Comparison of the pharmacodynamic activity of cefotaxime plus metronidazole with cefoxitin and ampicillin plus sulbactam.
OBJECTIVE
To compare the pharmacokinetic and pharmacodynamic activity of three drug regimens: cefotaxime plus metronidazole, cefoxitin, and ampicillin-sulbactam against two organisms frequently isolated in intraabdominal infection, Escherichia coli and Bacteroides fragilis.


METHODS
Open-label, three-way crossover study.


METHODS
Hartford Hospital Clinical Research Center.


METHODS
Nine healthy volunteers.


METHODS
Subjects received the following regimens: (1) a single 1-g intravenous dose of cefotaxime plus a single 500-mg oral dose of metronidazole; (2) two intravenous doses of cefoxitin, 2 g each dose given every 6 hours; and (3) two intravenous doses of ampicillin-sulbactam, 3 g each dose given every 6 hours.


RESULTS
Serum bactericidal titers and drug concentrations were measured over a 12-hour period. The cefotaxime-metronidazole regimen showed superior activity against E. coli compared with ampicillin-sulbactam and cefoxitin. The mean areas under the bactericidal activity curve (AUBC) for the three regimens were 550.2, 68.7, and 48.9, respectively (p = 0.0001). There was no significant difference in AUBC among the three regimens for B. fragilis. Serum concentrations of cefotaxime remained above the minimum inhibitory concentration (MIC) for E. coli significantly longer than did concentrations of ampicillin-sulbactam and cefoxitin (p = 0.0002 and p = 0.0023, respectively). Serum concentrations of metronidazole were still at 9 times the MIC for B. fragilis at the end of the 12-hour dosing interval; for ampicillin-sulbactam and cefoxitin concentrations remained above the MIC for one-half and less than one-fourth, respectively, of the dosing interval (p < 0.0001). The ratio of AUC:MIC was also favorable for metronidazole (212.2) compared with 63.4 for ampicillin-sulbactam and 9.2 for cefoxitin.


CONCLUSIONS
The combination of cefotaxime-metronidazole, even at the relatively low doses used in this study, provides coverage against gram-negative and anaerobic pathogens that is at least as effective as that of cefoxitin and ampicillin-sulbactam. In addition, its cost is considerably less expensive than that of the other regimens.
D000284:Administration, Oral; D000328:Adult; D000667:Ampicillin / Q000493:pharmacokinetics / Q000494:pharmacology; D001441:Bacteroides fragilis / Q000187:drug effects*; D002439:Cefotaxime / Q000493:pharmacokinetics / Q000494:pharmacology*; D002440:Cefoxitin / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008795:Metronidazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism; D013407:Sulbactam / Q000493:pharmacokinetics / Q000494:pharmacology
D008795:Metronidazole; C035444:sultamicillin; D002440:Cefoxitin; D000667:Ampicillin; D002439:Cefotaxime; D013407:Sulbactam