PROJECT SUMMARY Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), with high rates of associated neurologic morbidity and mortality. Among persons living with HIV infection, mortality can exceed 50%, with most deaths occuring within the first month after presentation. Despite the dismal prognosis of TBM, few trials have been performed to optimize the therapeutic approach to TBM, and none in adults in Africa. Two recent trials in Asia of high dose rifampin (RIF) to improve outcomes in TBM produced conflicting results. We have funding for a Phase II open-label, randomized controlled trial of two high dose RIF regimens—(1) intravenous RIF 20 mg/kg/day for 2 weeks followed by oral RIF 35 mg/kg/day for 6 weeks or (2) oral RIF 35 mg/kg/day for 8 weeks—compared with standard dose RIF 10 mg/kg/day for 8 weeks during the intensive phase of treatment in TBM patients with HIV infection age 18 years and older from 2 sites in Uganda (Mulago National Referral Hospital and Mbarara Regional Referral Hospital), which has one of the highest burdens of HIV/TB co-infection worldwide. For the proposed study, we will enhance the value of this trial by using an efficient factorial design to add a second drug, linezolid (LZD), which has demonstrated activity against Mycobacterium tuberculosis and excellent central nervous system penetration. This grant brings together an interdisciplinary group of collaborators from the United States and Uganda, leveraging a strong partnership between University of Minnesota and the Infectious Diseases Institute at Makerere University and existing research infrastructure for clinical trials in meningitis to achieve these aims: (1) to determine the cerebrospinal fluid (CSF) and plasma pharmacokinetics of adjunctive LZD 1200 mg daily in TBM patients receiving high or standard dose RIF and (2) to evaluate the tolerability of a 4-week course of LZD in TBM patients and correlate adverse events with CSF and plasma LZD exposure. In addition, this proposal will foster human resources and build capacity to develop a comprehensive TBM research program through training local study staff and junior investigators in the performance of neurocognitive testing and in clinical research methods, developing and refining study procedures for participant recruitment, data collection, CSF sampling and pharmacokinetic analyses, and promoting rigorous research practices through application of standardized protocols and quality assurance practices. The knowledge and experience gained from this trial will inform selection of a biologically optimal LZD dose and will prepare the study team for a Phase III trial evaluating use of adjunctive LZD to improve clinical outcomes in TBM, which will be the focus of a subsequent R01 application.

PROJECT NARRATIVE Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) with high rates of death and neurologic disability, particularly in individuals living with HIV infection. This open label randomized controlled trial will evaluate the pharmarcokinetics and tolerability of a 4-week course of adjunctive linezolid administered with high and standard dose rifampin early in the treatment of TBM in adults living with HIV in Uganda, which has a large burden of HIV/TB co-infection. The knowledge gained from this trial will be used to determine an optimal linezolid dose for a future efficacy trial of adjunctive linezolid to improve clinical outcomes in TBM.