Flucytosine

Oral
Systemic fungal infections
Adult: 50-150 mg/kg daily in 4 divided doses. Commonly used w/ amphotericin B or fluconazole in severe infections.
Renal impairment: Initiate at lower doses. Monitor plasma levels and adjust subsequent doses accordingly to prevent drug accumulation.

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).
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.

May be taken with or without food.

Hypersensitivity to flucytosine. Co-administration w/ antiviral nucleoside drugs and their analogues. Lactation.

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).

Nervous: Ataxia, confusion, hallucinations, psychosis, headache, paraesthesia, peripheral neuropathy, parkinsonism, seizures, vertigo, sedation. CV: Cardiac arrest, myocardial toxicity, ventricular dysfunction, chest pain. GI: Abdominal pain, dry mouth, bloating, diarrhoea, duodenal ulcer, GI haemorrhage, nausea, vomiting, ulcerative colitis, anorexia. Resp: Dyspnoea, resp arrest. Hepatic: Hepatic dysfunction, jaundice, elevated serum alkaline phosphatase, AST, ALT, and bilirubin. Genitourinary: Increased BUN and serum creatinine, azotaemia, crystalluria, renal failure. Endocrine: Hypoglycaemia. Haematologic: Leucopenia, anaemia, pancytopenia, thrombocytopenia, eosinophilia, agranulocytosis. Otic: Hearing loss. Dermatologic: Pruritus, rash, urticaria, photosensitivity, toxic epidermal necrolysis. Others: Fatigue, pyrexia, hypokalaemia, weakness.
Potentially Fatal: Bone marrow toxicity, acute hepatic injury.

Symptoms: GI effects (e.g. diarrhoea, nausea, vomiting), haematologic effects (e.g. leucopenia, thrombocytopenia), and hepatic effects (e.g. hepatitis). Management: Employ prompt gastric lavage or an emetic. Maintain adequate fluid intake. IV fluids may be given as necessary.

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.

Decreased rate of absorption w/ food.

May interfere w/ dual-slide enzymatic measurement of creatinine using Ektachem® or Vitros DT 60 analyser; use Jaffe reaction or other alkaline picrate method in determining serum creatinine.

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.
Absorption: Absorbed rapidly and almost completely from the GI tract. Bioavailability: 78-89%. Time to peak plasma concentration: W/in 1-2 hr (oral).
Distribution: Widely distributed in body tissues and fluids, including CSF. Crosses the placenta. Volume of distribution: 0.5-1 L/kg. Plasma protein binding: Approx 2-4%.
Metabolism: Undergoes minimal hepatic metabolism into 5-FU via deamination in yeasts and probably by gut bacteria.
Excretion: Via urine (approx 90%, as unchanged drug). Elimination half-life: 2.5-6 hr.

Intravenous: Store between 18-25°C. Oral: Store between 15-30°C.

Antifungals

D01AE21 - flucytosine ; Belongs to the class of other antifungals for topical use.
J02AX01 - flucytosine ; Belongs to the class of other systemic antimycotics.