A multicentre evaluation of pharmacokinetic/pharmacodynamic target attainment of piperacillin and tazobactam and the association with clinical outcomes in critically ill patients with sepsis and septic shock

OBJECTIVES: To characterize the population pharmacokinetics and pharmacokinetic/pharmacodynamic target attainment of piperacillin and tazobactam in critically ill patients with sepsis or septic shock in Malaysian intensive care units and to use the population pharmacokinetic model to estimate individual target attainment and explore associations with clinical outcomes. METHODS: Serial blood samples were collected on days 1 and 3 of therapy in this prospective multicentre study. Total plasma piperacillin and tazobactam concentrations were quantified using a validated chromatographic assay. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Monolix. Therapeutic exposure was defined as achieving 100% fT>16 mg/L for piperacillin and 85% fT>2 mg/L for tazobactam while remaining below the piperacillin toxicity threshold (<160 mg/L). RESULTS: Forty-five critically ill adults with sepsis or septic shock were recruited (median age, 61 years [range: 18-88]; median creatinine clearance (CLcr) 70 mL/min [range: 30-161]; 20 females). A one-compartment model with first-order elimination best described the pharmacokinetics for both drugs. Estimated CLcr significantly influenced drug clearance. Pre-defined therapeutic exposures were achieved in 54% and 44% on days 1 and 3, respectively. Patients attaining exposures were older and had lower CLcr. Clinical cure and ICU survival were numerically different across exposure groups, although these exploratory comparisons were not statistically significant. Simulations indicated that a 4.5 g loading dose followed by 4.5 g every 6 h as a continuous infusion achieved effective and safe exposures in patients with CLcr 50 to 130 mL/min. CONCLUSION: Continuous infusion is the most reliable strategy for achieving early piperacillin/tazobactam therapeutic exposures in patients with sepsis or septic shock.