Evaluating the Impact of Linezolid Metabolites: PNU‐142300 and PNU‐142586 on the Development of Linezolid‐Induced Thrombocytopenia in Adult Patients

Linezolid is a widely used antimicrobial agent in clinical practice; however, its usage is often limited by linezolid-induced thrombocytopenia (LIT). While prior studies have assessed linezolid plasma concentrations, the clinical relevance of its metabolites, PNU-142300 and PNU-142586, remains unclear. This study aimed to investigate the association between these metabolite concentrations and LIT, and to identify predictive thresholds. This study retrospectively analyzed patients treated with linezolid at Osaka Metropolitan University Hospital between January 2017 and December 2024. Patient characteristics, trough concentrations (C_trough), AUC₂₄, and pharmacokinetic parameters of linezolid and its metabolites were compared among patients with and without thrombocytopenia. Receiver operating characteristic (ROC) analysis identified thresholds for LIT prediction. Risk factors were assessed using multivariate logistic regression analysis. Forty-eight patients were included, with thrombocytopenia developing in 26 patients (54.2%). C_trough and AUC₂₄ of PNU-142300 and PNU-142586 were significantly higher in the thrombocytopenia group; meanwhile, linezolid C_trough and AUC₂₄ did not differ significantly. ROC analysis identified C_trough ≥1.43 µg/mL and AUC₂₄ ≥37.8 mg h/L for PNU-142586 as predictive thresholds. Multivariate analysis revealed that linezolid therapy ≥14 days (OR = 9.53, P = .044) and PNU-142586 C_trough ≥1.43 µg/mL (OR = 37.60, P = .002) as independent risk factors. Elevated PNU-142586 concentrations were associated with a higher cumulative incidence of LIT. Accumulation of linezolid metabolites, especially PNU-142586, is closely associated with LIT. Monitoring of PNU-142586 may improve the safety of linezolid therapy and support individualized dosing strategies.