title: Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis.
abstract: To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rokeya
authors.initials: R
authors.lastname: Tasneen
authors.forename: Si-Yang
authors.initials: SY
authors.lastname: Li
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Dinesh
authors.initials: D
authors.lastname: Taylor
authors.forename: Kathy N
authors.initials: KN
authors.lastname: Williams
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Khisimuzi E
authors.initials: KE
authors.lastname: Mdluli
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D064687:Diarylquinolines; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D055502:Secondary Prevention; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D064687:Diarylquinolines; D009593:Nitroimidazoles; D011804:Quinolines; C410767:pretomanid; C493870:bedaquiline