Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis

  • Waroonrat Sukarnjanaset
  • Sutep JaruratanasirikulEmail author
  • Thitima Wattanavijitkul
Original Paper


This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0–0.5, 0.5–2, 2–4 and 4–6 or 8 h after administration. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. The two compartment model best described the data. Piperacillin clearance (CL) was 5.37 L/h, central volume of distribution (V1) was 9.35 L, and peripheral volume of distribution was 7.77 L. Creatinine clearance (CLCr) and mean arterial pressure had a significant effect on CL while adjusted body weight had a significant impact on V1. Subtherapeutic concentrations can occur during the early phase of sepsis in critically ill patients with normal renal function. The usual dosage regimen, 4 g of piperacillin infused over 0.5 h every 6 h, could not achieve the target for susceptible organisms with MIC 16 mg/L in patients with CLCr ≥ 60 mL/min. Our proposed regimen for the patients with CLCr 60-120 mL/min was an extended 2 h infusion of 4 g of piperacillin every 6 h. Most regimens provided CFR ≥ 90% for the E. coli infection while there was no dosage regimen achieved a CFR of 90% for the P. aeruginosa infection.


Population pharmacokinetics Pharmacodynamics Piperacillin Critically ill patients Sepsis β-Lactams 



This work was supported by a faculty grant from the Faculty of Medicine, Prince of Songkla University and Chulalongkorn University graduate school thesis grant.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the Institutional Review Board (IRB) of the Faculty of Medicine, Prince of Songkla University (EC; 56-501-14-1). The authorized researchers were granted the right to extract the data from the database.

Informed consent

Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Supplementary material

10928_2019_9633_MOESM1_ESM.doc (104 kb)
Supplementary material 1 (DOC 104 kb)
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Supplementary material 2 (DOC 102 kb)
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Supplementary material 3 (DOC 102 kb)
10928_2019_9633_MOESM4_ESM.doc (184 kb)
Supplementary material 4 (DOC 183 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy Practice, Faculty of Pharmaceutical SciencesChulalongkorn UniversityBangkokThailand
  2. 2.Department of Medicine, Faculty of MedicinePrince of Songkla UniversityHat YaiThailand

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