Experimental application of the median-effect principle for in vitro quantification of the combined inhibitory activities of clavulanic acid and imipenem against IRT-4 beta-lactamase.
Inhibitor-resistant TEM beta-lactamases (IRT) have been identified in Enterobacteriaceae which, however, remained susceptible to cephalosporins. We evaluated the combined inhibitory activity of clavulanic acid and imipenem at ratios of 1:1 and 1:3 against IRT-4, using the median effect principle of Chou and Talalay. The combination of the two drugs, which produced a nearly additive effect, meant their concentrations could be lowered 1.3-4.9-fold, while maintaining a 50% inhibitory effect against the IRT-4 in comparison with each drug alone. From a therapeutic point of view, such a combination is not efficient but this method of Chou and Talalay, used for the first time to assay combined inhibitory activity of beta-lactamase inhibitors, could be used to evaluate new molecules and/or strategies to inactivate beta-lactamase.
Sotto
Albert
A
Laboratoire Universitaire de Thérapeutique, Service de Médecine Interne B, Hôpital Carémeau, rue du Professeur-Debré, 30029 Cédex, Nîmes, France. albert.sotto@chu-nimes.fr
Foulongne
Vincent
V
Sirot
Danielle
D
Labia
Roger
R
Jourdan
Jacques
J
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002969:Clavulanic Acids / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D015378:Imipenem / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
D000900:Anti-Bacterial Agents; D002969:Clavulanic Acids; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D015378:Imipenem; C088782:beta-lactamase IRT-4; D001618:beta-Lactamases