In vitro activity of contezolid and other comparators against clinical Staphylococcus and Enterococcus : a multicenter study in China

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OBJECTIVE: To evaluate the in vitro activity of contezolid against clinical Staphylococcus and Enterococcus isolates from across China, and compare its performance with linezolid and other key agents. METHODS: A total of 2510 non-duplicate Gram-positive cocci isolates were collected from 70 hospitals in seven Chinese regions. Minimum inhibitory concentrations (MICs) were determined using broth microdilution (BMD) per CLSI guidelines. MIC50/90 values, susceptibility rates, cumulative MIC curves and MIC distribution agreement between contezolid and linezolid were assessed. Linezolid-resistant isolates and contezolid-resistant isolates-defined as those based on CLSI 2025 linezolid breakpoints-underwent whole-genome sequencing and comprehensive screening for known oxazolidinone resistance determinants, including acquired resistance genes, 23S rRNA mutations and amino acid substitutions in ribosomal proteins L3, L4 and L22. RESULTS: Contezolid exhibited potent in vitro activity, with >99% of isolates inhibited at ≤4 mg/L and showed lower MIC50/90 than linezolid, with a consistently left-shifted cumulative MIC distribution. Cohen's kappa analysis supporting enhanced activity of contezolid. Notably, we report for the first time clinical isolates with contezolid MICs up to 16 mg/L. Whole-genome analysis of 14 linezolid-resistant isolates (including five resistant to contezolid) revealed universal presence of optrA, cfr, fexA and other resistance genes, alongside domain V 23S rRNA mutations and substitutions in ribosomal proteins L3 and L4, supporting a shared genetic basis and potential cross-resistance between the two agents. CONCLUSIONS: Contezolid demonstrated potent and consistent activity against drug-resistant Gram-positive cocci, supporting its potential as a therapeutic alternative to linezolid. Further studies are needed to confirm resistance mechanisms and clinical utility.