Abstract
Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug (MDR-) and extensively drug resistant-tuberculous meningitis (TBM), specifically, is nearly uniformly fatal, with little information to guide treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated TB drug with a low minimal inhibitory concentration (1-12 ng/mL) against Mycobacterium tuberculosis. It is used for pulmonary MDR-TB, but CNS pharmacokinetic (PK) data in TBM are not available. In the present study, we measured DLM concentrations in the brain and cerebrospinal fluid (CSF) of six rabbits, with and without experimentally-induced TBM, receiving single-dose DLM. We report steady-state CSF concentrations from three patients receiving DLM as part of multidrug-treatment who underwent therapeutic drug monitoring. Drug was quantified using LCMS/MS. In rabbits and humans, mean CSF concentrations (rabbit [1.26 ng/mL at 9h, 0.47 ng/mL at 24h]; human [48 ng/mL at 4h]) were significantly lower than plasma (rabbits [124 ng/mL at 9h, 14.5 ng/mL at 24h]; human [726 ng/mL at 4h]), but estimated free CSF/plasma ratio were >1. In rabbits, brain DLM concentrations were 5-fold higher than in plasma (mean 518 ng/mL at 9h, 74.0 ng/mL at 24h). All patients with XDR-TBM receiving DLM experienced clinical improvement and survival. Collectively, these results suggest that DLM achieves adequate concentrations in brain tissue. Despite relatively low total CSF drug levels, free drug may be sufficient and DLM may have a role in treating TBM. More studies are needed to develop a fuller understanding of its distribution over time with treatment, and clinical effectiveness.
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