Inhaled tigecycline therapy for pulmonary M. abscessus infections

总结 脓肿分枝杆菌 (MAB) 是一种引起慢性肺部感染的非结核分枝杆菌 (pMAB) 和既往患有肺部疾病的患者（尤其是囊性纤维化患者）有以下倾向： pMAB。由于 MAB 固有的抗生素耐药性，治疗通常很复杂且治愈率较低。 替加环素是一种甘氨酰环素类抗生素，对 pMAB 具有杀菌作用，且不会引发 细菌耐药机制。对于 pMAB 治疗，患者每天接受两次静脉注射 至少一个月的替加环素治疗导致显着的副作用，许多患者退出 治疗。替加环素有潜力成为 pMAB 治疗期间的一线药物， 新联合治疗方案的支柱，但为了充分发挥其治疗潜力，我们需要改进 替加环素的疗效与安全性/耐受性之间的比率，即其治疗指数。解决这个问题的一种方法 面临的挑战是开发易于给药且效果良好的替加环素吸入制剂 容忍的。在初步研究中，用 pMAB 的 GM-CSF KO 小鼠通过肺内气雾剂治疗 替加环素28天。整个治疗持续时间后的肺部细菌负荷表明，吸入 替加环素具有较高的剂量依赖性疗效，并且耐受性良好。在这里，我们假设气溶胶输送 替加环素是 pMAB 的可行治疗方法。在目标 1 中，避免替加环素的要求 重组后，我们将开发一种具有良好空气动力学特性的替加环素干粉制剂 适合吸入的特性。目标 2 将研究剂量、给药方案和结果之间的关系 不同体液、器官和组织中替加环素气溶胶的暴露。特别是，我们将研究 吸入与静脉注射替加环素的剂量-暴露关系及其在血浆、肺、 脓肿和上皮内衬液。在目标 3 中，我们建议测试功效、剂量、给药频率和 使用动物模型吸入替加环素对抗 pMAB 的持续时间。我们建议首先使用 GM-CSF KO 小鼠模型，随后，我们将在 pMAB 感染的 b-ENac Tg 小鼠中测试最佳方案，作为 囊性纤维化患者的代表性模型。最佳方案将在感染选定病毒的小鼠中进行验证 MAB 克隆 1 和 2 的临床分离株以及从囊性纤维化患者获得的分离株。目标4将 确定吸入替加环素在多药治疗中的疗效。如目标 3 中那样使用 pMAB 的小鼠（带有菌株 #21 或临床分离株）将采用吸入替加环素的二元或三元组合进行治疗 克拉霉素（口服）、氯法齐明（口服）、贝达喹啉（口服）。这些研究将由一个财团进行 科罗拉多州立大学、田纳西大学、三角研究所和国家大学的专家 犹太医院。我们共同努力，旨在提供一种效果良好的替加环素吸入治疗方案。 定义了空气动力学和 PK 特性，并为未来的临床前毒理学充分表征了体内功效 大型动物模型研究、IND 应用以及最终对患者给药。

Summary Mycobacterium abscessus (MAB) is a nontuberculous mycobacterium that causes chronic pulmonary infections (pMAB) and patients with pre-existing lung disease (especially cystic fibrosis patients) have a predisposition to pMAB. Due to MAB’s intrinsic antibiotic resistance, treatment is often complex and with low cure rates. Tigecycline, a glycylcycline class antibiotic, demonstrates bactericidal effects against pMAB without eliciting bacterial resistance mechanisms. For pMAB treatment, patients receive twice daily intravenous administration of tigecycline during at least one month resulting in significant side effects and many patients withdraw from treatment. Tigecycline has the potential to qualify as the first-line agent during therapy for pMAB and the backbone for new combination regimens but to achieve its fullest therapeutic potential, we need to improve tigecyclines ratio between efficacy and safety/tolerability, i.e. its therapeutic index. One approach to address this challenge is to develop inhalational formulations of tigecycline that are easy to administer and are well tolerated. In preliminary studies, GM-CSF KO mice with pMAB were treated by intrapulmonary aerosols of tigecycline for 28 days. The pulmonary bacterial burden after full treatment duration showed that inhaled tigecycline has high, dose-dependent efficacy, and is well tolerated. Here we hypothesize that aerosol delivery of tigecycline is a viable therapeutic approach for pMAB. In Aim 1, to avoid the tigecycline requirements for reconstitution, we will develop a dry powder formulation of tigecycline with well characterized aerodynamic properties suitable for inhalation. Aim 2 will study the relationship between dose, dosing regimen and resulting exposure of aerosols of tigecycline in different body fluids, organs and tissues. In particular, we will study the dose-exposure relationship of inhaled versus intravenous tigecycline and its availability in plasma, lung, abscesses and epithelial lining fluid. In Aim 3, we propose to test the efficacy, dose, dosing frequency, and duration of inhaled tigecycline against pMAB using animal models. We propose using first the GM-CSF KO murine model, subsequently, we will test the best regimen in b-ENac Tg mice with pMAB infection, as a representative model for cystic fibrosis patients. The best regimen will be validated in mice infected with selected clinical isolates from MAB clones 1 and 2 and isolates obtained from cystic fibrosis patients. Aim 4 will determine efficacy of inhaled tigecycline in multidrug therapies. Mice with pMAB as in Aim 3 (with strain #21 or clinical isolates) will be treated with binary or ternary combinations of inhaled tigecycline and clarithromycin (oral), clofazimine (oral), bedaquiline (oral). These studies will be performed by a consortium of experts located at Colorado State University, University of Tennessee, Research Triangle Institute and National Jewish Hospital. Working together, we aim to provide an inhalational therapy regimen of tigecycline with well- defined aerodynamic and PK properties and well characterized in vivo efficacy for future preclinical toxicology studies in larger animal models, IND application, and ultimately administration to patients.