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Home , Fungal keratitis, Natamycin

Cornea 19(5): 681–687, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia

Advances in the Management of Keratomycosis and Acanthamoeba

Denis M. O’Day, M.D., and W. Steven Head

Purpose. In the late 1960s, the management of 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 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 . 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, , 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 , 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 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 . 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 . 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 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 . 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 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 for topical administration. Amphotericin B, a polyene, was the Non-Polyene antibiotics (cyclohexamide and ) most well established. , which experienced a brief pe- 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- , high levels can be obtained in the corneal stroma.19,20 gal species, Fusarium, Aspergillus, and 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 (, , clo- A second step was the development of a much more systematic trimazole, and ) 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 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 , 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 the clinical evidence is overwhelming, especially when results are demonstrated excellent uptake in all ocular tissues as well as a compared with historical experience. Although the evidence was prolonged half-life of the drug.22 Efficacy has now been demon- not quite so strong, the accumulated data also supported the effi- strated for topical fluconazole in both animal studies and human cacy of natamycin against other filamentous fungal infections in- cases.52–54 Contributing to the value of this agent is the markedly cluding Aspergillus, the other major pathogenic fungal organism reduced protein binding compared to the imidazoles.21 worldwide.5,10,15,16,18 Less is known about the pharmacokinetics of be- The story behind the introduction of natamycin is interesting. cause of difficulties in solublizing the drug. However, protein Dr. Kaufman and his associates, Dr. Ron Wood and Dr. Emanuel binding is higher than with fluconazole.21 Despite this, clinical and Newark, studied pimaricin as a 5% suspension in animal models of experimental studies with systemically administered itraconazole Candida and Aspergillus keratitis.4,6 Primaricin was virtually in- indicate a remarkably enhanced therapeutic index compared to the soluble, so that formulating a useful topical preparation was a imidazoles.50,51,55–62 formidable task. Fortunately, the 5% suspension eventually used was found to be relatively nontoxic and efficacious.6 Studies later Routes of Administration showed the pharmacokinetic profile of this preparation to be ex- Thirty years ago, it made intuitively good sense to use antifungal tremely poor. As it turned out, the 5% concentration (the maxi- agents topically in as high a concentration as possible. It also mum achievable) was necessary to provide sufficient bioactive seemed logical to assume that agents injected subconjunctivally drug in the cornea, because 97% of the drug that entered the cornea would diffuse into the cornea, and it was believed that agents given quickly became biologically inactivated, probably owing to tissue systemically would also achieve corneal levels. There were no data binding.20 However, levels exceeding 500 ␮m/mL were achieved to support any of these beliefs. in the aqueous humor after intense topical administration after As a result of studies begun in the 1970s, we now know that removal of the corneal epithelium. Penetration into the cornea is topical administration is most likely to provide the best opportu- virtually blocked in the presence of an intact epithelium.20 Despite nity for achieving therapeutic corneal levels for all agents currently the adverse pharmacokinetics, therapeutic concentrations can be in use. Subconjunctival injection of amphotericin, natamycin, and achieved against many fungi known to infect the cornea. These all the except itraconazole is not efficacious. For itracona- clinical and laboratory studies firmly established natamycin as the zole given subconjunctivally, there is some evidence from animal drug of choice for treatment of filamentous fungal infections in the work to support efficacy, but no human studies have been re- cornea.46 ported.25 A recent development has been renewed interest in the

Cornea, Vol. 19, No. 5, 2000 MANAGEMENT OF KERATOMYCOSIS AND ACANTHAMOEBA KERATITIS 683 role of systemically administered agents in corneal disease.40,63 cases in a reasonable period of time. Yet another obstacle is the Although there is no evidence of significant corneal uptake of almost total absence of interest in the problem by the pharmaceu- systemically administered amphotericin B or the imidazoles (na- tical industry, despite the prevalence of fungal keratitis in many tamycin cannot be given systemically), sustained high levels of developing countries. One hopeful sign of progress, however, is fluconazole have been measured in the rabbit cornea and other the increase in research expertise, both in the laboratory and in the ocular tissues after systemic administration.21,22 Levels of biologi- clinic in countries where keratomycosis is a serious clinical prob- cally active itraconazole in the cornea and aqueous are much lem. As we move into the next century, we can expect that mo- lower.21 However, clinical experience with systemic itraconazole lecular biology will begin to play a major research role. With that suggests that efficacious levels may also be achieved.64–66 Thus, will come radically new approaches to treatment. There is a sig- these drugs may have a role, particularly in keratomycosis with nificant opportunity now for clinicians and scientists in developing anterior , after therapeutic keratoplasty or when countries and the West to collaborate in this new research. the infection has progressed to involve the .

Role of ACANTHAMOEBA KERATITIS A major controversy over the years has been the role of corti- costeroids in keratomycosis. Despite optimistic reports of success The first cases of Acanthamoeba infection in the cornea were when a was administered, the data from animal ex- recognized in 1973; however, the infection remained an oddity until the early 1980s when an epidemic began in the United periments, demonstrating a clearly adverse effect in the absence of 78–81 effective antifungal therapy, have been unsettling.29,33,67,68 At the States. After similar cases were recognized in Great Britain and then in many other countries, it became apparent that Acan- very least, they suggest that corticosteroid use should be avoided 82–85 until a therapeutic effect of antifungal treatment is discernible. A thamoeba keratitis was a worldwide problem. In the initial similar deleterious action with nonsteroidal anti-inflammatory cases of the epidemic, the infection was found to have been pre- agents has not been reported. cipitated by the use of salt tablets for the preparation of saline solution used for sterilization, but eventually other risk factors were identified including trauma; exposure to contaminated Therapeutic Keratoplasty lake, sea, or spring water; and changes in the environment such as The poor results with pharmacologic treatments provoked inter- flooding and even .84,86–89 In addition, est in the efficacy of therapeutic keratoplasty as a means of deb- cases were identified with no obvious precipitating cause.81 Acan- ulking the fungal mass or actually achieving a cure. Analysis of the thamoebae are not normally pathogens of the eye. Data from ani- results in several large series during the past 25 years attest to the mal studies suggest that an epithelial defect is necessary for infec- 5,69–77 value of this approach. Some authors have recommended tion to occur.84,90,91 However, the ability to bind to the corneal 70,72 therapeutic keratoplasty as the initial approach. Before the epithelium may also be a virulence factor.91 Once established, development of effective antifungal agents, penetrating kerato- Acanthamoebae are capable of progressive invasion into the plasty, despite its risks, probably offered the best chance to save stroma.92 They may eventually reach the deeper layers of the the eye. However, the preferred approach now is to reserve the cornea and even the anterior chamber.93,94 procedure for those cases in which pharmacologic treatment is Acanthamoebae present a unique therapeutic challenge in that failing. Keys to a successful result appear to be the use of large- they exist in two forms, trophozoites and cysts. Under adverse diameter grafts to ensure complete excision of the fungal mass, conditions, the organism readily encysts. Cysts may remain viable avoidance of corticosteroid administration postoperatively, and for many years and are resistant to desiccation, temperature ex- continuing antifungal therapy. tremes, and chemical damage.84 When the epidemic first began in the early 1980s, there was no known effective treatment. More- Conclusion over, the cause of the infection was not understood and because the Although much more is now known about keratomycosis and its clinical features were not described, most of the early cases were treatment, progress over the past two decades has been painfully recognized only when the disease was well established, having slow. The only new additions to the list of usable antifungal agents been misdiagnosed as or other infective have been the , and many agents that were believed to processes and having been treated in a variety of noneffective have potential 30 years ago have been eliminated from consider- ways. ation (Table 2). Studying fungal infection in the laboratory is a Thus, these early cases, many with advanced disease, having formidable task for many reasons, not the least of which is the failed to respond to what was largely empirical treatment, under- difficulty of designing suitable animal models. Clinical studies are went therapeutic penetrating keratoplasty in an attempt to save the also a problem because of the difficulty in identifying sufficient eye. The surgery, in turn, was prone to a host of complications as well as a recurrence of infection in the graft.95,96 The outcome was poor, as Illingworth and Cook84 point out in their excellent review, TABLE 2. Agents in use for keratomycosis: 2000 with either no useful vision or enucleation a common endpoint. Amphotericin B 0.15% topical Now, a decade later, the prognosis for Acanthamoeba keratitis is Natamycin 5% topical considerably more optimistic.85 Much more is known about its Miconazole 1% topical Fluconazole 1% topical, 100–400 mg/d by mouth pathophysiology and clinical features. Although it remains a seri- Itraconazole 200–400 mg/d by mouth ous and vision-threatening disease, appropriate pharmacologic Ketoconazole 200–400 mg/d by mouth strategies have been developed and the role of therapeutic kerato- 1% topical plasty is better understood.

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Clinicians treating these early cases were confronted with three TABLE 4. Agents in use for Acanthamoeba keratitis: 2000 questions, the answers to which were completely unknown. There Propamidine isethionate 0.1% was no obvious antiamoebic agent available for use in the eye. The Chlorhexadine 0.02% inflammation accompanying the infection was likely to be particu- (neomycin sulfate, , gramicidin) larly severe, but the appropriateness of corticosteroid therapy was Polyhexamethylene biguanide (PHMB) 0.02% unknown. Therapeutic keratoplasty was clearly an option, but its timing and efficacy in an absence of an understanding of the patho- tended to follow a prolonged and often slow course in which physiology of the disease were problematic. organisms might stay confined to the epithelium for a period be- fore beginning invasion of the corneal stroma. In such cases, ag- Antiamoebic Therapy gressive topical therapy was more likely to be curative. Brooks et A variety of antibiotics and antifungal agents with potential al.111 also demonstrated the efficacy of simple epithelial debride- antiamoebic activity were tried with largely disappointing results ment and later studies suggest that the combination of debridement (Table 3, and it was not until Wright et al.97 reported the successful and topical treatment might also be curative in some cases. use of 0.1% propamidine isethionate that progress began to be 84,87,98 made in the search for effective pharmacologic treatment. Therapeutic Keratoplasty Propamidine, freely available in the United Kingdom, but not au- The role of therapeutic keratoplasty in the management of Acan- thorized for use in humans by the Food and Drug Administration thamoeba keratitis also changed with increasing knowledge of the (FDA) in the United States, is a diamidine that is effective against infection. At the beginning of the outbreak, keratoplasty was often 99 trophozoites. As its use became more widespread either alone or necessary during the acute phase of the infection to save the eye. in combination with neosporin (neomycin) or other agents that also Now, because of prompt effective treatment, it is more likely to be have activity against trophozoites, an improvement in the outcome needed to restore vision after the infection has been con- 84,100–104 of treatment became apparent. However, propamidine, in trolled.85,95,96 The prognosis for therapeutic keratoplasty has cor- common with all other agents up to that time, was ineffective respondingly improved. against the cystic form. It was also toxic to the cornea with pro- longed use.105 Management of Inflammation The next significant development was the identification of the The remaining therapeutic question was how to control the se- efficacy of polyhexamethylene biguanide (PHMB).99,106 This vere inflammatory response frequently associated with this infec- compound is commercially available as a “pool cleaner” but not as tion. The hallmark of Acanthamoeba keratitis has been a severe a pharmacologic agent. PHMB kills Acanthamoeba in both the and persistent inflammation associated with progression of the cystic and trophozoite stage and appears to be relatively non- infection into the corneal stroma. Corticosteroid therapy to control toxic.107 Reports of its efficacy when used as a 0.02% topical inflammation has been controversial since the beginning of the preparation began with the paper by Larkin et al. in 1992.106 epidemic. It remains so today. The factors inciting the inflamma- Although the precise mode of action of PHMB against Acantham- tory response are not understood, but are presumably related to oeba is uncertain, it is likely to be similar if not the same as its Acanthamoeba antigens deposited in the corneal stroma. Whether disruptive action on the phospholipid bilayers on the bacterial cell the persistence of the inflammation indicates the presence of live wall.108 organisms is unknown. However, inflammation often intensifies With the identification of two agents of superior efficacy against after the initiation of antiamoebic therapy, and it has been sug- Acanthamoeba, one propamidine, active against trophozoite stage, gested that dying organisms may release potentially harmful anti- and the other, PHMB, capable of killing both cysts and trophozo- gen.112,113 Whether corticosteroids promote replication of Acan- ites, it was logical to consider combined drug therapy. By 1996, thamoeba is an important consideration that has not been studied. sufficient experience had been gained to demonstrate the success However, one in vitro experiment does suggest that corticosteroids of this approach. inhibit encystment of trophozoites.114 If this is true, persistence of Success has also been recently reported with hexamidine, chlor- the organisms such as trophozoites might render them more sus- hexidine, and clotrimazole.84,87,104,108,109 However, at the time of ceptible to antiamoebic agents. There are no additional studies to this writing, the combination of propamidine or PHMB along with support this hypothesis. a diamidine appears to be the treatment of choice (Table 4).110 No studies have been published that might resolve the question As experience was gained with this infection, both the clinical of corticosteroid use, but in several large series the authors note the features and the pathophysiology came to be better understood. In use of topical corticosteroid to control inflammation without fur- turn, this led to more rapid diagnosis and the realization that the ther comment.83,84,87,93,108 My own personal experience has been advanced cases that dominated the experience of the beginning of that corticosteroids are at times necessary to control the inflam- the epidemic were not necessarily typical. Rather, the infection mation, while treatment continues with specific antiamoebic therapy. Because inflammatory damage can be devastating to the TABLE 3. Agents with potential as ocular antiamoebic cornea in eyes infected with Acanthamoeba, this question remains agents: 1980 an important issue. Neomycin Clotrimazole Ketoconazole CONCLUSION Miconazole Paramomycin When one considers the state of knowledge about Acantham- Propamidine isethionate oeba infection at the time the epidemic began in the early 1980s,

Cornea, Vol. 19, No. 5, 2000 MANAGEMENT OF KERATOMYCOSIS AND ACANTHAMOEBA KERATITIS 685 progress has been truly remarkable. As a result, effective treatment 24. O’Day DM, Head WS, Robinson RD, et al. Ocular pharmacokinetics is now available for what appeared at the time to be an almost of saperconazole in rabbits. A potential agent against keratomycoses untreatable disease. It has to be noted, however, that none of the [published erratum appears in Arch Ophthalmol 1992;110:1597]. Arch Ophthalmol 1992;110:550–4. drugs recommended for the treatment of this condition is available 25. Klippenstein K, O’Day D, Robinson RD, et al. The qualitative evalu- to physicians in the United States, except under an IND from the ation of the pharmacokinetics of subconjunctivally injected antifun- FDA. Regrettably, there has been little interest from industry in gal agents in rabbits. Cornea 1993;12:512–6. developing therapeutic agents. 26. O’Day DM, Robinson R, Head WS. 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