Multidrug therapy is often required. Examples include antiviral therapy, nosocomial infections, and, most commonly, anti-Mycobacterium tuberculosis therapy. Our laboratory previously identified a mathematical approach to identify 2-drug regimens with a synergistic or additive interaction using a full factorial study design. Our objective here was to generate a method to identify an optimal 3-drug therapy. We studied M. tuberculosis isolate H37Rv in log-phase growth in flasks. Pretomanid and moxifloxacin were chosen as the base 2-drug regimen. Bedaquiline (plus M2 metabolite) was chosen as the third drug for evaluation. Total bacterial burden and bacterial burden less-susceptible to study drugs were enumerated. A large mathematical model was fit to all the data. This allowed extension to evaluation of the 3-drug regimen by employing a Monte Carlo simulation. Pretomanid plus moxifloxacin demonstrated excellent bacterial kill and suppressed amplification of less-susceptible pathogens. Total bacterial burden was driven to extinction in 3 weeks in 6 of 9 combination therapy evaluations. Only the lowest pretomanid/moxifloxacin exposures in combination did not extinguish the bacterial burden. No combination regimen allowed resistance amplification. Generation of 95% credible intervals about estimates of the interaction parameters α (α_s, α_r-p, and α_r-m) by bootstrapping showed the interaction was near synergistic. The addition of bedaquiline/M2 metabolite was evaluated by forming a 95% confidence interval regarding the decline in bacterial burden. The addition of bedaquiline/M2 metabolite shortened the time to eradication by 1 week and was significantly different. A model-based system approach to evaluating combinations of 3 agents shows promise to rapidly identify the most promising combinations that can then be trialed.

中文翻译：

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建立最佳的三药联合化疗方案。


通常需要多种药物治疗。例子包括抗病毒治疗、医院感染以及最常见的抗结核分枝杆菌治疗。我们的实验室之前确定了一种数学方法，使用完整的析因研究设计来确定具有协同或相加相互作用的 2 种药物治疗方案。我们的目标是找到一种方法来确定最佳的 3 种药物疗法。我们研究了烧瓶中对数期生长的结核分枝杆菌分离株 H37Rv。选择 Pretomanid 和莫西沙星作为基础 2 药方案。 Bedaquiline（加上 M2 代谢物）被选为第三种评估药物。列举了总细菌负荷和对研究药物不太敏感的细菌负荷。一个大型数学模型适合所有数据。这允许通过采用蒙特卡罗模拟来扩展对三种药物方案的评估。 Pretomanid 联合莫西沙星表现出出色的细菌杀灭作用并抑制不太敏感的病原体的扩增。在 9 项联合治疗评估中有 6 项中，总细菌负荷在 3 周内被消灭。只有最低的前托马尼/莫西沙星组合暴露量才不能消除细菌负荷。没有任何联合治疗方案会导致耐药性放大。通过 bootstrapping 生成关于相互作用参数 α（α _s 、α _rp和 α _rm ）估计值的 95% 可信区间表明相互作用接近协同。通过形成关于细菌负荷下降的 95% 置信区间来评估贝达喹啉/M2 代谢物的添加。添加贝达喹啉/M2代谢物使根除时间缩短了1周，且差异显着。 评估 3 种药物组合的基于模型的系统方法有望快速识别最有希望的组合，然后进行试验。