Pharmacodynamics of levofloxacin against Pseudomonas aeruginosa with reduced susceptibility due to different efflux pumps: do elevated MICs always predict reduced in vivo efficacy?

Antimicrobial Agents and Chemotherapy
David C GriffithMichael N Dudley

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...Continue Reading

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Citations

Jan 26, 2010·European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology·S A DunhamA A Miller
Nov 30, 2000·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·A Bryskier
Dec 21, 2010·Foodborne Pathogens and Disease·Bwalya LunguSteven C Ricke
Sep 14, 2011·Antimicrobial Agents and Chemotherapy·Catherine LlanesPatrick Plésiat
Mar 30, 2011·Antimicrobial Agents and Chemotherapy·David E GellerMichael N Dudley
Jan 9, 2013·Antimicrobial Agents and Chemotherapy·Vincent HernandezJacob J Plattner
Oct 5, 2012·Clinical Microbiology Reviews·Lucía Fernández, Robert E W Hancock
Apr 8, 2011·American Journal of Respiratory and Critical Care Medicine·David E GellerUNKNOWN Mpex 204 Study Group
Aug 15, 2009·Drugs·Xian-Zhi Li, Hiroshi Nikaido
Nov 25, 2014·Expert Review of Respiratory Medicine·Chris StockmannCatherine M T Sherwin
Mar 20, 2015·Clinical Microbiology Reviews·Xian-Zhi LiHiroshi Nikaido

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