title: Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis.
abstract: Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing 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, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Williams
authors.forename: Austin
authors.initials: A
authors.lastname: Minkowski
authors.forename: Opokua
authors.initials: O
authors.lastname: Amoabeng
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Dinesh
authors.initials: D
authors.lastname: Taylor
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wallis
authors.forename: Khisimuzi E
authors.initials: KE
authors.lastname: Mdluli
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D007538:Isoniazid / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D023303:Oxazolidinones / Q000008:administration & dosage / Q000627:therapeutic use; D011718:Pyrazinamide / Q000008:administration & dosage / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D023303:Oxazolidinones; C543015:PNU-100480; C410767:pretomanid; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine