Fungi: Candida albicans, C. glabrata, C. lusitaniae, C. krusei (less susceptible), Cryptococcus neoformans, Cladosporium spp., Phialophora spp., Fonsecaea pedrosoi, Saccharomyces cerevisiae, sporotrichosis, Rhodotorula, Penicillium, Paecilomyces, Aspergillus spp. (less susceptible)
Mechanism of Action:
Penetrates the fungal cell wall and is converted to 5-fluorouracil which competes with uracil, thus interfering with fungal RNA and protein synthesis.
Time-dependent Killing is most predictive of outcome, although AUC:MIC has some effects.
Absorption: 80 to 90% absorption following oral administration
Distribution: low protein binding (~ 4% at serum concentrations between 2 and 55 µg/mL); widely distributes in body water (volumes of distribution from 0.6 to 0.9 L/kg); penetrates into CNS, urine, peritoneal fluid, and respiratory system
Metabolism: minimal hepatic metabolism
Elimination: renal elimination (urine); up to 96% of the total dose may be eliminated as unchanged drug
Hematologic: leucopenia, thrombocytopenia, bone marrow aplasia
Gastric: intestinal perforation, ulcerating enterocolitis
Hepatic: elevated liver enzymes, hepatitis, jaundice, azotemia
Dermatologic: photosensitivity reaction
CNS (rare): headache, drowsiness, confusion, hallucinations
Oral dose: recommended dose 100 mg/kg/day in divided doses
Oral dose for severe infections: up to 250 mg/kg/day
Cryptococcal meningitis: 100 mg/kg/day
Disease state based dosing:
Renal Failure: Table 1
Hepatic failures: No dosage adjustment required.
Warnings: Use extreme caution in patients with renal impairment, bone marrow suppression, or in patients with AIDS; dosage modification required in patients with impaired renal function
Aluminum hydroxide/Magnesium hydroxide – delay absorption of flucytosine
Zidovudine, ganciclovir, trimethoprim-sulfamethoxazole – may potentiate hematological toxicity
Amphotericin B and foscarnet – may potentiate toxicities related to excessive flucytosine levels
Category C: Risk unknown. Human studies inadequate.
Therapeutic drug monitoring:
Goal: Serum flucytosine concentrations between 25 µg/mL and 100 µg/mL. Repeat assays on weekly basis.