Short course combination regimens for treatment of Mycobacterium avium pulmonary disease: a translational bench-to-bedside approach - Project Summary Nontuberculous mycobacteria (NTM) including Mycobacterium avium complex (MAC) are among the most difficult to treat etiological agents associated with pulmonary disease. Just between 2008-2015, the annual NTM lung disease incidence increased from 3.13% to 4.73% per 100,000 persons, and the annual prevalence changed from 6.78% to 11.7%. The current American Thoracic Society guidelines recommend a macrolide- ethambutol-rifamycin combination therapy for treatment of pulmonary MAC, where therapy continues for 12- months after converting one’s sputum culture to negative (no growth or microbiological clearance). We performed a meta-analysis and found that despite an average 18–23-month long therapy duration, the sustained sputum culture conversion rates at the end of therapy were only 54% with the macrolide containing regimen and 32% with macrolide-free regimens. Thus, there is need for safe, more effective, and shorter-course regimens for treatment of MAC pulmonary disease. However, there is a knowledge gap in the pharmacokinetics/pharmacodynamics-based guidelines on dose and combination regimen composition as well as information on the synergy/antagonism between the drugs, at the given dose, in the combination. As a result, the treatment regimen for MAC infections is largely empirical and driven by clinical experience. To fill in the knowledge gap, we devised a programmatic approach for unbiased screening of the drugs (old, new, and/or repurposed) for efficacy against MAC to perform dose selection using the principle of pharmacokinetics/pharmacodynamics. We use a pre-clinical hollow fiber system model of MAC (HFS-MAC) in tandem with a mouse model of MAC, clinical trial simulations, and time-to-extinction modeling using pre-clinical and clinical data to design and rank efficacious combinations of drugs for MAC killing and accurate estimates of therapeutic duration. The safety and toxicity profile of the drugs we propose to advance, in this grant proposal, for treatment of MAC pulmonary disease is well documented, data on human population pharmacokinetics are available, and the mechanism of action and the effective tissue penetration are also available for most of the proposed drugs. Thus, exposure targets for maximal kill, identified in the pre-clinical models can be translated to a clinical dose to treat patients with MAC pulmonary disease in a relatively shorter timeframe. We aim to shorten the therapy duration for pulmonary MAC from the current >18 months to <6 months.
