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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
  • 51 Downloads

Abstract

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.

Keywords

Population pharmacokinetics Pharmacodynamics Piperacillin Critically ill patients Sepsis β-Lactams 

Notes

Acknowledgements

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)
10928_2019_9633_MOESM2_ESM.doc (102 kb)
Supplementary material 2 (DOC 102 kb)
10928_2019_9633_MOESM3_ESM.doc (102 kb)
Supplementary material 3 (DOC 102 kb)
10928_2019_9633_MOESM4_ESM.doc (184 kb)
Supplementary material 4 (DOC 183 kb)

References

  1. 1.
    Allison MG, Heil EL, Hayes BD (2017) Appropriate antibiotic therapy. Emerg Med Clin North Am 35:25–42CrossRefGoogle Scholar
  2. 2.
    Tjandramaga TB, Mullie A, Verbesselt R, Schepper PJD, Verbist L (1978) Piperacillin: human pharmacokinetics after intravenous and intramuscular administration. Antimicrob Agents Chemother 14:829–837CrossRefGoogle Scholar
  3. 3.
    Schepper PJD, Tjandramaga TB, Mullie A, Verbesselt R, Hecken AV, Verberckmoes R, Verbist L (1982) Comparative pharmacokinetics of piperacillin in normals and in patients with renal failure. J Antimicrob Chemother 9:49–57CrossRefGoogle Scholar
  4. 4.
    Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA (1988) Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 158:831–847CrossRefGoogle Scholar
  5. 5.
    Drusano GL (2004) Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2:289–300CrossRefGoogle Scholar
  6. 6.
    Zelenitsky S, Nash J, Weber Z, Iacovides H, Ariano R (2016) Targeted benefits of prolonged-infusion piperacillin-tazobactam in an in vitro infection model of Pseudomonas aeruginosa. J Chemother 28:390–394CrossRefGoogle Scholar
  7. 7.
    Pea F, Viale P (2009) Bench-to-bedside review: appropriate antibiotic therapy in severe sepsis and septic shock - does the dose matter? Crit Care 13:214–226CrossRefGoogle Scholar
  8. 8.
    Zelenitsky SA, Ariano RE, Zhanel GG (2011) Pharmacodynamics of empirical antibiotic monotherapies for an intensive care unit (ICU) population based on Canadian surveillance data. J Antimicrob Chemother 66:343–349CrossRefGoogle Scholar
  9. 9.
    Kong L, Tang Y, Zhang X, Lu G, Yu M, Shi Q, Wu X (2017) Pharmacokinetic/pharmacodynamic analysis of meropenem for the treatment of nosocomial pneumonia in intracerebral hemorrhage patients by monte carlo simulation. Ann Pharmacother 51:970–975CrossRefGoogle Scholar
  10. 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
  11. 11.
    Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K (2016) Assessment of global incidence and mortality of hospital-treated sepsis. current estimates and limitations. Am J Respir Crit Care Med 193:259–272CrossRefGoogle Scholar
  12. 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
  13. 13.
    Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Tery KM, Levy MM (2017) Time to treatment and mortality during mandated emergency care for sepsis. New Engl J Med 376:2235–2244CrossRefGoogle Scholar
  14. 14.
    Joukhadar C, Frossard M, Mayer BX, Brunner M, Klein N, Siostrzonek P, Eichier HG, Muller M (2001) Impaired target site penetration of b-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 29:385–391CrossRefGoogle Scholar
  15. 15.
    Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J (2009) Piperacillin penetration into tissue of critically ill patients with sepsis-bolus versus continuous administration? Crit Care Med 37:926–933CrossRefGoogle Scholar
  16. 16.
    Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, Backer D, Layeux B, Wallemacq P, Vincent JL, Jacobs F (2010) Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 14:R126–R134CrossRefGoogle Scholar
  17. 17.
    Roberts JA, Kirkpatrick CMJ, Roberts MS, Dalley AJ, Lipman J (2010) First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents 35:156–163CrossRefGoogle Scholar
  18. 18.
    Sturm AW, Allen N, Rafferty KD, Fish DN, Toschlog E, Newell M, Waibel B (2014) Pharmacokinetic analysis of piperacillin administered with tazobactam in critically ill, morbidly obese surgical patients. Pharmacotherapy 34:28–35CrossRefGoogle Scholar
  19. 19.
    Udy AA, Lipman J, Jarrett P, Klein K, Wallis SC, Patel K, Kirkpatrick CMJ, Kruger PS, Paterson DL, Roberts MS, Roberts JA (2015) Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance? Crit Care 19:28CrossRefGoogle Scholar
  20. 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. 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
  22. 22.
    Hobbs AL, Shea KM, Roberts KM, Daley MJ (2015) Implications of augmented renal clearance on drug dosing in critically ill patients: a focus on antibiotics. Pharmacotherapy 35:1063–1075CrossRefGoogle Scholar
  23. 23.
    Andersen MG, Thorsted A, Storgaard M, Kristoffersson AN, Friberg LE, Obink-Hansen K (2018) Population pharmacokinetics of piperacillin in sepsis patients: should alternative dosing strategies be considered? Antimicrob Agents Chemother 62:e02306–e02317CrossRefGoogle Scholar
  24. 24.
    Di Giovamberardino G, Ferrannini M, Testore GP, Federici G, Pastore A (2009) High performance liquid chromatographic determination of plasma free and total tazobactam and piperacillin. J Chromatogr B 877:86–88CrossRefGoogle Scholar
  25. 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
  26. 26.
    Wurtz R, Itokazu G, Rodvold K (1997) Antimicrobial dosing in obese patients. Clin Infect Dis 25:112–118CrossRefGoogle Scholar
  27. 27.
    Jelliffe R (2002) Estimation of creatinine clearance in patients with unstable renal function, without a urine specimen. Am J Nephrol 22:320–324CrossRefGoogle Scholar
  28. 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
  29. 29.
    Zheng L, Sun Z, Li J, Zhang R, Zhang X, Liu S, Li J, Xu C, Hu D, Sun Y (2008) Pulse pressure and mean arterial pressure in relation to ischemic stroke among patients with uncontrolled hypertension in rural areas of China. Stroke 39:1932–1937CrossRefGoogle Scholar
  30. 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
  31. 31.
    Chen R, Qian Q, Sun MR, QianCY Zou SI, Wang ML, Wang LY (2016) Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with nosocomial infections. Eur J Drug Metab Pharmacokinet 41:363–372CrossRefGoogle Scholar
  32. 32.
    Chung EK, Cheatham SC, Fleming MR, Healy DP, Shea KM, Kays MB (2015) Population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients. J Clin Pharmacol 55:899–908CrossRefGoogle Scholar
  33. 33.
    Li C, Kuti JL, Nightingale CH, Mansfield DL, Dana A, Nicolau DP (2005) Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection. J Antimicrob Chemother 56:388–395CrossRefGoogle Scholar
  34. 34.
    Alobaid AS, Hites M, Lipman J, Taccone FS, Roberts JA (2016) Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: a structured review. Int J Antimicrob Agents 47:259–268CrossRefGoogle Scholar
  35. 35.
    Abdul-Aziz MH, Dulhunty JM, Bellomo R, Lipman J, Roberts JA (2012) Continuous beta-lactam infusion in critically ill patients: the clinical evidence. Ann Intensive Care 2:37CrossRefGoogle Scholar
  36. 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. 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
  38. 38.
    Bochud PY, Glauser MP, Carlet J, Calandra T (2002) Empirical antibiotic therapy for patients with severe sepsis and septic shock. In: Vincent JL, Carlet J, Opal SM (eds) The sepsis text. Kluwer Academic Publishers, Boston, pp 539–558CrossRefGoogle Scholar

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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