Inhibitory and Bactericidal activity of selected β-lactam agents alone and in combination with β-lactamase inhibitors compared with that of cefoxitin and metronidazole against cefoxitin-susceptible and cefoxitin-resistant isolates of the Bacteroides fragilis group

Abstract

The inhibitory activity of five β-lactam agents, alone and in combination with a β-lactamase inhibitor, was compared with that of cefoxitin and metronidazole against 300 β-lactamase producing Bacteroides fragilis group isolates. Each of the β-lactamase inhibitors significantly potentiated the activity of the respective β-lactam. In the presence of clavulanate, the MIC 90 (minimum inhibitory concentration) values of amoxicillin and ticarcillin were reduced 64-fold and 32-fold, respectively. Similarly, sulbactam enhanced the activity of ampicillin and cefoperazone 16-fold and 8-fold, respectively, whereas tazobactam potentiated the activity of piperacillin 16-fold. Few strains were resistant to the β-lactam-β-lactamase inhibitor combinations and were comprised of strains of B. fragilis, B. thetaiotamicron, and B. distasonis. Of the strains, 7% were resistant to cefoxitin, and none to metronidazole. Using time-kill kinetic studies, the bactericidal activity of the various β-lactam agents, with and without β-lactamase inhibitors, was determined and compared with that of cefoxitin and metronidazole against cefoxitin-susceptible and cefoxitin-resistant isolates of the B. fragilis group. Overall, metronidazole was the most bactericidal agent with all isolates being killed with ≤4 μg/ml at 24 hr. Ampicillin-sulbactam was the next most bactericidal agent with all isolates being killed with ≤16/8 μg/ml of ampicillin-sulbactam at 24 hr. Amoxicillin-clavulanate and cefoperazone-sulbactam had bactericidal activity similar to that of ampicillin-sulbactam. Piperacillin-tazobactam and ticarcillin-clavulanate were bactericidal at higher concentrations with all isolates killed with 64 μg/ml of piperacillin and 128 μg/ml of ticarcillin combined with their respective β-lactamase inhibitors. None of the β-lactam agents alone was able to kill more than 19 of the 26 isolates. We conclude that β-lactam agents combined with β-lactamase inhibitors have both inhibitory and bactericidal activity against cefoxitin-resistant members of the B. fragilis group provided that the concentrations achieved for these combinations are at the upper limits for maximum recommended dosing. Although isolates of the B. fragilis group have been reported to produce unusual β-lactamases that are refractory to β-lactamase inhibitors, none of the cefoxitin-resistant isolates tested in this study were resistant to the β-lactam-β-lactamase inhibitor combinations.