Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala,Sweden.
J Infect Dis. 2022 Jun 1;225(11):1876-1885. doi: 10.1093/infdis/jiab101.
Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling.
Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator.
Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively.
This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models.
鉴于结核病在全球的负担持续居高不下，需要有效的更短疗程治疗方案。我们使用结核感染小鼠模型和数学模型探索了两种新型抗结核药物方案的复发与治疗时间之间的关系以及方案间的差异。
用贝达喹啉和普托马尼德联合莫西沙星和吡嗪酰胺（BPaMZ）或利奈唑胺（BPaL）对结核分枝杆菌感染的小鼠进行长达 13 周的治疗。治疗完成后 12 周评估治愈率。异烟肼、利福平、吡嗪酰胺和乙胺丁醇（HRZE）的标准方案作为对照进行评估。
6 周的 BPaMZ 足以使所有小鼠治愈。相比之下，BPaL 治疗 13 周和 HRZE 治疗 24 周均未达到 100%的治愈率。根据数学模型预测，BPaMZ、BPaL 和 HRZE 达到 95%治愈率的概率预计分别为 1.6、4.3 和 7.9 个月。
这项研究为 BPaMZ 缩短 BPaL 和 HRZE 治疗时间提供了更多证据。为了优化利用临床前数据预测临床结果，并克服阻碍这种推断的局限性，我们主张将已发表的临床前数据捆绑到数学模型中。
