Abstract
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.
Highlights
Tuberculous meningitis (TB meningitis) is the most devastating form of tuberculosis (TB), especially among HIV-infected individuals and young children [1–3]
Despite the knowledge that key antimicrobials do not penetrate into the brain adequately and that immunopathology is the critical pathologic process, current treatments for TB meningitis are not optimized and continue to be based on those used for pulmonary TB [2]
Similar findings were noted in a patient with TB meningitis who underwent brain biopsy for clinical reasons, demonstrating parenchymal lesions with multinucleated giant cells and CD68+ cells (Figure 2, M and N, and Supplemental Figure 3)
Summary
Tuberculous meningitis (TB meningitis) is the most devastating form of tuberculosis (TB), especially among HIV-infected individuals and young children [1–3]. Rifampin has limited penetration into the CNS with current regimens and decreases rapidly after treatment initiation [12, 14], leaving room for advances in dose optimization for improved delivery. While differences in rifampin exposures in the two trials could explain these differences, it has been hypothesized that outcomes in TB meningitis may be more strongly associated with changes in intracerebral inflammation rather than bacterial killing. This is relevant, as intensified TB regimens with enhanced bacterial killing could worsen intracerebral inflammation due to the release of proinflammatory components during bacterial lysis. The role of high-dose rifampin in improving treatments for TB meningitis remains unknown
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