Flucytosine
Indications
Flucytosine is used for:
Systemic fungal infections
Adult Dose
Oral
Systemic fungal infections
Adult: 50-150 mg/kg daily in 4 divided doses. Commonly used w/ amphotericin B or fluconazole in severe infections.
Intravenous
Systemic fungal infections
Adult: 200 mg/kg daily in 4 divided doses via infusion over 20-40 min. Adjust dose to produce trough plasma levels of 25-50 mcg/mL. In severe systemic candidiasis, cryptococcal meningitis, and other severe infections, it is usually given in combination w/ amphotericin B or fluconazole.
Treatment duration is individualised based on sensitivity of the organism and patient response (usually ?7 days, except for cryptococcal meningitis when it is continued for at least 4 mth).
Child Dose
Candidiasis/Cryptococcus Infection
Child: 50-150 mg/kg/d div q6hr PO
Neonates (<28 days old): 80-160 mg/kg/d div q6hr PO
Renal Dose
Renal impairment:
CrCl (ml/min) Dosage Recommendation
<10 mL/min: 50 mg/kg; further doses should be based on plasma levels (not exceeding 80 mcg/mL).
10-<20 mL/min: 50 mg/kg 24 hrly.
20-40 mL/min: 50 mg/kg 12 hrly.
Administration
May be taken with or without food. Nausea & vomiting may be minimised if the dose is spaced over a 15-min period.
Contra Indications
Hypersensitivity to flucytosine. Co-administration w/ antiviral nucleoside drugs and their analogues. Lactation.
Precautions
Patient w/ blood dyscrasias or bone marrow depression, dihydropyrimidine dehydrogenase (DPD) deficiency, or those receiving radiation therapy. Renal and hepatic impairment.
Monitoring Parameters Monitor renal, hepatic, and haematologic functions prior to and during treatment (at least wkly in patients w/ renal impairment or blood dyscrasia).
Pregnancy-Lactation
Pregnancy Category: C
Lactation: excretion in milk unknown/not recommended
Interactions
May result in synergistic effect when combined w/ amphotericin B or fluconazole. May increase phenytoin plasma levels. Cytarabine antagonises the antifungal activity of flucytosine by competitive inhibition.
Potentially Fatal: Co-administration w/ antiviral nucleoside drugs (e.g. brivudine, sorivudine, and their analogues) may result in severe drug toxicity due to inhibition of DPD, a key enzyme involved in the metabolism of 5-FU.
Adverse Effects
Side effects of Flucytosine :
Frequency Not Defined
Confusion
Headache
Hallucinations
Dizziness
Drowsiness
Psychosis
Parkinsonism
Ataxia
Sedation
Rash
Photosensitivity
Pruritus
Urticaria
Temporary growth failure
Hypoglycemia
Hypokalemia
Nausea
Vomiting
Diarrhea
Abdominal pain
Loss of appetite
Bone marrow suppression
Anemia
Leukopenia
Thrombocytopenia
Elevated liver enzymes
Hepatitis
Azotemia
Peripheral neuropathy
Paresthesia
Weakness
Hearing loss
Elevated BUN and serum creatinine
Renal failure
Respiratory arrest
Anaphylaxis
Mechanism of Action
Flucytosine is a fluorinated pyrimidine antifungal that is taken up by cytosine permease into the fungal cells. It is rapidly converted to fluorouracil (5-FU) and subsequently into 5-fluorouridine triphosphate (FUTP), which is then incorporated into fungal RNA, resulting to faulty protein biosynthesis. 5-FU is also converted to fluorodeoxyuridine monophosphate which interferes w/ thymidylate synthase, thereby causing disruption of DNA synthesis.