Evaluation of contezolid's cerebrospinal fluid concentration and safety in tuberculous meningitis patients

Clinical Snapshot

Key Findings

• P Value: P = 0.008 for 2h CSF concentrations; P = 0.016 for 6h CSF concentrations; P = 0.008 for AUC comparison

• Effect Size: Contezolid CSF concentrations: 2h median 1.0806 μg/mL, 6h median 0.7920 μg/mL; Linezolid significantly higher at both timepoints

• Primary Outcome: CSF drug concentrations at 2h and 6h post-dose

• Nnt Or Sensitivity: Contezolid achieved concentrations above M. tuberculosis MIC (0.5 μg/mL) in all patients at 2h, but some fell below MIC at 6h

• Confidence Interval: Contezolid CSF AUC: 4.637 μg·h/mL (95% CI: 3.599-5.675) vs Linezolid: 12.537 μg·h/mL (95% CI: 7.8797-17.277)

Clinical Application

Requires CSF sampling capability and drug level monitoring; contezolid availability may be limited Relevant for Australian infectious disease and respiratory physicians managing MDR-TB; TGA approval status of contezolid unclear; may require special access scheme Adults with drug-resistant tuberculous meningitis where linezolid toxicity is a concern

Abstract

Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) with high mortality. This study evaluated the cerebrospinal fluid (CSF) concentration and safety of the novel oxazolidinone contezolid compared to linezolid in TBM patients. In this randomized prospective study, 10 TBM patients received either a linezolid-containing (n = 5) or contezolid-containing (n = 5) anti-TB regimen. CSF and blood concentrations were measured at 2 and 6 h post-dose. Peak (2 h) and trough (6 h) concentrations, area under the concentration-time curve (AUC), and safety were assessed. Contezolid CSF concentrations exceeded the Mycobacterium tuberculosis (Mtb) MIC (0.5 μg/mL) at 2 h (median: 1.0806 μg/mL, range: 0.9295-1.3165 μg/mL) but declined by 6 h (median: 0.7920 μg/mL, range: 0.1867-1.0194 μg/mL). Linezolid CSF concentrations were significantly higher than contezolid at both 2 h (median: 3.251 μg/mL, range: 1.9545-4.9636 μg/mL; P = 0.008) and 6 h (median: 1.623 μg/mL, range: 0.941-1.765 μg/mL; P = 0.016), remaining above MIC in all samples at 6 h. The mean CSF AUC for contezolid (4.637 μg·h/mL, 95% CI: 3.599-5.675) was significantly lower than that for linezolid (12.537 μg·h/mL, 95% CI: 7.8797-17.277; P = 0.008). Blood concentrations were higher than CSF for both drugs at all time points. No serious drug-related adverse events occurred. Contezolid effectively penetrates the blood-CSF barrier in TBM patients, achieving CSF concentrations above the MIC for Mtb. Although its CSF exposure was significantly lower than linezolid, its demonstrated penetration and safety profile suggest contezolid warrants further investigation as a potential treatment option for drug-resistant TBM.IMPORTANCETuberculous meningitis (TBM) is the deadliest form of tuberculosis, especially difficult-to-treat drug-resistant TBM. Finding new, effective, and safe medicines is critical. This study provides evidence in TBM patients that a newer antibiotic, contezolid, successfully reaches the infection site in cerebrospinal fluid (CSF) at levels expected to kill Mycobacterium tuberculosis. While linezolid achieved higher levels in CSF, contezolid still reached concentrations predicted to be effective and caused no serious side effects in our study. This is important because contezolid might offer a safer alternative to linezolid, which can have significant long-term toxicity. These promising results suggest contezolid could become a valuable new weapon against refractory drug-resistant TBM, potentially saving lives where current options are limited or too toxic.

References

1. 1.Huang, M., Wang, Y., Chen, T., Lu, Y., Chu, N., & Nie, W. (2023). Evaluation of contezolid's cerebrospinal fluid concentration and safety in tuberculous meningitis patients. Frontiers in Medicine, 10, 1224179. https://doi.org/10.3389/fmed.2023.1224179