Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients

Ann Pharmacother. 2009 Nov;43(11):1747-54. doi: 10.1345/aph.1M304. Epub 2009 Oct 6.

Abstract

Background: Prolonging the infusion of a beta-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 microg/mL to 64 microg/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 microg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (> or = 3.375 g every 8 h), but no regimen achieved a PTA greater than 90% at an MIC of 64 microg/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 microg/mL.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Drug Administration Schedule
  • Gram-Negative Bacterial Infections / drug therapy
  • Gram-Negative Bacterial Infections / metabolism
  • Gram-Negative Bacterial Infections / microbiology
  • Hospitalization*
  • Humans
  • Infusions, Intravenous
  • Microbial Sensitivity Tests / methods
  • Middle Aged
  • Monte Carlo Method*
  • Penicillanic Acid / administration & dosage
  • Penicillanic Acid / analogs & derivatives*
  • Penicillanic Acid / pharmacokinetics
  • Piperacillin / administration & dosage*
  • Piperacillin / pharmacokinetics*
  • Tazobactam

Substances

  • Penicillanic Acid
  • Tazobactam
  • Piperacillin