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Antimicrobial Agents and Chemotherapy, October 2007, p. 3642-3649, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00160-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Development of Resistance in Wild-Type and Hypermutable Pseudomonas aeruginosa Strains Exposed to Clinical Pharmacokinetic Profiles of Meropenem and Ceftazidime Simulated In Vitro{triangledown}

Beate Henrichfreise,* Irith Wiegand, Ingeborg Luhmer-Becker, and Bernd Wiedemann

Pharmaceutical Microbiology Unit, Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany

Received 4 February 2007/ Returned for modification 5 April 2007/ Accepted 23 July 2007

In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.

* Corresponding author. Mailing address: Pharmaceutical Microbiology Unit, Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany. Phone: 49 228 732111. Fax: 49 228 735267. E-mail: bhenrich{at}uni-bonn.de

{triangledown} Published ahead of print on 6 August 2007.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3642-3649, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00160-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bulitta, J. B., Ly, N. S., Yang, J. C., Forrest, A., Jusko, W. J., Tsuji, B. T. (2009). Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 53: 46-56 [Abstract] [Full Text]  


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