Dose and Administration

Oral

1. 25 - 37.5 mg/kg/dose every 6 hours ^8,9 .
2. The oral route should be the first line option, as the drug is well absorbed by this route. Use I.V. if N.B.M.

Intravenous

1. 25 mg/kg/dose every 6 hours ⁸

Indications

1. Congenital candidiasis, candida meningitis, fungal endocarditis, systemic candidiasis and, systemic fungal infections caused by other sensitive fungi.
2. Usually used in combination with Amphotericin.

Contraindications

1. Known hypersensitivity to flucytosine
2. Known sensitivity to trometamol (excipient in infusion solution).

Precautions

1. Bone marrow depression
2. Preterm infants, especially extreme immaturity.
3. Renal dysfunction.

Drug Interactions

• Amphotericin; Possible decrease in kidney function, resulting in reduced clearance of flucytosine ⁷
• Caution with other drugs with nephrotoxic potential.

Clinical Pharmacology

An antifungal agent with activity against Candida species, Cryptococcus neoformans and the pathogens of chromoblastomycosis ⁶. The drug penetrates the cell, is transformed to 5-fluorouracil which interferes with RNA synthesis. Resistance can develop during treatment and it is recommended that sensitivity tests are conducted before and during treatment ⁶. Synergism has been demonstrated in several species of pathogens when flucytosine is combined with amphotericin ⁶.

Flucytosine is well absorbed from the gastrointestinal tract. Widely distributed through body tissues and fluids and into the CSF ⁵. Low binding to plasma proteins. Approximately 80-90% of a given dose is excreted, unchanged via the kidney.

Possible Adverse Effects

1. Venous irritation, soft tissue injury at site of IV injection.
2. Rash
3. Gastrointestinal disturbances (vomiting, diarrhoea).
4. Alterations in liver function tests- possibly dose related and reversible. Hepatotoxicity ⁵
5. Bone marrow depression: especially leucopenia and thrombocytopenia (usually associated with toxic blood levels plus concurrent amphotericin administration, and with renal function impairment. Fatal agranulocytosis and aplastic anaemia have been reported⁵ .

Special Considerations

1. The oral preparation is unlicensed in New Zealand
2. Usually given in conjunction with amphotericin due to high risk of resistance when used alone.
3. Monitor:
   • Sensitivity of isolate before and during treatment
   • Renal Function:
     Mild renal failure- extend dose interval to every 12 hours
     Moderate renal failure – extend dose interval to every 24 hours
     Severe renal failure – dose according to serum levels ⁸.
   • Full blood count and liver function – daily at start of treatment, then twice weekly
   • Therapeutic Drug Monitoring (TDM):
     Steady state achieved in approximately one day.
     Peak level: 250 – 400 μmol/L. Take level at 15 to 30 minutes after end of I.V. infusion ¹⁰ or 2 hours after an oral dose ¹¹.
     Trough level: > 80 μmol/L (to avoid resistance)
4. Infusion contains chloride (34.4mmol/250 mL) ⁶