Tuberculous meningitis (
TB meningitis) is the most severe form of
tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose
rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d)
rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for
TB meningitis, where outcomes may also be associated with intracerebral
inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose
rifampin-containing regimen has significantly improved bactericidal activity for
TB meningitis over the first-line, standard-dose
rifampin regimen, without an increase in intracerebral
inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid
rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in
TB meningitis are an important driver of
rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose
rifampin in
TB meningitis with important implications for developing new
antibiotic treatments for
infections.