EFFECTIVENESS OF RIFABUTIN ALONE OR IN COMBINATION WITH ISONIAZID IN PREVENTIVE THERAPY OF MOUSE TUBERCULOSIS

The ever-increasing incidence of tuberculosis calls for the implementa tion of control measures, including new efficient, short-term preventi ve therapies to replace 6 to 12 months of isoniazid therapy. The effic acies of 12-week regimens of rifabutin or isoniazid given daily and th e combination of the two drugs administered intermittently were evalua ted in mice infected with Mycobacterium tuberculosis after vaccination with the bacillus Calmette-Guerin (BCG) to imitate some features of t he natural infection in humans with a low number of persisting bacteri a. Rifabutin at 10 mg/kg of body weight per day was highly effective a s early as the eighth week of treatment: all spleens were sterilized a nd the number of bacteria was drastically reduced in the lungs (mean /- standard deviation log CFU, 0.2 +/- 0.3, compared with 5.9 +/- 0.6 for untreated controls). No bacilli were found in the spleens or lungs of any of the animals treated for 12 weeks. The combination of rifabu tin at 10 mg/kg plus isoniazid at 25 mg/kg twice weekly was almost as effective as rifabutin daily: after 8 weeks of treatment only two of s ix mice harbored a small number of mycobacteria in their spleens and l ungs; at week 12, all spleens were sterilized and a total of eight col onies were isolated from the lungs of two of six mice. Daily isoniazid and once-weekly rifabutin plus isoniazid therapies were less effectiv e. Colonies randomly isolated from the spleens and lungs of mice from different experimental groups were also tested for their susceptibilit ies to the two drugs. The three surviving colonies from rifabutin-trea ted mice and all colonies from those administered rifabutin plus isoni azid remained fully susceptible to either drug. In contrast, 2 (18%) o f the 11 colonies randomly selected from isoniazid-treated mice became resistant to isoniazid (MIC, > 2 mu g/ml), although they were still s usceptible to rifabutin. Three months of treatment with rifabutin, eit her daily alone or twice a week combined with isoniazid, proved to be a valid candidate for tuberculosis preventive therapy.