Inhaled tigecycline therapy for pulmonary M. abscessus infections

吸入替加环素治疗肺部脓肿分枝杆菌感染

• 批准号: 10437923
• 负责人: Mercedes Gonzalez-Juarrero
• 金额: $ 79.41万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-29 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437923
• 关键词: Acute; Address; Adverse effects; Aerosols; Animal Model; Antibiotic Resistance; Antibiotics; Bacillus; Biological Availability; Body Fluids; C57BL/6 Mouse; Canis familiaris; Chronic; Clarithromycin; Clinic; Clinical; Clinical effectiveness; Colorado; Complex; Deposition; Dose; Drug Exposure; Drug Kinetics; Drug or chemical Tissue Distribution; Epithelial; Exhibits; Fiber; Formulation; Foundations; Frequencies; Future; Genus Mycobacterium; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hospitals; Hour; In Vitro; Infection; Inhalation; Inhalation Drug Administration; Inhalation Therapy; Institutes; Intravenous; Intravenous infusion procedures; Investigational New Drug Application; Knockout Mice; Light; Liquid substance; Lung; Lung Abscess; Lung diseases; Lung infections; Macrolides; Maximum Tolerated Dose; Modeling; Monitor; Mus; Mycobacterium abscessus; Nausea and Vomiting; Oral; Organ; Outcome; Patients; Pharmaceutical Preparations; Plasma; Powder dose form; Predisposition; Procedures; Property; Rattus; Regimen; Research; Resistance; Route; Safety; Symptoms; System; Tennessee; Testing; Tetracyclines; Therapeutic; Therapeutic Index; Tissues; Toxicology; Treatment Efficacy; Treatment Protocols; Universities; Vertebral column; Withdrawing Treatments; analog; bacterial resistance; bactericide; cystic fibrosis mouse; cystic fibrosis patients; effective therapy; efficacy testing; epithelial Na+ channel; flu; follower of religion Jewish; glycylcycline; human subject; improved; in vitro Assay; in vivo; intravenous administration; intravenous injection; liquid formulation; mouse model; non-tuberculosis mycobacteria; particle; pre-clinical; reconstitution; resistance mechanism; side effect; subcutaneous; synergism; tigecycline; treatment duration

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.

概括 脓肿分枝杆菌（MAB）是一种无结核分枝杆菌，会引起慢性肺部感染 （PMAB）和患有肺部疾病的患者（尤其是囊性纤维化患者）具有易感性 PMAB。由于MAB的固有抗生素耐药性，治疗通常很复杂且治愈率较低。 Tigecycline是一种糖基环素类抗生素，表现出对PMAB的细菌作用而无需引起 细菌抗性机制。对于PMAB治疗，患者每天接受两次静脉内治疗 在至少一个月内tigecycline的副作用，导致重大副作用，许多患者退出 治疗。 Tigecycline有可能在PMAB和PMAB治疗期间成为一线代理 用于新组合方案的骨干，但要发挥其最大的治疗潜力，我们需要改进 Tigecyclines有效性与安全性/易学性之间的比率，即其治疗指数。一种解决这个问题的方法 挑战是开发易于管理的tigecycline吸入公式，很好 容忍。在初步研究中，用PMAB的GM-CSF KO小鼠通过肺内气溶胶治疗 Tigecycline 28天。完整治疗持续时间显示遗传的肺细菌燃烧 Tigecycline具有较高的剂量依赖性效率，并且具有良好的耐受性。在这里，我们假设气溶胶输送 Tigecycline的属于PMAB的可行治疗方法。在AIM 1中，为了避免tigecycline要求 重组，我们将开发出具有良好表征空气动力学的Tigecycline的干粉公式 适合吸入的特性。 AIM 2将研究剂量，剂量方案和由此产生的关系之间的关系 在不同体液，器官和组织中tigecycline气溶胶的暴露。特别是，我们将研究 吸入与静脉内tigecycline的剂量暴露关系及其在血浆中的可用性，肺， 脓肿和上皮衬里。在AIM 3中，我们建议测试效率，剂量，给药频率，并 使用动物模型对PMAB的遗传tigecycline持续时间。我们首先建议使用GM-CSF KO 随后，我们将用PMAB感染来测试B-ENAC TG小鼠中最佳方案，作为A 囊性纤维化患者的代表性模型。最好的方案将在感染选定的小鼠中得到验证 从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意志 确定多药疗法中遗传的Tigecycline的效率。与AIM 3中的PMAB一样 ＃21或临床分离株）将使用遗传的tigecycline和二元或三元组合处理 克拉霉素（口服），氯富齐明（口服），贝达奎林（口服）。这些研究将由 位于科罗拉多州立大学，田纳西大学，研究三角研究所和国家的专家 犹太医院。我们共同努力，旨在提供tigecycline的意外治疗方案 定义的空气动力学和PK特性，并在体内效率良好，以供将来的临床前毒理学 在较大的动物模型，IND应用中进行研究，并最终对患者进行治疗。