Pharmacologic management of keratomycoses

SURVEY OF OPHTHALMOLOGY

VOLUME 33 * NUMBER 3 - NOVEMBER-DECEMBER

THERAPEUTIC

1988

REVIEW

SAIICHI MISHIMA AND JOEL MINDEL, EDITORS

Pharmacologic Management of Keratomycoses KARLA J. JOHNS, Department

M.D., AND DENIS M. O’DAY, M.D.

of Ophthalmology,

Vanderbilt

University School of Medicine,

Nashville,

Tennessee

Abstract. Fungal cornea1 infections can be very difficult to treat. An evolving understanding of the pharmacology of the currently available antifungal agents has led to improved medical treatment of the keratomycoses. The pharmacology, pharmacokinetics, spectrum of activity and toxicity of these agents is reviewed and promising new antifungal compounds and modes of treatment are discussed. (Surv Ophthalmol 33:178-188, 1988)

Key words. imidazoles

l

antifungal agents keratomycosis

l

l

fluorinated pyrimidines polyenes

l

fungal infection

l

with a better understanding of the epidemiology and pathology of keratomycoses. In addition, the pharmacology of existing antifungal compounds, as well as the indications and techinterventions, are better niques for surgical appreciated.

The management of keratomycosis continues to challenge the clinician. Although fungi are uncommon cornea1 pathogens, there is evidence to suggest that keratomycosis has become more common over the past two decades.“6 Improvements in diagnostic techniques and a greater clinical awareness have probably contributed to the increased number of cases being reported, but the widespread use of topical antibiotics and corticosteroids may also play a role. Over one hundred fungal species, representing a wide spectrum of filamentous fungi, yeasts and dimorphic organisms, have been reported as human cornea1 pathogens; yet we have relatively few effective ophthalmic antifungal agents available. To add to the difficulty in management, the therapeutic response to these agents varies widely from case to case. A number of factors have led to an improvement in the management of these difficult cornea1 infections. Although there have been no radical breakthroughs of the order seen with bacterial keratitis, clinical research over the last decade has provided

ophthalmologists

I. Characteristics

of Fungal Pathogens

Fungal ocular pathogens can be divided into three groups. The Iilamentous fungi are multicellular organisms that produce tubular projections known as hyphae. Hyphae may be septate, that is, having distinct divisions between cellular elements, or nonseptate. Multinucleate septate filamentous fungi are the most important group to cause corneal disease, and include Fusarium, Aspergillus and Penicillium

spp. The nonseptate

filamentous

fungi,

such as Phycomycetes and Rhizopus, are much less common as cornea1 pathogens. Yeasts, which comprise the second group, are unicellular organisms that reproduce by budding. Buds that fail to separate from the parent organism are known as pseu178

PHARMACOLOGIC

179

MANAGEMENT OF KERATOMYCOSES

dohyphae. Pseudohyphae can be distinguished from true hyphae by the absence of multiple nuclei and other cellular organelles. Can&z and Cryptococcus species are the yeasts most commonly involved in intraocular infections, but only Candida sp. appear to infect the cornea. Some fungi have the capacity to exist in both filamentous and nonfilamentcms fi)rma. The third group of fungi, the diphasic organisms, rarely, affect the cornea but are more c.ommonly responsible fbr hematogeneouslyspread ocular and orbital diseases. Thus, filamentous septate fungi and the yeasts are the most important common cornea1 pathogens. Keratomycosis is relatively uncommon in the Western world. As a result, it has been difficult to accumulate a broad experience with the disease. The literature abounds with single case reports, which are of value in that they provide insights into the management of difficult or unusual cases. However, ~hry c.ontribute little to our understanding of the illcidellce of’ particular fungal pathogens and their response to treatment. Over the years several centers in the United States have painstakingly collected their experience with thrse infections, publishing their data onl) when the number of’ cases became sufficient for analysis. In addition, ophthalmologists working in the tropical countries have now begun to describe their experience with substantial numbers ot cases:“,” As a result of these efrorts, a view of the relati\-e ti-equenc); of organisms likely to be encountered is beginning to emerge, providing a logical framework for discussing therapy45 (Tables 1 8c 2). The isolates vary by region. In the southern Unitet1 States, septate filamentous fungi are most likely to be encountered, whereas in the northern states infections caused bv Curdida species predominate. Worldwide, Fcmribn anti As,twgillus are the most notable fLIngal pathogens in both frequency and severity.“,” ~I’hc biology of. fungi in tissue has an important bearing on pharmacologic management. In the cornea, both yeasts and filamentous fungi are present only in filamentous forms. The hyphal cell memhranc is thus a crucial element in the development of eflftctive antifungal therapy. In addition to its barrier t’unction, the fungal cell membrane modulates electrolyte and solute exchange, and controls the internal homeostasis of the fungal cell. All cell membranes contain sterols, but ergosterol is a sterol ofthe plasma membrane that is unique to fungi. In mammalian cell membranes, the principal sterol is cholesterol. Most antifungal agents capitalize on this key difference in plasma membrane constituents in order to damage fungal cells while minimizing damage to host mammalian cells.

Filanientous

fungi Moniliaceae Fuss iuni solani Fusar-ium sp. Aspcr-gillus bp. (khr1. Sl’. Ikmatixtw (1urvularia 5p. OthT

I 54

6I ”4 -10

:<-t 36

hp.

1~east5

Candida .ilbicans (kndida sp. Other tullgi ‘1oral .-!daptcxl

from O’Day DM.‘”

Africa

India

CK

Filanentous fungi hlonili,iccae E‘usariutri solani Fusarium sp. Aspcrgillu3 sp, 0thc.r sp, Ik,K3li,,,,, (:urvularia sp. Other sp. Yeasts (kndida albicals (Lmditla sp, Other fungi ~I‘otal

Effective eradication of fungi is frequently dif‘ficult due to the deeply-invasive nature of‘ the infectious process. Penetration of the fungus through the cornea into the anterior chamber may occur. Therefore, an effective agent for treating fungal keratitis should exhibit pharmacologic properties that include excellent cornea1 and ocular penetration. In this review, we discuss the current agents used in the treatment of fungal keratitis.

II. Antifungal Agents Currently available antifungal agents vided into three groups: the polyenes, zoles and fluorinated pyrimidines.

can be dithe imida-

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33 (3) November-December

1988

JOHNS, O’DAY

A. POLYENES The first effective antifungal agents to be discovered were the polyenes (Fig. l).’ These compounds share a common molecular structure consisting of a conjugated double-bond system of variable size linked to mycosamine, an amino acid sugar. The various members of this group are classified according to the number of double-bonds present. Polyenes bind preferentially to ergosterol in the fungal thereby altering membrane plasma membrane, permeability and disrupting the fungal cell. It has been postulated that the larger polyenes (those with 35 or more carbon atoms), such as nystatin and amphortericin B, and smaller polyenes, such as natamycin, differ in the way that they interact with fungal cell membrane ergosterol. The larger polyenes, in binding to the cell membrane, are thought to create channels that span the cell membrane and allow electrolyte movement. Small polyenes, too small to bridge the width of the cell membrane, may alter membrane permeability by creating localized disruptions in the membrane.33

nysbtin

omehobddn 8

1. Nystatin Nystatin was the first polyene antibiotic to be identified by Hazen and Brown in 1950.2’ It has been recommended for topical ocular use, but corneal toxicity and poor ocular penetration limit its value. It is too toxic for parenteral administration. 2. Amphotericin

B

Amphotericin B, a heptaene polyene (7 double bonds), was the first polyene shown to be effective in treating systemic mycoses. Produced by Streptomycetes nodosus, it was identified in a soil culture from Venezuela in 1956 by Gold and colleagues.” Amphotericin B is insoluble in water, unstable at 37°C and degrades rapidly if exposed to light.4,4’ However, solubility is improved by the addition of deoxycholate. In vivo, amphotericin B rapidly becomes tissue bound, limiting the actual amount of drug that is bioactive.33 Methyl esterification of amphotericin B also enhances water solubility while maintaining good antifungal activity in vitro.3g However, amphotericin B methyl ester and similar analogues have not been developed further because of severe toxicity. Possible routes of administration that have been studied for amphotericin B in the treatment of keratomycoses include topical, subconjunctival, intracameral and intravenous. a. Pharrnucokinetics

and Pharmacology

Amphotericin B (Fungizone’“, Squibb Pharmaceuticals) is dispensed in 20 ml vials for intravenous (IV) use containing 50 mg of amphotericin B powder, 41 mg of sodium deoxycholate and a sodium

Fig. 2. Chemical structure of the polyenes.

phosphate buffer. The powder is initially reconstituted to a concentration of 5 mg/ml in 10 ml of sterile water for injection. For topical application, this solution is further diluted with sterile water to concentrations from 0.05% to 1%. Amphotericin B in solution should not be exposed to light. When stored at 36°C it retains potency for one week. Care must be taken to handle the solution in an aseptic manner as the preparation does not contain a bacteriostatic agent.41 The efficacy of topical amphotericin B has been studied clinically and experimentally using concentrations ranging from 0.05% to 1%.44,64*65The corneal epithelium appears to be a powerful barrier to cornea1 penetration of the drug. In a rabbit model, the cornea1 penetration of topical amphotericin B 0.15% in animals with intact epithelia was negligible. However, debridement of the epithelium greatly increased penetration and efficacy in one Candida

PHARMACOLOGIC

MANAGEMENT

o1hictzn.s animal modeL4” There is evidence to suggest amphotericin B can penetrate deep cornea1 stroma and enter the aqueous. Amphotericin B 0.15% administered topically was present in the cornea and aqueous of an animal eye inflamed by the intrastromal injection of clove oil. Although only 7%’ of the drug was found to be in a bioactive form in the cornea1 tissue and 5% in the aqueous, even this amount appeared adequate for susceptible organisms.‘4 Epithelial debridement substantially improved cornea1 penetration of this drug. Topical amphotericin B has been used to treat mycotic keratitis since 1959 although toxicity has been a troublesome complication.’ In a series of cases, Wood and colleagues diluted amphotericin B to a concentration of 0.15%. This preparation was efficacious and produced far less toxic effects than higher concentrations previously used.“4 Because of residual problems with toxicity even at this concentration, Wood reduced the concentration even fur-, ther to 0.05%. Even with this lower concentration the drug continued to show efficacy in another small series of cases.“’ The efficacy of dilute amphotericin B has also been established in experimental studies. Although the optimal rate of administration is unknown, animal experiments suggest that with very rapid administration (every 5 minutes for one hour) drug levels within the therapeutic range can rapidly be achieved in the cornea.44 After this intensive treatment period, a less frequent rate of administration may maintain adequate drug levels in the cornea. Subconjunctival administration of amphotericin B has been advocated for the treatment of fungal keratitis. Ilowever, the injections are quite painful and poorlv tolerated. Ulceration and necrosis of the overlying conjunctival epithelium may occur. III one animal study, subconjunctival injections of amphotericin B produced only trace amounts of the drug in the aqueous, in both normal corneas and in a chemical keratitis model.‘” The use of systemic amphotericin B in the treatment of fungal keratitis has not been studied experimentally to a significant extent. In one animal model of chemical keratitis, amphotericin B failed to penetrate into the aqueous after intravenous administration.” In addition, intravenous administration carries with it a serious risk of systemic toxicity including renal toxicity, chills, fever, phlebitis and anemia.“” For this reason, intravenous amphoteritin B is rarely indicated in the treatment of keratomycoses. b. efficacy

and Spectrum

In the treatment

of Activity

of systemic

mycoses,

181

OF KERATOMYCOSES

Amphoter-

icin B is most efficacious against yeasts, particularly Candida and Cqptococcus sp. The agent is much less useful in filamentous fungal infections. In the eye the situation is similar. Studies of experimental Cnndida &icons keratitis showed topical amphoteritin B in concentrations of 0.5%, to 0.075% to he superior in efficacy to 5% natamycin. Ilr tlucytosine, 1% miconazole, and 1% ketoconazole.“’ Amphotericin B also exerts antifungal activity against .4,sprrgillus but appears to be of limited usefulness against other filamentous fungi.‘” In addition to its direct fungicidal activity, amphotericin K has been shown to have immunoacijuvant properties. Administration of systemic amphotericin B in a murine model was associated with an increase in the number of antibody producing cells in the spleen and lymph nodes. Amphotericin B may interact with T-lymphocytes to enhance host resistance to infection.“” Whether topical amphotericin B also exhibits immunoacijuvant properties remains to be elucidated. C. Toxicity The toxic effects of topical amphotericin B appear to be related in part to the effects ofthe bile salt deoxycholate used as a solubilizer. They in&de chemosis, burning, epithelial clouding, and punctate epithelial erosions. In extreme cases the cornea may assume a greenish hue. In the rabbit topical amphotericin B 1%) retarded the healing of‘epithelial defects.” Topical toxicity ot‘amphotericin B can be minimized by using more dilute preparations (0.1.5s and less).“? Attempts have been made to ti)rmulate more water soluble analogues ofamphoteritin, such as amphotericin methyl ester hydrochloride. However, the development of’ leukoencephalopathy after the systemic administration of amphotericin methyl ester hydrochloride has dampened the enthusiasm for this compound.” 3. Natamycin

(Pimaricin)

Natarnycin is a tetraene polyene and is the only antifungal commercially available in the llnited States in a topical ophthalmic form (Natacyn’” 5%#, Alcon I,aboratories). The agent was discovered in 1958,“’ and it has proved itself to be the most valuable ocular antifungal agent discovered to date. n. Pharmncokinetics

and Pharmacolo‘q

Natacyn’” 5’%, the topical ophthalmic form ofnatamycin, is available in 15 ml glass bottles from Alcon Laboratories, Inc. These containers may be stored at room temperature or refrigerated, but care should be taken to avoid freezing, exposure to light and high temperatures. Like other polyenes, it is insoluble in water. The commercial preparation is

182

Surv Ophthalmol

33 (3) November-December

a suspension that must be shaken well before use. Natamycin often adheres to areas of cornea1 ulceration, perhaps increasing the duration of drug contact time. The drug cannot be administered systemically.” Although the optimal dosing schedule for topical administration is not known, a loading dose approach in which one drop is instilled into the conjunctival sac at half-hour intervals appears appropriate initially.45 This rate can then be gradually reduced to one hourly drop 6-8 times daily after the first 3-4 days of administration. Natamycin has been considered to be poorly absorbed by the cornea. However, its demonstrated efficacy in proven extensive fungal keratitis and the results of a recent experimental study suggest this may not be the case. Large amounts of radiolabeled natamycin can be detected in the cornea after intensive topical administration.‘” Moreover, substantial levels can be detected in the aqueous. What has been thought to be poor cornea1 penetration may actually be poor bioavailability, as we have recently found in our laboratory that only about 2% of total tissue natamycin in the cornea is in a bioavailable state. Fortunately, the relatively high total cornea1 drug concentration insures that adequate amounts of bioactive drug are available. As with amphoteritin B, the cornea1 epithelium is a major barrier to Removal of the epithelium cornea1 penetration. dramatically enhances penetration and eIIicacy.40 b. Efficacy

and Spectrum

1988

JOHNS,

B. IMIDAZOLES In 1965, the antiprotozoal compound thiabendazole, a substitutive benzamidazole, was shown to have antifungal activity in vitro.59 This discovery led to the development of a new class of potent antifun-

n

of Activity

Natamycin is most effective against the Iilamentous fungi and has been of particular use in the treatment of Fusarium and Aspergillus infections, the commonest cause of fungal keratitis around the world. However, treatment failures occur with this and other filamentous fungi. Numerous series of patients in the United States and elsewhere have established the primacy of natamycin in the treatment of fungal infections caused by Iilamentous Its adoption has been limited to an exfungi.. 20~28~34 tent only by cost. Yeasts such as Candida species tend to be less sensitive to treatment with natamycin than filamentous fungi.4’ c. Toxicity In general, topical natamycin is well tolerated. Cornea1 toxicity, usually in the form of punctate keratitis, is rare, although a low-grade inflammation may develop with prolonged use.34s4’ In an animal model, natamycin did not retard the healing of cornea1 epithelial defects.14 The development of conjunctival necrosis following subconjunctival injection precludes its use by this route.

O’DAY

Fig. 2. Chemical structure of the imidazoles.

PHARMACOLOGIC

MANAGEMENT

OF KERATOMYCOSES

gal agents. the imidazoles (Fig. 2). Three of these miconazole, clotrimazole, and ketoconazole - are now commercially available in the United States. In general, imidazoles exhihit fungistatic activities in vitro at low concentrations and fungicidal activity at high concentrations. They appear to have two distinct mechanisms of action. Inhibition of ergosterol synthesis is believed to be responsible for the fungistatic ;tc.tivity observed at low concentrations.“” Frank Iilngicidal activity observed at higher concentrations appears to he due to direct membrane damage to the tilngal cell wall that is unrelated to the inhihitions ofergostcbrol synthesis.” This fungicidal eff’ec t is dependent on the growth phase of the susceptible organism and is ohserved with clotrima/ale and miconazole. but not with ketoconazole.” However, the drug levels required to produce the fungitidal activity are higher than can be reasonably attained and sustained within ocular tissues. From a practical standpoint, the imidazole compouncls eshihit fungistatic activity only. In addition, the varianc.e in spectrum of activity among the imidazoles rnq be due in part to a differential afflnit) for phospholipid components of the fungal cell membrane.. iL’ 1. Clotrimazole Firy;t synthesized by the Rayer Research Laborarories in (;ckrmanv in 1967, clotrimazole is achlorinated t ritvl imida7ole.“” N. F’hnr)nucokinutic.s md Phnrrnmolog?l .4 topical ophthalmic preparation of clotrimazole can be made with 1% clotrimazole in arachis (peanut) oil.“’ Canesten’” (Bayer Laboratories), a commere-ial topical preparation, is not available in the L.‘nited States.?’ A dermatological cream containing clotriniazole 1% (L.otrimin’” cream 1%) is well tolerated when applied to the eye.“” Care must be taken, however, not to use the dermatologic lotion, which contains harmful alcohols. Clotrim;izole is poorly soluble in water and cannot be given parenterally. However, it is rapidly absorbed by mouth and satisfactory blood levels can be maintained for a week or two after the initiation oftherapy. L:nfortunately, clotrimazole induces the microsomal enzyme oxidation (MEOS) so that these drug levels cannot be maintained. Hepatotoxicity. nausea, and diarrhea have been reported with sys.temic administration.‘i” ” h. Ef/i’r,clrv_ crud S~ert~!/~~z of Acti-ijity In ifcft.Oclotrima~ole has broad antifungal activit) but appears to be of greatest value in the treatment of‘As/~~~~q~//~~,s infections in vivo.2i.4’

I 83

Topical clotrimazole 1% in arachis oil or as the dermatologic cream has been well tolerated in hllmans, bllt punctate keratopathv and ocular irritation have been reported from long-term IIW.' ‘I-he safetv and efficacy of suhconjunctival and intracam&al clotrimaznle have not been thorougtil~ evaluated. 2. Miconazole Miconazole. first synthesized in Belgium in 1969, is a phenethyl imidaznle. I’; In addition to its antifungal properties, miconazole also exhibits mild activity against gram positive bacteria.“”

.l‘he antitilngal activity of miconazole appears to result from an alterat.ion in the fungal cell wall that induces permeabilit) changes. It can he administered hv subconjunctival. topical and intravenous routes. In the rabbit, topical and suhcotl.j~rnctival administration ofmiconazole produce high (oncentrations in the cornea and the aqueous.” Lt’hen given intravenouslv it can be detected in the aqueous humor as well.” Intravenouslv administered miconazole has been used successfully to treat human cornea1 fiingal infections.“’ Mico~lazolc can be prepared for ropical administration ;I5 cl 1’4 drop in arachis oil or aa a ‘I9 cre;lni. The commercially available intravenous preparation (Monistat “‘1 can be administered topically ( 10 mg/ml) or by subconjunctival injection (5-l 0 mg). si The col-neal epithelium appears to be ;I potent barrier following topical administl.atioll. f lowever, the drug easily enters the dehrided co~-ne:~.‘-

Miconazole has a hroad spectrum of activity against yeast and filamentous flingi in vitro, although individual strains m;\! b<* resistant.” c. Toxic,itl: Topi& miconazole 1%. exhibits minimal toxicity characterized by conjunctival injection and punctate epithelial cornea1 erosions.“’ In a rabbit model, the rate of healing of epithelial defects was not retarded hy administration of lg miconazole drops.14 Similarly, subconjunctival miconazole appe;lrs to he well tolerated.’ ’ 3. Ketoconazole Ketocnnazole, a recently developed imidazole, shows great promise in the treatment of keratomycases. It inhihits ergosterol synthesis in viva, thus damaging the fungal cell wall and altering electrolyte concentration. The increased water soltlbility

184

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33 (3) November-December

1988

JOHNS,

NH

and enhanced systemic absorption are valuable properties of this drug that set it apart from earlier imidazoles.60 a. Pharmacology

and Pharmacokinetics

Chu and co-workers reported that ketoconazole can produce good drug levels in the cornea when administered topically, subconjunctivally, or orally.” More recently, Savani and associates reported high levels in the aqueous, but very low cornea1 levels 4 hours after an oral dose of 80 mg.54 Initial experience with ketoconazole in the treatment of human cornea1 infection has been promising. In one series, 20 of 29 patients with infections due to Aspergillus, Fusarium and Curvularia healed following treatment with this agent (P.A. Thomas et al, unpublished communication). In another study two patients with cornea1 ulcers caused by infection with Fusarium solani were successfully treated with orally administered ketoconazole 300 mg per day.24 Using combined therapy of topical and subconjunctival miconazole and oral ketoconazole, healing occurred in a series of 13 of 20 patients with fungal cornea1 ulcers.Y Ketoconazole can also be administered as a topical preparation in concentrations ranging from 1-5%.““,62 The optimal dosing schedule of topical ketoconazole has yet to be determined. b. Efficacy

and Spectrum

of Activity

In vitro, ketoconazole has a wide spectrum of activity. Clinically the agent appears effective against Candida, Aspergillus, Fusarium and C~urvuin one animal laria spp., in particular. 6o However, study ofa stromal Aspergillus infection, neither topical nor oral ketoconazole was effective in eradicating the infection, despite moderate sensitivity to the drug in vitro. 3o Further work is needed before the appropriate role of ketoconazole is elucidated fully. c. Toxicity Systemically administered ketoconazole appears to be relatively safe, although hepatotoxicity has been reported, as evidenced by increased liver enzymes. 41 The hepatotoxicity of systemic ketoconazole is usually reversible with cessation of the drug, although recovery may be slow; rarely, death has been reported. Topical preparations of ketoconazole are well-tolerated; 1% ketoconazole did not retard the closure of epithelial defects in the rabbit cornea.14 4. Econazole Econazole, a dichlorimidazole exhibits a wide spectrum of activity against Iilamentous fungi in vitro.48 It appears to be less effective than micona-

O’DAY

N H

BF

J

OJN

Fig. 3. Chemical ed pyrimidine.

structure

of flucytosine,

a fluorinat-

zole against Candida species.4’ A topical preparation of econazole 1% can be prepared and appears to be well-tolerated.Z6 There are no plans to market econazole in the United States at the present time. C. FLUORINATED

PYRIMIDINES

1. Flucytosine

Flucytosine (5-fluorocytosine) is a fluorinated pyrimidine (Fig. 3). First synthesized in 1957 as an antimetabolite in the treatment of leukemia, the antifungal properties of flucytosine were first described by Grunberg and colleagues in 1963.” a. Pharmacology

and Pharmacokinetics

Flucytosine is transported across the fungal cell membrane by a specific permease elaborated by certain fungi. Once in the cell, the agent is deaminated to fluorouracil, a thymidine analogue that blocks further fungal thymidine synthesis.7 Because mammalian cells do not normally metabolize flucytosine, it does not inhibit metabolic processes in mammalian cells. The drug is well absorbed by the gastrointestinal tract. Therapeutic levels can be achieved in adults with the administration of a dose of 50-150 mglkglday in divided doses7 Flucytosine is moderately soluble in water. A topical preparation can be made by dissolving the contents of a capsule of flucytosine in artificial tears.” The solution should be filtered before use to remove any undissolved flucytosine. Flucytosine has been used with success as a 1% solution topically.52 In a standardized animal model of Candida albicans keratitis, 1% flucytosine was ranked in efficacy behind 0.15% and 0.075% amphotericin B and 5% natamycin, but was found to be more efftcacious than 1% miconazole. 37The efficacy of subconjunctival flucytosine has yet to be established. b. Efficacy Flucytosine

and Spectrum is effective

of Activity against

yeasts,

including

PHARMACOLOGIC

Cundidu and C~tptococcu.s.4’ However, some fungal strains lack the specific permease to transport the drug into the cell and they are resistant to flucytosine.“’ Resistance can also be induced with prolonged therapy.‘” For this reason, flucytosine should not be administered alone in the treatment of keratomycoses. Its greatest usefulness appears to be as an ad.junct therap) in the treatment of yeast keratitis. c’. Toxicity Flucytosine given orally is well tolerated by patients. Mild gastrointestinal toxicity, including nausea, vomiting and diarrhea, has been reported. In some cases, hepatotoxicity may develop as evidenced by elevated levels of serum transaminase and alkaline phosphatase. 5-fluorocytosine in the gastrointestinal tract is metabolized by bacteria to fluorouracil; this metabolic product can produce bone marrow toxicity. Usually these gastrointestinal and liver manifestations can be reversed when the drug is stopped. Since flucytosine is largely excreted by the kidneys, caution should be exercised in patients with renal failure.4’ Topical flucytosine is well tolerated. In one animal study, the I%>solution did not impair epithelial wound healing.“’

III. Methods

18.5

MANAGEMENT OF KERATOMYCOSES

for Enhancing

Efficacy

‘I’he less than desirable efficacy of most antifungal agents has spurred attempts to enhance their efficacy. Perhaps the area that offers most promise, though it is not well understood at the moment, is the possibility of potentiating antifungal activity through the administration of several antifungal agents simultaneously. ‘I‘he pharmacology of such combinations is complex. but it is clear from in vitro studies that there is a possibility for antagonism as well as potentiation of antifungal activity. In addition, certain antibiotics, such as tetracycline and rifampin, seem to enhance the eflicacy of other agents. ‘1‘0 date, most studies have been carried out in vitro because ofthe lack ofa suitable animal model to study their effects precisely. In animal studies, the combination of amphoteritin H O..Y%and subconjunctival rifampin was found to be more &ective than amphotericin R alone.“7 Rifampin, an antibacterial agent, given alone is ineftectivc against fungi. Amphotericin B, by altering the firngal cell wall, ma)’ allow rifampin to enter the l’ungal cell where it inhibits RNA synthesis. There is also cGdence of synergy or at least an additive effect between ainphotericin K and 5_fluorocytosone, but this interaction is quite complex.’ In addition, the results of a recent study suggested that the combination of natamycin and ketoconazole was benefi-

cial in an animal model of Aspergillu~ infection.“” The concept of combination therapy appears to offer opportunities for increasing the efficacy of’existing agents, although detailed studies have vet to be done. There is, however, a risk of‘ an antagonistic etfect by combining antifungal agents. Antagonism between amphotericin R and the imidazoles has been demonstrated in an experimental model.’ 111vitro studies are contradictory on this point, producing evidence for both a potentiating and an antagonizing action. .I‘O some degree, this may be the c-onsecluence of the experimental design, but it may also reflect the complexity of the interaction between the antifungal agent and the organism. ‘l‘hus, it seems clear from several animal and in vitro studies that a number of factors determine whether a particular combination is antagonistic,. without any additive ef’fect, or able to potentiate the antitilngal activity. Such factors as the stage in the litk cycle ot’ the organism, the order of administration of the agents and their dosage appear to be important. Length of treatment may also be a factor. ‘I‘hese variables can be manipulated in vitro \t,itli ease but the rele\,ance of such experiments to tllr (linical situation is still unclear.

IV. Interaction of Antifungal Corticosteroids

and

The interaction between corticosteroids and topical antifungal agents is complex. When a cornea1 fungal infection is treated with c.orticosteroids alone, the result is a worsening of infection.” lIowever, the concomitant use ot‘corticostel.oids and antifungal agents remains controversial. One percent prednisolone acetate adversely influenced the efficacy of 5% natamycin, 1% flucytosine, and 1% miconazole applied topically, but did not adverse11 affect the efficacy of amphotericin H applied topically in an animal model of C:UWW keratomvcosis?’ 1x1a rabbit model of .+\/)P@~uA cornea1 il;fection, the simultaneous administratior~ of topic.al dexamethasone phosphate 0.00 I ‘% md topical natamycin 5% suppressed inflammatio~l without examerbating the fungal infectious process.” (%nically, the combination of topical amphoterit in H and topical corticosteroids has been used to suc~t~esstiill\ treat coi-neal infections.‘” With the current state ot’kno\vledgc the decision to introduce corticosteroids into the management of fungal keratitis should be approached with great caution. ~l’opical antifilngal ag:ent% arv largely fun@static at best and usually ot’uncrrtain et&a& in a given case. Suppressing the host response in this situation runs the risk of’ tipping the scales in favor of the infective agent.

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V. Principles

33 (3) November-December

of Treatment

The decision whether to treat a patient with an antifungal agent is influenced heavily by the interpretation of laboratory data.“.2”.2g,4” There is rarely justification for empirical treatment with antifungals without corroborating evidence of a fungal etiology. Drug toxicity and the necessity for prolonged treatment mitigate against the use of these agents empirically. Only in a vision-threatening situation, when the clinical findings are strongly suggestive of fungal infection, is the use of these agents without culture confirmation warranted.“.2”x4’ Treatment with an antifungal agent may be initiated on the basis of smear cytology alone, if the findings are clearcut and combined with the clinical evaluation.“,2g.4? In this instance it is unnecessary to await isolation and identification of a fungus which may be delayed for an extended period of time. When the cornea1 lesion has the appearance consistent with that of a fungal infection but the smear is negative, it is usually appropriate to withhold therapy while awaiting the culture results.“.2g*“2 Further attempts at obtaining an isolate should be made over the next 48 hours to resolve the diagnostic dilemma.4z These are differing views regarding the selection of the initial antifungal agent based on the smear cytology. Some investigators advocate topical natamycin 5% as the drug of first choice for superficial keratomycoses, regardless of whether septate hyphae or yeast elements are identified on the smear; additional antifungal agents are added for deep another theracornea1 infections. “z’J~ However, peutic viewpoint is that different initial antifungal agents should be chosen if the smear reveals yeast elements rather than hyphae.4s If a smear reveals unequivocal septate hyphal fragments, suggesting that a filamentous fungus is the pathogen, there is general agreement that natamycin 5% is the drug of choice.‘0~“~29~?g~42Initially the agent is administered hourly around the clock for several days. The dosage can then be gradually reduced. If natamycin is unavailable, 0.15% amphotericin B topically can be used.45 However, when yeasts or pseudohyphae are present in the smear, some investigators advocate treatment with topical 0.15% amphotericin B.45 Animal studies suggest that a loading dose approach, giving the agent every five minutes for one hour and then hourly, 5% may be a more may be of benefit. 43.44Natamycin expensive and less efficacious alternative than amphotericin B in the initial treatment of yeast keratomycoses.45 Once the organism has been identified by culture, the therapeutic regimen may be modified. However, most authors recommend natamycin for

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filamentous fungus infections regardless of the identification of the organism.‘0~“*z3,2Y~42Amphoteritin B appears to be less efficacious against hlamentous fungi and is probably best reserved for those situations where natamycin is unavailable.2R Some strains of Aspergillus, Cladosporium, and Penicillium spp. have been shown to be sensitive to flucytosine in vitro. Although treatment with topical flucytosine 1% hourly has been suggested,42 the efficacy of this form of therapy is unproven. Amphotericin B is indicated for the treatment of yeast infections. For the occasional strain that appears to be resistant to amphotericin B, topical miconazole appears to be a useful alternative.‘” At present there is little evidence to suggest any value to the performing of in vitro susceptibility testing.46 Clinical judgment is the most reliable indicator of therapeutic efftcacy. In contrast to the rapid response seen with effective treatment of bacterial infections in the cornea, fungal keratitis resolves slowly over a period of weeks. As a result it is sometimes difftcult to detect small changes in the clinical appearance. In addition, topical antifungal agent toxicity leading to irritation, chemosis and conjunctival injection can readily confuse the clinical picture. Recurrent corneal epithelial erosions may also occur as a result of drug toxicity. Signs of improvement of a fungal corneal ulcer include a lessening of pain, decrease in size of the infiltrate, disappearance of satellite lesions and rounding out of the feathery margins of the ulcer. Negative scrapings during treatment are not always an indication of fungal eradication as the fungus may become deep-seated and inaccessible to superficial isolation attempts. Therapy should be maintained for at least six weeks.”

VI. New Horizons in the Pharmacologic Management of the Keratomycoses Several members of the triazole group of azole compounds show promise of efficacy in ocular fungal infections. Intraconazole, an orally-active triazole derivative, has shown efficacy against Aspergillus, Cryptococcus and Candida in experimental and clinical studies.20 Fluconazole, another experimental triazole, is highly water soluble and has minimal tissue binding.7 Recent data suggests preferential uptake by the cornea with levels at least two times that of serum being achieved with a single oral dose.“4 Drugs such as these with good ocular penetration following systemic use offer for the first time an opportunity to treat fungal keratitis with effective systemic therapy. K582 (Myroridin K) is another new topical antifungal that has shown initial promise as an effective therapy against Candida. 47 It is a water soluble basic peptide antibiotic that is effective in a very low con-

PHARMACOLOGIC

MANAGEMENT

OF KERATOMYCOSES

centration against Candidu. In experimental studies it has been effective and well tolerated both subconjunctivally and topically.“’ New drug delivery systems are under investigation as a means of enhancing the penetration of currently available topical antifungals. Liposomes are lamellar phospholipid vesicles that can be used as drug carriers to enhance penetration.“” Their value in the treatment of cornea1 infective disease has yet to be studied and there appear to be substantial obstacles to be overcome before liposomes have a practical treatment modality.

VII. Summary The pharmacologic management of the keratomycoses requires an understanding of the antifungal agents currently available, their spectrum of activity and their limitations. Choice of initial therapy relies on interpretation ofthe smear. Subsequently, the therapy is modified by the results of the culture. Successful treatment of cornea1 fungal disease requires close follow-up over a prolonged period of time and keen clinical judgement. Currently available antifungal agents include polyenes, imidazoles and a fluorinated pyrimidine. New drugs on the horizon, most notably the orally-active triazole compounds, may provide promising new avenues of medical therapy for the keratomycoses. Acknowledgment

The authors assistance

wish to thank in the preparation

Ms. Susan Bigham for her of the manuscript.

References 1. Anderson B, Roberts SS, Gonzalez MD, Chick EW: Mycotic ulcerative keratitis. ,4&l ,lrch Ophthalmo~ 62: 169-I 79, 1959 2. Beggs WH: Mechanisms of.svnergistic interactions between amphotericin B and flue vtosine. / Antimirroh ChPmother I7:402-404, 1986 ’ 3. Beggs WH, Hughes CE: E:xploiration ofthe direct cell damaging action of antifungal azoles. Dicq Micro&o/ In/ccl Di.\ htl-3, 1987 4 Bindschadler DO, Bennett JE: A pharmacologic guide to the clinical use ofamphotericin B.J In/ccl Dis 170:427,1969 5 Brajthurg J, Kohayashi D, Medoff <;, Kobayashi <;S: Antifungal action of amphotericin B in combination with other polyene or imidazole antibiotics. J Infect Dis 146:138-146. 19x2 6 Chu W, Foster CS, Moran K, Giovanoni R: Intraocular penetration of ketoconaLole in rabbits. Inzlest Ophthalmol Vis Sri suppi 1x:133, 1979 7 Drouhet E, DuPont B: Evolution ofantifungal agents: past, present and future. KPZI lnf~ct Db Y (.supp/ l‘)tS4%14, i987 SL: Leukoenceohalooathv in x Ellis WG, Sohel RA, Ni&n patients treated with amphotericin B methy; ester: ,J kpct DL\ 1-W: 125-197. 3 1982 9. FilLsimons R. Peters AL, Med M: Miconazole and ketoconaLole as a satisfactory first-line treatment of keraromycosis. ,4)~ J Ophthalmol 101:60.5-608, 1986 and management ot 10 Forstcr RK, Rebel1 G: The diagnosis keratomvcoses. II. Medical and surgical management. Arch Ophthalmol Y3:l 134-I 136. 1975 I I. Forster RK: Fungal Diseases in Smohn G, Thofi RA (eds): 7%r, Cornmt S&nttfir Foundntion nnd Cliniral Pmctzre. Boston.

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This work was supported in part by a Senior Scientific lnvestigator grant from Research to Prevent Blindness and NIH grant EY-01621 (Denis O’Day, M.D.). Reprint requests should be addressed to Karla J. Johns, M.D., D-5217, Vanderbilt Medical Center North, Nashville,TN 37232.