Combined Amikacin and Azithromycin in an Inhaled Formulation for the Treatment of NTM

Though important progresses have been made in the reducing the prevalence of Mycobacterium tuberculosis infections in many regions of the world, non-tuberculous mycobacteria (NTM) continue to rise at an alarming rate. The M. avium complex (MAC) is the primary cause of NTM infections, accounting for about half of all cases. The current standard of care therapy for MAC includes a three-drug regimen of ethambutol, rifampicin, and a macrolide, azithromycin or clarithromycin, with the addition of FDA-approved amikacin liposome suspension for inhalation by nebulization for severe infections. Unfortunately, the current standard of care therapy is suboptimal with a significant proportion of patients demonstrating persistent or progressive disease. Moreover, azithromycin given orally is associated with complications including ototoxicity, prolongation of the QT interval, a measurement of the time between the start of the Q-wave and the end of the T-wave in electrocardiogram (ECG), and gastrointestinal symptoms. Amikacin as a nebulized liposomal preparation has drawbacks as well, including the time required to deliver the therapy, the necessity to clean the nebulizer, and the rupture of liposomes secondary to the method of delivery. Our overall goal is to develop an inhaled, fixed- dose combination (I-FDC) powder product containing both azithromycin and amikacin using our proprietary thin-film freeze-drying technology for delivering them as a single unit to the distal airways by oral inhalation. We hypothesize that inhaled azithromycin and amikacin combination will improve MAC treatment outcomes by increasing their concentrations simultaneously at the site of infection while decreasing their systemic exposure and thus side effects. We have already developed several prototype excipient-free, fixed-dose combination powders of azithromycin and amikacin at various weight ratios, with desirable aerosol performance properties for lung delivery. To achieve our overall goal and to test our hypothesis, we propose the following three specific aims: 1) to optimize the composition of the fixed-dose combination powders of azithromycin and amikacin and determine the effect of the ratio of azithromycin and amikacin in the powders on their activity against M. avium bacteria, both within and outside of macrophages; 2) to evaluate the pharmacokinetics and biodistribution of azithromycin and amikacin in a mouse model when they are administered as a fixed-dose combination powder into the lung; and 3) to assess the effectiveness of the optimized inhaled, fixed-dose combination powder of azithromycin and amikacin in a mouse model with M. avium infection in the lung. As an outcome, we expect to develop a novel effective inhaled combination therapy for MAC, a high mortality lung disease with limited treatment options using the low-risk developmental approach of drug repurposing and a novel excipient-free, inhaled pharmaceutical dry powder formulation of two antibiotics commonly used in MAC treatment. Similar products may also be developed for other NTM infections.