Mycobacterium abscessus (Mab) lung infections are extremely resistant to drug therapy and are growing in prevalence, particularly in the cystic fibrosis community where they are associated with decreased lung function and a high mortality rate. Current treatment guidelines recommend a two-year regimen of a combination of four antibiotics that are associated with numerous systemic toxicities that require regular monitoring, and treatments are successful in only 30% of cases. The noted virulence of Mab and recalcitrance to antibiotic therapy may be related to its ability to persist both extracellularly in biofilms and abscesses and intracellularly in macrophages. Delivery of antibiotics by the inhalation route is promising alternative for the treatment of Mab, as it would enable high drug concentrations at both sites of infection while minimizing systemic drug exposure. However, two promising inhaled antibiotics, clofazimine (CFZ) and liposomal amikacin (AMK), have resulted in little to no efficacy when utilized in vivo to treat chronic Mab lung infections, despite notable in vitro activity against Mab and in vivo activity against other mycobacterial species. Based upon the premise that inhaled monotherapy is ineffective, we have developed a patentable inhaled co- formulation of CFZ and AMK which will enable simultaneous delivery of these antibiotics to the site of Mab lung infection, thereby enabling the transition of the noted in vitro synergistic activity of the antibiotics to an in vivo environment. The proposed research seeks to optimize the mechanism of formulation engineering and composition CFZ-AMK powder through the in vitro and in vivo evaluation of composite spray dried CFZ-AMK particles and physically blended CFZ and AMK micronized powders prepared at varying mass ratios. The relationship between powder composition and properties will be determined through evaluation of powder aerosol performance using commercially available devices, modeling of in vitro dissolution rate, assessing extracellular and intracellular antimicrobial activity and determining in vivo pharmacokinetic parameters and efficacy in a chronic Mab infection model. The significance of this study is that it utilizes existing, already- proven-safe drugs and repurposes them in a patentable manner for simultaneous lung delivery and at-site synergistic activity, which will improve therapeutic outcomes in this extremely difficult to treat infection. The expected outcome is that inhaled CFZ-AMK fixed dose combination powders will successfully treat multiple facets of Mab lung disease, which will de-risk the transition from the pre-clinical to clinical stages.
Current treatment regimens for Mycobacterium abscessus (Mab) lung infections require a combination of multiple toxic drugs for prolonged periods, and exhibit success in only 30% of cases. Inhaled antibiotics are a promising approach to increase antibiotic levels at the site of Mab infection while reducing systemic exposure, but thus far inhaled monotherapy has proven ineffective for Mab treatment. Based upon promising in vitro synergistic activity, we propose to evaluate a novel inhaled co-formulation of amikacin and clofazimine for the treatment of Mab lung infections.
