Measuring Intralesional Bedaquiline Exposures in Cavitary TB Using Noninvasive In Vivo PET Imaging

目前的抗生素剂量建议和药物敏感性的临界点是基于血浆的。 浓度和以往的效力措施，没有关于感染地点的具体信息。自.以来 靶组织中不适当的抗生素浓度可导致治疗失败，选择耐药 生物体或毒性，几项研究和美国食品和药物管理局(FDA)支持测量 感染组织中的药物浓度。然而，目前用于检测组织药物水平的工具是侵入性的(需要 组织切除)，这在人类是困难的，通常被限制在一个时间点，即使在动物身上也是如此。 我们最重要的假设是，多种不同的病理状态，如空洞、肺炎、 和肺结核(TB)中的坏死性病变，在同一患者中同时发生。此外，这些 皮损也可能有不同的细菌负荷和抗生素暴露，这也会随着疾病的变化而变化。 进展和抗生素治疗。空洞是人类结核病的一个关键病理特征，也是一种 公认的感染传播、复发和治疗后出现耐药性的危险因素。 虽然腔壁有很高的细菌负荷(107-109)，但它们的血管形成较差，有较厚的纤维 胶囊。因此，虽然需要足够高的抗生素水平才能有效地杀灭龋齿中的细菌，但使用 在肺结核患者的PET生物成像中，我们已经证明了利福平暴露是矛盾的 在空洞壁中最低。 贝达奎林是一种含溴的二芳基喹啉，最近被批准用于治疗多种药物 耐多药结核病(TB)。然而，贝达奎兰在感染组织中的分布(如肉芽肿和 空洞性病变)尚未被广泛研究，而初步临床前研究报告了可变性 在干酪性坏死性肉芽肿小鼠的治疗反应中。虽然在治疗MDR方面非常有效- TB，Bedaquiline还可引起心脏事件(QT间期延长)，通过以下方式引起安全警告 监管机构。因此，有必要采用非侵入性方法来测量药物的生物分布。 贝达奎兰在感染组织(如龋齿)和其他靶器官中的作用，以告知适当的剂量和发育 有效的抗生素治疗，毒性最小。该项目的总体目标是利用我们的 在结核病动物模型和体内PET方面的专业知识，这是一项临床可翻译的技术。我们将发展高效 ~(76)溴-甜菜碱的放射性标记方法。使用结核分枝杆菌感染作为研究的模型 活体动物多室异质性坏死性病变的~(76)Br-贝达奎兰PET定量研究 和死后高分辨率/灵敏度放射自显影(&lt；10微米分辨率，亚纳克灵敏度) 将用于空洞性结核病的动物模型，以提供空洞性结核病的详细生物分布和时间动力学 在多个隔室内暴露的贝达奎兰。这一提议填补了一项重要的研究空白。 在结核病药物开发方面，并与NIAID结核病研究战略计划保持一致。

Current antibiotic dosing recommendations and breakpoints for drug susceptibility are based on plasma concentrations and historic measures of efficacy, without specific information at the infection sites. Since inappropriate antibiotic concentrations in target tissues can lead to treatment failure, selection of resistant organisms, or toxicity, several studies and the U.S. Food and Drug Administration (FDA) support measuring drug concentrations in infected tissues. However, current tools to detect tissue drug levels are invasive (require tissue resection), which is difficult in humans and generally limited to a single time point even in animals. Our overarching hypothesis is that multiple, heterogeneous pathological states, e.g. cavitation, pneumonia, and necrotic lesions in pulmonary tuberculosis (TB), occur simultaneously in the same patient. Moreover, these lesions can also have distinct bacterial burdens and antibiotic exposures, which also change with disease progression and antibiotic treatment. Cavitation is a key pathological feature of human TB and a well- recognized risk factor for transmission of infection, relapse, and emergence of drug resistance after treatment. While cavitary walls have high bacterial burden (107-109), they are poorly vascularized with thick fibrous capsules. Therefore, while adequately high antibiotic levels are need to effectively kill bacteria in cavities, using PET bioimaging in patients with pulmonary TB, we have demonstrated that rifampin exposure is paradoxically the lowest in cavitary walls. Bedaquiline, a bromine-containing diarylquinoline, was recently approved for the treatment of multi-drug resistant (MDR) tuberculosis (TB). However, bedaquiline distribution into infected tissues (e.g. granulomas and cavitary lesions) has not been studied extensively whilst preliminary preclinical studies have reported variability in the treatment response in mice with caseous necrotic granulomas. While highly effective in treating MDR- TB, bedaquiline can also cause cardiac events (QT-interval prolongation) leading to safety warnings by regulatory agencies. Therefore, there is a need for noninvasive methods to measure the biodistribution of bedaquiline in infected tissues (e.g. cavities) and other target organs to inform appropriate dosing and develop effective, antibiotic treatments with minimal toxicities. The overall goals of this project are to leverage our expertise in animal models of TB and in vivo PET, a clinically translatable technology. We will develop efficient radiolabeling methods for 76Br-bedaquiline. Using Mycobacterium tuberculosis infections as a model for heterogeneous necrotic-lesions in multiple-compartments, quantitative 76Br-bedaquiline PET in live animals and post-mortem high-resolution / sensitivity autoradiography (<10 µm resolution, sub-nanogram sensitivity) will be utilized in animal models of cavitary TB to provide detailed biodistribution and temporal kinetics of intralesional bedaquiline exposures in multiple-compartments. This proposal fulfills an important research gap in TB drug development and aligned with the NIAID Strategic Plan for TB Research.