Flucytosine

Mechanism: Flucytosine is taken up by fungal cells via cytosine permease and converted by cytosine deaminase (an enzyme absent in human cells) into 5-fluorouracil (5-FU). 5-FU is then converted to 5-fluorodeoxyuridine monophosphate (FdUMP), which inhibits thymidylate synthase, disrupting DNA synthesis. It is also incorporated into RNA as 5-fluorouridine triphosphate (FUTP), impairing protein synthesis. Selective toxicity arises because human cells lack significant cytosine deaminase activity, though gut flora can convert some flucytosine to 5-FU, contributing to toxicity.

Clinical use: Used in combination with amphotericin B for treatment of systemic mycoses, particularly Cryptococcus neoformans meningitis (classic combination in AIDS patients or immunocompromised hosts) and occasionally Candida infections. Synergistic combination therapy improves efficacy and reduces the emergence of resistance, which occurs rapidly with monotherapy due to single point mutations affecting cytosine permease or deaminase.

Pharmacokinetics: Well absorbed orally, widely distributed including CSF penetration (useful for CNS fungal infections), and primarily renally excreted (requires dose adjustment in renal impairment).

Adverse effects: Bone marrow suppression (anemia, leukopenia, thrombocytopenia) due to conversion of some drug to 5-FU in the gut and systemically; hepatotoxicity; GI disturbances. Toxicity is more pronounced in patients with renal insufficiency because of drug accumulation.

Key boards associations: Remember synergy with amphotericin B (which increases fungal cell membrane permeability, enhancing flucytosine uptake), especially for cryptococcal meningitis treatment regimen (induction: amphotericin B + flucytosine, followed by fluconazole maintenance).