Inhaled tigecycline therapy for pulmonary M. abscessus infections

总结 结核分枝杆菌（MAB）是一种非结核分枝杆菌，可引起慢性肺部感染 （pMAB）和既存肺病患者（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，治愈率很低。 替加环素是一种甘氨酰环素类抗生素，对pMAB具有杀菌作用， 细菌耐药机制对于pMAB治疗，患者接受每日两次静脉内给药 替加环素治疗至少一个月，导致显著的副作用，许多患者退出治疗。 治疗替加环素有可能成为pMAB治疗期间的一线药物， 但为了实现其最大的治疗潜力，我们需要改进 有效性和安全性/耐受性之间的替格列汀比率，即其治疗指数。解决这一问题的一种方法是 挑战是开发易于给药且良好地 容忍。在初步研究中，用pMAB的GM-CSF KO小鼠通过以下肺内气雾剂处理： 替加环素28天。完整治疗期后的肺细菌负荷显示，吸入 替加环素具有高的剂量依赖性功效，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的一种可行治疗方法。在目标1中，为了避免替加环素的要求， 重组，我们将开发一种替加环素的干粉制剂， 适合吸入的性质。目的2将研究剂量、给药方案和结果之间的关系。 替加环素气雾剂在不同体液、器官和组织中的暴露。我们会特别研究 吸入与静脉替加环素的剂量-暴露关系及其在血浆、肺 囊肿和上皮细胞衬液。在目标3中，我们建议测试疗效、剂量、给药频率和 使用动物模型的吸入替加环素对抗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， 囊性纤维化患者的代表性模型。最佳方案将在感染选定的 来自MAB克隆1和2的临床分离物和从囊性纤维化患者获得的分离物。目标4将 确定吸入替加环素在多药治疗中的疗效。如在Aim 3中使用pMAB的小鼠（使用菌株 #21或临床分离株）将用吸入性替加环素和替加环素的二元或三元组合治疗。 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， 位于科罗拉多州立大学、田纳西大学、三角研究所和国家 犹太医院我们共同努力，旨在提供一种替加环素吸入治疗方案， 明确的空气动力学和PK特性，并充分表征未来临床前毒理学的体内疗效 在更大的动物模型中的研究、IND应用以及最终对患者的施用。

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.