High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis
Camilo A. Ruiz-Bedoya, … , Carlos A. Pardo, Sanjay K. Jain
Camilo A. Ruiz-Bedoya, … , Carlos A. Pardo, Sanjay K. Jain
Published January 27, 2022
Citation Information: J Clin Invest. 2022;132(6):e155851. https://doi.org/10.1172/JCI155851.
View: Text | PDF
Research Article Infectious disease Microbiology Article has an altmetric score of 63

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

×

Figure 4

Treatment with a high-dose rifampin-containing regimen in rabbits.

Options: View larger image (or click on image) Download as PowerPoint
Treatment with a high-dose rifampin-containing regimen in rabbits. (A) E...
(A) Experimental schematic for multidrug treatment in New Zealand white rabbits with experimentally induced TB meningitis. Week –3 represents 3 weeks prior to initiation of TB treatments. (B) Bacterial burden (CFU per gram of brain tissue [log10]) (n = 3–4 animals/group per time point). (C) Rifampin brain concentration (μg/mL) (n = 3–4 animals/group with 1–2 samples/animal). (D) Representative images from untreated (left panel) rabbits or rabbits treated with 2 weeks of high-dose (middle panel) or standard-dose (right panel) rifampin-containing regimen demonstrating microglia (Iba-1 stain in red and DAPI nuclear stain in blue) density in brain tissues. (E) Quantification of Iba-1 signal (n = 1 animal/group). Data are represented as median ± IQR except for bacterial burden (CFU), which is presented as mean ± SD. Statistical comparisons were performed using 2-way ANOVA followed by Bonferroni’s multiple-comparison test (B) and 2-tailed Mann-Whitney-Wilcoxon test (C).