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bioRxiv · 10.1101/2024.12.03.626643

Distribution of contezolid in different tissues of mice and human patients infected with Mycobacterium abscessus

Li, Q.·Wang, Y.·Zhu, Q.·Lin, Y.·Chu, N.·Lu, Y.·Nie, W.
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Abstract

BackgroundLinezolid (LZD), while effective against Mycobacterium abscessus (MAB), can cause myelosuppression and peripheral neuropathy. Contezolid (CZD) shares a similar antimicrobial profile with improved safety, but biodistribution data remain limited. This study evaluated CZDs biodistribution in MAB-infected mice and humans and its therapeutic potential across infection sites. MethodsMICs of CZD and LZD against 32 clinical MAB isolates and three reference strains were determined. In MAB-infected mice, drug concentrations were quantified in plasma and pulmonary and cerebral tissues at 2, 4, and 8 hours post-administration. In MAB-infected patients, CZD concentrations in bone, plasma, and cerebrospinal fluid were measured at multiple time points and MAB counts in sputum cultures were assessed daily over 14 days. ResultsRespective MIC50 and MIC90 values were 8 and 32 {micro}g/mL (LZD) and 16 and 32 {micro}g/mL (CZD). Pharmacokinetic CZD and LZD level comparisons revealed peak CZD plasma levels within 2 hours, higher systemic CZD levels, comparable pulmonary tissue concentrations, and slightly lower CZD cerebral tissue penetration. In patients, CZD levels in ankle joint effusion samples reached 2.0885 {micro}g/mL at 6 hours, peaking in the posterior malleolus. Plasma CZD concentrations peaked at 8.2349 {micro}g/mL at 3 hours and dropped to 6.1065 {micro}g/mL by 6 hours, while CSF levels were 0.9295 and 0.792 {micro}g/mL at 3 and 6 hours, respectively. Sputum bacterial burden decreased rapidly within 24 hours of CZD treatment, with near-complete clearance by day 4. ConclusionCZD and LZD exhibit comparable tissue distribution but different site-specific penetration, supporting their potential for treating diverse MAB infections.

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Li, Q., Wang, Y., Zhu, Q., Lin, Y., Chu, N., Lu, Y., Nie, W.. 2024-12-03. Distribution of contezolid in different tissues of mice and human patients infected with Mycobacterium abscessus. https://doi.org/10.1101/2024.12.03.626643

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