Extreme variability in linezolid concentrations in the ICU: A case for routine therapeutic drug monitoring

Abstract Purpose Linezolid is an essential antimicrobial for treating multidrug-resistant gram-positive infections in critically ill patients. However, its pharmacokinetics (PK) are highly variable, potentially leading to subtherapeutic exposure or toxicity. Therapeutic drug monitoring (TDM) plays a critical role in guiding individualized dosing. Summary We describe a 66-year-old intensive care unit (ICU) patient treated with linezolid for vancomycin-resistant Enterococcus faecium (VRE) peritonitis and empyema. Despite standard dosing (600 mg IV every 12 hours), linezolid concentrations remained below the limit of quantification for 6 days, coinciding with persistent VRE isolation. A switch to continuous infusion (CI) at 2,400 mg/day achieved therapeutic levels (mean concentration [Cmean], 6.17 mg/L), but subsequent supratherapeutic exposure (Cmean, 12.12 mg/L; 24-hour area under the curve, 290.9 mg · h/L) led to adrenergic toxicity. Linezolid clearance declined from 14.6 to 6.2 L/h, unrelated to renal function, suggesting the influence of nonlinear elimination and alternate metabolic pathways. Following empyema drainage and ketamine withdrawal, PK parameters stabilized. This case highlights the extreme intraindividual PK variability of linezolid in critical illness. Contributing mechanisms may include ROS-driven CYP2J2 upregulation in acute lung injury, autoinhibition of metabolite formation, and drug interactions. CI enabled PK and pharmacodynamic target attainment when intermittent dosing failed but required TDM to avoid overexposure. Conclusion Routine TDM is essential to optimize the safely and effectively manage linezolid therapy in ICU patients. This case underscores the importance of integrating TDM with PK modeling to guide personalized dosing strategies in complex and dynamic clinical scenarios.