Project Summary Tuberculosis meningitis (TBM) is the most lethal form of tuberculosis disease with close to half of all patients’ affected experiencing severe disability or death and worse outcomes among patients with drug-resistant disease. Attaining adequate concentrations of anti-TB drugs in the central nervous system (CNS) is essential to the successful treatment of TBM, but critical knowledge gaps exist. Among the first-line TB drugs, available data has indicated that cerebrospinal fluid (CSF) concentrations of rifampin (RIF), considered the most important first-line drug, are approximately 20% of serum values and in most cases well below recommended Cmax concentrations. Regarding non-first-line drugs, two recent studies have examined the benefit of adding a fluoroquinolone for the treatment of drug-susceptible TBM with mixed results and there has been almost no report on the use of newly introduced drugs including delaminid and bedaquiline among patients with drug- resistant TBM. We propose a prospective observational study to evaluate the CSF drug concentrations of rifampin, levofloxacin (LEV), bedaquiline (BDQ), and delamanid (DEL) among patients being treated for TBM in the country of Georgia. Our overall study goals are to demonstrate to provide novel pilot data on a) factors associated with CNS penetration and on b) the CSF concentrations of newly introduced anti-TB drugs. We hypothesize that CSF drug concentrations of rifampin and levofloxacin will be associated with CSF inflammatory markers and time from initiating treatment and that CSF concentrations of bedaquiline and delamanid will be low. A better understanding of CSF drug concentrations will guide new and improved treatment options for patients afflicted TBM. The Specific AIMs of this proposal include: 1) To determine the clinical treatment outcomes of patients treated for drug-susceptible TBM with an intensified regimen. Primary outcomes of death and neurological disability and predictors of will be assessed 12 months after TBM treatment initiation. 2) To determine RIF and LEV CSF concentrations among patients being treated for drug-sensitive TBM. We will enroll 16 patients with confirmed or probable TBM from AIM 1 to compare the ratio of serum RIF (non- protein bound) and LEV to CSF concentrations and to estimate additional CSF parameters including Cmax and AUC. We will also evaluate whether time course of disease and the level of inflammation as characterized by CSF cellular and cytokine profile are associated with CSF drug concentrations. 3) To determine the CSF concentrations of newly introduced anti-TB drugs including BDQ and DEL among patient being treated for drug-resistant TBM. We will enroll 8 patients being treated for drug- resistant TBM with either BDQ or DEL. This exploratory aim will provide novel preliminary data on the CSF concentrations of these drugs and insight into whether current dosing strategies adopted from pulmonary TB recommendations are appropriate among patients with TBM.

Project Narrative There is an urgent need to identify optimal drug dosages and selection for patients with tuberculosis meningitis (TBM) given the reports of low anti-tuberculosis drug concentrations in cerebrospinal fluid (CSF) and extremely high rates of poor treatment outcomes. This proposed research will evaluate the variability and predictors of first and second-line CSF drug concentrations among patients with TBM as well as treatment outcomes among patients treated for drug-susceptible TBM using an intensified regimen containing a fluoroquinolone and an injectable agent. We aim to provide information that will help guide the study and selection of TBM treatment regimens and improve clinical outcomes among patients afflicted with this hard to treat form of TB disease.