title: The combination of rifampin plus moxifloxacin is synergistic for suppression of resistance but antagonistic for cell kill of Mycobacterium tuberculosis as determined in a hollow-fiber infection model.
abstract: Moxifloxacin is under development for expanded use against Mycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P = 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P = 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill.
authors.affiliation: Ordway Research Institute, Albany, New York, USA. gdrusano@ordwayresearch.org
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
authors.forename: Nicole
authors.initials: N
authors.lastname: Sgambati
authors.forename: Adam
authors.initials: A
authors.lastname: Eichas
authors.forename: David L
authors.initials: DL
authors.lastname: Brown
authors.forename: Robert
authors.initials: R
authors.lastname: Kulawy
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D024841:Fluoroquinolones; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects*; D008954:Models, Biological; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin; D012293:Rifampin
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