Pharmacokinetics of bedaquiline in cerebrospinal fluid (CSF) in patients with pulmonary tuberculosis (TB).

BACKGROUND

With current treatment options most patients with CNS TB develop severe disability or die. Drug-resistant tuberculous meningitis is nearly uniformly fatal. Novel treatment strategies are needed. Bedaquiline, a potent anti-TB drug, has been reported to be absent from CSF in a single report.

OBJECTIVES

To explore the pharmacokinetics of bedaquiline and its M2 metabolite in the CSF of patients with pulmonary TB.

PATIENTS AND METHODS

Individuals with rifampicin-resistant pulmonary TB established on a 24 week course of treatment with bedaquiline underwent a lumbar puncture along with multiple blood sample collections over 24 h for CSF and plasma pharmacokinetic assessment, respectively. To capture the expected low bedaquiline and M2 concentrations (due to high protein binding in plasma) we optimized CSF collection and storage methods in vitro before concentrations were quantified via liquid chromatography with tandem MS.

RESULTS

Seven male participants were enrolled, two with HIV coinfection. Using LoBind® tubes lined with a 5% BSA solution, bedaquiline and M2 could be accurately measured in CSF. Bedaquiline and M2 were present in all patients at all timepoints at concentrations similar to the estimated unbound fractions in plasma.

CONCLUSIONS

Bedaquiline and M2 penetrate freely into the CSF of pulmonary TB patients with a presumably intact blood-brain barrier. Clinical studies are urgently needed to determine whether bedaquiline can contribute meaningfully to the treatment of CNS TB.

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: [e-mail].