Comparative Pharmacodynamics of Intermittent and Prolonged Infusions of Piperacillin/Tazobactam Using Monte Carlo Simulations and Steady-State Pharmacokinetic Data from Hospitalized Patients

Abstract

Background: Prolonging the infusion of a β-lactam antibiotic enhances the time in which unbound drug concentrations remain above the minimum inhibitory concentration (fT>MIC). Objective: To compare the pharmacodynamics of several dosing regimens of piperacillin/tazobactam administered by intermittent and prolonged infusion using pharmacokinetic data from hospitalized patients. Methods: Steady-state pharmacokinetic data were obtained from 13 patients who received piperacillin/tazobactam 4.5 g every 8 hours, infused over 4 hours. Monte Carlo simulations (10,000 pts.) were performed to calculate pharmacodynamic exposures at 50% fT>MIC for 4 intermittent-infusion regimens (3.375 g every 4 and 6 h, 4.5 g every 6 and 8 h) and 4 prolonged-infusion regimens (2.25 g, 3.375 g. 4.5 g, and 6.75 g every 8 h [4-h infusion]) of piperacillin/tazobactam using pharmacokinetic data for piperacillin. Cumulative fraction of response (CFR) was calculated using MIC data for 6 gram-negative pathogens (Meropenem Yearly Susceptibility Test Information Collection, 2004-2007), and probability of target attainment (PTA) was calculated at MICs ranging from 1 μg/mL to 64 μ/g/mL Results: The CFR for 3.375 g every 4 hours (intermittent infusion) and 3.375–4.5 g every 8 hours (prolonged infusion) greater than or equal to 90.3% for Escherichia coli, Serratia marcescens, and Citrobacter spp. Increasing the prolonged-infusion dose to 6.75 g improved the CFR to greater than 90% for Enterobacter spp. For every regimen evaluated, the CFR was less than 90% for Klebsiella pneumoniae and Pseudomonas aeruginosa. At an MIC of 16 μg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (≥3.375 g every 8 h). but no regimen achieved a PTA greater than 90% at an MIC of 64 μ/g/mL. Conclusions: At doses greater than or equal to 3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses compared with standard regimens at MICs less than or equal to 16 μg/mL