Abstract
The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure–response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2–93.8) to 82.5 hour·mg/L (range 8.7–161.0) in plasma and from 3.5 hour·mg/L (range 1.2–9.6) to 6.0 hour·mg/L (range 0.7–15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.
Highlights
The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain
The objective of the current study was to define the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of rifampin, isoniazid, pyrazinamide, ethambutol, and levofloxacin in a subset of 237 patients enrolled into the trial and to investigate the relationships between drug exposures and survival
A total of 237 adult patients with a clinical diagnosis of tuberculous meningitis (TBM) were enrolled in this PK substudy, but samples from two patients could not be analyzed due to limited volumes, and two patients died without blood samples for drug concentration measurements
Summary
The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers. Our recent trial in 817 patients with TBM failed to demonstrate benefit on survival of higher dose rifampin (15 mg/kg/day vs 10 mg/kg/ day). What are the exposure–response relationships for antituberculosis drugs in the treatment of TBM and should the dose of rifampin, or other drugs, be increased to prevent death?. Pharmacokinetic properties of rifampin, isoniazid, pyrazinamide, ethambutol, and levofloxacin in plasma and cerebrospinal fluid were characterized in 237 patients with TBM. Higher doses of isoniazid for the treatment of TBM should be investigated, especially in fast acetylators
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