Sterilizing Activity of Novel TMC207-and PA-824-Containing Regimens in a Murine Model of Tuberculosis
Sterilizing Activity of Novel TMC207-and PA-824-Containing Regimens in a Murine Model of Tuberculosis
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DOI：
10.1128/aac.05293-11
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发表时间：
2011-12-01
影响因子：
4.9
通讯作者：
Nuermberger, Eric L.
中科院分区：
文献类型：
--
作者：
Tasneen, Rokeya;Li, Si-Yang;Nuermberger, Eric L.
为了真正改变结核病治疗的格局，需要含有至少两种新药的新方案，以简化对药物敏感和耐药结核病的治疗。作为正在进行的在小鼠模型中评估新型药物组合缩短治疗时间潜力的努力的一部分，我们进行了两个长期的、基于复发的实验。在第一个实验中，TMC 207加吡嗪酰胺，单独或与任何第三种药物组合，证明上级一线方案，包括利福平，吡嗪酰胺和异烟肼。基于1个月时的CFU计数，氯法齐明被证明是与TMC 207和吡嗪酰胺组合的最佳第三种药物，而PA-824的添加具有适度的拮抗作用。由于所有试验组的复发率均较低，因此复发结果不确定。在评价由TMC 207、吡嗪酰胺、PA-824、利福喷丁和氟沙星组成的3种药物组合的第二个实验中，TMC 207+吡嗪酰胺+利福喷丁或氟沙星是最有效的，在2个月的治疗中分别治愈了100%和67%的治疗小鼠。四个月的一线治疗方案没有治愈任何小鼠，而TMC 207，PA-824和阿托沙星的组合治愈了50%的治疗小鼠。结果揭示了新方案的新组成部分，有可能缩短药物敏感和耐药结核病的治疗时间，包括TMC 207，吡嗪酰胺，PA-824和强效氟喹诺酮的组合。
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.