Involvement of the MexXY-OprM efflux system in emergence of cefepime resistance in clinical strains of Pseudomonas aeruginosa.
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.
Hocquet
Didier
D
Laboratoire de Bactériologie, Hôpital Jean Minjoz, University of Franche-Comte, Besançon cedex, France. dhocquet@chu-besancon.fr
Nordmann
Patrice
P
El Garch
Farid
F
Cabanne
Ludovic
L
Plésiat
Patrick
P
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000502:physiology*; D001426:Bacterial Proteins / Q000502:physiology*; D000077723:Cefepime; D002511:Cephalosporins / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D026901:Membrane Transport Proteins / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002511:Cephalosporins; D026901:Membrane Transport Proteins; C402791:MexXY protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D000077723:Cefepime