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Antimicrobial Agents and Chemotherapy, July 2009, p. 2785-2790, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00018-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effect of MexXY Overexpression on Ceftobiprole Susceptibility in Pseudomonas aeruginosa{triangledown}

Ellen Z. Baum,* Steven M. Crespo-Carbone, Brian J. Morrow, Todd A. Davies, Barbara D. Foleno, Wenping He, Anne Marie Queenan, and Karen Bush{dagger}

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, New Jersey 08869

Received 6 January 2009/ Returned for modification 4 February 2009/ Accepted 30 April 2009

Ceftobiprole, an anti-methicillin-resistant Staphylococcus aureus broad-spectrum cephalosporin, has activity (MIC for 50% of strains tested, ≤4 µg/ml) against many Pseudomonas aeruginosa strains. A common mechanism of P. aeruginosa resistance to β-lactams, including cefepime and ceftazidime, is efflux via increased expression of Mex pumps, especially MexAB. MexXY has differential substrate specificity, recognizing cefepime but not ceftazidime. In ceftobiprole clinical studies, paired isolates of P. aeruginosa from four subjects demonstrated ceftobiprole MICs of 2 to 4 µg/ml at baseline but 16 µg/ml posttreatment, unrelated to β-lactamase levels. Within each pair, the level of mexXY RNA, but not mexAB, mexCD, and mexEF, increased by an average of 50-fold from baseline to posttreatment isolates. Sequencing of the negative regulatory gene mexZ indicated that each posttreatment isolate contained a mutation not present at baseline. mexXY expression as a primary ceftobiprole and cefepime resistance mechanism was further examined in isogenic pairs by using cloned mexXY and mexZ. Expression of cloned mexXY in strain PAO1 or in a baseline isolate increased the ceftobiprole MIC to that for the posttreatment isolate. In contrast, in posttreatment isolates, lowering mexXY expression via introduction of cloned mexZ decreased the ceftobiprole MIC to that for the baseline isolates. Similar changes were observed for cefepime. A spontaneous mutant selectively overexpressing mexXY displayed a fourfold elevation in its ceftobiprole MIC, while overexpression of mexAB, -CD, and -EF had a minimal effect. These data indicate that ceftobiprole, like cefepime, is an atypical β-lactam that is a substrate for the MexXY efflux pump in P. aeruginosa.

* Corresponding author. Mailing address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, NJ 08869. Phone: (908) 704-4320. Fax: (908) 707-3501. E-mail: EBaum{at}its.jnj.com

{triangledown} Published ahead of print on 11 May 2009.

{dagger} Present address: Biology Department, Indiana University, Bloomington, IN 47405.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2785-2790, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00018-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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