Antifungal drugs (Proceedings)


Antifungal drugs (Proceedings)

Oct 01, 2008

There are a number of classes of antifungal drugs. Research in antifungal drugs has increased dramatically in the last two decades with the advances in organ transplantation and the epidemic of AIDS. The original antifungal drug was amphotericin B representing the polyene family. Amphotericin B damages the ergosterol of the fungal cell membrane. The next group of drugs was the azoles that inhibit the synthesis of the fungal ergosterol in the cell membrane. These are an important group of fungistatic drugs. Members of this group include ketoconazole, itraconazole, fluconazole as well as newer member such as voriconazole and posaconazole. The allylamine group interferes with ergosterol production in a different manner than the azoles and is effective when azole resistance develops. Terbinafine is the representative of the allylamine group. The glucan synthesis inhibitors interfere with the synthesis of the glucan component of the fungal cell wall thereby providing a different mechanism of action than the other antifungal drugs. The development of many new drugs for fungal infection is encouraging but the high cost of many of the new drugs is prohibitive for long term treatment.

Amphotericin B is the oldest of the antifungal drugs and remains the "gold standard." It is effective against a wide range of fungal organisms and acts in a fungicidal manner damaging the ergosterol of fungal organisms. The damage of the ergosterol results in leakage of the cell and cell death. The need for intravenous administration and the nephrotoxicity of amphotericin B limits its usefulness in long term treatment of fungal infections. It is still very effective for initial treatment of fungal infections because of its rapid action and intravenous route. In dogs with blastomycosis involving the central nervous system it appears to be superior to itraconazole. In dogs with histoplasmosis of the intestinal tract, malabsorption precludes the oral administration of azoles. Amphotericin B can be given initially to restore the function of the intestinal tract so that oral drugs can be used. Short term use of amphotericin B can be done without significant renal damage. It is lifesaving in these situations. There are a number of new amphotericin B drugs that reduce the renal toxicity by lipid encapsulation of the drug. This may be especially useful in infections such as histoplasmosis where the encapsulated drug is phagocytosed by the same macrophages that contain the fungal organisms. This brings drugs and organisms together. The lipid encapsulated drug is expensive and requires an increased dose of amphotericin B.

To avoid amphotericin B renal toxicity, animals need to be well hydrated before giving the drug. Diuresis does not reduce renal toxicity in hydrated dogs but administration over a 3 to 4 hour period reduces renal damage. The drug should be given every 48 hours. BUNs should be done before each dose and drug discontinued as the BUN approaches 50 mg/dl. Starting drug dose in dogs is 0.5 mg/kg and 0.25 mg/kg in cats. There is minimal data on liposome encapsulated amphotericin B but a suggested starting dose is 1 mg/kg. Amphotericin B is as effective as intravenously available azoles but is much cheaper.

Ketoconazole is the first of the azole group of antifungal drugs. The newer azoles such as itraconazole and fluconazole are more effective than ketoconazole and have less toxicity. Ketoconazole frequently produces anorexia in cats. Ketoconazole has a place in the treatment of Malassezia in dogs and has some antiinflammatory effect in addition to its antifungal activity. Ketoconazole seems to be a fairly good drug for coccidioidomycosis but fluconazole is probably better.