Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Sci Rep. 2018 Apr 9;8(1):5714. doi: 10.1038/s41598-018-24067-x.
Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (RZHE), rifampicin-pyrazinamide-moxifloxacin-ethambutol (RZME) or rifampicin-pyrazinamide-moxifloxacin-isoniazid (RZMH). Treatment outcome was assessed in n = 3 mice after 9 different treatment lengths between 2-6 months. Next, we created a mathematical model that best fitted the observational data and used this for inter-regimen comparison. The observed data were best described by a sigmoidal E model in favor over linear or conventional E models. Estimating regimen-specific parameters showed significantly higher curative potentials for RZME and RZHE compared to RZMH. In conclusion, we provide a new design for treatment outcome evaluation in a mouse TB model, which (i) provides accurate tools for assessment of the relationship between treatment length and predicted cure, (ii) allows for efficient comparison between regimens and (iii) adheres to the reduction and refinement principles of laboratory animal use.
临床前结核病 (TB) 治疗结果的评估主要在小鼠中进行。目前的设计方案在选定的时间点比较不同方案的复发率，但缺乏关于治疗时间长短与治疗结果之间相关性的信息，而这对于有效地评估方案的缩短治疗潜力是必需的。因此，我们开发了一种新方法。将结核分枝杆菌北京基因型菌株感染 BALB/c 小鼠，并使用利福喷丁-吡嗪酰胺-异烟肼-乙胺丁醇（RZHE）、利福平-吡嗪酰胺-莫西沙星-乙胺丁醇（RZME）或利福平-吡嗪酰胺-莫西沙星-异烟肼（RZMH）进行治疗。在 2-6 个月之间的 9 种不同治疗长度后，对 n = 3 只小鼠的治疗结果进行评估。接下来，我们创建了一个最佳拟合观测数据的数学模型，并使用该模型进行方案间比较。观察到的数据最好由有利于线性或传统 E 模型的 S 型 E 模型来描述。估计方案特异性参数显示，与 RZMH 相比，RZME 和 RZHE 具有更高的治疗潜力。总之，我们为小鼠 TB 模型中的治疗结果评估提供了一种新的设计，（i）为评估治疗时间长短与预测治愈率之间的关系提供了准确的工具，（ii）允许在方案之间进行高效比较，（iii）符合实验室动物使用减少和优化原则。
