A 35-year-old HIV patient with a CD4 count of 80 cells/mm3 develops CNS cryptococcosis. After induction with liposomal amphotericin B and flucytosine, he is started on oral fluconazole maintenance. Flucytosine exerts antifungal activity through a unique mechanism. After entering fungal cells via cytosine permease, it is converted to:

• A 5-fluorodeoxyuridine monophosphate (5-FdUMP), which inhibits thymidylate synthase, disrupting fungal DNA synthesis — in addition to RNA misincorporation ✓
• B 5-fluorouridine triphosphate (5-FUTP), which is incorporated into fungal RNA in place of uridine, disrupting protein synthesis
• C 5-fluorouracil glucuronide, which inhibits ergosterol synthesis by blocking C-14 demethylase
• D Fluconazole, through de-esterification in the fungal cytoplasm, thereby functioning as a prodrug of the azole

Explanation

Flucytosine enters fungi via cytosine permease (absent in human cells) and is deaminated by fungal cytosine deaminase to 5-fluorouracil (5-FU). Within the cell, 5-FU is converted to both 5-FUTP (incorporated into RNA, disrupting protein synthesis) and 5-FdUMP (inhibiting thymidylate synthase, blocking dTMP synthesis and DNA replication). Both mechanisms contribute to antifungal activity. Resistance develops rapidly if used alone, necessitating combination with amphotericin B. Flucytosine does not inhibit ergosterol synthesis (that is azoles and amphotericin B) and is not a prodrug of fluconazole.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.