Sterilizing Activities of Novel Combinations Lacking First- and Second-Line Drugs in a Murine Model of Tuberculosis

Novel oral regimens composed of new drugs with potent activity againstMycobacterium tuberculosis and no cross-resis-tance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tu-berculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a mu-rine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sut-ezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations com-posed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapen-tine plus clofazimine> clofazimine> rifapentine> PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against suscepti-ble isolates may shorten the duration of treatment further. Novel oral regimens composedmostly or entirely of new drugswith potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for tuberculosis (TB), including multidrug