Mycobacterium kansasii (M. kansasii) is the second most common non-tuberculous mycobacteria (NTM) causing disease in both immune-competent and immune-compromised patients. In contrast to other NTMs, M. kansasii pulmonary disease resembles that of tuberculosis and may therefore be a target for tuberculosis-like short-course chemotherapy. Currently the course of chemotherapy recommended by the American Thoracic Society is a combination regimen of isoniazid (300 mg/day), rifampin (600 mg/day), and ethambutol (15-25 mg/kg/day) given daily for at least 12 months beyond when the bacteria is no longer cultured from the sputum. This prolonged duration is far longer than the 6-month tuberculosis regimen. The drug doses currently recommended are not optimized for M. kansasii nor rigorously studied in combination with other drugs of potential synergy, antagonism or additivity in the pre-clinical models, rather obtained from tuberculosis drug trials. As a result, the treatment outcomes are relatively poor despite such a long therapy duration. The studies proposed here will ? (1) determine the optimal dose of isoniazid, rifampin, and ethambutol for treatment of M. kansasii, (2) add the drugs at exposure showing synergy/additivity between drug pair to develop optimal dose combination regimen, (3) perform mathematical modeling and clinical trial simulations to determine the therapy duration with new regimen. Since the proposed drugs are already in use for treatment of M. kansasii with known safety and toxicity data, we expect our new regimens can readily be advanced into the clinics. Our approach is less time-consuming compare to the traditional drug development strategies that can take years from lead optimization to combination therapy development.
Among the non-tuberculous mycobacteria (NTM), Mycobacterium kansasii is the second most common cause of pulmonary disease that resembles with tuberculosis in clinical presentation. The current standard treatment regimen is administered for 18-24 months, well beyond the short-course chemotherapy of 6-months for tuberculosis. Our hypothesis is that the optimal drug exposures for M. kansasii will be different from those established for M. tuberculosis. Using pre-clinical drug development tools to perform rigorous pharmacokinetic/pharmacodynamics studies, we aim to optimize the dose of standard drugs (isoniazid, rifampin and ethambutol) to design a M. kansasii specific treatment regimen with the ability to suppress acquired drug resistance. We expect the optimal exposure combination could treat M. kansasii in 6-months or less.
