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

Abstract

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.

FIG. 1

Number of viable M. tuberculosis organisms in spleens and lungs of infected mice after once-daily treatment for 5 days per week for 4 weeks with different doses of RIF, RPT (rifapentine), or KRM given as monotherapy. Infected untreated mice from control groups were sacrificed 1 week (early controls [EC]) and 4 weeks (late controls [LC]) after infection. Results are means (open bars) ± standard deviations (solid bars).