Preventive therapy of tuberculosis with rifapentine in immunocompetent and nude mice

The effectiveness of intermittent administration of rifapentine (RPT), with or without isoniazid (INH), for preventive therapy of tuberculosis was evaluated in immunocompetent (normal) and nude mice. After infection with a small inoculum of Mycobacterium tuberculosis H37Rv, normal mice developed a chronic and nonfatal infection, and the bacterial population became relatively stable after an initial period of limited multiplication. On the other hand, nude mice developed an acute and fatal infection, and all untreated mice died within 5 wk, with very high colony-forming-unit (CFU) counts in their organs. Various degrees of bactericidal activity were shown in normal mice after daily treatment with rifampin (RMP) plus pyrazinamide (PZA) for 13 wk, INH daily for 26 wk, or RPT once weekly for 13 or 26 wk or once fortnightly for 26 wk. The activity of RPT was significantly enhanced when INH was added at the same dosing frequency. In nude mice the response of M. tuberculosis infection to certain regimens was less favorable than that in normal mice, suggesting that preventive therapy may be less effective in severely immunodeficient hosts even during treatment. After chemotherapy was stopped, virtually all nude mice relapsed within 12 wk regardless of the regimen administered, whereas no or very few relapses were observed in normal mice that had been treated with RMP + PZA daily for 13 wk, or RPT alone or RPT + INH once weekly for 26 wk. The latter three regimens and RPT + INH once weekly for 13 wk may be applied for fixed-duration preventive therapy in human immunodeficiency virus (HIV)-negative subjects. Because relapse of tuberculosis was almost unavoidable in nude mice after stopping chemotherapy, immunodeficient hosts, such as HIV-positive subjects, may require lifelong preventive therapy for tuberculosis. Because RPT alone or RPT + INH once weekly displayed significant bactericidal activity against M. tuberculosis, and RPT + INH once fortnightly prevented the bacterial population from increasing in nude mice, the three regimens may be considered for trials of lifelong preventive therapy in HIV-positive subjects.