Flucytosine (5-flucytosine, 5-FC; Ancoban) is a fluori-nated pyrimidine analogue of cytosine that was origi-nally synthesized for possible use as an antineoplastic agent. 5-FC is converted to 5-fluorouracil inside the cell by the fungal enzyme cytosine deaminase. Subse-quently, 5-FC metabolites interfere with fungal DNA synthesis by inhibiting thymidylate synthetase. Incor-poration of these metabolites into fungal RNA may in-hibit protein synthesis.
5-FC is well absorbed orally, with greater than 90% bioavailability. The serum half-life is 3 to 5 hours, with serum levels peaking 4 to 6 hours after a single dose. The drug is widely distributed in body fluids, with cere-brospinal fluid levels 60 to 80% of serum levels.The drug also penetrates well into urine, aqueous humor, and bronchial secretions. Minimal serum protein binding al-lows more than 90% of each dose to be excreted in the urine; significant dosage reductions are required in the presence of renal impairment. 5-FC can be removed by both hemodialysis and peritoneal dialysis. 5-FC conver-sion to toxic metabolites may occur in mammalian cells to a limited extent, which accounts for 5-FC toxicity.
Flucytosine has significant antifungal activity against C. albicans, other Candida spp., C. neoformans, and the fungal organisms responsible for chromomycosis. Not considered the drug of choice for these fungal infec-tions, 5-FC does remain useful as part of combination therapy for systemic candidiasis and cryptococcal meningitis and as an alternative drug for chromomyco-sis. When it is used as monotherapy, resistance and clinical failure are common. Potential mechanisms for drug resistance include decreased fungal cell mem-brane permeability and reduced levels of fungal cytosine deaminase. Combination therapy with am-photericin B and flucytosine in the treatment of cryptococcal meningitis and deep-seated Candida in-fections, such as septic arthritis and meningitis, permits reduced dosing of amphotericin B and prevents the emergence of 5-FC resistance. When higher doses of amphotericin B are used, combination therapy with 5-FC confers no additional clinical benefit except in the treatment of Candida endophthalmitis, where tis-sue penetration remains problematic.
When 5-FC is prescribed alone to patients with normal renal function, skin rash, epigastric distress, diarrhea, and liver enzyme elevations can occur. When it is pre-scribed to patients with renal insufficiency or to patients receiving concurrent amphotericin B therapy, blood lev-els of 5-FC may rise, and bone marrow toxicity leading to leukopenia and thrombocytopenia is common. 5-FC serum levels should be closely monitored in patients with renal insufficiency. Because of baseline leukope-nia, 5-FC is often not tolerated by end-stage HIV-infected patients with disseminated fungal infection.
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