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JAC Advance Access published online on February 18, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki030
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JAC © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved
Received August 17, 2004
Revised December 18, 2004
Accepted December 22, 2004

Original article

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

Philippe Dupont 1, Didier Hocquet 1, Katy Jeannot 1, Pascal Chavanet 2, and Patrick Plésiat 1*

1 Laboratoire de Bactériologie, Centre Hospitalier Universitaire J. Minjoz, 25030 Besançon, France
2 Service des Maladies Infectieuses, Centre Hospitalier Universitaire du Bocage, 21034 Dijon, France

* To whom correspondence should be addressed.
Patrick Plésiat, E-mail: patrick.plesiat{at}univ-fcomte.fr


  Abstract

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 ≥ 0.25 mg/L) or levofloxacin (MIC ≥ 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.

Keywords: resistance; Monte Carlo simulation; efflux.
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