TB meningitis is the deadliest form of TB, killing one in four, with mortality even higher in people living with HIV or those with drug-resistant TB (hard-to-treat TB). Bedaquiline is the first new drug to be developed for TB in decades and has had a significant impact on treatment outcomes when used in a multi-drug regimen for drug-resistant TB.
The A5343 DELIBERATE study investigated the effect of bedaquiline and delamanid, alone or in combination, on the QT interval (QT measures the electrical activity of this heart contraction process or the time it takes for the heart muscle to contract and then recover). A pharmacokinetic sub-study aimed to measure the concentrations of bedaquiline and delamanid in cerebrospinal fluid collected from the participants through an opt-in lumbar puncture. This was undertaken because guidelines for the treatment of TB meningitis emphasize the use of drugs with known central nervous system penetration, but the penetration of bedaquiline into the cerebrospinal fluid up until now has been unknown.
This sub-study recruited 12 participants, seven of whom received bedaquiline and had bedaquiline levels measured in their cerebrospinal fluid. Bedaquiline was detected in all samples and was found at concentrations similar to the expected unbound (active) fraction in plasma. This suggests that unbound bedaquiline (the portion not bound to proteins in plasma) is able to penetrate across the blood-cerebrospinal fluid barrier. It is possible that bedaquiline may have a role to play in the treatment of TB meningitis. It can be included in multi-drug regimens where drug-resistance is confirmed while additional evidence on its contribution to successful treatment outcomes is explored.
Key takeaway: This sets the stage to test whether bedaquiline can be used to help people with TB meningitis.
Upton, C.M.; Steele, C.I.; Maartens, G.; Diacon, A.H.; Wiesner, L.; Dooley, K.E.; Pharmacokinetics of bedaquiline in cerebrospinal fluid (CSF) in patients with pulmonary tuberculosis (TB). J Antimicrob Chemother; 2022 May 29;77(6):1720-1724.