Systemic Antifungal Therapy

Chapter 263

Systemic Antifungal Therapy

Over the past three decades, immunocompromise associated with human immunodeficiency virus infection and transplantation medicine has resulted in the emergence of opportunistic fungi as increasingly important causes of morbidity and mortality in human patients. The subsequent demand for safer and more effective antifungal therapies has led to the development of new pharmacologic agents that selectively target components unique to fungi (such as the cell wall), as well as the reformulation of drugs with good efficacy but a narrow therapeutic window (such as amphotericin B) in ways that make them less toxic. In addition, new drugs with a broader spectrum of activity have been developed in classes of drugs (such as the azoles) that traditionally have been valuable for the treatment of fungal infections in veterinary patients. Consequently, veterinarians recently have gained access to a number of new antifungal drugs with high efficacy and low toxicity that, despite being limited in use in some patients because of high cost, hold significant promise for the treatment of mycotic infections in small animal patients. The purpose of this chapter is to provide indications, initial drug protocol recommendations, and information concerning potential toxicities for the antifungal drugs most frequently prescribed to dogs and cats (Table 263-1). For amphotericin products, the drug generally is dosed repeatedly to a cumulative drug target as described. For the other antifungal drugs, duration of therapy varies with the fungal species and clinical manifestations in the individual case. However, the duration of therapy is generally weeks to months.

TABLE 263-1

Drugs Used for Systemic Antifungal Therapy in Dogs and Cats

Drug* Dosage Formulations
Amphotericin B deoxycholate 0.5-1 mg/kg IV infusion three times weekly to a cumulative dose of 4-8 mg/kg (dogs)
0.25 mg/kg IV infusion three times weekly to a cumulative dose of 4-6 mg/kg (cats)
50-mg vial (reconstitute with 10 ml sterile water, then dilute to 0.1 mg/ml with 5% dextrose for IV infusion)
Amphotericin B lipid complex 1-3 mg/kg IV infusion three times weekly to a cumulative dose of 12-36 mg/kg (dogs)
1 mg/kg IV infusion three times weekly to a cumulative dose of 12 mg/kg (cats)
100-mg vial (dilute to 1 mg/ml in 5% dextrose for IV infusion); although each 100-mg vial is labeled for single use only, the doses for each treatment can be aliquoted into sterile vials and used for up to 1 wk after the 100-mg vial is opened
Itraconazole 5-10 mg/kg/day PO (dogs)
5 mg/kg q12h PO (25 or 50 mg per cat)
100-mg capsule
10-mg/ml oral solution
Fluconazole 5-10 mg/kg/day PO or IV (dogs)
50-100 mg per cat per day PO (cats)
50-mg, 100-mg, 150-mg, 200-mg oral tablets; 150-mg oral capsule
10-mg/ml, 40-mg/ml powder for oral suspension
100 ml or 200 ml of 2-mg/ml solution for IV infusion
Voriconazole 4 mg/kg q12h PO or IV (dogs)
Do not use in cats
50-mg, 200-mg oral tablets
40-mg/ml powder for oral suspension
200-mg vial (reconstitute with sterile water to 10 mg/ml for IV infusion)
Posaconazole 5 mg/kg q24h PO (dogs and cats) 40-mg/ml powder for oral suspension
Ketoconazole 10-15 mg/kg q12h PO (dogs)
5-10 mg/kg q24h PO (cats)
200-mg oral tablet
Caspofungin 1 mg/kg IV infusion q24h (dogs) 50-mg, 70-mg vials (dilute in 0.9% saline for IV infusion)
Flucytosine 50 mg/kg q6-8h PO (cats)
Do not use in dogs
250-mg, 500-mg oral capsules
Terbinafine 10-30 mg/kg q24h PO (dogs and cats) 250-mg oral tablets

*For amphotericin products, the drug generally is dosed repeatedly to a cumulative drug target as described. For the other antifungal drugs, duration of therapy will vary by the fungal agent and clinical manifestations in the individual case. However, the duration of therapy generally is weeks to months.

Amphotericin B

Amphotericin B, a polyene antibiotic, traditionally has been the treatment of choice for invasive fungal infections in human and veterinary patients because it is highly active against a wide range of fungal organisms. Because it is absorbed poorly from the gastrointestinal tract, amphotericin B must be given parenterally. Following intravenous administration, amphotericin B is highly protein bound and then is redistributed quickly to tissues. It acts by binding to ergosterol in the fungal cell membrane; this compromises membrane stability and alters permeability, which leads quickly to leakage of cell contents and cell death. Although amphotericin B has greater affinity for fungal ergosterol than for mammalian cholesterol, its clinical usefulness has been hampered by dose-limiting nephrotoxicity, which may be mediated by direct renal epithelial cytotoxicity as well as renal vasoconstriction. As a result, when the original formulation of amphotericin B (amphotericin B deoxycholate [Fungizone]) is used for the treatment of systemic mycoses in dogs and cats, nephrotoxicity may occur before an effective cumulative dose can be administered. However, the development of novel delivery systems for amphotericin B in the early 1990s resulted in three newer (albeit more expensive) formulations with reduced nephrotoxicity and improved organ-specific drug delivery: amphotericin B lipid complex (Abelcet), amphotericin B colloidal dispersion (Amphotec), and liposomal amphotericin B (AmBisome).

Amphotericin B is used for the initial treatment of rapidly progressive or severe systemic mycoses (for which oral azoles are not likely to act quickly enough) or treatment of systemic mycoses that fail to respond to azole therapy, and provides a less expensive alternative to parenteral azole therapy in the treatment of fungal disease of the gastrointestinal tract when frequent vomiting precludes the use of oral medications. Amphotericin B has been used successfully in both human and veterinary patients for the treatment of blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, aspergillosis, hyalohyphomycosis, phaeohyphomycosis, sporotrichosis, zygomycosis, disseminated candidiasis, and rarely pythiosis.

Amphotericin B Deoxycholate

Amphotericin B deoxycholate typically is administered as a series of intravenous infusions. Dogs receive 0.5 to 1 mg/kg IV three times weekly to a cumulative dose of 4 to 8 mg/kg or until azotemia develops; cats receive 0.25 mg/kg IV three times weekly to a cumulative dose of 4 to 6 mg/kg. Each dose should be diluted in 5% dextrose and administered to a well-hydrated patient over 10 minutes to 5 hours. Sodium loading and longer infusion times may reduce nephrotoxicity and diminish infusion-related adverse effects, such as trembling, pyrexia, and nausea. Infusion-related adverse effects also may be lessened by pretreatment with diphenhydramine (0.5 mg/kg IV or PO), aspirin (10 mg/kg PO) or other nonsteroidal antiinflammatory drugs, or a physiologic dose of a glucocorticoid. Not all animals experience infusion-related adverse effects, so nonsteroidal antiinflammatory drugs and glucocorticoids should be only administered if such adverse effects are likely based on previous observations. Additionally, tolerance to infusion-related adverse effects often occurs over time, which reduces the need for pretreatment with antiinflammatory drugs. Saline diuresis before administration of amphotericin B may decrease its effect on renal blood flow and should be considered in patients with preexisting renal disease or those at high risk of nephrotoxicity. Other adverse effects reported in humans treated with amphotericin B include hypokalemia, distal renal tubular acidosis, hypomagnesemia, anemia, and nephrogenic diabetes insipidus.

Serum levels of blood urea nitrogen (BUN) and creatinine should be measured before each infusion. If azotemia develops, infusions should be discontinued until it has resolved. Amphotericin B–induced azotemia usually is reversible, but it may take weeks to months for BUN and creatinine levels to return to baseline. Permanent renal damage is more likely to occur in patients with underlying renal disease and in those that are receiving other nephrotoxic drugs concurrently.

A protocol for subcutaneous administration of amphotericin B was developed with the intent of decreasing nephrotoxicity and avoiding the need for prolonged vascular access, and its use for the treatment of cryptococcosis was described by Malik and colleagues (1996) in three dogs and three cats. Amphotericin B deoxycholate (0.5 to 0.8 mg/kg) was diluted in 400 ml (for cats) or 500 ml (for dogs) of 0.45% NaCl/2.5% dextrose and administered subcutaneously two to three times per week to a cumulative dose of 8 to 26 mg/kg. Although this protocol was successful in the six patients described, sterile abscesses caused by local tissue irritation occurred at concentrations higher than 20 mg/L, which is unavoidable in very large dogs. In addition, sterile abscesses often are seen even in smaller dogs for which more dilute concentrations are attainable. Despite this significant adverse affect, this protocol provides an alternative for antifungal therapy when financial limitations preclude the use of triazoles or amphotericin B lipid complex.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Systemic Antifungal Therapy

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