Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis
- 51 Downloads
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.
KeywordsPopulation 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.
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.
Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
- 10.Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:801–810CrossRefGoogle Scholar
- 12.Vincent JL, Marshall JC, Ñamendys Silva SA, Franois B, Martin-Loeches I, Lipman J, Reinhart K, Antonelli M, Pickkers P, Nijmi H, Jimenez E, Sakr Y (2014) Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir Med 2:380–386CrossRefGoogle Scholar
- 20.Obrink-Hansen K, Juul RV, Storgaard M, Thomsen MK, Hardlei TF, Brock B, Kreilgaard M, Gjedsted (2015) Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations? Antimicrob Agents Chemother 59:7018–7026CrossRefGoogle Scholar
- 21.Tsai D, Stewart P, Goud R, Gourley S, Hewagama S, Krishnaswamy S, Wallis SC, Lipman J, Roberts JA (2016) Pharmacokinetics of piperacillin in critically ill australian indigenous patients with severe sepsis. Antimicrob Agents Chemother 60:7402–7406Google Scholar
- 25.Sukarnjanaset W, Wattanavijitkul T, Jarurattanasirikul S (2018) Evaluation of FOCEI and SAEM estimation methods in population pharmacokinetic analysis using NONMEM® across rich, medium, and sparse sampling data. Eur J Drug Metab Pharmacokinet 1:1–10. https://doi.org/10.1007/s13318-018-0484-8 Google Scholar
- 28.European Committee on Antimicrobial Susceptibility Testing (2018) Antimicrobial wild type distributions of microorganisms, version 5.26. https://mic.eucast.org/Eucast2/. Accessed 1 Aug 2018
- 30.Kim YK, Jung JA, Choi HK, Bae IG, Choi WS, Hur J, Jin SJ, Kim SW, Kwon KT, Lee SR, Shin JG, Kiem S, pharmacokinetics-pharmacodynamics of antibiotics working group under korean society for chemotherapy (2016) Population pharmacokinetic analysis of piperacillin/tazobactam in korean patients with acute infections. Inf Chemother 48:209–215CrossRefGoogle Scholar
- 36.Alobaid AS, Wallis SC, Jarrett P, Starr T, Stuart J, Lassig-Smith M, Mejia JLO, Roberts MS, Roger C, Udy AA, Lipman J, Roberts JA (2017) Population pharmacokinetics of piperacillin in nonobese, obese, and morbidly obese critically ill patients. Antimicrob Agents Chemother 61:1–12CrossRefGoogle Scholar
- 37.Vojtová V, Kolár M, Hricová K, Uvizl R, Neiser J, Blahut L, Urbanek K (2011) Antibiotic utilization and Pseudomonas aeruginosa resistance in intensive care units. New Microbiol 34:291–298Google Scholar