title: Old drugs, new purpose: retooling existing drugs for optimized treatment of resistant tuberculosis.
abstract: Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization-defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. kdooley1@jhmi.edu
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.forename: Carole D
authors.initials: CD
authors.lastname: Mitnick
authors.forename: Mary
authors.initials: M
authors.lastname: Ann DeGroote
authors.forename: Ekwaro
authors.initials: E
authors.lastname: Obuku
authors.forename: Vera
authors.initials: V
authors.lastname: Belitsky
authors.forename: Carol D
authors.initials: CD
authors.lastname: Hamilton
authors.forename: Mamodikoe
authors.initials: M
authors.lastname: Makhene
authors.forename: Sarita
authors.initials: S
authors.lastname: Shah
authors.forename: James C M
authors.initials: JC
authors.lastname: Brust
authors.forename: Nadza
authors.initials: N
authors.lastname: Durakovic
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents