ. Treatment of otomycosis due to
Aspergillus niger with tolnaftate. St. Luke Hospital
Gazette 1966;1:668.
23. Maher A, Bassiouny A, Moawad MK, et al. Otomy-
cosis: an experimental evaluation of six antimyotic
agents. J Laryngol Otol 1982;96:20513.

24. Liston SL, Siegel LG. Tinactin in the treatment of
fungal otitis externa. Laryngoscope 1986;96:699.
25. Rohn GN, Meyerhoff WL, Wright CG. Ototoxicity
of topical agents. Otolaryngol Clin North Am
1993;26:74758.
26. Morizono T, Sikora MA. Ototoxicity of ethnol in
the tympanic cleft in animals. Acta Otolaryngol
1981;92:3340.
27. Manning SC. Mycoses. In: Paparella MM, Schum-
rick DA, Gluckman JL, et al, editors. Otolaryngol-
ogy. 3rd ed. Philadelphia: WB Saunders; 1991.
p. 595.
28. Lucente FE. Fungal infections of the external ear.
Otolaryngol Clin North Am 1993;26:9951006.
29. Than KM, Naing KS, Min M. Otomycosis in
Burma and its treatment. Am J Trop Med Hyg
1980;29:6203.
30. Fairbanks DNF. Pocket guide to antimicrobial
therapy in head and neck surgery. Alexandria (VA):
The American Academy of Otolaryngology-Head
& Neck Surgery Foundation; 1991. p. 36.
31. Glasgold AI, Boyd JE. Otitis externa: control of bac-
terial and mycological infectionsa preliminary
report. Eye Ear Nose Throat Mon 1973;52:946.
32. Morizono T, Johnstone BM. Ototoxicity of chlor-
amphenicol ear drops with propylene glycol as a
solvent. Med J Aust 1975;2:6348.
Topical Antifungals 139
33. Morizono T, Paparella MM, Juhn SK. Ototoxicity
of propylene glycol in experimental animals. Am J
Otolaryngol 1980;1:3939.
34. Vassalli L, Harris DM, Gradini R, et al. Inflamma-
tory effects of topical antibiotic suspensions con-
taining propylene glycol in chinchilla middle ears.
Am J Otolaryngol 1988;8:15.
35. Pickett BP, Shinn JB, Smith MFW. Ear drop oto-
toxicity: reality or myth? Am J Otol 1997;
18:78291.
36. Neibart E, Gumprecht J. Antifungal agents and the
treatment of fungal infections of the head and neck.
Otolaryngol Clin North Am 1993;26:112331.
37. Jahn AF, Hawke M. Infections of the external ear.
In: Cummings CW, Frederickson JM, Harker LA, et
al, editors. Otolaryngologyhead and neck surgery.
2nd ed. St. Louis (MO): Mosby Year Book; 1993.
p. 278794.
38. Kwok P, Hawke M. Clotrimazole power in the
treatment of otomycosis. J Otolaryngol 1987;
16:398.
39. Cohen CR, Thompson JW. Otitic candidiasis in
children: an evaluation of the problem and effec-
tiveness of ketoconazole in 10 patients. Ann Otol
Rhinol Laryngol 1990;99:42731.
40. Fairbanks DNF. Otic topical agents. Otolaryngol
Head Neck Surg 1980;88:32731.
 CHAPTER 16

Surgical Disinfectants and Antiseptics

Andrew R. Scott, BM, BS, MPhil, FRCS(ORL-HNS),
Narayanan Prepageran, MBBS, FRCS(Ed), FRCS(Glas), MS(ORL),
and John A. Rutka, MD, FRCSC

Potential ototoxicity of topical skin preparations was
first highlighted by Bicknell in 1971.1 Fourteen patients
from a series of 97 who underwent myringoplasty
experienced a severe sensorineural hearing loss within
the first 6 months of the operation, 13 having dead ears.
The only common factor appeared to be the use of
chlorhexidine (0.5% in 70% spirit) for preoperative
sterilization. All cases had dry perforations, and the
presumed mechanism of ototoxicity was that the ster-
ilizing agent had entered the inner ear via the round
window membrane (RWM).
CHLORHEXIDINE
Chlorhexidine is an ingredient in various preparations
available for preoperative hand and general skin disin-
fection in concentrations varying between 0.015% and
5%, depending on the preparation and its intended
use; the higher concentrations are generally for hand
washing of the surgical team.2 It is available in aqueous
solution, in 70% alcohol, or combined with cetrimide
and has a broad spectrum of antimicrobial activity.2
The chlorhexidine molecule is positively charged and
acts by disrupting the cell membrane and precipitating
the cytoplasm of the susceptible microbe.3
Since the publication of Bicknells original clinical
paper in 1971, several animal studies have been per-
formed to examine the potential ototoxicity of chlor-
hexidine. Aursnes examined morphological changes in
the organ of Corti and also, in a separate study, on the
vestibular neuroepithelium of guinea pigs exposed to
chlorhexidine via topical application to the middle ear.
Damage was observed in the sensory epithelia of both
sites and was related to the concentration of chlorhex-
idine, the duration of exposure, and the time lapse after
exposure.4,5 Similar studies were carried out by Igarashi
and colleagues on cats.6,7 Two different concentrations
of chlorhexidine (2% and 0.05%) were applied, and
saline was used as a control substance in the contralat-
eral ears. In the cochlear study, nine animals were sac-
rificed and examined immediately after completion of
application of the test solution whereas another three
were looked at 4 weeks later. Again, damage to the sen-
sory epithelium was seen and was related to the con-
centration of chlorhexidine applied and the time lapse
after exposure (ie, the injury had progressed in the
period following exposure). Specifically, hair cell
degeneration with loss of hair bundles was observed on
electron microscopy. Further, the damage was more
apparent in the lower cochlear turns, as would be
expected if the portal of entry was via the RWM. The
vestibular damage included degeneration of afferent
nerve endings with dilatation of the nerve terminals
and degenerative changes of the mitochondria within
the nerve terminals. These changes were evident on
both type 1 and type 2 vestibular hair cells.
In a further study to examine the ototoxicity of
antiseptics in an animal model, an electrophysiologic
approach was employed.8 Perez and colleagues used
auditory brainstem responses (ABRs) to measure audi-
tory function and the relatively new technique of short-
latency vestibular evoked potentials (VEPs) to measure
vestibular function. VEPs can be measured in response
to angular and linear acceleration. The first peak of the
VEP represents the compound action potential (CAP)
of the vestibular nerve and is therefore dependent on
(and hence a measure of) end-organ function.8 Rats
were used as the animal model, and each initially
underwent a right-sided surgical labyrinthectomy. Sub-
sequent testing could then be performed on animals
with only unilateral cochleovestibular function, sim-
plifying interpretation of the VEPs and avoiding mask-
ing issues with ABRs. In addition to the test solutions,
saline was used as a negative control and gentamicin
(known to be ototoxic) as a positive control to check
experimental conditions. The rats were randomly
assigned to receive topical application of one of the test
solutions or controls. The chlorhexidine group received
a dose of 0.5% chlorhexidine in aqueous solution. In all
five animals that received chlorhexidine the VEPs and
ABRs were completely abolished, similar to the findings

with gentamicin and at postmortem examination. All
in the saline group preserved normal function. This
model, therefore, clearly demonstrates cochlear and
vestibular loss of function following chlorhexidine
application. Nonetheless, direct extrapolation to
humans is always difficult owing to possible species
effects and anatomical differences, particularly in the
region of the RWM.
ALCOHOLS
Alcohols are used alone or in combination with other
disinfectant agents for skin preparation. They are also
used as excipients for a wide variety of agents. One of
the problems in assessing ototoxicity of many prepara-
tions is identifying which of the components is poten-
tially ototoxic. Further, some evidence shows that
topical alcohol on its own may be toxic to the inner ear.
When Perez and colleagues evaluated VEPs and ABRs
following topical antiseptics (described above), 70%
ethyl alcohol was also evaluated. Complete loss of both
ABR and VEP was observed in two of five animals, and
a loss or elevated ABR threshold was observed in the
remaining three (VEPs remaining normal). This clearly
raises concern for all alcohol-based preparations.
IODINE
Iodine-containing skin preparations are numerous and
may be aqueous or alcohol based, with or without a
detergent. In 1982 Morizono and Sikora examined the
ototoxicity of two commonly used povidone-iodine
preparations applied topically to chinchilla middle
ears.9 They compared povidone-iodine scrub, which
contains a detergent (0.75% available iodine), and
povidone-iodine solution, which does not (1% avail-
able iodine). Ringers solution was used as a diluent and
control. The main outcome measures were CAPs
recorded from the round window in response to tone
bursts (a method of assessing cochlear dysfunction);
these were recorded during the first 2 hours in one
group of animals and at 24 hours in another group. A
toxic effect on cochlear function was reported with the
povidone-iodine scrub even at a 1:100 dilution. The
povidone-iodine solution produced measurable toxic
effects at concentrations greater than 1:4. Further, the
cochlea appeared to be affected in a gradient manner,
with the higher frequencies of the basal turn being
most susceptible. This fits with the presumed route of
toxicity via the RWM. The authors postulated that the
presence of detergent in the scrub may allow the solu-
tion to diffuse through the RWM more easily, thus
accounting for the increased effects. However, the pos-
sibility that the detergent is directly toxic must be con-
sidered.10 Again, extrapolating these results to humans
is difficult. The chinchilla RWM is six times thinner
than that of humans, and hence the risk to humans may
be overstated.9 In another animal study by Aursnes in
Surgical Disinfectants and Antiseptics 141
1982, topical iodine toxicity was assessed morphologi-
cally in guinea pigs. Evidence of damage to the organ
of Corti and also to vestibular receptors was observed
with alcohol-based iodine preparations (70% alcohol)
but not with aqueous preparations.11 The potential
direct toxicity of alcohol must also be considered and
indeed may have accounted for all of the damage seen.
Povidone-iodine was also evaluated in the previously
described study by Perez using VEPs and ABRs as out-
come measures.8 In all five animals exposed to povi-
done-iodine solution (10%), there was no apparent
effect on VEPs, with only a minimal effect, if any, on
ABRs. The effect on ABR was a prolongation of the
latency of the first wave, without change in amplitude.
The authors discussed that this may be accounted for
by a minimal conductive hearing loss secondary to
thickening of the middle ear mucosa observed in this
test group. Overall, the evidence for topical ototoxicity
of iodine in skin preparation solutions appears to be
low but conflicting at this time.
QUATERNARY AMMONIUM COMPOUNDS
Quaternary ammonium compounds have been used as
biocides since the 1930s.12 Benzalkonium chloride, ben-
zethonium chloride, and cetrimide are members of this
group of compounds used for skin disinfection.
Cetrimide is probably best known in combination with
chlorhexidine as Savlon. Benzalkonium chloride and
benzethonium chloride are also used as preservatives in
some drug preparations. In particular, benzalkonium
chloride is a component of some ototopical prepara-
tions including Floxin Otic, Betnesol, Predsol,
Gentisone HC, Genticin, Garamysin, Predsol-N,
Betnesol-N, and Vista-Methasone.2,3
The potential ototoxicity of benzalkonium chlo-
ride and benzethonium chloride was tested in an ani-
mal model by Aursnes in 1982.13 Each compound was
administered topically to guinea pig middle ears in a
concentration of 0.1% in both aqueous and alcohol
bases (70%). When examined morphologically, using
phase contrast microscopy, damage to the neuroep-
ithelium of both cochlear and vestibular parts of the
inner ear was observed. The extent of damage was
related to the duration of exposure to the test com-
pound as well as the time from exposure to sacrifice.
Possible ototoxicity to Savlon has been reported in
the veterinary literature. Vestibular dysfunction was
observed in 12 dogs and 3 cats following topical ear
treatment by the veterinary practitioner.14 In eight of
the cases it was confirmed that the ear canal had been
rinsed with Savlon in the presence of a tympanic mem-
brane perforation. Of course, ototoxicity may have
been a result of the chlorhexidine component. How-
ever, the authors conducted their own study on the
cetrimide (15%) component alone.14 This was instilled
into unilateral middle ears of two guinea pigs. Signs of
142 Topical Toxicity
vestibular dysfunction on the treated side were
observed after 2.5 hours. These included rotation of the
head with the treated ear down, deviation of the eyes
toward the treated side, nystagmus with a fast compo-
nent away from the treated side, and a tendency to cir-
cle toward the treated side. The signs resolved within
24 hours. Cetrimide ototoxicity is suggested.
PROPYLENE GLYCOL
Propylene glycol is one of the most common solvents
used as a vehicle for drug delivery. It is used in some
topical ear preparations, including chloramphenicol
ear drops, Molcer, Audax, Audicort, and Tri-Adcortyl.2
Morizono and colleagues addressed the question of
ototoxicity of propylene glycol in an animal model.15
They looked at the functional effects as well as the mor-
phologic effects of propylene glycol in varying concen-
trations on the guinea pig and chinchilla ear. Cochlear
microphonics were measured in the guinea pigs, and
endocochlear potentials were measured in guinea pigs
and chinchillas. Ringers solution was used as the dilu-
ent and as a control. They found that a 50% solution or
stronger always caused a reduction in the cochlear
microphonics. The effects at lower concentrations var-
ied among the guinea pigs, but one animal had record-
able changes with only a 10% solution, although it was
applied for 6 days. Dose-related changes in the endo-
cochlear potentials were also noted. Histological
changes in the inner ear included destruction and ossi-
fication of the scala tympani and scala vestibuli and dis-
tortion of the organ of Corti. Inflammation of the
middle ear mucosa was also reported. In a previous
similar study, Morizono reported an irreversible reduc-
tion in cochlear microphonics with a 10% solution of
propylene glycol after only 24 hours.16 Other morpho-
logic studies have been conflicting. Stupp and col-
leagues and Parker and James reported inner ear hair
cell loss following topical application of propylene gly-
col to the middle ear.17,18 Vernon and colleagues, how-
ever, found only middle ear changes and no hair cell
loss above that found in the control animals.19 It is
obviously possible to have loss of function despite nor-
mal morphology; the physiologic outcomes may be
more sensitive.
ACETIC ACID
Acetic acid is a weak acid that is often included in otic
preparations for its antiseptic properties; for example it
is a component of aluminum acetate, Otomize, and
VoSol.2,20 In 1989, Ikeda and Morizono investigated the
ototoxicity of acetic acid in an animal model.20 The
effects of VoSol (2% acetic acid, 3% propylene glycol
diacetate, 0.02% benzethonium chloride, and 0.015%
sodium acetate dissolved in propylene glycol), 2% acetic
acid (dissolved in perilymph and adjusted to pH 4 with
NaOH), and a strong nonorganic acid (perilymph
adjusted to pH 4 with HCl) were compared. Changes in
endocochlear potentials and endolymph pH were
recorded. VoSol and the acetic acid solution caused a
depression of endocochlear potential and marked acid-
ification of endolymph whereas the HCl solution did
not. Further, the effect of VoSol was significantly more
than that of acetic acid alone, suggesting a direct or syn-
ergistic action of the propylene glycol component. The
authors postulated that the effects of acetic acid were a
result of its ability to cross the RWM and interfere with
enzymatic processes in the stria vascularis.
SKIN PREPARATION: RECOMMENDATIONS
The choice of ototopical agent in treating infection can
only be made based on the perceived benefit balanced
against the known risk for the specific patient circum-
stances encountered. But what of prophylactic use of
preparations to attempt to sterilize the ear prior to
surgery? Most surgeons would accept that it is desirable
to reduce the bacterial load around the operative site as
much as is safely possible, and it seems sensible to con-
tinue to apply skin preparation solutions to the pinna
and skin surrounding the ear. However, it is not neces-
sary to instill or apply these solutions to the ear canal if
there is a risk of them entering the middle ear either via
a perforation or during the procedure, particularly if
they are potentially ototoxic. To this end, it is standard
practice and teaching to occlude the ear canal with a
temporary barrier (ie, cotton wool) when the skin
preparation is applied to prevent it entering the ear
canal. Anecdotally, such practice does not appear to
increase the number of postoperative wound infections.
However, some surgeons feel it necessary to attempt to
disinfect the ear canal prior to surgery, and usually an
aqueous iodine solution is recommended.2123 Certainly
on the available evidence (mostly animal), aqueous
iodine preparations have the least potential for ototox-
icity. Another strategy is to flush the ear canal first with
the disinfectant and then with saline to remove it.24 This
seems reasonable when the tympanic membrane is
known prior to surgery to be intact.
The available evidence indicates that all of the
major types of skin preparation solutions have the
potential to be ototoxic. Chlorhexidine should be
avoided, and aqueous solutions are preferable to
alcohol-based ones.
SUMMARY
Animal models have demonstrated that nearly all
commonly used topical disinfectants, antisep-
tics, and excipients appear to be ototoxic should
they enter into the middle ear. Based on extrap-
olation from these experiments and on the few
series reports in humans, all chlorhexidene and
alcohol-based preparations should be avoided
during ear surgery when a tympanic membrane

perforation is present unless a temporary barrier
is applied to prevent middle ear exposure.
The resultant ototoxicity appears directly related
to the concentration, duration of exposure, and
the time lapse from exposure of the agent used.
Of all the solutions available at the time of
writing, aqueous iodine preparations are the
safest of all topically applied agents in humans.
REFERENCES
1. Bicknell PG. Sensorineural deafness following
myringoplasty operations. J Laryngol Otol 1971;
85:95761.
2. British Medical Association, Royal Pharmaceutical
Society of Great Britain. British National Formu-
lary. BNF45 (March 2003). London: Pharmaceuti-
cal Press; 2003.
3. Mosbys drug consult. Elsevier; 2003. Available at:
http://www3.us.elsevierhealth.com/DrugConsult/
(accessed August 2003).
4. Aursnes J. Vestibular damage from chlorhexidine
in guinea pigs. Acta Otolaryngol 1981;92:89100.
5. Aursnes J. Cochlear damage from chlorhexidine in
guinea pigs. Acta Otolaryngol 1981;92:25971.
6. Igarashi Y, Suzuki J. Cochlear ototoxicty of
chlorhexidine gluconate in cats. Arch Otorhino-
laryngol 1985;242:16776.
7. Igarashi Y, Oka Y. Vestibular ototoxicity following
intratympanic applications of chlorhexidine glu-
conate in the cat. Arch Otorhinolaryngol 1988;
245:2107.
8. Perez R, Freeman S, Sohmer H, Sichel JY. Vestibu-
lar and cochlear ototoxicity of topical antiseptics
assessed by evoked potentials. Laryngoscope
2000;110:15227.
9. Morizono T, Sikora MA. The ototoxicity of topi-
cally applied povidone-iodine preparations. Arch
Otolaryngol 1982;108:2103.
10. Austin DF. Ototoxicity of detergents. Arch Oto-
laryngol 1982;108:808.
11. Aursnes J. Ototoxic effect of iodine disinfectants.
Acta Otolaryngol 1982;93:21926.
12. Russell AD. Introduction of biocides into clinical
practice and the impact on antibiotic-resistant
bacteria. J Appl Microbiol 2002;92 Suppl:121S35S.
Surgical Disinfectants and Antiseptics 143
13. Aursnes J. Ototoxic effect of quaternary ammonium
compounds. Acta Otolaryngol 1982;93:42133.
14. Galle HG, Venker-van Haagen AJ. Ototoxicity of
the antiseptic combination chlorhexidine/cetrim-
ide (Savlon): effects on equilibrium and hearing.
Vet Q 1986;8:5660.
15. Morizono T, Paparella MM, Juhn SK. Ototoxicity
of propylene glycol in experimental animals. Am J
Otolaryngol 1980;1:3939.
16. Morizono T, Johnstone BM. Ototoxicity of chlor-
amphenicol ear drops with propylene glycol as
solvent. Med J Aust 1975;2:6348.
17. Stupp H, Kupper K, Lagler F, et al. Inner ear con-
centrations and ototoxicity of different antibiotics
in local and systemic application. Audiology
1973;12:35063.
18. Parker FL, James GW. The effect of various topical
antibiotic and antibacterial agents on the middle
and inner ear of the guinea-pig. J Pharm Pharma-
col 1978;30:2369.
19. Vernon J, Brummett R, Walsh T. The ototoxic
potential of propylene glycol in guinea pigs. Arch
Otolaryngol 1978;104:7269.
20. Ikeda K, Morizono T. The preparation of acetic
acid for use in otic drops and its effect on endo-
cochlear potential and pH in inner ear fluid. Am J
Otolaryngol 1989;10:3825.
21. Jackson CG. Principles of temporal bone and skull
base surgery. In: Glasscock ME, Gulya AJ, editors.
Surgery of the ear. 5th ed. Hamilton (ON): BC
Decker Inc; 2003. p. 271.
22. Shea MC Jr. Tympanoplasty: the undersurface
graft techniquetranscanal approach. In: Brack-
mann DE, Shelton C, Arriaga MA, editors. Oto-
logic surgery. 2nd ed. Philadelphia: WB Saunders
Co; 2001. p. 106.
23. Jackson CG, Glasscock ME, Strasnick B. Tym-
panoplasty: the undersurface graft technique
postauricular approach. In: Brackmann DE, Shel-
ton C, Arriaga MA, editors. Otologic surgery. 2nd
ed. Philadelphia: WB Saunders Co; 2001. p. 116.
24. Mandolis S. Closure of tympanic membrane perfo-
rations. In: Glasscock ME, Gulya AJ, editors. Surgery
of the ear. 5th ed. Hamilton (ON): BC Decker Inc;
2003. p. 407.
 Interventions
CHAPTER 17
Genetic Factors in Aminoglycoside Ototoxicity
Nathan Fischel-Ghodsian, MD
Aminoglycosides, which include gentamicin, strepto-
mycin, and tobramycin, are a group of clinically impor-
tant antibiotics that in Western countries are mainly
used in hospitalized patients with aerobic gram-
negative bacteria or in patients with tuberculosis.1,2 In
East Asia, aminoglycosides are often used as first-line
outpatient therapy for relatively minor infections, such
as otitis media and bronchitis. They are highly polar
cations, are generally not thought to be metabolized,
and are excreted almost entirely by glomerular filtra-
tion. Their main toxicities involve the auditory, vestibu-
lar, and renal systems. 1,2 The renal impairment is
usually reversible, whereas the vestibular and auditory
ototoxicity is frequently irreversible. Although all of
the aminoglycosides are capable of affecting both
cochlear and vestibular function, some (streptomycin
and gentamicin) produce predominantly vestibular
damage, others (amikacin, neomycin, kanamycin) pre-
dominantly cochlear damage, whereas tobramycin, for
example, affects both equally.1
In the United States, approximately 4 million
courses of aminoglycosides are administered annually.3
It is estimated that at least 2 to 5%, and in some stud-
ies up to 25%, of patients treated with these antibiotics
develop clinically significant hearing loss.46
OVERVIEW OF THE PATHOLOGIC AND
SUSPECTED MECHANISMS FOR AMINOGLYCOSIDE
CELLULAR TOXICITY
Structural and Functional Changes in
Aminoglycoside Ototoxicity
Animal and human temporal bone studies implicate
the cochlear neuroepithelium as the primary site of
injury associated with aminoglycoside ototoxicity,7,8
although occasionally neural destruction without
cochlear hair cell damage has been described.9 In gen-
eral, the damage is first seen in the outer hair cells of the
basal turn, and in more severe cases degenerative
changes extend into the upper cochlear turns and inner
hair cells.10 At the same time varying degrees of atrophy
of the stria vascularis can be observed.10 Some investi-
gators describe the appearance of swollen mitochon-
dria in the supranuclear portion of the cell as one of the
earliest ultrastuctural changes within the hair cells.11
Others have observed an increase in lysosomes, prolif-
eration of the endoplasmic reticulum, and formation of
Hensens bodies as the first ultrastructurally identifiable
changes.12 Later changes include the appearance of
multivesicular bodies, clumping of nuclear chromatin,
formation of giant, fused stereocilia, and, finally, extru-
sion of cell content.11 Associated with the morphologic
changes are functional changes, the earliest of which is
the decrease in cochlear microphonics.13 This is an
apparently reversible phenomenon owing to blockage
of ion-selective transduction channels in the hair
cells.14 Later elevations of auditory nerve thresholds are
observed, with the eventual occurrence of permanent
functional impairment.5,15
Mechanisms for Aminoglycoside-Induced
Cellular Toxicity
Aminoglycoside toxicity is thought to affect mainly kid-
ney and ear because the drugs are concentrated in renal
tubular cells and in the perilymph and endolymph of
the inner ear.16,17 The precise mechanism of hair cell
toxicity in the ear is unclear. The first step is the best
understood: the positively charged aminoglycosides are
attracted to the negatively charged glycocalyx present
on the apical surface of the hair cells; the drugs are then
bound to the stereocilia, which, in competition with
Ca2+, leads to a reversible interference with transduction
channels.14,18,19 The second step is thought to be the
entrance of the drugs into the cell, possibly from the
basal side, and interference with the biochemical
machinery of the cell. The precise mechanism of this
step, however, is speculative; that is, the binding of the
drug to phospholipids may or may not cause membrane
damage, or interference with the protein-producing or
processing machinery of the cell, or disturbed nucleic

acid synthesis.18,20,21 More recently, an activation of
gentamicin via the formation of an iron-gentamicin
complex followed by free radical formation within the
cell as the damage-producing intermediary has been
described (see Chapter 9, Mechanisms for Amino-
glycoside Ototoxicity: Basic Science Research).22
The wide variety of structural and functional
abnormalities described with aminoglycoside toxicity
underscores the need to identify those factors that are
primary events and those that are secondary responses
to injury. Identification of the genetic basis of many
inherited and acquired diseases could serve as a model
for identifying primary events. For example, sickle cell
disease with its various clinical signs of anemia, predis-
position to severe infections, severe pain, strokes, and
other various abnormalities, could be reduced to a sin-
gle point mutation in the -globin gene.23 Similarly, the
complex symptoms and pathologic and biochemical
changes of some cancers could be reduced to single
genetic events, with Philadelphia chromosomeposi-
tive chronic myelocytic leukemia and acute promyelo-
cytic leukemia as other examples.24,25 The identification
of primary events is an important step to develop pre-
ventive and therapeutic modalities.26
GENETIC SUSCEPTIBILITY FOR AMINOGLYCOSIDE
OTOTOXICITY
Evidence for Genetic Factors prior to
Molecular Testing
Although anecdotal reports of patients who lost hear-
ing after a single dose of aminoglycosides are not
uncommon, formal evidence for individual suscepti-
bility to aminoglycoside ototoxicity is difficult to doc-
ument in the literature. All retrospective studies lack
detailed information on some of the parameters
related to drug toxicity, such as drug dose, renal func-
tion at the time of drug administration, peak and
trough blood levels of the drug during administration,
kind and doses of concomitant medications with pos-
sible ototoxicity, and details of the underlying disease
treated with the antibiotic.1,27 One prospective study
implicated length of treatment, bacteremia, fever level,
and liver function with ototoxicity while, surprisingly,
finding no correlation with plasma levels of the drug.6
The question of individual variability in susceptibility
was not addressed.
Nevertheless, the existence of families with mul-
tiple individuals with ototoxic deafness induced by
aminoglycoside exposure was noticed early on. The
first families with more than two members with strep-
tomycin-induced hearing loss were initially described
in the Japanese literature in 1957.28 Prazic and col-
leagues described in 1964 a family with four sisters who
developed hearing loss after streptomycin injections.29
In 1971 Tsuiki and Murai described 16 families in
Genetic Factors in Aminoglycoside Ototoxicity 145
which two or more members had aminoglycoside oto-
toxicity.30 Konigsmark and Gorlin in 1976 summarized
most existing descriptions of familial aminoglycoside
ototoxicity and concluded that inheritance of the pre-
disposition was probably autosomal dominant with
incomplete penetrance. However, they also noted that
no male-to-male transmission had been seen and con-
cluded that the inheritance could be multifactorial.31 In
1989 Higashi reviewed the literature and concluded
that the most likely explanation for the maternal inher-
itance observed was on the basis of a mitochondrial
deoxyribonucleic acid (DNA) defect.28 In 1991 Hu and
colleagues in China described another 36 families with
maternally transmitted predisposition to aminoglyco-
side ototoxicity and concluded also that a mito-
chondrial defect might be responsible for this
predisposition.32
Additional evidence for a genetic basis for amino-
glycoside susceptibility comes from animal studies.
Macaque monkeys are apparently immune to the oto-
toxic effects of dihydrostreptomycin, whereas patas
monkeys appear to be highly sensitive to that drug.33
The mechanism of this differential susceptibility has
not been established but very likely is because of
genetic differences in these two species.
The model emerging from these data seems to
indicate that at very high total cumulative dose and
drug levels most individuals will exhibit toxicity,
whereas at lower cumulative drug levels, aminoglyco-
side ototoxicity results from genetic susceptibility in at
least some cases. The genetic susceptibility factors can
be at multiple levels, including drug uptake, drug inter-
actions within the cell, or at the level of tissue response
to the injury.
Identification of the First Aminoglycoside-
Susceptibility Mutation: The A1555G Mutation in
the 12S Ribosomal Ribonucleic Acid Gene
The pattern of maternal transmission of susceptibility
to aminoglycosides was the first hint that mutations in
the mitochondrial chromosomes could be the molecu-
lar basis for this susceptibility. Since the bactericidal
effect of aminoglycosides occurs through altering the
fidelity of translation of the genetic code34 and since
mitochondria are evolutionarily derived from bacteria,
in 1993 we proposed that susceptible individuals had
altered protein synthesis in the mitochondria when
exposed to aminoglycosides.35 We also proposed that
the mitochondrial 12S ribosomal ribonucleic acid
(rRNA) gene was the most likely gene to harbor such
mutations since the small rRNA had been shown to
bind to aminoglycosides and to harbor resistance muta-
tions in bacteria and in the mitochondria of yeast and
Tetrahymena.3638
In 1993 the same group analyzed the mitochondrial
genome of three Chinese families with 15 members with
146 Interventions
aminoglycoside ototoxicity and a pattern of inheritance
compatible with maternal inheritance. We identified a
A1555G mutation in the 12S rRNA gene in all three fam-
ilies and did not find this sequence change in 278 con-
trol individuals.35 Interestingly, this mutation lay exactly
in the region of the gene for which the resistance muta-
tions in yeast and Tetrahymena had been described and
in which aminoglycoside binding had been previously
documented in bacteria.3638 In addition, the mutation
made the mitochondrial RNA gene in this region more
similar to the bacterial rRNA gene.35
Subsequently, the same mutation was found in
families with aminoglycoside ototoxicity from all eth-
nic backgrounds and geographic origins.3944 Amino-
glycoside ototoxicity owing to the A1555G mutation
has also been described in a relatively small number of
individuals of different ethnic backgrounds with no
family history.39,45,46 Although the mutation is nearly
always found in homoplasmy, two reports from Spain
describe several families with the A1555G mutation in
a heteroplasmic state.42,47
It needs to be stressed that the A1555G mutation
appears to be a deafness-predisposing mutation in a
broader sense. Although aminoglycosides appear to be
a major trigger for the phenotypic expression of this
mutation, families with this mutation have been
described with hearing loss without exposure to
aminoglycosides,35,43 as well as families with hearing-
impaired members of whom only some were exposed
to aminoglycosides.40,42,43,48 In this regard we postulated
that instead of environmental factors such as amino-
glycosides, allelic variants of nuclear genes can also
interact with the A1555G mutation in such a way as to
precipitate hearing loss.49,50 A major locus for such a
modifier gene has been localized to chromosome 8,51,52
and two additional modifier genes have recently been
implicated through a candidate gene approach.53,54
Other Mitochondrial Predisposing Mutations
Since the A1555G mutation in the mitochondrial 12S
rRNA gene accounts for only a minority of aminogly-
coside ototoxicity, other susceptibility mutations pos-
sibly can be found in the same gene. DNA from 35
Chinese patients with sporadic aminoglycoside oto-
toxicity and without the A1555G mutation was ana-
lyzed for sequence variations in the 12S rRNA gene.
Three sequence changes were found; only one of them,
an absence of a thymidine at position 961 with vary-
ing numbers of cytosines inserted (961Cn), appeared
likely to be a pathogenic mutation.55 Analysis of 34
similar patients in the United States of varying ethnic
backgrounds did not reveal this mutation, but an Ital-
ian family with 5 maternally related members who all
became deaf after aminoglycoside treatment were
found to have the 961Cn mutation.56 This sequence
change was not found in 799 control individuals.55 A
recent report based on a newborn screening program
in Texas has found a significantly higher rate of the
961Cn mutation, with seven positive results of 1,173
unselected samples.57 A different study on 721 samples
from a repository of deaf probands in the United States
revealed a frequency of 1.2% for the 961Cn muta-
tion.58 It is not clear how many of these probands, if
any, were exposed to aminoglycosides. At this stage the
evidence for the 961Cn mutation as a predisposing
mutation for aminoglycoside ototoxicity is equivocal,
but prudence would suggest that individuals with this
mutation should avoid these antibiotics, in particular
if there is a family history of hearing loss after amino-
glycoside administration.
A third mitochondrial mutation predisposing to
aminoglycoside ototoxicity was recently identified in a
large Chinese pedigree with maternally inherited hear-
ing loss. 59 Family members in the maternal line
demonstrated hearing ranging from severe hearing loss
to normal hearing and when exposed to aminoglyco-
sides had a subsequent severe to profound hearing loss.
Mutational analysis of the mitochondrial 12S rRNA
gene did not reveal the A1555G or 961Cn mutations.
However, a homoplasmic C to T transition mutation
was identified at position 1494 in the 12S rRNA gene
and was not seen in 300 ethnically matched individu-
als. Interestingly, and convincingly, this mutation leads
to a nucleotide pairing 1494T-A1555 in the penulti-
mate loop of the 12S rRNA in the aminoglycoside
binding region, very similar to the base pairing gener-
ated by the A1555G mutation, 1494C-G1555. In both
cases the mitochondrial gene became more similar to
the bacterial gene and thus presumably more suscepti-
ble to aminoglycoside toxicity.
Nuclear Inherited Predisposing Genes
Mutations in the mitochondrial 12S ribosomal rRNA
gene are found in only a minority of patients with
aminoglycoside ototoxicity, thus leaving open the pos-
sibility that nuclear-encoded genes involved in the
uptake, intracellular trafficking and binding, and dis-
posal of aminoglycosides can also be predisposing
genes to ototoxicity. It is also possible that the regen-
eration capability of the sensory epithelium is depen-
dent on the genetic makeup of the individual and that
some of the distinctions between reversible and irre-
versible ototoxicity are dependent on such regenera-
tion differences.6062
In an effort to clone some of these putative nuclear
factors, Fischel-Ghodsian and colleagues decided to
implement a yeast genetic approach. In analogy to the
earlier observation that aminoglycoside-resistance
mutations were found in the mitochondrial small
rRNA gene, they undertook to clone genes that when
overexpressed in yeast would lead to aminoglycoside
resistance. Another advantage of identifying genes that

could function as an aminoglycoside sink, inactivat-
ing the function of the antibiotic, would be their poten-
tial therapeutic potential. Exhaustive screening of 35
yeast genome equivalents for genes that, when overex-
pressed, confer neomycin resistance led to the identifi-
cation of eight such genes.63,64 Two of these genes seem
to lower the intracellular concentration of active
aminoglycosides by chemical modification (an acetyl-
transferase gene) and another through pumping the
drug (efflux mechanism) out of the cell (a member of
the adenosine triphosphate binding cassette trans-
porters, which includes the P-glycoprotein involved in
chemotherapy resistance). The mechanism of amino-
glycoside resistance remains unknown for the six other
genes. It is also interesting that none of the genes
selected plays any role in oxidative stress reduction,
which is one of the toxicity mechanisms proposed.22
The genes selected were good candidates for identifica-
tion of the human homologues and for sequence analy-
sis in patients. The presumed mode of inheritance in
patients is autosomal recessive since in a dominant
model male-to-male transmission would have been
observed. Loss of function appears to be more com-
monly associated with autosomal recessive mutations,
and it is easy to envision models where reduced func-
tion of a P-glycoproteinlike molecule can lead to
increased cellular damage.
These genes might also provide a basis for the
development of therapeutic options to prevent or treat
aminoglycoside ototoxicity, possibly with local admin-
istration of ear drops in the future.
A similar approach was taken by Li and colleagues
when showing that mutant alleles of MTO1, encoding
a mitochondrial protein of unknown function, mani-
fest respiratory-deficient phenotype only when cou-
pled with the yeast mutation corresponding to the
A1555G mutation.65
A complementary effort to clone nuclear genes with
aminoglycoside-susceptibility mutations uses a candi-
date gene approach. Candidate genes, such as the human
homologues of the genes identified in yeast models
described above, are identified and tested for mutations
in patients with aminoglycoside ototoxicity. Additional
candidate genes are based on genetic studies in
Escherichia coli that implicate ribosomal protein sub-
units S4, S5, and S12 in aminoglycoside sensitivity.6668
Single amino acid changes in these proteins lead to drug-
resistant or drug-dependent phenotypes. Other ribo-
somal proteins have been cross-linked to streptomycin,
and although these might also be candidates for amino-
glycoside action, the genetic studies more directly define
genes that functionally interact with these antibiotics.
The human homologues of S4, S5, and S12 in the mito-
chondrial ribosome would then be the best candidate
genes in which to search for susceptibility mutations.
Eukaryotic counterparts to two of these candidate genes
Genetic Factors in Aminoglycoside Ototoxicity 147
have been cloned. These mitochondrial ribosomal pro-
tein genes are the yeast nam9 gene (the E. coli S4 homo-
logue)69 and the Drosophila technical knockout (tko)
gene (the E. coli S12 homologue).70 As a first step, John-
son and colleagues cloned the human mitochondrial
ribosomal protein S1271 and screened 40 amino-
glycoside-sensitive patients without mitochondrial
mutations. No mutation was identified in the coding
region, promoter, or 3 untranslated region of the gene.
PATHOPHYSIOLOGY OF AMINOGLYCOSIDE
OTOTOXICITY
Notably, the A1555G and C1494T mutations lie exactly
in the region of the gene for which the resistance muta-
tions in yeast and Tetrahymena have been described
and in which aminoglycoside binding has been docu-
mented in bacteria. 3638 In addition, the mutation
makes the mitochondrial RNA gene in this region more
similar to the bacterial rRNA gene.35 Since aminogly-
cosides are concentrated within cochlear cells and
remain there for prolonged periods,17 it has been pro-
posed that susceptible individuals with the A1555G
mutation have increased binding to aminoglycosides
leading to altered protein synthesis in the mitochon-
dria.36 The tissue specificity is presumably owing to the
concentration of the drug in those cells. Subsequent
binding experiments have proven that increased bind-
ing to the mitochondrial 12S rRNA occurs.72 However,
when examining lymphoblastoid cell lines of individu-
als with the A1555G mutation, exposure of the cell
lines to high concentrations of neomycin or paro-
momycin led to a decreased rate of growth in glucose
medium and reduced synthesis of mitochondrial pro-
teins, but no mutant proteins were detected.73,74 Simi-
lar results of decreased protein synthesis but no mutant
proteins were obtained in Japan using mitochondrial
transfer from human skin fibroblast line with the
A1555G mutation to p0 HeLa cells exposed to very high
levels of streptomycin.75 This may indicate that the
effect of aminoglycosides in these cell lines could be
nonspecific and be different than in the cochlea,
perhaps because of different transport of the antibiotic
into the mitochondria.
CLINICAL RELEVANCE OF THE
GENETIC PREDISPOSITION TO AMINOGLYCOSIDE
OTOTOXICITY
Prevalence of Inherited Susceptibility to
Aminoglycoside Ototoxicity
In China, use of aminoglycosides is widespread, Hu and
colleagues found that 22% of all deaf-mutes in one dis-
trict of the city could trace the cause of hearing loss to
aminoglycoside use.32 Of those, 28% had other relatives
with aminoglycoside ototoxicity.32 In all familial cases
of aminoglycoside ototoxicity examined to date, a mito-
148 Interventions
chondrial susceptibility mutation has been identi-
fied.35,3944,48,56,59 In two different populations of spo-
radic Chinese patients, 4 of 78 and 2 of 36 patients were
found to have a predisposing mitochondrial mutation,
implying that 5 to 6% of sporadic Chinese patients have
this mutation.39,45,55 Combining these numbers from
the familial and sporadic cases, one-third of patients
with aminoglycoside ototoxicity in China appear to
have the A1555G mutation, and a tiny minority appear
to have the C1494T or 961Cn mutation.
In the United States, where aminoglycosides are
used much more sparingly, it is rare to find families with
several members who lost their hearing after aminogly-
cosides. A medical record review in two US institutions
led to the identification of 41 patients with hearing loss
after the administration of aminoglycosides. Molecular
analysis revealed that seven of them (17%) had a mito-
chondrial susceptibility mutation. Four of these
patients had some family history of maternal relatives
with the same diagnosis.46 The lower frequency in the
United States compared with China may be because of
the higher frequency of severe concomitant disease
leading to hearing loss in the United States, such as renal
disease or meningitis, the lower stringency used in
selecting patients, or ethnic differences.
Clinical Phenotype of Individuals with the
A1555G Mutation
In the initial studies with Chinese families, the most
common history of aminoglycoside ototoxicity indi-
cated that patients with the mitochondrial susceptibil-
ity mutation developed severe hearing loss after small
doses and with relatively immediate onset. However, in
one study of 41 patients in the United States, the
entrance criteria for aminoglycoside ototoxicity had
been defined very loosely.46 Surprisingly, three of the
seven affected patients had only tinnitus and very mild
or no initial hearing loss and later had progressive hear-
ing loss over many years, in one case leading to a diag-
nosis 17 years after aminoglycoside administration.46 A
search for another sequence change in the same gene,
which might modulate the severity of the hearing loss,
led to only one possible sequence change, a homo-
plasmic C1525T change, in one of the three patients.46
In addition to this clinical variability in the phenotypic
expression of aminoglycoside ototoxicity, there is also
some evidence that the ototoxicity in patients with the
A1555G mutation is restricted to the cochlea and that
the vestibular system is not affected. One patient with
profound hearing loss after streptomycin had, on
extensive testing, normal vestibular function.76 Less
extensive testing on the four patients with the A1555G
mutation did not reveal any vestibular abnormality.
This tissue specificity of the A1555G mutation remains
not well understood.49,50
Prevention and Therapy of Aminoglycoside
Ototoxicity
The most critical clinical issue remains to increase the
awareness of physicians and other health care providers
of the existence of these susceptibility mutations. It is
tragic to see reports of 3 Chinese families with 15 mem-
bers who became deaf after aminoglycoside exposure,
12 Spanish families with 40 family members, and 1 Ital-
ian family with 5 family members; even in the United
States, 4 of the 7 patients had other family members
with aminoglycoside ototoxicity. Proper family history
taking can significantly reduce the frequency of amino-
glycoside-induced hearing loss. At a minimum every
individual set to receive aminoglycosides should be
asked for such a family history, and family members of
an individual who became deaf after aminoglycosides
should be warned that they are at risk for aminoglyco-
side ototoxicity. The use of alternative antibiotics is
usually possible. In countries where molecular tests are
available, testing for the three known susceptibility
mutations should be performed. Identification of such
mutations will allow targeted counseling of family
members and is highly likely to increase compliance as
well. A negative result does not rule out a familial cause
but, because of the putative autosomal recessive inher-
itance, will put mainly siblings of the patient at risk.
Population screening for disease-susceptibility
mutations has not yet become a fully integrated part of
clinical practice. However, as the price for such tests
comes down, and the number of useful tests increases,
it becomes possible to hope that the early screening
panels for healthy individuals will include screening
for the aminoglycoside-susceptibility mutations. Such
panels should definitely include the A1555G mutation.
Although it is not yet clear whether screening for the
961Cn and C1494T mutations is appropriate and cost
effective, one recommends erring on the side of testing.
In the longer term, prevention of aminoglycoside
ototoxicity might also be possible in a more direct way.
The elucidation of the molecular mechanism of amino-
glycoside ototoxicity might lead to the identification of
those parts of the drug that are necessary for the bac-
tericidal activity and those that are responsible for the
toxicity. It will then be possible to create new amino-
glycosides in which the toxicity part has been altered.
Currently no therapies exist to treat aminoglyco-
side ototoxicity after the damage has occurred.
Approaches using iron-chelating drugs, N-methyl-D-
aspartate antagonists, and neurotrophic factors have
been promising in animal models,23,77,79 and it is likely
that these drugs interfere with downstream effects of
the primary events. In the longer term it might be pos-
sible to locally administer molecules that bind amino-
glycosides and prevent their toxic activities in the
cochlea. This could be done after hearing loss is

documented but before irreversible hair cell destruc-
tion occurs. Such an approach, in combination with
mitotic regeneration of the sensory epithelium after
hair cell loss, opens the possibility that aminoglycoside
ototoxicity can be preventable and treatable.6062
SUMMARY
Ototoxicity is the major irreversible toxicity of
aminoglycosides and occurs in a dose-dependent
and idiosyncratic fashion. Research has now
clearly demonstrated that there is a genetic basis to
aminoglycoside ototoxicity in at least some cases.
Three mitochondrial mutations (the first, the
A1555G mutation, discovered in 1993) have
been identified in the mitochondrial 12S rRNA
gene, which account for ototoxicity in 17 to 33%
of cases. Although it is likely that mutations in
nuclear genes predispose to aminoglycoside oto-
toxicity as well, none of these have yet been
identified.
The clinical phenotype associated with the mito-
chondrial mutations can be atypical (ie, not
occurring after small dose exposure or with rel-
ative immediate onset), in that in some patients
the hearing loss is only noticed years after the
aminoglycoside exposure and in that the
vestibular system may remain preserved.
Ototoxicity associated with these mutations is
preventable through a combination of taking
family histories and molecular screening.
Future research may further elucidate the genetic
factors predisposing to aminoglycoside ototoxi-
city and result in the development of nontoxic
aminoglycoside analogs or in treatment strate-
gies that prevent irreversible cochlear damage.
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 CHAPTER 18
Audiologic Monitoring for Ototoxicity
Kathleen C. M. Campbell, PhD
Clinically, audiologic monitoring for ototoxicity is gen-
erally performed for one of two purposes. The most
common purpose is to detect ototoxic changes before
hearing in the speech frequency range, and thus com-
munication, is affected. When changes are detected
early, the physician can consider alternative treatment
protocols, possibly with less ototoxic medications. The
second purpose is to monitor changes, when and if
they occur, even when it is known that the treatment
regimen cannot be safely altered, as in some cancer
treatments. In the second case, the purpose of moni-
toring is to assist the patient and family in maintaining
communication as hearing loss develops. This assis-
tance may include counseling, communication strate-
gies, amplification, and assistive listening devices.
Certainly, preventing hearing loss and maintaining
communication is a major quality-of-life issue, partic-
ularly for patients and families dealing with serious,
and possibly life-threatening, illness.
Audiologic monitoring for ototoxicity is also a very
active area of research. Several clinical and research
centers are comparing different monitoring and analy-
sis techniques for various patient populations. Further
new drugs are being developed that appear to have
excellent therapeutic efficacy without ototoxic side
effects.1 Other drugs are being developed specifically to
prevent ototoxicity when delivered either before or in
combination with ototoxic drugs.28
Currently there are three main approaches to audi-
ologic monitoring for ototoxicity: the basic audiologic
assessment, high-frequency audiometry, and oto-
acoustic emissions (OAEs). Depending on the tests
purpose and patient considerations, they may be used
separately or in combination. It should be noted that all
of these approaches require a baseline evaluation,
preferably prior to any ototoxic drug administration, so
that later results have a meaningful basis for compari-
son. Given the high incidence of preexisting hearing
loss in the population at large, any assessment for oto-
toxicity without a baseline evaluation will be difficult to
interpret in regard to cause.9 In those cases, the patient
or family may inaccurately attribute a long-standing,
but newly diagnosed, hearing loss to the current or
recent medical treatment.
THE BASIC AUDIOLOGIC ASSESSMENT
The basic audiologic assessment is an important part of
most ototoxicity monitoring programs.10 The basic
audiologic assessment may not detect the early ototoxic
changes detected by high-frequency audiometry and
OAEs, but it assesses the patients hearing in the speech
frequency range for communication, assesses word
recognition ability, and detects whether a conductive
component is contributing to any hearing loss or
change in hearing over time. Although rare, occasion-
ally an ototoxic medication may selectively cause low-
or midfrequency hearing loss, best evaluated by testing
in the conventional frequency range. If the patients
treatment protocol cannot be altered even if ototoxic
hearing loss is detected, the ototoxicity monitoring
protocol may include only the basic audiologic assess-
ment with monitoring in the conventional frequency
range to determine when the patient needs assistance
with any development of hearing loss.
At baseline, the basic audiologic assessment
should include pure tone air-conduction thresholds
for the conventional frequency range (2508000 Hz),
the frequency range needed for normal speech percep-
tion. Standard modified Hughson-Westlake threshold
procedures should be routinely employed. 11 Word
recognition (speech discrimination) measures should
be included, using 50-word lists. If air-conduction
thresholds are greater than or equal to 10 dB HL,
bone-conduction threshold testing should be included
to determine if any air-bone gaps exist, which would
indicate a conductive component. Tympanometry at
baseline is also recommended to assist in determining
if a middle ear disorder may be present. Conductive
hearing losses can be common in pediatric popula-
tions, among infectious disease patients, such as those
154 Interventions
receiving aminoglycoside antibiotics, and in patients
immunosuppressed by chemotherapy regimens.
Therefore, any possible conductive component must
be parceled out to determine if later threshold changes
are sensorineural and possibly attributable to the oto-
toxic medication or conductive and attributable to
other changes.
After the baseline evaluation, basic assessment fol-
low-up evaluations will generally comprise only pure
tone air-conduction threshold tests unless a change in
hearing threshold is noted. If a significant change is
noted, the entire basic assessment should be repeated,
including bone-conduction threshold testing and tym-
panometry, to check for a conductive or middle ear
component to the loss. Also word recognition testing
should be repeated to assist in determining the commu-
nicative impact on the patient. If 50-word lists have been
used, standardized interpretation criteria can be used to
determine if the change is significant.12 Sometimes,
because patient populations receiving ototoxic medica-
tions may tire easily, audiologists prefer to use 25-word
lists or half-lists; however, interpreting significant
change for word recognition is then more difficult.
At the baseline assessment, patients should also be
counseled to avoid noise exposure during and, in the
case of cisplatin and aminoglycoside antibiotics, for
several months following drug administration. Noise
exposure can exacerbate the ototoxicity of both amino-
glycosides1315 and cisplatin1619 although prior noise
exposure may not potentiate cisplatin ototoxicity.20
Over the years, several significant change criteria
have been suggested for determining ototoxic change.
Although simple test-retest variability for each thresh-
old should not exceed 5 dB, that criterion is too strin-
gent for determining ototoxic threshold shift,
particularly in these patient populations. Early studies
of ototoxic threshold shift proposed criteria of either
15 dB or greater at one or more frequencies21 or 20 dB
or greater at any one frequency.22 However, Brummet
and Morrison reported that these thresholds were
exceeded even in control subjects over time.23 Similarly,
Meyerhoff and colleagues in a study of patients receiv-
ing tobramycin or vancomycin reported that 15 dB
shifts at a single frequency or an average of 5 dB shifts
across frequencies occurred equally in both negative
and positive directions, indicating random variability.24
The most widely used and validated criteria for
determining ototoxic threshold shift were published by
the American Speech-Language-Hearing Association
(ASHA).25 Significant ototoxic change must meet one
of the following three criteria: (1) 20 dB or greater
decrease at any one test frequency, (2) 10 dB or greater
decrease at any two adjacent frequencies, or (3) loss of
response at three consecutive frequencies where
responses were previously obtained. Changes are always
computed relative to baseline measures and must be
confirmed by repeat testing, generally within 24 hours.
These criteria minimize random variability by using
adjacent test frequencies. It has been demonstrated that
these criteria are sensitive to ototoxic change and have
not been shown to yield false-positive findings for air-
conduction threshold testing in either the conventional
or high-frequency ranges.4,26,27
HIGH-FREQUENCY AUDIOMETRY AND
OTOACOUSTIC EMISSIONS
High-frequency audiometry comprises air-conduction
threshold testing for the frequencies above 8000 Hz.
Threshold testing in the extended high-frequency
(EHF) range, between 10000 Hz and 20000 Hz, can
usually detect aminoglycoside-induced or cisplatin-
induced ototoxicity before changes in the conventional
frequency range occur.2834 EHF testing can generally
detect these changes early because most ototoxic
changes first affect the basal turn, or high-frequency
region, of the cochlea before progressing to lower-
frequency regions.3537
High-frequency audiometry is now well estab-
lished and widely used in ototoxicity monitoring pro-
grams. Test procedures are similar to testing in the
conventional frequency range. High-frequency audio-
metry was first proposed and studied several decades
ago. 3841 However, lack of commercially available
equipment and standard calibration references limited
its clinical acceptance for many years. Further, even
among individuals with normal hearing in the con-
ventional frequency range, wide differences exist for
EHF thresholds.42 Because of that high intersubject
variability, no standard EHF threshold reference has
been developed as it has for the conventional frequency
range (ie, dB HL). However, ototoxicity monitoring
compares each subjects hearing thresholds to his or
her own threshold at baseline and not to thresholds of
other subjects. Consequently, high intersubject thresh-
old variability at baseline is not an issue for ototoxic-
ity monitoring; only intrasubject variability is. When
EHF testing equipment was first being developed,
intrasubject variability was also problematic because of
the transducer effects. The transducers first used for
the EHF highly directional waveforms resulted in
acoustic variances when coupled to the ear. Numerous
investigations addressed these issues and resulted in
significant improvements.4246 Currently, intrasubject
variability over time for EHF, using standardized clin-
ical procedures and commercially available equipment,
is no higher than for air-conduction threshold testing
in the conventional frequency range.1,26,4751 Further,
high-frequency audiometry can be conducted in a
quiet hospital room if necessary. 52 Obtaining EHF
auditory brainstem response (ABR) thresholds to
monitor ototoxicity bedside using a portable unit has
been investigated but has not obtained widespread

clinical use.53,54 However, EHF ABR testing remains an
area of investigation.55
High-frequency audiometry may not be applicable
to all patients. Patients with hearing loss in the con-
ventional frequency range may not have measurable
hearing in the EHF range.56,57 Even when accounting
for hearing thresholds in the conventional frequency
range, the elderly have disproportionately poorer EHF
thresholds,58,59 which may limit monitoring capabilities
in that frequency range.58 Some individuals may have
better hearing in the EHF than in conventional fre-
quency ranges, but these cases are rare.60
Because patients receiving ototoxic medications
are usually seriously ill, sometimes extended audiologic
behavioral testing requiring careful attention and
patient responses are problematic. Consequently, sev-
eral investigators have been working to develop abbre-
viated EHF monitoring protocols using a restricted
frequency range.27,53,54,61
OAEs are another option for monitoring ototoxic-
ity. OAEs are acoustic signals generated by the cochlear
outer hair cells and transmitted from the cochlea
through the middle ear to the ear canal, where they can
be detected and recorded with a sensitive low-noise
microphone (see Chapter 1, Anatomy and Physiology
of the Cochlea). Although many normal ears generate
OAEs spontaneously, spontaneous OAEs (SOAEs) are
not widely used clinically. SOAEs are frequently absent
even in normal ears and are generally absent in
hearing-impaired ears, thus providing a limited basis
for monitoring. The OAEs most commonly used clini-
cally are transient OAEs (TOAEs) and distortion-
product OAEs (DPOAEs). Both TOAEs and DPOAEs
are elicited in response to an acoustic stimulus. TOAEs
are elicited in response to a series of transient signals,
usually clicks, and generally elicit a broad-spectrum
cochlear response. DPOAEs are elicited in response to
a series of two simultaneous tones. The DPOAEs pri-
mary tones are called F 1 (lower frequency) and F2
(higher frequency) but elicit a cochlear response of a
different frequency, predominantly 2 F1 F2.
OAEs have several advantages over behavioral mea-
sures. They are quick, are generally inexpensive, and
require no behavioral response from the patient. Thus,
they can be obtained on even comatose patients. There-
fore, OAEs can be advantageous for ototoxicity moni-
toring because many of these patients are too ill to
comfortably provide reliable behavioral responses over
long time periods. Further, like high-frequency
audiometry, TOAE 6265 and DPOAE 6668 responses
change before hearing thresholds in the conventional
frequency range. Thus, they detect ototoxicity early,
providing the physician and patient with the option of
changing the treatment protocol before irreversible
changes in the speech frequency range occur. Currently,
it is not known whether high-frequency audiometry or
Audiologic Monitoring for Ototoxicity 155
OAEs consistently provide the earliest indication of
ototoxic change. Research in that area continues.
Although both TOAEs and DPOAEs change before
hearing thresholds in the conventional frequency
range, DPOAEs appear to provide an earlier indication
than do TOAEs. 68 This advantage probably exists
because DPOAEs can measure at higher frequencies
than can TOAEs, thus being more sensitive to the
cochlear frequency areas first affected. Further,
DPOAEs can often be recorded in the presence of more
severe sensorineural hearing loss than can TOAEs,
rendering more patients eligible for OAE monitor-
ing.6971 DPOAEs can also provide some indication of
degree and configuration of hearing loss if those data
cannot be obtained behaviorally.72,73
One of the primary advantages of high-frequency
audiometry over OAEs is that the significant change
criteria for EHF testing are well established with excel-
lent specificity and sensitivity.25 A variety of significant
change criteria have been proposed for interpreting
OAEs,68,74 but none yet have universal acceptance. The
sensitivity and specificity of these criteria now need to
be documented on large-scale patient populations.
Both high-frequency audiometry and OAEs will be
problematic in patients with hearing loss, particularly
the elderly, because there may be no responses or lim-
ited responses available for monitoring.56,57,75,76 How-
ever Ress and colleagues found that DPOAEs could be
recorded in a greater number of patients than could
EHF thresholds and that they were equally sensitive in
detecting ototoxic change in those patients who could
be tested using both measures.67 The mean age of sub-
jects in their study was 62 years. Thus, presbycusis was
probably a factor for several of their subjects.
One disadvantage of OAEs is that they cannot be
reliably recorded in the presence of otitis media.77 As
previously discussed, the patient populations receiving
ototoxic medications may be particularly susceptible to
otitis media, which can interfere with OAE ototoxicity
monitoring.78 Thus, OAEs should probably not be the
sole method of ototoxicity monitoring because inter-
ruptions in monitoring may occur whenever otitis
media is present. High-frequency audiometry can be
conducted in the presence of otitis media, but it cannot
then be assumed that any changes in the EHF range are
secondary to ototoxicity. Whenever changes in any
responses are noted, a complete assessment is needed to
determine if a conductive component may be con-
tributing to the observed differences.
PEDIATRIC TESTING
Children pose special challenges for ototoxicity moni-
toring. Hearing preservation is particularly critical in
this patient population because they are still acquiring
speech and language and have many decades of life
ahead of them. Their communication abilities will
156 Interventions
greatly affect the quality of their current and future life.
However, young children, particularly when they are ill,
may not be able to provide sufficient behavioral infor-
mation for monitoring, particularly for both conven-
tional and high-frequency audiometry. OAEs, requiring
no behavioral responses, seem ideal, but otitis media78
or crying65 can preclude reliable recordings for ototox-
icity monitoring. ABR testing, particularly with EHF
capabilities, holds promise but is currently time-
consuming and may require sedation for toddlers.
Repeated sedation for monitoring may be inadvisable
for this population. Nonetheless, an experienced audi-
ologist, employing various test techniques, including
behavioral, electrophysiologic, and OAE measures, can
generally monitor these patients successfully.
OTOTOXICITY TESTING FOR CLINICAL TRIALS
Currently the US Food and Drug Administration
(FDA) does not have specific Good Clinical Practice
(GCP) guidances for monitoring ototoxicity in patients
receiving new drugs. A detailed protocol, however, by
Campbell and colleagues in 2003 for a phase I clinical
trial of a new glycopeptide antibiotic that monitors for
both cochleotoxicity and vestibulotoxicity appears
especially promising in its applicability.1 All audiologic
methods were submitted to the FDA in advance of
phase I study data collection, and results were accepted
in the subsequent reports. That study included air-con-
duction testing in the conventional and EHF ranges,
bone-conduction testing as indicated, and tympanom-
etry and word recognition at baseline. Patient inclusion
and exclusion criteria and replicability criteria were
very strict to avoid false-positive or false-negative find-
ings. The Dizziness Handicap Inventory (DHI) addi-
tionally was employed to monitor for potential
vestibulotoxicity. This study may serve as a helpful
model for others performing clinical trials of new drugs
in which ototoxicity monitoring is needed.
OTOTOXICITY MONITORING SCHEDULES
It is preferable to obtain the baseline evaluation prior to
the patient receiving ototoxic medications and before
the patient is connected to intravenous or monitoring
equipment that may produce high ambient acoustic or
electrical noise levels. For platinum-based chemother-
apy patients, this is generally possible because the
chemotherapy is prescheduled. Because cisplatin can
cause marked hearing loss following a single adminis-
tration, predrug baseline testing is essential.79 For infec-
tious disease patients, aminoglycoside administration
may occur on an emergency basis, so prior audiologic
assessment may not be possible. Fortunately, even
kanamycin, one of the most ototoxic aminoglycosides,
generally does not cause demonstrable cochleotoxicity
for at least 72 hours after administration.80,81 Conse-
quently, baseline testing for aminoglycosides may occur
prior to or within the first 2 days after drug initiation.
However, predrug baseline testing is optimal.
Follow-up visits should occur just prior to each
round of platinum-based chemotherapy, after any tem-
porary threshold shift has had time to recover and
before the patient is connected to intravenous or mon-
itoring equipment. This schedule will also allow
patients to be tested when they are feeling at their best,
thus providing more reliable behavioral responses.
Because platinum-based chemotherapy can cause
delayed hearing loss, a follow-up test should also occur
a few months after chemotherapy cessation. Generally
this testing can be coordinated with a medical follow-
up visit. If the patient also received head and neck radi-
ation, monitoring for the next year or two is advisable
because hearing loss may continue to progress.
For aminoglycoside antibiotics, weekly or biweekly
monitoring is generally recommended. Because amino-
glycosides can also cause delayed hearing loss, follow-
up testing should also be scheduled a few months after
drug discontinuation.
Ototoxicity monitoring is most commonly per-
formed for patients receiving multiple-dose platinum-
based chemotherapy and long-term (generally more
than 5 days) aminoglycoside antibiotic administration.
However, ototoxicity may occur secondary to a wide
variety of agents, and monitoring protocols may need
to be designed accordingly. For some drugs, the inci-
dence of ototoxicity is so low that prospective monitor-
ing may not have been scheduled. Consequently, the
patient may not be referred for audiologic testing until
hearing loss is suspected. In those cases, the same crite-
ria for ototoxic change can be applied if baseline data
are available. If baseline data are not available, inter-
pretation can be problematic.
MONITORING FOR TINNITUS AND
VESTIBULOTOXICITY
Tinnitus is a common side effect of many ototoxic
drugs,82 particularly cisplatin,34 but currently no formal
monitoring procedures have been developed specifi-
cally for tinnitus. Most studies do not report how they
assessed tinnitus and apparently rely primarily on
patient self-report. Further, whether or not tinnitus
onset precedes EHF threshold shift or changes in OAEs
has not been formally investigated, although tinnitus is
frequently considered an early indicator of ototoxicity.
When monitoring patients for ototoxicity, formally
questioning them about any tinnitus symptoms at each
appointment would be advisable.
Although the vestibulotoxicity of some drugs, par-
ticularly certain aminoglycosides, is well established,82
no standardized, widely accepted guidelines for
vestibulotoxicity monitoring exist (see Chapter 19,
Monitoring Vestibular Ototoxicity). Some vestibular
testing protocols would be impractical for weekly

monitoring, particularly for this patient population. A
recent study by Campbell and colleagues used the DHI
to monitor for vestibular or balance changes in a phase
I study of a new glycopeptide.1 The DHI, a simple ques-
tionnaire, was administered just prior to each audio-
logic assessment for ototoxicity monitoring. The DHI
was not initially designed for ototoxicity monitoring
but is the most commonly used and best validated self-
assessment scale for dizziness and dysequilibrium.8389
In the Campbell and colleagues study, the DHI served
as a quick, noninvasive, cost-effective method of mon-
itoring vestibular and balance function and yielded no
false-positive or false-negative findings in that patient
population.1 However, the glycopeptide in that study
was not found to be either cochleotoxic or vestibulo-
toxic. For the purposes of vestibulotoxicity monitoring,
the DHI could probably be abbreviated by eliminating
questions irrelevant for that purpose.
OTHER CONSIDERATIONS: ENVIRONMENTAL
CHEMICALS
Although it is well known that environmental chemi-
cals such as organic solvents, asphyxiant gases, and
heavy metals can cause hearing and vestibular disor-
ders,9092 workers exposed to these solvents may not be
monitored for ototoxicity. In some cases, these workers
may be monitored for noise-induced hearing loss in
their environment, with the potential concomitant role
of chemical ototoxins overlooked. It may be advisable
to consider regular monitoring for ototoxicity in work-
ers routinely exposed to these agents.
SUMMARY
A wide array of audiologic test techniques are
available to monitor ototoxicity in various
patient populations. Test techniques employed
and the testing schedule may vary according to
the drug involved, the patients age, and the abil-
ity to perform behavioral testing.
The purpose of audiologic monitoring is to
detect early changes in hearing from ototoxic
agents that might influence continued treatment
and to assist both the patient and family mem-
bers in maintaining communication should a
hearing loss occur.
Pretreatment baseline audiometry should be
performed whenever possible.
As most ototoxic agents affect high-frequency
hearing initially, EHF audiometry and OAEs
(preferably DPOAEs) may provide the earliest
evidence for impending ototoxicity, before con-
ventional speech frequencies are affected.
Audiologic monitoring for platinum-based
chemotherapy should occur prior to each round
of treatment and for the 1 to 2 years afterward if
Audiologic Monitoring for Ototoxicity 157
there has been concomitant radiation to the
head and neck. For aminoglycosides, monitoring
is recommended every 1 to 2 weeks while on
therapy and for at least 4 to 6 months after drug
discontinuation. Patients exposed to environ-
mental chemicals should have their hearing
assessed on a regular basis.
Ototoxicity monitoring is a very active area of
research. Current techniques are constantly
being compared, and new techniques are being
investigated. In the future, there is hope that oto-
protective agents will prevent ototoxicity in
most patients.
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 CHAPTER 19
Monitoring Vestibular Ototoxicity
Vitaly E. Kisilevsky, MD, R. David Tomlinson, PhD, Paul J. Ranalli, MD, FRCPC,
and Narayanan Prepageran, MBBS, FRCS(Ed), FRCS(Glas), MS(ORL)


The goal of vestibular monitoring when potentially
ototoxic medications are administered should be to
provide information about the vestibular system that
would allow for timely intervention before an
irreversible vestibulotoxic event occurs.
In everyday life, maintaining ones balance
depends on information from visual, vestibular, and
proprioceptive systems that are centrally integrated at
the level of the vestibulocerebellum.1 Recent advances
in vestibular testing provide a variety of measurement
tools for assessing these systems. Laboratory tests com-
monly used to evaluate the balance system include
electronystagmography (ENG), rotational chair (sinu-
soidal and pseudorandom), sacculocolic testing,
vestibular evoked potentials, and computerized
dynamic posturography (CDP). Along with these
quantitative or so-called objective tests for physical
performance measurements, there are several clinical
bedside tests and subjective self-reported measures.
A flaw all vestibular-monitoring paradigms share
(especially those involving quantitative testing) is an
inability to recognize subtle changes in function indica-
tive of impending vestibulotoxicity that does not always
correlate with changes in the ability to perform ones
daily activities. Conversely, one benefit of subjective
measures is their direct real-time relation to daily
function. Recognition that an individual might be
experiencing early signs or symptoms of vestibulotox-
icity is important as any window of time for recovery is
often short. For this reason, proper objective and sub-
jective monitoring of vestibular function may help
recognize toxic effects and prevent permanent damage.
ANATOMICAL BASIS FOR VESTIBULAR
MONITORING
Maintaining body equilibrium and posture in daily
activity is a complex function involving multiple
sensory organs. Specific reflexes related to the vestibu-
lar system result in stereotypic motor responses for eye
movements, postural control, and perceptual outputs.
In short, multiple sensory inputs from the vestibu-
lar end-organs, the visual system, and the somatosen-
sory and proprioceptive systems are integrated at the
level of the brainstem and cerebellum and are subse-
quently influenced by the cerebral cortex. Second-order
neurons in the vestibular nuclei form specific vestibu-
lospinal and vestibulocerebellar tracts. Connection
between vestibular and oculomotor nuclei, in part via
the medial longitudinal fasciculus, forms the anatomic
basis of the vestibulo-ocular reflex (VOR) (see Chap-
ter 2, Physiology of the Vestibular System).
NEURAL BASIS OF THE VOR
Traditionally, the VOR has been believed to depend on
two pathways: a direct pathway known as the three-
neuron arc and an indirect pathway thought to involve
the reticular formation. This is now known to be an
oversimplification. Two different neuron types in the
vestibular nuclei are involved in the generation of the
VOR: position-vestibular-pause (PVP) cells and floc-
cular target neurons (FTNs). Each forms its own three-
neuron arc. PVP cells receive input from the labyrinth
and project to the appropriate oculomotor nuclei. They
do not receive input from the cerebellum. Unlike PVP
cells, FTNs receive direct input from the cerebellar floc-
culus. Whereas the PVP cell pathway is relatively
unmodifiable, the FTNs change their firing profiles
whenever a change in VOR performance is required.
For example, if a subject wears 2 magnifying glasses,
since the size of the seen world is doubled, the VOR
gain must also double. This gain increase is almost
completely a result of changes in FTN, rather than PVP,
firing profiles. Basically, following adaptation to the
magnifying glasses, the same rotation produces a much
larger change in FTN firing than is observed prior to
the adaptation. Compensation for peripheral lesions
requires a similar gain increase. Since the flocculus is
known to be required for proper compensation follow-
ing peripheral vestibular lesions, FTNs are thought to
162 Interventions
CBLM
LR
FTN VI
VIII
PVP
Figure 19-1 Basic wiring of the horizontal VOR. CBLM =
cerebellum; FTN = floccular target neuron; LR = lateral
rectus muscle; PVP = position-vestibular-pause cell;
VI = VIth nucleus; VIII = VIIIth nerve.
play a major role. The basic layout from the horizontal
VOR is shown in Figure 19-1. For simplification, only
the direct excitatory pathways are shown.
NEUROPHYSIOLOGICAL BASIS FOR
COMPENSATION FOLLOWING UNILATERAL
VESTIBULAR LOSS
Several facts are necessary to understand the conse-
quences of unilateral peripheral vestibular lesions (as
might occur from topical ototoxicity). The primary
afferent neurons arising from the canals and otoliths are
spontaneously active (tonic activity). As a result, hor-
izontal rotation to the right results in an increase in
firing in the right lateral canal (a branch of the superior
vestibular) nerve and a corresponding decrease in firing
in the left lateral canal nerve. Because of the way the
information is processed in the vestibular nuclei, any
difference between the firing rates on the two sides is
interpreted as a rotation, and vestibular eye movements
will be generated to compensate for this rotation.
The six canals on the two sides form three func-
tional pairs. The two lateral canals form one pair,
whereas the superior canal on one side and the poste-
rior canal on the other side form another pair. Since
there are two superior and two posterior canals in total,
these four canals form two functional pairs (Figure 19-
2). In each case, a rotation of the head in the plane of
the canals results in an increase in firing in one mem-
ber of the pair and a decrease in the other member.
Immediately following complete unilateral
vestibular lesions, two main things happen: (1) the
VOR gain drops to about half of its normal value
because of the loss of input from one side and (2) a
spontaneous nystagmus (away from side of lesion)
develops because there is now a difference in firing
between the lesioned side and the normal side. The
LSC RSC
LPC RPC
Figure 19-2 The right superior canal (RSC) and the left pos-
terior canal (LPC) are parallel and so form a functions pair,
as do the right posterior canal (RPC) and the left superior
canal (LSC).
reason for the gain decrease can easily be understood by
looking at Figure 19-3. Since type I secondary vestibu-
lar neurons, such as PVP cells, receive excitation from
the ipsilateral and inhibition from the contralateral
labyrinth, they effectively respond to the difference in
firing between the two VIIIth nerves. Following a uni-
lateral lesion, when the head moves, only the healthy
labyrinth will respond, and so the change in firing in
the PVP cell will only be half as large as normal. Both
of these deficits need to be corrected for full compen-
sation. In addition, this compensation requires the
integrity of the cerebellum. Spontaneous nystagmus
will largely resolve without any intervention simply
because the brain knows that a rotation cannot be
going on indefinitely. As a result, the imbalance in
activity levels in the two vestibular nuclei that exists fol-
lowing a unilateral lesion largely disappears within a
few days as the tonic activity in the nucleus sponta-
NORMAL
_
I II I
+ +
+
LESION
I _ II I
+ +
+
X
Figure 19-3 Type I secondary vestibular neurons receive
excitatory input from the ipsilateral labyrinth and inhibition
from the contralateral labyrinth via type II neurons. Follow-
ing a lesion (X), the type II neuron no longer receives any
input and so the type I neuron contralateral to the lesion will
generate half as large a response as normal when the
head moves.

neously recovers. Recalibration of the VOR, however,
takes somewhat longer. Further, this recalibration can
occur only if the brain knows that something is still
wrong. It knows this because the low VOR gain results
in image motion on the retina (retinal blur) when-
ever the head moves. Thus compensation requires both
head movements and intact vision. Again, this step
requires cerebellar integrity.
Experiments have shown that FTNs receive input
from the cerebellum, whereas PVP cells do not. Not
surprisingly, since the cerebellum is required for VOR
compensation, FTNs show large changes in their firing
profiles when the VOR gain is changed, whereas PVP
cells change very little.
In summary, the VOR is based on two parallel
pathways through the vestibular nuclei, a highly mod-
ifiable FTN pathway and a relatively fixed PVP cell
pathway. Compensation is believed to require that all
three componentsthe FTNs, the PVP cells, and the
cerebellumbe intact.
WHY COMPENSATION IS NEVER TRULY COMPLETE
Despite the ability of the brain to compensate for
vestibular lesions, this compensation is incomplete. Hal-
magyi and Curthoys showed that when very rapid head
turns (head thrusts) were used to invoke the VOR, rota-
tions toward the lesioned side evoked eye movements of
much lower gain than rotations toward the healthy
side.2 Further, this asymmetry shows little or no recov-
ery with time. Likely this maintained asymmetry causes
many patients with unilateral lesions to continue to
complain that they experience disorientation or resid-
ual imbalance during rapid head movements, even
though their rotation test results are normal.
Since regular rotation testing shows no such asym-
metry, what is different about these rapid head thrusts
used by Halmagyi and Curthoys? Over the last few years,
several experimenters have attempted to answer this
question, but the success has been incomplete. The head
thrust is different from regular rotation testing because
the frequencies and accelerations are much higher in
head thrusts than can be attained using rotation chairs.
Currently both of these factors are believed to play a
role. High-frequency stimuli, particularly if those stim-
uli involve high accelerations, exhibit large asymmetries,
whereas low-frequency stimuli do not. The reasons are
beyond the scope of this chapter, but they may be related
to the high-frequency performance of the FTN pathway.
Despite these limitations, compensation in healthy
individuals for unilateral lesions is quite good, largely
because each canal in a functional pair is able to sense
rotation in both directions. Thus, within limits, the
information sensed by the remaining healthy canal is
able to replace that lost through the lesion. However,
this presupposes that the remaining side is healthy.
Should a bilateral lesion occur, compensation will be
Monitoring Vestibular Ototoxicity 163
poor as there is no other source of information with the
necessary high-frequency performance. Although
visual following mechanisms and even the cervico-ocu-
lar reflex may be augmented to help, neither is able to
replace the lost vestibular input.
PATHOPHYSIOLOGIC BASIS FOR
VESTIBULAR MONITORING
Vestibular toxicity can vary from a minimal, clinically
undetectable disturbance to a devastating complete
bilateral loss of vestibular function. The degree of
vestibular loss for the most part depends on the extent
of cellular damage within the vestibular end-organ.
With vestibular ototoxicity, the initial and most exten-
sive hair cell damage occurs in the apex of the cristae
and the striolar regions of the maculae. Further hair cell
loss extends toward the peripheral vestibular receptors,
and there is additional damage to the otoconial mem-
brane and the otolith structures themselves.3 When
streptomycin, for example, is given to animals, hair cell
damage is most pronounced in the central part of
crista, type I hair cells being more vulnerable than
type II hair cells.4
Takumida and colleagues, Meza and colleagues,
and Norris have demonstrated that aminoglycoside
antibiotics attack and first destroy the stereocilia and
the sensory cells of the cristae without damaging the
attached first-order neurons.57 This destructive action
on the sensory cells without damage to the rest of the
vestibular system has been verified by experiments on
cats with streptomycin by Norris and Shea8 and in
guinea pigs with gentamicin by Kimura and colleagues.9
Morphological studies of the human vestibular organ
after intratympanic treatment with gentamicin have
demonstrated different stages of degeneration of hair
cells. Many hair cells were totally missing, and a com-
mon finding demonstrated type I sensory cells to be
vacuolated more than type II cells. In addition, neural
elements showed signs of degeneration with severe
swelling of regions of the nerve terminals. No clear
synaptic areas with normal morphology were
observed.10 A human temporal bone study of amino-
glycoside ototoxicity by Tsuji and colleagues demon-
strated significant hair cell loss, especially type I hair
cells, in all three cristae, but not for the maculae.11
There was no significant loss of Scarpas ganglion cells.
In contrast to aminoglycosides, heavy metal intox-
ication results in damage to the central vestibular sys-
tem. Gozdzik-Zolnierkiewicz and Moszynski found
segmental demyelination and axonal degeneration of
the VIIIth nerve in young guinea pigs with chronic lead
intoxication.12 Examination of the central nervous
system (CNS) in patients with mercury poisoning
revealed a selective sensitivity of the granule-cell layer
of the neocerebellum and demyelination of the sub-
cortical and brainstem white matter.13
164 Interventions
CLINICAL FEATURES OF VESTIBULAR TOXICITY
REQUIRING MONITORING
The clinical features that make monitoring of vestibu-
lar function for ototoxicity a challenge include its grad-
ual or apparently sudden development, its delayed
onset from beginning of treatment, the possible spon-
taneous reversibility of vestibular symptoms, and the
striking difference in clinical presentation in patients
with unilateral and bilateral vestibular loss.
Systemic ototoxicity typically causes a bilateral,
simultaneous, symmetric loss of vestibular function
manifested by symptoms and signs of ataxia and oscil-
lopsia (visual blurring with head movement) but with-
out a history of vertigo (defined as a hallucination of
movement). The absence of vertigo in these patients
may be confusing if one is looking for typical symp-
toms of acute unilateral vestibular disorder. As such, a
bilateral process would not cause significant asymme-
try of electrical activity at the level of the vestibular
nucleus in the brainstem (ie, an individual would not
perceive any hallucination of movement at rest), and
the bilateral process might be slow enough to allow
some central compensatory mechanism to occur. Not
all patients, however, are able to compensate for a bilat-
eral vestibular loss, and interruptions in the VOR and
vestibulospinal tract inputs can have a devastating
effect on their daily activities.*
As demonstrated in animal studies, the entry of
ototoxic drugs such as aminoglycosides into the
labyrinthine fluids is slow for perilymph and extremely
slow for endolymph. As a result, it takes time for the
drug to reach significant concentrations, which may
account for the delay in onset of clinical symptoms.14
Once in the inner ear fluids, the drug is slowly elimi-
nated from the perilymph but persists for extended
periods of time in the endolymph. This further explains
why ototoxicity may continue even after the drug is
withdrawn. The pattern of degeneration in aminogly-
coside toxicity seems to depend on the dosing schedule,
total cumulative dosage, and route of administration.
High but brief peak plasma levels apparently yield
markedly lower inner ear tissue concentrations than do
plateau plasma levels.15
As pointed out by Black and Pesznecker,3 the true
incidence of vestibular ototoxicity may be underesti-
mated as the initial ototoxic destruction of hair cells
occurs well outside the normal active and passive head
movement frequency range for the vestibular system.
*There is no real way to compensate for a complete bilateral
loss as there is simply no other major source for the missing
vestibular information. People may learn to live without it,
but the compensation is mainly psychological rather than
physiological. Thus, a person with a complete bilateral loss
has no VOR, at least as long as the head movements are
passive. However, compensation may occur to a limited
extent if the lesions are incomplete.
Subclinical vestibular dysfunction from ototoxic
therapy, especially resulting from posterior cristae
(semicircular canal) or otolithic injury, is also difficult
to document. Most patients who receive potentially
vestibulotoxic medications systemically are severely ill,
hospitalized, or on bed rest. Laboratory vestibular test-
ing can rarely be performed because of the patients
general condition. Unfortunately, symptoms of
vestibular ototoxicity are usually first noted only when
patients start to ambulate without help. They demon-
strate an ataxic gait and lose their balance in the dark
and when moving quickly. They may need to hold on
to a wall for support. In the absence of vertigo, these
symptoms are often assumed to be a result of an under-
lying metabolic, orthopedic, neurologic, or possibly
psychiatric disorder.
Considering the differences in the clinical presenta-
tion of bilateral and unilateral vestibular loss, the guide-
lines for vestibular monitoring should be tailored for the
specific therapeutic protocol a patient is receiving.
Prepageran and colleagues have reported several cases of
systemic vestibulotoxicity in patients properly moni-
tored for plasma-level aminoglycoside concentrations.16
They found that an increased risk for gentamicin oto-
toxicity included a prolonged duration of treatment as
the only risk factor (greater than 14 days). This confirms
the finding of other investigators that vestibulotoxicity
may be seen even when serum antibiotic levels remain
within the therapeutic range.17 The prolonged and
hence total cumulative dose of gentamicin (typically
more than 2.5 g) has more impact on probability of oto-
toxicity than does peak serum level concentration. Sev-
eral other factors influencing the risk for systemic
ototoxicity include the dosage regimen (single vs multi-
ple), concurrent diuretic therapy, renal impairment, and
the underlying disease process (Table 19-1).
The development of vestibulotoxicity following
topical treatment demands a high index of clinical sus-
picion and an ability to distinguish whether the vestibu-
Table 19-1 Risk Factors for Aminoglycoside
Vestibulotoxicity
Drug related Known vestibulotoxic agent,
prolonged (>1014 days) treatment
Patient related Age
Renal insufficiency (before or during
treatment)
Genetic susceptibility, repeated
treatment courses
Physician related Concurrent diuretic and other known
ototoxic drug administration
Failure to recognize early symptoms of
vestibular loss
Failure to recognize ototoxicity as the
cause of vestibular loss

lar signs are a result of toxicity or the underlying ear dis-
ease. Kisilevsky and colleagues reported symptoms and
signs of vestibulotoxicity on average after 18 days in
patients treated with topical gentamicin for their mid-
dle ear condition.18 The duration was somewhat shorter
(11 days) in patients with unilateral Menieres disease
(with normal middle ears) who underwent chemical
ablation of vestibular function with commercially
available topical gentamicin administration. The risk of
development of topical ototoxicity varied, depending
on the condition of the middle ear, duration of treat-
ment, and dosage regimen. As demonstrated by Inoue
and colleagues, low-dose gentamicin treatment appar-
ently caused less damage to the vestibular system than
did highly concentrated topical gentamicin.19
The timing of the appropriate clinical and labora-
tory vestibular testing can sometimes be based on the
known pharmacokinetics of an ototoxic medication
and the treatment protocol used. Experience with top-
ical aminoglycosides for ablation of vestibular function
in Menieres disease demonstrates that when a highly
concentrated gentamicin was employed for chemical
ablation, the duration for the development of ototoxi-
city was briefer than in the treatment with commer-
cially available drops.20,21 Recognition and prevention
of possible ototoxic effects depend on timely reassess-
ment during treatment.
LABORATORY EVALUATION OF VOR
The goal of VOR testing is to determine whether the
labyrinthine end-organ and the CNS pathways are
functioning normally. A normal response is obtained
only when all components of the reflex arc are intact.
As demonstrated in avian experiments by Goode and
colleagues,22 the VOR can be eliminated with amino-
glycoside antibiotic treatment and apparently recovers
as hair cells regenerate. Recovery of the VOR highly
correlates with the regeneration of type I hair cells. To
Table 19-2 Relative Advantages and Limitations of Laboratory Vestibular Tests
Laboratory
Vestibular Test Advantages
ENG caloric Possibility of separate side stimulation
Availability
Highly sensitive for unilateral loss
Rotating chair Allows for high-frequency testing
Physiologic stimulus
Allows differentiation between central and peripheral impairment
CDP Assesses overall balance performance
Directly reflects ability of everyday activity
May identify abnormalities in case of normal ENG caloric
Useful in rehabilitation and quantification of overall balance
CDP = computerized dynamic posturography; ENG = electronystagmography; SCC = semicircular canal.
Monitoring Vestibular Ototoxicity 165
date, no human data, however, can be found to conclu-
sively support these findings (Table 19-2).
ENG
Various systems are currently available for recording
eye movements. Historically, ENG is the most available
and widely used vestibular test.
The principle of ENG is based on the measurement
of changes in the corneoretinal potential that occurs
with eye movements with respect to electrodes placed
around the eyes. Recordings are usually made with a
three-electrode system using differential amplifiers.
The difference in electrical potential between these
electrodes is amplified, graphed, and digitally stored.
The ENG test battery includes (1) oculomotor test-
ing for evaluation of CNS function, (2) measurement
of spontaneous nystagmus, (3) positional testing for
conditions such as benign positional vertigo or atypi-
cal positional nystagmus, and (4) caloric testing.
The caloric test, despite its limitations, remains the
time-honored gold standard for evaluating a unilateral
vestibular deficit. The caloric test uses a nonphysiologic
stimulus (water or air) to induce endolymphatic flow in
the semicircular canals (SCCs) by creating a tempera-
ture gradient from one side of the canal to the other.
The caloric response is provoked by two mechanisms:
endolymph convection, which depends on head posi-
tion and accounts for about 80% of the response, and
direct thermal effect, which is independent of head
position and accounts for approximately 20% of the
response.23 The caloric test is specifically a test of the
horizontal SCC since this canal develops the largest
temperature gradient, being anatomically nearest to the
external auditory canal.
Being the only vestibular test allowing stimulation
of each labyrinth separately, the caloric test has proved
to be highly sensitive for unilateral peripheral vestibular
lesions. The use of caloric testing, however, is limited in
Disadvantages
Tests mainly lateral SCC
Nonphysiologic stimulus
Low sensitivity in bilateral loss
Tests only low frequencies
Bilateral simultaneous stimulation only
Stimulation in horizontal plane only
Lower than in caloric side sensitivity
Unable to localize site of lesion within
vestibular system
Possibility of learning curve in case
of malingering
166 Interventions
cases of bilateral vestibular loss, resulting from, for
example, systemic ototoxicity. Thus, it is not surprising
that in patients with bilateral vestibular loss, caloric
responses are usually symmetrically depressed. 24
Another limitation of caloric testing is that it only allows
for low-frequency stimulation. Standard caloric stimu-
lation, in fact, is equivalent to a very low-frequency rota-
tion of 0.002 to 0.004 Hz.25 This frequency falls far below
the normal physiologic range of the vestibular system.
Although low-frequency VOR responses can be severely
affected by acute and chronic ototoxicity, both the
sensitivity and specificity of the caloric test for sym-
metric loss of vestibular function remain poor.
ROTATIONAL TESTING
Rotational chair testing offers the opportunity to test
the VOR with a range of rotational stimuli, using a
physiologic stimulus (rotation) that is quantifiable. The
chair is usually rotated at frequencies ranging from
0.01 to 1.2 Hz. The most advanced systems have the
capability of delivering high-torque rotation at
frequencies of 1.0 to 4.0 Hz to evaluate high-frequency
function. Unlike caloric testing, the rotatory stimulus
to the SCC affects both labyrinths simultaneously. Eye
movement responses to acceleration are used to detect
asymmetries in the vestibular system. The velocity and
amplitude of the nystagmus are measured to calculate
the gain and phase that are used as the main output
measures. Gain is the ratio of the output (eye velocity)
to the input (chair velocity). Phase describes the tem-
poral (timing) relationship between the input and out-
put. Significant reductions in gain are consistent with a
bilateral peripheral vestibular loss and are useful in
confirming and quantifying results obtained from
caloric testing.
Standard rotational test battery includes tests of
optokinetic nystagmus (OKN), the VOR, and
visualvestibular interaction. Baloh and colleagues
reported that lesions of the peripheral vestibular system
characteristically impair only the VOR, whereas lesions
of the central system impair OKN and visualvestibu-
lar interaction.26 As reported by Minor, the caloric test
identified the side of unilateral vestibular hypofunction
more often (in 56%) than did rotational chair testing (in
20%).27 Caloric responses taken together with rotatory
chair data provided information about the vestibulo-
toxic effects of treatment not obtainable from a single
modality. In 1980 Tomlinson and colleagues reported
their experience with the high-frequency stimulation
rotation test.28 Use of this technique demonstrated bet-
ter correlation with symptoms in comparison with
caloric testing in patients with a bilateral peripheral
loss.29 Black and colleagues, however, have reported
larger decline in VOR function at lower stimulus fre-
quencies compared with the high frequencies in subjects
suffering from aminoglycoside-induced toxicity.30 Over
a period of about a year, VOR high-frequency gains
recovered to within normal limits. In a study by OLeary
and colleagues, patients exposed to gentamicin ototox-
icity were tested with active head movements to deter-
mine their high-frequency (26 Hz) VOR responses.31
VOR improvement correlated with patients reported
reduction of symptoms. In more advanced systems the
use of the magnetic scleral coil eye movement record-
ings provides the most accurate recordings, especially
during high-frequency rotation. As demonstrated by
Prepageran and colleagues, this method allows for doc-
umentation of symptomatic high-frequency vestibular
loss undiagnosed by other modalities.32
INTEGRATED VISUAL-VESTIBULAR-
PROPRIOCEPTIVE ASSESSMENT
Observation of a patients ability to maintain balance
has been used for more than a century to evaluate
vestibular function. The Romberg test, in which the
patients ability to stand with open eyes is compared
with performance with eyes closed, is the classic exam-
ple. A computer-controlled moving platformcom-
puterized dynamic posturography (CDP)provides
quantitative evaluation of both sensory and motor
components of postural control along with the brain
interaction of sensory inputs.
This test measures an individuals balance while
visual and somatosensory cues are intact or altered,
creating conflicting multisensory inputs.
Investigation of the relationship between VOR
function and CDP performance by Crane and Demer
in 1998 demonstrated that gaze velocity measurements
during CDP are sensitive to vestibular loss.33 These
results support the work of Hamid, who reported dif-
ferences in VOR gain in patients with vestibular loss
and vestibular hypofunction.34 In patients with a uni-
lateral vestibular deficit, VOR gain was normal or
hyperactive, whereas total vestibular loss was accompa-
nied by minimal or absent VOR gain.
Pospiech and colleagues reported the use of CDP
for the evaluation of balance in persons exposed to
ototoxic substances.35 They found a statistically signif-
icant increase in abnormal results in exposed workers
than in a normal control group. Dimitri and colleagues
recently included CDP in the multivariate vestibular
testing for bilateral Menieres disease and aminoglyco-
side ototoxicity.36 They reported an increase in test
sensitivity in identifying bilateral vestibular hypo-
function when ENG, sinusoidal harmonic acceleration,
and CDP were simultaneously used. In addition, CDP
can be used to measure physical therapy outcomes in
patients with bilateral vestibular loss. Since there is a
statistically significant correlation between improve-
ment in CDP composite scores and clinical changes,
CDP evaluation may have an application in vestibular
rehabilitation.36

Because information obtained from CDP is based
on the vestibulospinal reflex and stimulation of SCC
and otolith organs simultaneously, this test alone
cannot delineate the site of lesion within the vestibular
system. Use of CDP in vestibular monitoring of oto-
toxicity is therefore primarily limited to screening and
for the monitoring of vestibular rehabilitation.
BEDSIDE CLINICAL VESTIBULAR TESTS
Limitations in laboratory vestibular testing increase the
practical role of bedside clinical tests for monitoring
vestibular toxicity.
Patients with a bilateral vestibular loss often com-
plain of objects jumping or jiggling with head
movements. This symptom of oscillopsia is caused by
the bilateral loss of VOR function and subsequent
inability to stabilize visual images on the retina. Exces-
sive retinal slip not only causes oscillopsia but also
impairs visual acuity.
DYNAMIC VISUAL ACUITY TESTING
(OSCILLOPSIA TESTING)
Evaluation of dynamic visual acuity (DVA) assesses the
detection of poor VOR function. A particularly helpful
development in the assessment of oscillopsia can be
found in the works of Longridge and Mallinson.37,38 They
proposed a dynamic illegible E (DIE) test for monitoring
patients receiving aminoglycoside antibiotics. During the
oscillopsia test, the head is passively oscillated at a fre-
quency of about 1 to 2 Hz. The patient is asked to read
the lowest possible line on a Snellen chart at rest and dur-
ing passive head rotation. A drop in acuity of three lines
or more is considered significant for a bilateral vestibu-
lar loss, as might occur from systemic ototoxicity.39
Computerized DVA testing was later developed
and allows for more precise measurement by control-
ling for head velocity. As reported by Herdman and col-
leagues, a computerized DVA test improved the
accuracy of the assessment of vestibular deficits.40 This
test was reliable in distinguishing between normal sub-
jects and patients with vestibular loss and was useful in
determining unilateral versus bilateral vestibular hypo-
function. It is important to take into account, however,
the normal changes in VOR gain that may be present in
patients who wear glasses. With myopic lenses, VOR
gain is reduced, and with hyperopic lenses, VOR gain is
increased. When using this test in patients with long-
standing vestibular loss, the possibility of compensa-
tion should also be considered. Tian and colleagues
reported the effectiveness of DVA in detection and lat-
eralization of unilateral vestibulopathy.41 They found
90% sensitivity and 100% specificity of this technique
at high frequency and acceleration (2,800/s2) in detec-
tion of unilateral vestibular deafferentation.
Monitoring Vestibular Ototoxicity 167
PostHead-Shake Nystagmus
The discovery of nystagmus after repetitive head
shaking is a well-recognized clinical sign that was first
noted by Barany in 1907.42 Observation of posthead-
shake nystagmus (HSN) after vigorous horizontal head
shake has been ascribed to the activation of a latent
vestibular asymmetry. If the integrity of vestibular sys-
tem is intact, the central mechanism of velocity storage
system helps to sustain slow-phase velocity when the
vestibular stimulus is of low frequency. In patients with
unilateral lesions, horizontal post-HSN may be
observed with fixation eliminated by Frenzel glasses.
The slow phase is initially directed toward the impaired
ear and the fast phase away from the side of the lesion.
Hain reported that HSN was a sensitive indication of
the existence and location of a unilateral vestibular
lesion.43 Asawavichiangianda and colleagues found sta-
tistically significant correlation between the presence of
HSN and peripheral vestibular dysfunction versus
psychogenic dizziness. 44 The results of their study
indicate, however, that HSN was neither specific nor
sensitive for vestibular dysfunction.
High-Frequency Horizontal Head Thrust
Halmagyi and Curthoys in 1988 described a horizontal
head thrust test for clinical diagnosis of unilateral
vestibular loss.2 During this maneuver, the patients
head is quickly turned while the patient is asked to
focus on a midline target. In case of unilateral canal
paresis, one large or several small oppositely directed,
compensatory refixation saccades may be elicited by
rapid horizontal head rotation toward the affected side.
This finding is usually supported by the patients com-
plaint of blurred vision during quick head movements
toward the affected side. In studying the relationship of
HSN and head thrust to caloric testing, Harvey and col-
leagues found low sensitivity for both HSN and head
thrust for detecting peripheral vestibular disease.45
However, the positive predictive value for both tests
when combined was 80%. Thus, when both tests are
positive, there is an 80% chance of a true vestibular
lesion. In addition, they found that both HSN and head
thrust could accurately predict the side of the lesion in
patients with vestibular pathology. Unlike the post-
HSN test, the high-frequency horizontal head thrust
was able to provide evidence of bilateral vestibular
impairment when present.
SUBJECTIVE EVALUATIONS
Health care providers should always consider and take
seriously vocalized complaints by the patient concern-
ing feelings of dizziness and imbalance. Vague com-
plaints are generally ignored until a vestibulotoxic
event occurs. Health care providers often do not anti-
cipate complaints such as oscillopsia (visual blurring of
168 Interventions
head movement), for example, in an individual receiv-
ing a potentially ototoxic agent systemically.
The Dizziness Handicap Inventory (DHI) is a
validated subjective measure that easily allows patients
to evaluate ongoing well-being.46 The aforementioned
DIE test is another example of a quasiobjective test
that can easily be performed at the bedside and may
provide early information concerning impending
vestibulotoxicity.37,38
In the absence of a specific vestibular monitoring
test that can provide real-time information concerning
the vestibular system, vigilance must be constant.
Reversibility for vestibulotoxicity depends on early
recognition and cessation of the causative agent.
SUMMARY
No one protocol exists that can monitor, equally
and safely, all variants of vestibulotoxicity.
Adequate monitoring ideally would include a
determination of baseline vestibular function
before the start of a potentially ototoxic treat-
ment and sequential testing during therapy on a
regular basis (ie, weekly for aminoglycosides).
Possibility for the development of vestibulotox-
icity following potentially ototoxic treatment
demands a high index of clinical suspicion.
Prevention of possible ototoxic effects depends
on timely assessment during treatment that real-
istically involves the need for frequent clinical
tests of vestibular function (ie, DVA testing,
high-frequency head thrust). A patients subjec-
tive reports of changes in well-being should
never be ignored.
If ototoxicity occurs, repeated testing may pro-
vide sufficient information regarding any spon-
taneous vestibular improvement and, if CDP is
used, the efficacy of vestibular rehabilitation.
REFERENCES
1. Baloh R, Honrubia V. Clinical neurophysiology of
the vestibular system. Contemporary neurology
series. Philadelphia: FA Davis Co; 1979. p. 4760.
2. Halmagyi GM, Curthoys IS. A clinical sign of canal
paresis. Arch Neurol 1988;45:7379.
3. Black FO, Pesznecker SC. Vestibular ototoxicity.
Clinical consideration. Otolaryngol Clin North
Am 1993;26:71336.
4. Lindeman H. Regional differences in sensitivity of
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6. Meza G, Lopez I, Paredes M, et al. Cellular target
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8. Norris CH, Shea JJ. Selective chemical vestibulec-
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chemical ablation of vestibular function using
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intratympanic gentamicin treatment of Menieres
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20. Kaplan DM, Hehar SS, Bance ML, Rutka JA. Inten-
tional ablation of vestibular function using
commercially available topical gentamicin-
betamethasone eardrops in patients with Menieres

disease: further evidence for topical eardrop oto-
toxicity. Laryngoscope 2002;112:68995.
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AG. Chemical labyrinthectomy: local application
of gentamicin for the treatment of unilateral
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simultaneous binaural bithermal caloric testing: a
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26. Baloh RW, Sakala SM, Yee RD, et al. Quantitative
vestibular testing. Otolaryngol Head Neck Surg
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27. Minor LB. Intratympanic gentamicin for control
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specify completion of therapy. Am J Otol 1999;
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28. Tomlinson RD, Saunders GE, Schwarz DWF.
Analysis of human vestibulo-ocular reflex during
active head movements. Acta Otolaryngol 1980;
94:5360.
29. Larsby B, Hyden D, Odkvist LM, et al. Caloric and
rotatory tests in patients with uni- and bilateral
vestibular loss. Acta Otolaryngol Suppl 1984;412:
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30. Black FO, Peterka RJ, Elardo SM. Vestibular reflex
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31. OLeary DP, Davis LL, Li S. Predictive monitoring
of high-frequency vestibulo-ocular reflex rehabili-
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 CHAPTER 20
Ototoxic Damage to Hearing: Otoprotective Therapies
Thomas R. Van De Water, PhD, and Leonard P. Rybak, MD, PhD
In response to ototoxic damage by either an amino-
glycoside antibiotic or a chemotherapeutic agent, there
are in general two ways by which damaged sen-
sorineural cells of the cochlea can die. The damaged
sensorineural cells of the auditory receptor can be elim-
inated by either necrosis or apoptosis or by a mixture
of these two processes within the injured cochlea. These
two cell death processes have distinct histologic and
biochemical profiles that can be used to identify them.
Necrosis generally occurs in areas of the organ of
Corti that have sustained the greatest degree of damage.
The histologic features of necrotic cell death include
swelling of the mitochondria and the nucleus, dissolu-
tion of cellular organelles, and lysis of the affected
cochlear sensory cell with degradation of its deoxy-
ribonucleic acid (DNA). Because necrotic cell death
occurs rapidly and only in those sensory cells that have
sustained a high level of internal damage, it is extremely
difficult to prevent necrosis through treatment of dam-
aged cochlear sensory cells. The best approach to pre-
vent cell loss from necrosis is to prevent the damage
from occurring to the sensory cells of the cochlea.
The second form of cell death that eliminates dam-
aged cochlear sensory cells is apoptosis, also known as
programmed cell death. However the term pro-
grammed cell death in general refers to the apoptosis
that occurs naturally during normal development and
is a normal physiologic process for reducing the num-
ber of cells within a maturing organ to a physiologically
relevant number and also for sculpting the shape of
body parts and organs (eg, transition of a limb paddle
to a hand with distinct digits). Here, the term apopto-
sis refers to cell death that is unwanted and occurs in
response to ototoxic damage to inner ear sensory cells.
In the process of apoptosis of damaged cochlear
sensory cells, a biochemical cascade of intracellular sig-
naling activates cell death molecules that are present
within normal cells in pro-forms that are inactive
(eg, procaspase-3). During the process of apoptosis the
cytoplasm condenses, both the ribosomes and the
mitochondria aggregate, the nuclear chromatin con-
denses and aggregates, and as the cell dies small cellu-
lar fragments termed apoptotic bodies form. One of the
delineating characteristics of apoptotic cell death is the
enzymatic cleavage of the affected cells DNA into
180 bp internucleosomal fragments, also termed DNA
laddering. Other characteristics of apoptosis are gener-
ation of reactive oxygen species (ROS) and other free
radicals, intracellular acidification, reduction of or a
complete loss in the membrane potential of the cells
mitochondria, activation of caspases (eg, caspase-3),
and externalization of phosphatidyl serine residues.
Apoptosis can occur over a series of days after the ini-
tial insult and is often the result of cumulative damage
occurring within a cochlear sensory cell owing to on-
going generation of ROS and other free radicals, release
of cytochrome-c from damaged mitochondria, and
activation of intracellular cell death molecules (eg, cas-
pases) within the damaged cell (Figure 20-1).1,2
Unlike necrotic cell death of cochlear sensory cells,
the apoptosis of injured cochlear sensory cells can be
lessened or in some cases completely prevented by
interventional otoprotective therapies that target the
process of apoptosis within the affected cochlear sen-
sory cells. These interventional therapies are known
collectively as otoprotection and have been applied as
part of treatments aimed at lessening ototoxic damage
to the cochlear neurosensory cells and to hearing from
both aminoglycosides and chemotherapeutic agents.
AMINOGLYCOSIDE ANTIBIOTICS:
OTOPROTECTION
Aminoglycosides are highly effective antimicrobial
agents whose efficacy and use in the treatment of life-
threatening aerobic gram-negative bacterial infections
have been severely limited because of both nephrotoxic
and ototoxic side effects at high dosages or when large
cumulative dose levels are achieved after extended
usage. Aminoglycosides cause a loss of hearing acuity
through the generation of ROS and other free radicals
 Ototoxic Damage to Hearing: Otoprotective Therapies 171

Extrinsic Cell Death OTOTOXIN Intrinsic Mitochondrial

Receptor Pathway Cell Death Pathway
Injury

TNF family Oxidative stress

receptors (eg, Fas) ROS
Stress kinase HNE
Procaspase-8
pathways
Active caspase-8 (eg, c-jun) MAPK/JNK
Active (low concentration)
caspase-8 BID
(high concentration) Apoptosome
BIM Mitochondrion

dATP Smac/Diablo BCL2 BCIXL

APAF-1 Cyto C
Cyto C
Procaspase-9
BAX
Active caspase-8

Activation of downstream
caspases (eg, caspase-3)
IAPs

Apoptotic substrates
(eg, degradation of
proteins and DNA)

Apoptosis

Figure 20-1 This flow chart depicts both the extrinsic cell death receptor pathway and the intrinsic mitochondrial cell death
pathway that can be activated by exposure to an ototoxin. The extrinsic pathway involves the activation of receptors of a mem-
ber of the tumor necrosis factor (TNF) family such as activation of Fas receptors with a Fas ligand. This brings attached pro-
caspase-8 molecules into close association and through autocatalysis results in their conversion into active caspase-8 molecules.
At high concentration caspase-8 can act directly on downstream effector procaspase molecules and activate these effector cas-
pases (eg, caspase-3) that affect the apoptosis of the injured sensory cell. Lower levels of activated caspase-8 can cross over into
the intrinsic pathway via the activation of the proapoptotic member of the Bcl-2 family BID. The intrinsic pathway involves
oxidative stress and the formation of reactive oxygen species (ROS) causing lipid peroxidation damage to cellular membranes
with the formation of a natural toxin, ie, 4-hydroxyl-2,3-nonenal (HNE), that activates the mitogen-activated protein kinase
(MAPK)/c-jun-N-terminal kinase (JNK) cell death signal cascade, resulting in damage to the mitochondrial membranes and
formation of pores in the outer mitochondrial membrane by a proapoptotic member of the Bcl-2 family (ie, BAX). Two anti-
apoptotic members of the Bcl-2 family, ie, BCL2 and BCL XL , both try to stabilize this membrane and inhibit pore formation by
BAX. BIM, a proapoptosis member of the Bcl-2 family, acts to block the antiapoptotic effects of BCL 2 and BCL XL. Pore forma-
tion releases cytochrome c (Cyto C) from the inner compartment of the damaged mitochondrion, and once Cyto C is within
the cytoplasm of the injured sensory cell it forms complexes with procaspase-9 and APAF-1 in the presence of dATP to form
the apoptosome, which converts procaspase-9 into active caspase-9. Activated caspase-9 activates downstream effector procas-
pase molecules, and these molecules (eg, caspase-3) cleave apoptotic substrates within the cell, affecting its death via apopto-
sis. Both activator caspases and effector caspases can be inhibited by naturally occurring inhibitor of apoptosis molecules (IAPs),
but these molecules themselves are the targets of activated effector caspase molecules.

that directly damage the auditory hair cells.39 Because
aminoglycosides remain an important class of antibi-
otics that are still used to treat difficult life-threatening
infections and to treat such diseases as cystic fibrosis
(inhalation therapy; 16% of treated patients develop a
bilateral sensorineural hearing loss), 10 many com-
pounds have been tried as otoprotectant molecules to
prevent the ototoxic side effects of these antibiotics.
This chapter discusses many of the otoprotective
molecules used to protect hearing and to prevent the
loss of auditory sensory cells via aminoglycoside-
induced apoptosis of these cells.
SPIN-TRAPPING AGENTS
Alpha-phenyl-tert-butyl-nitrone
It is well known that external ear canal antibiotic drops
that contain aminoglycoside antibiotics have the
172 Interventions
potential to cause a hearing loss if they enter the mid-
dle ear cavity through an opening in the tympanic
membrane.1116
Alpha-phenyl-tert-butyl-nitrone (PBN) is a spin-
trap molecule that can effectively trap and inactivate
ROS and other free radicals. PBN given systemically
and when applied to the round window membrane
(RWM) prior to application of an aminoglycoside otic
drop medication was able to prevent the ototoxic effect
of this preparation as determined by a loss of sensitiv-
ity of the cochlear action potential in the high-
frequency range.17 This is the only report on the use of
a spin-trap molecule for this application, and to date
there have been no further studies to determine if this
approach could be used in a clinically relevant applica-
tion. This report provides evidence that otic drop
preparations containing aminoglycoside antibiotics
(eg, neomycin) generate ROS and other free radicals
when applied to the RWM and that this oxidative stress
plays a role in the ototoxic side effect of these otic drop
preparations.
ANTIOXIDANTS
The primary function of antioxidant molecules is
either to prevent the formation of or to detoxify ROS
and other free radical molecules formed in affected
cells during oxidative stress. By limiting a cells expo-
sure to ROS and other free radicals, the internal dam-
age within a cell is also limited; the level of internal
damage determines whether a cell will self-repair or
commit to a program of suicide (ie, apoptosis).
Glutathione
Glutathione (GSH) is an endogenous thiol-containing
amino acid that is part of every cells natural defense
against excessive oxidative stress. GSH can detoxify
ROS and other toxic molecules (eg, 4-hydroxy-2,3-
nonenal; HNE) created within a cell under oxidative
stress. GSH molecules are present within mitochondria
and are critical to the cells ability to neutralize the
effect of oxidative stress and therefore critical to a hair
cells viability when subjected to the oxidative stress
created by exposure to an aminoglycoside antibiotic.
Two articles that initially showed a relationship
between nutritional status of laboratory animals, their
GSH levels, and increased susceptibility of the cochlea
to ototoxic damage from exposure to aminoglycoside
antibiotics created an interest in GSH as an otoprotec-
tant molecule.18,19 Studies with isolated outer hair cells
in vitro demonstrated that GSH attenuated the ototoxic
effect of gentamicin metabolites on these sensory
cells. 20,21 A study that looked at the relationship
between diet and GSH levels within cochlear tissues
clarified the issue of the protective effect of GSH
against aminoglycoside-induced hearing loss.22 This
study showed that supplementing the diet of amino-
glycoside-exposed laboratory animals with the
monoethyl ester of GSH (GSHe) was effective only in
protecting against hearing loss if the animals were
nutritionally deprived (ie, low-protein diet). Similarly,
if the animals were on a normal protein diet, and there-
fore had normal levels of GSH within their cochlear tis-
sues, there was no otoprotective effect achieved by
GSHe supplementation of their diet. GSH levels within
the outer hair cells (OHCs) of the cochlea are distrib-
uted in a base-to-apex pattern that mirrors the suscep-
tibility of the OHCs to the toxic effects of
aminoglycosides, with the lowest levels of GSH found
in the OHCs in the base of the cochlea and the highest
levels in the most apical OHCs.23 This recent observa-
tion supports the importance of the natural otoprotec-
tive ability of GSH within the cochlea. The higher the
level of GSH within an OHC, the greater its ability to
resist the ototoxic effect of an aminoglycoside antibi-
otic because there is a base-to-apex gradient in OHC
susceptibility to aminoglycosides. For GSH to function
as an otoprotectant molecule it must be intracellular; it
is not cell permeable. The GSH molecule must be ester-
ified (ie, GSHe) in order for it to pass through the cell
membrane to act as an otoprotectant molecule. Local
application of GSHe to the cochlea via the RWM may
be an effective approach for using this otoprotective
molecule against aminoglycoside ototoxicity, but as yet
there are no animal studies with GSHe.
Methionine
Methionine (Met) is a thiol containing naturally occur-
ring essential amino acid that possesses both anti-
oxidant and metal-chelating properties. It has been
shown to prevent gentamicin-mediated formation of
free radicals in a cell-free in vitro test, in cell cultures,
and when injected systemically to significantly attenu-
ate the amount of gentamicin-induced free radical for-
mation and hearing loss.24 Protection of hearing by
systemic administration of D-Met was partial but did
extend to all frequencies tested (ie, 318 kHz), and
therefore the potential of methionine as an otoprotec-
tant therapy against aminoglycoside ototoxicity may
warrant additional investigation. Whether a high level
of systemically administered D-Met would interfere
with the antimicrobial efficacy of the aminoglycosides
has yet to be determined.
Iron Chelators: Deferoxamine and 2,3-
Dihydroxybenzoate
Two well-characterized iron chelators, deferoxamine
(DFO) and 2,3-dihydroxybenzoate (DHB), have been
demonstrated to be highly effective in the prevention of
gentamicin-induced hearing loss in a guinea pig model
of ototoxicity.25 This study also showed that treating the
guinea pigs with these iron chelators did not diminish
the effective plasma levels of available gentamicin within

the treated animals. A later study using electron para-
magnetic resonance spectroscopy and a spin-trapping
agent (5,5-dimethyl-pyrroline-N-oxide; DMPO)
demonstrated in cochlear tissue isolates that treatment
of these isolates with DFO prevented the formation of
ROS and other free radicals normally generated by expo-
sure of this cochlear tissue to ototoxic levels of gentam-
icin and kanamycin.4 A series of studies that followed
have shown that iron chelators can be highly effective
otoprotective agents that substantially diminish the oto-
toxic side effects of aminoglycoside treatment on both
hair cell integrity and the oxidative stress-induced hear-
ing loss that results from aminoglycoside treatment. The
use of these iron chelators had no effect on either the lev-
els or antimicrobial efficacy of aminoglycoside antibi-
otics.2630 The main drawback of using iron chelators as
otoprotectant molecules against the ototoxic effects of
aminoglycoside antibiotics is their toxic side effects
when used at levels high enough to be otoprotective.
Salicylate
Salicylates are among the most commonly used drugs,
especially in the form of aspirin (ie, acetylsalicylate)
that is rapidly converted to salicylate in serum within 15
to 30 minutes of ingestion. Salicylate (2-hydroxyben-
zoate) is a potent antioxidant and free radical scavenger
that when interacting with free radicals (ie, hydroxyl
radicals) forms the chelator molecule 2,3-dihydroxy-
benzoic acid, which converts to the highly effective iron
chelator DHB. A study of the otoprotective capability of
salicylate when coadministered with gentamicin in
guinea pigs demonstrated that this treatment provided
both a high level of protection against drug-induced
hearing loss and protection of hair cell integrity.31 Sali-
cylate treatment did not interfere with either the serum
levels of the administered aminoglycoside or with its
antimicrobial efficacy and the levels required for pro-
tection of hearing corresponded to levels presently used
in patients receiving aspirin therapy for arthritis. The
results of a clinical trial performed in China are being
evaluated for aspirin otoprotection against aminogly-
coside ototoxicity (for a more in-depth discussion of
these results see Chapter 9, Mechanisms for Amino-
glycoside Toxicity: Basic Science Research).
Tanshinone
Tanshinone is an extract of Salviae miltiorrhizae that
contains diterpene quinones and phenolic acids that
possess potent antioxidant properties. Produced in
China, tanshinone is a traditional herbal medicine
available over the counter and known by the name
Danshen. The results of an initial study of the otopro-
tective properties of tanshinone both in vitro and in
vivo against aminoglycoside ototoxicity are very
promising, with suppression of the formation of ROS
and other free radicals by gentamicin in an in vitro
Ototoxic Damage to Hearing: Otoprotective Therapies 173
system and protection against both hearing loss and
loss of auditory hair cells following kanamycin expo-
sure in vivo.32 Tanshinone was also demonstrated not to
interfere with the antimicrobial action of the amino-
glycoside antibiotic kanamycin. These findings are very
encouraging because this is a widely used herbal med-
icine with strong antioxidant and otoprotective prop-
erties that does not interfere with the antimicrobial
efficacy of the aminoglycoside antibiotic tested. Further
studies are warranted.
Superoxide Dismutase
Superoxide dismutase (SOD) is a naturally occurring
antioxidant defense molecule that protects cells from an
excess of superoxide produced during oxidative stress by
dismutating superoxide into hydrogen peroxide mole-
cules that can be inactivated through the action of the
antioxidant molecule catalase. SOD has a molecular
weight greater than 30 kDa; because of its large size it is
difficult to use in direct application as an otoprotective
agent against the ototoxic effects of aminoglycosides. An
additional consideration is that the half-life of SOD in
the body is very short, approximately 6 minutes. Evi-
dence for its otoprotective capability comes from both
transgenic animals that were genetically engineered to
overexpress Cu/Zn SOD (SOD1) and from gene therapy
experiments where a vector was used to overexpress
either SOD1 or Mn SOD (SOD2). Overexpression of
SOD1 in a transgenic mouse conveyed protection
against kanamycin-induced hearing loss in the overex-
pressing animals.33 Adenoviral vector overexpression of
SOD2 was more effective as an otoprotective therapy (ie,
protecting both hair cells and hearing) against amino-
glycoside ototoxicity than was the adenoviral vector
overexpression of SOD 1.34 These gene therapy results
are encouraging; however, many questions remain to be
addressed before gene therapy can be considered for
application as an inner ear therapy in the clinic. An in
vitro study with organ of Corti explants from neonatal
mice has demonstrated that an SOD mimetic, M40403
(a manganese-based nonpeptidyl molecule), can pro-
vide some protection of the auditory hair cells in the
explants from the ototoxic effect of gentamicin.35 These
results with the SOD mimetic were encouraging, but
this approach needs to be tested in an animal model to
determine efficacy in vivo and if this type of therapy
would have any unwanted side effects.
INHIBITORS OF CELL DEATH PATHWAYS
The mitogen-activated protein kinase (MAPK) cell
death signaling pathway was first implicated in amino-
glycoside-induced auditory hair cell loss in an in vitro
study that reported the use of an inhibitor of this
pathway to protect the hair cell in aminoglycoside-
challenged organ of Corti explants.
174 Interventions
CEP 1347, A MAPK Pathway Inhibitor
CEP 1347 is a derivative of the indolocarbazole K252a
and blocks the MAPK signal pathway at the level of the
mixed lineage kinases (eg, MLK-3). The in vitro results
of an initial study with CEP 1347 have shown that this
MAPK pathway inhibitor can protect auditory hair cells
within neomycin-challenged neonatal rat organ of
Corti explants from the toxic effect of this aminogly-
coside antibiotic.36 The results of a second experimen-
tal series studying in vivo aminoglycoside-induced
hearing and hair cell losses has shown that CEP 1347
when administered systemically can partially protect
both hair cells and hearing from the ototoxic effect of
gentamicin.37 This in vivo study also demonstrated the
protection of vestibular hair cells against the vestibulo-
toxic effect of gentamicin. This type of therapeutic
approach is encouraging; however, no data are available
to determine the affect of CEP 1347 administration on
the antimicrobial action of gentamicin and any possible
deleterious affects of long-term systemic administra-
tion of a MAPK pathway inhibitor (ie, CEP 1347).
c-Jun N-Terminal Kinase Inhibitory Peptide
c-Jun N-terminal kinase inhibitory peptide (D-JNKI-1)
is a chemically synthesized cell-permeable JNK ligand
that blocks JNK-mediated activation of its target mol-
ecules, that is, c-Jun. D-JNKI-1 is an efficient inhibitor
of the action of all three JNK isoforms and is made by
linking the 20 amino acid terminal JNK-inhibitory
sequence (ie, the JNK-binding domain of JIP-1/IB1) to
a 10amino acid HIV-TAT transporter sequence. The
results of in vitro and in vivo studies demonstrate that
local application of the D-JNKI-1 peptide can protect
both auditory hair cells and hearing from the ototoxic
effects of neomycin.38 This study confirms the original
observation that the MAPKJNK cell death signal path-
way is involved in the apoptosis of oxidative stress-
injured auditory hair cells and that the blocking of the
MAPK cell death signal pathway is an effective way to
prevent aminoglycoside-induced hair cell and hearing
losses. At present it is not known if treatment of the
inner ear with D -JNKI-1 peptide would effect the
antimicrobial efficacy of an aminoglycoside antibiotic,
but since the D-JNKI-1 treatment was via local appli-
cation it is highly unlikely that it would have a systemic
effect on the actions of an aminoglycoside.
Caspase Inhibitors
Caspases are a family of cysteine proteases that are pre-
sent within the cells of normal healthy tissue in inactive
(procaspase) forms. The procaspase configuration of a
caspase is quiescent, and in order for a caspase to
become active it requires cleavage of its prodomain.
After the prodomain has been cleaved from the procas-
pase molecule, the caspase molecule is activated and can
now act upon and cleave a specific tetrapeptide
sequence (this sequence varies for each member of the
caspase family) in targeted proteins, which can include
both the cytoskeletal and nuclear proteins of an oxida-
tive stress-damaged auditory hair cell. Many members
of the caspase family of proteases (eg, caspases-3, -8, and
-9) have been proven to participate in the regulation
and execution of apoptosis of oxidative stress-damaged
hair cells, which can be the result of a cells response to
a high level of internal injury (eg, aminoglycoside-
induced damage). Caspases were found to participate in
the apoptotic cell death of gentamicin-damaged
vestibular hair cells. Explants of utricular maculae
excised from both adult guinea pigs and adult gerbils
were exposed to ototoxic levels of gentamicin and pro-
tected by addition of a broad-spectrum pancaspase
inhibitor (either z-VAD-fmk or BAF) to the culture
medium.39 The explants with the pancaspase inhibitor
treatment showed a significant level of protection
against gentamicin-initiated loss of vestibular hair cells
and a significant reduction in the number of apoptotic
hair cell nuclei. This finding of pancaspase protection of
vestibular hair cells from aminoglycoside-initiated
apoptosis was confirmed in another in vitro study that
used post-hatch white leghorn chickens for a source of
utricular maculae explants and neomycin as the oto-
toxic drug.40 The pancaspase inhibitors added to the
culture medium were the same used in the previous
study (z-VAD-fmk and BAF), and both of these
inhibitors were highly effective in preventing amino-
glycoside-induced death of hair cells. The first proof
that specific members of the caspase family of cysteine
proteases are involved in the apoptosis of both auditory
and vestibular hair cells after an ototoxic insult have
been reported in two recent in vitro studies, avian basi-
lar papilla explants and mouse utricular explants. The
study of chick basilar papilla explants exposed to an
ototoxic level of gentamicin used fluorescent-labeled
peptide substrates for caspases-3, -8, and -9 to detect
their activation within the ototoxin-exposed basilar
papilla explants.41 The results of this in vitro study show
that gentamicin-damaged auditory hair cells degenerate
and undergo apoptosis in a caspase-dependent manner
and that the initiator caspases-8 and -9 and a down-
stream effector caspase, caspase-3, are activated in
aminoglycoside-damaged auditory hair cells. This study
used the general caspase inhibitor z-VAD-fmk to pre-
vent caspase activation, so no conclusions could be
drawn about the action or efficacy of specific caspase
inhibitors in this ototoxin damage model. However, the
adult mouse utricular explantneomycin study
reported the use of a combination of the following:
(1) in situ substrate detection for specific caspases;
(2) immunolabeling of activated caspases; and (3) cas-
pase inhibitors with known specificity.42 Initially, a

pancaspase inhibitor was used to confirm that caspases
were involved in the apoptosis of these ototoxin-
damaged vestibular hair cells. The results of this study
confirm the activity of casapses-8, -9, and -3 in the
apoptosis of ototoxin-damaged vestibular hair cells;
additionally, this study shows that caspase-8 plays only
a minor role in the process of apoptosis of aminoglyco-
side-damaged hair cells, whereas caspases-9 and -3 were
found to have major roles in the apoptosis of these dam-
aged hair cells. When specific caspase inhibitors were
used to prevent hair cell death, the caspase-8 inhibitor
(z-IETD-fmk) had no significant effect on either pre-
venting neomycin-induced hair cell death or the down-
stream activation of procaspase-3. In contrast, the
caspase-9specific inhibitor (z-LEHD-fmk) prevented
both neomycin-induced hair cell death and the down-
stream activation of procaspase-3 in these ototoxin-
exposed utricular explants. Currently, there are no
reported studies to determine whether downstream
effector caspases-6 and -7 participate in the process of
apoptotic cell death of hair cells that eliminates these
aminoglycoside-damaged sensory cells. All of the cas-
pase inhibitor studies discussed in this section were per-
formed in vitro, so it is not currently known whether
these irreversible inhibitors of caspases (eg, z-VAD-fmk,
a pancaspase inhibitor) will be effective when delivered
in vivo (eg, perfused into the scala tympani).
Caspases-9 and -3 appear to be essential compo-
nents in the apoptotic cell death of aminoglycoside-
damaged inner ear hair cells, whereas caspase-8 has
been shown to play only a minor role in this cell death
process. These in vitro results are encouraging; how-
ever, there are as yet no animal studies demonstrating
that caspase inhibitors can work in the intact animal to
protect against aminoglycoside-induced hair cell loss
and the loss of hearing. The action of caspase inhibitors
on the antimicrobial action of aminoglycosides also
needs to be defined.
GROWTH FACTORS
Glial Cell LineDerived Neurotrophic Factor
Glial cell linederived neurotrophic factor (GDNF) is
a member of the transforming growth factor-beta
(TGF-) family. In both in vitro and in vivo studies
GDNF has been shown to partially protect hair cells for
aminoglycoside ototoxicity.43 It has also been shown to
have a neuroprotective effect on oxidative stressed
VIIIth nerve ganglion neurons in vitro.43 In addition,
the use of an adenoviral vector to overexpress GDNF in
the inner ear has been shown to be as effective as GDNF
protein in partially protecting the auditory hair cells,
hearing, and vestibular hair cells from the ototoxic
effects of aminoglycosides (eg, gentamicin) in vivo.44,45
These results with GDNF are promising because this
Ototoxic Damage to Hearing: Otoprotective Therapies 175
growth factor appears to offer a partial level of otopro-
tection to both the hair cells and the neurons of the
cochlea. Studies are needed to determine that GDNF
does not interfere with the antimicrobial action of the
aminoglycosides and to develop a safe and effective
route for the delivery of GDNF. Direct infusion into the
scala tympani and delivery via a gene therapy vector are
at present not approved methods of delivery of oto-
protective agents into the cochlea of a patient.
Members of the Neurotrophin Family: Brain-
Derived Neurotrophic Factor, Neurotrophin Type 3,
and Neurotrophin Type 4/5
The auditory neurons of the spiral ganglion depend on
the auditory hair cells that they innervated for their
health and survival because the hair cells supply trophic
support for these neurons. The results of gene null-
mutation experiments have demonstrated that both
brain-derived neurotrophic factor (BDNF) and neu-
rotrophin type-3 (NT-3) are important neurotrophins
for the maturation and survival of VIIIth nerve neu-
rons, with BDNF suggested to be most important for
the neurons of Scarpas ganglion and NT-3 most
important for the spiral ganglion neurons.46 However,
in vivo neurotrophin infusion experiments have deter-
mined that either of these neurotrophins (ie, BDNF or
NT-3) is adequate to support the survival of spiral gan-
glion neurons following an aminoglycoside-induced
loss of auditory hair cells.47,48 There is some indication
from the results of in vitro studies that BDNF, NT-3,
and NT-4/5 can have a neuroprotective capability when
VIIIth nerve neurons are subjected to neurotoxic mol-
ecules.4951 An in vivo study combined NT-3 with an N-
methyl-D-aspartate (NMDA) antagonist (ie, MK 801)
to prevent hearing loss from exposure to amikacin, and
this approach provided partial protection to the hear-
ing receptor.52 The main application of BDNF and
NT-3 therapy appears to be protecting and supporting
the health and survival of the auditory neurons. The
action of neurotrophins on the antimicrobial action of
aminoglycoside antibiotics is currently unknown and
needs to be determined.
Transforming Growth Factor-Alpha
Transforming growth factor-alpha (TGF-) is a mem-
ber of the epithelial growth factor (EGF) family and has
been suggested to be involved in the repair of damaged
hair cells. An in vitro study using both hair cell counts
and real-time confocal Ca ++ imaging have demon-
strated that TGF- can protect auditory hair cells from
the ototoxic effect of neomycin.53 This observation,
although robust, was made in isolated organ of Corti
explants. Experiments have never been attempted in
vivo, and there is no information of the possible effect
176 Interventions
of TGF- treatment on the antimicrobial action of any
of the aminoglycoside antibiotics.
AMINOGLYCOSIDE OTOPROTECTION RESEARCH
TO DATE: SOME CONCLUSIONS
Several otoprotective agents have been shown to be
effective against aminoglycoside ototoxicity. Some of
these agents have been demonstrated not to interfere
with the antimicrobial actions of the aminoglycoside
antibiotics, but many of these otoprotective agents have
not been evaluated for possible interference by these
compounds. Novel routes of drug administration will
be required for some of the otoprotective compounds
to be effective. At present only two routes of adminis-
tration are currently available and approved. These are
direct injection through the tympanic membrane into
the middle ear cavity and delivery to the RWM via a
Silverstein MicroWick; the middle earRWM catheter
produced by Durect Corporation and approved by the
US Food and Drug Administration (FDA) is no longer
commercially available. 5456 Clinical trials are in
progress in China, testing the efficacy of aspirin against
aminoglycoside ototoxicity; the initial results are
encouraging (see Chapter 9, Mechanisms for Amino-
glycoside Toxicity: Basic Science Research), but more
trials will be needed to test other promising agents such
as D-Met and D-JNKI-1 peptide to determine the dose,
timing, and route of administration. The herbal medi-
cine approach to otoprotection needs additional explo-
ration as suggested by the very encouraging results of
an initial animal study with the Chinese herbal anti-
oxidant compound tanshinone.32
CHEMOTHERAPEUTIC AGENTS: CISPLATIN
OTOPROTECTION
Cisplatin is a highly effective chemotherapeutic agent
used to treat a variety of soft tissue neoplasms. To
achieve therapeutic cures, the doses of cisplatin have
been escalated. Unfortunately, ototoxicity, nephro-
toxicity, and neurotoxicity can occur. In some series,
every patient treated with cisplatin had hearing loss (see
Chapter 6, Ototoxicity of Platinum Compounds).57
Thiol Compounds
Several potentially protective drugs have been tested
against cisplatin ototoxicity because of their efficacy in
preventing nephrotoxicity. Several agents tested ini-
tially in animals contain thiol groups. These include
sodium thiosulfate, D-Met, L-Met, diethyldithiocarba-
mate (DDTC), methylthiobenzoic acid, lipoic acid, L-N
acetylcysteine, and amifostine.
Sodium thiosulfate has been shown to protect
against cisplatin ototoxicity in guinea pigs and in ham-
sters.58,59 Unfortunately, this drug neutralized the anti-
tumor effect of cisplatin. To avoid this problem, a study
was conducted using intracochlear administration of
sodium thiosulfate. Perfusion of sodium thiosulfate
into the cochleae of guinea pigs completely prevented
cisplatin-induced hearing loss as revealed by no change
in compound action potential threshold and by no
change in distortion-product otoacoustic emission
audiograms. Cochlear hair cells and the stria vascularis
were well preserved in the animals receiving sodium
thiosulfate protection.60 On the other hand, chronic
RWM application of sodium thiosulfate using an
osmotic minipump implanted in guinea pigs treated
with systemic cisplatin provided no protection against
ototoxicity.61
Intracochlear perfusion of thiourea also provided
partial protection against cisplatin ototoxicity in guinea
pigs. Ears treated with thiourea had significantly fewer
outer hair cells lost, although the brainstem auditory
evoked potential threshold did not differ from that of
animals treated with cisplatin alone.62 Thus, thiourea
appeared to be less effective as a protective agent
against cisplatin ototoxicity.
Another sulfur-containing drug, mesna (sodium
2-mercaptoethane sulfonate), also interferes with the
antitumor activity of cisplatin. The free thiol group of
mesna reacts with cisplatin in the circulation, forming
an inactive complex. Therefore, this drug has not been
pursued as a chemoprotector against cisplatin in clini-
cal trials.63
DDTC has been shown to effectively prevent cis-
platin ototoxicity in rats. Animals pretreated with
DDTC had significantly smaller elevations of auditory
brainstem response thresholds compared with animals
receiving cisplatin alone.64 It was also effective in pre-
venting hair cell destruction in hamsters treated with
cisplatin.59 However, patients given DDTC as a protec-
tive agent against cisplatin toxicity experienced side
effects. These unpleasant side effects included numb-
ness in the arm into which it was being infused,
diaphoresis, chest discomfort, flushing, agitation, and
elevation of systolic blood pressure.
The combination of DDTC and cisplatin treat-
ment in melanoma B16-bearing mice was compared
with the antitumor efficacy of cisplatin alone. The
efficacy of cisplatin against this tumor was reduced by
half in mice administered DDTC in combination with
cisplatin.65
Amifostine protects against cisplatin nephrotoxic-
ity. However, it was not found to be effective against
cisplatin ototoxicity in hamsters.59 It is metabolized to
an active metabolite that is selectively taken by normal
tissues. However, because amifostine has unpleasant
side effects, including transient hypotension, nausea,
and vomiting, it is not an ideal protective agent.
Experimental studies in rats have shown that 4-
methylthiobenzoic acid (MTBA) is an excellent protec-
tive agent against cisplatin ototoxicity. In vitro studies

demonstrated that adding MTBA to organotypic
cultures of the organ of Corti prevented hair cell loss
attributed to cisplatin exposure.66 Pretreatment of rats
with this agent prior to cisplatin prevented elevation of
auditory brainstem response thresholds and loss of
outer hair cells in the cochlea.67 An added benefit asso-
ciated with this protective agent was prevention of
weight loss and protection against cisplatin-induced
nephrotoxicity. 68 Boogaard and colleagues demon-
strated that MTBA did not interfere with the antineo-
plastic efficacy of cisplatin.69 To our knowledge, no
clinical trials of MTBA protection against cisplatin oto-
toxicity have yet been performed.
D-Met was found to provide excellent protection
against cisplatin-induced hearing loss (elevation of
brainstem auditory evoked potential threshold) and
loss of outer hair cells in rats.70 It was also found to pre-
vent damage to the stria vascularis.71 D-Met provided
cytoprotection against cisplatin toxicity without com-
promising antitumor activity in an animal model of
ovarian cancer.72 Rats bearing an aggressive form of
breast cancer were protected against both cisplatin oto-
toxicity and nephrotoxicity. It was suggested that both
L- and D-Met reduced the ability of cisplatin to kill an
aggressive form of breast cancer in vitro and in vivo.73
However, when L-Met was delivered to the RWM
of systemically treated rats bearing this aggressive form
of breast cancer, there was excellent protection against
ototoxicity without compromising the chemothera-
peutic efficacy of cisplatin.74 Similarly, application of
D-Met to the RWM prior to administering cisplatin to
the RWM in chinchillas provided excellent protection
against hair cell loss and prevented elevation of audi-
tory brainstem response thresholds.75 Chronic admin-
istration of D-Met to the RWM of guinea pigs using an
implanted osmotic minipump in animals treated with
systemic cisplatin prevented changes in distortion-
product otoacoustic emissions on days 3 and 4 of
treatment. Unfortunately, no differences in morphol-
ogy could be seen on electron microscopy of the
cochlea of guinea pigs treated with D-Met versus saline
on the RWM in combination with systemic cisplatin.61
The intratympanic administration of D-Met is a poten-
tially useful route of providing this protective agent
because it would not be likely to interfere with the
antitumor efficacy of cisplatin. A study of cisplatin
pharmacokinetics suggested that cisplatin concentra-
tions in blood might be reduced by the administration
of D-Met.76 However, extremely large doses of D-Met
were employed in that study, so the significance of
these findings is unclear.
Alpha-lipoic acid is an endogenous antioxidant
with free radical scavenging properties that can act as a
chelator for heavy metals and as a potent therapeutic
agent against oxidative tissue injury. Pretreatment of
rats with lipoic acid prior to cisplatin revealed dose-
Ototoxic Damage to Hearing: Otoprotective Therapies 177
dependent protection against cisplatin ototoxicity.
Elevation of auditory brainstem response thresholds
was reduced, and the antioxidant system in cochlear tis-
sues (glutathione and antioxidant enzymes) was pre-
served in protected animals.77
Ebselen acts as a mimic for glutathione peroxidase
and as a scavenger for peroxynitrite radicals. Rats pre-
treated with Ebselen prior to cisplatin had nearly com-
plete protection against hearing loss, glutathione
depletion, and lipid peroxidation in the cochlea.77
Phosphonic Acid Antibiotics
Fosfomycin is a phosphonic acid derivative that has
antibiotic activity. It was initially reported to protect
against cisplatin ototoxicity in guinea pigs.78
However, subsequent studies have shown no pro-
tection against cisplatin effects on the inner ear of
experimental animals.59
Antioxidants
Sodium salicylate has been found to protect rats against
cisplatin ototoxicity and nephrotoxicity without com-
promising the antitumor action in rats bearing a highly
metastatic form of breast cancer. The loss of outer hair
cells was prevented, as was the elevation of brainstem
auditory evoked potential thresholds in cisplatin-treated
rats pretreated with sodium salicylate. The chemothera-
peutic efficacy of cisplatin on suppression of tumor mass
and cancer cell metastasis was unaffected by salicylate.
The mechanism of salicylate action is unclear. It may act
as a scavenger of free radicals generated by cisplatin, and
it may prevent the activation of the transcription factor
nuclear factor kappa B (NF-B).79 Salicylate could also
be acting as an iron chelator.
Vitamin E (-tocopherol) is a slow-acting free
radical scavenger that has been shown to prevent cis-
platin nephrotoxicity and endothelial cell damage. In
both guinea pigs and rats, cisplatin ototoxicity was
reduced by pretreatment with vitamin E.80,81 Hair cell
loss was prevented, and auditory function was pre-
served. Local administration of a water-soluble form of
vitamin E (Trolox) prevented the ototoxicity of cis-
platin applied to the RWM of guinea pigs.82
L-N-Acetylcysteine (L-NAC) is an antioxidant used
clinically as an antidote against acetaminophen poi-
soning and as a mucolytic agent to clear the airways. In
vitro experiments with organ of Corti organotypic cul-
tures have shown that this protective agent protects the
outer hair cells and spiral ganglion cells against cis-
platin damage in a dose-dependent manner. This drug
may directly scavenge free radicals and is a precursor
for the natural antioxidant glutathione.83 The antitu-
mor efficacy of cisplatin was reduced by half in
melanoma B16-bearing mice when L-NAC was admin-
istered in combination with cisplatin.65 This raises con-
cerns that this protective agent could diminish the
178 Interventions
antineoplastic efficacy of cisplatin in patients.
Glutathione ethyl ester, but not glutathione, was found
to reduce the auditory brainstem response threshold
shifts and outer hair cell loss observed in the rat after
cisplatin. However, this protection was only partial.84
Aminoguanidine is an inhibitor of inducible nitric
oxide synthase. It also is an antioxidant that can react
with and scavenge hydroxyl radicals. Pretreatment of
rats with aminoguanidine reduced the ototoxicity of
cisplatin. It significantly reduced the production of
malondialdehyde, a marker for lipid peroxidation, in
the cochlear tissues of rats receiving cisplatin. It
reduced the elevation of auditory brainstem responses
compared with those recorded in rats treated with cis-
platin alone, but it did not reduce the amount of nitric
oxide produced. Therefore, it was concluded that
aminoguanidine may act more as a free radical scav-
enger than as an inhibitor of nitric oxide synthesis in
the cochlea exposed to cisplatin.85
Peptides
The peptides -melanocytestimulating hormone (-
MSH) and the nonmelanotropic adrenocorticotropic
hormone (ACTH)/MSH (4-9) analog Org 2766 have
been shown to ameliorate cisplatin ototoxicity. Both
outer hair cell survival and recovery of the compound
action potential threshold are significantly enhanced by
both peptides.86
Adenosine Receptor Agonists
Adenosine receptor agonists have been found to protect
against cisplatin ototoxicity in chinchillas. Cisplatin
applied to the RWM of the chinchilla produced signifi-
cant loss of hair cells in the cochlea with concomitant
elevation of auditory brainstem response thresholds.
Pretreatment with adenosine A1 receptor agonist R-
phenylisopropyladenosine (R-PIA) or 2-chloro-N-
cyclopentyladenosine (CCPA) prevented hair cell loss,
reduced brainstem auditory evoked potential threshold
elevations, and reduced the increase in malondialde-
hyde (an index of lipid peroxidation). The effect of R-
PIA was abrogated by application of the adenosine A1
receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine
(DPCPX). Not only did the application of the adenosine
A2 receptor agonist 2-[4-(2-p-carboxyethyl) phenyl-
amino]-5N-ethylcarboxamidoadenosine (CGS) not
protect against cisplatin ototoxicity, it exacerbated it.87
R-PIA also potentiated the protective effect of L-N-
acetylcysteine on hair cells in the organotypic culture of
the organ of Corti exposed to cisplatin. Nearly complete
protection of hair cells was afforded by the combined
application of these two agents in combination with cis-
platin.66 These findings suggest that adenosine A1 recep-
tor agonists might be administered on the RWM for
protection against cisplatin ototoxicity.
Inhibitors of Cell Death Pathways
The in vitro application of inhibitors of enzymes in the
cell death pathway, caspases, has shown promise in pro-
tection against cisplatin toxicity for hair cells in vitro.
Treatment of cisplatin-exposed cochlear explants, both
prior to and during cisplatin administration, with
inhibitors of caspase-1 or caspase-3, resulted in a near
total prevention of DNA degradation in the hair cells,
as indicated by terminal deoxynucleotidyl transferase-
mediated deoxyuridine triphosphate nick end labeling
(TUNEL). These findings correlated with an increase in
hair cell survival in the explants treated with caspase
inhibitors in combination with cisplatin. However,
damage to the stereocilia on the hair cells did occur in
cultures protected by caspase inhibitors. Separate cul-
tures of spiral ganglion cells treated with cisplatin
required the presence of both caspase inhibitor and
neurotrophins to prevent apoptotic cell death.88
Pifithrin is a low-molecular-weight inhibitor of
TP53 (ie, p53). It has been found to provide significant
protection against cisplatin-induced cochlear and
vestibular hair cell loss in cochlear and utricular organ-
otypic cultures. Control cultures were devoid of TP53
immunolabeling, TP53 protein on Western blots, and
caspase-1 and caspase-3 labeling. Cisplatin exposure
increased expression of TP53, caspase-1 and caspase-3
labeling, and apoptosis of cochlear and vestibular hair
cells. Adding pifithrin to cisplatin-treated cultures
resulted in a dose-dependent increase in hair cell sur-
vival, suppression in TP53 expression, and caspase-1
and -3 labeling. Temporary suppression of TP53 with
pifithrin affords significant protection against the oto-
toxic and vestibulotoxic effects of cisplatin.89 Many
tumors are already deficient in TP53, so TP53 inhibi-
tion may not interfere with the antitumor action of cis-
platin in those cases. Future studies need to focus on
the safety of TP53 inhibition in combination with cis-
platin chemotherapy.
Cultured auditory neurons exposed to cisplatin
undergo cell death following exposure to cisplatin. A
proposed molecular pathway from cellular insult to
apoptosis is the activation and expression of immedi-
ate early genes, especially c-Jun. The activity of c-Jun
is regulated by phosphorylation and activation of
various components of the stress kinase pathway. The
phosphorylation cascade required for c-Jun activation
is mediated, in part, by c-Jun N-terminal kinase (JNK).
The treatment of these neurons with curcumin, an
upstream inhibitor of JNKc-Jun interaction, rescued
auditory neurons from cell death caused by cisplatin.
Treatment with c-Jun antisense oligonucleotide also
protected neurons from cisplatin-induced cell death.90
Whether such treatments will protect auditory hair
cells from cisplatin-induced cell death remains to
be determined.

The transduction of neurotrophin-3 using a viral
vector successfully protected spiral ganglion cells from
cisplatin ototoxicity both in vitro and in vivo in aged
mice.91 The ability to deliver neurotrophins to the inner
ear in this manner suggests that neurotrophin-based
gene therapy may be a useful preventive treatment for
ototoxic injury in the future.
CARBOPLATIN OTOPROTECTION
Carboplatin is unique among ototoxic agents in caus-
ing preferential destruction of the inner hair cells in
chinchillas, but in guinea pigs outer hair cell loss occurs
and inner hair cells remain intact.92 Chinchillas treated
with systemic carboplatin were found to have 84% loss
of inner hair cells. Animals pretreated with D-Met prior
to carboplatin treatment had a significantly lower loss
of inner hair cells compared with chinchillas treated
with carboplatin alone.93 In guinea pigs, sodium thio-
sulfate administered 1 to 8 hours after carboplatin
decreased carboplatin-induced ototoxicity but was not
effective when given 24 hours after carboplatin. In a
lung cancer cell line in vitro, sodium thiosulfate com-
bined with a tumoricidal dose of carboplatin com-
pletely blocked the cell killing.94
Carboplatin has been used to treat brain tumors.
The blood-brain barrier is first opened with mannitol,
then carboplatin is administered intravenously. This
protocol results in hearing loss in 79% of patients.
However, when sodium thiosulfate was administered
intravenously 2 or 4 hours after carboplatin, when the
blood-brain barrier had closed, patients were protected
against hearing loss.95,96 Because thiosulfate is given
after the blood-brain barrier has closed, there appears
to be no interference with the antitumor effect of
carboplatin.95
PLATINUM OTOPROTECTION RESEARCH TO
DATE: SOME CONCLUSIONS
Several protective agents have been shown to be effec-
tive against cisplatin and carboplatin ototoxicity. Some
of these agents also interfere with the antitumor effect
of these drugs. Novel routes of drug administration
may overcome some of these problems that may limit
the usefulness of chemoprotection. Additional clinical
trials are needed to determine the dose, timing, and
route of administration of protective agents to develop
an effective protocol for chemoprotection against
platinum toxicity while preserving the desired thera-
peutic effect.97
A schematic diagram of cell death pathways that
may be activated and participate in the loss of auditory
sensory cells in response to ototoxic damage caused by
aminoglycoside antibiotics and chemotherapeutic
agents is presented in Figure 20-1.
Ototoxic Damage to Hearing: Otoprotective Therapies 179
SUMMARY
Ototoxic injury to cochlear hair cells results in
cellular death from apoptosis or necrosis. Both
processes have distinct histologic and bio-
chemical profiles. Because cellular necrosis is
difficult to prevent, interventional strategies
broadly known as otoprotection have been
directed for the most part to lessen and if possi-
ble prevent apoptosis from occurring. Current
research for the prevention of aminoglycoside
and platinum-based chemotherapy ototoxicty
appears promising from both in vitro studies
and a few animal models studied to date.
Several otoprotective agents have been shown to
be effective against aminoglycoside ototoxicity.
Agents under investigation have included spin-
trapping agents (alpha-phenyl-tert-butyl-
nitone), antioxidants (glutathione and
methionine, iron chelators, salicylates, tanshi-
none, and SOD), inhibitors of cell death path-
ways and certain growth factors (ie, GDNF,
BDNF, neurotrophins, and TGF-).
Novel routes of drug administration will be
required for some compounds to be effective
against aminoglycoside ototoxicity. Delivery of
otoprotective agents via the round window
membrane has significant advantages whereby
middle ear instillations can be used to prevent
ototoxic injury from occurring.
Studied otoprotective agents for cisplatin ototox-
icity have included thiol compounds, fosfomycin,
certain antioxidants (eg, salicylates vitamin E),
peptides, adenosine receptor agonists, and
inhibitors of cell death pathways (eg, pifithrin,
curumin, neurotrophin-3). Human studies are
anticipated in the not too distant future.
Intratympanic administration strategies for oto-
protection have the advantage of providing inner
ear protection while not interfering with the anti-
tumor efficacy of platinum-based chemotherapy.
Future research protocols in humans will likely
include this methodology. Additional trials are
needed to determine the dose, timing, and route
of administration for otoprotective agents
against platinum-based compounds.
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51. Zheng JL, Stewart RR, Gao WG. Neurotrophin-
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52. Duan M, Agerman K, Ernfors P, Canlon B. Com-
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182 Interventions
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67. Kamimura T, Whitworth CA, Rybak LP. Effect of
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71. Campbell KCM, Meech RP, Rybak LP, Hughes LF.
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73. Reser D, Rho M, Dewan D, et al. L- and D-methio-
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77. Rybak LP, Whitworth C, Somani S. Application of
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81. Kalkanis JG, Whitworth C, Rybak LP. Vitamin E
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 Therapeutic Uses of Ototoxic Effects
CHAPTER 21
Systemic Treatment of Bilateral Menieres Disease
Sumit K. Agrawal, MD, and Lorne S. Parnes, MD, FRCSC
DEFINITION OF MENIERES DISEASE
Menieres disease can be defined as the idiopathic syn-
drome of endolymphatic hydrops. The Committee on
Hearing and Equilibrium of the American Academy of
OtolaryngologyHead and Neck Surgery (AAO-HNS)
published guidelines for reporting the results of treat-
ment of Menieres disease in 1972 and 1985. These
guidelines were most recently updated in 1995.
Although diagnosis can be confirmed only by post-
mortem histopathologic analysis of temporal bones,
the AAO-HNS guidelines can be used clinically to diag-
nose Menieres disease and classify it as definite, prob-
able, or possible.
The criteria for definite Menieres disease consist of
(1) two or more definitive spontaneous episodes of ver-
tigo lasting 20 minutes or longer, (2) audiometrically
documented hearing loss on at least one occasion,
(3) tinnitus or aural fullness, and (4) the exclusion of
other causes. Probable Menieres disease requires only
one episode of vertigo along with the three other crite-
ria. Possible Menieres disease requires that other causes
be excluded while consisting of either episodic vertigo
of the Menieres type without associated hearing loss or
sensorineural hearing loss, fluctuating or fixed, with
chronic dysequilibrium.1
PATHOPHYSIOLOGY
Numerous theories exist regarding the etiology and
pathophysiology of Menieres disease. An over-
accumulation of endolymph is thought to result in
endolymphatic hydrops, which in turn causes a distor-
tion in the membranous labyrinth.2 The most accepted
theory is the inadequate absorption of endolymph by
the endolymphatic sac.3 This is supported by studies
examining animal models,4,5 the finding of perisaccu-
lar ischemia and fibrosis in patients with hydrops,6 and
computed tomography (CT) and magnetic resonance
imaging (MRI) studies suggesting hypoplastic endo-
lymphatic drainage systems.710
Although temporal bone studies of patients with
Menieres disease almost always show endolymphatic
hydrops, the presence of endolymphatic hydrops may
be secondary to other causes and occur in the absence
of clinical Menieres disease.11,12 The mechanism by
which endolymphatic hydrops causes vertigo and hear-
ing loss is much debated in the literature. Schuknecht
postulated that membrane ruptures within the inner
ear cause leakage of potassium-rich endolymph into
the sodium-rich perilymph (ie, the Na+K+ intoxica-
tion theory), which subsequently alters endocochlear
potentials, resulting in a profound depolarization with
deactivation of electrical activity along the VIIIth
nerve; the acute unilateral loss of electrical activity
thereby causes the hearing loss and vertigo experienced
by patients.13 With the repair of membrane ruptures,
the acute attack would subside and hearing and balance
would be restored.14
DEMOGRAPHICS
The incidence of Menieres disease varies from 7.5 to
157 per 100,000; no significant difference in race or sex
has been shown.15 The peak incidence occurs in patients
40 to 60 years of age. 3 The incidence of bilateral
Menieres disease is highly variable in the literature,
with ranges of 2 to 78%.16 This is likely because the stage
of Menieres disease varies at the time of diagnosis and
different diagnostic criteria are used (AAO-HNS guide-
lines vs audiometric data only). Whereas some authors
have found a decreased likelihood of bilateral involve-
ment if it has not occurred within 5 years, others have
found that the incidence of bilateral disease increases
over time.1719 Kitahara surveyed 15 institutions in
Japan and found that the incidence of bilateral disease
rose from 9.1% in the first year to 41.5% after 20 years.20
NATURAL HISTORY
The natural history of Menieres disease is quite vari-
able. Friberg and colleagues studied 161 patients over

9 years and found patients on average had a 50 dB aver-
age pure-tone hearing loss, a 53% speech discrimina-
tion score, and a 50% caloric response reduction.17 The
mean frequency of attacks decreased over 20 years, and
the incidence of bilateral disease increased to 47%.
Patients can often have several attacks followed by long
remissions. One study found spontaneous cessations of
vertigo in 57% of patients after 2 years and 71% of
patients after 8.3 years.21
HISTORY OF STREPTOMYCIN-INDUCED
VESTIBULOTOXICITY
Streptomycin sulfate was first developed in 1944 by
Shatz and colleagues.22 In 1945, Hinshaw and Feldman
reported the first clinical trial using this drug in tuber-
culosis patients.23 Treatment of these patients with
streptomycin led to the realization that the drug was
ototoxic, and detailed accounts of vestibular distur-
bances in these patients were published.2325 Although
streptomycin is metabolized to dihydrostreptomycin,
which by itself causes severe vestibulotoxicity and
cochlear damage,26 the effects on the vestibular system
were shown to occur prior to the effects on cochlear
function.27 In 1946, Hawkins considered these charac-
teristics and suggested the use of streptomycin sulfate
in order to prevent vertigo in Menieres disease.28
Fowler was the first to use intramuscular strepto-
mycin sulfate (ISS) for vertigo in 1948.29 He treated
four patients, who all had a resolution of their vertigo.
In the following 3 years, Van Deinse,30 Hamberger and
colleagues,31 Hanson,32 and Ruedi33 all treated 3 to
5 patients and had response rates of 66 to 100%. In
1956, Shuknecht was the first to systematically use abla-
tive therapy with ISS in eight patients with Menieres
disease.34 Since that time he and his colleagues have
published on 20 patients followed over 25 years.3538
Although there was a 95% response rate in terms of
vertigo control with no significant hearing loss, ablative
therapy caused patients to develop severe oscillopsia
and ataxia for several months. Planned subtotal abla-
tion using titration ISS was first introduced by Graham
and colleagues in 1982 and later by Silverstein in
1983.3942 This has also been shown to be effective in
controlling vertigo but with a decreased incidence and
severity of ataxia and oscillopsia compared with abla-
tive therapy.
MECHANISM OF ACTION IN MENIERES DISEASE
Aminoglycosides inhibit ribosomal protein synthesis in
order to exert their antibiotic properties (see Chapter 8,
Clinical Aminoglycoside Ototoxicity). In the inner
ear, aminoglycosides have been shown to affect both the
sensory neuroepithelium and endolymph-secreting
cells. In the vestibular apparatus, aminoglycosides pri-
marily affect the hair cells of the crista ampullaris and
the macula of the saccule and utricle.43,44 Cochleotoxic
Systemic Treatment of Bilateral Menieres Disease 185
effects of aminoglycosides have been linked to degen-
eration of neural cells, ganglion cells, and the organ of
Corti, as well as to the loss of hair cells and supporting
structures. 45,46 In terms of endolymph production,
which has been linked to the dark cells of the crista
ampullaris, 47 aminoglycosides have been shown to
damage the secretory epithelium before the sensory
neuroepithelium.4850 Therefore, aminoglycosides may
actually reverse endolymphatic hydrops in addition to
ablating the vestibular function; this may explain why
certain patients experience a relief from vertigo with
subtotal ablation (intact caloric responses).51 In the
search for aminoglycosides with a wide therapeutic
index, gentamicin was found to be relatively less
cochleotoxic than streptomycin and less cumulative in
the inner ear than tobramycin.52
INDICATIONS FOR SYSTEMIC THERAPY
Current indications for ISS include (1) active bilateral
Menieres disease and (2) Menieres disease in an only
hearing ear.28,41,53,54 In bilateral incapacitating Menieres
disease, only a limited number of options are available.
For example, endolymphatic sac surgery could techni-
cally be performed on both sides with minimal risk to
hearing. However, the efficacy has been reported to be
as low as 50%, and long-term benefits have been ques-
tioned.5558 Vestibular nerve sections have also been
performed in bilateral Menieres disease but resulted in
oscillopsia.59 Menieres disease in the only hearing ear
also poses a challenge, and vestibular nerve sections
have been contraindicated because of the significant
risk to hearing.60 Intratympanic gentamicin therapy is
now widely used, but the average rate of hearing loss is
30%.61 Toth and Parnes found that a weekly titration
method significantly reduced the rate of hearing loss62;
however, a certain subset of patients may develop a
sudden, severe, and irreversible hearing loss. 63
Labyrinthectomy is obviously contraindicated in both
of these scenarios as it would destroy both hearing and
vestibular function.
REVIEW OF TREATMENT REGIMENS
Two main protocols have been used to administer ISS.
The first, ablative ISS, was introduced by Schuknecht in
1956 and was based upon dosing regimens used for
treating tuberculosis.34 Intramuscular injections of
streptomycin sulfate were administered, 1 g bid, until
there was no response to ice water caloric stimulation.
Patients were hospitalized, and the total dose ranged
from 21 to 72 g. All patients developed a profound
ataxia, wide-based gait, and oscillopsia but slowly
resumed normal function over 2 to 9 months.
In 1984, Graham and colleagues proposed titration
ISS in an effort to prevent oscillopsia and ataxia.39 Base-
line studies were conducted including (1) air, bone, and
speech audiometry, (2) electronystagmography (ENG),
186 Therapeutic Uses of Ototoxic Effects
and (3) blood work including complete blood count,
blood urea nitrogen, and creatinine. Intramuscular
injections of streptomycin sulfate were administered, 1
g bid, for 5 days (total 10 g), and repeat baseline stud-
ies were performed 3 days following. According to Gra-
ham, treatment should be suspended when symptoms
cease, when vestibular function subsides rapidly, should
hearing decline, or if the patient becomes oscillopsic.28
If the patient did not meet these criteria, treatment con-
tinued for 3 days (total 6 g), and then 2 weeks were
allowed to pass before repeating baseline studies. The
ISS treatment continued, as necessary, in 2-day incre-
ments (total 4 g), with a minimum of 2 weeks before
retesting.28 The incidence and severity of ataxia and
oscillopsia using titration ISS were lower than with
ablative ISS and appeared to be equally effective for
vertigo control.
The frequency of monitoring with different pro-
tocols has varied in the literature. Schuknecht realized
that unmonitored daily dosing would lead to a rapid
decline in vestibular function and oscillopsia and that
intermittent monitoring of inner ear function was nec-
essary.34 Initial protocols repeated studies only once a
total of 20 g of streptomycin was given; however, doses
less than this can control vertigo or cause oscillop-
sia.39,40,60 It is now advocated to increase monitoring
frequency and decrease dosage in patients with
reduced vestibular or renal function.53 Older patients
often require a smaller total dose of streptomycin to
suppress vestibular responses, and patients who
already have reduced caloric responses may be more
difficult to titrate.28
RESULTS
Although systemic streptomycin treatment for
Menieres disease was initiated over 50 years ago, the
world literature is still limited to a small number of case
series. Comparison of these studies is difficult as they
often use different protocols, have varying follow-up
time, have different criteria for Menieres disease, and
fail to report important details. Balyan and colleagues
compiled an excellent table summarizing their litera-
ture review.54 Table 21-1 has been adapted from their
work with minor revisions and updates.
Ablative ISS therapy used a total streptomycin dose
of 8 to 90 g. The majority of studies had a 100% relief
from vertigo, with the overall range being 50 to 100%.
Nearly all patients developed severe ataxia and oscillop-
sia, which slowly resolved over the following 9 months.
The rates of mild residual dysequilibrium were quite high
and ranged from 50 to 100%. Hearing was preserved or
improved in nearly all studies, with only Wilson and
Schuknecht revealing a hearing loss in four ears.38
Titration ISS used less total streptomycin than abla-
tive ISS, ranging from 5 to 70 g. There was excellent
relief of vertigo attacks, with the total range of 66 to
100%. The incidence and severity of post-treatment
dysequilibrium, ataxia, and oscillopsia were less than the
ablative ISS group, with the majority of studies quoting
an incidence of 50%. Hearing loss was noted in only one
study by Langman and colleagues, where cochlear func-
tion was reduced in 13 ears.60 As the minimum follow-
up was 2 years, it is difficult to ascertain whether this
was a direct result of streptomycin treatment or sec-
ondary to the natural progression of the disease. Post-
treatment caloric responses were not described.
COMPLICATIONS OF THERAPY
In 1952, the New England Journal of Medicine pub-
lished a riveting account by a physician recounting his
own experience with vestibular dysfunction caused by
streptomycin therapy for tuberculous arthritis.64 Side
effects often experienced during the initial titration
include pain at the injection site; numbness and tin-
gling around the mouth, fingers, and toes; marked
nausea; transient oscillopsia (even with active caloric
responses); and skin rash.28,41 Following ablative ther-
apy, Silverstein states that all patients experience a
direction-changing nystagmus, dysequilibrium, pro-
found ataxia, oscillopsia, and wide-based gait.41 No
details regarding the direction-changing nystagmus
were provided by the author. Intuitively, one would not
expect nystagmus to be present as simultaneous bilat-
eral vestibular ablation should not result in vestibular
asymmetry.
Wilson and Schuknecht found that following
vestibular ablation, all 20 patients were able to resume
normal activity within 2 to 9 months, contrary to the
clinical experience of most physicians.38 Patients who
have been inadvertently ablated by systemic aminogly-
cosides for treatment of a severe infection are usually
permanently disabled unless they recover vestibular
function as demonstrated by regained caloric
responses. One possible explanation could be that Wil-
son and Schuknechts patients were able to recover
some vestibular function over time. Jackson and Arcieri
reviewed 69 patients suffering from gentamicin-
induced ototoxicity and found that labyrinthine dys-
function was reversible in more than 50% of patients if
the drug was promptly discontinued.65 However, if
Wilson and Schuknechts patients did recover their
vestibular function over time, it is somewhat surprising
that they did not have a recurrence of their Menieres
symptoms over their 25-year follow-up.38 This is per-
haps secondary to the aminoglycoside effect on the
dark cells of the crista ampullaris and the resulting
decrease in endolymph production.
During titration therapy, one-third of patients may
develop oscillopsia in the early stages of treatment
despite active bithermal responses. This oscillopsia
almost always disappears with the discontinuation of
the drug; however, if oscillopsia is present with ablated
Table 21-1 Literature Review

Total Total Relief of Residual Dysequilibrium, Follow-up

Authors Cases Dose (g) Vertigo (%) Ataxia, or Oscillopsia (%) Hearing (no. of patients) (yr)

Ablative
Fowler, 194829 4 2533 2 (50) 2 (50) Unchanged (2), NR (2) 0.51

Van Deinse, 194930 3 4056 2 (66) NR NR 0.4

Hamberger et al, 194931 4 5590 4 (100) 2 (50) Unchanged (3), improved (1) 0.20.5

Hanson, 195132 5 4086 5 (100) 3 (60) Unchanged (2), improved (3) 1.54

Ruedi, 195133 3 840 2 (66) 0 NR 0.20.5

Schuknecht, 195634 8 2172 8 (100) 8 (100) Improved (5), unchanged (3) 14.9

Gunther, 195967 8 3058 8 (100) NR Improved (8) Up to 3

Jatho, 196368 2 3061 2 (100) NR Unchanged (2) 10

Graybiel et al, 196737 4 22.554 4 (100) 4 (100) Unchanged (1),* improved (4)* 2.14

Singleton and Schuknecht, 196836 15 13.589 15 (100) 15 (100) Unchanged (17),* improved (6),* worsened (4)* 0.61.2

Wilson and Schuknecht, 198038 20 13.589 19 (95) 10 (50) Unchanged (30),* improved (6),* worsened (4)* 116

Silverstein, 198441 13 2154 13 (100) 13 (100) Improved (5), NR (8) NR

Titration
Graham et al, 198439 8 3060 8 (100) 5 (62) Unchanged (5), improved (3) 0.42

Silverstein, 198441 7 1534 2 (66) NR Unchanged (4), improved (3) 1.11.5

Graham and Kemink, 198458 20 1060 18 (90) 11 (55) Unchanged (15), improved (5) 15

Moretz et al, 198769 7 2070 7 (100) 4 (57) Unchanged (6), improved (1) 0.53.5

Langman et al, 199060 19 550 12 (63) 9 (47) Unchanged (17),* improved (8),* worsened (13)* 29.3

LaRouere et al, 199353 3 1032 2 (66) 3 (100) Improved (3) 1.85

Balyan et al, 199854 13 1625 13 (100) 4 (31) Unchanged (16),* improved (4)* 29

Adapted from Balyan et al.54

Systemic Treatment of Bilateral Menieres Disease

NR = not reported
*Reported in number of ears.
187

Only 3 patients treated for vertigo, the remainder for hearing loss.
188 Therapeutic Uses of Ototoxic Effects
caloric responses on ENG, it is generally permanent.28
The ataxia experienced following titration therapy is
much less severe than with ablative therapy and has a
quicker resolution.41 Mild persistent dysequilibrium
has been found to be extremely common following ISS
therapy and is felt to be a universal side effect.53 Black
and colleagues found that rotational chair testing was
not predictive of rapid vestibular decline but may help
to predict long-term dysequilibrium.66 Therefore, using
rotatory chair testing during ISS may help to prevent
long-term dysequilibrium.53
In most studies (see Table 21-1), hearing was found
to be stable or to improve during treatment with ISS.
This hearing gain has been found to be transient, and
ISS likely does not change the natural progression of
Menieres disease.41,53 Although Wilson and Schuck-
necht38 and Langman and colleagues60 found patients
with a progressive hearing loss during long-term follow-
up, it is difficult to differentiate whether this is sec-
ondary to the ISS or to the underlying disease process.53
Despite more than 50 years of experience with ISS
therapy for Menieres disease, scarcely more than
100 cases are documented in the literature worldwide.
Considering that bilateral Menieres disease is fairly
common, clinicians seem reluctant to use ISS therapy
as their first line of treatment, likely for concern of
inducing permanent dysequilibrium.
SUMMARY
ISS therapy is an important therapeutic consid-
eration in treating patients with incapacitating
bilateral Menieres disease or patients with
Menieres disease affecting their only hearing
ear.
Ablative ISS therapy has been found to be very
effective in controlling vertigo, but post-treat-
ment ataxia and oscillopsia are often severe.
Titration ISS therapy has been shown to be
equally efficacious in controlling disabling ver-
tigo and reduces the incidence and severity of
post-treatment vestibular dysfunction.
Although persistent mild dysequilibrium is
common, the world literature suggests that it is
well tolerated by most patients. In most cases,
patients experience either a transient improve-
ment or no change in hearing following strepto-
mycin therapy. Overall, ISS-associated hearing
loss is rare.
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190 Therapeutic Uses of Ototoxic Effects
52. Lange G. Gentamicin and other ototoxic antibi-
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53. LaRouere MJ, Zappia JJ, Graham MD. Titration
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GD. What I think of sac surgery in 1989. Am J Otol
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57. Schuknecht HF. Pathology of Menieres disease as
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59. Fisch UP. Excision of Scarpas ganglion. Arch Oto-
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60. Langman AW, Kemink JL, Graham MD. Titration
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61. Berryhill WE, Graham MD. Chemical and physical
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63. Nedzelski JM, Chiong CM, Fradet G, et al. Intra-
tympanic gentamicin instillation as treatment of
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64. JC. Living without a balancing system. N Engl
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in man: a survey and controlled analysis of clinical
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66. Black FO, Peterka RJ, Elardo SM. Vestibular reflex
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67. Gunther H. Erfahrungen bei der Streptomycinbe-
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 CHAPTER 22
Intratympanic Gentamicin in the Treatment of
Menieres Disease
Brian W. Blakley, MD, PhD, FRCSC


The history of intratympanic aminoglycoside use is an
interesting demonstration of how medical treatments
are adopted. There are no large randomized controlled
trials and few p values to show that this therapy is
better than older methods. There are as many effective
protocols as there are authors in the literature and no
clear indication that any protocol is better than
another. Still, the use of intratympanic aminoglyco-
sides has essentially eliminated the need for surgery for
vestibular disorders. This can be interpreted to repre-
sent a victory for good clinical judgment over deci-
sions from the p values of evidence-based medicine.
Ten or 15 years ago, this chapter would probably
not have been published. In North America, treatment
focused on vestibular neurectomy, labyrinthectomy, and
endolymphatic sac surgery for Menieres disease when it
did not respond to conservative therapy. The notion of
placing toxic agents into the middle ear was considered
risky because an optimal protocol had not been estab-
lished. The optimal protocol has still to be established,
but our understanding of topical aminoglycoside ther-
apy in Menieres disease has certainly increased.
HISTORY
Streptomycin was the first aminoglycoside developed.
In 1944, it was marketed after validation by the first
nationally coordinated, privately funded drug evalua-
tion in history (see Chapter 8, Clinical Aminoglyco-
side Ototoxicity).1 The ototoxicity of streptomycin
soon became apparent, but there was usually no other
choice, so the drug became widely used. Fowler was the
first to exploit this toxicity systemically to treat patients
with Menieres disease. 2 In 1957, Schuknect used
intratympanic streptomycin injections to treat
Menieres disease in eight patients.3 Gentamicin was
introduced to the market in 1964 and is currently the
most widely used aminoglycoside. It is particularly
popular in underdeveloped countries because it is inex-
pensive. Although intratympanic treatment had been
used in Europe for some time,4,5 the technique was not
widely used in North America until Nedzelski and col-
leagues popularized it in the1990s.6,7
Intratympanic Aminoglycosides in the Treatment of
Menieres Disease
The current literature on intratympanic aminoglyco-
sides is relatively large and growing. In 1997, 11 papers
addressed the clinical methods of intratympanic
aminoglycoside administration.8 By 2000, there were
18 papers.9 A literature review as of August 2003 iden-
tified 41 papers that addressed the clinical use of
intratympanic aminoglycosides.
Some general comments can be made. First, the
use of intratympanic streptomycin has been aban-
doned in favor of intratympanic gentamicin (ITG).
Possible reasons for this preference are that gentamicin
causes less hearing loss, is less painful to inject, and is
easier to obtain. The first two reasons do not have
strong research support, and the recent increase in
tuberculosis has resulted in greater availability of strep-
tomycin. Nevertheless gentamicin is well established, so
it will likely remain the intratympanic drug of choice.
Almost all authors start with the 40 mg/mL stock
solution of gentamicin, and most buffer it to give 20 to
27 mg/mL. The middle ear is filled, so only about
0.75 mL (or 20 mg of gentamicin) is used.
Second, for every clinicians philosophy of treat-
ment there is an effective protocol. In medical litera-
ture, the average response or the most likely outcome
has been traditionally used to characterize treatments
or approaches. There is a growing realization in med-
ical research that variability may be as important as the
mean. Small variability suggests consistency. Large vari-
ability may be associated with uncertainty and lack of
understanding, even if the mean is the same. Herein the
impact of variability measured simply by the statistical
standard deviation of the mean is considered.
Third, widely varying protocols yield similar
results. The usual doseresponse relation that exists for
systemic drugs does not appear to apply to ITG. This
192 Therapeutic Uses of Ototoxic Effects
Table 22-1 Control of Vertigo and Hearing Loss
Percentage Vertigo Control (%)
(from 41 Publications)
Mean (SD) 85 (8.7)
Range 56100
Different authors used different criteria for vertigo control (from 41 publications) and hearing loss (from 33 publications). Some authors did
not report hearing loss. In many papers the percentages were calculated from data provided in the paper. The standard deviation relative to
the mean percentage for vertigo control (8.7 vs 85%) is much smaller than that for hearing loss (19 vs 22%). These data suggest more incon-
sistent results for hearing loss than for vertigo control.
bothers some clinicians, but why should there be only
one valid paradigm?
Fourth, not everyone is the same. No author has
published perfect results for all patients. What does
this tell us? Could it be that individual differences
mandate different protocols? Can we ever chemically
dissect vestibular from cochlear hair cells? Several
genetically related special sensitivities to systemic
aminoglycosides have been described. Are these
important in ITG (see Chapter 17, Genetic Factors in
Aminoglycoside Ototoxicity)?
Questions about ITG in the Literature
What is the best way to deliver ITG therapy? The lit-
erature on ITG contains a wide variety of methods,
which all claim success. Not a single paper indicates
that the ITG is not effective in controlling vertigo.
Although some may find the variety of doses and
methods confusing and upsetting, the message prob-
ably is that many protocols can be effective and have
similar safety records. Table 22-1 contains summary
data regarding the success of controlling vertigo and
the percentage of hearing loss from the 41 papers
reviewed.3,4,6,1047 Some authors have published one or
more updates of their experience. An attempt was
made to include only those papers with actual data
and eliminate redundant reports from the same
authors.
Weaknesses of the ITG literature include the
following:
1. Different definitions of vertigo control and
hearing loss are employed. Although it is opti-
mal to use the classification of the American
Academy of Otolaryngology-Head and Neck
Surgery (AAO-HNS),48 several papers were
published before these guidelines were avail-
able, and some of the best papers come from
Europe, where these guidelines are less com-
monly used. Some authors simply did not use
the guidelines.
2. There is no consensus regarding terminology,
testing, outcome, administration method, or
many other factors.
Percentage Hearing Loss (%)
(from 33 Publications)
22 (19)
095
3. The studies are typically one persons observa-
tions about his or her own patients reflecting
his or her personal bias. Cutting-edge clini-
cians who reported unusually large numbers
of patients may be overapplying the diagnosis,
which invalidates their research results.
Although it would be nice if all studies followed
the same format, this is not the independent, creative
nature of research. In fact, the inconsistencies in meth-
ods are probably not too important when 41 studies are
available. For example, in Table 22-1 the percentage of
vertigo control is around 85%, with a standard devia-
tion that is only about 10% of the mean. This variabil-
ity seems small, so the results are fairly consistent. For
hearing loss the story is somewhat different. The stan-
dard deviation for hearing loss is almost as large as the
mean. This implies much variability in hearing loss.
Hearing loss is a main concern with ITG that needs
attention. There appears to be no particular relation-
ship between hearing loss and control of vertigo.
Eleven of 41 papers indicated follow-up times
greater than 1 year, and 10 of these had follow-up times
greater than 2 years. Of these, five studies reported
recurrence rates averaging 21%, with a standard devia-
tion of 8.3%, that were treated successfully with ITG.
DOSE
The dose of gentamicin is often thought of in the
same manner as a systemic dosea number of mil-
ligrams, concentration, or rate to be applied. Papers in
the literature employed cumulative doses of gentamicin
from 0.24 to 720 mg. Some of the tiny amounts
reported as effective might be difficult to believe.
Although commercially available topical gentamicin
had been used for years in ears with perforations with
few apparent problems, it is possible that these small
amounts could cause problems. Imamura and Adams
found that 2 mg of gentamicin applied to guinea pig
round windows resulted in overt degeneration, was
too destructive for research purposes, and had to be
diluted.49 The effective dose seems to vary by greater
than three orders of magnitude. Application of sys-
temic philosophy to ITG is flawed. ITG administration
 Intratympanic Gentamicin in the Treatment of Menieres Disease
should be considered as topical treatment. In topical
skin treatments, for example, the dose consists of
applications of medication concentrations empirically
found to be effective. The treatment is repeated until
the desired effect is achieved.
METHOD OF DELIVERY AND THERAPEUTIC
END POINT
The many basic delivery techniques can be classified
as follows:
1. Direct injections (n = 25). Direct injection is
Some authors hoped to ablate function. Others
defined as an injection with a needle through
wished only to reduce vestibular function. The end
the tympanic membrane without any tempo-
point philosophies can be classified as follows:
rary device. Direct injections are the most
popular and simplest of the delivery techniques.
Advantages include simplicity and the ability
to titrate therapy and stop treatment if needed.
2. Catheters and tympanostomy tube assemblies
(n = 7) of various designs that were left in
place during treatment without pump or
other device. The gentamicin was delivered
intermittently into the catheter or tube, and in
two cases pressure was applied afterward.
Sometimes the catheter was attached to the
tube for each instillation; other times the
catheter was left intact, and the patient wore
the assembly between applications. Catheters
and tubes were more prominent in papers for
which total ablation was the goal. If a catheter
was used, gentamicin was likely to be admin-
istered several times per day. Catheters appear
more appropriate if total ablation is the goal
because other end points are likely to be over-
shot. The effects of gentamicin on the cochlea
may take weeks or even months to evolve.32,50,51
When the full effect develops, hearing loss
is likely.
3. Pumps (n = 2) placed into the inner ear or on
the round window membrane. Pumps
included direct infusion into the scala tym-
pani, permeable membranes contacting the
round window, and, in one case, an insulin-
infusion pump. The pump placement requires
surgical implantation, which most patients see
as a disadvantage. It has been suggested that
the round window should be cleaned or
inspected to allow the gentamicin to enter
properly, but the evidence that this is reason-
able is lacking. One author recommended that
the round window be obliterated before
intratympanic therapy. The tendency is to
administer a larger amount of gentamicin if a
pump is used, as opposed to intermittent
injections. This is acceptable when total abla-
tion is the goal.
193
4. Surgical placement of sponge or wicks (n = 2)
of a gentamicin-soaked wick or device directly
against the round window without an addi-
tional pump was used by two authors. Surgery
is required, which may be perceived as a dis-
advantage. Sponges, wicks, and pump applica-
tions do not easily permit titration or
cessation of therapy if allergy, hearing loss, or
other reasons arise.
5. There were five papers for which the method
was not clear.
a. First sign or symptom of inner ear distur-
bance (n = 8). Criteria included signifi-
cant imbalance or hearing loss and rarely
vertigo or nystagmus or some nonspecific
clinical assessment. Of the five studies
that reported relapse rates, all used the
injection method. For three, the first sign
of inner ear symptom was the end point,
and for two the end point was unclear.
Given time, vestibular and cochlear hair
cells may regenerate, 52,54 and function
may even recover.55,57
b. Cessation of spells (n = 3). This end
point becomes problematic in patients
who have infrequent spells. Table 22-2
shows that this was used only by authors
who performed injections and did not
require devices for a specified duration of
treatment.
c. Ablation (n = 5) as assessed by caloric
testing was the goal for at least two
papers. It is likely that others with unclear
methods had total ablation in mind as
well. Three papers contrasted total abla-
tion with subtotal ablation. One paper
reported that there was no difference in
outcome, but the other two reported that
ablated patients did better.
d. Completion of a preset course (n = 8),
such as a certain number of injections or
insertion of a wick or sponge, which does
not permit cessation of therapy. The
number of injections to be employed and
the amount of gentamicin in the wick was
arbitrary. Considering the variability in
hearing loss and the lack of evidence that
more applications provide better vertigo
control, employing a preset number of
injections or treatments seems illogical.
e. The final outcome was inconsistent or
unclear in 20 papers.
194 Therapeutic Uses of Ototoxic Effects
Table 22-2 Methods of Delivery and Philosophy of End Point (n = 41)
First Cessation
Symptom of Spells
Injections 6 3
Catheter/tube 1 0
Pump 1 0
Sponge, wick 0 0
Unclear 0 0
Total by end point 8 3
The number of papers using various delivery methods and the philosophy for treatment end point for clinical papers that applied ITG to
human patients are displayed. For papers that used more than one method or end point the largest number of patients used of each is shown.
The method of delivery of gentamicin to the inner ear is partially dependent on the end point. Methods that are difficult to stop (wick, pump,
sponge) are more likely to be used if total ablation is the goal of treatment.
Table 22-2 shows the combinations of method and
end point. Analysis of variance with the Wilks lambda
adjustment indicated no significant overall effect
(p = .54) of method or end point on the percentage of
either vertigo control or hearing loss. Although several
authors used the repeated caloric testing or serial
audiograms in end point determination, evidence sup-
porting better results for objective testing over clinical
assessment was absent or weak.
DISCUSSION
ITG therapy is indicated essentially only for the acute
attacks of Menieres disease. Chronic imbalance, tinni-
tus, aural fullness, and hearing loss are inappropriate
uses for this therapy. It appears that differences in
methods and end point of treatment may not be
important determinants of clinical outcome. ITG
results in control of vertigo spells in about 85% of
patients, but the degree of hearing loss varies. By defi-
nition, hearing loss is present in Menieres disease, and
it is expected to fluctuate. ITG does not seem to change
that. Nevertheless, there are several reports of moder-
ate losses becoming profound with ITG therapy. There
are no reports yet that the systemic genetic susceptibil-
ities to aminoglycosides58,59 have adverse effects in ITG
therapy. The 1555G mutation affects hearing loss pre-
sumably by reducing the adenosine triphosphate gen-
eration process in mitochondria.
In future, it is possible that protective agents may
be concomitantly applied to try to reduce ITG-induced
cochlear toxicity. Currently at least 30 compounds
reduce ototoxicity for various agents. One or more of
these agents will likely be useful to protect the auditory
system and permit the desired effect on the vestibular
hair cells. These protective agents are typically thiols
(SH) containing compounds that act as antioxidants.
It is probably not a coincidence that oxygen and sulfur
Preset Total
Ablation Course Unclear Method
0 5 11 25
1 1 4 7
0 0 1 2
0 2 0 2
1 0 4 5
2 8 20 41
are in the same chemical family in the periodic table. It
is plausible that some of these antioxidants will have
therapeutic effects on hair cells60 in addition to their
protective effects against ototoxicity.
The genetic susceptibilities are not changeable, but
oxidation states may be. Probably when we better
understand the biochemistry of oxidation in vivo, we
will be able to exploit this knowledge for use in ITG,
offering toxicity and protection in sophisticated ways to
retain or augment cochlear function yet induce the
hoped for vestibular deafferentation.
Treatment of conservative failures of Menieres dis-
ease has progressed from primarily surgical to primar-
ily medical in the past 10 to 15 years. This has been
good for patients, and it should continue. Applied bio-
chemical and nonsurgical therapy to the inner ear
appears to be the way of the future.
CONCLUSION
How do we decide which protocol is best? Philosophers
often credit William of Ockham with first insisting that
the simplest course is usually the best. If there are no
advantages to other methods then the simplest, safest,
and cheapest method is chosen.
SUMMARY
ITG treatment is currently indicated for
Menieres disease that is significant, is disabling,
and has failed conservative medical therapy as
determined by good clinical judgment.
Before treatment it is important to counsel
patients that ITG is destructive and that function
cannot be regenerated once lost. The clinical
recurrence rate may be about 20%, and retreat-
ment may be required. Hearing may become
worse in about 25 to 30% and can be profound
in the affected ear.
 Intratympanic Gentamicin in the Treatment of Menieres Disease
The main goal of ITG is long-term control of
acute vertigo spells. Permanent or transient
imbalance, tinnitus, or other complications such
as pain or drug allergy may occur.
Injection techniques are best performed with
the smallest spinal needle available through an
aural speculum through the tympanic mem-
brane, filling the middle ear, at weekly intervals
or less often. Topical anesthetic such as injected
lidocaine or topical phenol may be used but
may cause as much discomfort as the actual
needle.
ITG therapy should be stopped when the patient
describes imbalance or hearing loss or some
other new sign or symptom of inner ear
dysfunction.
Quantitative measurements of cochleovestibular
function should be obtained with audiometry
and electronystagmographic calorics before and
after treatment.
Follow-up for 1 year posttreatment would be
recommended on clinical grounds.
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 Medicolegal Concerns
CHAPTER 23
Medicolegal Aspects of Ototoxicity
Peter Rhatican, JD, Sloan H. Mandel, LLB, and John A. Rutka, MD, FRCSC
Editors Note: This chapter is an introduction to the law
as it applies regarding the concepts of negligence, standard
of care, harm, and disclosure. Clinical cases of ototoxicity
are presented to which Mr Peter Rhatican and Mr Sloan
Mandel, both esteemed and well-respected trial lawyers in
the United States and Canada, respectively, respond.
Although their responses are in agreement for the most
part, their dialogues demonstrate a diversity of opinion
from a legal perspective; law, like medicine, has few
absolutes. In order to provide full disclosure to the reader,
our contributing lawyers were presented with informa-
tion that might be considered the equivalent of an expert
opinion that can be found in Appendix 1. Although the
law occasionally differs between these countries, overall,
one is more impressed with the similarities across the
borders rather than the differences.
MEDICOLEGAL CONCEPTS
The majority of medical malpractice suits against
physicians are based on a claim of negligence.
Although the law does not demand perfection, allega-
tions of negligence extend not only to acts the physi-
cian is said to have committed in error but also to the
steps it is suggested the physician should have taken
but failed to take. The alleged omission on the part of
the physician usually constitutes the majority of claims
for negligence.
For a medicolegal action based on a claim of neg-
ligence to be successful, four elements must be estab-
lished or proven1:
1. There must be a duty of care owed to the
patient.
2. There must be a breach of duty of that care.
3. The patient must have suffered some harm
or injury.
4. The breach of duty of care must have caused or
materially contributed to the harm or injury.
STANDARD OF CARE
Although physicians are not expected to be correct
every time, they are expected to exercise reasonable
care, skill, and judgment in arriving at a diagnosis. The
physician is also required to properly treat the patient
in accordance with current and accepted standards of
care, refer the patient, or obtain a consultation when
the patient is not responding to treatment or is beyond
the competence of the treating physician. The physician
is also expected to arrange for coverage when absent
and to adequately instruct patients about their treat-
ment and follow-up care.
In order to determine if there has been a breach of
duty to the patient the courts have generally considered
the standard of care to be that required of a reasonable
prudent physician colleague in similar circumstances. It
is important to realize that medical science has not yet
reached the stage where the law ought to presume that
all treatment afforded a patient must have a successful
outcome and that anything less suggests negligence.
The appropriate measure is, therefore, the level of
reasonableness and not a standard of perfection.
Breach of duty or care toward the patient is usually
not enough to demonstrate negligence. It must be
demonstrated that the patient suffered some harm or
injury as a result of the actions or inactions of the
physician.
For the purpose of definition, Harm is defined
broadly as an unexpected or normally avoidable out-
come that negatively affects the patients health and/or
quality of life which normally occurs (or occurred) in
the course of health care treatment and is not due
directly to the patients illness.2
Medicolegal actions are never entirely black and
white because there are usually several mitigating cir-
cumstances, including other factors that could have
caused or contributed to the same result for which the
physician could not be faulted. For this reason the plain-
tiff must therefore establish on a balance of probability

(ie, within reasonable medical certainty) that the alleged
breach of duty contributed to the injury sustained.
Defining Standard of Care
Sloan Mandel
Regardless of whether you live in the United States or
Canada, the legal principles involved are plain enough
but are not always easy to apply to a particular set of
circumstances. Every medical practitioner must bring
to the task a reasonable degree of skill and knowledge
and must exercise a reasonable degree of care.
Peter Rhatican
In addition, if we further define the standard of care as
a species of obligation, when the health care provider
enters into a professional relationship with the patient,
the obligation assumed by the provider is to exercise in
treating the patient the degree of care, knowledge, and
skill ordinarily possessed and exercised in similar situ-
ations by a normal, prudent practitioner of the same
experience and standing.
The definition of this duty is surprisingly not what
was learned in medical school or, for that matter, what is
contained in medical books or treatises within the field.
Medicine is active as well as it is traditional. Although
anatomy may not change, the technology, methods, and
procedures applied to that anatomy do. Because of these
advances from research, clinical studies, and the experi-
mental components inherent in the field of medicine,
one must look to the periodicals and journals to witness
and discern the evolving nature of ones field. More
importantly the standard of care is often found within
the interaction and interplay that occurs daily between
health care providers. The sharing of information with
peers in the professional setting or quasi-educational
environment at continuing medical education lectures
and seminars provides the opportunity to familiarize
one with the current thinking in the field.
Standard of Care versus Community Standard
of Care
Sloan Mandel
Some defense counsel have suggested that a lesser stan-
dard of care is required from a rural practitioner than
from a physician practicing in an urban center. To the
extent that such a premise exists (which is debatable),
the submission is no longer well received by our courts.
If the physician in a rural setting has less access to nec-
essary resources, this may be considered by the court.
This does not imply that a lesser standard of care is
required. Further, historical disadvantages to the rural
physician have been greatly reduced by advances in
transportation (eg, air ambulance), technology (eg, the
Internet), and timely access to specialized care.
Medicolegal Aspects of Ototoxicity 199
Peter Rhatican
When the standard is at issue in court, the standard
of care is initially expressed by an expert. For the
experts opinion to be acceptable, testimony must relate
to generally accepted medical standards, not merely to
the standards personal to the expert. Community stan-
dards of care are not and should not be distinguished
from the generally accepted standard of medical prac-
tice. Knowledge, experience, and training know no
political boundaries. The combination of personal
experience, learned knowledge from persons with ade-
quate training and experience, and current information
imparted through recognized periodicals, journals, and
updated texts provides to the practitioner the only
boundaries (or evidence) of what constitutes the
accepted conduct within the discipline of medicine.
The community standard concept conjures the
notion that Los Angeles, California, has a different stan-
dard from Toronto, Ontario. This image does not
belong in the minds of providers and should be disre-
garded. Nevertheless, we should never lose sight that
although medicine is not an exact science, there are
common understandings relative to its practice. The
standard of care is measured neither by the personal
opinion of the providers nor by the behavior of
providers in their practice community. Rather, a uni-
versal approach is preferred over the limitation estab-
lished by personal views and political boundaries.
The generally accepted standard of care does not
exist independently of the health care providers exer-
cise of reasonable judgment. An evaluation of a
providers reasonable judgment must be measured by
an objective standard and not based on a providers
good faith or honesty. Motivation has no role in deter-
mining negligence. For the exercise of judgment to
meet the required standard of care the following cir-
cumstances must be met:
1. The selection of a differential diagnosis from
those contained in a medically reasonable dif-
ferential
2. The selection among acceptable and medically
reasonable causes of treatment that applies to
the presenting diagnosis.
Once the selection of a reasonable diagnosis and
medically reasonable course of treatment is made then
the application of knowledge, care, and skill of the
provider becomes the hallmark in determining whether
or not there exists a breach of duty to the patient. For
example, no issue relating to the exercise of reasonable
judgment exists once the acceptable surgical procedure
is selected should a surgical mishap occur or where
medication is selected from recognized alternatives
should the patient sustain an adverse reaction. The
standard of care is objective, whereas the exercise of
200 Medicolegal Concerns
judgment takes into account choices that fall within the
reasonable medical options.
DISCLOSURE
When a physician becomes aware while treating a
patient that a harm has occurred in the course of
receiving treatment that can be reasonably be expected
to affect the patients health or quality of life, then it is
the physicians obligation to inform the patient about
the harm sustained. Reluctance to disclose such infor-
mation is understandable; the physician may feel guilt
and shame, have concerns that the patient will become
more distressed and lose confidence in the physicians
competence, and fear legal repercussions.
Although more disclosure may mean there will be
some lawsuits that otherwise might never see the light
of day, a recent study suggests that patient dissatisfac-
tion about medical harm is frequently generated by
physician attitude and denial rather than the adverse
effect itself.3 The majority of patients want a simple and
honest explanation of what happened and, where
appropriate, an apology. When patients get neither or
are rejected they feel doubly wronged and not infre-
quently seek legal counsel.
Ototoxicity
Ototoxicity can be broadly defined as the tendency of
certain substances to cause functional impairment
and cellular damage to the tissues of the inner ear
and especially to the end organs of the cochlear and
vestibular divisions of the 8th cranial nerve that can
occur from systemic or topical administration.4
The following medicolegal cases illustrate ototox-
icity that occurred during the treatment of a medical
condition.
Case 1: Systemic Gentamicin Ototoxicity
In September 1995 a 63-year-old white female with
type 2 noninsulin-dependent diabetes was admitted
to hospital for the first time with a cellulitis of her right
foot and a suspected osteomyelitis of her right fourth
toe that followed minor trauma. There was a previous
history of peripheral vascular disease, hypercholes-
terolemia, and hypertension.
There was general consensus among the residents
and the attending staff internist to treat her infection
aggressively intravenously for 6 weeks with triple
antibiotic therapy, which included cefazolin, metron-
idazole, and gentamicin. A direct aspirate from the
infected interphalangeal joint came back 72 hours later
demonstrating 3+ -hemolytic streptococci sensitive
to cefazolin, metronidazole, gentamicin, and penicillin,
among others.
While in hospital her clinical condition improved
on treatment. Parameters of renal function and moni-
tored serum gentamicin levels remained within the
expected range, and she was discharged home 2 weeks
later on clindamycin 600 mg PO bid and gentamicin
260 mg once daily to be provided intravenous by a vis-
iting nurse. The family physician agreed to assume care
of the patient at this point. Arrangements were made
for weekly serum creatinine and serum gentamicin
trough levels to be taken and for the family physician
to be informed of these results. Between days 15 and 28
of treatment, serum creatinine levels rose from 66 to
122 mmol/L (normal 50 to 115 mmol/L). Serum trough
gentamicin levels rose from 2.0 to 3.4 mg/L (normal
< 2 mg/L). Nothing was done to alter the treatment reg-
imen. On treatment day 29 the patient vocalized com-
plaints of generalized dizziness to the visiting nurse.
Despite repeated complaints that something was not
right, treatment continued until day 35 when she
became acutely imbalanced and ataxic. The patient
now complained of visual blurring, her horizon
appeared unsteady, and she was unable to stand. No
hearing loss was noted subjectively. The gentamicin
was subsequently discontinued by the family physician.
Unfortunately, her condition has not improved.
When assessed 2 years later the patient continues to be
wheelchair bound despite having undergone attempts
at vestibular rehabilitation. Her clinical examination
points to a bilateral vestibular loss (bilateral positive
head thrust maneuver,5 positive oscillopsia test,6 gait
ataxia, etc), which has been confirmed with electronys-
tagmography (ENG) calorics. A bilateral caloric reduc-
tion indicative of a bilateral peripheral (inner ear)
vestibular loss has been identified. An intracranial mag-
netic resonance imaging (MRI) scan was unremark-
able. Upon questioning, the patient denies having been
told about the adverse effects of the medications she
had been placed on and the risks of treatment.
Evidence of Medical Negligence
Peter Rhatican
I believe there is evidence of medical negligence here.
Arguably the family physician and the visiting nurse
deviated from recognized standards applicable to their
respective disciplines. The hospital and its staff internist
and residents did not appear to deviate from reasonable
medical standards. The hospital, of course, would be
liable only under the respondent superior theory:
namely, the employer takes a hit for its employees.
Sloan Mandel
Given this particular patients case history, there are
facts that would be considered by appropriately
qualified medical experts to support a finding of med-
ical negligence.
Osteomyelitis can be a severe and limb-threatening
infection (taking into account the heightened risk this

patients diabetes and peripheral vasculature posed); it
would have been appropriate for the medical team to
treat this infection aggressively. There is no question
that they would have been criticized if they had not.
Until the cultures came back and the strain of
bacteria was identified, it was appropriate to treat this
womans infection with triple antibiotic therapy. How-
ever, when it was known 72 hours later that the bacteria
was sensitive to a variety of antibiotics (including cefa-
zolin, metronidazole, penicillin, and gentamicin) there
ought to have been a review regarding what antibiotic
therapy was best suited to treat this particular patients
infection. Following that review the most responsible
physician ought to have been consulted and the patient
advised of the risks and benefits associated with the var-
ious alternatives. If the physician were prudent, the dis-
cussion would have been charted with reasonable detail.
The failure to discuss the various risks and bene-
fits associated with the treatment alternatives might
possibly give rise to a double-barreled negligence
claim. The patient might allege, for example, that the
hospital physicians failed to obtain her informed con-
sent when prescribing gentamicin therapy, especially
after the microbiology results returned 72 hours later.
Apart from the failure to obtain an informed con-
sent, should the patient allege that the treatment team
breached the standard of care and that the breach
resulted in avoidable harm, the court would very likely
consider the following facts:
The patients underlying condition typically
required 6 weeks of antibiotic therapy.
There were less risky treatments available with-
out risk for ototoxicity.
The patient was not advised about those symp-
toms that may develop as a result of gentamicin
therapy.
There is reportedly a 1 to 2% overall risk for
ototoxicity when a patient receives systemic
gentamicin therapy. The risk is relative, however,
and significantly increases when gentamicin
therapy is in excess of 14 days and when evi-
dence of renal impairment occurs that is typi-
cally associated with elevated serum trough
(preinjection) gentamicin levels.
Peter Rhatican
The family physician and visiting nurse take on a dif-
ferent standard relative to the influence their conduct
had on the ultimate injury sustained by the patient.
As a baseline, the family physician had a duty to
obtain the prior laboratory results from the hospital.
After that the family physician had the duty to monitor
the weekly reports for any fluctuation to detect trends
toward toxicity. The facts reveal significant changes
over the ensuing 2 weeks (weeks 3 and 4 of treatment),
Medicolegal Aspects of Ototoxicity 201
namely the serum creatinine levels rose from 66 to
122 mmol/L (normal 50 to 114 mmol/L) and the serum
trough gentamicin levels rose from 2.0 to 3.4 mg/L
(theraputic range to minimize ototoxicity would be
< 2 mg/L). These rising levels should have alerted the
family physician that the patient was slipping into renal
failure and was certainly at a heightened risk for oto-
toxicity. The experience, knowledge, and skill ordinar-
ily possessed and exercised in similar situations by the
average member of the medical profession mandated
that the family physician alter the treatment or in the
alternative consult on an urgent basis the internist who
had initially prescribed the therapy or perhaps a
nephrologist and an otolaryngologist in order to deter-
mine the danger the patient faced. The failure of the
family physician to act suggests a departure from
accepted standards.
In analysis of the doctors culpability one must rec-
ognize the maxim that you cannot act on something
you are unaware of. It has been established that the vis-
iting nurse, either out of ignorance or forgetfulness,
failed to make known to the physician the patients
complaints of generalized dizziness on day 29 of
treatment. Complaints of acute imbalance, ataxia, an
unsteady horizon, and visual blurring with head move-
ment, all symptoms of a bilateral vestibular loss, pre-
sented in the fifth week (day 35 of treatment). The
family physician finally responded to the gentamicin
menace and appropriately discontinued the drug. One
wonders if events might have unfolded differently if the
visiting nurse had stressed to the family physician her
concern about the patient when she first began experi-
encing dizziness. Although the profession of nursing
has continued to expand and evolve, it primarily
remains a profession of fact gatherers and fact
reporters. Notwithstanding, the ultimate interpretation
and conclusion relative to those facts still remain with
the family physician.
In my opinion the failure to gather the facts or,
having gathered the facts, failing to report these facts to
the most responsible physician levies a departure from
accepted nursing standards. The nurses responsibility
in this case was to administer the gentamicin, but
implicit in this act, the nurse was also required to be
aware of gentamicins adverse effects, especially those
pertaining to ototoxicity and nephrotoxicity. For this
reason the nurse would also be held accountable for
what happened.
Sloan Mandel
One of the reasons patients may be discharged from
hospital to home nursing care has to do with cost. It is
certainly cheaper to treat a patient at home than in
hospital. Presumably if this patient had been kept in
hospital one might reasonably argue that she would
have been monitored more diligently (as she appeared
202 Medicolegal Concerns
to be during the first 2 weeks of treatment). There might
have been a few more checks and balances in place that
could have allowed for a timely discontinuation of her
gentamicin before toxicity occurred and to minimize
the development of her bilateral vestibular loss.
Although other forms of therapy (including hospi-
talization) might be more expensive, cost containment
is not a defense for inappropriate care. In the leading
American authority of Wickline v. the State of Califor-
nia, the California Court of Appeal stated the following:
While we recognize, realistically, that cost conscious-
ness has become a permanent feature of the health
care system, it is essential that cost limitation
programs not be permitted to corrupt medical
judgment.
In the Canadian case of Law Estate v. Simice, the
British Columbia Superior Court noted the following:
If it comes to a choice between a physicians respon-
sibility to his or her individual patient and his or her
responsibility to the medicare system overall, the
former (the patient) must take precedence in a case
such as this.
Sending this patient out into the community with-
out the appropriate infrastructure and reporting net-
work to react timely to changes indicating pending
ototoxicity was dangerous. Any savings from an
extended hospitalization have certainly been lost by the
cost to society of this patients current clinical status,
not to mention the costs involved in a medical mal-
practice suit.
Legal Research
Sloan Mandel
After having acquired the available medical records (eg,
from past hospitalizations and other treating physi-
cians) and receiving information from the patient
directly, the first step in any medical malpractice inves-
tigation would be to retain an appropriately qualified
medical expert to review the available information and
to provide guidance to counsel. Often the medical
expert will be in a position to refer you to authoritative
medical texts, literature, and case studies. Within your
office, nonmedical personnel may also conduct
research via the Internet, medical libraries, and
reported legal cases.
Peter Rhatican
The initial interview with the client and family is very
extensive. One records not only the relevant personal
information but also the clients past medical history,
including major illnesses, major hospitalizations, pre-
vious treating physicians, medications (past and pre-
sent), and family medical history.
Your expert on liability in this case of systemic gen-
tamicin ototoxicity must be familiar with standards
applicable to infectious diseases and internal medicine
generally (if we assume the staff physician at the hospi-
tal was an internist). In order to flesh out the extent of
the damages and make sure the damages are not attrib-
utable to other medical conditions it would be necessary
to have the damages assessed by specialists. For exam-
ple, an infectious diseases expert could address the rela-
tionship of her osteomyelitis with the patients
underlying diabetes and peripheral vascular disease.
The recognized and medically reasonable courses of
treatment coupled with the potential adverse reactions
to these treatment modalities are better explained by
those who specialize in that area. Clearly, an opinion
regarding symptomatic bilateral vestibular loss would
be appropriate from a neurologist or an otoneurologist.
Both would be in the best position to educate the judge
or jury in matters involving the diagnosis, treatment,
and prognosis as well as how as a practical matter the
resultant disability impacts on the individuals quality of
life and for how long.
Responsibility of Health Care Professionals
Peter Rhatican
Clearly all the health care professionals in this case (ie,
the hospital physicians, the family physician, and the
visiting nurse) shared in the responsibility for the
health and welfare of the patient. Nevertheless, the the-
ories of liability differ somewhat (ie, informed consent
vs medical liability), and in that difference you will find
a differential in the apportionment of liability.
Sloan Mandel
As a general rule when addressing the standard of care
of the involved health care professionals, the court gen-
erally wishes to compare apples with apples and
oranges with oranges. More particularly, if we agree
that the family practitioner breached the standard of
care then expert evidence should be given by a family
practitioner to address the care provided (eg, Were lev-
els requisitioned with appropriate frequency? Was there
timely follow-up once levels were taken?).
In this case the internist who prescribed gentam-
icin after 72 hours (when the culture results came back
demonstrating a bacterial organism sensitive to less
toxic antibiotics) would also be a target defendant in
my opinion. A physician of equal qualification should
be retained to comment upon the quality of care pro-
vided by this individual.
The laboratory that measured the serum creati-
nine and gentamicin trough levels may also be a poten-
tial target (ie, how quickly did the laboratory respond
in notifying the treating physician of the elevated
levels, and what recommendations were given, if any?)

A pharmacologist or toxicologist might also be appro-
priate to retain.
A nurse should also be retained to address the
quality of care provided by the visiting nurse and to
review the nursing protocols for intravenous amino-
glycoside delivery in a home setting (ie, Was she aware
or should she have been aware of the elevated levels,
and what should she have done when the patient vocal-
ized complaints of dizziness?).
Recommendations for Physicians and Allied Health
Care Professionals
Sloan Mandel
My recommendations to the health care team would be
as follows:
Know and discuss with your patient the risks
and benefits associated with different treatment
alternatives.
Review your recommendations when new infor-
mation is known about the patients condition.
If the family physician agrees to assume outpa-
tient care, then the family physician must ensure
that the patient understands the risks associated
with the proposed care and that the patient is
appropriately monitored (through timely and
frequent contact with the patient, the labora-
tory, and the nurse).
The family physician and the nurse should be
knowledgeable about the risks associated with
the therapy proposed and the signs and symp-
toms of potential concern.
The laboratory should have a written protocol
regarding what efforts are to be taken when
abnormal levels are discovered.
Case 2: Topical Gentamicin Drop Ototoxicity
A 48-year-old white male ironworker involved in sky-
scraper construction inadvertently perforated his left
tympanic membrane (TM) with a cotton swab while
cleaning his ear in March 1997. At the time he experi-
enced some pain and a little bleeding from the ear
canal. He was aware of a mild hearing loss but had no
dizziness or imbalance. He saw an otolaryngologist
3 days later having developed a slightly purulent dis-
charge from the ear.
On examination the otolaryngologist noted a safe
central TM perforation. The ear canal appeared moist,
and a scant amount of discharge was noted through the
perforation. A diagnosis of a traumatic central TM per-
foration was made with secondary infection. Audiom-
etry revealed a mild right conductive hearing loss in the
left ear; the sensorineural (inner ear) reserve appeared
normal. The patient was prescribed an oral aminopeni-
cillin and two standard bottles of commercially avail-
able topical gentamicin sulfate drops (3 mg/mL). He
Medicolegal Aspects of Ototoxicity 203
was asked to use the drops, 3 drops tid for 7 days, and
then to stop.
The patient used the drops as recommended but
continued of his own volition to use them beyond
7 days. The discharge had stopped 4 days into treat-
ment. Drops continued to be used until day 15 of treat-
ment, when he became acutely vertiginous, nauseated,
and imbalanced. The patient stopped the drops and was
reviewed 2 weeks later by the same otolaryngologist
who had originally treated him.
Examination now revealed the TM perforation to
have healed. The otoneurologic examination was normal
apart from a positive left high-frequency, head thrust
maneuver5 and right-beating posthead-shake nystag-
mus.7 Repeat audiometry was essentially normal apart
from a slight sensorineural loss at 8000 Hz in the left ear.
The previous mild conductive hearing loss had resolved.
An electronystagmogram revealed an absent left caloric
response. An intracranial MRI scan was normal.
Although his balance slowly improved, he was
unable to return to his job as an ironworker for
6 months. At present his only symptoms appear to be
slight unsteadiness when moving his head quickly.
Patient Harm Leading to Medicolegal Action
Peter Rhatican
There is no question the patient suffered harm as a
result of the treatment he received. However, the clini-
cal indications (ie, the development of a secondary
infection following a traumatic TM perforation) sup-
ported the treatment that was prescribed. Even if topi-
cal fluoroquinolone drops without risk of ototoxicity
had been widely available at the time (which they were
not in 1997), the dosage and administration of the pre-
scribed aminoglycoside in this case history would be
considered reasonable.
The impact of the patients noncompliance needs
to be considered. When the patient did not discontinue
the drops after the purulent discharge stopped, against
an amended medical order, he played brinkmanship
with his health and contributed significantly to his ulti-
mate injury. Failure to follow the instructions of the
prescribing physician (whether not taking or extending
its use) is still considered noncompliance. In my opin-
ion it was the physicians reasonable medical judgment
that insulated against liability, not necessarily the out-
come of the treatment chosen. In this case there is no
question that the patients sequelae were related more
to the duration the drops were used, not to the initial
choice of medication.
Sloan Mandel
I add one practical consideration. Although the patient
suffered harm, if we are to fully assume that he was fully
capable of returning to work, driving a car, and engag-
204 Medicolegal Concerns
ing in most of his premorbid activities, then the harm
this patient has suffered may not justify the costs and
risks associated with pursuing a medicolegal action.
Patients Case for Physician Responsibility
Peter Rhatican
When the physician gives instructions to a patient who
is capable of understanding the instructions, the physi-
cian has the right to expect the patients compliance.
One might argue that the physician failed to educate
the patient about the risks for topical aminoglycoside
ototoxicity, but in 1997 the world literature still quoted
a low apparent relative risk of 1 in 10,000 for its devel-
opment. Nevertheless, the physician did not mention
this to the patient, nor was a follow-up arranged for at
the end of the prescribed treatment courseboth of
which might have prevented the development of topi-
cal ototoxicity.
If I was arguing this case on behalf of the patient, I
would plead that the drops were used in what would
have been considered an off-label indication (ie, in the
treatment of middle ear infection) that did not have US
Food and Drug Administration approval and that the
physician failed to disclose what harm noncompliance
could have resulted in. The devil is in the details, and
it is important to remember that the communication
and follow-up stages of treatment are no less compul-
sory in the physicianpatient relationship. These pleas
might represent fertile ground for building a case
against the treating physician.
Sloan Mandel
One would also submit that the treating physician
ought not to have prescribed a quantum of medication
that exceeded the 7-day dosage. In doing so the physi-
cian unnecessarily exposed the patient to potentially
avoidable harm.
Standard of the Times
Sloan Mandel
With respect to the issue of standard of care, the year
in which this case history occurred is of significant
importance. By 2000, topical fluoroquinolone drops
were widely available and were known to be equally as
effective as topical gentamicin, without the risk of oto-
toxicity. One could argue that it was a breach of care
not to prescribe (or at least discuss the use of) the less
risky form of therapeutic treatment.
Peter Rhatican
Conversely, the generally recognized standard of care is
not necessarily time bound. By 199798 there was
growing recognition, if not necessarily widespread
acceptance, within the entire medical community that
topical gentamicin drops reaching the middle ear could
result in clinical ototoxicity, for example. Around this
time fluoroquinolone drops were also being introduced
as an effective alternative to the aminoglycosides with-
out risk of ototoxicity. The question of timing ulti-
mately begs the question: Were the standards of care
met when advising and treating the patient? The gen-
erally expected scope of physician knowledge as to the
specific injury potential of topical aminoglycosides
(vestibular vs cochlear) is a material fact that would
certainly need to be ascertained relative to the year.
Case 3: Topical Toxicity from Surgical Disinfectants
and Preparatory Solutions
In an effort to standardize surgical preparatory solu-
tions essentially as a cost-saving measure, the hospital
in question requested that all surgeons move to a 2%
chlorhexidine solution. The change went through the
standard process, which involved a literature review,
and was passed by the pharmacy committee at the hos-
pital, which included representatives from every surgi-
cal department or division before implementation.
Otolaryngologists on staff at the hospital were
informed of the change by the head of the department
in a written communication. An aqueous solution of
iodine had been used previously for ear surgery.
Approximately 3 months later, staff otolaryngolo-
gists identified that six of their patients had sustained
a profound unilateral sensorineural hearing loss fol-
lowing routine tympanoplasty surgery. During the
same time frame, 15 similar operations had been per-
formed. The discovery took place during scheduled
departmental morbidity and mortality rounds. In the
previous 5 years there had been no sensorineural hear-
ing loss documented as directly related to the proce-
dure itself.
As concerned physicians they immediately discon-
tinued the use of chlorhexidine and disclosed to all the
patients by writing who had undergone tympanoplasty
surgery during that time frame their concern that any
hearing impairment postsurgery might have resulted
from the surgical preparatory solution used. Of inter-
est, the one surgeon who routinely used a temporary
barrier (cotton batten) to prevent the preparatory solu-
tion from entering the middle ear had no reported
cases of sensorineural hearing loss.
Preventable Profound Hearing Loss
Peter Rhatican
Logic dictates that where there is evidence in the world
literature of extreme inner ear toxicity in mammals to
chlorhexidine and a few studies in humans implicating
chlorhexidine with profound unilateral sensorineural
deafness, there is little to support its appropriateness in
otologic surgery.

The hearing loss was preventable. The physicians
could have certainly decided it was not in the best inter-
est of the patient to change the old protocol for the sur-
gical preparatory solutions. Having changed the
protocol, however, an instruction for the use of a tem-
porary barrier in those cases involving perforation of
the TM should have been mandated. Their inability to
recognize the inherent toxicity of chlorhexidine put the
whole group of patients at risk for total hearing loss in
the presence of a TM perforation, which was unlikely
to cause the same complication on its own.
Apportioning Blame
Sloan Mandel
Although the hospital, the surgeons, and the members
of the pharmacy committee would all be named as
defendants to the litigation, the hospital and the mem-
bers of the pharmacy committee would be the primary
targets. If the surgeon was following hospital protocol
(a protocol, I might add, that would need to have been
approved by the pharmacy committee at the hospital),
it might be difficult to fault the surgeon given this par-
ticular scenario. It may be said, however, that the sur-
geon ought to have used a temporary barrier.
Nevertheless, it is not clear as to whether or not the fail-
ure to do so would be considered a breach of care.
Peter Rhatican
There is no question the hospital must answer for its
medical decisions, and it certainly has the right to rely
upon its committees in making changes in pharmaceu-
tical protocols. Nonetheless, the hospital has a corre-
sponding duty to the patients by making the hospital a
safe facility for the treatment it rendered.
The otolaryngologists must certainly shoulder
some of the responsibility as they acted in concert with
the hospital in establishing a protocol best suited for
the hospital financially. By defective reasoning, they
placed all surgical patients with a TM defect to a
greater risk of inner ear injury than from the untreated
natural history. Although they would likely be insu-
lated from individual liability by virtue of the fact they
were providing a service to the hospital most likely in
compliance with their contract for surgical privileges,
the fact that as a group they claimed surprise to find six
patients with profound sensorineural hearing loss after
the use of chlorhexidine was approved is indicative of
their joint failure to raise objections on behalf of their
joint patients.
Appropriateness of Surgeon Warning
Sloan Mandel
It was the ethical and fiduciary obligation of the sur-
geons to issue a warning once discovered. If the hospi-
tal had reasonable assurances from the surgeons that
Medicolegal Aspects of Ototoxicity 205
each potentially affected patient would receive an
appropriate warning, then there would have been no
reason to issue a second warning.
Peter Rhatican
In general the premise that a cost-saving effort was
implemented at the cost of increasing the risk of per-
manent injury to a class of patients is never a satisfac-
tory substitute for good medicine. If this premise were
true, then surely a warning to the patient by both the
surgeon and the hospital was warranted. Had the sur-
geon recognized the potential for chlorhexidine toxic-
ity, then timely actions could have been taken to reduce
or eliminate the risk (ie, using a temporary barrier).
Case 4: Cisplatin Ototoxicity
A 25-year-old male university student was recently
diagnosed with metastatic testicular carcinoma. Inves-
tigations confirmed liver involvement. He underwent a
right orchiectomy and following surgery was sched-
uled for combination chemotherapy, which included
high-dose cisplatin at 75 mg/m2 for 5 days with three
repeat cycles. He was advised by his oncologists that the
adverse effects of cisplatin therapy include nephrotox-
icity, neuropathy, and hearing loss from cochlear injury.
Prechemotherapeutic audiometry appeared normal.
Within 48 hours of chemotherapy he was identi-
fied to have a significant hearing loss of more than
15 dB between 4000 and 8000 Hz and noticed some dif-
ficulty hearing in competing background noise. Frank
discussions ensued with his oncologists, and he was
advised that although his cisplatin dosage could be
reduced it could conversely affect the expected remis-
sion rate (ie, this cancer was definitely curable). The
patient decided to continue his present treatment
course, and his hearing continued to further deterio-
rate. His cancer appeared to respond, and remission
was achieved after the cycles of chemotherapy had been
completed. His hearing further deteriorated, and he
was left with a 40 to 60 dB sensorineural hearing loss
over a 2000 to 8000 Hz range. Aural rehabilitation was
arranged, and he was fitted with hearing aids. He is able
to continue his university studies but continues to have
difficulty in competing background noise situations.
Patient Grounds for Negligence
Sloan Mandel
Before undertaking a preliminary liability investiga-
tion, I would not offer an opinion regarding the success
of the claim. In order to rule out the possibility of neg-
ligence, it would be necessary to undertake an appro-
priate investigation at significant cost.
Hearing loss seems to be an unfortunate but gen-
erally accepted risk of the necessary treatment, so the
patient would not be successful in his claim. However,
206 Medicolegal Concerns
if the patient wished to pursue and fund the cost of an
investigation, then I would ensure that the appropriate
experts are retained to provide the necessary opinions.
Peter Rhatican
The use of cisplatin would have been considered neces-
sary by the oncologist to treat a life-threatening malig-
nancy. The toxic side effects would have been generally
accepted within that setting. The notion that the physi-
cian may be held liable under these circumstances is
unsupportable. The physician fully explained the dele-
terious side effects of the chemotherapy, including the
potential for hearing loss from cochlear injury. The
physician also revealed to the patient that once the
hearing loss manifested itself, reducing the dosage of
the chemotherapeutic agent would likely reduce the
success of remission. The patient actively participated
in his therapy management to the extent of recognizing
the downside of hearing loss in this race for survival.
There are no viable grounds to assert that there was
a deviation from recognized standards of medical care.
There is no lack of informed consent. In this difficult
condition, both the physician and the patient became
painfully aware of the sacrifices that might be necessary
to survive this imminently treatable malignancy.
Informed Consent and Medicolegal Action:
What if Hearing Loss due to Treatment Had Not
Been Discussed?
Peter Rhatican
In my home state of New Jersey there would be grounds
for a medicolegal action. The New Jersey Supreme
Court has explained that
the foundation for the physicians duty to disclose in
the first place is found in the idea that it is the pre-
rogative of the patient, not the physician, to deter-
mine for himself the direction in which his interests
seem to be.8
The choice of the treatment plan is for the patient
to make and is not one of pure medical judgment com-
mitted to the physicians direction. In this scenario the
exclusion of facts to the patient renders the physician in
a tenuous position. Clearly the duty requires the physi-
cian to disclose. However, one must then evaluate
whether or not under the circumstances (ie, a treatable
malignancy in a young man) a reasonable individual
would have refused chemotherapy even if the risks were
known. Although the physician was wrong in not
disclosing the potential harm to hearing, on balance, a
reasonably prudent patient would most likely have
accepted the treatment.
Sloan Mandel
Even if this patient had not been advised about the
potentially cochleotoxic effects of cisplatin, I doubt he
would be successful in his claim. In determining
whether or not a patient will be successful in an
informed consent case the Canadian courts apply a
modified objective test. More particularly a judge or
jury will be asked to determine what a reasonable per-
son in this patients particular position would have
done knowing the risks involved. In this particular cir-
cumstance a court or jury would place great weight on
the fact that the underlying condition, if untreated, is
terminal. Provided that there were not other less risky
equally efficacious treatment options available, it is
likely that the reasonable patient would have elected
cisplatin treatment in any event.
REFERENCES
1. Evans KG. A medicolegal handbook for physicians
in Canada. 5th ed. Ottawa: Canadian Medical Pro-
tective Association; 2002.
2. Policy Statement #1-03. Disclosure of harm: Col-
lege of Physicians and Surgeons of Ontario. Dia-
logue 2003;11(3):112.
3. Wu AW. Handling hospital errors: is disclosure the
best defence? Ann Intern Med 1999;131:9702.
4. Hawke M, Jahn AF. Diseases of the ear: clinical and
pathologic aspects. Philadelphia (PA): Lea &
Febiger; 1987.
5. Halmagyi M, Curthoys IS, Aw ST, et al. The human
vestibulo-ocular reflex after unilateral vestibular
deafferentation. The results of high acceleration
impulsive testing. In: Sharpe J, Baraber HO, edi-
tors. The vestibularocular reflex and vertigo. New
York: Raven Press; 1993. p. 4554.
6. Chambers BR, Mai M, Barber HO. Bilateral
vestibular loss, oscillopsia and the cervico-ocular
reflex. Otolaryngol Head Neck Surg 1985;
93:4037.
7. Fujimoto M, Mai M, Rutka J. A study in the
phenomenon of head shaking nystagmus: its pres-
ence in a dizzy population. J Otolaryngol 1993;
22:376401.
8. Largey v Rothman, 110 NJ 204 at 214 (1988).
 APPENDIX 1
Information Provided to Lawyers


CASE 1: SYSTEMIC GENTAMICIN OTOTOXICITY
Overview of Systemic Gentamicin Ototoxicity
Gentamicin is a member of the aminoglycoside class of
antibiotics. It is a bactericidal agent that is active
against some gram-positive and many gram-negative
(eg, Pseudomonas, Escherichia coli, and Klebsiella
species) bacteria not usually sensitive to commonly
prescribed antibiotics, such as penicillin,
cephalosporin, and macrolideshence its continued
use. It is poorly absorbed through the gastrointestinal
tract and must be administered intravenously or intra-
muscularly. Gentamicin is excreted via the kidney. It is
relatively inexpensive (which hospital pharmacies love)
compared with the newer antibiotics available (eg,
third-generation cephalosporins and fluoro-
quinolones).13 Antimicrobial resistance is relatively
low (which microbiologists love).4
Clinical Indications
Gentamicin has been used in the treatment of infective
disorders such as osteomyelitis, infective endocarditis,
and abdominal sepsis.1 All of these conditions typically
require a prolonged treatment course in patients
who often are very ill and initially in an intensive
care setting.
Toxicity
Gentamicins major side effects are nephrotoxicity, oto-
toxicity, and neuromuscular blockade.5 It is recom-
mended that gentamicin be avoided in patients who are
pregnant and in those who have renal failure. The oto-
toxicity with systemic gentamicin is usually vestibular
in nature, presenting with imbalance, ataxia, and oscil-
lopsia (visual blurring with head movement).6,7 Gen-
tamicin vestibulotoxicity tends to be permanent
(although it is estimated that if gentamicin is stopped
immediately upon onset of symptoms there is approx-
imately a 50% chance of reversibility).8
Multiple versus Single Daily Dosing
In patients with normal renal function gentamicin was
conventionally given every 8 hours (multiple daily dos-
ing). By the mid-1990s meta-analyses revealed that a
combined dose could be given once a day (single daily
dosing) without loss of effect and without placing the
patient at risk for increasing nephrotoxicity.1,4,9 The
meta-analyses could not, however, address whether sin-
gle daily dosing protocols resulted in a greater degree of
ototoxicity.10 Single daily dosing had one important
advantage over multiple daily dosingits ease of
administration made it ideal for outpatient and home-
care administration (publicly funded hospitals, insur-
ance companies, and patients liked the fact that more
expensive inpatient treatment could be minimized).
But is treatment with systemic gentamicin always in the
best interest of the patient, even if it can be delivered on
an outpatient basis?
Risk Factors
To date, risks for ototoxicity are usually quoted at 1 to
2% for all those receiving systemic gentamicin.8,11 How-
ever, we have identified several risk factors that place an
individual at greater risk for ototoxicity. Risk factors for
gentamicin vestibulotoxicity include the following12,13:
1. Prolonged treatment course > 14 days with a
cumulative dosage > 2.5 g
2. Development of renal failure during treat-
ment (ie, rising creatinine levels)
3. Use of concomitant ototoxic agents, such as
diuretics and macrolide antibiotics (eg, ery-
thromycin)
4. Elevated serum trough (preadministration
levels) antibiotic levels
5. Previous history of ototoxicity
Of all the risk factors, prolonged treatment course
appears to be the most important.6 There had been
208 Appendix 1
great hopes that monitoring serum gentamicin levels
could prevent ototoxicity from occurring.14 Although
monitoring may reduce the risk somewhat, there is a
body of evidence in the world literature of patients
who had normal serum levels and did not develop renal
toxicity or other risk indications yet who went on to
develop gentamicin vestibulotoxicity.6
Note that at the present time there are equally effi-
cacious and safer antibiotics to use without risk for oto-
toxicity (albeit more expensive and as such possibly
precluded from home or outpatient treatment).
1. Evidence Supporting an Action of Medical
Negligence
In the absence of other causes the patient has been
diagnosed with a bilateral peripheral vestibular loss
from ototoxicity. Consider the following:
a. Osteomyelitis can be a severe and limb-
threatening infection, especially in diabet-
ics and those with peripheral vascular
disease.
b. Until cultures were known, it would have
been appropriate to treat with triple
antibiotic therapy.
c. Although diabetics with chronic osteo-
myelitis tend to have polymicrobial infec-
tions, a deep aspirate from the joint in a
first-time infection would be evidence
that the streptococcus cultured was
responsible for her infection.15,16
d. Cultures demonstrated that the strepto-
coccus cultured was sensitive to all agents
independently and even to straight-
forward penicillin.
e. Treatment for a suspected osteomyelitis
usually requires a minimum of 6 weeks of
antibiotic therapy.16,17
f. The patient was not told about the well-
recognized adverse effects of gentamicin
(ie, if the patient were advised at first
onset of symptoms it may have resulted in
an earlier discontinuation of her gentam-
icin with possible spontaneous recovery
of vestibular function).
g. Toxicity is the result of prolonged admin-
istration of gentamicin and is evidenced
by the development of renal impairment
during treatment.
2. Legal Research
a. How do you research a case like this to
determine its merits (what resources do
you use)?
b. How do you go about getting an expert
opinion?
c. How many expert opinions would you
need in this case (do you need an infec-
tious disease experts opinion, a micro-
biologists opinion, a neurotoxicologists
opinion)?
3. Responsibility of Health Care Professionals
a. The hospital internist prescribed triple
antibiotic therapy when cultures a few
days later revealed a bacteria that safer
agents could have treated without relying
on gentamicin.
b. The family physician failed to act (ie, by
discontinuing the gentamicin or altering
its dose) on rising levels of serum creati-
nine and trough levels of gentamicin that
suggested the patient was slipping into
renal failure.
c. The visiting nurse failed to take seriously
the complaints of the patient (she was
also unaware that gentamicin was pri-
marily vestibulotoxic, not cochleotoxic)
and did not notify the treating physician.
4. Recommendations for Physicians and Allied
Health Care Professionals
CASE 2: TOPICAL GENTAMICIN OTOTOXICITY
Overview of Topical Aminoglycoside
Drop Ototoxicity
Topical aminoglycoside drops (with or without a
steroid component) have been used in the topical treat-
ment of ear disease owing to their efficacy, low resis-
tance, and low per unit cost.18 Because of their activity
against gram-negative organisms they have been specif-
ically indicated for the treatment of external otitis and
chronic otitis media (where gram-negative polymicro-
bial infections are the norm). 1921 Until fluoro-
quinolones such as ciprofloxacin were introduced,
there were no oral antibiotic agents available for the
majority of gram-negative organisms. Topical treat-
ment ideally delivers a high concentration of the antibi-
otic to areas that are difficult for systemic antibiotics to
reach tissue levels adequate to fight infection.
Clinical Indications
Topical aminoglycoside drops are typically prescribed
for the treatment of a discharging ear. This is despite
there being no official US Food and Drug Administra-
tion (FDA) approval for a middle ear indication. Use
would therefore represent an off-label indication.
Toxicity
There has been sufficient documentation in animal
models that topical aminoglycosides are toxic to the

inner ear. In humans, instillation of concentrated
gentamicin into, for example, the middle ear (at con-
centrations often > 10 times that found in commer-
cially available topical drops) has been therapeutically
used to cause vestibular deafferentation in the treat-
ment of Menieres disease.23 Nevertheless, up until
1997 or so little evidence in the world literature sup-
ported a significant concern regarding topical amino-
glycoside ototoxicity in humans treated for middle ear
sepsis.24,25 In a 1992 survey most US otolaryngologists
acknowledged that although there was a risk for oto-
toxicity they felt comfortable prescribing aminoglyco-
side drops in the presence of a tympanic membrane
(TM) perforation on the basis that any untreated mid-
dle ear sepsis carried a higher risk for ototoxicity than
did the treatment itself.26
Introduction of Fluoroquinolone and Recognition
of Topical Ototoxicity
In 199798 topical fluoroquinolone drops were intro-
duced into the US market. These agents were effective
and carried no risk for ototoxicity. They were, however,
usually more expensive. One of the medications,
ofloxacin, even received FDA approval for middle
ear use.
Around the same time studies in the US and Euro-
pean literature began demonstrating inadvertent oto-
toxicity from commercially available gentamicin-
containing drops. The toxicity, however, was identified
to be primarily vestibular in nature, not cochlear (sim-
ilar to that seen in systemic ototoxicity and perhaps the
main reason why it had been missed for so long).25,27,28
Risk Factors for Topical Aminoglycoside Ototoxicity
Risk factors for topical gentamicin ototoxicity (the top-
ical agent most studied) appear to be directly related to
duration of treatment (> 7 days), especially when used
in the presence of a dry TM perforation.25,27,29 For this
reason it has been suggested that patients requiring
topical aminoglycoside drops have weekly reviews to
determine the need for continued treatment and
should be instructed to stop drops once the discharge
has stopped.18
1. Harm Leading to a Medicolegal Action
a. Although he missed 6 months of work he
is now able to perform most of his pre-
morbid activities (driving a car, returning
to work, etc).
b. He has only slight imbalance with fast
movements of his head.
c. His physical examination suggests a loss of
left vestibular activity, which is confirmed
with electronystagmography testing.
d. There was no evidence to suggest another
pathology apart from the gentamicin drops
Information Provided to Lawyers 209
(the infection had stopped many days
prior, there was no evidence of a viral upper
respiratory tract infection that might have
resulted in a vestibular loss, etc).
2. Responsibility of Patient versus Lack of Treating
Physician Follow-up
a. Topical treatment was indicated and the
duration of recommended treatment
(7 days) would be considered reasonable.
b. The treating physician did not warn the
patient of ototoxicity (rate of cochlear
toxicity, not vestibular, has been quoted as
1 in 10,000)was there a lack of
informed consent? 24
c. The drops were used in what would be
considered an off-label indication (no
FDA approval but within the community
of practicing otolaryngologists it would
be considered standard of care to use the
drops).24,26
3. Year of Incident
a. Since 199798 there has been a general
awareness that topical aminoglycoside
drops are ototoxic when used in a pro-
longed fashion in the presence of a dry
middle ear.
b. In 199798 topical fluoroquinolone drops
were introduced that did not carry risk
for ototoxicity and were demonstrated to
be equally effective even if used in an off-
label fashion.
CASE 3: TOPICAL TOXICITY FROM SURGICAL
DISINFECTANTS AND PREPARATORY SOLUTIONS
Overview of Ototoxicity from Topical Disinfectants
Chlorhexidine is an agent available for preoperative
hand washing and general skin disinfection in prepa-
rations that range in concentration from 0.015 to 5%.30
It is positively charged and acts by disrupting the cell
membrane and precipitating the cytoplasm of suscep-
tible bacteria.31
Ototoxicity
Animal models have demonstrated how extremely toxic
chlorhexidine and other alcohols can be to the inner ear
if they reach the middle ear through a TM perforation.
Toxicity appears to be directly related to the concentra-
tion and the contact time with the round window mem-
brane of the inner ear. Toxicity appears to occur within
hours and is both cochlear and vestibular.3235 A 1971
article by Bicknell identified profound unilateral deaf-
ness in 14 of 97 (14%) patients who had undergone
routine tympanoplasty surgery; the only common
210 Appendix 1
factor was a 0.5% chlorhexidine solution in 70%
spirit.36 (Otherwise there have been only a few sporadic
case reports of disinfectant ototoxicity in humans.)
Prevention
There is no evidence-based medicine to demonstrate
that use of disinfectants prevents infection from occur-
ring in middle ear surgery, although it makes good
sense to reduce bacterial load wherever possible. Only
aqueous-based (not alcohol-based) iodine solutions are
relatively safe to use in the presence of a TM perfora-
tion.3739 When the TM is intact there need be no worry
about the preparatory solution used. When a TM per-
foration is present, a temporary barrier (a plug of cot-
ton) is often used to prevent the solution from entering
the middle ear.
1. Prevention of Profound Hearing Loss
There appears to be no agreed upon standard regard-
ing a temporary barrier to prevent preparatory solution
from entering the middle ear. Some surgical texts have
specifically addressed this issue and have stated that
preparatory solutions in the middle ear should be
avoided whenever possible. Others have not addressed
this issue. Clinical experience points to aqueous iodine
solutions being the safest in humans.
2. Apportioning Blame
a. The hospital wished to proceed to a stan-
dardized preparatory solution, one rea-
son for which was to save money.
b. The recommended change passed
through the pharmacy committee at the
hospital following a review of the litera-
ture (not necessarily specific to ear
surgery); representatives included mem-
bers of all departments, including oto-
laryngology.
c. The surgeon would have had the last best
chance to avoid toxicity by using a tem-
porary barrier.
d. In general, the odds of a complete sen-
sorineural hearing loss as a complication
of tympanoplasty surgery are 1 in 1,000
operations.3840
e. Reports of toxicity from preparatory
solutions in the ear are quite rare; one
large retrospective series was written up
more than 30 years ago.36
3. Appropriateness of Surgeons Issuing Warning
CASE 4: CISPLATIN OTOTOXICITY
Overview of Cisplatin Ototoxicity
Cisplatin is a chemotherapeutic agent that has typically
resulted in durable remissions in solid cancers such as
ovarian and testicular cancer and significant action in
cancer of the head and neck, cervix, prostate, bladder,
lung, esophagus, uterus, and brain.41 Its systemic
pharmacodynamics, antitumor specificity, and cellular
mechanisms of antitumor action are well understood.41,42
Ototoxicity
The cellular and molecular interactions leading to toxic
dose-limiting side effects are not as well understood.42
Toxicities include permanent high-frequency sen-
sorineural hearing loss (range of 20 to 90% in those
receiving cisplatin) and peripheral neuropathy as well
as dose-related renal impairment from tubular necro-
sis and interstitial nephritis.4347 There is significant
variability in presentation and susceptibility to cis-
platin-mediated ototoxicity. However, it is generally
accepted that high-dose therapy may be more
cochleotoxic. Accompanying tinnitus (unwanted hear
noise) may be transient or permanent and is estimated
to occur in 7% of clinical trials (range 2 to 36%).41
Despite these risks cisplatin administration is consid-
ered necessary to treat life-threatening conditions, and
as such, the toxic side effects are often accepted under
the circumstances.
Prevention
Hearing loss appears to be permanent despite treat-
ments with prehydration or mannitol administra-
tion.41,48 In other words, there is no treatment that will
universally protect the inner ear from cisplatin toxicity,
although some research agents are quite promising.41,42,48
1. Grounds for Negligence
The physician demonstrated full disclosure of the risks
and benefits of chemotherapy (including hearing loss),
and it was the patients ultimate decision to carry on
with therapy for a very treatable malignancy.
2. Role of Informed Consent
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3. Bertino JS, Rorschafer JC. Editorial response.
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whose time has not yet come. Clin Infect Dis
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4. Levison ME. New dosing regimen for aminoglyco-
side antibiotics. Ann Intern Med 1992;117:6934.
5. John JF. What price success? The continuing saga
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glycoside antibiotics. J Infect Dis 1988;158:16.

6. Halmagyi M, Fattore C, Curthoys IS, Wade S. Gen-
tamicin vestibulotoxicity. Otolaryngol Head Neck
Surg 1994;111:5714.
7. Black FO, Pesznecker S. Vestibular ototoxicity: clin-
ical considerations. Otolaryngol Clin North Am
1993;26:71336.
8. Jackson GG, Arcieri G. Ototoxicity of gentamicin
in man: a survey and controlled analysis of clinical
experience in the United States. J Infect Dis
1971;124 Suppl:1307.
9. Bailey TC, Little JR, Littenberg B, et al. A meta-
analysis of extended-interval dosing versus mul-
tiple daily dosing of aminoglycosides. Clin Infect
Dis 1997;24:78695.
10. Aminoglycosides once daily? [editorial] Drug Ther
Bull 1997;35(5):367.
11. Arcieri GM, Falso F, Smith HM, Hobson CB. Clin-
ical research with gentamicin: incidence of adverse
effects. Med J Aust 1970;Suppl:304.
12. Rutka J, Alberti PW. Toxic and drug-induced dis-
orders in otolaryngology. Otolaryngol Clin North
Am 1984;17:76174.
13. Rutka J. Disorders of immunosuppression. In:
Gray RJ, Rutka JA, editors. Recent advances in oto-
laryngology. 6th ed. London (UK): Churchill Liv-
ingstone; 1988. p. 22343.
14. Lerner SA, Matz GJ. Suggestions for monitoring
patients with aminoglycoside antibiotics. Oto-
laryngol Head Neck Surg 1978;87:2228.
15. Wheat LJ, Allan SD, Henry M, et al. Diabetic foot
infections: bacterial analysis. Ann Intern Med
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16. Lipsky BA, Pecoraro RE, Wheat L. The diabetic
foot: soft tissue and bone infection. Infect Dis Clin
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17. Gilbert DN, Moellering RC, Sande MA, editors.
The Sanford guide to antimicrobial therapy.
29th ed. Vienna (VA): Antimocrobial Inc; 1999.
18. Bath AP, Walsh RM, Bance ML, Rutka JA. Ototox-
icity of topical gentamicin preparations. Laryngo-
scope 1999;109:108893.
19. Lancaster JL, Mortimore S, McCormick M, Hart
CA. Systemic absorption of gentamicin in the
management of active mucosal chronic otitis
media. Clin Otolaryngol 1999;24:4359.
20. Acuin J, Smith A, MacKenzie I. Interventions for
chronic suppurative otitis media [systematic
review]. Cochrane Ear Nose and Throat Disorders
Group. Cochrane Database of Systematic Reviews,
2003;(1).
21. Hannley MT, Denneny JC, Holzer SS. Use of oto-
topical antibiotics in treating 3 common ear con-
ditions. Otolaryngol Head Neck Surg 2000;122:
93440.
22. Roland PS, Rutka J, Haynes DS. Antibiotic ototox-
icity: pathology, management and medicolegal
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(1 Suppl):116.
23. Nedzelski JM, Schessel DA, Bryce GE, Pfleiderer
AG. Chemical labyrinthectomy: local application
of gentamicin for the treatment of unilateral
Menieres disease. Am J Otol 1992;13:1822.
24. Roland PS. Clinical ototoxicity of topical antibiotic
drops. Otolaryngol Head Neck Surg 1994;110:
598602.
25. Wong DL, Rutka JA. Do aminoglycoside otic
preparations cause ototoxicity in the presence of
tympanic membrane perforations? Otolaryngol
Head Neck Surg 1997;116:40410.
26. Lundy LB, Graham MD. Ototoxicity and ototopi-
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J Otol 1993;14:1416.
27. Marais J, Rutka J. Ototoxicity of topical ear drops.
Clin Otolaryngol 1998;23:3607.
28. Walby P. Stewart R, Kerr AG. Aminoglycoside ear
drop ototoxicity: a topical dilemma? Clin Oto-
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29. Kaplan DM, Hehar SS, Bance ML, Rutka JA. Inten-
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30. British National Formulary 45, March 2003.
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32. Aursnes J. Vestibular damage from chlorhexidine
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33. Aursnes J. Cochlear damage from chlorhexidine in
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34. Igarashi Y, Suzuki J. Cochlear ototoxicity of
chlorhexidine gluconate in cats. Arch Otol Rhinol
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35. Igarashi Y, Oka Y. Vestibular ototoxicity following
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36. Bicknell PG. Sensorineural deafness following
myringoplasty operations. J Laryngol Otol 1971;
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38. Shea MC. Tympanoplasty: the undersurface graft
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39. Jackson CG, Glasscock ME, Strasnick B. Tym-
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40. Mandolis S. Closure of tympanic membrane per-
forations. In: Glasscock ME, Gulya AJ, editors.
Surgery of the ear. 5th ed. Hamilton (ON):
BC Decker Inc; 2003. p. 40019.
41. Schweitzer VG. Ototoxicity of chemotherapeutic
agents. Otolaryngol Clin North Am 1993;26:75989.
42. Schweitzer VG. Cisplatinum-induced ototoxicity:
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Larygngoscope 1993;103 Suppl 59:152.
43. Gratton MA. The interaction of cisplatinum and
noise on the peripheral auditory system. Hear Res
1990;50:21124.
44. Saferstein RL. Cisplatinum nephrotoxicity. Am J
Kidney Dis 1986;8:35667.
45. Daugaard G. Cisplatinum nephrotoxicity: review.
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46. Walsh TJ, Clark AW, Parhad IM, Green WR.
Neurotoxic effects of cisplatinum therapy. Arch
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47. Forastiere AA, Takasugi BJ, Baker SR, et al. High
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48. Fausti SA, Henry JA, Schaffer HI, et al. High-
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 APPENDIX 2
Summary of The 2004 AAO-HNS Consensus
Panel Recommendations


SUMMARY OF THE 2004 AMERICAN ACADEMY OF
OTOLARYNGOLOGYHEAD AND NECK SURGERY
CONSENSUS PANEL RECOMMENDATIONS
REGARDING POTENTIALLY OTOTOXIC
ANTIBIOTICS FOR MIDDLE EAR USE
In 2003 Jonas Johnson, then president of the American
Academy of OtolaryngologyHead and Neck Surgery
(AAO-HNS), charged a panel of physicians with the
responsibility to develop a consensus position on the use
of potentially ototoxic antibiotic topical drops in the
treatment of ear disease based on evidence-based med-
icine. Previous AAO-HNS position statements adopted
in 1994 and reaffirmed in 1998 had recognized the
appropriateness of using available topical preparations,
including those containing aminoglycosides, in the
treatment of external and middle ear disorders despite
their potential for ototoxicity, provided the benefits of
therapy outweighed the risks and no equally effective,
less potentially hazardous treatments were available. The
need to revisit this specific issue was based on the per-
ceived increase in claims against physicians alleging top-
ical iatrogenic ototoxic injury, political developments
and practice guidelines in countries such as Canada and
the United Kingdom limiting the use of potentially
ototoxic topical antibiotics, the introduction of non-
ototoxic preparations (specifically topical fluoro-
quinolones) to the marketplace, and the fact that no
systematic evidence-based review of these issues had
been performed. All consensus documents such as this
without exception will need to be revisited from time to
time. This dynamic process is necessary if recommenda-
tions are to remain germane to the practice of medicine:
former recommendations may change to reflect subse-
quent evidence from published clinical and basic science
research. Readers wishing a more detailed explanation of
the consensus panels recommendations are requested to
review the March 2004 supplement to Otolaryngology
Head and Neck Surgery: Official Journal of the American
Academy of OtolaryngologyHead and Neck Surgery.1
RECOMMENDATIONS OF THE CONSENSUS PANEL
ON OTOTOPICAL ANTIBIOTICS
1. When possible, topical antibiotic preparations
free of potential ototoxicity should be pre-
ferred over ototopical preparations that have
the potential for ototoxic injury if the middle
ear and mastoid are open.
2. If used, potentially ototoxic antibiotic prepa-
rations should be used only in infected ears.
Use should be discontinued shortly after the
infection has resolved.
3. If potentially ototoxic antibiotic drops are pre-
scribed for use in the open middle ear or mas-
toid, the patient should be warned of the risk
of ototoxicity.
4. If potentially ototoxic antibiotics are pre-
scribed, the patient should be specifically
instructed to call the physician or return to his
or her office if the patient develops the
following:
Dizziness or vertigo
Hearing loss (or additional hearing loss if
hearing impairment was part of the original
condition)
Tinnitus
5. If the tympanic membrane is known to be
intact and the middle ear and mastoid are
closed, then the use of potentially ototoxic
preparations presents no risk of ototoxic
injury.
REFERENCE
1. Roland PS, Stewart MG, Hannley M, et al. Con-
sensus panel on the role of potentially ototoxic
antibiotics for topical middle ear use: introduction,
methodology and recommendations. Otolaryngol
Head Neck Surg 2004;130(3 Suppl):S516.
 APPENDIX 3

Major Groups of Agents Recognized

to be Ototoxic in Humans

AMINOGLYCOSIDES LOOP DIURETICS

amikacin ethacrynic acid
dihydrostreptomycin furosemide
gentamicin
kanamycin MACROLIDES
neomycin azithromycin
netilmicin clarithromycin
streptomycin erythromycin
tobramycin
NONSTEROIDAL ANTI-INFLAMATORY
ANTISEPTIC/DISINFECTANT AGENTS DRUGS (NSAIDS)
alcohol
chlorhexidine TOPICAL ANTIBIOTICS
all aminoglycosides
ARSENICALS chloramphenicol
polymyxin
CYTOTOXIC AGENTS
bleomycin TRADITIONAL AGENTS
carboplatin acetylsalicylic acid (ASA)
cisplatin quinine
nitrogen mustard
vinca alkaloids VANCOMYCIN
(in conjunction with aminoglycosides, primarily)
IRON-CHELATING AGENTS (FE 2+)
deferoxamine
 Index

A free radicals, 97f topical, 134138

ABR, 13f, 154 inducing cellular toxicity application of, 137
chlorhexidine, 140 mechanisms for, 144145 for otomycosis, 137t
lead, 36 multiple-daily vs. once daily dosing, Antimycotics, 111112
Acetic acid, 135, 142 8687 Antioxidants, 172173, 177178
for otomycosis, 137t nephrotoxicity of, 8485 Antiseptics, 111112, 135136, 140143,
Acetylcysteine, 176 neuromuscular blockade, 86 215
ACTH/MSH, 178 otoprotection research, 176 for otomycosis, 137t
Actin fibers, 7 ototoxicity of, 8289 AOM, 121
Acute otitis media (AOM), 121 genetic factors in, 144149 Apoptosis, 9495, 170
Adaptation, 24 genetic susceptibility to, 145147 free radical formation, 9596
Adenosine receptor agonists, 178 mechanisms for, 9398 Arachidonic acid metabolism
A1555G mutation nitric oxide, 96 salicylates, 31
clinical phenotype of, 148 pathophysiology of, 147 Arsenicals, 215
in 12S ribosomal ribonucleic acid gene, prevention and therapy of, 148149 ASHA
145146 risk factors for, 86t ototoxic threshold shift criteria, 154
Alcohol, 135, 141, 209210 ROS, 9697 Aspergillus, 134
for otomycosis, 137t structural and functional changes in, Aspirin, 28
Alexanders law, 24 144 ATP receptors, 9t
Alpha-lipoic acid, 177 pharmacokinetics of, 94 Audax, 142
Alpha-melanocyte-stimulating hormone recommendations for, 8889 Audicort, 142
(alpha-MSH), 178 renal monitoring, 8788 Audiologic assessment, 153154
Alpha-MSH, 178 serum monitoring, 8788 Auditory brainstem response (ABR), 13f,
Alpha-phenyl-tert-butyl-nitrone, 171172 structure of, 93 154
Alpha-tocopherol, 177 toxicity of, 8486 chlorhexidine, 140
Aluminum acetate, 142 tympanostomy tubes, 118 lead, 36
AMD-473, 68 vestibulotoxicity Auditory electrical pathway
clinical status of, 62t risk factors for, 164t furosemide, 4445
American Academy of Otolaryngology in vitro activity, 83 Auditory potentials
Head and Neck Surgery Consensus AMPA, 9t salicylates, 30
Panel Recommendations Amphotericin B Azithromycin, 102103
ototopical antibiotics, 213 for otomycosis, 137t Azoles, 136
potentially ototoxic antibiotics for ototoxicity of, 112 Azosemide
middle ear use, 213 Anemia ototoxicity of, 46
American Speech Language Hearing with carboplatin, 67
Association (ASHA) with cisplatin, 61
ototoxic threshold shift criteria, 154 Antibiotics. See also Aminoglycosides B
Amifostine, 176 middle ear effects of, 107111 Bacteroides fragilis, 130
Amikacin, 84 ototopical BAO-HNS, 121
availability of, 83t American Academy of Basilar membrane, 1, 5, 14
Aminoglycosides, 170171, 215. See also OtolaryngologyHead and Neck mechanics of, 1314
Topical aminoglycosides Surgery Consensus Panel Bechterews nucleus, 22
activity of, 93 Recommendations, 213 Bedside clinical vestibular tests, 167
availability of, 83t topical, 215 Benzalkonium chloride, 110, 141
cell death, 9495 Antifungals, 136 Benzethonium chloride, 141
clinical indications for, 8283 for otomycosis, 137t Bifonazole, 136
216 Index

Bladder cancer historical development of, 130 duct, 10

cisplatin for, 55, 55t human studies, 131132 electrophysiology, 1213
Blame, 205, 210 proprietary agents containing, 131 fluid spaces, 24
Bleomycin therapeutic use of, 130131 lateral wall, 45
for testicular cancer, 51t Chlorhexidine, 140141, 209210 neural structure, 810
Boric acid, 135 ABR, 140 physiology of, 1016
for otomycosis, 137t Chlorhexidine gluconate position of, 1f
Bottcher cells, 5, 6 ototoxicity of, 112 potentials, 1213
Brain-derived neurotrophic factor, 175 Chloromycetin Otic, 131 scalae, 2f
Brainstem potentials, 13 Cholesteatoma standing current in, 11f
British Association of Otorhinolaryngol- Cortisporin Otic Suspension, 110f, 111f vasculature, 3f, 4
ogistsHead and Neck Surgeons Chronic suppurative otitis media (CSOM), Cochlea microphonics (CM), 1213
(BAO-HNS), 121 121 Cochlear potentials
Bumetanide Cinchona bark, 33 salicylates, 30
ototoxicity of, 4546 Ciprofloxacin Colymycin
middle ear effects of, 108 animal studies, 129
C Cisplatin, 178 Coly-Mycin S
Caloric tests, 165 for bladder cancer, 55, 55t cochlear ototoxicity, 115
advantages and limitations of, 165t for cervical cancer, 54 Coly-Mycin S Otic, 128
Candida, 134, 137 chemistry of, 61 Compensation, 24, 163
CAP, 12, 13 clinical pharmacology, 5052, 61 Compound action potential (CAP), 12, 13
Carbenicillin clinical status of, 62t Computerized dynamic posturography
middle ear effects of, 107111 clinical uses of, 5057, 61 (CDP), 161
Carboplatin, 6667 for epithelial ovarian cancer, 5254, 52t tests
chemistry, 66 intraperitoneal, 54 advantages and limitations of, 165t
clinical pharmacology, 66 indications for, 61 Conductive hearing loss, 153
clinical status of, 62t interactions with other ototraumatic Cortisporin Otic Solution, 128129
clinical use of, 66 agents, 6566 Cortisporin Otic Suspension, 109
indications for, 66 leukopenia with, 61 basal cochlear turn, 117f
mechanism of action, 66 for lymphoma, 56 cholesteatoma, 110f, 111f
otoprotection, 179 mechanism of action, 50, 61 cochlear ototoxicity, 115
ototoxicity of, 67 nephrotoxicity of, 5051 middle ear effects of, 108
pathophysiology of, 67 neurotoxicity of, 50 organ of Corti, 117f
toxicity of for non-small cell lung cancer, 56 outer hair cell, 116f
nonotological manifestations of, 6667 otoprotection, 176177 propylene glycol, 110
Caspase inhibitors, 174175 ototoxicity of, 6163, 205, 210 Cresylate, 135
Caspases, 178 characteristics of, 64 for otomycosis, 137t
CDP, 161 clinical presentation of, 60t Crista, 21f
tests epidemiology of, 6364 CSF
advantages and limitations of, 165t historical development of, 60 composition of, 2t
Ceftazidime pathophysiology of, 6465 CSOM, 121
mucosal hemorrhage associated with, predisposing factors, 60t Cyclooxygenase pathways
109f risk factors, 65 salicylates, 31
Cell death, 170 pharmacokinetics, 50 Cytotoxic agents, 215
aminoglycosides, 9495 for small cell lung cancer, 5556
pathways, 95f for squamous cell head and neck
free radical formation, 9596 cancer, 5455 D
mitogen-activated protein kinase for testicular cancer, 51t DDTC, 176
(MAPK) signaling pathway, 173175 testis germ cell tumors, 5152 Deafness
pathways toxicity of, 50 mercury, 3536
inhibitors of, 173174, 178179 nonotological manifestations of, 61 Deferoxamine, 7678, 172173
Central vestibular system, 22 C-Jun N-terminal protein kinase (JNK), 95 ototoxicity of, 7678
CEP 1347, 174 C-Jun N-terminal protein kinase mechanism of, 78
Cerebrospinal fluid (CSF) inhibitory peptide (D-JNK-1), 174 minimizing, 77
composition of, 2t Clarithromycin, 103 Deiters cell, 6, 6f, 7, 11
Cervical cancer Clinical topical ototoxicity, 121122 Deiters nucleus, 22
cisplatin for, 54 Clotrimazole, 136 Desferrioxamine. See Deferoxamine
Chemotherapeutic agents, 176177 for otomycosis, 137t Dexamethasone
Children ototoxicity of, 112 middle ear effects of, 109
ototoxicity monitoring, 155156 CM, 1213 ototoxicity of, 116
Chlamydia, 130 Cochlea DHI, 168
Chloramphenicol, 130132 anatomy of, 110 Diethyldithiocarbamate (DDTC), 176
animal studies, 131 blood supply, 4 2,3-dihydroxybenzoate, 172173
ear drops, 142 salicylates, 31 Disclosure, 200
 Index 217

Distortion product otoacoustic emissions FTN, 161 Hearing

(DPOAE), 15f, 155 Furosemide ototoxic damage, 170179
Diuretics ototoxicity of, 4345 toxicity criteria for, 63t
loop, 215 administration route, 44 Hearing loss
Dizziness Handicap Inventory (DHI), 168 biochemical changes, 45 A1555G mutation
D-JNK-1, 174 bolus dosing, 44 in 12S ribosomal ribonucleic acid
D-Met, 176, 177 clinical manifestations of, 4344 gene, 146
Domoic acid, 9t mechanisms of, 4445 conductive, 153
DPOAE, 15f, 155 morphologic and histologic changes, control of, 192t
Dynamic visual acuity, 26 45 mercury, 3536
Dynamic visual acuity testing (oscillopsia rate of infusion, 44 profound
testing), 167 preventable, 204205, 210
quinine, 34
E G salicylates, 29, 32
Ebselen, 177 Garasone ear drops sensorineural
Econazole, 136 Menieres disease, 125f with deferoxamine, 76, 77t
EHF, 154 vestibular ablation, 124 ethacrynic acid, 42
Electronystagmography (ENG), 161 vestibulotoxicity of, 123 Heavy metals, 3536
Endocochlear potential GDNF, 175 Hensens cells, 6
ethacrynic acid, 43 Genetic factors High-frequency audiometry, 154155
furosemide, 4445 in aminoglycoside ototoxicity, 144149 High-frequency head thrust (Halmagyi
Endolymph, 11 clinical relevance of, 147149 maneuver), 2526, 25t
Endolymphatic sac Gentamicin. See also Topical gentamicin High-frequency horizontal head thrust, 167
fluid availability of, 83t Horizontal vestibulo-ocular reflex (VOR)
composition of, 2t cochlear ototoxicity, 114115 wiring of, 162f
Endolymph electrolytes indications for, 207 Hughson-Westlake threshold procedures,
ethacrynic acid, 43 intratympanic 153
ENG, 161 delivery of, 192193 Hydrocortisone
ENG caloric tests, 165 dose of, 193 middle ear effects of, 109
advantages and limitations of, 165t end point, 193194 Hypoalbuminemia
ENG tests, 165166 multiple vs. single daily dosing, 207 furosemide, 45
Environmental chemicals, 157 otorrhea, 118
ERCC1, 69 risk factors, 207208 I
Erythromycin, 101102 systemic ototoxicity IAC, 21
ototoxicity of case study, 200 Ifosfamide
mechanisms of, 103104 information provided to lawyers, for testicular cancer, 51t
predisposing factors for, 101102 207208 IHC, 1, 6, 7f, 11
risk factors for, 102 toxicity of, 207 stereocilia, 8
Escherichia coli, 130 Gentian violet, 135136 Indacrinone
Ethacrynic acid for otomycosis, 137t ototoxicity of, 46
ototoxicity of, 4243 ototoxicity of, 112 Informed consent, 206
clinical manifestations of, 42 Glial cell line-derived neurotrophic factor Inherited factors
mechanisms of, 4243 (GDNF), 175 in aminoglycoside ototoxicity, 144149
morphologic and histologic changes, GluR, 9t Inner hair cells (IHC), 1, 6, 7f, 11
43 Glutamate, 9t stereocilia, 8
Etoposide Glutathione, 172 Integrated visual-vestibular-proprioceptive
for testicular cancer, 51t Griseofulvin assessment, 166167
Excision repair cross-complementing 1 ototoxicity of, 112 Internal auditory canal (IAC), 21
(ERCC1), 69 Growth factors, 175176 Intratympanic gentamicin
Extended high-frequency (EHF), 154 delivery of, 192193
Extrinsic cell death receptor pathway dose of, 193
flow chart, 171f H end point, 193194
Habituation, 24 Iodine, 141
F Haemophilus influenzae, 130 Iron-chelating agents, 7678, 172173, 215
Floccular target neurons (FTN), 161 Hair cells, 2223, 23f
Fluconazole, 137 glycogen metabolism J
Fluoroquinolone, 209 ethacrynic acid, 43 JNK, 95
middle ear effects of, 108 Half-lists, 154
Fosfomycin Halmagyi maneuver, 2526, 25t K
animal studies, 129130 Head and neck cancer Kainic acid, 9t
Framycetin cisplatin for, 5455 Kanamycin
chronic otitis media, 118 Head shake test, 25t, 26 availability of, 83t
Free radicals Health care professionals cochlear ototoxicity, 114115
aminoglycosides, 97f responsibility of, 202203, 208 interacting with cisplatin, 6566
218 Index

Ketoconazole, 137 Methionine, 172 Norepinephrine

Ketolides, 103 Methylthiobenzoic acid, 176 salicylates, 31
Klebsiella pneumoniae, 130 4-methylthiobenzoic acid (MTBA), NSAID, 215
176177 ototoxicity of, 33
L Miconazole Nuclear inherited predisposing genes,
Laboratory vestibular tests for otomycosis, 137t 146147
advantages and limitations of, 165t ototoxicity of, 112 Nystagmus, 24
Labyrinthine artery, 4 Micromonospora, 82 characteristics of, 25t
Lateral olivocochlear bundles, 6, 10 Mitogen-activated protein kinase (MAPK) optokinetic, 166
Lawyers cell death signaling pathway, 173175 post-head-shake, 167
information provided to, 207210 Molcer, 142 vestibular-induced
Lead Monitoring vestibular ototoxicity, 161168 fixation of, 26
ABR, 36 Motion Nystatin, 136
ototoxicity of, 36 physiology of, 23f for otomycosis, 137t
Left posterior canal (LPC), 162f MTBA, 176177 ototoxicity of, 112
Legal research, 202, 208 Mycobacterium avium, 102
Leukopenia Mycobacterium tuberculosis O
with cisplatin, 61 streptomycin for, 84 OAE. See Otoacoustic emissions (OAE)
Linear acceleration receptor, 22f Mycoplasma, 130 Ofloxacin
Lipoic acid, 176 middle ear effects of, 108
L-Met, 176, 177 N tympanic membrane, 110f
L-N-acetylcysteine (L-NAC), 177 Nausea OHC. See Outer hair cells (OHC)
Loop diuretics, 215 with carboplatin, 67 OKN, 166
ototoxicity of, 4246 with cisplatin, 61 Optokinetic nystagmus (OKN), 166
LPC, 162f Neck cancer Organ or Corti, 57, 6f, 7f, 11, 14
Lymphoma cisplatin for, 5455 neurotransmitters within, 9t
cisplatin for, 56 Necrosis, 9495, 170 receptors within, 9t
Nedaplatin, 6768 Oscillopsia test, 25t, 26
M clinical pharmacology, 67 Oscillopsia testing, 167
Macrolides, 101104, 215 clinical status of, 62t Osseous labyrinth, 1
Macular stimulation, 23f clinical use of, 67 Osseous spiral lamina, 11
Malaria indications for, 67 Otitis media
Plasmodium falciparum, 33 mechanisms of action, 67 acute, 121
MAPK toxicity of, 67 chronic suppurative, 121
cell death signaling pathway, 173175 nonotological, 67 Otoacoustic emissions (OAE), 10, 154155
M-cresyl acetate solution (Cresylate), 135 Negligence mechanics of, 1415
for otomycosis, 137t patient grounds for, 205206 salicylates, 3031
Medial olivocochlear bundles, 6, 10 Neisseria meningitidis, 130 Otomize, 142
Medical negligence, 200202 Neomycin Otomycosis, 134
evidence supporting action of, 208 availability of, 83t acetic acid for, 137t
Medicolegal action cochlear ototoxicity, 114115 alcohol for, 137t
harm leading to, 209 ototoxicity of, 116 boric acid for, 137t
Membranous labyrinth, 1, 3f Neomycin/polymyxin B drops, 130 clotrimazole for, 137t
Menieres disease Netilmicin debridement, 134
defined, 184 availability of, 83t gentian violet for, 137t
demographics of, 184 Neural integrator, 22 miconazole for, 137t
Garasone ear drops, 125f Neuromuscular blockade nystatin for, 137t
vestibular ablation, 124 aminoglycosides, 86 tolnaftate for, 137t
intratympanic gentamicin, 191195 Neurotrophin family, 175 Otoprotective therapies, 170179
history of, 191 Neurotrophin type-3, 175 Ototopical agents
mechanism of, 185 Neurotrophin type 4/5, 175 middle ear effects of, 107112
natural history of, 184185 NMDA receptors, 9t Ototopical antibiotics
pathophysiology of, 184 Node of Ranvier, 8 American Academy of Otolaryngology
systemic treatment of, 184189 Noise Head and Neck Surgery Consensus
complications of, 186188 aminoglycosides ototoxicity, 154 Panel Recommendations, 213
indications for, 185 cisplatin ototoxicity, 154 Ototoxic agents, 215
review of, 185186 Nonmelanotropic adrenocorticotropic Ototoxicity
topical gentamicin, 124 hormone (ACTH)/MSH, 178 audiologic monitoring for, 153157
vestibulotoxicity, 165 Non-NMDA glutamate receptors, 9t clinical topical, 121122
Mercury, 3536 Non-small cell lung cancer defined, 9394
deafness, 3536 cisplatin for, 56 medicolegal aspects of, 198206
hearing loss, 3536 Nonsteroidal anti-inflammatory drugs monitoring schedules, 156
Mesna, 176 (NSAID), 215 pediatric monitoring, 155156
Metabotropic receptors, 9t ototoxicity of, 33 testing for clinical trials, 156
 Index 219

Outer hair cells (OHC), 1, 6, 6f, 11 proprietary agents containing, 128129 historical overview, 28
stereocilia, 57, 12 recommendations for safe use, 130 norepinephrine, 31
Ovarian cancer therapeutic use, 128 ototoxicity of, 2832
cisplatin for, 5254, 52t toxicity of, 129 biochemistry of, 3132
paclitaxel-carboplatin vs. paclitaxel- Polysorbate, 137 manifestations of, 3233
cisplatin, 53t Position-vestibular-pause (PVP), 161 mechanisms of, 29
Oxaliplatin, 68 Post-head-shake nystagmus, 167 pathology of, 2930
chemistry of, 68 Post-tympanostomy tube otorrhea physiology of, 3031
clinical pharmacology of, 68 (PTTO), 121 pharmacokinetics, 2829
clinical status of, 62t Potassium sorbate, 137 prostaglandin, 31
clinical use of, 68 Preparatory solutions Salviae miltiorrhizae, 173
indications for, 68 topical toxicity, 204, 209210 Satraplatin, 68
mechanism of action, 68 Profound hearing loss clinical status of, 62t
toxicity of, 68 preventable, 204205, 210 Savlon, 141
Ozolinone Propylene glycol, 135, 136, 142 Scala media, 2, 2f
ototoxicity of, 46 tympanic membrane, 111f fluid
Prostaglandin composition of, 2t
P salicylates, 31 Scala tympani, 2, 2f, 14
Paclitaxel-carboplatin Proteus, 130 fluid
vs. paclitaxel-cisplatin Pseudomonas, 83, 84 composition of, 2t
for ovarian cancer, 53t Pseudomonas aeruginosa, 121, 130 Scala vestibuli, 2f, 14
Paromomycin PTTO, 121 fluid
availability of, 83t Pure tone air-conduction thresholds, 153 composition of, 2t
Patient harm Purkinjes cells, 22 Scarpas ganglion, 21
medicolegal action, 203204 PVP, 161 SCC, 21
Pediatric ototoxicity monitoring, 155156 P2X2, 9t Schwalbes nucleus, 22
Penicillin G Semicircular canals (SCC), 21
middle ear effects of, 107111 Q Sensorineural hearing loss (SNHL)
Peptides, 178 Quaternary ammonium compounds, with deferoxamine, 76, 77t
Perilymph, 3 141142 ethacrynic acid, 42
electrolytes Quinine Sensory cells, 1
ethacrynic acid, 43 hearing loss, 34 Skin preparation, 142
Peripheral vestibular system, 2122 ototoxicity of, 3334 Small cell lung cancer
anatomic organization of, 21f biochemistry of, 34 cisplatin for, 5556
Physician follow-up historical overview of, 3334 SNHL
vs. patient responsibility, 209 manifestations of, 34 with deferoxamine, 76, 77t
Physician responsibility mechanisms of, 3435 ethacrynic acid, 42
patients case for, 204 morphology of, 34 SOAE, 14
Pifithrin, 178 physiology of, 34 SOD, 173
Pillar cells, 6, 7 pharmacokinetics, 34 Sodium salicylate, 28, 177
Piretanide Quisqualic acid, 9t Sodium thiosulfate, 69, 176177
ototoxicity of, 46 R Solvents, 136
Plasma Rickettsia, 130 SP, 12, 13
fluid Right superior canal (RSC), 162f Spectinomycin
composition of, 2t Rotating chair tests availability of, 83t
Plasmodium falciparum malaria, 33 advantages and limitations of, 165t Speech discrimination, 153
Platinum compounds Rotational testing, 166 Spinal vestibular nucleus, 22
chemotherapeutic discovery Round window membrane Spin-trapping agents, 171172
history of, 6061 topical gentamicin, 122 Spiral ligament, 5
clinical status of, 62t Round window membrane (RWM), 14 Spiral modiolar artery, 4
in clinical trial, 68 antifungals, 135 Spiral modiolar vein, 4
otoprotection, 69 cross section, 118f Spontaneous otoacoustic emissions
otoprotection research, 179 Round window niche (SOAE), 14
ototoxicity of, 6069 cross section, 118f Squamous cell head and neck cancer
toxicity profiles of, 63t RSC, 162f cisplatin for, 5455
tumor resistance, 6869 RWM, 14 Standards of care, 198200
Polyenes, 136 antifungals, 135 vs. community standard of care, 199200
Polymyxin B, 116 cross section, 118f defined, 199
animal studies, 129 Steroidal anti-inflammatory agents,
Polymyxin E, 116 S 108109
Polymyxins, 128130 Salicin, 28 Streptococcus pneumoniae, 130
animal studies, 129130 Salicylates, 173 Streptomyces, 82
historical development of, 128 arachidonic acid metabolism, 31 Streptomycin
mechanism of action, 128 hearing loss, 29, 32 availability of, 83t
220 Index
cochlear ototoxicity, 114115
for Mycobacterium tuberculosis, 84
Streptomycin-induced vestibulotoxicity,
185
Streptomycin sulfate
for Menieres disease, 185186
Strial marginal cells, 11
Stria vascularis, 5f, 11
Sulfacetamide
middle ear effects, 108
Summating potential (SP), 12, 13
Superoxide dismutase (SOD), 173
Surgeon warning, 205
Surgical disinfectants, 140143
topical toxicity, 204, 209210
Systemic gentamicin ototoxicity
case study, 200
information provided to lawyers,
207208
T Topical preparations
Tanshinone, 173
Tectorial membrane, 5, 12
Testicular cancer
bleomycin for, 51t
chemotherapy of, 51t
cisplatin for, 5152, 51t
etoposide for, 51t
metastatic seminomas, 52
Tetrahymena, 145, 146
Thiol compounds, 176177
Thrombocytopenia
with carboplatin, 6667
with cisplatin, 61
with nedaplatin, 67
Tinnitus
monitoring for, 156157
quinine, 34
salicylates, 3233
TOAE, 14, 155
Tobradex
ototoxicity of, 116
Tobramycin
availability of, 83t
ototoxicity of, 116
Tolnaftate, 137
for otomycosis, 137t
ototoxicity of, 112
Topical aminoglycoside
experimental studies, 122123
ototoxicity of
individual variability, 125
vestibulotoxicity
clinical studies, 123125
Topical aminoglycosides
cochlear ototoxicity, 114119
drop ototoxicity, 208209
ototoxicity of
risk factors for, 209
round window membrane, 122
vestibular toxicity of, 121126
Topical antibiotics, 215
Topical antifungals, 134138
application of, 137
for otomycosis, 137t
Topical gentamicin
drop ototoxicity, 203
Menieres disease, 124
ototoxicity of, 208209
clinical indications, 208
round window membrane, 122
vestibular ablation
Menieres disease, 124125
vestibular ototoxicity, 123
ototoxicity of, 121122
solvents used in, 109110
Torsemide
ototoxicity of, 46
Transforming growth factor-alpha,
175176
Transient evoked otoacoustic emissions
(TOAE), 14, 155
Tri-Adcortyl, 142
Trimethoprim-sulfacetamide-polymyxin B
(TSP)
human studies, 130
TSP
human studies, 130
Tunnel of Corti, 7
Tympanic membrane
cholesteatoma, 112f
ofloxacin, 110f
propylene glycol, 111f
sulfacetamide, 108f
U Vinorelbine
Utriculoendolymphatic valve of Bast, 3
V bilateral peripheral, 25
Vancomycin, 215
VEPT
chlorhexidine, 140
Vertigo
control of, 192t
quinine, 34
Vestibular dysfunction
clinical manifestations of, 2425
Vestibular evoked potentials (VEPT)
chlorhexidine, 140
Vestibular function
clinical tests of, 2526, 25t
Vestibular loss
unilateral
neurophysiological basis for
compensation, 162163
unilateral peripheral, 2425
Vestibular monitoring
anatomical basis for, 161162
pathophysiologic basis for, 163
Vestibular nerve, 22
Vestibular neurons, 162f
Vestibular ototoxicity
monitoring, 161168
Vestibular system
anatomy of, 2123
applied physiology, 23
peripheral, 2122
anatomic organization of, 21f
physiology of, 2027
schematic representation of, 20f
Vestibular tests
advantages and limitations of, 165t
bedside clinical, 167
Vestibulo-ocular reflex (VOR), 20
gain, 24
horizontal
wiring of, 162f
laboratory evaluation of, 165
neural basis of, 161162
suppression test, 25t, 26
Vestibulotoxicity
monitoring for, 156157, 164165
streptomycin-induced, 185
Vinblastine
ototoxicity of, 79
Vinca alkaloids
ototoxicity of, 7879
Vincristine
ototoxicity of, 7879
ototoxicity of, 79
Visual loss
Vitamin E (alpha-tocopherol), 177
VOR. See Vestibulo-ocular reflex (VOR)
VoSol, 142
W
Willow bark, 28
Word recognition, 153
Word recognition testing, 154