Antifungals for Integumentary Disease in Animals

Itraconazole is a synthetic, broad-spectrum antifungal drug belonging to the imidazole family. It is a potent inhibitor of ergosterol (a main membrane lipid of fungi) synthesis. Fungal cells are thus unable to maintain the integrity of plasma membranes, which leads to cell wall rupture. Even at high dosages, it does not alter hormone concentrations in rats, dogs, or humans. Itraconazole should be administered with food to decrease pH and increase absorption; concurrent administration of antacids, H₂-blockers, and cholinergics is contraindicated.

Itraconazole is effective against dermatophytes, Malassezia, Candida, Cryptococcus, Histoplasma, Blastomyces, and Sporothrix spp as well as the protozoans Leishmania and Trypanosoma. For dermatophytosis in dogs, the dosage is 5 mg/kg, PO, every 24 hours until mycological cure. For systemic mycoses, the dosage is 5–10 mg/kg, PO, every 24 hours for 60 days; however, addition of amphotericin B should be considered in rapidly progressing infections. For treatment of dermatophytosis and systemic mycoses in cats, the dosage is 5 mg/kg, PO, every 24 hours. For dermatophytosis in cats, the dose is administered once daily for 7 days on alternating weeks for three treatment cycles (ie, treatment in week 1, 3, and 5).

A severe, dose-related ulcerative dermatitis (due to vasculitis) occurs in 5%–10% of dogs administered itraconazole in doses >10 mg/kg. If the condition is identified early, drug withdrawal leads to resolution; if not recognized early, severe, extensive necrosis and sloughing can develop.

The primary antifungal mechanism of action of itraconazole seems to be the same as that of ketoconazole; however, ketoconazole has a lower potency, increased toxicity, and a narrower spectrum of activity than itraconazole. Because the therapeutic effect of ketoconazole is delayed, amphotericin B is often used in combination for cases of serious systemic disease.

For dermatophytosis, ketoconazole (10 mg/kg, PO, every 24 hours for 4–8 weeks) is active against Trichophyton verrucosum, T equinum, T mentagrophytes, Microsporum canis, and M nanum. Ketoconazole is also active against the yeast Malassezia pachydermatis (10 mg/kg, PO, every 24 hours for 3 weeks) and Cryptococcus neoformans (10 mg/kg, PO, every 24 hours for 6–18 months). For candidiasis, the dosage is 10 mg/kg, PO, every 24 hours for 6–8 weeks. In some chronic cases, a maintenance dose of 2.5–5 mg/kg can be administered. Coccidioidomycosis responds better to ketoconazole than to amphotericin B in many instances, with a minimal treatment period of 12 months in animals with disseminated disease. Blastomycosis, histoplasmosis, and cryptococcosis may be treated with a combination of ketoconazole and amphotericin B (the combination is not more effective than the latter alone; however, there are fewer nephrotoxic signs). For blastomycosis, a 4–6 mg/kg total dose of amphotericin B is combined with ketoconazole (20 mg/kg, PO, every 24 hours for 60–90 days in dogs, and 10 mg/kg, PO, every 24 hours for 60–90 days in cats). For histoplasmosis, amphotericin B (2–4 mg/kg total dose) is combined with ketoconazole (20 mg/kg, PO, every 24 hours for 4–6 months in dogs, and 10 mg/kg, PO, every 24 hours for 9–12 months in cats).

Ketoconazole inhibits cortisol synthesis and has been used to treat canine pituitary-dependent hyperadrenocorticism at 10 mg/kg, PO, every 24 hours for life. If the cortisol level is still above resting levels after 10 days, the dosage may be increased to 15 mg/kg, PO, every 24 hours.

Ketoconazole requires an acidic environment for optimal absorption, so H₂-blockers or antacids should not be administered concurrently.

In dogs, the most common adverse effects are inappetence, vomiting, pruritus, alopecia, and reversible lightening of the coat. Anorexia may be reduced by administering the dose with food. Cats appear to be more sensitive to ketoconazole, and some clinicians do not recommend use of ketoconazole in this species. Clinical signs of toxicosis include anorexia, fever, depression, diarrhea, and increased liver enzymes. Dosages >10 mg/kg, PO, every 24 hours are rarely administered. Hepatotoxicity (cholangiohepatitis and increased liver enzymes) has also been reported.

Fluconazole is a fungistatic triazole compound with a mode of action similar to that of ketoconazole. However, it does not affect mammalian hormone synthesis. Because of its small molecular size and low protein binding, it may be more useful in treating CNS mycoses.

Fluconazole is primarily used in the treatment of systemic mycoses such as Cryptococcus, Histoplasma, and Blastomyces spp. It has activity against dermatophytes but has the highest minimum inhibitory concentration (MIC) compared with itraconazole, ketoconazole, terbinafine, or griseofulvin for both Microsporum or Trichophyton spp. The dosage is 2.5–10 mg/kg, PO, every 24 hours in dogs for 56–64 days. Cats with cryptococcosis can be administered 2.5–10 mg/kg, PO, every 12 hours for at least 2 months beyond clinical remission (approx 8 months). Fluconazole does not require low pH for absorption and can be administered with or without food.

Fluconazole has had limited use in small animals. In humans, it can cause occasional gastrointestinal adverse effects (eg, vomiting, diarrhea, anorexia, and nausea).

Terbinafine is an allylamine compound that interferes with fungal sterol biosynthesis at an early stage, causing deficiency of ergosterol, intracellular accumulation of squalene, and fungal cell death. It achieves high concentrations in hair follicles, hair, sebum-rich skin, nail plates, and nails. In humans, serum concentrations exceeding the minimum inhibitory concentration may be found for up to 3 weeks after treatment has ended. There are anecdotal reports of its use against Trichophyton, Microsporum, and Epidermophyton. The dosage in cats is 10–30 mg/kg, PO, every 24 hours until mycological cure. In dogs, it is well absorbed at a dose of 30 mg/kg, PO; however, it does not accumulate or persist in the skin as it does in humans or cats. In humans, rare cases of hepatic toxicity occur, along with gastrointestinal signs (eg, nausea, vomiting, and diarrhea) and skin signs (eg, urticaria, itch, and erythema). Clinical efficacy of terbinafine in horses has not been well established.

Griseofulvin has a very low solubility in water; gastrointestinal absorption is variable and incomplete with the micronized form. Absorption may be enhanced by administration with a fat-containing meal or by formulations using polyethylene glycol or very small particles (micronization). The ultramicronized form is nearly 100% absorbed.

Griseofulvin is concentrated in skin (the highest concentration is in the stratum corneum), hair, nails, fat, skeletal muscle, and liver and can be found in the stratum corneum within 4 hours after dosing. It is also secreted in sweat and is deposited in keratinocytes and remains tightly bound during differentiation, so new skin growth is the first to be clear of infection. It is effective only against dermatophytes (eg, Microsporum, Trichophyton, and Epidermophyton).

In dogs, adverse effects (eg, vomiting, diarrhea) and increased liver enzyme activity predominate. In cats, anemia, leukopenia, vomiting, diarrhea, depression, pruritus, fever, and ataxia have been noted. Bone marrow suppression (usually manifest as neutropenia) may occur idiosyncratically, especially in feline immunodeficiency virus (FIV)-positive cats and in kittens. The FIV status of cats should be determined before use, and griseofulvin should be avoided in kittens < 8 weeks old. Reactions may be more common and severe in Persian, Himalayan, Siamese, and Abyssinian cats. Teratogenicity is a major problem in all species.

Hemograms should be monitored every 2 weeks and close observation maintained. Leukopenia is more common in FIV-positive cats, so screening should be done before initiating treatment.

Amphotericin B is a lipophilic polyene from Streptomyces nodosus that binds to sterols (especially ergosterol), causing increased permeability and leakage of nutrients and electrolytes. It is poorly absorbed from the gastrointestinal tract and must be administered parenterally. Intravenous administration gives good penetration, except into muscle, bone, eye tissue, or synovial fluid.

Amphotericin B is used in progressive or disseminated deep mycosis. It may be combined with flucytosine or minocycline for treatment of Candida and Cryptococcus. Rifampin potentiates the effect of amphotericin B on Aspergillus (which is usually resistant to amphotericin alone), Candida, and Histoplasma.

Amphotericin B is insoluble in water and is prepared as a solution for IV injection by forming a colloidal dispersion with sodium deoxycholate. Because it is inactivated by sunlight, it should be stored in the dark. Dilution with large volumes of 5% glucose (10 mg of amphotericin B per 100 mL fluid) is recommended to reduce nephrotoxicity. The dilution should be administered over 2–6 hours. If a bolus is administered in 10–60 mL of dextrose (via a butterfly catheter), supplemental fluid diuresis is helpful. Amphotericin B is administered at 0.15–0.5 mg/kg every 48 hours until a total cumulative dose of 4–12 mg/kg is reached. Renal toxic effects are monitored by electrolytes or urinalysis at least weekly (urinalysis detects toxicosis earlier than serum biochemical analysis); BUN concentration, creatinine concentration, PCV, and total plasma protein concentration should be checked before each dose. Monthly maintenance treatment is recommended to avoid relapses.

The major adverse effect that occurs with amphotericin B is nephrotoxicity—most dogs incur some kidney damage. The damage is not correlated with either total dose or duration of treatment. The causes of nephrotoxicity include vasoconstriction, impaired acid excretion, and direct tubular injury. Cats are more sensitive, so lower doses are recommended. Adverse effects such as fever, nausea, and vomiting are less severe if diphenhydramine (0.5 mg/kg, IV), aspirin (10 mg/kg, PO), or hydrocortisone sodium succinate (0.5 mg/kg, IV) is administered before amphotericin B.

Flucytosine is a fluorinated pyrimidine that was developed as an antineoplastic agent. It interferes with RNA metabolism and protein synthesis in fungal cells. It is well absorbed and enters the CNS in high concentrations. Most of the drug is excreted unchanged in the urine.

Flucytosine is effective against Cryptococcus neoformans, Candida, and other yeasts but has little or no effect on other fungi. Resistance develops frequently; thus, it is administered in combination with amphotericin B. It is used almost exclusively for treatment of cryptococcosis. The dosage in dogs and cats is 25–50 mg/kg, PO, every 6–8 hours for 42 days.

Gastrointestinal tract disturbances (vomiting, diarrhea, and anorexia), bone marrow suppression (anemia, leukopenia, and thrombocytopenia), and cutaneous eruption (depigmentation, ulceration, exudation, and crust formation) are the most common adverse effects.

The mechanism of action of iodide against fungal organisms is unknown; no fungicidal effects occur in vitro. It is used in small animals for sporotrichosis, in cattle for actinomycosis and actinobacillosis, and in horses for mycetomas, zygomycosis, and Sporothrix schenckii. Dogs are treated with potassium iodide (40 mg/kg, PO, every 12 hours for 60 days), cats with potassium iodide (20 mg/kg, PO, every 12–24 hours for 60 days), cattle with sodium iodide (60 mg/kg, IV, every 7 days), and horses (sporotrichosis) with sodium iodide (40 mg/kg, IV, every 24 hours for 2–5 days) followed by potassium iodide (2 mg/kg, PO, every 24 hours for 60 days).

In small animals, vomiting, diarrhea, depression, and inappetence (especially in cats) may develop. Ocular and nasal discharge, scaling, and a dry coat also may be evident in dogs. In large animals, seromucoid discharge, lacrimation, cough, variable appetite, joint pain, and seborrhea sicca with partial alopecia may develop. Systemic iodide may also cause abortion and should not be used in pregnant or lactating animals.

• Malik et al. Combination chemotherapy of canine and feline cryptococcosis using subcutaneously administered amphotericin B. Aust Vet J 1996;73(4):124-128.

• Also see pet health content regarding drugs used to treat skin disorders.