Reinforcing old warriors to treat Mycobacterium kansasii in shorter duration

项目摘要 堪萨斯分枝杆菌（M. kansasii）是第二常见的非结核分枝杆菌（NTM） 在免疫能力正常和免疫功能低下的患者中引起疾病。与其他NTMs相比，M. Kansasii肺病与结核病相似，因此可能是结核样 短程化疗目前美国胸科推荐的化疗疗程 社会是异烟肼（300毫克/天），利福平（600毫克/天），乙胺丁醇（15 - 25 mg/kg/天），持续至少12个月，直至痰中不再培养出细菌。 这种延长的持续时间远远长于6个月的结核病治疗方案。目前的药物剂量 建议不针对M进行优化。Kansasii也没有严格研究与其他药物的组合， 在临床前模型中的潜在协同作用、拮抗作用或相加作用，而不是从结核病药物中获得 审判因此，尽管治疗持续时间如此长，但治疗结果相对较差。研究 本文提出的方法将：（1）确定异烟肼、利福平和乙胺丁醇治疗M的最佳剂量。 kansasii，（2）在暴露时添加药物，显示药物对之间的协同作用/加和性，以开发最佳剂量 联合方案，（3）进行数学建模和临床试验模拟以确定治疗方法 新方案的持续时间。由于所提出的药物已经用于治疗M。Kansasii与已知 安全性和毒性数据，我们希望我们的新方案可以很容易地进入临床。我们的做法是 与传统的药物开发策略相比， 优化联合治疗开发。

PROJECT SUMMARY 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.