Polyene Antibiotics

Polyene antibiotics used to treat systemic mycoses include amphotericin B (AMB) and lipid-complexed AMB. AMB is produced by the microorganism Streptomyces nodosus and is considered the gold standard for antifungal therapy.^1,2 Parenteral administration is required because gastrointestinal absorption is poor. Following intravenous (IV) administration, AMB is protein bound and then redistributes from the blood to the tissues. Metabolic pathways of AMB are poorly understood. Biphasic elimination occurs, with an initial half-life of 2 to 4 days and a terminal half-life of 15 days.³ Only a small amount undergoes renal and biliary elimination, and central nervous system (CNS) penetration is poor. AMB binds to ergosterol in fungal cell membranes, increasing membrane permeability to cause cell death. There is also affinity for cholesterol found in mammalian cell membranes, which explains its toxic effects. Parenteral administration might make AMB a more desirable treatment than oral drugs in animals with severe gastrointestinal fungal disease because they may absorb oral drugs poorly.

Dosing protocols for AMB include intermittent administration until a cumulative dosage has been achieved, with interruption of therapy in the event of azotemia. Cats typically receive lower intermittent and cumulative dosages than dogs (Table 199-1). To reduce nephrotoxicity, AMB usually is infused in 5% dextrose and administered IV over 1 to 5 hours. Blood urea nitrogen and urine sediment evaluation should be measured before each dose. Identification of tubular casts in urine sediment is an earlier indicator of ongoing renal tubular damage than serum biochemical test results, and the treatment regimen should be altered if casts are identified. If blood urea nitrogen exceeds 50 mg/dl, the drug should be discontinued until azotemia resolves.² Administration of 0.9% saline IV before giving AMB decreases the incidence of nephrotoxicity in people.⁴ Medications with known nephrotoxicity should not be given concurrently with AMB.

Table 199-1 Drug Dosages to Treat Common Systemic Fungal Infections in Dogs and Cats

Lipid-complexed AMB drugs are newer preparations and have the advantage of being less nephrotoxic than AMB, even when administered at higher cumulative dosages. Formulations that are approved for use in people include AMB-lipid complex (ABLC, Abelcet), AMB colloidal dispersion (Amphotec), and liposome-encapsulated AMB (AmBisome).¹ All of these compounds require parenteral administration. Few head-to-head comparisons of these drug preparations make comparisons of efficacy difficult.⁵ Abelcet has been used successfully to treat blastomycosis in dogs.⁶ The main disadvantage of these drugs is a significantly greater expense compared with AMB.

Azole Antifungals

The azole antifungal drugs inhibit the fungal P-450 enzyme necessary for development of ergosterol in fungal cell walls.⁵ Itraconazole and fluconazole are newer drugs than ketoconazole with fewer side effects and are mainstays of therapy for veterinary systemic mycoses. These drugs are administered orally, with peak plasma concentrations occurring within 6 to 14 days. Ketoconazole and itraconazole are weak bases, lipophilic, and protein bound. Absorption is improved in an acid environment, and uptake may be impaired with concurrent use of antacids or histamine-2 receptor antagonists. Distribution occurs through most tissues except the CNS and urine. Fluconazole is minimally protein bound, highly water soluble, and crosses the blood-brain, blood-ocular, and blood-prostate barriers.^1,2 Drugs that are metabolized by the hepatic P-450 enzyme system (especially histamine-2 receptor antagonists) may delay metabolism of azole antifungals, especially ketoconazole, thereby resulting in higher plasma drug concentrations.³

Ketoconazole has been effective as a sole agent for treatment of systemic mycoses, but it is less effective than AMB. In serious systemic fungal infections, combination therapy with AMB and ketoconazole may allow reduced dosage and toxicity while maintaining efficacy. Side effects of ketoconazole therapy include GI upset, which may be reduced by administering with meals and dividing the dosage into multiple smaller doses daily. Of the commonly used azole antibiotics, ketoconazole is the most likely to induce mammalian P-450 enzyme systems to cause elevations in hepatic transaminases and alkaline phosphatase. Clinical hepatitis that may be fatal has been recognized.^1,3

Itraconazole has been effective as a sole agent in blastomycosis, histoplasmosis, coccidioidomycosis, and cryptococcosis. Absorption is most consistent when administered with a meal. Itraconazole more selectively inhibits fungal P-450 enzymes than mammalian P-450 enzymes to limit hepatotoxicity. Mild hepatic transaminase elevation can still occur.^1,7

Cutaneous reactions consisting of localized ulcerative dermatitis and vasculitis occur in a small percentage of dogs receiving itraconazole; dermal lesions resolve following discontinuation of therapy.² Itraconazole is available from many veterinary formulating pharmacies at a reduced cost compared with the brand name pharmaceutical preparation (Sporanox); however, efficacy of generic preparations has not been proven. The commercially available liquid form may be better absorbed orally, especially in cats.⁸ An IV injectable form is available for treatment of severe, resistant fungal infections.²

Fluconazole crosses the blood-brain barrier better than the other azole antifungals and has more consistent oral absorption on an empty stomach. Therefore it is indicated for CNS involvement in systemic mycoses and for anorexic animals. Fluconazole has been used successfully to treat cryptococcosis in cats.⁹ Fluconazole is metabolized minimally and is excreted mostly in an intact form in the urine. The dosage of fluconazole should be reduced in animals with decreased glomerular filtration rates.²

Voriconazole is a synthetic derivative of fluconazole that has been approved by the US Food and Drug Administration and is available to veterinarians. It is licensed for use in humans to treat invasive aspergillosis and oropharyngeal candidiasis in immunocompromised patients. Cost is prohibitive for routine use, and there are no published reports of use in dogs or cats.^1,2