To assess early piperacillin exposure in critically ill patients receiving continuous infusion piperacillin-tazobactam, identify clinical determinants of underexposure and overexposure, and evaluate piperacillin concentrations across organ dysfunction phenotypes.

Retrospective, single-center observational study.

A 20-bed medical-surgical intensive care unit of a university hospital.

All consecutive adult critically ill patients receiving continuous-infusion piperacillin–tazobactam with at least one total plasma piperacillin concentration measurement.

None.

Observed plasma piperacillin concentrations were measured at predefined time points (day 1, day 3 and day 7). Target attainment was defined as total plasma concentrations of 80–160 mg/L, corresponding to 4–8 times the minimum inhibitory concentration of Pseudomonas aeruginosa .

A total of 350 patients were included, contributing 775 piperacillin measurements. At first sampling (day 1), 30% of patients were underexposed, 35% achieved the target range, and 35% were overexposed. In multivariable analyses, underexposure was less frequent in older patients and in those with renal dysfunction or shock, while male sex was independently associated with a higher risk of underexposure. Overexposure was strongly associated with renal dysfunction, higher bilirubin concentrations, and higher daily piperacillin dose. Piperacillin concentrations were highest in patients with combined hepato-renal dysfunction.

Only one-third of critically ill patients achieved target piperacillin exposure at initial therapeutic drug monitoring during continuous infusion. Early deviations from target concentrations were frequent and primarily determined by renal dysfunction despite routine dose adjustment. These findings support early individualized dosing strategies integrating organ function assessment and therapeutic drug monitoring to optimize piperacillin exposure.