Optimizing Linezolid Dosing for Nosocomial Urinary Tract Infections in Critically Ill Patients with Renal Impairment.

Background: This study characterized the urinary pharmacokinetics and pharmacodynamics (PK/PD) of linezolid (LNZ) in critically ill patients with renal impairment and nosocomial multidrug-resistant Gram-positive urinary tract infections (UTIs). The aim was to address therapeutic challenges arising from limited treatment options and uncertain urinary excretion, to establish optimized dosing strategies.

Methods: A prospective observational study was conducted in ICU patients with renal impairment. LNZ plasma and urine concentration and urine volume were analyzed to develop semi-mechanistic population PK model. Simulations evaluated dosing regimens based on PK/PD target (AUC/MIC ≥ 80) and toxicity threshold (C ≥ 8 mg/L).

Results: A plasma/bladder urine joint model described PK in 20 critically ill patients (median age 85, APACHE-II 20) using 398 plasma/urine samples. Estimated clearances: non-renal (CL) 4.9 L/h, renal (CL) 0.261 L/h, urine (CL) 0.062 L/h. Renal excretion accounted for 5% of the dose at eGFR 30 mL/min/1.73m². Urinary LNZ exposure increased with eGFR; age significantly increased plasma exposure. Simulations indicated 600 mg Q12h achieved sufficient urinary exposure for eGFR 15-60 mL/min/1.73m², but not for eGFR <15 mL/min/1.73m². Lower eGFR correlated with higher plasma toxicity risk.

Conclusions: Renal function was positively associated with LNZ urinary exposure. The standard LNZ 600 mg Q12h was appropriate for treating UTIs in renal impairment patients, except for those with eGFR < 15 mL/min/1.73 m². The use of extended infusion may help mitigate the risk of toxicity while maintaining urinary exposure.