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Flucytosine (5-fluorocytosine) is a fluorinated pyrimidine related to fluorouracil that was initially developed as an antineoplastic agent. It should be stored in airtight containers protected from light. Solutions for infusion are unstable and should be stored at 15–20°C. Usually, it is given PO in capsules.
Antifungal Activity
Mode of Action
Flucytosine is converted by cytosine deaminase in fungal cells to fluorouracil, which then interferes with RNA and protein synthesis. Fluorouracil is metabolized to 5-fluorodeoxyuridylic acid, an inhibitor of thymidylate synthetase. DNA synthesis is then halted. Mammalian cells do not convert large amounts of flucytosine to fluorouracil and, thus, are not affected at usual dosage levels.
Fungal Resistance
Resistance to flucytosine can develop rapidly even during the course of treatment; this precludes its use as the sole treatment for mycotic infections. The mechanisms of resistance are not completely understood.
Antifungal Spectra
The following are the main organisms usually sensitive to flucytosine: Cryptococcus neoformans, Candida albicans, other Candida spp, Torulopsis glabrata, Sporothrix schenckii, Aspergillus spp, and agents of chromoblastomycosis (Phialophora, Cladosporium). The other fungi responsible for systemic mycoses and dermatophytes are resistant to flucytosine.
Pharmacokinetic Features
Absorption and Distribution
Flucytosine is rapidly and well absorbed from the GI tract with plasma levels peaking in 1–2 hr in animals that have received the drug for several days. The drug is widely distributed in the body with a volume of distribution approximating the total body water. Flucytosine is minimally bound to plasma proteins. There is excellent penetration into body fluids such as the CSF, synovial fluids, and aqueous humor.
Biotransformation and Excretion
Nearly all (85–95%) of an oral dose is excreted unchanged. Flucytosine is principally excreted by glomerular filtration (>80%). The clearance of flucytosine is approximately equivalent to that of creatinine. In renal failure, elimination of flucytosine is markedly impaired.
Pharmacokinetics
With normal renal function, the plasma half-life of flucytosine is usually 2–4 hr but may be up to 200 hr with oliguria. Serum levels of 50–100 μg/mL are usually in the therapeutic range.
Therapeutic Indications and Dose Rates
The more common indications for flucytosine include cryptococcal meningitis, used together with amphotericin B (~30% of the isolates develop resistance during the course of treatment); candidiasis (~90% of isolates are usually sensitive); aspergillosis (some strains are sensitive at <5 μg/mL); chromomycosis (some strains are very sensitive); and sporotrichosis (some cases may respond).
General dosages for flucytosine are 25–50 mg/kg and 30–40 mg/kg, PO, tid-qid in dogs and cats, respectively. The dose rate and frequency should be adjusted as needed for the individual animal. Dosage modification is essential in renal failure. Flucytosine serum levels should be monitored if possible.
Special Clinical Concerns
Adverse Effects and Toxicity
Flucytosine is often well tolerated over long periods, but toxic effects may be seen when serum levels are high (>100 μg/mL). These include GI signs (nausea, vomiting, diarrhea) and reversible hepatic and hematologic effects (increased liver enzymes, anemia, neutropenia, thrombocytopenia). In dogs, erythemic and alopecic dermatitis may be seen but subsides when the drug is discontinued.
Interactions
There is synergistic antifungal activity between amphotericin B and ketoconazole, and the combination may retard the emergence of strains resistant to flucytosine. The renal effects of amphotericin B prolong elimination of flucytosine. If flucytosine is used together with immunosuppressive drugs, severe depression of bone marrow function is possible.
Effects on Laboratory tests
Alkaline phosphatase, AST, ALT, and other liver leakage enzymes increase. RBC, WBC, and platelet counts decrease.
Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP
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