Changes in fecal flora and comparative multiple-dose pharmacokinetics of ceftibuten, cefpodoxime proxetil and amoxycillin/clavulanate

Abstract

Objective: To investigate changes in fecal flora and multiple-dose pharmacokinetics with the oral antibiotics ceftibuten 400 mg daily and cefpodoxime proxetil (CPX) 200 mg every 12 h, compared to amoxycillin/clavulanate 500/125 mg every 8 h during and following 1 week of medication. Methods: In an open randomized triple crossover design, 18 (nine female, nine male) healthy volunteers received each drug for 7 days, followed by a 'washout' period of 4 weeks. Serum and urine levels of the substances were determined by bioassay, and for ceftibuten isomers by high-pressure liquid chromatography. Statistical analysis of quantitative aerobic and anaerobic cultures of feces was performed, and β-lactamase activity was determined. Results: Ceftibuten showed a mean C(max) of 18.9 (SD 3.0) mg/L, a terminal half-life of 2.89 h, and an AUC(tot) of 100 (21.8) mg.h/L; protein binding was 63.7 (5.1)%, and accumulation was marginal. Cefpodoxime proxetil had a C(max) of 1.92 (0.61) mg/L, a terminal half-life of 1.97 (0.42) h and an AUC(tot) of 10.8 (3.3) mg.h/L; no accumulation was seen. Amoxycillin and clavulanate had C(max) values of 7.15 (2.16) mg/L and 3.39 (1.31) mg/L, terminal half-life values of 1.03 (0.15) h and 0.93 (0.17) h, AUC(tot) values of 20.0 (4.2) mg.h/L and 8.87 (3.10) mg.h/L, and there was no accumulation. Statistical analysis for ech microorganism in fecal samples showed significant differences between amoxycillin/clavulanate and the two third-generation cephalosporins, but virtually no differences between ceftibuten and cefpodoxime proxetil. Eleven of 12 volunteers reported loose stools (days 2-7, mean duration 4.4 (SD 2.7) days) with amoxycillin/clavulanate, but nobody during ceftibuten administration and one volunteer during cefpodoxime proxetil administration. Conclusions: Ceftibuten showed excellent and cefpodoxime favorable pharmacokinetic properties, with significantly less pronounced fecal flora changes and intestinal side effects compared to amoxycillin/clavulanate. The multiple crossover design allows powerful microbiological statistical analysis and pharmacokinetic parameter comparisons.