title: Comparison of the bactericidal activities and post-antibiotic effects of the Des-F(6)-quinolone BMS-284756, levofloxacin, and ciprofloxacin against methicillin-susceptible and methicillin-resistant Staphylococcus aureus.
abstract: The bactericidal activities and post-antibiotic effects of BMS-284756 (T-3811ME), levofloxacin, and ciprofloxacin were evaluated against a methicillin-susceptible and a methicillin-resistant Staphylococcus aureus strain. Minimum inhibitory concentrations (MICs), minimum bactericidal concentrations, post-antibiotic effects, and post-antibiotic sub-MIC effects were determined and time-kill studies were performed for BMS-284756, levofloxacin, and ciprofloxacin. At 4-times and 10-times the MIC, time-kill kinetics over 3 h and over 24 h were similar for all three quinolones when effects were considered as multiples of the MIC. All three quinolones achieved a 3 log10 reduction in cfu/ml within 2 h. At 10-times the MIC, the post-antibiotic effects of BMS-284756, levofloxacin, and ciprofloxacin were 1.6-2.6 h for the methicillin-susceptible Staphylococcus aureus strain and 1.5-1.9 h for the methicillin-resistant Staphylococcus aureus strain. When actual concentrations were considered, BMS-284756 achieved results comparable to levofloxacin and ciprofloxacin at concentrations nearly 10-fold less. When relating the pharmacokinetic properties of the three quinolones to their in vitro activities, the resulting Cmax/MIC and AUC/MIC ratios were. respectively, 120-240.7 and 1,321.7-2,643 for BMS-284756, 22.8 and 190 for levofloxacin, and 5.9-11.9 and 54.8-109.6 for ciprofloxacin. The greater in vitro activity and favorable human pharmacokinetics of BMS-284756 may translate to improved clinical effectiveness of this agent compared to currently marketed quinolones.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Microbiology, Wallingford, CT 06492, USA. brenda.ryan@bms.com
authors.forename: B M
authors.initials: BM
authors.lastname: Ryan
authors.forename: C E
authors.initials: CE
authors.lastname: Mazzucco
authors.forename: L E
authors.initials: LE
authors.lastname: Lawrence
authors.forename: H
authors.initials: H
authors.lastname: Ho
authors.forename: G
authors.initials: G
authors.lastname: Warr
authors.forename: J F
authors.initials: JF
authors.lastname: Barrett
authors.forename: M
authors.initials: M
authors.lastname: Frosco
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001770:Blood Bactericidal Activity; D002939:Ciprofloxacin / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D024841:Fluoroquinolones; D006801:Humans; D007211:Indoles; D064704:Levofloxacin; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000494:pharmacology*; D015363:Quinolones; D012680:Sensitivity and Specificity; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D007211:Indoles; D015363:Quinolones; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D008712:Methicillin; C419689:garenoxacin