Novel Short-Course Therapy and Morphism Mapping for Clinical Pulmonary Mycobacterium kansasii

Abstract

Standard therapy (isoniazid, rifampin, and ethambutol), with or without a macrolide, for pulmonary Mycobacterium kansasii lasts more than a year. Therefore, shorter treatment duration regimens are required. ABSTRACT Standard therapy (isoniazid, rifampin, and ethambutol), with or without a macrolide, for pulmonary Mycobacterium kansasii lasts more than a year. Therefore, shorter treatment duration regimens are required. We used data from 32 Taiwanese patients treated with standard therapy who were followed using repetitive sampling-based sputum M. kansasii time-to-positivity in liquid cultures to calculate kill slopes (γ) based on ordinary differential equations and time-to-extinction of each patient’s bacterial burden. The γ was 0.18 (95% confidence interval [CI] = 0.16 to 0.20) log10 CFU/ml/day on standard therapy. Next, we identified the M. kansasii time to extinction in the hollow-fiber system model of pulmonary M. kansasii disease (HFS-Mkn) treated with standard therapy, which was a γ of 0.60 (95% CI = 0.45 to 0.69) log10 CFU/ml/day. The γ and time-to-extinction values between the two data sets formed structure-preserving maps based on category theory: thus, we could map them from one to the other using morphisms. This mapping identified a multistep nonlinear transformation factor for time to extinction from HFS-Mkn to patients. Next, a head-to-head study in the HFS-Mkn identified median time to extinction for standard therapy of 38.7 (95% CI = 29.1 to 53.2) days, isoniazid-rifampin-ethambutol-moxifloxacin therapy of 21.7 (95% CI = 19.1 to 25) days, isoniazid-rifampin-moxifloxacin therapy of 22 (96% CI = 20.1 to 24.5) days, and rifampin-moxifloxacin-tedizolid therapy of 20.7 (95% CI = 18.5 to 29) days. Our transformation-factor based translation predicted the proportion of patients of 90.7 (88.74 to 92.35)% achieving cure with standard therapy at 12\u2009months, and 6-month cure rates of 99.8 (95% CI = 99.27 to 99.95)% for isoniazid-rifampin-ethambutol-moxifloxacin, 92.2 (90.37 to 93.71)% for isoniazid-rifampin-moxifloxacin, and 99.9 (99.44 to 99.99)% for rifampin-moxifloxacin-tedizolid. Thus, rifampin-moxifloxacin-tedizolid and isoniazid-rifampin-ethambutol-moxifloxacin are predicted to be short-course chemotherapy regimens for pulmonary M. kansasii disease.