Bacteriostatic and bactericidal activities of eight fluoroquinolones against MexAB-OprM-overproducing clinical strains of Pseudomonas aeruginosa

J Antimicrob Chemother. 2005 Apr;55(4):518-22. doi: 10.1093/jac/dki030. Epub 2005 Feb 18.


Objectives: To assess the impact of stable overproduction of efflux system MexAB-OprM on the bacteriostatic and bactericidal activities of fluoroquinolones against clinical Pseudomonas aeruginosa strains.

Methods: The minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) of eight fluoroquinolones (pefloxacin, norfloxacin, ofloxacin, moxifloxacin, levofloxacin, ciprofloxacin, trovafloxacin and grepafloxacin) were determined for nine post-therapy resistant isolates of P. aeruginosa overexpressing MexAB-OprM. Clinical significance of low-level resistance conferred by the efflux mechanism was evaluated with a Monte Carlo simulation.

Results: Compared with their pre-therapy susceptible counterparts, seven out of the nine post-therapy efflux mutants exhibited a modest two- to eight-fold increase in resistance to all the fluoroquinolones tested. Interestingly, stronger variations in resistance (up to 64-fold) were observed in two other mutants, one of which had acquired a GyrB target mutation in addition to efflux under chemotherapy. Time-kill experiments showed that MexAB-OprM up-regulation did not confer tolerance to fluoroquinolones as the ratio of MBC to MIC was less than 4 for most of the strains. To gain an insight into the clinical significance of resistance conferred by MexAB-OprM, a Monte Carlo simulation was conducted with various fluoroquinolone regimens. With this model, low levels of resistance to ciprofloxacin (MIC > or = 0.25 mg/L) or levofloxacin (MIC > or = 1 mg/L), such as those due to overproduced MexAB-OprM, were predicted to result in poor clinical outcomes.

Conclusions: Altogether, these data strongly suggest that when derepressed, MexAB-OprM provides P. aeruginosa with a resistance that may be sufficient to impair the efficacy of single therapy with highly potent fluoroquinolones, such as ciprofloxacin and ofloxacin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Outer Membrane Proteins / biosynthesis*
  • Drug Resistance, Bacterial / physiology
  • Fluoroquinolones / pharmacology*
  • Gene Expression
  • Membrane Transport Proteins / biosynthesis*
  • Microbial Sensitivity Tests
  • Mutation
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / genetics


  • Anti-Bacterial Agents
  • Bacterial Outer Membrane Proteins
  • Fluoroquinolones
  • Membrane Transport Proteins
  • MexA protein, Pseudomonas aeruginosa
  • MexB protein, Pseudomonas aeruginosa
  • OprM protein, Pseudomonas aeruginosa