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 (AUC₂₄/MIC ≥ 80) and toxicity threshold (C_ss,min ≥ 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_NR) 4.9 L/h, renal (CL_R) 0.261 L/h, urine (CL_U) 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.