title: A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.
abstract: BACKGROUND
  The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination.
  
  
  METHODS
  We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (TMIC) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression.
  
  
  RESULTS
  TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem TMIC> 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem TMIC> 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment.
  
  
  CONCLUSIONS
  We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children.
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Devyani
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Tuberculosis Research, Department of Medicine Department of International Health, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Tuberculosis Research Center, Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas Department of Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058491:Bacterial Load; D002648:Child; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D024841:Fluoroquinolones / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D000069349:Linezolid / Q000494:pharmacology / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology; D047090:beta-Lactams / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D047090:beta-Lactams; C107057:fropenem; D000069349:Linezolid; D000077266:Moxifloxacin
keywords: disseminated tuberculosis; hollow fiber model; regimen design; time-to-positivity