Population pharmacokinetics and optimized dosing of piperacillin-tazobactam in hematological patients with febrile neutropenia

Hematological patients with febrile neutropenia receiving piperacillin-tazobactam may experience pharmacokinetic alterations that compromise drug exposure. We aimed to characterize the population pharmacokinetics of piperacillin in plasma and provide optimized dosing recommendations for this patient population. A population pharmacokinetic analysis was conducted in patients who received piperacillin-tazobactam as part of the BEATLE study, which compared the efficacy, safety, and pharmacokinetic/pharmacodynamic target attainment of β-lactams administered in extended infusion versus short 30 min infusion in adult hematological patients with febrile neutropenia. Monte Carlo simulations were performed to evaluate, for each dosing regimen, the probability of attaining (i) an efficacy target of unbound piperacillin concentrations above the minimum inhibitory concentration (MIC) of the bacteria for the entire dosing interval (100% ƒ<i>T</i>_>MIC), and (ii) a toxicity threshold of ≥160 mg/L. A total of 44 patients and 221 plasma concentrations were included. A one-compartment model best described piperacillin plasma pharmacokinetics, with Cockcroft-Gault creatinine clearance (CrCL) significantly influencing drug clearance. Dosing simulations showed that extended and continuous infusions were superior to short 30 min infusions in the attainment of 100% ƒ<i>T</i>_>MIC, even for bacteria with low to intermediate MIC (≤2-4 mg/L). In patients with higher CrCL (>90 mL/min) or infections caused by less susceptible Gram-negative bacilli (MIC: 8-16 mg/L), only continuous infusions of 12-16 g/day were likely to achieve 100% ƒ<i>T</i>_>MIC. These findings support the use of extended or continuous infusions of piperacillin in the initial management of patients with febrile neutropenia, particularly in patients with higher CrCL or when infections caused by less susceptible pathogens, such as <i>Pseudomonas aeruginosa</i>, are suspected.