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Int J Antimicrob Agents. 2009 May;33(5):417-20. doi: 10.1016/j.ijantimicag.2008.10.029. Epub 2009 Jan 20.

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

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1
Université de Nantes, Nantes Atlantique Universités, Thérapeutiques Cliniques et Expérimentales des Infections, EA 3826, Faculté de Médecine, Nantes F-44000, France. david.boutoille1@aliceadsl.fr

Abstract

In this study, the in vivo impact of the MexAB-OprM efflux system on antipseudomonal beta-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: 15 g and 18 g for TIC; 12 g and 16 g for PIP/TAZ; and 3g and 6g for CFZ. TIC, PIP/TAZ and CFZ exhibited minimum inhibitory concentrations of 64, 8 and 2 microg/mL, respectively, against PAO4098E and 0.5, 0.5 and 1 microg/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.

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