Linezolid dosing in critically ill patients undergoing various modalities of renal replacement therapy: a pooled population pharmacokinetic analysis

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Altered pharmacokinetics (PK) of linezolid is pronounced in critically ill patients undergoing different modalities of renal replacement therapy (RRT). This study aimed to provide a pooled population PK analysis of linezolid in RRT patients and to evaluate the pharmacodynamic (PD) target attainment of linezolid standard dosing (600 mg q12h). A total of 414 pooled linezolid concentration observations from 69 patients undergoing intermittent hemodialysis (IHD), sustained low-efficiency dialysis (SLED), or continuous renal replacement therapy were used to develop the population PK model. Probability of target attainment (PTA) for the efficacy markers of 85% T>MIC and AUC/MIC>100 was evaluated, and the risk of toxicity was estimated based on the trough concentration threshold of 10 mg/L. Linezolid concentration data were adequately described by a two compartmental model. Renal function and body weight were identified as significant modifiers for endogenous clearance of linezolid. Simulations demonstrated that the PTA of 85% T>MIC and AUC/MIC>100 targets was all unacceptably low (0-58.6%, MIC ≥ 1 mg/L) in RRT patients with preserved renal function, while desirable 85% T>MIC attainment (≥ 90%, MIC ≤ 2 mg/L) was achieved in anuric RRT patients. The predicted risk of toxicity is negligible (<1.0%) in the patients with preserved renal function (regardless of the RRT modalities), while the probability of reaching the trough level of 10 mg/L was high (17.9-20.9%) for anuric patient population undergoing IHD or SLED. In conclusion, standard linezolid dosing is adequate for anuric RRT patients with an MIC ≤ 2 mg/L.