Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2012 Jun;56(6):3114-20. doi: 10.1128/AAC.00384-12. Epub 2012 Apr 2.
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.
需要新的抗结核药物组成的口服新方案，这些药物对结核分枝杆菌具有强大的活性，与现有药物无交叉耐药性，以缩短并简化耐多药和敏感结核病的治疗。作为评估新型药物组合在小鼠模型中缩短治疗时间潜力的持续努力的一部分，我们进行了两项长期、基于复发的实验。在第一项实验中，几种含有处于 2/3 期试验的新药物（TMC207 [贝达喹啉]、PA-824 和 PNU-100480 [舒他西林] 和/或氯法齐明）的 3 种和 4 种药物组合被证明优于利福平、吡嗪酰胺和异烟肼的一线方案。TMC207 加 PNU-100480 是最有效的药物组合。在第二项实验中，评估了由 TMC207 和吡嗪酰胺与利福喷丁、氯法齐明、PNU-100480 或两者组成的 3 种和 4 种药物组合，提高 TMC207 和吡嗪酰胺杀菌活性的药物顺序如下：利福喷丁加氯法齐明≥氯法齐明≥利福喷丁＞PNU-100480。结果揭示了潜在的新建筑块，用于普遍有效的耐多药结核病短程方案。针对敏感分离株加入吡嗪酰胺可能进一步缩短治疗时间。
