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 6

Imaging studies in patients with TB meningitis.

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Imaging studies in patients with TB meningitis. (A and B) 11C-Rifampin P...
(A and B) 11C-Rifampin PET/CT to study rifampin exposures. (A) MRI T2 FLAIR maximum intensity projection (MIP) (right) with the corresponding 11C-rifampin PET AUC overlaid as a heatmap (left). (B) 11C-Rifampin brain/plasma AUC ratios in brain regions with and without vasogenic edema in a patient with TB meningitis (n = 1 patient with 7 VOI) and in brains of patients with pulmonary TB, but without meningitis (n = 11 patients, 1 VOI per patient). (C–E) Another cohort of patients with TB meningitis who underwent serial MRI during TB treatment was used to assess the blood-brain barrier disruption (n = 4 patients). (C) Representative MRI axial sections with DWI and T1 after contrast at treatment initiation (left) and after 3 months of treatment (subject 1, Supplemental Table 1). (D) Changes in brain T1 after contrast volume (cm3) during TB treatment (n = 3; no contrast was administered for subject 4 with chronic renal disease). (E) Changes in brain diffusion (ADC [mm2/s]) for all 4 patients. All patients received 2 months of initiation treatment with HRZ with or without fluoroquinolones, followed by continuation phase with at least 12 months of HR treatment. Panel C and the corresponding T2 FLAIR are shown in Supplemental Figure 18A. Data are represented as median ± IQR. Statistical comparisons were performed using 2-way ANOVA followed by Bonferroni’s multiple-comparison test (B) and 2-tailed Mann-Whitney-Wilcoxon test (D and E). TB drug treatments are abbreviated. BBB, blood-brain barrier; T1 post, T1 after contrast image.