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在感染部位达到足够的抗生素浓度， 病原体所在的地方。但是，除少数例外，当前的抗生素剂量建议是 基于可实现的血浆浓度，没有有关药物浓度位点的特定信息 感染。但是，血浆药物水平与感染部位的药物水平不太相关。腔病变， 这是人类结核病（TB）的标志，药物渗透有限，因此是一种风险 治疗衰竭，复发和抗生素耐药性的出现因素。直接组织测量 具有侵入性，只有在临床指示时才能在人类中进行 即使在动物模型中，时间点也是如此。另外，鉴于多个病理上不同的TB病变并存 在同一感染的宿主同时，一个或几个易于康复病变的测量是 遵守采样偏见。最后，目前设计用于功效的抗生素治疗策略（例如> 85％） 人口水平，但忽略了受试者间和受试者的异质性。较短的治疗方法可以治愈 例如> 70％，需要识别患者处于危险治疗失败或需要更长治疗的工具。 我们已经开发了新颖的工具来执行无创，同时和公正的，多偏见 抗生素浓度时间曲线的原位测量。首先是人类，全身动态11C-rifampin 在新鉴定的 患有利福平敏感的结核病患者。宠物在空间分室的利福平暴露于 同一患者的多个病理上不同的结核病病变，腔内rif蛋白暴露低。 重复的PET/CT测量结果表明利福平暴露轨迹的独立时间演变 在同一患者的不同病变中。通过PET/CT在实验中重新介绍了类似的发现 感染兔子用腔TB的兔子，并使用后验尸分析确认。宠物的综合建模 空心纤维细菌杀伤曲线实验中捕获的浓度时间剖面鉴定为35 mg/kg/天 需要在四个月内治愈rifampin的空洞疾病。优化的抗生素剂量可以 缩短当前治疗。相反，次优剂量是治疗衰竭和抗生素的主要因素 阻力，世界卫生组织宣布为对人类健康的十大威胁之一。 我们的总体目标是利用我们在新颖的体内成像工具中的专业知识，Cavitary TB的动物模型 和空心纤维系统以获取有关结核病处理的机械见解：a）测量空间和 针对多药耐药结核病（Bedaquiline，假胺，LineZolid）活跃的结核病药物的时间分布 方案）并优化Cavitary TB治疗； b）确定导致治疗失败的关键因素，长期 术语（无复发）治愈或能够指导治疗； c）发展成像（病原体特异性或X射线照相 - 基于）生物标志物，用于早期鉴定患有治疗衰竭或需要更长治疗的受试者。