Flucytosine  (PDF Version)

Antibiotic Class:

Antifungal agent

Antimicrobial Spectrum:

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.

Pharmacodynamics:

Time-dependent Killing is most predictive of outcome, although AUC:MIC has some effects.

Pharmacokinetics:

Absorption:  80 to 90% absorption following oral administration

Distribution:  low protein binding (~ 4% at serum concentrations between 2 and 55 g/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

Adverse Effects:

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

Dosage:

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.

Contraindications/Warnings/Precautions:

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

Drug Interactions:

Non-CYP mediated:

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

Pregnancy:

Category C: Risk unknown. Human studies inadequate.

Monitoring Requirements:

Therapeutic drug monitoring:

Goal:  Serum flucytosine concentrations between 25 g/mL and 100 g/mL.   Repeat assays on weekly basis.

Brand names/Manufacturer: