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.
A scanning electron photomicrograph of Cryptococcus neoformans (magnification X1,200). Image copyright Dennis Kunkel Microscopy,
Inc.
|
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.
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
Table 1: Recommended Dosages of Antifungals in Dogs and Cats*
|
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.
Potential indications
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