title: Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux pumps.
abstract: To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and DeltaK767 (knockout strain). Efficacy (Delta log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10(5) CFU/thigh) and high (10(7) CFU/thigh) inoculums. At 10(5) CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (-2.82, -1.88) and K767+ (-2.24, -2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (-2.74 and -2.19, respectively). Similar magnitudes of kill were observed at the 10(7) inocula. Except for DeltaK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against DeltaK767. DeltaK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on beta-lactam agents in vivo warrant further research.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
authors.forename: Christine T
authors.initials: CT
authors.lastname: Ong
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tessier
authors.forename: Chonghua
authors.initials: C
authors.lastname: Li
authors.forename: Charles H
authors.initials: CH
authors.lastname: Nightingale
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000077723:Cefepime; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D015378:Imipenem / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000077731:Meropenem; D051379:Mice; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013848:Thigh / Q000382:microbiology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D002511:Cephalosporins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D013845:Thienamycins; D015378:Imipenem; D000077723:Cefepime; D000077731:Meropenem