title: In vivo impact of the MexAB-OprM efflux system on beta-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 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.
authors.affiliation: 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
authors.forename: David
authors.initials: D
authors.lastname: Boutoille
authors.forename: Cédric
authors.initials: C
authors.lastname: Jacqueline
authors.forename: Virginie
authors.initials: V
authors.lastname: Le Mabecque
authors.forename: Gilles
authors.initials: G
authors.lastname: Potel
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caillon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D015169:Colony Count, Microbial; D004697:Endocarditis, Bacterial / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008962:Models, Theoretical; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D047090:beta-Lactams / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D047090:beta-Lactams