Affinity of cephalosporins for beta-lactamases as a factor in antibacterial efficacy

Strains of Escherichia coli, Enterobacter aerogenes, and Enterobacter cloacae that were resistant to ceftazidime (MIC greater than 16 micrograms/ml) but susceptible to BMY 28142 (MIC less than 4 micrograms/ml) were found to contain higher levels of beta-lactamase activity (50- to 3,340-fold) than control strains of the corresponding species. Ceftazidime was at least as resistant as BMY 28142 to hydrolysis by these enzymes. However, the apparent Ki of BMY 28142 for each enzyme was larger (8- to greater than 20-fold) than that of ceftazidime; i.e., the affinity of these enzymes for BMY 28142 appeared to be lower than that for ceftazidime. Thus, BMY 28142 was affected less than ceftazidime by a mechanism of resistance that depends, at least in part, on the relative affinities of cephalosporins for the beta-lactamases of these species. These results indicate that the affinity between a beta-lactamase and a cephalosporin may be a distinguishing factor in the evaluation of beta-lactamase-resistant cephalosporins and suggest that affinity can play a major role in susceptibility to highly beta-lactamase-resistant cephalosporins.