Beyond Rifampin: Evaluating Rifapentine and Rifabutin as Alternative Treatments for Tuberculous Meningitis

BACKGROUND: Tuberculous meningitis (TB meningitis), the most severe form of tuberculosis, carries high mortality and neurological sequelae, and current rifampin-based regimen are limited by poor central nervous system penetration. Alternative rifamycins like rifapentine and rifabutin, with different pharmacokinetic profiles, are effective for treating drug-susceptible pulmonary tuberculosis, with rifapentine now forming the basis of a World Health Organization-approved 4-month daily rifapentine-moxifloxacin regimen, and retrospective studies showing that rifabutin-based regimens are effective and well tolerated, however, both drugs still need dedicated evaluation in TB meningitis. METHODS: Mice were intracranially inoculated with Mycobacterium tuberculosis and treated with rifamycin (rifampin, rifapentine, or rifabutin)-based regimens at human equipotent doses. We assessed the bactericidal activities of the 3 regimens, rifamycin tissue concentrations, brain inflammation (brain magnetic resonance imaging, tissue immunofluorescence, cytokines), and neuronal injury. RESULTS: Both rifapentine- and rifabutin-containing regimens demonstrated bactericidal activity in the brain, similar to or better than the standard rifampin-containing regimen, as well as reduced neuroinflammation and brain injury. CONCLUSIONS: Alternate rifamycins, rifapentine and rifabutin, show therapeutic activity and neuroprotective effects, supporting their evaluation in clinical trials for treating TB meningitis.