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
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Campion, J. J.
Right arrow Articles by Evans, M. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Campion, J. J.
Right arrow Articles by Evans, M. E.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 2005, p. 2189-2199, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2189-2199.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus

Jeffrey J. Campion,1 Philip Chung,2 Patrick J. McNamara,2 William B. Titlow,1 and Martin E. Evans1*

Division of Infectious Diseases, Department of Internal Medicine, College of Medicine,1 Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky2

Received 13 September 2004/ Returned for modification 20 January 2005/ Accepted 5 February 2005

Previously, we demonstrated the importance of low-level-resistant variants to the evolution of resistance in Staphylococcus aureus exposed to ciprofloxacin in an in vitro system and developed a pharmacodynamic model which predicted the emergence of resistance. Here, we examine and model the evolution of resistance to levofloxacin in S. aureus exposed to simulated levofloxacin pharmacokinetic profiles. Enrichment of subpopulations with mutations in grlA and low-level resistance varied with levofloxacin exposure. A regimen producing average steady-state concentrations (Cavg ss) just above the MIC selected grlA mutants with up to 16-fold increases in the MIC and often additional mutations in grlA/grlB and gyrA. A regimen providing Cavg ss between the MIC and the mutant prevention concentration (MPC) suppressed bacterial numbers to the limit of detection and prevented the appearance of bacteria with additional mutations or high-level resistance. Regimens producing Cavg ss above the MPC appeared to eradicate low-level-resistant variants in the cultures and prevent the emergence of resistance. There was no relationship between the time concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of mutations that appeared in grlA/B or gyrA. Our pharmacodynamic model described the growth and levofloxacin killing of the parent strains and the most resistant grlA mutants in the starting cultures and correctly predicted conditions that enrich subpopulations with low-level resistance. These findings suggest that the pharmacodynamic model has general applicability for describing fluoroquinolone resistance in S. aureus and further demonstrate the importance of low-level-resistant variants to the evolution of resistance.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Internal Medicine, Room MN672, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536-0298. Phone: (859) 323-8178. Fax: (859) 323-8926. E-mail: Martin.Evans{at}uky.edu.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2189-2199, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2189-2199.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kesteman, A.-S., Ferran, A. A., Perrin-Guyomard, A., Laurentie, M., Sanders, P., Toutain, P.-L., Bousquet-Melou, A. (2009). Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of Klebsiella pneumoniae in a Rat Lung Infection Model. Antimicrob. Agents Chemother. 53: 4740-4748 [Abstract] [Full Text]  
  • Allen, G. P., Hankins, C. D. (2009). Evaluation of the mutant selection window for fluoroquinolones against Neisseria gonorrhoeae. J Antimicrob Chemother 64: 359-363 [Abstract] [Full Text]  
  • Ferran, A. A., Kesteman, A.-S., Toutain, P.-L., Bousquet-Melou, A. (2009). Pharmacokinetic/Pharmacodynamic Analysis of the Influence of Inoculum Size on the Selection of Resistance in Escherichia coli by a Quinolone in a Mouse Thigh Bacterial Infection Model. Antimicrob. Agents Chemother. 53: 3384-3390 [Abstract] [Full Text]  
  • Firsov, A. A., Smirnova, M. V., Lubenko, I. Yu., Vostrov, S. N., Portnoy, Y. A., Zinner, S. H. (2006). Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model. J Antimicrob Chemother 58: 1185-1192 [Abstract] [Full Text]  
  • Chung, P., McNamara, P. J., Campion, J. J., Evans, M. E. (2006). Mechanism-Based Pharmacodynamic Models of Fluoroquinolone Resistance in Staphylococcus aureus.. Antimicrob. Agents Chemother. 50: 2957-2965 [Abstract] [Full Text]  


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