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High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis. | LitMetric

AI Article Synopsis

  • Tuberculous meningitis (TB meningitis) is a severe form of TB that requires a lengthy 12-month treatment and has high rates of illness and death.
  • High-dose rifampin (35 mg/kg/d) shows potential benefits over standard-dose rifampin (10 mg/kg/d) in treating TB meningitis, as indicated by studies in mice and rabbits that found improved bactericidal activity without increased inflammation.
  • Advanced imaging techniques revealed significant changes in the blood-brain barrier during treatment, suggesting that these changes are crucial for how rifampin penetrates the brain, offering new insights for developing better antibiotic treatments.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920328PMC
http://dx.doi.org/10.1172/JCI155851DOI Listing

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