In induction therapy for cryptococcal meningitis, flucytosine is given with amphotericin B partly to limit emergence of resistance. Resistance develops rapidly during monotherapy because:

• A Cryptococcus upregulates ABC transporters pumping out flucytosine
• B Loss of fungal cytosine deaminase or uracil phosphoribosyltransferase prevents conversion to 5-FU metabolites ✓
• C Mutation of the target ribosomal 28S subunit reduces binding
• D Cryptococcus acquires a bacterial beta-lactamase-like hydrolase

Explanation

Flucytosine enters fungi via cytosine permease and is converted by cytosine deaminase to 5-fluorouracil, then to active nucleotides inhibiting thymidylate synthase and RNA processing. Human cells lack cytosine deaminase, explaining selective toxicity. Single point mutations inactivating cytosine deaminase or uracil phosphoribosyltransferase arise readily, so flucytosine is never used alone. Efflux pumps explain azole resistance in Candida, not flucytosine failure in Cryptococcus.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.