Flucytosine an antifungal agent | indications, dose and precaution

Flucytosine (also known as 5-FC or 5-fluorocytosine) is an antifungal agent. It is converted to fluorouracil in the fungal cell where it inhibits fungal DNA synthesis and once incorporated into fungal RNA, affects protein synthesis.


Antibiotic Class: Antifungal agent
Treatment of serious fungal infections




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)



Indications

Treatment of serious fungal infections including: Endocarditis, Meningitis, Septicemia, Urinary tract infections, pulmonary infections.

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 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

Dosage

Cryptococcal disease (including meningitis): 25mg/kg/dose given 6 hourly.
Other infections: 25-37.5mg/kg/dose given 6 hourly.
Rarely doses up to 50mg/kg/dose given 6 hourly have been used. However the lower dose may be sufficient for sensitive organisms

Contraindications

Flucytosine is contraindicated in patients with a history of hypersensitivity to flucytosine or any component of the preparation

Precaution

Concurrent treatment with nephrotoxic agents can reduce the excretion of flucytosine and increase the risk of toxicity.
Renal impairment can increase the risk of haematological toxicity; dosage adjustments are required.
There is an increased risk of serious blood dyscrasia in patients with bone marrow suppression, those currently taking myelosuppressive drugs, undergoing radiation therapy or patients with advanced HIV infection. Careful monitoring is required as this may be irreversible

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

Adverse effects

Common: anaemia, leucopenia, thrombocytopaenia (risk increased with plasma concentrations of more than 100mg/L), diarrhoea, nausea, vomiting, elevated liver enzymes (dose related), rash.

Rare: headache, sedation, vertigo, hepatic necrosis, agranulocytosis, GI haemorrhage, allergic reactions, toxic epidermal necrolysis, seizures, confusion, hallucinations, cardiotoxicity.

Contraception in males and females

Females of childbearing potential under treatment must use effective contraceptive during treatment and for one month after treatment. Male patients (or their female partners of childbearing potential) must use effective contraception during treatment and for three months after treatment.

Use in pregnancy and lactation

Flucytosine has been shown to be teratogenic and embryotoxic in rats when given in oral or parenteral doses of 40 mg/kg body weight per day onwards (240 mg/m2 or 0.043 times the human daily dose). The flucytosine metabolite 5-fluorouracil is genotoxic in mice and in vitro, embryotoxic and teratogenic in mice and rats, and is classified as possible human teratogen. Malformations occurred (defects in the nervous system, palate, skeleton, tails, and limbs) in several species, including rat and Syrian Golden hamsters. Embryotoxic effects (small foetus, resorption) are also observed in monkeys treated with 5-FU. There are no data on the excretion of flucytosine in human milk. Breastfeeding is contraindicated during flucytosine treatment.

Brand names/Manufacturer:
· ALCOBON (ICN, NZ) (Pacific - NZ)
· ALCOBON (Roche – IRELAND, SOUTH AFRICA)
· ANCOBON (ICN - USA)
· ANCOTIL (Hoffmann-La Roche – CANADA, BRAZIL) (CSP – FRANCE) (ICN - ITALY, UK, GERMANY, NETHERLANDS, SWITZERLAND, AUSTRIA, DENMARK, IRELAND, MALAYSIA, AUSTRALIA, SINGAPORE) (MEDILINK – SWEDEN, NORWAY) (Valeant –HONG KONG)
· NOVO-TRIPHYL (NOVOPHARM (CANADA))



Reference
https://reference.medscape.com/drug/flucytosine-342589
http://www.antimicrobe.org/drugpopup/Flucytosine.htm
https://academic.oup.com/jac/article/46/2/171/881387
https://www.drugbank.ca/drugs/DB01099
https://www.drugs.com/mtm/flucytosine.html
https://www.uptodate.com/contents/pharmacology-of-flucytosine-5-fc
https://pubchem.ncbi.nlm.nih.gov/compound/Flucytosine
https://www.sciencedirect.com/topics/medicine-and-dentistry/flucytosine

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