Diagnostics and Pharmacotherapy for Severe Forms of TB

 描述（由申请人提供）：绝大多数结核病（TB）病例发生在资源有限的环境中，尽管有潜在的治愈性治疗，但TB的死亡人数超过任何其他单一细菌病原体。死亡率最高和资源消耗最多的是严重的结核病，包括耐多药结核病和被忽视的儿童结核病、结核性脑膜炎和结核性败血症。药代动力学变异性（次优循环药物浓度）似乎越来越常见，并且特别可通过剂量增加采取行动，但尚未在多中心前瞻性队列或最严重形式的TB疾病中进行研究。此外，传统的结核病药物敏感性测试是粗糙的：它使用一种浓度的药物，因此不允许量化耐药性。我们的初步工作表明，定量敏感性将更好地为药物选择提供信息，并可适用于现场分子诊断平台，最终为最棘手的结核病提供高产，个性化和可操作的结果。该提案将统一来自4个不同结核背景的研究中心（坦桑尼亚、乌干达、孟加拉国、西伯利亚）的合作者，以加强实验室资源、培养人员和建立研究基础设施，从而前瞻性地研究药代动力学变异性和M.结核病耐药性（MIC）及其对治疗结果的双重影响。ICIDR的一半以上资金用于国际合作网站。这一建议可立即促进区域结核病治疗方案，并将建立传染病分子诊断和现场流行病学的广泛能力。

 DESCRIPTION (provided by applicant): The vast majority of tuberculosis (TB) cases occur in resource-limited settings and despite potentially curative therapy, deaths from TB outweigh any other single bacterial pathogen. The highest rates of mortality and greatest consumption of resources reside with severe forms of TB disease, including multidrug-resistant (MDR)-TB and the neglected disease states of pediatric TB, TB meningitis and TB sepsis. Pharmacokinetic variability (suboptimal circulating drug concentrations) appears increasingly common and is particularly actionable through dose increase but has not been studied in multisite prospective cohorts or for the most severe forms of TB disease. Additionally, conventional drug-susceptibility testing for TB is crude: it uses one concentration of drug and therefore does not allow for quantification of resistance. Our preliminary work suggests quantitative susceptibility will better inform drug choice and can be adapted to fieldable molecular diagnostic platforms to ultimately deliver high-yield, individualized and actionable results for the most burdensome of TB disease. This proposal will unify established collaborators from 4 sites of diverse TB context (Tanzania, Uganda, Bangladesh, Siberia) to strengthen laboratory resources, develop personnel and build research infrastructure to study prospectively the extent and mechanisms of pharmacokinetic variability and M. tuberculosis drug-resistance (MIC) and their dual impact on treatment outcome. Over half of this ICIDR funding goes to the international collaborative sites. This proposal can contribute immediately to regional algorithms of TB treatment and will also build broad capacity for infectious disease molecular diagnostics and field epidemiology.