title: In vitro pharmacodynamic evaluation of garenoxacin against quinolone-resistant Streptococcus pneumoniae.
abstract: The bactericidal activity and resistance selectivity of garenoxacin against Streptococcus pneumoniae with mutations in ParC (S79F) or both GyrA (S81F) and ParC (D83Y and K137N) were investigated using in vitro pharmacokinetic models simulating plasma concentrations for a standard clinical regimen [400mg once daily (q.d.)]. The efficacy of garenoxacin was compared with that of levofloxacin (500 mg q.d.) and moxifloxacin (400mg q.d.). Garenoxacin showed excellent bactericidal activity against S. pneumoniae, including quinolone-resistant S. pneumoniae (QRSP), achieving ratios of area under the plasma concentration-time curve over 24h to minimum inhibitory concentration (AUC(0-24)/MIC) ≥ 26.3, without emerging resistant subpopulations. The area above the killing curves was greater and the time to achieve 99.9% killing was shorter for garenoxacin than the corresponding values for levofloxacin and moxifloxacin. No resistant subpopulations and no additional substitution of amino acids in GyrA or ParC emerged following treatment with garenoxacin. On the other hand, in the parC mutant strain, levofloxacin and moxifloxacin treatment caused an increase in the frequency of the resistant population and an additional substitution of amino acids in GyrA (levofloxacin, S81Y/F/C; moxifloxacin, S81Y or E85K). In QRSP with mutations in GyrA and ParC, levofloxacin had no bactericidal activity, whilst the bactericidal activity of moxifloxacin was less than that of garenoxacin; moreover, an additional substitution of amino acids in ParC (S79Y) was noted. In conclusion, garenoxacin corresponding to an oral dose of 400mg showed excellent bactericidal activity against S. pneumoniae, including QRSP, without the emergence of resistant mutants.
authors.affiliation: Research Laboratories, Toyama Chemical Co. Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan. yoshiko fukuda@toyama-chemical.co.jp
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takahata
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sugiura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shinmura
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nomura
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics; D027101:DNA Topoisomerase IV / Q000235:genetics; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D020125:Mutation, Missense; D015363:Quinolones / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D015363:Quinolones; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; C419689:garenoxacin