Flucytosine (5-fluorocytosine or 5FC)
Flucytosine (Ancotil, Ancobon) is a fluorinated pyrimidine analogue that was developed in 1957 at Roche Laboratories. Flucytosine is metabolized in fungal cells via the pyrimidine salvage pathway, where it acts as a subversive substrate. Metabolism produces toxic nucleotides that interfere with nucleic acid and protein synthesis. After transport into the fungal cell it is converted to 5-fluorouracil (5-FU) by the protein cytosine deaminase and then subsequent metabolites inhibit the enzyme thymidylate synthetase. Reduced thymidine leads to reduced DNA synthesis. Mammalian cells do not contain cytosine deaminase.
Flucytosine has now been added to the WHO essential medicines list.
Dose & Delivery
Flucytosine is available as tablets (500 and 250 mg) and as an IV formulation (2.5 g of flucytosine in 250 ml normal saline).
Fungi the drug is active against
Flucytosine is generally active against the medically important yeasts Cryptococcus neoformans and Candida spp. Candida krusei and C. neoformans have higher MICs than other species. Occasional outbreaks of resistant isolates of Candida spp. have been described. Flucytosine has some anti-Aspergillus activity, with uncertainty about the rapidity of development of resistance. Flucytosine is active against Phialophora spp, Cladosporium spp and Exophiala spp. In contrast, Fusarium spp, Mucorales spp, Madurella spp. Microsporum spp., Trichophyton spp. and Epidermophyton spp., Blastomyces dermatitidis, Paracoccidioides brasiliensis, Histoplasma capsulatum and Coccidioides immitis are resistant to flucytosine.
The standard dose of flucytosine is 100–150 mg/kg per day, in four divided dosages (ie 37.5 mg/kg 6-hourly), unless there is reduced renal function. Significantly lower dosages may be as effective and are being studied. It is usually given with amphotericin B in the treatment of cryptococcal meningitis, and less often for invasive candidiasis or invasive aspergillosis.
If the creatinine clearance is >40 ml/minute, standard dosage can be used. If the creatinine clearance is 20–40 ml/min, the same dose given 12-hourly is appropriate. If the creatinine clearance is <20 ml/min, once daily 37.5 mg/kg dose can be given. Flucytosine is removed by haemodialysis and optimal serum levels of flucytosine can be achieved with single doses of 25–30 mg/kg body weight after each dialysis. Neonates on standard doses tend to have higher levels than adults for unclear reasons.
Metabolism, distribution and excretion
Flucytosine is excreted almost entirely by glomerular filtration and dose reduction necessary with renal dysfunction. Various algorithms are available to ensure dosage reduction results in effective and nontoxic drug levels.
As it is so water soluble, it gets into urine, CSF, peritoneal fluid, cardiac vegetations and the eye in good concentrations.
There are few clinically relevant pharmacokinetic interactions with flucytosine. Careful monitoring of flucytosine serum levels is required when co-administered with potentially nephrotoxic agents such as amphotericin B. View drug interactions database. [Link to TDM section]
Oral flucytosine is generally well tolerated, but occasionally causes nausea and diarrhea. Sometimes more severe gastrointestinal symptoms occur. Skin rashes have occasionally been observed, including a photosensitive rash. Flucytosine suppresses bone marrow function probably via the production of its metabolite and has been reported in 6–22% of patients. Myelosuppression is more likely with elevated flucytosine serum levels. Transient hepatomegaly and elevated transaminase levels are occasionally seen, especially if there are sustained high serum levels. Flucytosine is teratogenic at concentrations lower than those used for cryptococcal meningitis and should be avoided, especailly during early pregnancy.
Structure of flucytosine.