title: In vitro pharmacodynamics of moxifloxacin versus levofloxacin against 4 strains of Streptococcus pneumoniae: 1 wild type, 2 first-step parC mutants, and 1 pump mutant.
abstract: Levofloxacin binds topoisomerase IV, whereas moxifloxacin preferentially binds DNA gyrase. Most 1st-step pneumococcal mutants have alterations in the parC gene of topoisomerase IV. Because of differential binding affinity, moxifloxacin may have superior activity against 1st-step mutants compared with levofloxacin. The purpose of this work was to compare rates and extent of bacterial killing of genetically characterized Streptococcus pneumoniae with moxifloxacin and levofloxacin. Four strains of S. pneumoniae were used: a wild type, 2 first-step parC mutants, and a pump mutant. Using an in vitro pharmacodynamic model run in duplicate, we exposed bacteria to unbound moxifloxacin and levofloxacin peaks of 2 and 4.5 mg/L, respectively, which emulated clinical dosing. Additional experiments were done in which the area under the curve (AUC)/MIC ratio of 1 agent was matched to the competing drug's clinical dose AUC/MIC ratio. Time kill curves were analyzed for rate and extent of bacterial kill and regrowth. Pre- and postexposure MIC and polymerase chain reaction (PCR) testing were done. Moxifloxacin and levofloxacin displayed similar rates and extent of bacterial kill for the wild type, efflux pump type, and parC mutant 27-1361B. Moxifloxacin initially achieved a faster rate of kill, regardless of the AUC/MIC ratio, against parC mutant 7362 (P < 0.05) but not an advantage in time to 3 log kill. Postexposure MIC values were elevated for strain 7362 in 2 moxifloxacin experiments and 1 levofloxacin experiment. Post-PCR analysis revealed new gyrA mutations for all 3 isolates. Both moxifloxacin and levofloxacin are effective against multiple strains of S. pneumoniae.
authors.affiliation: Antibiotic Pharmacodynamic Research Institute, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schafer
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Hovde
authors.forename: Dana
authors.initials: D
authors.lastname: Simonson
authors.forename: John C
authors.initials: JC
authors.lastname: Rotschafer
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001372:Aza Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics; D027101:DNA Topoisomerase IV / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D024841:Fluoroquinolones; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests / Q000379:methods; D050296:Microbial Viability; D000077266:Moxifloxacin; D009154:Mutation; D015242:Ofloxacin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D000077266:Moxifloxacin