Population Pharmacokinetic Analysis of Rifampicin in Plasma, Cerebrospinal Fluid, and Brain Extracellular Fluid in South African Children with Tuberculous Meningitis.

Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this analysis, we characterize the distribution of rifampicin in cerebrospinal fluid (CSF), lumbar (LCSF) and ventricular (VCSF), and brain extracellular fluid (ECF). Children with TBM were included in this pharmacokinetic analysis. Sparse plasma, LCSF, and VCSF samples were collected opportunistically, as clinically indicated. Brain ECF was sampled using microdialysis (MD). Rifampicin was quantified with liquid chromatography with tandem mass spectrometry in all samples, and 25-desacetyl rifampicin in the plasma samples. The data were interpreted with nonlinear mixed-effects modeling, with the CSF and brain ECF modeled as "effect compartments." Data were available from 61 children, with median (min-max) age of 2 (0.3 to 10) years and weight of 11.0 (4.8 to 49.0) kg. A one-compartment model for parent and metabolite with first-order absorption and elimination via saturable hepatic clearance described the data well. Allometric scaling, maturation, and auto-induction of clearance were included. The pseudopartition coefficient between plasma and LCSF/VCSF was ~5%, while the value for ECF was only ~0.5%, possibly reflecting low recovery of rifampicin using MD. The equilibration half-life between plasma and LCSF/VCSF was ~4 h and between plasma and ECF ~2 h. Our study confirms previous reports showing that rifampicin concentrations in the LCSF are lower than in plasma and provides novel knowledge about rifampicin in the VCSF and the brain tissue. Despite MD being semiquantitative because the relative recovery cannot be quantified, our study presents a proof-of-concept that rifampicin reaches the brain tissue and that MD is an attractive technique to study site-of-disease pharmacokinetics in TBM.

A pilot study of inflammatory mediators in brain extracellular fluid in paediatric TBM.

Tuberculous meningitis (TBM) is the most fatal form of tuberculosis and frequently occurs in children. The inflammatory process initiates secondary brain injury processes that lead to death and disability. Much remains unknown about this cerebral inflammatory process, largely because of the difficulty in studying the brain. To date, studies have typically examined samples from sites distal to the site of disease, such as spinal cerebrospinal fluid (CSF) and blood. In this pilot study, we examined the feasibility of using direct brain microdialysis (MD) to detect inflammatory mediators in brain extracellular fluid (ECF) in TBM. MD was used to help guide neurocritical care in 7 comatose children with TBM by monitoring brain chemistry for up to 4 days. Remnant ECF fluid was stored for offline analysis. Samples of ventricular CSF, lumbar CSF and blood were collected at clinically indicated procedures for comparison. Inflammatory mediators were quantified using multiplex technology. All inflammatory markers, with the exception of interleukin (IL)-10 and IL-12p40, were detected in the ECF. Cytokine concentrations were generally lower in ECF than ventricular CSF in time-linked specimens. Individual cases showed ECF cytokine increases coinciding with marked increases in ECF glycerol or decreases in ECF glucose. Cytokine levels and glycerol were generally higher in patients with more severe disease. This is the first report of inflammatory marker analysis from samples derived directly from the brain and in high temporal resolution, demonstrating feasibility of cerebral MD to explore disease progression and possibly therapy response in TBM.