title: Relative potential for selection of quinolone-resistance-determining-region mutations in Streptococcus pneumoniae by gemifloxacin, gatifloxacin and moxifloxacin.
abstract: Serial passage of a clinical isolate of Streptococcus pneumoniae, in the presence of moxifloxacin, gatifloxacin or gemifloxacin, gave rise to resistant isolates. Non-susceptibility as defined by Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) breakpoints arose on Days 10, 11, and 12 with gatifloxacin, gemifloxacin, and moxifloxacin respectively. Moxifloxacin and gatifloxacin selected for a single step quinolone-resistant-determining-region (QRDR) mutation in DNA gyrase (GyrA) on Day 4 and 7 respectively, whereas gemifloxacin selected simultaneously for multi-step mutations in gyrase and topoisomerase IV (ParC) on Day 17 and activated a non-reserpine inhibited efflux mechanism by Day 4. As found in clinical isolates, mutations included Ser-81-Phe and Glu-85-Lys in GyrA and Ser-79-Phe or Asp-83-Tyr in ParC. At high MICs, moxifloxacin showed a previously unreported 4 amino-acid deletion in GyrB as well as a more unusual substitution Ser-79-Leu/Ile in ParC. Gemifloxacin showed a 2- to 16-fold greater activity than moxifloxacin or gatifloxacin against strains with two or more QRDR mutations, however, its potency did not translate to nonsusceptibility and gemifloxacin MIC values were either at or well above the CLSI nonsusceptible breakpoint concentration.
authors.affiliation: Toronto Centre for Antimicrobial Research and Evaluation (ToCARE), Dept. of Microbiology, Mount Sinai Hospital, Canada. jdeazavedo@mtsinai.on.ca
authors.forename: J C S
authors.initials: JC
authors.lastname: De Azavedo
authors.forename: C L
authors.initials: CL
authors.lastname: Duncan
authors.forename: L
authors.initials: L
authors.lastname: Kilburn
authors.forename: J
authors.initials: J
authors.lastname: Downar
authors.forename: B
authors.initials: B
authors.lastname: Kong
authors.forename: S
authors.initials: S
authors.lastname: Lad
authors.forename: D E
authors.initials: DE
authors.lastname: Low
authors.forename: D J
authors.initials: DJ
authors.lastname: Bast
mesh_terms: D019943:Amino Acid Substitution / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D027081:DNA Gyrase / Q000235:genetics; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology; D000077734:Gatifloxacin; D000077735:Gemifloxacin; D006801:Humans; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation / Q000187:drug effects*; D009287:Naphthyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D012641:Selection, Genetic; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D009287:Naphthyridines; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D000077734:Gatifloxacin; D000077735:Gemifloxacin; D000077266:Moxifloxacin