The Treatment of Tuberculosis
The Treatment of Tuberculosis
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DOI：
10.1002/cpt.2261
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发表时间：
2021-06-05
影响因子：
6.7
通讯作者：
Davies, Geraint R.
中科院分区：
文献类型：
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作者：
Peloquin, Charles A.;Davies, Geraint R.
结核病(TB)仍然是全世界传染性死亡的主要原因，而贫困是一个主要驱动因素。临床上，结核病分为“潜伏型”结核病和“活动性”结核病，治疗方法各不相同。结核病药物可显示“早期杀菌活性(EBA)”和/或“杀菌活性”(清除持久性细菌)。异烟肼对前者效果较好，利福平对后者效果较好。吡津酰胺和乙胺丁醇完成了对药物敏感的结核病的一线治疗方案，各自发挥着特定的作用。耐药结核病是一个日益令人担忧的问题，部分可通过改变用途的药物(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)和新药(包括贝达奎兰、前托马尼德和地拉曼德)来解决。一个挑战是选择不重叠的药物不良反应档案。QTC间期延长就是这样一个问题，但到目前为止，它是可控的。药物对中枢神经系统、骨骼和肺结核病空洞等生物体的渗透仍然是一个重要的挑战。大多数结核病药物的药效学可以用曲线下面积(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/药效学实验。这些实验可能会加速选择最有效、最短的治疗方案，以治疗甚至是极端耐药的结核病。这些发现可以通过优化每个患者的药物暴露，使用治疗性药物监测和剂量个别化来转化为人类。
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.