Measuring Intralesional Drug Exposures in Cavitary TB using Noninvasive In Vivo PET Imaging

使用无创体内 PET 成像测量空洞结核病灶内药物暴露

• 批准号: 10427206
• 负责人: Sanjay Jain
• 金额: $ 73.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427206
• 关键词: Aftercare; Anatomy; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Autopsy; Autoradiography; Binding Proteins; Biodistribution; Cause of Death; Characteristics; Chemicals; Clinical; Data; Disease; Dose; Drug Exposure; Drug Kinetics; Early identification; Emission-Computed Tomography; Evolution; Extinction (Psychology); Fiber; Goals; Health; Heterogeneity; Human; Image; Imaging Device; Immune; In Situ; Infection; Inflammation; Kinetics; Lesion; Linezolid; Link; Lung; Mass Spectrum Analysis; Measurement; Measures; Modeling; Multidrug-Resistant Tuberculosis; Multimodal Imaging; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Oryctolagus cuniculus; Outcome; Parents; Pathologic; Patients; Penetration; Pharmaceutical Preparations; Phenotype; Plasma; Population; Positron-Emission Tomography; Property; Recommendation; Recurrence; Regimen; Relapse; Research; Resistance; Rifampin; Risk Factors; Sampling Biases; Site; Strategic Planning; System; Time; Tissue Sample; Tissues; Tracer; Translating; Treatment Factor; Treatment Failure; Treatment outcome; Tuberculosis; World Health Organization; X-Ray Computed Tomography; analog; antimicrobial; bactericide; base; bioimaging; clinically translatable; cohort; density; design; drug development; early detection biomarkers; effective therapy; emerging antibiotic resistance; experimental study; first-in-human; human disease; imaging biomarker; in vivo; in vivo imaging; insight; macrophage; molecular imaging; novel; novel therapeutics; pathogen; pharmacokinetic model; radiological imaging; tool; treatment optimization; treatment risk; treatment strategy; tuberculosis drugs; tuberculosis treatment

Effective treatment of infections depends on achieving adequate antibiotic concentrations at infection sites, where the pathogen resides. However, with few exceptions, current antibiotic dosing recommendations are based on achievable plasma concentrations, without specific information on drug concentrations at the site of infection. However, plasma drug levels do not correlate well with those at infection sites. Cavitary lesions, which are the hallmark of human tuberculosis (TB), have limited drug penetration and consequently are a risk factor for treatment failure, recurrence, and the emergence of antibiotic resistance. Direct tissue measurements are invasive, can be performed in humans only when clinically indicated, and generally provide data at a single time-point even in animal models. Additionally, given that multiple, pathologically distinct TB lesions coexist within the same infected-host simultaneously, measurements from one or a few easily accessible lesions are subject to sampling bias. Finally, current antibiotic treatment strategies are designed for efficacy (e.g. >85%) at a population level, but ignore the inter- and intra-subject heterogeneity. While shorter treatments could cure e.g. >70%, tools to identify patients at-risk for treatment failure or requiring longer treatments are needed. We have developed novel tools to perform noninvasive, simultaneous and unbiased, multi-compartment in situ measurements of antibiotic concentration-time profiles. First-in-human, whole-body dynamic 11C-rifampin positron emission tomography (PET) and computed tomography (CT) were performed in newly identified patients with rifampin-susceptible TB. PET demonstrated spatially compartmentalized rifampin exposures in the multiple, pathologically distinct TB lesions in the same patient, with low cavitary tissue rifampin exposures. Repeat PET/CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patient. Similar findings were re-capitulated by PET/CT in experimentally infected rabbits with cavitary TB and confirmed using post-mortem analyses. Integrated modeling of the PET- captured concentration-time profiles in hollow-fiber bacterial kill-curve experiments identified that 35 mg/kg/day of rifampin is needed to achieve cure in four months for cavitary disease. Optimized antibiotic dosing could shorten current treatments. Conversely, suboptimal dosing is a major factor for treatment failure and antibiotic resistance, which the World Health Organization declared as one of the top ten threats to human health. Our overall goals are to leverage our expertise in novel in vivo imaging tools, animal models of cavitary TB and hollow-fiber systems to gain mechanistic insights about TB treatments: a) measure the spatial and temporal distribution of TB drugs active against multi-drug resistant TB (bedaquiline, pretonamid, linezolid regimen) and optimize cavitary TB treatments; b) identify the key factors contributing to treatment failure, long- term (relapse-free) cure or able to guide treatments and; c) develop imaging (pathogen-specific or radiography- based) biomarkers for early identification of subjects at-risk for treatment failure or requiring longer treatments.

感染的有效治疗取决于感染部位是否达到足够的抗生素浓度， 病原体所在的地方。然而，除了少数例外，目前的抗生素剂量建议是 基于可达到的血浆浓度，没有有关部位药物浓度的具体信息 感染。然而，血浆药物水平与感染部位的相关性并不好。空洞病变， 这是人类结核病 (TB) 的标志，药物渗透有限，因此存在风险 治疗失败、复发和抗生素耐药性出现的因素。直接组织测量 是侵入性的，只有在有临床指征时才能在人类身上进行，并且通常一次性提供数据 即使在动物模型中也是如此。此外，考虑到多个病理学上不同的结核病灶共存 同时在同一受感染宿主内，对一个或几个容易接近的病变进行测量 受抽样偏差的影响。最后，当前的抗生素治疗策略是针对以下情况设计的疗效（例如 >85%）： 群体水平，但忽略了受试者间和受试者内的异质性。虽然较短的治疗时间可以治愈 例如>70%，需要工具来识别有治疗失败风险或需要更长时间治疗的患者。 我们开发了新颖的工具来执行无创、同步和公正的多隔室治疗 抗生素浓度-时间曲线的原位测量。首个人体全身动态 11C-利福平 正电子发射断层扫描（PET）和计算机断层扫描（CT）在新发现的 利福平敏感结核病患者。 PET 显示空间分区的利福平暴露 同一患者体内存在多个病理学上不同的结核病灶，且空洞组织利福平暴露量较低。 重复 PET/CT 测量证明利福平暴露轨迹的独立时间演变 同一患者的不同病变部位。 PET/CT 在实验中重现了类似的发现 感染了空洞结核的兔子并通过尸检分析进行了确认。 PET 的集成建模 在中空纤维细菌杀灭曲线实验中捕获的浓度-时间曲线表明，35 mg/kg/天 需要服用利福平才能在四个月内治愈空洞病。优化抗生素剂量可以 缩短目前的治疗时间。相反，次优剂量是治疗失败和抗生素使用的主要因素 世界卫生组织将其列为人类健康十大威胁之一。 我们的总体目标是利用我们在新型体内成像工具、空洞结核动物模型方面的专业知识 和中空纤维系统，以获得有关结核病治疗的机制见解：a）测量空间和 抗多重耐药结核病药物（贝达喹啉、普托酰胺、利奈唑胺）的时间分布 方案）并优化空洞结核治疗； b) 确定导致治疗失败的关键因素，长期 长期（无复发）治愈或能够指导治疗； c) 进行成像（病原体特异性或放射线照相） 基于）生物标志物，用于早期识别有治疗失败风险或需要更长时间治疗的受试者。