Comparison of a Novel Regimen of Rifapentine, Tedizolid, and Minocycline with Standard Regimens for Treatment of Pulmonary Mycobacterium kansasii

The combination of isoniazid, rifampin, and ethambutol is recommended by the American Thoracic Society (ATS) for treatment of pulmonary Mycobacterium kansasii, while the British Thoracic Society (BTS) recommends clarithromycin, rifampin and ethambutol. Unfortunately, therapy duration for both regimens lasts for years. In this study, we administered tedizolid, minocycline, clarithromycin, and rifapentine as monotherapy as well as novel combinations in the intracellular hollow-fiber model system of M. kansasii (HFS-Mkn) in a 28-day study. The ATS and BTS regimens were used as comparators. Repetitive sampling was used to validate the intended intrapulmonary pharmacokinetics of each drug and to monitor changes in M. kansasii burden. As monotherapy, tedizolid at an observed area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC of 5.85 and minocycline at an AUC(0-24)/MIC of 5.77 failed to kill the bacteria below day 0 (stasis), clarithromycin at an AUC(0-24)/MIC of 2.4 held the bacterial burden at stasis, but rifapentine at an AUC(0-24)/MIC of 140 killed 2 log(10) CFU/ml below stasis. The BTS regimen kill slope was -0.083 +/- 0.035 CFU/ml/day, which was significantly superior to the ATS regimen slope of -0.038 +/- 0.038 CFU/ml/day. The rifapentine-tedizolid-minocycline combination kill slope was -0.119 +/- 0.031 CFU/ml/day, superior to that of the ATS regimen and comparable to that of the BTS regimen. In conclusion, the BTS regimen and the novel rifapentine-tedizolid-minocycline regimen showed better kill of intracellular bacteria in the HFS-Mkn. However, the efficacy of the new combination regimen remains to be tested in clinical settings.