title: Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization.
abstract: OBJECTIVE
  To determine the potential for delafloxacin to select for resistant mutants in methicillin-resistant Staphylococcus aureus (MRSA), including isolates with existing mutations in the quinolone resistance determining region (QRDR).
  
  
  METHODS
  Susceptibility testing by broth microdilution was performed on 30 MRSA clinical isolates. For four of these isolates, the presence or absence of mutations in the QRDR was characterized. Resistance selection was performed on these four isolates by spreading cells on drug-containing agar plates followed by incubation for 48 h. Resistance frequencies and mutant prevention concentrations (MPCs) were calculated for each; PCR amplification and sequencing were performed using standard methods to characterize mutations in the QRDR. Growth rate analysis was performed and relative fitness was determined.
  
  
  RESULTS
  Delafloxacin demonstrated potent in vitro activity against this set of MRSA isolates, with MICs of 0.008-1 mg/L and an MIC(50) and MIC(90) of 0.03 and 0.5 mg/L, respectively. Spontaneous delafloxacin resistance frequencies for the MRSA strains were 2 × 10(-9) to <9.5 × 10(-11). Delafloxacin MPCs were one to four times the MIC for any isolate, lower than those of comparator quinolones. Some delafloxacin-selected mutants showed a fitness cost when co-cultured with the parent strain.
  
  
  CONCLUSIONS
  Delafloxacin demonstrates excellent antibacterial potency and exhibits a low probability for the selection of resistant mutants in MRSA. Although mutants can be selected at low frequencies in vitro from quinolone-resistant isolates, delafloxacin MICs and MPCs remain low and a fitness cost can be observed. Consequently delafloxacin warrants further investigation for the potential treatment of drug-resistant MRSA infections.
authors.affiliation: Biology Department, Rib-X Pharmaceuticals, Inc, New Haven, CT 06511, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Remy
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Tow-Keogh
authors.forename: Timothy S
authors.initials: TS
authors.lastname: McConnell
authors.forename: James M
authors.initials: JM
authors.lastname: Dalton
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Devito
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D009154:Mutation; D016133:Polymerase Chain Reaction; D015363:Quinolones / Q000494:pharmacology*; D012641:Selection, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D015363:Quinolones