In vivo impact of the MexAB-OprM efflux system on β-lactam efficacy in an experimental model of Pseudomonas aeruginosa infection

Abstract

In this study, the in vivo impact of the MexAB-OprM efflux system on antipseudomonal β-lactam efficacy was investigated. The respective activities of human simulated regimens of ticarcillin (TIC), piperacillin/tazobactam (PIP/TAZ) and ceftazidime (CFZ) on two isogenic mutants of Pseudomonas aeruginosa PAO1, namely PAO4098E overexpressing MexAB-OprM and PAO4098ET which is OprM-depleted, were evaluated in an experimental rabbit endocarditis model. The following human daily doses by intermittent administration or continuous infusion were simulated: 15g and 18g for TIC; 12g and 16g for PIP/TAZ; and 3g and 6g for CFZ. TIC, PIP/TAZ and CFZ exhibited minimum inhibitory concentrations of 64, 8 and 2μg/mL, respectively, against PAO4098E and 0.5, 0.5 and 1μg/mL against PAO4098ET. Against PAO4098E, only the high-dose regimens of CFZ were effective, with the most significant effect being achieved by continuous infusion. In contrast, all the tested regimens were effective against PAO4098ET. In the most difficult-to-treat infections due to P. aeruginosa exhibiting the efflux system MexAB-OprM, CFZ at high doses and by continuous infusion should be preferred to TIC and PIP/TAZ.