Abstract
The ability of beta-lactamase inhibitors to induce class I beta-lactamases in certain organisms in vitro suggests a potential for antagonism in vivo. Therefore, a study was designed to assess the ability of sulbactam and clavulanate to induce beta-lactamases in two strains each of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and Pseudomonas aeruginosa both in vitro and in vivo. Induction in vitro was observed only with S. marcescens and P. aeruginosa and generally only when inhibitor concentrations greater than 2 micrograms/ml were examined. A mouse model of lethal infection, designed to detect in vivo antagonism arising from beta-lactamase induction, was used to determine what effect sulbactam and clavulanate would have on the 50% protective doses (PD50s) of cefoperazone and ticarcillin. Antagonism (a significant increase in the PD50) was observed in only 4 of 32 tests. Three of these involved antagonism of cefoperazone by clavulanate, and one involved antagonism of cefoperazone by sulbactam. In 6 of 32 tests, enhancement of efficacy (a significant decrease in PD50) was observed. In four of these, sulbactam enhanced cefoperazone; in one, sulbactam enhanced ticarcillin; and in one, clavulanate enhanced ticarcillin. Four of the six cases of enhancement occurred when the beta-lactamase inhibitor was given at the time of challenge. None of these positive or negative in vivo effects were predicted by in vitro tests. These data suggest that beta-lactamase inhibitors can influence the in vivo potency of their companion drug in both a beneficial and detrimental fashion against organisms with class I beta-lactamases and that these effects cannot be predicted from in vitro assays.
Highlights
The ability of,lactamase inhibitors to induce class I W-lactamases in certain organisms in vitro suggests a potential for antagonism in vivo
A mouse model of lethal infection, designed to detect in vivo antagonism arising from P-lactamase induction, was used to determine what effect sulbactam and clavulanate would have on the 50% protective doses (PD50s) of cefoperazone and ticarcillin
Since an animal model of lethal infection which can detect in vivo antagonism via induction of class I,lactamases has been developed previously (7), a study was designed to (i) use this model to determine the influence of sulbactam and clavulanate on the efficacies of cefoperazone and ticarcillin and (ii) determine whether in vitro tests for induction predicted the results observed in vivo
Summary
The ability of ,-lactamase inhibitors to induce class I W-lactamases in certain organisms in vitro suggests a potential for antagonism in vivo. Four of the six cases of enhancement occurred when the ,I-lactamase inhibitor was given at the time of challenge None of these positive or negative in vivo effects were predicted by in vitro tests. The in vitro data suggest that it is possible for these 3-lactamase inhibitors to antagonize the activity of their companion drug in vivo by inducing class I f-lactamases Since an animal model of lethal infection which can detect in vivo antagonism via induction of class I ,-lactamases has been developed previously (7), a study was designed to (i) use this model to determine the influence of sulbactam and clavulanate on the efficacies of cefoperazone and ticarcillin and (ii) determine whether in vitro tests for induction predicted the results observed in vivo
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