Population Pharmacokinetics of Piperacillin/Tazobactam across the Adult Lifespan

BACKGROUND: Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. INTRODUCTION: Using an opportunistic study design we evaluated the pharmacokinetics (PK) of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults. METHODS: A total of 121 adult patients were included. The population PK models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination. RESULTS: Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the PK of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥65 years of age. CONCLUSION: The simulations suggested that adults ≤50 years of age infected with organisms with higher minimum inhibitory concentrations (MICs) may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT>MIC, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher MICs.