Pharmacokinetics of an extended 4-hour infusion of piperacillin-tazobactam in critically ill patients undergoing continuous renal replacement therapy.

ABSTRACT

STUDY OBJECTIVE: To evaluate the pharmacokinetic and pharmacodynamic profiles of piperacillin-tazobactam administered as a 4-hour infusion in critically ill patients undergoing continuous renal replacement therapy (CRRT). DESIGN: Prospective, observational, pharmacokinetic study. SETTING: Intensive care unit of a tertiary care hospital in Montréal, Canada. PATIENTS Twenty critically ill adults who were undergoing continuous venovenous hemodiafiltration and receiving a 4-hour infusion of piperacillin 4 g-tazobactam 0.5 g every 8 hours for a documented or suspected infection. INTERVENTION Blood samples were collected every hour over an 8-hour dosing interval. Prefilter and postfilter blood samples, and effluent and urine samples were also collected. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of patients who achieved an unbound piperacillin plasma concentration above a target minimum inhibitory concentration (MIC) of 64 mg/L (MIC that inhibits 90% of isolates for Pseudomonas aeruginosa) for at least 50% of the dosing interval; 18 (90%) of the 20 patients achieved this outcome. In all patients, the free piperacillin concentrations were above the Pseudomonas aeruginosa breakpoint of 16 mg/L for the entire time interval. Regarding piperacillin pharmacokinetic parameters, the median (interquartile range) minimum unbound plasma concentration was 65.15 mg/L (51.30-89.30), maximum unbound plasma concentration was 141.3 mg/L (116.75-173.90), sieving coefficient was 0.809 (0.738-0.938), total clearance was 65.82 ml/minute (53.79-102.87), and renal clearance was 0.16 ml/minute (0.05-3.04). The median CRRT dose was 32.0 ml/kg/h (25.0-39.8). CONCLUSIONS: Administration of a 4-hour infusion of piperacillin-tazobactam was associated with a favorable pharmacodynamic profile in patients undergoing CRRT. Concentrations associated with maximal activity were attained in our patients.