High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis
Camilo A. Ruiz-Bedoya, Filipa Mota, Elizabeth W. Tucker, Farina J. Mahmud, Maria I. Reyes-Mantilla, Clara Erice, Melissa Bahr, Kelly Flavahan, Patricia de Jesus, John Kim, Catherine A. Foss, Charles A. Peloquin, Dima A. Hammoud, Alvaro A. Ordonez, Carlos A. Pardo, Sanjay K. Jain
Camilo A. Ruiz-Bedoya, Filipa Mota, Elizabeth W. Tucker, Farina J. Mahmud, Maria I. Reyes-Mantilla, Clara Erice, Melissa Bahr, Kelly Flavahan, Patricia de Jesus, John Kim, Catherine A. Foss, Charles A. Peloquin, Dima A. Hammoud, Alvaro A. Ordonez, Carlos A. Pardo, Sanjay K. Jain
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Research Article Infectious disease Microbiology

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

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.

Authors

Camilo A. Ruiz-Bedoya, Filipa Mota, Elizabeth W. Tucker, Farina J. Mahmud, Maria I. Reyes-Mantilla, Clara Erice, Melissa Bahr, Kelly Flavahan, Patricia de Jesus, John Kim, Catherine A. Foss, Charles A. Peloquin, Dima A. Hammoud, Alvaro A. Ordonez, Carlos A. Pardo, Sanjay K. Jain

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Figure 1

Study design.

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Study design. Cross-species studies were performed in mice, rabbits, and...
Cross-species studies were performed in mice, rabbits, and humans to address key questions regarding the use of high-dose rifampin for TB meningitis. Longitudinal, multimodal imaging studies in live animals, supported by postmortem assays, were designed to evaluate the bactericidal activity of high- versus standard-dose rifampin regimens as well as lesion-specific, intracerebral inflammation. Studies to assess intracerebral, lesion-specific rifampin exposures and expression of efflux pumps (e.g., MDR-1) were performed with the goal of identifying pathways that could be modulated to optimize rifampin delivery to the CNS. We also studied the effect of dexamethasone on rifampin levels, intracerebral inflammation, and the efficacy of rifampin-containing regimens. Multimodal imaging in the same cohort of animals was utilized to explore the mechanisms underlying the spatiotemporal changes in lesion-specific, rifampin brain exposures, and localized blood-brain barrier disruptions (18F-py-albumin PET/CT). Postmortem analyses to assess vessel pathology at high resolution were also performed (clarified whole mouse brains — iDISCO protocol). Finally, longitudinal imaging studies in 2 cohorts of patients were analyzed to understand the spatiotemporal changes in rifampin exposures and localized blood-brain barrier disruptions during TB treatment and correlated with the findings from the animal studies. LC–MS/MS, liquid chromatography and tandem mass spectrometry; IHC, immunohistochemistry; BBB, blood-brain barrier.