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

Background Tuberculous meningitis (TB meningitis), the most severe form of tuberculosis (TB), 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 TB, with rifapentine now forming the basis of a WHO-approved 4-month daily rifapentine-moxifloxacin regimen, and retrospective studies showing that rifabutin-based regimens are effective and well-tolerated, 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 three regimens, rifamycin tissue concentrations, brain inflammation [brain magnetic resonance imaging (MRI), 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. Conclusion Alternate rifamcyins, rifapentine and rifabutin, show therapeutic activity and neuroprotective effects, supporting their evaluation in clinical trials for treating TB meningitis.