191. High-Dose Rifampin-containing Regimens for the Treatment of TB Meningitis

Abstract Background TB meningitis is the most severe form of tuberculosis (TB), associated with high morbidity and mortality. High-dose rifampin (35mg/kg/day) is safe in adults and substantially improves the bactericidal activity of standard TB regimen. However, there is conflicting data regarding its benefit in TB meningitis where outcomes may also be associated with intracerebral inflammatory responses. Methods A novel mouse and a validated rabbit model of TB meningitis utilizing intracranial Mycobacterium tuberculosis infections were used for these studies (Fig. 1). Animals received high-dose (35 mg/kg/day) or standard-dose (10 mg/kg/day) rifampin in combination with isoniazid, pyrazinamide and dexamethasone at human equipotent dosing. Bacterial burden, multi-modality positron emission tomography (PET) imaging, tissue drug concentrations, markers of neuroinflammation, and vascular leak were measured. Imaging data from a patient with TB meningitis was analyzed and correlated with the findings in animals. Figure 1. Mouse model of TB meningitis replicates human histopathology hallmarks. (A) Scheme of infection. (B) Histopathology hematoxylin-eosin (H&E) and acid-fast bacilli (AFB) staining in a representative M. tuberculosis-infected mouse shows regions of meningitis, ventriculitis, choroiditis, necrotizing and non-necrotizing granulomas. The bar represents 100µm. (C) Images show immunofluorescence of microglia activation in red (Iba-1) and nuclear stain in blue (DAPI). The rabbit model of TB meningitis has been described previously (Tucker et al. Dis Model Mech. 2016 and Tucker et al. Sci Transl Med. 2018). Animal studies were approved by the Johns Hopkins Animal Care and Use Committee. Results Administration of the high-dose rifampin regimen achieved four times higher brain concentration than the standard-dose regimen and displayed higher bactericidal activity in both mice and rabbits (P Conclusion Our cross-species findings suggest that an intensified high-dose rifampin regimen is more efficacious than the standard treatment for TB meningitis without an increase in neuroinflammation. Vascular leak decreases during TB treatment and may account for decreases in rifampin permeability over time. These studies have important implications for antimicrobial development for TB meningitis. Disclosures Charles A. Peloquin, Pharm.D., Nothing to disclose Alvaro A. Ordonez, MD, Cubresa (Consultant)Fujirebio Diagnostics (Research Grant or Support) Sanjay K. Jain, MD, Fujirebio Diagnostics, Inc., USA (Research Grant or Support)Novobiotic LLC, USA (Research Grant or Support)T3 Pharma, Switzerland (Research Grant or Support) Sanjay K. Jain, MD, Fujirebio Diagnostics, Inc., USA (Individual(s) Involved: Self): Research Grant or Support; Novobiotic LLC, USA (Individual(s) Involved: Self): Research Grant or Support; T3 Pharma, Switzerland (Individual(s) Involved: Self): Research Grant or Support