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

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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. IMPORTANCE: Tuberculous 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.
Funding Information
  • Beijing Municipal Health Commission Excellent Clinical Research Program for Research-Oriented Wards (BRWEP2024W042160104 and BRWEP2024W042160109)
  • Beijing Municipal Health Commission Dengfeng Program (G202511062)
  • the Beijing Tongzhou District Science and Technology Program Project (WS2024017)
  • Guangzhou National Laboratory 2024 Special Project on Tuberculosis Short-Course Therapy (GZNL2024A01030)
  • Tongzhou District Health Development Research Reserve Program, Tongzhou District Commission of Science and Technology of Beijing Municipality of China (KJ2023CX048)

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