Evaluation of cephalosporins/cephamycins with antianaerobic activity by integrating microbiologic and pharmacokinetic properties.
When evaluating antimicrobial agents, in vitro microbiologic activity and pharmacokinetics are important factors, but these data are usually not assessed simultaneously. The purpose of the study was to compare cefoxitin, cefotetan, ceftizoxime, cefotaxime (CT), desacetylcefotaxime (DACT), and CT/DACT (1:1 ratio) by integrating their microbiologic activity against clinical isolates of Bacteroides fragilis with their pharmacokinetic properties. Minimal inhibitory concentrations (MIC) were determined by the agar dilution method. Steady-state serum concentration--time profiles were simulated for 2-gm doses in a 70-kg patient using ADAPT software and pharmacokinetic data from published studies. Serum protein binding (%) of each agent was also obtained from published studies and used to calculate the unbound serum concentration--time profiles. As estimates of pharmacodynamic activity, time below the MIC (T less than MIC) and percentage of the dosing interval below the MIC (% INT less than MIC) were calculated for individual isolates using total and unbound serum concentrations. Data analysis included MIC50, MIC90, range, breakpoint susceptibility, and analysis of variance for T less than MIC and % INT less than MIC (Scheffé post-hoc test, P less than 0.05). The MIC90 of cefotetan was at least a twofold dilution lower than the other agents. However, using unbound (pharmacologically active) serum concentrations, T less than MIC and % INT less than MIC for ceftizoxime (at a simulated eight-hour dosing interval) were significantly smaller than with the other antibiotic regimens. Integration of in vitro and pharmacokinetic data may provide additional information to assist in the evaluation of antimicrobials. For B fragilis from our institution, the pharmacodynamic profile of unbound ceftizoxime is superior to the other antianaerobic cephalosporins/cephamycins tested.
Kays
M B
MB
College of Pharmacy, Medical University of South Carolina, Charleston.
White
R L
RL
Friedrich
L V
LV
Del Bene
V E
VE
D001421:Bacteria, Anaerobic / Q000187:drug effects*; D001441:Bacteroides fragilis / Q000187:drug effects; D002439:Cefotaxime / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D015313:Cefotetan / Q000493:pharmacokinetics / Q000494:pharmacology; D002440:Cefoxitin / Q000493:pharmacokinetics / Q000494:pharmacology; D015296:Ceftizoxime / Q000493:pharmacokinetics / Q000494:pharmacology; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D002513:Cephamycins / Q000493:pharmacokinetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008826:Microbial Sensitivity Tests
D002511:Cephalosporins; D002513:Cephamycins; D015313:Cefotetan; C029281:desacetylcefotaxime; D002440:Cefoxitin; D015296:Ceftizoxime; D002439:Cefotaxime