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