Traditional Anti Fungal Logic Agents

Vol. 22, No. 5 May 2000

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Refereed Peer Review

FOCAL POINT ★Several traditional antifungal compounds are still widely used and recommended for many cutaneous fungal disorders.

KEY FACTS ■ Amphotericin B continues to be a recommended treatment option for several invasive fungal infections despite the need for intravenous administration and the possibility of nephrotoxicity. ■ Interest in the antifungal drug amphotericin B has been renewed because encapsulated formulations, have a higher margin of safety than does the traditional formulation. ■ Potassium iodide remains an economical, efficient initial treatment of choice for canine sporotrichosis. ■ Although ineffective against yeast, griseofulvin is highly effective against dermatophytes and remains the treatment of choice. ■ Cats are apparently susceptible to the adverse effects of griseofulvin therapy.

Traditional Antifungal Dermatologic Agents Centre Vétérinaire DMV, Ville St-Laurent, Quebec

Caroline de Jaham, DMV, MSc Université de Montréal

Manon Paradis, DMV, MVSc North Carolina State University

Mark G. Papich, DMV, MS ABSTRACT: In the past two decades, remarkable advances have occurred in the treatment of cutaneous fungal diseases. New generations of antifungal drugs have altered the therapeutic approaches to both systemic and superficial mycoses of companion animals. To understand these advances and their impact in veterinary dermatology, traditional therapies and their clinical applications are reviewed. The pharmacokinetics, methods of action, principal adverse effects, and dermatologic uses of polyenes, iodides, and griseofulvin are summarized.

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ntifungal agents target the cytoplasmic membrane and nucleus of cells (Figure 1). Older antifungal agents, including ampheroticin B, remain the mainstay of treatment of certain fungal infections despite the advent of newer agents (Table I). The antifungal agents discussed in this article include the polyenes, flucytosine, iodides, and griseofulvin.

POLYENES The two clinical polyene macrolide antibiotics used in veterinary dermatology are nystatin and amphotericin B. Approximately 87 polyene antibiotics have been developed since the discovery of nystatin in 1950.1 Nystatin Because systemic administration of nystatin is associated with a high risk for toxicity, only the topical preparation is used in veterinary medicine. Nystatin, a common ingredient in over-the-counter products, is active against the yeast Malassezia pachydermatis, a frequent complicating organism of otitis externa. Topical ear preparation of nystatin has been incriminated as an occasional cause of allergic contact dermatitis in the topical treatment of canine otitis externa.2 Amphotericin B Discovered in 1956,3 amphotericin B was the first effective systemic antifungal agent and rapidly became the treatment of choice for systemic mycoses. The drug is still recommended for invasive fungal infections despite its renal toxicity

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and the need for intravenous (IV) administration. Interest in this drug has been renewed because encapsulated formulations, such as amphotericin B lipid complex, have a higher margin of safety than does the traditional formulation (amphotericin B deoxycholate).

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The metabolism of amphotericin B is not clearly understood. It is incorporated into cholesterol cell membranes at various times, resulting in complicated elimination and distribution of the drug during cellular metabolism.5

TABLE I Class and Site of Action of Antifungal Agents Class

Agents

Site of Action

Polyenes

Amphotericin B, nystatin, natamycin

Bind to ergosterol and disrupt cell membranes

Miscellaneous

Flucytosine

Inhibits RNA synthesis Interferes with spindle microtubules Unknown Inhibits qualene epoxidase

Clinical Use Amphotericin B is active Griseofulvin Mechanism of Action against Blastomyces dermatiAmphotericin B binds irtidis, Histoplasma capsulatum, reversibly to ergosterol, the Cryptococcus neoformans, Iodides principal sterol in the cell Coccidioides immitis, MucoTolnaftate membrane of fungi. This rales, Candida species, Asbinding results in cell death pergillus species, Sporothrix caused by altered cellular schenckii, and Fusarium permeability and leakage of intracellular constituents. species. The minimum inhibitory concentration of amAmphotericin B binds to a lesser extent to other sterols photericin B varies for each group of fungi. The drug is (e.g., cholesterol) in mammalian cells. This interaction most commonly used to treat blastomycosis, histoplasaccounts for most of the toxicity and side effects in mosis, and coccidioidomycosis, all of which can have mammals. Amphotericin B is fungicidal in sufficiently cutaneous manifestations as markers of systemic infechigh concentrations but is considered fungistatic at tion. Despite the availability of newer agents, ampholower concentrations.1 tericin B combined with flucytosine has remained the treatment of choice for humans with cryptococcosis.6 Pharmacokinetics Fungal resistance rarely develops during treatment Amphotericin B is poorly absorbed from the gaswith amphotericin B; however, relapse may occur when trointestinal tract, thereby necessitating IV infusion. therapy is discontinued.4 Concurrent use of other drugs (e.g., flucytosine, the azole derivatives) improves the The drug binds primarily to protein, resulting in poor overall efficacy of therapy and has been shown to repenetration of body fluids (e.g., cerebrospinal fluid), duce the number of relapses.7,8 Amphotericin B remains but intrathecal administration of amphotericin B has 4 a mainstay of initial therapy; but because of the need been described.

Nucleus Contains nucleic acid • Site of griseofulvin activity: interferes with spindle microtubules, thereby inhibiting nucleic acid synthesis • Site of flucytosine activity: converts to 5-fluorouracil in cytoplasm of fungi, thereby inhibiting RNA synthesis

Cytoplasmic Membrane Contains ergosterol as the major sterol • Site of amphotericin B activity: binds to ergosterol and disrupts the cell membrane • Site of azole activity: inhibits the enzyme lanosterol 14-demethylase, thereby inhibiting ergosterol synthesis • Site of allylamine activity: inhibits squalene epoxidase enzyme, thereby inhibiting ergosterol synthesis Cell Wall Contains chitin

Figure 1—Schematic representation of a fungal cell and target sites of action of antifungal agents.

ERGOSTEROL ■ CELLULAR METABOLISM ■ FLUCYTOSINE ■ FUNGAL RESISTANCE

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for hospitalization, intensive patient monitoring, laboratory testing, and fluid administration during IV therapy, the cost of amphotericin B treatment is similar to that of the newer, more expensive azole derivatives. Dose regimens of amphotericin B to treat specific diseases in companion animals have been reviewed, and this information should be consulted before veterinarians attempt treatment using amphotericin B.4,9

Administration and Dose Amphotericin B is usually administered IV, and rapid and slow IV infusion techniques for amphotericin B have been described.9,10 The rapid IV infusion technique involves administration of boluses of 0.25 to 0.5 mg/kg amphotericin B diluted in 30 to 120 ml of 5% dextrose over 10 to 15 minutes. Although these techniques have been widely used, the risk for renal toxicity is higher with this method than with slower infusion techniques. 10 The slower technique requires an indwelling catheter and 0.25 to 0.5 mg/kg amphotericin B diluted in 250 to 1000 ml of 5% dextrose administered slowly for 4 to 6 hours. Before beginning each treatment, the packed cell volume, total protein, creatinine, blood urea nitrogen, and potassium should be measured and urinalysis performed. Regardless of the IV infusion technique used, amphotericin B should only be administered every other day to minimize adverse effects. Amphotericin B has also been used orally for localized treatment of gastrointestinal candidiasis.11,12 More recently, subcutaneous infusion of 0.5 to 0.8 mg/kg amphotericin B diluted in 400 or 500 ml of 0.45% saline containing 2.5% dextrose (for dogs and cats, respectively) has been successful in treating cryptococcosis. Two dogs and three cats received infusions two to three times a week for several months, and local irritation was only observed when concentrations of amphotericin B exceeded 20 mg/L.13 Adverse Effects The most common and serious side effect of amphotericin B administration is both acute and chronic nephrotoxicosis. Although clinical signs of early and acute reversible nephrotoxicosis can occur with each daily dose, permanent renal dysfunction is related to the total cumulative dose of amphotericin B. A maximum total cumulative dose of 4 to 8 mg/kg is commonly described; but the total cumulative dose, and ultimately the treatment duration, is always limited by nephrotoxicosis.4 Cats are more sensitive to this disorder than are dogs, and the maximum cumulative dose recommended in cats is 4 mg/kg.14 Several treatments have been used to prevent or delay nephrotoxicosis associated with am-

photericin B administration. Concomitant administration of mannitol, sodium bicarbonate, furosemide, dopamine, and aminophylline has been tried empirically or experimentally; some of these agents have shown empiric beneficial effects.4 Pretreatment diuresis with saline-containing fluids helps decrease nephrotoxicity.4,14 The availability of new formulations of amphotericin B in a lipid or cholesterol complex allows administration of amphotericin B at higher doses with greater safety.15 Three formulations are now available: an amphotericin B–cholesteryl sulfate complex; a liposomal complex of amphotericin B; and an amphotericin B lipid complex, which is a suspension of amphotericin B combined with two phospholipids. The amphotericin B lipid complex was shown to be safe and effective for treating blastomycosis in dogs at a dose of 8 to 12 mg/kg.16 The liposomal complex of amphotericin B was used in another study of 13 dogs for treatment of Leishmania infantum at a dose of 3 to 3.3 mg/kg.17 Although clinical improvement was rapid, the dogs remained positive for Leishmania. Lipid and cholesterol formulations (3 mg/kg or more) can be administered at higher doses than can the conventional formulation (0.25 to 0.5 mg/kg) and thus produce greater efficacy with less toxicity.18,19 Decreased toxicity is attributed to selective transfer of the amphotericin B lipid complex, which releases the drug directly to the fungal cell membrane and spares mammalian cell membranes. Reduced drug concentrations in the kidneys as well as release of fewer inflammatory cytokines from the amphotericin B lipid complex than with the conventional formulation may also prevent adverse reactions. Administration of amphotericin B as a subcutaneous infusion also allows higher cumulative doses to be administered without producing marked azotemia.13 Other adverse effects caused by IV administration of amphotericin B are hypotension, vomiting, tremors, pyrexia, hypokalemia, anemia, and anorexia. Because phlebitis should be expected with IV administration, the catheter site should be alternated.4

MISCELLANEOUS SYSTEMIC AGENTS The miscellaneous class of antifungal agents include the systemic compounds flucytosine, potassium and sodium iodide, and griseofulvin. Also included in this class are numerous topical agents, such as tolnaftate, which is commonly used in human dermatology. Flucytosine Flucytosine is a fluorinated pyrimidine that is converted into 5-fluorouracil in the cytoplasm of fungi containing the enzyme cytosine permease.4 This inhibits RNA synthesis and leads to cell death. Flucytosine is well ab-

AZOLE DERIVATIVES ■ RENAL TOXICITY ■ LEISHMANIA INFANTUM

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sorbed orally and is excreted predominantly in urine in an unchanged form. Flucytosine has been used in conjunction with amphotericin B13 and ketoconazole20 to treat cryptococcosis in companion animals.

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Pharmacokinetics Griseofulvin is weakly water soluble and is erratically absorbed from the gastrointestinal tract. Enhanced absorption depends on several factors,1 including concomitant dietary fat intake, dose regimen (twice daily instead of once daily), formulation with polyethylene glycol, and particle size (microsized or ultramicrosized). The half-life of griseofulvin is much shorter in animals than in humans, necessitating a higher dose rate in animals.31 Within 48 to 72 hours after discontinuation of therapy, griseofulvin is no longer detected in the stratum corneum, suggesting that nothing binds the drug within the skin.32 Griseofulvin is metabolized primarily by the liver to 6–desmethylgriseofulvin and its glucuronide conjugate.

Iodides In 1903, the use of iodides was first described to treat human sporotrichosis.21 Both sodium and potassium iodide Figure 2—Cutaneous sporotrichosis ulceration in a cat. have been successfully used to manage cutaneous and lymphocutaneous forms of sporotrichosis in dogs and cats22–25 (Figure 2). Potassium iodide remains an economical and efficient initial treatment for canine sporotrichosis.26 The precise mechanism of action and pharmacokinetics of these drugs are unknown. The iodides are administered orally as a 20% solution. Dogs have been treated with 10 to 40 Figure 3—Microsporum canis dermatophytosis in a Sphinx mg/kg every 8 to 12 hours. cat. Note the crusted and mildly hyperpigmented annular Because cats are more suscep- lesion on the digit. Clinical Use tible to the effects of iodides, Although griseofulvin is highdoses of 10 mg/kg every 12 ly effective against Microspohours are sufficient.22,26 rum, Trichophyton, and Epidermophyton dermatophytes, The most common adverse reactions to the iodides it is ineffective against yeasts.33 Griseofulvin is still recare signs of iodism, which include oculonasal discharge, ommended as an efficient initial therapy for most cases dry haircoat, excessive scaling, vomiting, anorexia, cenof dermatophytosis in small animals because side effects tral nervous system depression, and collapse. 24–26 If are predictable and the drug is cost-effective.34–36 Fungal iodism is observed, medication should be stopped for 1 resistance is uncommon but may vary according to geoweek and then started at lower doses. graphic locations. Recently in Europe, an in vitro study reported more than 88% activity of griseofulvin against Griseofulvin several strains of Microsporum canis.37 Griseofulvin was isolated as a metabolic product of the mold Penicillium griseofulvum in 1939 but was igAdministration and Dose nored until 1958 when it cured experimentally induced Doses ranging from 22 to 60 mg/kg every 12 hours dermatophytosis in guinea pigs. 27 Griseofulvin was for the microsized formulation and 2.5 to 15 mg/kg evthereafter widely used to treat dermatophytosis in both ery 12 hours for the ultramicrosized formulation have humans and animals28 (Figure 3). been recommended to treat dermatophytosis.34–36 Although optimum dose regimens have not been estabMechanism of Action lished, 25 mg/kg every 12 hours of the microsized forGriseofulvin inhibits nucleic acid synthesis and cell mulation and up to 50 or 60 mg/kg every 12 hours for mitosis metaphase by interfering with the function of problematic cases are commonly accepted.34–36 Griseo29 spindle microtubules. Griseofulvin is a fungistatic anfulvin should always be administered with a fatty meal. tifungal that has antiinflammatory properties and may A teaspoon of corn or sunflower oil can be added to enmodulate immune response.30 hance absorption. SPOROTRICHOSIS ■ IODISM ■ DERMATOPHYTOSIS ■ SPINDLE MICROTUBULES

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Adverse Effects Cats seem to be susceptible to the adverse effects of griseofulvin therapy. The most common side effects in small animals include vomiting, diarrhea, and anorexia.38,39 Idiosyncratic reactions and bone marrow suppression (neutropenia, anemia, pancytopenia) have also been reported. Cats with feline immunodeficiency virus seem to be more predisposed to griseofulvin-induced neutropenia.40 Breed predilection to adverse effects among certain feline breeds may exist; Persian, Siamese, and Abyssinian cats have exhibited adverse effects more often.36,38 However, these breeds may be overrepresented because they may be more likely to be presented for treatment than the general feline population. Other unusual side effects, such as ataxia and pruritus, have also been reported with griseofulvin therapy.38,39 Griseofulvin is known to be a potent teratogen and is contraindicated in pregnant animals.41 Sperm abnormalities have also been reported in laboratory animals;42 therefore, the agent should be administered cautiously in active male reproducers. REFERENCES 1. Gupta AK, Sauder DN, Shear NH: Antifungal agents: An overview. Part I. J Am Acad Dermatol 30: 677–698, 1994. 2. Rosychuk RAW: Management of otitis externa. Vet Clin North Am Small Anim Pract 24:921–952, 1994. 3. Armstrong D, Schmitt HJ: Older drugs, in Ryley JF (ed): Handbook of Experimental Pharmacology: Chemotherapy of Fungal Diseases. Berlin, Springer-Verlag, 1990, pp 439–453. 4. Greene CE: Antifungal chemotherapy, in Greene CE (ed): Infectious Diseases of Dogs and Cats. Philadelphia, WB Saunders Co, 649–658, 1989. 5. Atkinson AJ, Bennett JE: Amphotericin B pharmacokinetics in humans. J Antimicrob Chemother 13:271–276, 1978. 6. Van Der Horst CM, Saag MS, Cloud GA, et al: Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 337:15–21, 1997. 7. Hill P, Moriello KA, Shaw SE: A review of systemic antifungal agents. Vet Dermatol 6:59–66, 1995. 8. Legendre AM, Selcer BA, Edwards DF, Stevens R: Treatment of canine blastomycosis with amphotericin B and ketoconazole. JAVMA 184:1249–1254, 1984. 9. Noxon JO: Systemic antifungal chemotherapy, in Kirk RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders Co, 1989, pp 1101–1105. 10. Rubin SI, Krawiec DR, Gelberg H, Shanks RD: Nephrotoxicity of amphotericin B in dogs: A comparison of two methods of administration. Can J Vet Res 53:23–28, 1989. 11. Guillot J, Chermette R, Maillard R: Les candidoses des carnivores domestiques: Actualisation à propos de 10 cas. Point Vét 28:51–60, 1996. 12. Stevens DA: Oral amphotericin B as an antifungal agent. J Mycol Med 6(Suppl II):1–2, 1996. 13. Malik R, Craig AJ, Wigney DI, Martin P, Love DN: Combination chemotherapy of canine and feline cryptococcosis using subcutaneously administered amphotericin B. Aust Vet J 73:124–128, 1996. 14. Legendre AM: Antimycotic drug therapy, in Bonagura JD, Kirk RW (eds): Current Veterinary Therapy. XII. Philadel-

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38. Helton KA, Nesbitt GH, Caciolo PL: Griseofulvin toxicities in cats: Literature review and report of seven cases. JAAHA 22: 453–458, 1986. 39. Scott DW: Fungal disorders: Feline dermatology 1900– 1978: A monograph. JAAHA 16:349–356, 1980. 40. Shelton GH, Grant CK, Linenberg ML, Abkowitz JL: Severe neutropenia associated with griseofulvin therapy in cats with feline immunodeficiency virus infection. J Vet Intern Med 4:317–319, 1990. 41. Scott DW, De Lahunta AD, Schultz RD, et al: Teratogenesis in cats associated with griseofulvin therapy. Teratology 11:79–86, 1975. 42. Wyrobek AJ, Bruce WR: Chemical induction of sperm abnormalities in mice. Proc Natl Acad Sci USA 72:4425–4429, 1975.

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About the Authors Dr. de Jaham is affiliated with the DMV Veterinary Center, Dermatology Service, Ville St-Laurent, Québec, Canada. Dr. Paradis is affiliated with the Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, Québec, Canada. Drs. de Jaham and Paradis are Diplomates of the American College of Veterinary Dermatology. Dr. Papich, who is a Diplomate of the American College of Veterinary Clinical Pharmacology, is affiliated with the Department of Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.