Fourth-Generation Fluoroquinolone

Penetration into the Aqueous

Humor in Humans
J. P. McCulley, MD, FACS, D. Caudle, MS, J. D. Aronowicz, MD, W. E. Shine, PhD
Purpose: To compare the penetration and levels of the fourth-generation fluoroquinolones moxifloxacin
0.5% ophthalmic solution and gatifloxacin 0.3% solution in the aqueous humor (AH) in humans after topical
application with published levels of other available fluoroquinolones under similar dosing conditions.
Design: Prospective, randomized, double-masked clinical trial.
Participants: Forty-six patients undergoing cataract extraction.
Methods: Patients scheduled for routine phacoemulsification and intraocular lens implantation were provided either moxifloxacin 0.5% ophthalmic solution (n 22) or gatifloxacin 0.3% ophthalmic solution (n 24) to
use 4 times daily the day before surgery plus 1 drop 1 hour before the surgical entry into the anterior chamber
on the day of surgery. This regimen simulated a realistic postoperative dosing schedule. Aqueous humor samples
were obtained and analyzed by high-pressure liquid chromatography. Aqueous humor fluoroquinolone concentrations were calculated by peak comparison with a known concentration peak for ciprofloxacin that was used
as an internal standard. These values were compared with published concentrations of other available fluoroquinolones under similar dosing conditions.
Results: The mean age of the moxifloxacin 0.5% group was 67.89.7 years, whereas that of the gatifloxacin
0.3% group was 69.98.7 years. The moxifloxacin AH concentration was 1.861.06 g/ml, and that of
gatifloxacin was 0.940.72 g/ml. This 2-fold difference was statistically significant (P 0.001).
Conclusions: Aqueous humor antibiotic concentrations achieved at the time of cataract surgery after topical
application can serve as an effective surrogate for what can be achieved with typical postoperative topical dosing
(e.g., 4 times daily). Both fourth-generation fluoroquinolones achieved a greater AH concentration after 4 times
daily dosing relative to prior-generation fluoroquinolones. Moxifloxacin 0.5% ophthalmic solution achieved a
2-fold higher aqueous humor concentration than gatifloxacin 0.3% ophthalmic solution. The superior penetration
of moxifloxacin into the AH may be attributed partially to its high degree of lipophilicity, greater solubility at neutral
pH, and higher concentration in the commercial formulation. The enhanced penetration of moxifloxacin 0.5%
ophthalmic solution may provide better protection against ocular infections. Ophthalmology 2006;113:955959
2006 by the American Academy of Ophthalmology.

Due to the recent emergence of resistance ocular pathogens,

a growing need for new ophthalmic antibiotics has arisen.1
The optimal molecule should possess the characteristics of
better gram-positive coverage (especially against streptoOriginally received: June 14, 2005.
Accepted: January 8, 2006.
Manuscript no. 2005-530.
From the Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas.
Presented at: American Academy of Ophthalmology meeting, October
2004, New Orleans, Louisiana, and Association for Research in Vision and
Ophthalmology meeting, May 2005, Fort Lauderdale, Florida.
The study was supported by a grant from Alcon Laboratories, Inc., Fort
Worth, Texas, and an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York.
Dr McCulley serves as a consultant for Alcon Laboratories, Inc. Ms
Caudle, Dr Aronowicz, and Dr Shine have no financial interest in the
products discussed in the article.
Correspondence to James P. McCulley, MD, Department of Ophthalmology, University of Texas Southwestern Medical School at Dallas, 5323
Harry Hines Boulevard, Dallas, TX 75390-9057. E-mail: James.McCulley@
UTSouthwestern.edu.
2006 by the American Academy of Ophthalmology
Published by Elsevier Inc.

cocci) than previous agents; efficacy against resistant organisms, such as resistant Staphylococci; efficacy against atypical mycobacteria; and better penetration into the aqueous
humor (AH) with dosing 4 times daily (in general, priorgeneration topical fluoroquinolones do not penetrate into
aqueous at therapeutic levels), and treated patients should
demonstrate a lower tendency to develop resistant organisms.
Two fluoroquinolone antibiotics, moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution, were developed to
address increasing resistance concerns. Both medications are
approved for the treatment of bacterial conjunctivitis.
There are several considerations when assessing a postoperative antibiotic ocular surgical prophylaxis model. Human subjects with healthy uninflamed ocular surfaces and
eyes are preferred. The dosing regimen for the patient
should reflect a realistic topical frequency, with no routine
systemic dosing. Concentrations at the beginning of surgery
may provide a surrogate to assess achievable postoperative
concentrations, provided that the dosing regimen is relevant
to anticipated postoperative dosing.
ISSN 0161-6420/06/$see front matter
doi:10.1016/j.ophtha.2006.01.061

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Ophthalmology Volume 113, Number 6, June 2006

The aim of this study was to compare the penetration of
moxifloxacin 0.5% ophthalmic solution and gatifloxacin
0.3% ophthalmic solution into the AH in humans after 4
times daily topical application (the day before surgery plus
1 drop 1 hour before surgery) with published levels with
other fluoroquinolones using similar dosing protocols. The
goal of this regimen was to simulate a real-life postoperative
dosing schedule.

Patients and Methods

Preoperative Fluoroquinolone Dosing
This was a prospective, randomized, double-masked clinical trial.
Institutional review board approval was obtained before initiation
of the study. Moxifloxacin 0.5% ophthalmic solution or gatifloxacin 0.3% ophthalmic solution was administered 1 drop 4 times
daily to the appropriate eye 1 day before planned routine phacoemulsification in otherwise normal human eyes. The patients were
dosed 1 drop of the appropriate antibiotic to the randomized eye 1
hour before obtaining an aqueous sample on the day of surgery.
Aqueous samples were obtained without contamination from the
ocular surface. The samples were frozen immediately for future
high-pressure liquid chromatography analysis.

Quantitative Fluoroquinolone Procedure

One microliter of 75-mol/l ciprofloxacin was added as an internal
standard to a 20-l aliquot of the patient sample, and high-pressure
liquid chromatography was performed. The Waters 515 pump was
equipped with a U6K injector, Atlantis dC18 54.6150-mm
column, and a 2475 multiwavelength fluorescence detector that
operated at excitation and emission wavelengths of 293 nm and
500 nm, respectively (Waters Corp., Milford, MA). The column
temperature was set at 30 C. The high-pressure liquid chromatography mobile phase was comprised of 43% aqueous acetonitrile, 10-mmol/l sodium dodecyl sulfate, 10-mmol/l tetrabutylammonium acetate, and 25-mmol/l citric acid (adjusted to pH 3.5).2 The
concentration of the patient fluoroquinolone was calculated from the
known amount of the ciprofloxacin standard and the relative area of
the 2 chromatographic peaks. This procedure was repeated as many
times as permitted by the original volume of the patient sample.

Figure 1. Two representative chromatograms showing the internal standard, ciprofloxacin, and gatifloxacin and moxifloxacin peaks. The 2 chromatograms are normalized to the ciprofloxacin peak.

67.89.7 years, whereas that of the gatifloxacin 0.3% group was

69.98.7 years. There was not a significant difference between the
2 groups based on age.
Two representative chromatograms of moxifloxacin and gatifloxacin with a ciprofloxacin internal standard are shown in Figure 1. Mean
aqueous concentrations ( standard deviation) were 1.861.06
g/ml (n 22) for moxifloxacin 0.5% ophthalmic solution and
0.940.72 g/ml (n 24) for gatifloxacin 0.3% ophthalmic solution.
This 2-fold greater penetration into the AH for moxifloxacin was
statistically significant (P 0.001). The penetration values from
the current study relative to published minimum inhibitory concentration (MIC) values1 for moxifloxacin and gatifloxacin are
shown in Figures 2 and 3.

Results
Table 1 shows the patient demographic characteristics from this
study. The mean age of the moxifloxacin 0.5% group was
Table 1. Patient Demographic Characteristics of Groups
Receiving Moxifloxacin 0.5% Ophthalmic Solution and
Gatifloxacin 0.3% Ophthalmic Solution
Characteristic

Moxifloxacin Group

Gatifloxacin Group

Age (yrs)
Gender
Male
Female
Ethnicity
Caucasian
African-American
Hispanic

67.89.7

69.98.7

10
12

7
17

20
1
1

21
3
0

956

Discussion
The increasing number of ophthalmic surgical procedures
and the increase in resistance to older fluoroquinolones have
created a need for more effective therapeutic agents for the
prevention and treatment of ocular infections. It is estimated
that nearly 3 million cataract and 1.3 million laser-based
refractive surgical procedures were performed in 2004 in
the United States.4 Recent reports suggest that the incidence
of bacterial infections after cataract and refractive surgery is
rising.57 The increasing risk of surgical complications such
as postoperative endophthalmitis and keratitis accentuates
the need for potent new antibiotics for the prevention and
treatment of these potentially sight-threatening ocular infections. Recent guidelines from the Medicare National Surgi-

McCulley et al Fourth-Generation Fluoroquinolone Penetration into the Aqueous

Gatifloxacin

3.5

Gaps in MPC (~10 x MIC) coverage for susceptible

organisims
2

0.94 g/ml

0.09

0.11

0.38

0.22

FQ

S.
a

ur
eu

ci
sp
.

ia
on

En
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um

cal Infection Prevention Project point out the benefits of

preoperative and postoperative antibiotic therapy.8
In recent years, surgeons have shown a greater preference for clear corneal incisions over scleral tunnel procedures.9 There are reports of a rise in postoperative endophthalmitis cases after clear corneal incisions.5,7,10 This rise in
endophthalmitis rates may not be related to the placement of
the incision but may be due to the fact that the wound is not
always watertight. The surgeon may attempt to stop the
leakage using stromal hydration. However, this assumes
that the intraocular pressure (IOP) will be maintained immediately after surgery and that the hydrated wound will not
be dehydrated rapidly by the corneal endothelium.11 In fact,
the IOP after surgery may drop to below 5 mmHg.12 Stromal hydration may last for only a few minutes, and then the
seal of the wound is not maintained. McDonnell et al
conducted a study using optical coherence tomography to
examine the effects of the clear corneal cataract incision
technique on corneal wound leakage.11 These investigators
found that the wound tended to open and close with changes
in IOP. They concluded that transient reductions in IOP
introduce the potential for fluid to flow across the cornea
and to be imbibed into the AH. This provides an opportunity
for contamination of the AH. In a retrospective study that
reported a very low endophthalmitis rate (0.0084% from
July 1995 to July 2002) at our institution, it was hypothesized that contributing factors were preoperative antisepsis,
preoperative and postoperative topical antibiotic prophylaxis, maintenance of a sterile surgical environment, and
insurance at the conclusion of surgery of a watertight
wound, without stromal hydration.13
The risk of sight-threatening postoperative infections
underscores the need for effective prophylactic antibiotics.
The ideal perioperative antibiotic should possess several
important therapeutic attributes.14 The agent should have a
broad spectrum of antibacterial activity. High potency

St
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p.
pn
e

S.

au

re

sp
FQ
R

co
cc
i
te
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En

Figure 2. Moxifloxacin gram-positive minimum inhibitory concentrations (MICs) in relation to the mean moxifloxacin aqueous humor concentration achieved after 4-times-daily dosing the day before surgery plus 1
dose 1 hour before surgery.1,30,31 FQR fluoroquinolone resistant; FQS
fluoroquinolone susceptible; MPC mutant prevention concentration; S.
Staphylococcus; Strep. Streptococcus.

S.
au
re
us

us

0.05

ia
e
on
um
ne

St
re
p.
p

S.
au
re
us

is

FQ
S

rm
id
pi
de
S.
e
FQ
S

0.19

0.09

0.06

0.05

FQ
S

rm
id
is

1.75

pi
de

1.86 g/ml

g/ml

Obtained MPC (~10 x MIC) for all susceptible organisms

against gram-positive organisms is especially beneficial because these pathogens are estimated to contribute to up to
94% of endophthalmitis cases.15 Favorable penetration
characteristics are needed to deliver the antibiotic to the
target ocular tissues. Finally, high degrees of safety and
tolerability of the medication are key factors that contribute
to the successful healing of the cornea after surgery. Moxifloxacin 0.5% ophthalmic solution has been shown in a
variety of in vivo and human studies to possess these
beneficial characteristics.1,3,16 23
The current study results compare favorably with other
penetration studies that utilized a 4-times-daily dosing,
pulse dosing, or a combination of the 2 dosing strategies.
The dosing frequency utilized in the current study is relevant to both cataract and refractive surgical procedures. A
recent clinical study by Kim et al showed AH concentrations
of 1.80 g/ml for moxifloxacin and 0.48 g/ml for gatifloxacin
after 1 drop of antibiotic every 10 minutes for 4 doses beginning 1 hour before cataract surgery.24 This pulse dosing regimen produced AH moxifloxacin concentrations that were comparable to our results of 1.86 g/ml (using 4-times-daily
administration the day before surgery and 1 additional dose 1
hour before surgery). Katz et al reported AH moxifloxacin
concentrations of 1.74 g/ml with 4-times-daily dosing the day
before surgery plus 1 drop every 15 minutes for 4 doses before
surgery.25 Solomon et al showed a 2-fold higher AH concentration for moxifloxacin over gatifloxacin1.31 g/ml and
0.63 g/ml, respectivelywith 4-times-daily dosing for 3
days before surgery and 1 dose every 15 minutes for 3 doses 1
hour before surgery.26 These results suggest rapid penetration
of moxifloxacin to the AH and ocular tissues.
Penetration studies with earlier-generation fluoroquinolones have often included pulse dosing after several days of
4-times-daily dosing. Price et al, for example, utilized a
3-day 4-times-daily regimen augmented by 4 doses in the
hour before sampling.27 A concentration of 1.14 g/ml was

S.
e

g/ml

Moxifloxacin

FQ
S

Figure 3. Gatifloxacin gram-positive minimum inhibitory concentrations

(MICs) in relation to the mean gatifloxacin aqueous humor concentration
achieved after 4-times-daily dosing the day before surgery plus 1 dose 1
hour before surgery.1,30,31 FQR fluoroquinolone resistant; FQS fluoroquinolone susceptible; MPC mutant prevention concentration; S.
Staphylococcus; Strep. Streptococcus.

957

Ophthalmology Volume 113, Number 6, June 2006

achieved in the AH with this pulse dosing protocol. Solomon et al reported 0.15 g/ml of ciprofloxacin in the
aqueous of patients who had been dosed 4 times daily for 3
days, followed by 1 dose every 15 minutes for 3 doses 1
hour before surgery.26 Bucci dosed patients 4 times daily for
2 days before surgery (without pulse dosing on the day of
surgery) and reported concentrations of 0.28 and 0.07 g/ml
for levofloxacin 0.5% and ciprofloxacin 0.3%, respectively.28 Comparisons between our study results and those from
the published literature have some limitations because they
were conducted at different times under varying conditions.
Clinical studies using either 4-times-daily dosing or a combination of 4-times-daily and pulse dosing with ciprofloxacin, ofloxacin, and levofloxacin produced AH antibiotic
concentrations up to 27-fold lower than those observed with
moxifloxacin 0.5% ophthalmic solution in our study. Taken
together, these results demonstrate that moxifloxacin has
greater AH penetration than the other fluoroquinolone antibiotics.
Studies have been conducted to examine the reasons for the
enhanced penetration properties of moxifloxacin. Rusinko et al
reported that moxifloxacin was the most soluble of the fluoroquinolones studied (ciprofloxacin, gatifloxacin, levofloxacin,
lomefloxacin, moxifloxacin, norfloxacin, and ofloxacin; Invest
Ophthalmol Vis Sci 35[suppl]:4907, 2004). If other factors are
essentially equivalent, then a higher aqueous solubility should
yield a higher bioconcentration in the tear film. Moxifloxacin
also was reported to be more lipophilic than these other
fluoroquinolones. A correlation between corneal penetration
and fluoroquinolone lipophilicity has been established.29
Owen et al showed that the apparent corneal penetration
coefficient of moxifloxacin was 3.6-fold greater and its
appearance on the endothelial side 2 times faster than that of
gatifloxacin (Invest Ophthalmol Vis Sci 45:abstract 4910,
2004). Although the drug penetration was greater, the corneal permeability to carboxyfluoroscein was 1.6-fold lower
after exposure to moxifloxacin 0.5% ophthalmic solution
compared with gatifloxacin 0.3% ophthalmic solution. This
demonstrated that moxifloxacin maintained better corneal
integrity. These results suggest that the superior corneal
penetration of moxifloxacin is due to the inherent characteristics of the moxifloxacin molecule, and not to changes to
the corneal epithelial intercellular (gap) junctions.
An important consideration regarding the penetration of
a topical antibiotic is ability to achieve a concentration well
above the MIC for a given microorganism. The mutant
prevention concentration (MPC) is generally maximum concentration of the drug/MIC 8 to 10.30 The MPC can also be
defined as the antibiotic concentration threshold that would
require 2 simultaneous mutations.31 When comparing the AH
concentrations achieved in the current study with MPCs derived from the MICs from the Mather et al study, moxifloxacin
achieved MPCs for fluoroquinolone-susceptible Staphylococcus aureus, fluoroquinolone-susceptible coagulase-negative
Staphylococcus, Streptococcus pneumoniae, Streptococcus
veridens, Enterococci species, and Bacillus species (Fig 3). Of
these organisms, gatifloxacin did not attain MPCs for S. pneumoniae, S. veridens, Enterococci species, or Bacillus species or the MIC for fluoroquinolone-resistant S. aureus.1

958

Aqueous humor antibiotic concentrations achieved at the

time of cataract surgery after topical application were
shown to be effective surrogates for what can be achieved
with typical postoperative topical dosing (e.g., 4 times
daily). When compared with published reports, the fourthgeneration fluoroquinolones achieved greater AH concentrations after dosing than prior-generation fluoroquinolones. In
addition, moxifloxacin 0.5% ophthalmic solution achieved a
2-fold higher AH concentration than gatifloxacin 0.3% ophthalmic solution. Aqueous humor concentrations for moxifloxacin 0.5% ophthalmic solution were substantially above
those needed for common pathogens with clinically relevant
dosing (i.e., 4 times daily).32 The superior and clinically
significant penetration of moxifloxacin into the AH may be
attributed to its high degree of lipophilicity, greater solubility at neutral pH, and higher concentration in the commercial formulation. This enhanced penetration provides AH
moxifloxacin concentrations at or above the MPCs for a
variety of pathogenic microorganisms and may provide
greater protection against ocular infection. The results of the
current study as well as other published studies provide
support for the utility of moxifloxacin 0.5% ophthalmic
solution for use in surgical prophylaxis.

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