title: Pharmacodynamics of levofloxacin against Pseudomonas aeruginosa with reduced susceptibility due to different efflux pumps: do elevated MICs always predict reduced in vivo efficacy?
abstract: The Pseudomonas aeruginosa efflux pumps MexAB-OprM, MexCD-OprJ, and MexEF-OprN play an important role in susceptibility to fluoroquinolones in vitro. To determine if levofloxacin MICs arising from different levels of expression of efflux pumps result in a proportional reduction in the response to levofloxacin in vivo, isogenic strains of P. aeruginosa were tested with levofloxacin in two mouse models of infection (sepsis and neutropenic mouse thigh models). The levofloxacin 50% effective doses (ED(50)s) increased proportionally with the MICs for most strains. Similarly, the 24-h area under the concentration-time curve (AUC)/MIC ratio that resulted in 90% of the maximum bactericidal activity (90% E(max)) exceeded 75 for all strains except those with elevated MICs due to MexEF-OprN overexpression. In these strains, levofloxacin ED(50)s were 2- to 10-fold lower than the ED(50)/MIC ratios in the other strains and 90% E(max) AUC/MIC ratios were 2- to 4-fold lower than those predicted from pharmacodynamic modeling of efficacy against other strains. These data show that while the MexEF-OprN efflux pump can provide P. aeruginosa resistance to levofloxacin in vitro, it appears to be less efficient in providing resistance to levofloxacin in animal models of infection.
authors.affiliation: Mpex Pharmaceuticals, Inc. 3030 Bunker Hill St., Suite 200, San Diego, CA 92109, USA. dgriffith@mpexpharma.com
authors.forename: David C
authors.initials: DC
authors.lastname: Griffith
authors.forename: Erik
authors.initials: E
authors.lastname: Corcoran
authors.forename: Denene
authors.initials: D
authors.lastname: Lofland
authors.forename: Angela
authors.initials: A
authors.lastname: Lee
authors.forename: Deidre
authors.initials: D
authors.lastname: Cho
authors.forename: Olga
authors.initials: O
authors.lastname: Lomovskaya
authors.forename: Michael N
authors.initials: MN
authors.lastname: Dudley
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D017353:Gene Deletion; D005798:Genes, Bacterial; D064704:Levofloxacin; D008297:Male; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000382:microbiology; D015242:Ofloxacin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C470189:MexC protein, Pseudomonas aeruginosa; C121980:MexD protein, Pseudomonas aeruginosa; C470190:OprJ protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; C105708:OprN protein, Pseudomonas aeruginosa; D064704:Levofloxacin; D015242:Ofloxacin