title: Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy.
abstract: Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens.
  
  
  OBJECTIVE
  The emergence and spread of multidrug-resistant M. tuberculosis are a major threat to global public health. Linezolid is an oxazolidinone that is licensed for human use and has demonstrated potent activity against multidrug-resistant M. tuberculosis. However, long-term use of linezolid has shown to be toxic in patients, often resulting in thrombocytopenia. We examined therapeutic linezolid regimens in an in vitro model to characterize the exposure-toxicity relationship. The antibacterial activity against M. tuberculosis was also assessed for these regimens, including the amplification or suppression of resistant mutant subpopulations by the chosen regimen. Higher exposures of linezolid resulted in greater antibacterial activity, but with more toxicity and, for some regimens, increased resistant mutant subpopulation amplification, illustrating the trade-off between activity and toxicity. These findings can provide valuable insight for designing optimal dosage regimens for linezolid that are part of the long combination courses used to treat multidrug-resistant M. tuberculosis.
authors.affiliation: Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA Ashley.Brown@medicine.ufl.edu.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Brown
authors.affiliation: Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.affiliation: Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Adams
authors.affiliation: Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Rodriquez
authors.affiliation: Biosciences Division, SRI International, Harrisonburg, Virginia, USA.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Jambunathan
authors.affiliation: Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.
authors.forename: Dodge L
authors.initials: DL
authors.lastname: Baluya
authors.affiliation: Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Brown
authors.affiliation: Alpert Medical School, Division of Infectious Diseases, Brown University, Miriam Hospital, Providence, Rhode Island, USA.
authors.forename: Awewura
authors.initials: A
authors.lastname: Kwara
authors.affiliation: Biosciences Division, SRI International, Harrisonburg, Virginia, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
authors.affiliation: Division of AIDS, NIAID, Bethesda, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hafner
authors.affiliation: Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
mesh_terms: D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D002460:Cell Line; D002470:Cell Survival; D004353:Drug Evaluation, Preclinical; D006801:Humans; D000069349:Linezolid / Q000008:administration & dosage* / Q000009:adverse effects*; D050296:Microbial Viability; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D000069349:Linezolid