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Despite the widespread pediatric use of linezolid, data on its hematologic toxicity-particularly among children exposed to anticancer chemotherapy-remain limited and inconsistent. This study aimed to evaluate linezolid-induced hematotoxicity through pharmacokinetic analysis, with an emphasis on chemotherapy-exposed pediatric patients. This dual-center prospective study assessed linezolid pharmacokinetics and clinical profiles in chemotherapy-stratified pediatric cohorts, examining associations with hematologic toxicity. Among 229 pediatric patients (65 with cancer), hematologic toxicity occurred in 43.2%, with significantly higher risks of leukopenia (hazard ratio [HR] 20.29, 95% confidence interval [CI]: 3.98-103.38), neutropenia (HR 2.60, 95% CI: 1.00-6.77), and thrombocytopenia events (HR 7.08, 95% CI: 2.19-22.92) in cancer patients. Median linezolid trough and peak concentrations were 2.60 mg/L (interquartile range [IQR] 1.42-4.06) and 12.00 mg/L (IQR 9.5-14.19), respectively. Among cancer patients, trough concentrations above 7 mg/L elevated leukopenia (HR 6.33, 95% CI: 1.36-29.42) and anemia event (HR 8.72, 95% CI: 1.98-38.37) risk. Prolonged therapy exceeding 14 days elevated the risk of anemia events (HR 2.17; 95% CI: 1.08-4.35), while durations beyond 28 days also increased the risk of neutropenia events (HR 3.58; 95% CI, 1.37-9.32). At equivalent daily doses, twice-daily dosing resulted in higher peak concentrations (19.65 vs 13.67 mg/L; P = 0.020) and a greater incidence of anemia events (62.50% vs 25.00%; P = 0.033) compared to thrice-daily regimens. Linezolid frequently causes hematologic toxicity in children, particularly in chemotherapy recipients. Risk is also driven by high concentrations (peak > 15 mg/L, trough > 7 mg/L in cancer patients), prolonged therapy, and twice-daily dosing, necessitating careful monitoring and dose optimization.