Antifungals that Affect Nucleic Acid Synthesis

ANTIFUNGALS THAT AFFECT NUCLEIC ACID SYNTHESIS

Flucytosine

5-Flucytosine (5FC), which was originally developed as an anticancer drug, is anantimetabolite analog of cytosine. It is a potent inhibitor of RNA, DNA, and ultimately protein synthesis. 5FC enters the cell aided by a permease, where it is converted to 5-fluorouracil by the action of cytosine deaminase. After further modification, 5FC is incor-porated into what becomes defective RNA. Its effect on DNA synthesis is through its conversion to another metabolite (5-fluorodeoxyuridine), which is a potent inhibitor of thymidylate synthetase.

Flucytosine is well absorbed after oral administration. It is active against most clini-cally important yeasts, including C. albicans and C. neoformans, but has little activity against molds or dimorphic fungi. A significant limitation is the development of resis-tance that can occur by single-step mutation during therapy. Potential resistance limits flucytosine use to mild yeast infections or treatment in combination with amphotericin B for life-threatening systemic infections. Use in combination reduces the chance for ex-pression of flucytosine resistance and allows a lower dose of amphotericin B to be used. In some instances, the combination is synergistic. The primary toxic effect of flucytosine is a reversible bone marrow suppression that can lead to neutropenia and thrombocytope-nia. This effect is dose related and can be controlled by drug monitoring.