Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered by continuous infusion and intermittent dosing

David S. Burgess, Travis Waldrep

    Research output: Contribution to journalArticle

    49 Scopus citations

    Abstract

    Background: Although intermittent bolus dosing is currently the standard of practice for many antimicrobial agents, beta-lactams exhibit time-dependent bacterial killing. Maximizing the time above the minimum inhibitory concentration (MIC) for a pathogen is the best pharmacodynamic predictor of efficacy. Use of a continuous infusion has been advocated for maximizing the time above the MIC compared with intermittent bolus dosing. Objective: This study compared the pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered as an intermittent bolus versus a continuous infusion against clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae. Methods: Healthy volunteers were randomly assigned to receive piperacillin 3 g/tazobactam 0.375 g q6h for 24 hours, piperacillin 6 g/tazobactam 0.75 g continuous infusion over 24 hours, and piperacillin 12 g/tazobactam 1.5 g continuous infusion over 24 hours. Five clinical isolates each of P aeruginosa and Kpneumoniae were used for pharmacodynamic analyses. Results: Eleven healthy subjects (7 men, 4 women; mean ± SD age, 28 ± 4.7 years) were enrolled. Mean steady-state serum concentrations of piperacillin were 16.0 ± 5.0 and 37.2 ± 6.8 μg/mL with piperacillin 6 and 12 g, respectively. Piperacillin/tazobactam 13.5 g continuous infusion (piperacillin 12 g/tazobactam 1.5 g) was significantly more likely to produce a serum inhibitory titer ≥1:2 against P aeruginosa at 24 hours than either the 6.75 g continuous infusion (piperacillin 6 g/tazobactam 0.75 g) or 3.375 g q6h (piperacillin 3 g/tazobactam 0.375 g). There were no statistical differences against K pneumoniae between regimens. The median area under the inhibitory activity-time curve (AUIC) for the 13.5 g continuous infusion was higher than that for 3.375 g q6h and the 6.75 g continuous infusion against both P aeruginosa and K pneumoniae (P ≤ 0.007, 13.5 g continuous infusion and 3.375 g q6h vs 6.75 g continuous infusion against K pneumoniae). The percentage of subjects with an AUIC ≥125 was higher with both 3.375 g q6h and the 13.5 g continuous infusion than with the 6.75 g continuous infusion against P aeruginosa and K pneumoniae (both, P < 0.001 vs 6.75 g continuous infusion against K pneumoniae). Conclusions: Piperacillin 12 g/tazobactam 1.5 g continuous infusion consistently resulted in serum concentrations above the breakpoint for Enterobacteriaceae and many of the susceptible strains of P aeruginosa in this study in 11 healthy subjects. Randomized controlled clinical trials are warranted to determine the appropriate dose of piperacillin/tazobactam.

    Original languageEnglish (US)
    Pages (from-to)1090-1104
    Number of pages15
    JournalClinical Therapeutics
    Volume24
    Issue number7
    DOIs
    StatePublished - Jan 1 2002

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    Keywords

    • Continuous infusion
    • Pharmacodynamics
    • Pharmacokinetics
    • Piperacillin/tazobactam

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmacology (medical)

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