Reply to Upton et al

To the Editor—We thank Upton et al [1] for taking an interest in our article and for raising excellent points about the interpretation of our cerebrospinal fluid (CSF) pharmacokinetic results [2]. We agree that our results provide no definitive answers on the role of newly implemented drugs such as bedaquiline and delamanid for the treatment of tuberculosis meningitis (TBM), including drug-resistant disease, and we wholeheartedly encourage others to continue explore their use further through clinical practice and research endeavors.

The point about the “stickiness” of bedaquiline is valid and important to consider. For additional detail on our CSF collection procedure, we used a prepared lumbar puncture kit; CSF was collected through a 3.5-inch spinal needle and a 3-way stopcock directly into polypropylene specimen vials, pipetted into polypropylene cryovials, and frozen at −80°C until shipment and analysis. While the lack of plastic tubing decreased potential drug loss, it is possible that some of the bedaquiline adsorbed to the polypropylene vials, as has been described previously in a pilot experiment [3]. We applaud the work by Upton and colleagues [4] to test and fine tune collection strategies to more accurately measure CSF bedaquiline concentrations. This provides an invaluable technique for future bedaquiline CSF pharmacokinetic research and will allow for better comparison of results between studies and patients.

Our limit of detection for bedaquiline, delamanid, and clofazamine was validated only to 0.01 µg/mL and not lower, owing to lack of funding for full low-end validation of these drugs in artificial CSF. In our Supplementary Tables 1–5 [2], we categorized CSF drug concentration results as either below the limit of detection or 0, with these below-limit samples having an amount detected below 0.01 µg/mL. More than 50% of the CSF samples we collected had a detectable amount for bedaquiline, clofazimine, and delamanid; however, we chose not to report these values, given lack of validation and potential for inaccuracy. Following the lead of Upton and colleagues, we agree that a lower limit of detection should be validated and used for CSF detection of these drugs to better illuminate the diffusion of free drug into CSF.

We hope that our research stimulates further and innovative research into the clinical pharmacology of TBM. The high mortality rate for drug-resistant TBM shown by our group and others necessitates more investigation aimed at improving treatment options [5, 6]. In a search of clinicaltrials.gov, we found no currently registered TBM trials using bedaquiline, delamanid, or pretomanid. This is stark contrast to the abundance of clinical trial activity in drug-resistant pulmonary tuberculosis [7]. However, innovative translational research in TBM is being done, including work evaluating dynamic positron emission tomography to study drug distribution into brain parenchyma [8, 9].

This work has provided a novel way to evaluate brain concentrations, and results to date have shown promising results for pretomanid and that bedaquiline accumulates at higher concentrations in the brain versus CSF, highlighting that CSF analysis may offer an incomplete picture. We encourage others to use our results as launching pad to further study the clinical pharmacology of TBM.

Notes

Financial support. This work was supported in part by the National Institutes of Health, including the Fogarty International Center (grant D43 TW007124) and the National Institute of Allergy and Infectious Diseases (grant R03 AI139871).