ABSTRACT Mortality from cryptococcal and TB-meningitis in individuals with HIV is unacceptably high and better therapeutics are needed. The future landscape of treatment against these infections involves either development of new therapeutics, which has been slow, and/or the optimization of current therapeutics with improved formulations or dosing regimens. The CNS is a significant site of infection for these pathogens; however, current understanding of drug penetration into the CNS is limited, based on cerebrospinal fluid (CSF) concentrations. However, CSF is not brain tissue. Furthermore, pharmacokinetic targets for therapy have been largely based on systemic or plasma concentrations with limited pharmacology assessments performed in CSF or brain parenchyma. Improved understanding of drug exposure to and within the brain compartments where pathogens reside, and how these exposures relate to pathogen clearance will be critical in the development and optimization of effective regimens. Our long-term objective is to reduce mortality from CNS infections. Herein, we aim to use pharmacokinetic/pharmacodynamics modeling to: 1) define CSF drug concentrations or AUC/MIC ratios, that predict rate of fungal clearance 2) determine the relationship between CSF drug concentrations and with inflammation, resistance, neurocognitive outcome, and survival 3) determine drug distribution in brain parenchyma using post-mortem specimens This project builds on existing research collaboration, infrastructure, and progress made with our R21 NS108344. This project represents a unique synergy between existing strengths of the study team members. Early stage-investigator Melanie Nicol, PharmD, PhD has advanced training in clinical pharmacology and performing drug distribution and pharmacokinetic studies. Robert Lukande, MMed, PhD is an experienced pathologist who can provide expertise in the performance and interpretation of autopsies. Drs. David Meya and David Boulware are leaders in cryptococcal and TB meningitis and lead multiple clinical trials in these areas, allowing us access to research participants on a variety of drug regimens. The findings from this R01 are expected to fill critical gaps in our understanding of the dose-concentration-response relationships of antifungal and anti-TB drugs for the treatment of CNS infections in individuals with advanced HIV and ultimately reduce mortality with improved regimens. The R01 will also support critical infrastructure and capacity building in Uganda in regards to drug distribution assays and the implementation of autopsy procedures.