Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes

Abstract

The ability of ,-lactamase inhibitors to induce class I W-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 P-lactamases in two strains each of Enterobacter cloacae, Citrobacterfreundii, 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 ,ug/ml were examined. 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. 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 ,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. These data suggest that P-lactamase inhibitors can influence the in vivo potency of their companion drug in both a beneficial and detrimental fashion against organisms with class I P-lactamases and that these effects cannot be predicted from in vitro assays.Previous studies have shown that B-lactamase inhibitors are in vitro inducers of chromosomal, class I P-lactamases in certain strains of the family Enterobacteriaceae and Pseudomonas aeruginosa (4,11,12,16,(18)(19)(20). Quantitatively, clavulanate induces higher levels of ,-lactamase than does sulbactam, although induction with these compounds is usually manifest only at high, clinically unachievable concentrations (6,12,(18)(19)(20). The in vivo effects of these compounds against organisms possessing class I enzymes are unknown. However, 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. Clinically, this could result in treatment failure. 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. MATERIALS AND METHODSBacterial strains. Two strains each of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and P. aeruginosa were used in this study. These strains were clinical isolates that ...

Clavulanate Induces Expression of the Pseudomonas aeruginosa AmpC Cephalosporinase at Physiologically Relevant Concentrations and Antagonizes the Antibacterial Activity of Ticarcillin

“…The antagonism observed between clavulanate and ticarcillin in this study contradicts what has been observed clinically or in animal models of infection (4,15). This discrepancy most likely relates to the presence or absence of host defenses.…”

“…However, for ticarcillin-clavulanate, the ability of clavulanate to induce expression of the P. aeruginosa AmpC cephalosporinase (8,20,22) could antagonize the antibacterial activity of ticarcillin in the combination. In immunocompetent mice and humans infected with P. aeruginosa, antagonism between clavulanate and ticarcillin has not been observed (4,15). However, the potential for antagonism in the absence of ade-quate host defenses, i.e., neutropenic patients, has not been systematically studied.…”

Efficacy of ampicillin-sulbactam is not dependent upon maintenance of a critical ratio between components: sulbactam pharmacokinetics in pharmacodynamic interactions

“…To date, the optimal dosing and utilization of ␤-lactamase-inhibitor-␤-lactam combinations have not been extensively studied. Cavalieri et al previously reported that the sequential dosing of sulbactam prior to cefoperazone and ticarcillin in mice enhanced the activities of these combinations against some strains of Enterobacter cloacae and Serratia marcescens producing inducible group 1 ␤-lactamases (5). This increase in efficacy was seen despite the fact that group 1 ␤-lactamases are the least susceptible of all ␤-lactamases to inhibition by sulbactam.…”