Evaluation of rifalazil in a combination treatment regimen as an alternative to isoniazid-rifampin therapy in a mouse tuberculosis model.

The newer rifamycin, rifalazil (RLZ) (previously known as KRM-1648), has been shown in prior experiments to be a highly potent drug against Mycobacterium tuberculosis. In this report, we studied the efficacy of RLZ in combination with pyrazinamide (PZA) and ethambutol (EMB) in a long-term in vivo experiment and compared their activity with the isoniazid (INH)-rifampin (RIF) combination which is presently used in the clinic. Combinations of RLZ with PZA alone or with both PZA and EMB were both found to have sterilizing activities comparable to that of the INH-RIF combination but significantly better activity with respect to relapse of infection. These results suggest that RLZ, or other agents with similar activity, could be combined with available agents to act as a potential alternative drug regimen to the currently used INH-RIF combination.

Evaluation of rifapentine in long-term treatment regimens for tuberculosis in mice.

Besides direct bactericidal activity, long-term effectiveness is one of the most important features to consider when developing new drugs for chemotherapy. In this study, we evaluated the ability of rifapentine (RFP), in monotherapy and combination therapy, to completely eradicate a Mycobacterium tuberculosis infection and to prevent relapse posttreatment in a Swiss mouse model. The combination of RFP, isoniazid (INH), and pyrazinamide (PZA) administered daily resulted in an apparent clearance of M. tuberculosis organisms in the lungs and spleens of infected mice after 10 weeks of treatment. However, 3 months after the cessation of therapy, bacterial regrowth occurred in mice treated for a 12-week period, indicating a relapse of infection. In intermittent treatment regimens of RFP in combination with INH and PZA, sterilization was achieved when mice were treated two to five times per week for 9 weeks. Bacterial growth was still observed in the once-weekly treatment group. Our results show that mouse models can predict important parameters for new drugs. We stress the necessity for long-term posttreatment observation in animal models for the routine evaluation of new drugs for antituberculosis chemotherapy.