No abstract

Metabolism of 5-fluorocytosine-6-¹⁴C (5-FC) was studied in mice, rats, rabbits and dogs after oral and subcutaneous, single and repeated administration. In the urines of all species, intact 5-FC accounted for more than 90% of the total radioactivity at any time of the various treatment schedules. The average proportion of the urinary metabolites was around 5% in dogs, 3% in rabbits, 2.5% in rats and 2% in mice of the total radioactivity. At repeated dosage, there was an increase of metabolites in mice but a decrease in rats treated subcutaneously. Neither increase nor decrease was observed in rabbits (treated orally) and dogs. Two metabolites were identified, α-fluoro-β-ureido-propionic acid (FUPA) and α-fluoro-β-alanine, the latter occurring mainly after oral treatment. These compounds represent probably that part of 5-FC which was deaminated to 5-fluorouracil (5-FU) or directly to 5-fluorodihydrouracil.

Pharmacokinetic studies were performed on the systemic antimycotic agent 5-fluorocytosine (5-FC) by giving 2 g orally to 10 healthy adult volunteers and to 40 patients with renal impairment of various degree (serum creatinine concentration varying from 1.0 to 16.4 mg/l00 ml) including 5 nephrectomized or anuric patients. The microbiological method used for the measurement of the serum and urinary concentrations of the drug is described in detail. In 20 patients endogenous creatinine clearance was determined in addition to the serum creatinine concentration. The average biological half-life of 5-FC in serum was 2.89 h in the healthy individuals (range 2.36–3.99 h) but in the patients, it was significantly prolonged with increasing serum creatinine concentration and decreasing creatinine clearance. The average half-life in the five nephrectomized or anuric patients was 85.0 h (29.9–250 h). A linear correlation was found to exist between the elimination rate constant of the drug and creatinine clearance, and based on this, a 5-FC dosage schedule has been proposed for patients with impaired kidney function. 5-FC is eliminated almost exclusively by the kidneys but has no renal toxicity. Provided that dosage is adapted accordingly, the drug is appropriate for chemotherapeutic treatment of patients with renal impairment which is a relative contraindication to amphotericin B.

In a prospective Swiss multicenter study, 119 children (aged three weeks to 15.5 years) with acute bacterial meningitis were treated with single daily doses of ceftriaxone (100 mg/kg on days one and two and 60 mg/kg thereafter). All patients were randomly assigned to either short course (four, six, seven days) or full course (eight, 12, 14 days) therapy depending on whether they had contracted meningococcal, Haemophilus influenzae type b or pneumococcal meningitis. Bacteriological cure was obtained in 92 children who fully completed the study and in all the 20 culture-positive of the 27 children secondarily excluded from the study for failure to meet all bacteriological and initial safety criteria for continuation in protocol (secondary exclusions). Complete clinical recovery was noted in 105 of 119 patients (88%) and was as frequent in the short course (91%) as in the full course (89%), and as in the secondary exclusion (81%) group. All patients survived. At follow-up examination three to six months after hospital discharge only seven infants and seven children (11.8%), mostly those with poor presentation on admission (p = 0.0012), showed residual neurological sequelae. Side effects of antibiotic therapy were minor but more frequent, albeit not statistically significant (p = 0.065), in children receiving the full course therapy. The results of this study suggest that short course treatment of acute bacterial meningitis in children with single daily ceftriaxone monotherapy is as efficacious as full course therapy and at least as well tolerated.

No abstract