Although griseofulvin is the only antifungal approved for systemic administration by the Food and Drug Administration (FDA) for veterinary use, a variety of systemic antifungals are available for use in veterinary medicine. With the introduction of generic formulations, prescribing many of them is no longer cost-prohibitive. The development of newer antifungals such as itraconazole, fluconazole, voriconazole, and posaconazole has been spurred on by the occurrence of resistance in fungal organisms, as seen in bacteria.
This review addresses the mechanisms of action, potential indications, pharmacokinetics, adverse effects, and recommendations for the use of several azole antifungal drugs—ketoconazole, itraconazole, fluconazole, voriconazole, and posaconazole—as well as terbinafine in veterinary patients. The azole antifungal drugs were first discovered in the early 1970s, with ketoconazole being the first orally active azole antifungal.1 The azoles have a broad spectrum of antifungal activity, but important differences exist. Terbinafine is not an azole antifungal drug, but it has a broad spectrum of activity against many yeast and fungal organisms. See Table 1 for the recommended dosages for these antifungals.
A scanning electron photomicrograph of Cryptococcus neoformans (magnification X1,200). Image copyright Dennis Kunkel Microscopy, Inc.
MECHANISM OF ACTION
The azole antifungal drugs have a similar mechanism of action, which is inhibiting the cytochrome P (CYP)-450-dependent enzyme, lanosterol-14alpha-demethylase. This enzyme is responsible for forming ergosterol. Ergosterol depletion results in disruption of cell wall function. Lanosterol-14alpha-demethylase is present in most species of yeasts and molds with the exception of Pythium species.2 Lanosterol-14alpha-demethylase is also present in Leishmania species, which explains the variable activity of the azoles in leishmaniasis.3-5 The azoles have a higher affinity for fungal CYP than they do for mammalian CYP; however, adverse effects in mammals are due in part to inhibiting mammalian CYP. Decreased synthesis of testosterone, cortisol, cholesterol, and androgens may occur during azole administration.1
Terbinafine's mechanism of action differs from that of the azoles. It inhibits the enzyme squalene epoxidase with a net effect of decreasing ergosterol formation.1 The different mechanism of action results in a different adverse effects profile (i.e. terbinafine does not inhibit mammalian CYP and has fewer drug-drug interactions) and may be efficacious in organisms resistant to the azoles.
Ketoconazole is still used regularly in veterinary medicine, but its use is being supplanted by some of the newer antifungal agents. Ketoconazole, which is available as 200-mg tablets, is an affordable alternative when itraconazole or voriconazole are cost-prohibitive. However, ketoconazole has a lower efficacy against many fungal organisms compared with itraconazole and voriconazole, and ketoconazole may have a greater potential for adverse effects. The typical cost of ketoconazole treatment for a 44-lb (20-kg) dog (10 mg/kg orally twice a day) is about 50¢/day.
Table 1: Recommended Dosages of Antifungals in Dogs and Cats*
Ketoconazole is typically effective for the systemic treatment of otitis and dermatitis caused by Malassezia species as well as of infections caused by Candida species and dermatophytosis caused by Microsporum canis.1,6 Ketoconazole has also been used to treat blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and aspergillosis, but itraconazole is considered more efficacious in treating these infections.1