| 2020 | Telacebec (Q203)-containing intermittent oral regimens sterilized mice infected with Mycobacterium ulcerans after only 16 doses. | PLoS Negl Trop Dis | Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas Tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field. |
| 2020 | Comparison of a Novel Regimen of Rifapentine, Tedizolid, and Minocycline with Standard Regimens for Treatment of Pulmonary Mycobacterium kansasii. | Antimicrob Agents Chemother | The combination of isoniazid, rifampin, and ethambutol is recommended by the American Thoracic Society (ATS) for treatment of pulmonary , 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 (HFS-) 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 burden. As monotherapy, Tedizolid at an observed area under the concentration-time curve from 0 to 24 h (AUC)/MIC of 5.85 and minocycline at an AUC/MIC of 5.77 failed to kill the bacteria below day 0 (stasis), clarithromycin at an AUC/MIC of 2.4 held the bacterial burden at stasis, but rifapentine at an AUC/MIC of 140 killed 2 log 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- However, the efficacy of the new combination regimen remains to be tested in clinical settings. |