ACTIVITY OF KRM-1648 IN COMBINATION WITH ISONIAZID AGAINST MYCOBACTERIUM-TUBERCULOSIS IN A MURINE MODEL

The activity of KRM-1648, alone and in combination with isoniazid, was compared with those of isoniazid, rifampin, and the combination of ri fampin plus isoniazid in a murine model of tuberculosis, Four-week-old female CD-1 mice were infected intravenously with approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms, Treatment was started 1 week postinfection and was given by gavage 5 days per week, The duration of the treatment phase was 12 weeks, with groups of mice sacrificed at 2, 4, 6, 8, and 12 weeks, For the observation phase, ad ditional groups of treated mice were sacrificed at 4, 8, 16, and 24 we eks after the cessation of treatment, Viable cell counts were determin ed from homogenates of the spleens and the right lungs, KRM-1648 was t he most active single agent evaluated and resulted in no detectable CF Us in the spleens and lungs by the end of 6 weeks of treatment. Neithe r rifampin nor isoniazid reduced cell counts to undetectable levels, e ven after 12 weeks of treatment, The combination of KRM-1648 plus ison iazid was much more active than rifampin plus isoniazid, KRM-1648 plus isoniazid resulted in the apparent sterilization of organs at 6 month s following the cessation of treatment, The promising activity of KRM- 1648 may allow for ultra-short-course therapy of tuberculosis, i.e., t reatment regimens of 1 months or less.