Cerebrospinal Fluid and Tuberculous Meningitis

To theEditor—We read with interest the recent publication by Kempker et al regarding the cerebrospinal fluid (CSF) penetration of second-line tuberculosis (TB) drugs [1]. The authors conducted serial serum and CSF sampling in patients treated for tuberculous meningitis (TBM) to measure the concentrations of linezolid, cycloserine, clofazimine, delamanid, and bedaquiline. CSF concentrations of clofazimine, delamanid, and bedaquiline were below the limit of detection in the CSF, and the authors concluded that the utility of these drugs for treatment of TBM is uncertain. TBM, contributing 1%–2% of the annual global TB burden, is the form of TB most likely to cause severe disability or death [2]. As many TBM trials are focused on optimizing the dose of first-line TB drugs, we applaud the authors for exploring novel drugs. Bedaquiline was first approved by the United States Food and Drug Administration in 2012 and was first measured in CSF of a patient with multidrug-resistant TBM in 2016; in that study, bedaquiline was below the limit of quantification at all time points [3]. There are 2 challenges with measuring bedaquiline in CSF. First, bedaquiline has high protein binding (>99.9%) and adsorbs to collection, storage, and analysis equipment [4]. Second, only unbound drug is available to penetrate the blood–brain and blood–CSF barriers, so the limits of quantification of an assay must be low enough to measure the drug that diffuses freely into CSF, which would be roughly 1/1000th of total drug concentrations in plasma. The authors used a lower limit of quantification of 0.01 μg/mL, which is too high for the expected CSF concentrations for a plasma range of 0.36–3.15 µg/mL the authors found in their study participants.