Flucytosine

Flucytosine is converted by cytosine deaminase in fungal cells to fluorouracil, which then interferes with RNA and protein synthesis. Fluorouracil is metabolized to 5-fluorodeoxyuridylic acid, an inhibitor of thymidylate synthetase. DNA synthesis is then halted. Mammalian cells do not convert large amounts of flucytosine to fluorouracil and, thus, are not affected at usual dosage levels.

Resistance to flucytosine can develop rapidly even during the course of treatment; this precludes its use as the sole treatment for mycotic infections. The mechanisms of resistance are not completely understood.

The following are the main organisms usually sensitive to flucytosine: Cryptococcus neoformans, Candida albicans, other Candida spp, Torulopsis glabrata, Sporothrix schenckii, Aspergillus spp, and agents of chromoblastomycosis (Phialophora, Cladosporium). The other fungi responsible for systemic mycoses and dermatophytes are resistant to flucytosine.

Flucytosine is rapidly and well absorbed from the GI tract, with plasma levels peaking in 1–2 hr in animals that have received the drug for several days. The drug is widely distributed in the body, with a volume of distribution approximating the total body water. Flucytosine is minimally bound to plasma proteins. There is excellent penetration into body fluids such as the CSF, synovial fluids, and aqueous humor.

Nearly all (85%–95%) of an oral dose is excreted unchanged. Flucytosine is principally excreted by glomerular filtration (>80%). The clearance of flucytosine is approximately equivalent to that of creatinine. In renal failure, elimination of flucytosine is markedly impaired.

With normal renal function, the plasma half-life of flucytosine is usually 2–4 hr but may be up to 200 hr with oliguria. Serum levels of 50–100 mcg/mL are usually in the therapeutic range.

Flucytosine is often well tolerated over long periods, but toxic effects may be seen when serum levels are high (>100 mcg/mL). These include GI signs (nausea, vomiting, diarrhea) and reversible hepatic and hematologic effects (increased liver enzymes, anemia, neutropenia, thrombocytopenia). In dogs, erythemic and alopecic dermatitis may be seen but subsides when the drug is discontinued.

There is synergistic antifungal activity between amphotericin B and ketoconazole, and the combination may retard the emergence of strains resistant to flucytosine. The renal effects of amphotericin B prolong elimination of flucytosine. If flucytosine is used together with immunosuppressive drugs, severe depression of bone marrow function is possible.

Treatment with flucytosine increases alkaline phosphatase, AST, ALT, and other liver leakage enzymes, and decreases RBC, WBC, and platelet counts.