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Antimicrobial Agents and Chemotherapy, June 2003, p. 1887-1894, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1887-1894.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Genetic and Phenotypic Variations of a Resistant Pseudomonas aeruginosa Epidemic Clone

Laboratoire de Bactériologie,¹ Service d'Hygiène hospitalière et d'Epidémiologie moléculaire,² Hôpital Jean Minjoz, Besançon, France, and Departement de Génétique et de Microbiologie, Centre Médical Universitaire, Geneva, Switzerland³

Received 4 September 2002/ Returned for modification 22 October 2002/ Accepted 26 February 2003

From May 1997 to December 2001, a serotype O:6 multidrug-resistant strain of Pseudomonas aeruginosa colonized or infected 201 patients in the University Hospital of Besançon (France). The susceptibility profile of this epidemic clone to fluoroquinolones and aminoglycosides was relatively stable during the outbreak but showed important isolate-to-isolate variations (up to 64-fold) in the MICs of ß-lactams. Analysis of 18 genotypically related isolates selected on a quaterly basis demonstrated alterations in the two DNA topoisomerases II and IV (Thr83Ile in GyrA and Ser87Leu in ParC) and production of an ANT(2")-I enzyme. Although constitutively overproduced in these bacteria, the MexXY efflux system did not appear to contribute significantly to aminoglycoside resistance. ß-Lactam resistance was associated with derepression of intrinsic AmpC ß-lactamase (with isolate-to-isolate variations of up to 58-fold) and sporadic deficiency in a 46-kDa protein identified as the carbapenem-selective porin OprD. Of the 18 isolates, 14 were also found to overproduce the efflux system MexAB-OprM as a result of alteration of the repressor protein MexR (His107Pro). However, complementation experiments with the cloned mexR gene demonstrated that MexAB-OprM contributed only marginally to ß-lactam and fluoroquinolone resistance. Of the four isolates exhibiting wild-type MexAB-OprM expression despite the MexR alteration, two appeared to harbor secondary mutations in the mexA-mexR intergenic region and one harbored secondary mutations in the putative ribosome binding site located upstream of the mexAB oprM operon. In conclusion, this study shows that many mechanisms were involved in the multiresistance phenotype of this highly epidemic strain of P. aeruginosa. Our results also demonstrate that the clone sporadically underwent substantial genetic and phenotypic variations during the course of the outbreak, perhaps in relation to local or individual selective drug pressures.

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