Multiple dose pharmacokinetics, safety, and effects on faecal microflora, of cefepime in healthy volunteers.

In a randomized, double-blind, placebo-controlled study in 12 healthy volunteers pharmacokinetics, safety and impact on the faecal microflora of cefepime were determined. For eight days eight volunteers received cefepime 1000 mg bd by constant infusion over 30 min, four volunteers received placebo. Concentrations of cefepime in serum and urine were measured by bioassay and HPLC. The correlation between the two methods was good and the bioassay results were used for pharmacokinetic calculations. The faecal flora was analysed twice before the study, twice during the study and four times after cefepime administration. There were no significant differences in the pharmacokinetic parameters between days 1 and 8. The following values (mean +/- S.D.) represent day 1. The maximum concentration of 72.69 +/- 12.2 mg/L immediately after infusion decreased to 0.56 +/- 0.17 mg/L after 12 h. The mean 12 h recovery in urine was 93.69 +/- 2.14%. Pharmacokinetic parameters based on an open two-compartment model were as follows (mean +/- S.D.): area under the curve, 142.65 +/- 18.35 mg.h/L; elimination half-life 110.3 +/- 8.3 min; steady state volume of distribution 16.0 +/- 1.9 L/70 kg; total clearance, 107.0 +/- 16.0 mL/min; renal clearance 103.0 +/- 15.2 mL/min. No accumulation was observed during the eight day study period with cefepime at this dosage; trough levels on days 2-7 ranged from 0.52 +/- 0.26 mg/L to 0.90 +/- 0.33 mg/L. In the cefepime treated group the following side-effects were noted: headache (5), fatigue (4), nausea/stomach ache (2), soft stool (2), transient scotoma (1). Side-effects in the placebo group were: headache (2) fatigue (3), nausea/stomach-ache (1), soft stool (2) and photophobia (1). During cefepime administration a decrease in the number of Escherichia coli and bifidobacteria in faeces was observed, whereas Bacteroides spp. and clostridia showed a slight increase. The numbers of faecal bacteria returned to normal 20 to 48 days after the study was completed.

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