Sterilizing Activity of Novel TMC207- and PA-824-Containing Regimens in a Murine Model of Tuberculosis

• Published in: Antimicrobial Agents and Chemotherapy 2011-12, Vol.55 (12), p.5485-5492
• Main Authors: Tasneen, Rokeya, Li, Si-Yang, Peloquin, Charles A, Taylor, Dinesh, Williams, Kathy N, Andries, Koen, Mdluli, Khisimuzi E, Nuermberger, Eric L
• Format: Article
• Language: English
• Subjects: animal disease models; Animals; antibacterial properties; Antibiotics, Antitubercular; Antibiotics, Antitubercular - administration & dosage; Antibiotics, Antitubercular - pharmacology; Antibiotics, Antitubercular - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents; Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacology; Antitubercular Agents - therapeutic use; Bacterial diseases; Biological and medical sciences; Colony Count, Microbial; combination drug therapy; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; drug resistance; Drug Therapy, Combination; Experimental Therapeutics; fluoroquinolones; Human bacterial diseases; Infectious diseases; isoniazid; Medical sciences; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; new drugs; Nitroimidazoles; Nitroimidazoles - administration & dosage; Nitroimidazoles - pharmacology; Nitroimidazoles - therapeutic use; Pharmacology. Drug treatments; Quinolines; Quinolines - administration & dosage; Quinolines - pharmacology; Quinolines - therapeutic use; relapse; Secondary Prevention; Treatment Outcome; tuberculosis; Tuberculosis and atypical mycobacterial infections; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Multidrug-Resistant - microbiology; Tuberculosis, Pulmonary; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - microbiology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.05293-11

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.