Flucytosine

Flucytosine is an oral (and in some places intravenous) fluorinated pyrimidine used only in combination with another antifungal. Its main role is cryptococcal meningitis, where adding it to amphotericin B lowers mortality and speeds clearance of yeast from cerebrospinal fluid. Resistance develops rapidly when used alone. Bone marrow suppression and hepatotoxicity are dose-dependent and rise sharply in kidney failure.

Class. Pyrimidine analogue antifungal.

Mechanism. Converted by fungal cytosine deaminase to 5-fluorouracil, which is incorporated into RNA and inhibits thymidylate synthase and DNA synthesis. Human cells lack the enzyme, but gut bacteria convert some drug, which contributes to toxicity.

Pharmacokinetics. Over 90% absorbed orally, minimal protein binding, excellent tissue and cerebrospinal fluid penetration. Half life 3 to 6 hours in normal kidney function and up to 85 hours in kidney failure. About 90% excreted unchanged in urine.

Cryptococcal meningitis (induction, with amphotericin B). - 100 mg/kg daily orally in four divided doses (25 mg/kg every 6 hours), based on ideal body weight. - Duration: 7 days with amphotericin B deoxycholate (short-course regimen), 14 days with liposomal amphotericin B or in a single-dose liposomal regimen. - Loading dose: none. Maximum: 150 mg/kg daily in rare specialist use; routine 100 mg/kg daily.

Invasive candidiasis (resistant or deep-seated; with amphotericin B). 100 to 150 mg/kg daily in four divided doses.

Children. 100 mg/kg daily in four doses; neonates and infants need level monitoring.

Kidney-adjusted dosing. - CrCl 20 to 40 mL/min: 25 mg/kg every 12 hours. - CrCl 10 to 20 mL/min: 25 mg/kg every 24 hours. - CrCl under 10 mL/min: 25 mg/kg every 48 hours, or dose after dialysis, adjusted to levels.

Therapeutic drug monitoring. Peak 2 hours after a dose 30 to 80 mg/L; avoid over 100 mg/L. Trough 25 to 50 mg/L is acceptable.

Contraindications. Known dihydropyrimidine dehydrogenase deficiency, hypersensitivity, and use during pregnancy.

Serious adverse effects. Neutropenia, thrombocytopenia, pancytopenia, hepatitis, enterocolitis with severe diarrhoea, and fatal toxicity in dihydropyrimidine dehydrogenase deficiency.

Common adverse effects. Nausea, vomiting, diarrhoea, abdominal pain, rash and raised transaminases.

Interactions. Cytarabine antagonises its effect; zidovudine, co-trimoxazole, ganciclovir and other marrow suppressants add toxicity; nephrotoxic drugs (amphotericin B, aminoglycosides) raise levels.

Common prescribing errors. Using it as monotherapy, dosing on actual weight in obesity, not reducing for kidney function, and not checking blood counts.

Special groups. - Pregnancy: avoid; teratogenic in animals. - Breastfeeding: avoid. - Children: monitor levels and counts. - Older adults: reduced clearance; adjust to kidney function. - Kidney impairment: reduce to 25 mg/kg every 12, 24 or 48 hours as CrCl falls under 40 mL/min, adjusted to levels. - Liver impairment: monitor liver tests; no fixed adjustment.

Regional points. Access to flucytosine is limited in many low-resource settings, and its absence shapes cryptococcal regimens; the combination with amphotericin B is superior to fluconazole alone and should be used where it can be obtained.

Formulations. Capsules 250 mg and 500 mg; intravenous infusion 10 mg/mL (where available).

Administration. Give capsules a few at a time over 15 minutes to reduce nausea; with or without food.

Baseline. Full blood count, creatinine, liver tests, potassium, pregnancy test.

Monitoring. Full blood count and creatinine twice weekly; liver tests weekly; drug levels where available.

Stopping thresholds. Stop for neutrophils under 0.5 x 10^9/L or platelets under 50 x 10^9/L (or fall by half), ALT over five times the upper limit of normal, or severe diarrhoea.

Referral and escalation. Specialist review for cryptococcal meningitis and any marrow suppression.