Clinical Impact of Anti-TB Drug Levels and M. Tuberculosis Susceptibility

描述(由申请人提供)： 摘要 Pi：Heysell，Scott K项目：1K23AI099019-01标题：抗结核药物水平和结核分枝杆菌敏感性的临床影响登录号：3398392 = 注意：此摘要摘自应用程序，未经SRA校对。如果应用程序扫描过程有问题，提取的文本可能不正确或不完整。 = 尽管接受多种药物治疗，但全球范围内结核病(TB)治疗失败的比例高达20%。在弗吉尼亚州，我们发现糖尿病是延迟反应的一个重要风险因素。在我们在坦桑尼亚的协作站点，与那些药物敏感的结核病患者相比，耐多药结核病患者的死亡风险更高。在这两个环境中，我们都发现血清药物水平与结核病药物相比很低，然而，血清药物水平在控制结核病方面的最佳使用仍不清楚。为了告知这一问题，我们开发了一种结核病药物活性测试，它是在结核病治疗期间用患者的血浆或血清和他们的自体结核病分离株进行的，允许测量药物水平和分离株的相对耐药性。因此，在这项提案中，我们将比较(1)药物水平、(2)结核分枝杆菌药物敏感性(MIC)和(3)结核病药物活性分析与治疗失败风险患者的相关治疗结果-弗吉尼亚州的糖尿病患者和坦桑尼亚的耐多药结核病患者。该提案利用了现有的国家结核病控制计划，即对糖尿病患者进行早期药物水平监测和剂量调整，并将进一步在坦桑尼亚耐多药结核病转诊医院Kibong‘oto National TB医院建立耐多药结核病患者队列。通过NIH结核病易感性R01、NIH/Fogarty UVA-坦桑尼亚培训补助金和弗吉尼亚州卫生部，为该提案的所有方面提供了积极的资金和基础设施。我的职业发展计划包括导师指导，研究生水平的课程工作，以及诊断开发、现场研究、结核病药理学和耐多药结核病队列设计方面的出版基准。这项提案的完成将使我能够成为这些领域的独立调查员。项目叙述结核病(TB)治疗失败，尽管有多种药物治疗。目前，在许多结核病流行/资源有限的环境中，没有衡量药物活性的实用工具。拟议的项目将研究两个面临治疗失败风险的人群：糖尿病患者和耐多药结核病患者。这些研究的完成将为使用三种可能的方法提供信息：药物水平、结核分枝杆菌药物最低抑菌浓度和一种新的结核病药物活性分析，该方法可以在能够进行结核病培养的环境中进行。

DESCRIPTION (provided by applicant): Abstract PI: HEYSELL, SCOTT K Project: 1K23AI099019-01 Title: Clinical Impact of Anti-TB Drug Levels and M. Tuberculosis Susceptibility Accession Number: 3398392 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== Worldwide tuberculosis (TB) treatment failure occurs in up to 20% of individuals despite multidrug therapy. In Virginia we have found diabetes to be a significant risk factor for delayed response. At our collaborative site in Tanzania, patients with multidrug-resistant (MDR)-TB are at increased risk of death compared to those with drug-susceptible TB. In both settings we have found low serum drug levels to TB medications, however the best use of serum drug levels in managing TB remains unclear. To inform this problem we have developed a TB drug activity assay that is performed with a patient's plasma or serum while on TB therapy and their autologous TB isolate that allows a metric of both drug levels and relative resistance of the isolate. In this proposal, therefore, we will compare (1) drug levels, (2) M. tuberculosis drug susceptibility (MIC), and (3) the TB drug activity assay to relevant treatment outcomes in patients at risk of poor treatment failure- diabetics in Virginia and those with MDR-TB in Tanzania. The proposal leverages an existing state TB control initiative of early drug level monitoring and dose adjustment in diabetics, and will further establish a cohort of MDR-TB patients at Kibong'oto National TB Hospital, the Tanzanian referral hospital for MDR-TB. Active funding and infrastructure for all aspects of the proposal exist through an NIH R01 for TB susceptibility, an NIH/Fogarty UVA-Tanzania Training Grant, and the Virginia Department of Health. My career development plan includes mentorship, graduate level coursework, and publication benchmarks in diagnostic development, field research, TB pharmacology, and MDR-TB cohort design. Completion of this proposal will allow me to become an independent investigator in these fields. PROJECT NARRATIVE Tuberculosis (TB) treatment failure occurs despite multidrug therapy. Currently there are not practical tools for measurement of drug activity in many TB-endemic/ resource-limited settings. The proposed project will study two populations at-risk of treatment failure: those with diabetes and those with multidrug-resistant TB. Completion of these studies will inform the use of three potential methodologies: drug levels, M. tuberculosis drug MICs, and a novel TB drug activity assay which can be performed in settings capable of TB culture.