title: Antipneumococcal activity of DK-507k, a new quinolone, compared with the activities of 10 other agents.
abstract: Agar dilution MIC determination was used to compare the activity of DK-507k with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, amoxicillin, cefuroxime, erythromycin, azithromycin, and clarithromycin against 113 penicillin-susceptible, 81 penicillin-intermediate, and 67 penicillin-resistant pneumococci (all quinolone susceptible). DK-507k and sitafloxacin had the lowest MICs of all quinolones against quinolone-susceptible strains (MIC at which 50% of isolates were inhibited [MIC50] and MIC90 of both, 0.06 and 0.125 microg/ml, respectively), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. MICs of beta-lactams and macrolides rose with those of penicillin G. Against 26 quinolone-resistant pneumococci with known resistance mechanisms, DK-507k and sitafloxacin were also the most active quinolones (MICs, 0.125 to 1.0 microg/ml), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Mutations in quinolone resistance-determining regions of quinolone-resistant strains were in the usual regions of the parC and gyrA genes. Time-kill testing showed that both DK-507k and sitafloxacin were bactericidal against all 12 quinolone-susceptible and -resistant strains tested at twice the MIC at 24 h. Serial broth passages in subinhibitory concentrations of 10 strains for a minimum of 14 days showed that development of resistant mutants (fourfold or greater increase in the original MIC) occurred most rapidly for ciprofloxacin, followed by moxifloxacin, DK-507k, gatifloxacin, sitafloxacin, and levofloxacin. All parent strains demonstrated a fourfold or greater increase in initial MIC in <50 days. MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, and levofloxacin. Four strains were subcultured in subinhibitory concentrations of each drug for 50 days: MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Exposure to DK-507k and sitafloxacin resulted in mutations, mostly in gyrA.
authors.affiliation: Department of Medicine, Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Browne
authors.forename: Bülent
authors.initials: B
authors.lastname: Bozdogan
authors.forename: Catherine
authors.initials: C
authors.lastname: Clark
authors.forename: Linda M
authors.initials: LM
authors.lastname: Kelly
authors.forename: Lois
authors.initials: L
authors.lastname: Ednie
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kosowska
authors.forename: Bonifacio
authors.initials: B
authors.lastname: Dewasse
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jacobs
authors.forename: Peter C
authors.initials: PC
authors.lastname: Appelbaum
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology; D005798:Genes, Bacterial / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010403:Penicillin Resistance; D012110:Reserpine / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics
chemical_list: D000890:Anti-Infective Agents; D000995:Antitubercular Agents; C480349:DK-507k; D024841:Fluoroquinolones; D012110:Reserpine; C076246:sitafloxacin; D027081:DNA Gyrase