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Antimicrobial Agents and Chemotherapy, July 2008, p. 2455-2462, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01107-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Resistance and Virulence of Pseudomonas aeruginosa Clinical Strains Overproducing the MexCD-OprJ Efflux Pump

Department of Bacteriology, University of Franche-Comté, Faculty of Medicine, F-25030 Besançon, France,¹ Commissariat à l'Energie Atomique, Laboratoire de Biochimie et de Biophysique des Systèmes Intégrés, F-38054 Grenoble, France,² Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland³

Received 22 August 2007/ Returned for modification 28 October 2007/ Accepted 4 May 2008

Since their initial description 2 decades ago, MexCD-OprJ-overproducing efflux mutants of Pseudomonas aeruginosa (also called nfxB mutants) have rarely been described in the clinical setting. Screening of 110 nonreplicate clinical isolates showing moderate resistance to ciprofloxacin (MIC from 0.5 µg/ml to 4 µg/ml) yielded only four mutants (3.6%) of that type harboring various alterations in the repressor gene nfxB. MexCD-OprJ upregulation correlated with an increased resistance to ciprofloxacin, cefepime, and chloramphenicol in most of the clinical strains, concomitant with a higher susceptibility to ticarcillin, aztreonam, imipenem, and aminoglycosides. Evidence was obtained that this increased susceptibility to aminoglycosides results from the impaired activity of efflux pump MexXY-OprM. Furthermore, MexCD-OprJ upregulation was found to impair bacterial growth and to have a strain-specific, variable impact on rhamnolipid, elastase, phospholipase C, and pyocyanin production. Review of patient files indicated that the four nfxB mutants were responsible for confirmed cases of infection and emerged during long-term therapy with ciprofloxacin. Taken together, these data show that, while rather infrequent among P. aeruginosa strains with low-level resistance to ciprofloxacin, MexCD-OprJ-overproducing mutants may be isolated after single therapy with fluoroquinolones and may be pathogenic.

Published ahead of print on 12 May 2008.