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JAC Advance Access published online on April 27, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl159
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 31, 2006
Revised March 30, 2006
Accepted April 3, 2006

Original article

Pharmacodynamic activity of garenoxacin against ciprofloxacin-resistant Streptococcus pneumoniae

George G. Zhanel 1 *, Joanne James 2, Sheldon Derkatch 2, Nancy Laing 3, Ayman M. Noreddin 4, and Daryl J. Hoban 5

1 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 5th floor, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Canada R3E 0W3; Department of Clinical Microbiology, MS673 Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9; Department of Medicine, MS673 Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9
2 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 5th floor, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Canada R3E 0W3
3 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 5th floor, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Canada R3E 0W3; Department of Medicine, MS673 Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9
4 College of Pharmacy, University of Minnesota, 1208 Kirby Drive, Duluth, MN 55812, USA
5 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 5th floor, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Canada R3E 0W3; Department of Clinical Microbiology, MS673 Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9

* To whom correspondence should be addressed.
George G. Zhanel, E-mail: ggzhanel{at}pcs.mb.ca


  Abstract

Background: The pharmacodynamic parameter that best correlates with bacteriological eradication for fluoroquinolones is the free (f) area under the 24 h serum concentration curve (AUC24) to MIC (fAUC24/MIC) ratio. This study assessed garenoxacin fAUC24/MIC against ciprofloxacin-resistant Streptococcus pneumoniae using an in vitro pharmacodynamic model.

Methods: A total of 14 S. pneumoniae including 1 fluoroquinolone-susceptible and 13 ciprofloxacin-resistant S. pneumoniae (ParC, efflux, ParC with efflux, and ParC and GyrA) were studied. The quinolone-resistance determining regions (QRDRs) of parC and gyrA were sequenced and efflux was assessed using a reserpine assay. S. pneumoniae with garenoxacin MICs (mg/L) [number of strains] studied were: 0.03 [1], 0.06 [2], 0.12 [2], 0.25 [2], 0.5 [3], 1 [2] and 2 [2]. The in vitro pharmacodynamic model was inoculated with 1 x 106 cfu/mL and garenoxacin was dosed once daily at 0 and 24 h to simulate fAUC24 and t1/2 obtained after standard oral doses in healthy volunteers (400 mg once daily, free AUC24 20 mg·h/L, t1/2 16 h). Sampling was performed over 48 h to assess viable growth.

Results: Garenoxacin fAUC24/MIC achieved in the model ranged from 12 to 800. Garenoxacin fAUC24/MIC 200-800 was bactericidal (≥3 log10 killing) at 6, 24 and 48 h against ciprofloxacin-resistant S. pneumoniae mutants including ParC mutants only, efflux mutants only and ParC/efflux mutants. Garenoxacin fAUC24/MIC 48-96 was bactericidal (≥3 log10 killing) at 24 and 48 h against all ciprofloxacin-resistant S. pneumoniae mutants. Garenoxacin fAUC24/MIC ≤ 24 (against ParC and GyrA mutants) resulted in a bacteriostatic effect with regrowth at 24 and 48 h.

Conclusions: Garenoxacin was bactericidal against ciprofloxacin-resistant S. pneumoniae at fAUC24/MIC ≥ 48. Garenoxacin fAUC24/MIC ≤ 24 resulted in a bacteriostatic effect with regrowth at 24 and 48 h.

Keywords: S. pneumoniae; resistance; fluoroquinolones.
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