title: Pharmacodynamic activity of garenoxacin against ciprofloxacin-resistant Streptococcus pneumoniae.
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 10(6) 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 (> or = 3 log(10) 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 (> or = 3 log(10) killing) at 24 and 48 h against all ciprofloxacin-resistant S. pneumoniae mutants. Garenoxacin fAUC24/MIC < or = 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 > or = 48. Garenoxacin fAUC24/MIC < or = 24 resulted in a bacteriostatic effect with regrowth at 24 and 48 h.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba 5th floor, Basic Medical Sciences Building, Winnipeg, Canada R3E 0W3. ggzhanel@pcs.mb.ca
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Joanne
authors.initials: J
authors.lastname: James
authors.forename: Sheldon
authors.initials: S
authors.lastname: Derkatch
authors.forename: Nancy
authors.initials: N
authors.lastname: Laing
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Noreddin
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Hoban
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; C419689:garenoxacin