EDITORIAL
The Challenge of Controlling Infectious Keratitis
CATHERINE E. OLDENBURG AND THOMAS M. LIETMAN
B
LINDNESS OWING TO INFECTIOUS DISEASES HAS
been dramatically reduced in the past few decades.
Trachoma, leprosy, and onchocerciasis were once
leading causes of visual loss but are now considered
controlled over most of the world. Corneal ulcers stubbornly
remain as the fourth-leading causes of blindness.1 Although
population-based incidence studies of corneal ulceration are
few and far between, those available suggest that the major-
ity of this burden is in the developing world. The incidence
of corneal ulcers has been estimated at 11–27 per 100 000 in
the United States2,3 and an order of magnitude higher, at
113–799 per 100 000, in South Asia.4–6 Tropical
institutions are noting an increase in culture-proven fungal
ulcers, which has in part been attributed to global warming.7
Even with standard-of-care treatment, outcomes can be
poor.8 Treatment is often not guided by microbiology
studies, and outcomes are worse if the chosen antimicrobial
is not active against the causative organism.9 Any interven-
tion that dramatically reduced visual loss from corneal ulcers
would be a major ophthalmic breakthrough.
In this issue of the Journal, Isenberg and associates report
findings from a randomized controlled trial comparing
topical povidone-iodine with the topical antibiotics
neomycin–polymyxin B–gramicidin in the Philippines,
and separately to ciprofloxacin in India.10 They find no
significant difference in time to cure or time to recovery
between povidone-iodine and antibiotics in either setting.
Perhaps more importantly, the confidence intervals of their
efficacy estimates suggest that if there were a difference
between treatments, it would likely be small.
One potential advantage to povidone-iodine is that
resistance is less documented than to our mainstay
antibiotics, and arguably may not develop. Antimicrobial
resistance is of increasing concern owing to increased anti-
biotic use in both humans and animals.11 Ulcers fare worse
when organisms are less susceptible to antibiotic or anti-
fungal therapy, although the correlation is not perfect.12
See Accompanying Article on page 244.
Accepted for publication Jan 17, 2017.
From the Francis I. Proctor Foundation for Research in Ophthalmology
and the Department of Ophthalmology, University of California, San
Francisco School of Medicine, San Francisco, California.
Inquiries to Thomas M. Lietman, Department of Ophthalmology,
University of California, San Francisco School of Medicine, 513
Parnassus Ave., San Francisco, CA 94143-0412; e-mail: tom.lietman@
ucsf.edu
0002-9394/$36.00 © 2017 ELSEVIER INC. ALL
http://dx.doi.org/10.1016/j.ajo.2017.01.011
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Ulcer studies are consistent with a 90-60 rule, where 90%
of susceptible organisms respond well, whereas only 60%
of resistant organisms do.13 Whether povidone-iodine
would substantially improve clinical outcomes in isolates
resistant to other agents is unknown.
Another advantage of povidone-iodine may be that it
has an effect against multiple pathogens, at least in vitro.
Based on clinical signs alone, cornea specialists have diffi-
culty differentiating bacteria from fungus as an etiology,
let alone gram-positive from gram-negative bacteria.14
Broad-spectrum antimicrobials such as povidone-iodine
could be useful in facilities without adequate microbiolog-
ical laboratories. Povidone-iodine has in vitro efficacy
against a variety of organisms, although in vivo efficacy
would have to be demonstrated.
Povidone-iodine does have some modest disadvantages.
Although povidone-iodine itself is inexpensive, it is not
widely available in dropper bottles. Commercial ocular anti-
biotics are becoming more and more common throughout
the developing world and are affordable to an increasing
portion of the population. Another theoretical disadvantage
is that povidone-iodine is thought not to penetrate cells.
Thus it may not be particularly effective against, for example,
the subgroup of Pseudomonas strains that are invasive.15
To show that a new antimicrobial is as effective as the
standard of care can be difficult. Equivalence or noninfer-
iority trials can suggest comparable efficacy, but they
require a noninferiority threshold to have been prespeci-
fied. Some ophthalmologists might not consider the
neomycin-polymyxin and ciprofloxacin used in this study
as optimal for bacterial keratitis. More convincing might
have been a comparison against a later-generation fluoro-
quinolone or a combination of fortified antibiotics. Though
a null finding may be owing to a lack of difference in the
agents tested, it may just reflect the lack of ability to find
a difference. The vast majority of randomized controlled
trials assessing treatment for microbial keratitis have found
no statistically significant difference. In fact, a recent
review was unable to find a trial that had ever found a
significant difference between antibiotics for bacterial
keratitis.16 This may be because the particular antimicro-
bial is not important, or it may be because commonly
used surrogate markers such as time to cure are not a partic-
ularly sensitive way to assess any difference.
A safe, inexpensive agent that is effective against a
broad range of pathogens without selecting for resistant
RIGHTS RESERVED. xv
strains could be an important contribution. Isenberg’s
study suggests a possible role for povidone-iodine in
settings where commercial antibiotics are not available,
or where the determination of etiologic agent is difficult.
Adjunctive use in combination with the current standard
of care might offer some benefit. Additional evidence may
be necessary before povidone-iodine could be recommen-
ded as a first-line therapy when other choices are avail-
able. Ideally, povidone-iodine would be compared
against the standard of care over much of the world,
which would be a fourth-generation fluoroquinolone or
fortified antibiotics. Demonstrated clinical efficacy against
a broad spectrum of bacterial pathogens would be helpful,
as would efficacy against nonbacterial etiologies that
might confuse the clinical diagnosis, such as fungi and
parasites.
FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: THE FOLLOWING AUTHORS HAVE NO
financial disclosures: Catherine E. Oldenburg and Thomas M. Lietman. All authors attest that they meet the current ICMJE criteria for authorship.
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APRIL 2017