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Antimicrobial Agents and Chemotherapy, April 2006, p. 1347-1351, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1347-1351.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Involvement of the MexXY-OprM Efflux System in Emergence of Cefepime Resistance in Clinical Strains of Pseudomonas aeruginosa

Didier Hocquet,1* Patrice Nordmann,2 Farid El Garch,1 Ludovic Cabanne,2 and Patrick Plésiat1

Laboratoire de Bactériologie, Hôpital Jean Minjoz, University of Franche-Comte, Besançon, France,1 Service de Bactériologie-Virologie, Hopital de Bicêtre, Assistance Publique/Hôpitaux de Paris, Faculté de Médecine Paris-Sud, Univesité Paris XI, K-Bicêtre, France2

Received 12 August 2005/ Returned for modification 2 October 2005/ Accepted 29 January 2006

Cefepime (FEP) and ceftazidime (CAZ) are potent ß-lactam antibiotics with similar MICs (1 to 2 µg/ml) for wild-type strains of Pseudomonas aeruginosa. However, recent epidemiological studies have highlighted the occurrence of isolates more resistant to FEP than to CAZ (FEPr/CAZs profile). We thus investigated the mechanisms conferring such a phenotype in 38 clonally unrelated strains collected in two French teaching hospitals. Most of the bacteria (n = 32; 84%) appeared to stably overexpress the mexY gene, which codes for the RND transporter of the multidrug efflux system MexXY-OprM. MexXY up-regulation was the sole FEP resistance mechanism identified (n = 12) or was associated with increased levels of pump MexAB-OprM (n = 5) or MexJK (n = 2), synthesis of secondary ß-lactamase PSE-1 (n = 10), derepression of cephalosporinase AmpC (n = 1), coexpression of both OXA-35 and MexJK (n = 1), or production of both PSE-1 and MexAB-OprM (n = 1). Down-regulation of the mexXY operon in seven selected strains by the plasmid-borne repressor gene mexZ decreased FEP resistance from two- to eightfold, thereby demonstrating the significant contribution of MexXY-OprM to the FEPr/CAZs phenotype. The six isolates of this series that exhibited wild-type levels of the mexY gene were found to produce ß-lactamase PSE-1 (n = 1), OXA-35 (n = 4), or both PSE-1 and OXA-35 (n = 1). Altogether, these data provide evidence that MexXY-OprM plays a major role in the development of FEP resistance among clinical strains of P. aeruginosa.

* Corresponding author. Mailing address: Laboratoire de Bactériologie, Hôpital Jean Minjoz, 25030 Besançon cedex, France. Phone: 33 3 81 66 82 86. Fax: 33 3 81 66 89 14. E-mail: dhocquet{at}chu-besancon.fr.

Antimicrobial Agents and Chemotherapy, April 2006, p. 1347-1351, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1347-1351.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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