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Advances in the Management of Keratomycosis and Acanthamoeba Keratitis

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Advances in the Management of Keratomycosis and Acanthamoeba Keratitis Cornea 19(5): 681–687, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Advances in the Management of Keratomycosis and Acanthamoeba Keratitis Denis M. O’Day, M.D., and W. Steven Head Purpose. In the late 1960s, the management of fungal keratitis was initiation of a focused research program on ophthalmic fungal a serious unresolved problem. Little was known of the epidemi- disease at Moorefield’s and elsewhere. ology of the disease, and there were no antifungal agents formu- At about the same time Dr. Herbert Kaufman, who was in lated for use in the eye. Methods. A thorough review of the lit- Gainesville, FL, and aware of the problem of fungal keratitis erature was done back to 1969 on clinical reports and experimental among orange pickers who had corneal injuries with vegetable studies for keratomycosis and Acanthamoeba keratitis. Results. contamination, had obtained some pimaricin, then used in the pro- Since 1969, through basic and clinical research, the epidemiology 3 of the disease worldwide is better understood. One new topical cessing of cheese, (Mycofarm Ltd., Delft, Holland). He and his antifungal agent, natamycin, with efficacy against filamentous associates investigated the antifungal properties of this agent as a fungi has been developed and the pharmacokinetics of topically possible substitute for the sulfonamides, then used for fungal in- applied antifungal drops have been explored. Progress has been fection, although of little real value. His studies and the work of slow but the prognosis for keratomycosis has immeasurably im- Dr. Dan Jones, Dr. Robert Sexton, and others at the Bascom- proved over the period. Acanthamoeba was first recognized as an Palmer Eye Institute in Miami led to the introduction of the only ocular pathogen in 1973 and was the cause of an epidemic in the new ophthalmic antifungal preparation in the past 30 years.4–7 1980s caused by contaminated contact lens, although other risk What each of these investigators realized at the time was the in- factors were also identified. At the onset of the epidemic, there was adequate state of knowledge of the pathogenicity of ophthalmic no known treatment, but as a result of intense research efforts, fungal infections and the lack of any effective therapy. within a few years a well-defined therapeutic approach had been developed that had a significant impact on the prognosis for this Before the discovery of the antifungal properties of pimaricin initially devastating infection. For both infections, the role of cor- (now known as natamycin), the only agent available for treatment ticosteroids for controlling the inflammation remains controver- with any hope of efficacy was amphotericin B. The prognosis for sial, but the place for keratoplasty is now well defined. Conclu- successful therapy was extremely bleak. There were of course, sions. Although there has been steady progress in the management several preparations including the polyene nystatin and griseoful- of both infections, continued research is the way to define more vin, but no efficacy studies had ever been performed (Table 1). effective medical and surgical therapy. Hampering any advance in an understanding of these infections Key Words: Acanthamoeba keratitis—Keratomycosis. was a virtually complete ignorance of the epidemiology. Not only was the prevalence of fungal infection unknown, but there was little understanding of the relative importance of different fungi, in terms of their virulence and geographic distribution. KERATOMYCOSIS The events in the late 1960s and early 1970s in the United The modern era for the treatment of keratomycosis began in Kingdom and the United States were critical to setting the stage for London, England, and in Gainesville, FL, in the late 1960s. In progress up to the present time. Serious work began on identifying 1967, an ophthalmologist in Singapore sent a patient who had important pathogens, thus bringing a sense of order to what ap- sustained a penetrating corneal injury to Professor Barry Jones at peared to be an impossibly chaotic field of possibilities. As a Moorefield’s Eye Hospital in London. The organism isolated was result, by the World Corneal Congress in 1987, the prevalence and Fusarium solani. Ultimately, the eye was lost, but only after pro- geographic distribution of fungal keratitis around the world could longed but futile therapeutic attack, incorporating both medical be mapped.8 This was an important step for it provided a practical and surgical treatment.1 In the course of managing the patient, research focus on the principal corneal pathogens. Professor Jones and his group conducted a wide-ranging review of The therapeutic issues that faced researchers in the late 1960s the then-current knowledge. Their efforts culminated in a “Sym- were substantial. Not only was there a pressing need to sort out the posium on Direct Fungal Infection of the Eye”2 in 1969 and the efficacy of existing preparations, more effective compounds also had to be found. Then there was the question of developing animal models for testing the efficacy of pharmacologic preparations and Submitted January 30, 2000. Revision received March 7, 2000. Ac- cepted March 11, 2000. treatment strategies, as well as investigating the pharmacokinetics From the Department of Ophthalmology and Visual Sciences, Vander- of existing and new therapeutic agents. bilt University Medical School, Nashville, Tennessee, U.S.A. Address correspondence and reprint requests to Dr. D.M. O’Day, Medi- cal Center East, Room 8032, Department of Ophthalmology and Visual Development of Antifungal Agents Sciences, Vanderbilt University Medical School, Nashville, TN 37232- The past 25 years have been witness to solid progress on all 8808, U.S.A. E-mail denis.m.o’[email protected] fronts. Although it is regrettably true that no one has been able to 681 682 D.M. O’DAY AND W.S. HEAD TABLE 1. Agents with potential for use as antifungal agents in A variety of other agents were evaluated for possible use as 115 keratomycosis: 1969 ophthalmic preparations. All were systemic fungal agents modified Polyene antibiotics for topical administration. Amphotericin B, a polyene, was the Non-Polyene antibiotics (cyclohexamide and griseofulvin) most well established. Flucytosine, which experienced a brief pe- Imidazoles riod of popularity, was rapidly discarded after its limited spectrum Diamidines 47 Dithiocarbamates and its capacity for rapidly induced resistance were recognized. Pyrimidines Amphotericin B was first used topically on an empirical basis as Hydroxyquinolones Mercurials a 0.5–1% preparation. Its spectrum of activity, pharmacokinetics, and toxicity was not well understood. As a result, it gained an ill-deserved reputation for toxicity and an apparent lack of effi- cacy. In 1976, Wood and associates,48 in a series of cases treated repeat the unique achievement of developing a new ophthalmic with a dilute preparation (0.15%), demonstrated efficacy with a antifungal preparation, advances in epidemiology, diagnosis, remarkable lack of toxicity. Studies in an animal model subse- therapeutics, and pharmacokinetics have enabled us to exploit quently confirmed the observations of Wood et al.,36,38,49 and by more effectively both new and existing systemic agents in the the early 1980s the ocular pharmacokinetics of topical amphoteri- treatment of keratomycosis. cin B were well established.19,20 At concentrations of 0.15%, it is An important step forward was the identification of Fusarium efficacious against susceptible organisms (mostly yeasts) and is solani as an important corneal pathogen in tropical climates, first virtually nontoxic. Topically, amphotericin B was shown to pen- in the United States and then in the rest of the world. This led etrate the corneal epithelium poorly, but in the nonepithelized eventually to the recognition that among the large number of fun- cornea, high levels can be obtained in the corneal stroma.19,20 gal species, Fusarium, Aspergillus, and Candida are the most Despite initial high hopes, isolated case reports of efficacy and prevalent and perhaps also the most pathogenic.1,2,5,7,9–14 experimental studies, the imidazoles (miconazole, econazole, clo- A second step was the development of a much more systematic trimazole, and ketoconazole) turned out to be a disappointing approach to the understanding of the pharmacology of topical an- group of agents. Difficulties with solubility, poor pharmacokinet- tifungal agents than had previously been possible.15–25 This was ics, and a limited spectrum of activity all combined to make these by the development of practical animal models of disease4,15,26–44 fungistatic agents inferior to amphotericin B.26,33,49 and by the increased reporting of a series of clinical In the 1980s, a second generation of azole compounds, the tria- cases.1,2,5,7,10,45 zoles, became available as systemic agents. Two of them, itracona- The efficacy of natamycin in the treatment of infections caused zole and fluconazole, showed considerable promise in the treat- by Fusarium, particularly F. solani, was convincingly demon- ment of systemic infections owing to Candida.50,51 As well, there strated in successive case series.1,5,7,9,10 Although randomized was evidence of therapeutic activity, particularly with itracona- controlled studies have not been performed because of the diffi- zole, against Aspergillus infections.51 culty in assembling sufficient cases in a reasonable period of time, Animal studies with systemically administered fluconazole
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