College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
Clin Pharmacol Ther. 2021 Dec;110(6):1455-1466. doi: 10.1002/cpt.2261. Epub 2021 Jun 5.
Tuberculosis (TB) remains a leading cause of infectious death worldwide, and poverty is a major driver. Clinically, TB presents as "latent" TB and active TB disease, and the treatment for each is different. TB drugs can display "early bactericidal activity (EBA)" and / or "sterilizing activity" (clearing persisters). Isoniazid is excellent at the former, and rifampin is excellent at the latter. Pyrazinamide and ethambutol complete the first-line regimen for drug-susceptible TB, each playing a specific role. Drug-resistant TB is an increasing concern, being met, in part, with repurposed drugs (including moxifloxacin, levofloxacin, linezolid, clofazimine, and beta-lactams) and new drugs (including bedaquiline, pretomanid, and delamanid). One challenge is to select drugs without overlapping adverse drug reaction profiles. QTc interval prolongation is one such concern, but to date, it has been manageable. Drug penetration into organism sanctuaries, such as the central nervous system, bone, and pulmonary TB cavities remain important challenges. The pharmacodynamics of most TB drugs can be described by the area under the curve (AUC) divided by the minimal inhibitory concentration (MIC). The hollow fiber infection model (HFIM) and various animal models (especially mouse and macaque) allow for sophisticated pharmacokinetic/pharmacodynamic experiments. These experiments may hasten the selection of the most potent, shortest possible regimens to treat even extremely drug resistant TB. These findings can be translated to humans by optimizing drug exposure in each patient, using therapeutic drug monitoring and dose individualization.
结核病（TB）仍然是全球传染病死亡的主要原因，而贫困是一个主要驱动因素。临床上，TB 表现为“潜伏”TB 和活动性 TB 疾病，治疗方法也不同。TB 药物可以显示“早期杀菌活性（EBA）”和/或“杀菌活性”（清除持久菌）。异烟肼在前者方面表现出色，利福平在后者方面表现出色。吡嗪酰胺和乙胺丁醇完成了对敏感 TB 的一线治疗方案，每种药物都发挥着特定的作用。耐药性 TB 是一个日益令人关注的问题，部分原因是使用了重新定位的药物（包括莫西沙星、左氧氟沙星、利奈唑胺、氯法齐明和β-内酰胺类药物）和新药（包括贝达喹啉、普托马尼德和德拉马尼德）。一个挑战是选择没有重叠不良反应谱的药物。QTc 间期延长就是这样一个问题，但迄今为止，它是可以控制的。药物进入组织避难所（如中枢神经系统、骨骼和肺结核空洞）的渗透仍然是一个重要的挑战。大多数 TB 药物的药效动力学可以通过 AUC 除以最小抑菌浓度（MIC）来描述。中空纤维感染模型（HFIM）和各种动物模型（特别是小鼠和猕猴）允许进行复杂的药代动力学/药效动力学实验。这些实验可以通过优化每个患者的药物暴露来加速选择最有效、最短的治疗方案，即使是极耐药性 TB。通过治疗药物监测和剂量个体化来优化每个患者的药物暴露，可以将这些发现转化为人类。
