Inhaled tigecycline therapy for pulmonary M. abscessus infections

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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.