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）：结核病是全球巨大的公共卫生问题，也是由于传染病而导致的第二大死亡原因。多药（MDR）结核病的全球出现是有效TB控制的重要障碍。用于治疗MDR-TB的二线抗TB药物（SLDS）的反应率远低于治疗易感性结核病的药物。最近的报告强调了在SLD治疗期间出现额外耐药性的实质性风险。关于MDR-TB治疗过程中扩增耐药性机制的关键知识差距。我们的初步数据表明，结核病腔可能是进一步耐药性发育的部位。在这种背景下，我们假设MDR-TB患者的肺腔促进了耐药性耐药性的耐药性的发展和扩增。对SLD药代动力学（包括组织渗透特性和耐药性机制）的增强了解将有助于指导改善MDR-TB治疗和预防策略。该提案的具体目的包括：1）确定血浆中关键SLDS（左氧氟沙星和capreomycin）的药代动力学，在接受MDR-TB治疗的患者中，在血浆，肺组织和洞穴肺中的药代动力学。利用佐治亚共和国接受辅助手术的MDR-TB患者组成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，包括肺腔，肺腔，结核分枝杆菌（MTB）的最高浓度的部位（MTB）。 2）研究从痰，肺和腔肺组织中回收的MTB分离株的表型和基因型耐药性谱。我们建议进行整个基因组测序和生物信息学分析，以比较来自同一患者不同部位的成对MTB分离株（腔，更正常的肺组织，痰液），以确定蛀牙是耐药性发展和扩增的部位，并研究了疗养环境中MTB的人群动力学。 3）确定SLD组织水平与从切除的腔肺中MTB分离株中其他耐药性突变的发展之间的关系。我们将使用来自AIM 1和2的药代动力学和基因组测序数据以及药代动力学建模，以评估低药物浓度是否与耐药性升高有关。拟议的调查将提供有关放大耐药性机制的新数据，并将挑战我们目前剂量SLDS并治疗患有空白疾病的MDR-TB患者的方式。候选人我的长期目标是成为结核病（TB）的独立临床和转化研究者和全球领导者，重点是耐药结核病的机制，传播和毒力。 K23奖对于我的职业发展至关重要，并为研究和研究培训提供受保护的时间。已经制定了培训计划，将培训目标与研究建议的每个特定目标联系起来。在这个K23奖励期间，我将建立临床研究，药代动力学研究设计和建模，进行微透析，包括DNA测序在内的细菌基因组学以及进行生物信息信息分析的细菌基因组学。我的职业发展计划结合了正式的教学法，实验室培训以及指导的动机以及针对全球结核病优先事项的相关研究经验。由临床结核病研究，基因组学和药代动力学领域的公认领导者组成的多学科团队将在奖励期间提供专业和科学的指导。 K23奖项将允许研究和积累其他数据，这些数据随后可以作为随后的R01应用程序的基础，该应用集中在转化研究上，涉及研究肺腔。环境埃默里大学的大量智力和物理资源，并与佐治亚州国家结核病和肺部疾病中心（NCTBLD）的合作伙伴建立了合作，为进行这项翻译研究提供了独特的机会。格鲁吉亚NCTBLD与埃默里大学（Emory University）的生产合作历史悠久，包括众多正在进行的资助的研究项目（包括NIH Fogarty Grant的地点）。埃默里大学（Emory University）是一所研究密集于大学，每年拥有超过十亿美元的研究资金。埃默里（Emory）的传染病司有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领域。埃默里·罗林斯公共卫生学院，埃默里全球健康研究所和亚特兰大临床和翻译科学研究所（ACTSI，NIH资助的CTSA）为增强职业，发展和研究培训提供了更多的优质资源。该提案还将受益于与佛罗里达大学的合作 传染病药代动力学实验室（IDPL）。 IDPL是全国性抗菌药物浓度的参考实验室，在执行微透析方面具有广泛的专业知识。