Intra Cavitary Pharmacokinetics and Drug Resistance in Pulmonary Tuberculosis

肺结核的腔内药代动力学和耐药性

• 批准号: 8703004
• 负责人: Russell Ryan Kempker
• 金额: $ 18.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703004
• 关键词: Address; Antitubercular Agents; Award; Bacillus (bacterium); Bioinformatics; Biological Assay; Capromycin; Cause of Death; Cessation of life; Clinical; Clinical Data; Clinical Research; Clinical Sciences; Collaborations; Communicable Diseases; Country; DNA Sequence; Data; Data Analyses; Development; Development Plans; Disease; Dose; Drug Kinetics; Drug Resistant Tuberculosis; Drug resistance; Drug usage; Environment; Epidemic; Evolution; Expert Opinion; Extreme drug resistant tuberculosis; Faculty; Failure; Florida; Funding; Future; Genetic; Genomics; Goals; Grant; Hand; Institutes; Investigation; Knowledge; Laboratories; Lead; Learning; Lesion; Levaquin; Link; Lung; Lung diseases; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Microdialysis; Molecular; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Operative Surgical Procedures; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Plasma; Population; Population Dynamics; Prevalence; Prevention; Prevention strategy; Property; Public Health; Public Health Schools; Pulmonary Tuberculosis; Recording of previous events; Reporting; Research; Research Design; Research Personnel; Research Priority; Research Project Grants; Research Proposals; Research Training; Resected; Resistance; Resistance development; Resistance profile; Resources; Risk; Role; Sampling; Serum; Site; Specimen; Sputum; Structure of parenchyma of lung; Study Subject; Study models; Techniques; Testing; Therapeutic; Time; Tissue Sample; Tissues; Training; Translational Research; Tuberculosis; United States National Institutes of Health; Universities; Virulence; Western Asia Georgia; World Health Organization; base; career; career development; cohort; combat; experience; genome sequencing; global health; improved; innovation; member; mycobacterial; novel; pharmacokinetic model; public health relevance; research and development; research study; resistance mechanism; resistance mutation; response; transmission process; treatment response; treatment strategy; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Tuberculosis is an enormous global public health problem and the second leading cause of death due to an infectious disease. The global emergence of multidrug-resistant (MDR) TB is a significant barrier to effective TB control. Response rates to second-line anti-TB drugs (SLDs) used to treat MDR-TB are much lower than those for treatment of drug susceptible TB. Recent reports highlight the substantial risk of development of additional drug resistance during SLD treatment. Critical knowledge gaps exist regarding the mechanisms of amplified drug resistance during treatment of MDR-TB. Our preliminary data suggests that the TB cavity may be the site of further drug resistant development. With this background, we have hypothesized that pulmonary cavities in patients with MDR-TB facilitate the development and amplification of drug resistance as a result of sub-therapeutic intra-cavitary SLD concentrations. An enhanced understanding of SLD pharmacokinetics including tissue penetration properties and mechanisms of drug resistance will help guide improved MDR-TB treatment and prevention strategies. The Specific AIMs of this proposal include: 1) To determine the pharmacokinetics of key SLDs (levofloxacin and capreomycin) in plasma, pulmonary tissue, and cavitary lung among patients undergoing treatment for MDR-TB. Utilizing a unique patient cohort of MDR-TB patients undergoing adjunctive surgery in the Republic of Georgia and an innovative microdialysis method we will assess SLD concentrations among various compartments including pulmonary cavities, the site of the highest concentration of M. tuberculosis (MTB). 2) To investigate phenotypic and genotypic drug resistance profiles of MTB isolates recovered from sputum, lung, and cavitary lung tissue. We propose to perform whole genome sequencing and bioinformatics analysis comparing paired MTB isolates from different sites in the same patients (cavity, more normal lung tissue, sputum) to determine if cavities are sites of drug resistance development and amplification and to study population dynamics of MTB within the cavitary environment. 3) To determine the relationship between SLD tissue levels and the development of additional drug resistance mutations in MTB isolates from resected cavitary lung. We will use the pharmacokinetic and genomic sequencing data derived from AIMS 1 and 2 along with pharmacokinetic modeling to assess if low drug concentrations are associated with increasing drug resistance. The proposed investigations will provide novel data on mechanisms of amplified drug resistance and will challenge the way we currently dose SLDs and treat MDR-TB patients with cavitary disease. Candidate My long-term goal is to become an independent clinical and translational investigator and global leader in tuberculosis (TB) focusing on the mechanisms, transmission, and virulence of drug-resistant TB. A K23 award would be critical to my career development and provide protected time for research and research training. A Training Plan has been developed that links a training goal to each of the specific aims of the research proposal. During this K23 award period, I will build expertise in clinical research, pharmacokinetics study design and modeling, performing microdialysis, bacterial genomics including DNA sequencing, and performing bioinformatics analysis. My career development plan combines formal didactics, laboratory training, and hands on mentoring with relevant research experiences that address global TB priorities. A multi-disciplinary team of recognized leaders in clinical TB research, genomics, and pharmacokinetics will provide professional and scientific mentorship during the award period. The K23 award will allow for the investigation and accumulation of additional data that can subsequently serve as the basis for a subsequent R01 application focused on translational research involving investigation of the pulmonary cavity. Environment The substantial intellectual and physical resources of Emory University and established collaborations with partners in the country of Georgia at the National Center for Tuberculosis and Lung Disease (NCTBLD) provide a unique opportunity to carry out this translational research. The Georgian NCTBLD also has a long history of productive collaborations with Emory University including numerous ongoing funded research projects (including the site of a NIH Fogarty grant). Emory University is a research-intensive university with over half a billion dollars in research funding each year. The Emory Division of Infectious Diseases has 59 full time faculty members including leaders in clinical TB, pharmacokinetics and bacterial genomics research. The Emory Rollins School of Public Health, Emory Global Health Institute, and the Atlanta Clinical and Translational Science Institute (ACTSI, the NIH-funded CTSA) provide further excellent resources for career enhancement, development and research training. The proposal will also benefit from collaboration with the University of Florida Infectious Diseases Pharmacokinetics Laboratory (IDPL). The IDPL is a national reference laboratory for anti-mycobacterial drug concentrations and has extensive expertise in performing microdialysis.

描述（由申请人提供）：结核病是一个巨大的全球公共卫生问题，也是因传染病导致死亡的第二大原因。全球出现的耐多药结核病是有效控制结核病的重大障碍。用于治疗耐多药结核病的二线抗结核药物（SLDs）的应答率远低于治疗药物敏感结核病的应答率。最近的报告强调了在SLD治疗期间产生额外耐药性的重大风险。在耐多药结核病治疗过程中，关于耐药性增强的机制存在严重的知识空白。我们的初步数据表明，结核腔可能是进一步耐药发展的场所。在此背景下，我们假设耐多药结核病患者的肺腔由于亚治疗性腔内SLD浓度而促进耐药性的发展和扩大。加强对SLD药代动力学的了解，包括组织渗透特性和耐药机制，将有助于指导改进耐多药结核病的治疗和预防策略。本提案的具体目的包括：1)确定耐多药结核病治疗患者血浆、肺组织和空腔肺中关键SLDs（左氧氟沙星和卷曲霉素）的药代动力学。利用格鲁吉亚共和国接受辅助手术的耐多药结核病患者的独特患者队列和创新的微透析方法，我们将评估包括肺腔在内的各个腔室的SLD浓度，肺腔是结核分枝杆菌（MTB）浓度最高的部位。2)研究从痰、肺和肺腔组织中分离的结核分枝杆菌的表型和基因型耐药谱。我们建议进行全基因组测序和生物信息学分析，比较来自同一患者不同部位（腔，更正常的肺组织，痰）的配对MTB分离物，以确定腔是否是耐药发展和扩增的场所，并研究腔环境中MTB的种群动态。3)确定切除空腔肺MTB分离株中SLD组织水平与其他耐药突变发生的关系。我们将使用来自AIMS 1和2的药代动力学和基因组测序数据以及药代动力学模型来评估低药物浓度是否与耐药性增加有关。拟议的研究将提供关于耐药性增强机制的新数据，并将挑战我们目前给药和治疗伴有空洞病的耐多药结核病患者的方式。我的长期目标是成为一名独立的临床和转化研究者，以及结核病（TB）领域的全球领导者，重点研究耐药结核病的机制、传播和毒力。K23奖对我的职业发展至关重要，并为我的研究和研究培训提供有保障的时间。已经制定了一项培训计划，将培训目标与研究计划的每个具体目标联系起来。在K23奖期间，我将在临床研究、药代动力学研究设计和建模、微透析、细菌基因组学（包括DNA测序）和生物信息学分析方面积累专业知识。我的职业发展计划将正式教学、实验室培训和实践指导与解决全球结核病重点问题的相关研究经验相结合。由结核病临床研究、基因组学和药物代动力学领域公认的领导者组成的多学科团队将在奖励期间提供专业和科学指导。K23授予将允许调查和积累额外的数据，这些数据随后可以作为后续R01申请的基础，重点是涉及肺部调查的转化研究。埃默里大学丰富的智力和物质资源以及与格鲁吉亚国家结核病和肺病中心（NCTBLD）的合作伙伴建立的合作关系为开展这项转化研究提供了独特的机会。格鲁吉亚NCTBLD与埃默里大学也有长期的富有成效的合作，包括许多正在进行的资助研究项目（包括NIH福格蒂资助的网站）。埃默里大学是一所研究型大学，每年的研究经费超过5亿美元。埃默里大学传染病部有59名全职教职员工，其中包括临床结核病、药代动力学和细菌基因组学研究的领导者。埃默里罗林斯公共卫生学院、埃默里全球卫生研究所和亚特兰大临床与转化科学研究所（ACTSI，美国国立卫生研究院资助的CTSA）为职业提升、发展和研究培训提供了进一步的优秀资源。该提案还将受益于与佛罗里达大学的合作