title: Comparative pharmacodynamics of garenoxacin, gemifloxacin, and moxifloxacin in community-acquired pneumonia caused by Streptococcus pneumoniae: a Monte Carlo simulation analysis.
abstract: OBJECTIVE
  This study used Monte Carlo simulations to assess the potential for attainment of pharmacodynamic targets with the fluoroquinolones garenoxacin, gemifloxacin, and moxifloxacin against Streptococcus pneumoniae in serum and epithelial lining fluid (ELF) from hospitalized patients with community-acquired pneumonia (CAP).
  
  
  METHODS
  Data on the free AUC over 24 hours (fAUC(0-24)), a measure of drug exposure, were derived from previously described population pharmacokinetic models for therapeutic doses of the 3 fluoroquinolones. MIC distribution data for S pneumoniae were obtained from the Canadian Respiratory Organism Susceptibility Study. These data were used to produce the ratio of fAUC(0-24) to the MIC(90) (fAUC(0-24)/MIC(90)), a pharmacodynamic predictor of bacterial eradication. Monte Carlo simulations were used to analyze the potential for garenoxacin 400 mg QD, gemifloxacin 320 mg QD, and moxifloxacin 400 mg QD to achieve target fAUC(0-24)/MIC(90) ratios of 30, 40, 100, and 120 against S pneumoniae in serum and ELF from hospitalized patients with CAP. Target ratios of 30 and 40 were used to assess the probability of bacterial eradication, while ratios of 100 and 120 were used to assess the probability of preventing development of resistance.
  
  
  RESULTS
  Monte Carlo simulations indicated that all 3 fluoroquinolones had a high probability (>90%) of attaining target fAUC(0-24)/MIC(90) ratios of 30 and 40 against S pneumoniae in both serum and ELF. Garenoxacin 400 mg QD was associated with a >95% probability of achieving target fAUC(0-24)/MIC(90) ratios of 100 and 120 in both serum and ELF. Both gemifloxacin 320 mg QD and moxifloxacin 400 mg QD were associated with high probabilities of attaining fAUC(0-24)/MIC(90) ratios of 100 and 120 in ELF (>95%); the probability of gemifloxacin and moxifloxacin attaining these targets in serum ranged from 78.3% to 88.0%.
  
  
  CONCLUSIONS
  Based on these simulations, garenoxacin 400 mg QD, gemifloxacin 320 mg QD, and moxifloxacin 400 mg QD appeared likely to achieve target serum and ELF concentrations against S pneumoniae in hospitalized patients with CAP, with a low potential to select for resistance.
authors.affiliation: Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota 55812, USA. noreddin@umn.edu
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Noreddin
authors.forename: Angela A
authors.initials: AA
authors.lastname: Reese
authors.forename: Melissa
authors.initials: M
authors.lastname: Ostroski
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Hoban
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D019540:Area Under Curve; D001372:Aza Compounds / Q000378:metabolism / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000188:drug therapy / Q000382:microbiology; D024841:Fluoroquinolones / Q000378:metabolism / Q000494:pharmacology*; D000077735:Gemifloxacin; D006801:Humans; D009010:Monte Carlo Method; D000077266:Moxifloxacin; D009287:Naphthyridines / Q000378:metabolism / Q000494:pharmacology*; D011008:Pneumococcal Infections / Q000188:drug therapy*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D009287:Naphthyridines; D011804:Quinolines; D000077735:Gemifloxacin; D000077266:Moxifloxacin; C419689:garenoxacin