Open AccessInvolvement of the MexXY-OprM Efflux System in Emergence of Cefepime Resistance in Clinical Strains of Pseudomonas aeruginosa
Author(s) -
Didier Hocquet,
Patrice Nordmann,
Farid El Garch,
Ludovic Cabanne,
Patrick Plésiat
Publication year - 2006
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.50.4.1347-1351.2006
Subject(s) - efflux , pseudomonas aeruginosa , microbiology and biotechnology , cefepime , biology , pseudomonadaceae , derepression , ceftazidime , operon , pseudomonadales , multiple drug resistance , antibiotics , bacteria , gene , genetics , escherichia coli , gene expression , psychological repression
Cefepime (FEP) and ceftazidime (CAZ) are potent beta-lactam antibiotics with similar MICs (1 to 2 mug/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 beta-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 beta-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.