title: Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol.
abstract: BACKGROUND
  Ethambutol is used for the treatment of tuberculosis in cases where there is isoniazid resistance. We examined the emergence of drug resistance to ethambutol monotherapy in pharmacokinetic-pharmacodynamic studies of a hollow-fiber system.
  
  
  METHODS
  Dose-effect and dose-scheduling studies were performed with ethambutol and log-phase growth Mycobacterium tuberculosis to identify exposures and schedules linked to optimal kill and resistance suppression. In one study, after 7 days of daily ethambutol, 300 mg isoniazid per day was administered to each system to determine its early bactericidal activity.
  
  
  RESULTS
  Efflux-pump blockage reduced the mutation frequency to ethambutol 64-fold. In dose-effect studies, ethambutol had a maximal early bactericidal activity of 0.22 log10 colony-forming units/mL/day, as is encountered in patients. By day 7, resistance to both ethambutol and isoniazid had increased. Previous exposure to ethambutol halted isoniazid early bactericidal activity. Daily therapy, as opposed to more intermittent therapy, was associated with the least proportion of efflux-pump-driven resistance, consistent with a time-driven effect. Microbial kill was best explained by the ratio of area under the concentration-time curve to minimum inhibitory concentration (r2 = 0.90).
  
  
  CONCLUSIONS
  The induction of an efflux pump that reduces the effect of multiple drugs provides an alternative pathway to sequential acquisition of mutations in the development of multiple drug resistance.
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113, USA.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.forename: Sandirai
authors.initials: S
authors.lastname: Musuka
authors.forename: Carleton
authors.initials: C
authors.lastname: Sherman
authors.forename: Claudia
authors.initials: C
authors.lastname: Meek
authors.forename: Richard
authors.initials: R
authors.lastname: Leff
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial; D004977:Ethambutol / Q000493:pharmacokinetics / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*
chemical_list: D000995:Antitubercular Agents; D026901:Membrane Transport Proteins; D004977:Ethambutol; D007538:Isoniazid