Synthetic Antifungal Agents Flucytosine

Flucytosine is related to fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B. It is well absorbed orally. It is poorly protein-bound and penetrates well into all body fluid compartments including the CSF. It is eliminated by glomerular filtration. Toxicity is more likely to occur in AIDS patients and in the presence of renal insufficiency.

Flucytosine is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.

Clinical Use: Active against Cryptococcus neoformans, some Candida species, and the dematiaceous molds that cause chromoblastomycosis. Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis.

Adverse Effects: The adverse effects of flucytosine result from metabolism (intestinal flora) to the toxic antineoplastic compound flucytosine. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently.

Azoles

Azoles are synthetic compounds that can be classified as imidazoles and triazoles. The imidazoles consist of ketoconazole, miconazole, and clotrimazole. The triazoles include itraconazole and fluconazole.

The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. The specificity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects.

Azoles are active against many Candida species, Cryptococcus neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis), the dermatophytes, and, Aspergillus infections (itraconazole). Adverse Effects: The azoles are relatively nontoxic. The most common adverse reaction is minor gastrointestinal upset. Most azoles cause abnormalities in liver enzymes and, very rarely, clinical hepatitis.