Pharmacokinetic Assessment of MDR-TB Drugs in the Treatment of TB Meningitis

Rationale: MDR-TBM is a devastating disease with high mortality and severe neurologic sequelae among survivors.  We recognize the importance of sufficient drug concentrations at the site of infection for efficacy of anti-TB drugs and believe it is likely that drug distribution into brain and CSF varies over the course of treatment as inflammation and BBB and blood-CSF barrier leakiness changes. The WHO’s most recent guidelines on MDR-TB treatment prioritizes fluoroquinolones, bedaquiline, linezolid, clofazimine, and cycloserine for treatment of MDR-TB, yet there is no guidance on treatment of MDR-TBM.  In order to improve our understanding of optimal dosing and combinations of these drugs for MDR-TBM, we propose to leverage our ongoing work focused on the PK of MDR-TB drugs as well as RePORT sites in three countries with high local rates of MDR-TB to characterize PK, outcomes, and longitudinal biomarkers over time with treatment. This opportunistic PK/safety/outcomes study is akin to P1026S in the IMPAACT network that leveraged network sites to inform dosing of antiretroviral agents and TB drugs for pregnant women.

Aims:
Aim 1 (PK): Measure plasma and CSF concentrations of second-line TB drugs used to treat MDR-TB including fluoroquinolones, amikacin, linezolid, clofazimine, bedaquiline, and delamanid, and use these measurements to develop a population PK model that describes drug disposition, including penetration coefficient into CSF in TBM.
Aim 2 (PD): Assess the relationship between PK parameters, minimum inhibitory concentrations (MICs) and mutations identified by sequencing, and clinical outcomes, namely survival and functional status.
Aim 3 (Exploratory): Evaluation of CSF biomarkers including chemistry tests, cell counts, cytokines, and proteins to predict 6 month functional status measured by WHODAS2.