Flucytosine

Pharmacokinetics

Flucytosine can be given orally, and peak serum concentrations occur within 1–2 hours in patients with normal renal function. The absorption of flucytosine can be delayed by food or antacids. Flucytosine is minimally bound to plasma proteins. It penetrates into the CSF, vitreous humor, peritoneal fluid, inflamed joints, and other fluid compartments. There are several methods for determining serum concentrations, particularly the creatinine iminohydrolase assay, which makes use of the spurious creatinine increase in serum, as measured by the Kodak Ektachem analyser, an apparatus widely available and providing a low cost method compared with HPLC [ ]. Flucytosine accumulates in patients with renal insufficiency, resulting in potentially toxic serum concentrations. About 90% of the dose is excreted unchanged in the urine. Dose adjustments in renal insufficiency can be made in proportion to the reduction in creatinine clearance [ ]. Metabolism occurs to a limited extent [ ]. There is evidence that some flucytosine (5-fluorocytosine) is converted into 5-fluorouracil by the intestinal flora [ , ]; 5-fluorouracil may also be present as an impurity in the original formulation or after prolonged storage [ ].

Increases in hepatic transaminases and depression of hemopoiesis are the principal adverse effects of flucytosine; conversion of flucytosine to fluorouracil is thought to be responsible in most cases [ ]. The conversion of flucytosine to fluorouracil by micro-organisms in the human intestinal microflora has been studied in vitro using viable and non-viable Escherichia coli at different concentrations of flucytosine [ ]. Flucytosine conversion was also studied in fecal specimens from three neutropenic patients at the start of antimicrobial/antifungal prophylaxis (C/A regimen) and 1 week later. Flucytosine concentrations fell by an average of 72%, 71% and 72% after incubation for 48 hours with viable Escherichia coli organisms 1010/ml in suspension in broth containing flucytosine 13, 130, and 1300 μg/ml respectively. There was a 44% reduction in flucytosine concentrations when non-viable Escherichia coli were used, showing that bacterial viability is not necessary for this conversion. When fecal specimens from two patients were investigated before the C/A regimen, there was significant flucytosine conversion, whereas there was no conversion in the corresponding fecal specimens after 1 week of the C/A regimen.

General adverse effects and adverse reactions

The toxicity and drug interactions of flucytosine have been reviewed [ ]. Nausea, vomiting, and diarrhea are common. Enterocolitis is infrequent. Hepatic dysfunction, hepatitis, and even hepatic necrosis and blood disorders, including fatal aplastic anemia, can occur [ ]. Severe reactions mainly occurred at a time when the importance of high serum concentrations (in excess of 100 μg/ml) of flucytosine in causing these adverse reactions was not recognized. The importance of parenteral versus intravenous administration in the development of enterocolitis is unclear. In some patients there were adverse effects, such as hepatotoxicity or eosinophilia, that were idiosyncratic and not related to flucytosine concentrations. Hypersensitivity reactions can occur. Neither teratogenic nor tumor-inducing effects have been recorded.

Observational studies

Experience with flucytosine monotherapy of cryptococcosis has been reviewed in 27 patients treated between 1968 and 1973 who were selected for this form of therapy on the basis of criteria associated with good prognosis [ ]. Flucytosine was given as primary therapy to 18 patients and as secondary therapy (following failure of amphotericin deoxycholate) to nine patients in dosages of 4–10 g/day in four divided doses for 8 weeks. Toxicity associated with flucytosine was uncommon and mild. Mild leukopenia (nadir 3–4 × 10 ⁹ /l) developed in three patients, and mild thrombocytopenia (101 × 10 ⁹ /l) and worsening anemia occurred in one patient each. Therapy was stopped early or changed in two patients. In the first, therapy was stopped after 31 days because of a white cell count of 4.1 × 10 ⁹ /l; despite the shortened course of therapy, the patient achieved a long-term cure, and the leukopenia was ultimately believed to be secondary to sarcoidosis. There was bone marrow suppression in the second patient shortly after the withdrawal of flucytosine (because of failure to respond); later resumption of flucytosine during amphotericin therapy for this critically ill patient was associated with severe bone marrow suppression and death.

Comparative studies

Combination therapy with fluconazole (200 mg/day for 2 months) and flucytosine (150 mg/kg/day for the first 2 weeks; n = 30) has been compared with fluconazole monotherapy (200 mg/day for 2 months; n = 28) in a randomized open trial in Ugandan patients with AIDS-associated cryptococcal meningitis [ ]. Patients in both groups who survived for 2 months received maintenance therapy with fluconazole (200 mg three times per week for 4 months). There were no serious adverse events in any of the patients. The combination therapy prevented death within 2 weeks and significantly increased the survival rate at 6 months (32% versus 12%). However, the rate of positive cryptococcal antigen titers remained high at 2 months after treatment in both groups.