This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Drusano, G. L.
Right arrow Articles by Louie, A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Drusano, G. L.
Right arrow Articles by Louie, A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 2009, p. 2266-2273, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01680-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Differing Effects of Combination Chemotherapy with Meropenem and Tobramycin on Cell Kill and Suppression of Resistance of Wild-Type Pseudomonas aeruginosa PAO1 and Its Isogenic MexAB Efflux Pump-Overexpressed Mutant{triangledown}

G. L. Drusano,* Weiguo Liu, Christine Fregeau, Robert Kulawy, and Arnold Louie

Ordway Research Institute, Albany, New York

Received 19 December 2008/ Returned for modification 3 March 2009/ Accepted 4 March 2009

The drug interaction terminology (synergy, additivity, antagonism) relates to bacterial kill. The suppression of resistance requires greater drug exposure. We examined the combination of meropenem and tobramycin for kill and resistance suppression (wild-type Pseudomonas aeruginosa PAO1 and its isogenic MexAB-overexpressed mutant). The drug interaction was additive. The introduction of MexAB overexpression significantly altered the 50% inhibitory concentration of meropenem but not that of tobramycin, resulting in the recovery of a marked increase in colony numbers from drug-containing plates. For the wild type, more tobramycin-resistant isolates than meropenem-resistant isolates were present, and the tobramycin-resistant isolates were harder to suppress. MexAB overexpression unexpectedly caused a significant increase in the number of tobramycin-resistant mutants, as indexed to the area under the curve of slices through the inverted U resistance mountain. The differences were significant, except in the absence of meropenem. We hypothesize that the pump resulted in the presence of less meropenem for organism inhibition, allowing more rounds of replication and also affecting the numbers of tobramycin-resistant mutants. When resistance suppression is explored by combination chemotherapy, it is important to examine the impacts of differing resistance mechanisms for both agents.

* Corresponding author. Mailing address: Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208. Phone: (518) 641-6410. Fax: (518) 641-6304. E-mail: gdrusano{at}ordwayresearch.org

{triangledown} Published ahead of print on 16 March 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2266-2273, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01680-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»