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Antimicrobial Agents and Chemotherapy, May 2006, p. 1633-1641, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1633-1641.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Interplay of Efflux System, ampC, and oprD Expression in Carbapenem Resistance of Pseudomonas aeruginosa Clinical Isolates

John Quale,* Simona Bratu, Jyoti Gupta, and David Landman

Division of Infectious Diseases, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Box 77, Brooklyn, New York 11203

Received 17 January 2006/ Returned for modification 17 February 2006/ Accepted 28 February 2006

Carbapenems are important agents for the therapy of infections due to multidrug-resistant Pseudomonas aeruginosa; the development of carbapenem resistance hampers effective therapeutic options. To assess the mechanisms leading to resistance, 33 clinical isolates with differing degrees of carbapenem susceptibility were analyzed for the expression of the chromosomal ß-lactamase (ampC), the porin that is important for the entry of carbapenems (oprD), and the proteins involved in four efflux systems (mexA, mexC, mexE, and mexX). Real-time reverse transcriptase PCR was performed using primers and fluorescent probes for each of the target genes. The sequencing of regulatory genes (ampR, mexR, nalC, nalD, mexT, and mexZ) was also performed. Diminished expression of oprD was present in all imipenem- and meropenem-resistant isolates but was not required for ertapenem resistance. Increased expression of ampC was not observed in several isolates that were overtly resistant to carbapenems. Increased expression of several efflux systems was observed in many of the carbapenem-resistant isolates. Increased efflux activity correlated with high-level ertapenem resistance and reduced susceptibility to meropenem and aztreonam. Most isolates with increased expression of mexA had mutations affecting nalC and/or nalD. Two isolates with mutations leading to a premature stop codon in mexZ had markedly elevated mexX expressions, although mutations in mexZ were not a prerequisite for overexpression. ß-Lactam resistance in clinical isolates of P. aeruginosa is a result of the interplay between diminished production of oprD, increased activity of ampC, and several efflux systems.

* Corresponding author. Mailing address: Division of Infectious Diseases, Box 77, SUNY-Downstate, 450 Clarkson Avenue, Brooklyn, NY 11203. Phone: (718) 270-2148. Fax: (718) 270-2465. E-mail: jquale{at}downstate.edu.

Antimicrobial Agents and Chemotherapy, May 2006, p. 1633-1641, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1633-1641.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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