title: Pharmacodynamic activity of fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae.
abstract: The susceptibility and pharmacodynamic activity of ciprofloxacin and new fluoroquinolones were studied against low-level (MIC 4 mg/L) and high-level (MIC 16 mg/L) ciprofloxacin-resistant Streptococcus pneumoniae. An in vitro pharmacodynamic model simulating free fluoroquinolone (protein unbound) serum concentrations, using Cp(max) and AUC(0-24) achieved (in healthy volunteers) after standard oral doses that are used for community-acquired respiratory infections, was used to compare bacterial killing by five fluoroquinolones against six ciprofloxacin-resistant S. pneumoniae isolates (four different resistance mutant phenotypes: ParC, efflux, ParC with efflux, and ParC and GyrA) obtained from an ongoing Canadian respiratory organism surveillance study. The potency (MIC only) of fluoroquinolones was gemifloxacin > moxifloxacin > gatifloxacin > levofloxacin > ciprofloxacin. Ciprofloxacin (free AUC(0-24)/MIC 0.9-3.5) produced no reduction of growth at 6, 24 or 48 h compared with the initial inoculum in all six strains. Levofloxacin (free AUC(0-24)/MIC 18-35) was bactericidal (> or = 3 log(10) killing) at 6, 24 and 48 h for the ParC as well as the efflux mutants, but only bactericidal at 24 h for the ParC with efflux strain. Levofloxacin (free AUC(0-24)/MIC 4.4) demonstrated no reduction of growth relative to the initial inoculum against the ParC and GyrA mutants. Gatifloxacin and moxifloxacin (free AUC(0-24)/MIC 48 and 60, respectively) were bactericidal at 6, 24 and 48 h against the ParC, efflux, and ParC with efflux mutants, but demonstrated little to no growth reduction (free AUC(0-24)/MIC 6 and 7.5, respectively) in ParC and GyrA mutants. Gemifloxacin (free AUC(0-24)/MIC 67-133) was bactericidal (> or = 3 log(10) killing) at 6, 24 and 48 h in all low-level ciprofloxacin-resistant S. pneumoniae mutants. Against two of the ParC and GyrA mutants, gemifloxacin (free AUC(0-24)/MIC 32) was bactericidal at 6, 24 and 48 h but against one ParC and GyrA mutant (free AUC(0-24)/MIC 16) gemifloxacin demonstrated reduced activity with initial killing at 24 h but with subsequent regrowth. These data indicate that ciprofloxacin produces no inhibition of growth of low- or high-level ciprofloxacin-resistant S. pneumoniae, whereas gatifloxacin, levofloxacin and moxifloxacin (moxifloxacin>gatifloxacin>levofloxacin) were bactericidal for low-level resistant strains but produced little or no inhibition of high-level resistant strains. Gemifloxacin at simulated free AUC(0-24)/MIC > or = 32, was bactericidal against low- and high-level resistant strains. When simulated free AUC(0-24)/ MIC was <16, gemifloxacin allowed regrowth of high-level ciprofloxacin-resistant strains.
authors: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada. ggzhanel@pcs.mb.ca
authors: George G
authors: GG
authors: Zhanel
authors: Danielle
authors: D
authors: Roberts
authors: Andrew
authors: A
authors: Waltky
authors: Nancy
authors: N
authors: Laing
authors: Kim
authors: K
authors: Nichol
authors: Heather
authors: H
authors: Smith
authors: Ayman
authors: A
authors: Noreddin
authors: Tracy
authors: T
authors: Bellyou
authors: Daryl J
authors: DJ
authors: Hoban
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000032:analysis / Q000235:genetics; D004352:Drug Resistance, Microbial; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D004269:DNA, Bacterial; D002939:Ciprofloxacin