European Journal of Clinical Pharmacology

, Volume 75, Issue 9, pp 1219–1226 | Cite as

Vancomycin population pharmacokinetics for adult patients with sepsis or septic shock: are current dosing regimens sufficient?

  • A. J. Heffernan
  • A. Germano
  • F. B. Sime
  • Jason A. RobertsEmail author
  • E. Kimura
Pharmacokinetics and Disposition



Vancomycin is commonly used for the management of severe infections; however, vancomycin dosing may be challenging in critically ill patients. This observational study aims to describe the population pharmacokinetics of vancomycin in adult patients with sepsis or septic shock.


A single-centre retrospective review of adult patients with sepsis or septic shock receiving vancomycin with therapeutic drug monitoring was undertaken. Blood samples taken 1 h after the vancomycin infusion cessation and 30 min prior to the next dose were assayed using the Vitros Crea Slide method. Vancomycin concentrations determined on different days were included. A pharmacokinetic model was developed using Pmetrics for R. Monte Carlo dosing simulations were performed using the final model.


Vancomycin concentrations were available for 27 adult patients admitted to the intensive care unit with sepsis or septic shock. A one-compartment pharmacokinetic model with inter-occasion variability of clearance and volume of distribution before and after 72 h adequately described the data. Creatinine clearance normalized to body surface area was included as a covariate on vancomycin clearance. The clearance and volume of distribution within 72 h of admission were 7.29 L/h and 54.20 L, respectively. Monte Carlo simulations suggested that for patients with a creatinine clearance of ≥ 80 mL/min/1.73 m2, vancomycin doses of ≥ 2 g every 8 h are required to consistently achieve key therapeutic targets.


Vancomycin doses ≥ 2 g every 8 h in adult patients with sepsis or septic shock with a creatinine clearance ≥ 80 mL/min/1.73 m2 are likely needed to achieve an optimal therapeutic exposure.


Vancomycin Pharmacokinetics Therapeutic drug monitoring Sepsis Septic shock 



A.J.H. would like to acknowledge funding from a Griffith School of Medicine Research Higher degree scholarship. F.B.S. acknowledges funding from the University of Queensland Post-doctoral Fellowship. J.A.R. would like to recognize funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065).

Authors’ individual contributions

A.J.H.—conceptualisation, data analysis, writing—original draft.

A.G.—conceptualisation, data curation, project administration, writing—review and editing.

F.B.S.—data analysis, writing—review and editing.

J.A.R.—conceptualisation, data analysis, writing—review and editing.

E.K.—conceptualisation, data curation, funding acquisition, project administration, writing—review and editing.

Funding information

E.K. and A.G. would like to acknowledge funding from the Science and Technology Secretariat of Paraná State, Brazil for this project.

Compliance with ethical standards

Conflict of interest

No authors report any relevant conflicts of interest to declare.


Waiver of informed consent was granted by the local ethics committee (CAAE 62009816.9.0000.0104).

Supplementary material

228_2019_2694_MOESM1_ESM.docx (27 kb)
ESM 1 (DOCX 26 kb)


  1. 1.
    Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, le Gall JR, Payen D, Sepsis Occurrence in Acutely Ill Patients Investigators (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34:344–353CrossRefGoogle Scholar
  2. 2.
    Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:1589–1596CrossRefGoogle Scholar
  3. 3.
    Zelenitsky S, Rubinstein E, Ariano R, Iacovides H, Dodek P, Mirzanejad Y, Kumar A, Cooperative Antimicrobial Therapy of Septic Shock-CATSS Database Research Group (2013) Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock. Int J Antimicrob Agents 41:255–260CrossRefGoogle Scholar
  4. 4.
    Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, Dalovisio JR, Levine DP (2009) Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 66:82–98CrossRefGoogle Scholar
  5. 5.
    Mohammedi I, Descloux E, Argaud L, Le Scanff J, Robert D (2006) Loading dose of vancomycin in critically ill patients: 15 mg/kg is a better choice than 500 mg. Int J Antimicrob Agents 27:259–262CrossRefGoogle Scholar
  6. 6.
    Sunder S, Jayaraman R, Mahapatra HS, Sathi S, Ramanan V, Kanchi P, Gupta A, Daksh S, Ram P (2014) Estimation of renal function in the intensive care unit: the covert concepts brought to light. J Intensive Care 2:31. CrossRefGoogle Scholar
  7. 7.
    Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW (2012) Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit 34:467–476CrossRefGoogle Scholar
  8. 8.
    Mentre F, Escolano S (2006) Prediction discrepancies for the evaluation of nonlinear mixed-effects models. J Pharmacokinet Pharmacodyn 33:345–367CrossRefGoogle Scholar
  9. 9.
    Moreno RP, Metnitz PGH, Almeida E, Jordan B, Bauer P, Campos RA, Iapichino G, Edbrooke D, Capuzzo M, le Gall JR, on behalf of the SAPS 3 Investigators (2005) SAPS 3—from evaluation of the patient to evaluation of the intensive care unit. Part 2: development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med 31:1345–1355CrossRefGoogle Scholar
  10. 10.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefGoogle Scholar
  11. 11.
    Jelliffe R, Jelliffe S (1972) A computer program for estimation of creatinine clearance from unstable serum creatinine levels, age, sex, and weight. Math Biosci 14:17–24CrossRefGoogle Scholar
  12. 12.
    Reardon J, Lau TT, Ensom MH (2015) Vancomycin loading doses: a systematic review. Ann Pharmacother 49:557–565CrossRefGoogle Scholar
  13. 13.
    Burdet C, Pajot O, Couffignal C, Armand-Lefevre L, Foucrier A, Laouenan C et al (2015) Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia. Eur J Clin Pharmacol 71:75–83CrossRefGoogle Scholar
  14. 14.
    Chavada R, Ghosh N, Sandaradura I, Maley M, Van Hal SJ (2017) Establishment of an AUC0-24 threshold for nephrotoxicity is a step towards individualized vancomycin dosing for methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 61.
  15. 15.
    Roberts JA, Taccone FS, Udy AA, Vincent JL, Jacobs F, Lipman J (2011) Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother 55:2704–2709CrossRefGoogle Scholar
  16. 16.
    Thomson AH, Staatz CE, Tobin CM, Gall M, Lovering AM (2009) Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations. J Antimicrob Chemother 63:1050–1057CrossRefGoogle Scholar
  17. 17.
    Llopis-Salvia P, Jimenez-Torres NV (2006) Population pharmacokinetic parameters of vancomycin in critically ill patients. J Clin Pharm Ther 31:447–454CrossRefGoogle Scholar
  18. 18.
    Mangin O, Urien S, Mainardi JL, Fagon JY, Faisy C (2014) Vancomycin pharmacokinetic and Pharmacodynamic models for critically ill patients with post-sternotomy mediastinitis. Clin Pharmacokinet 53:849–861CrossRefGoogle Scholar
  19. 19.
    Yamamoto M, Kuzuya T, Baba H, Yamada K, Nabeshima T (2009) Population pharmacokinetic analysis of vancomycin in patients with gram-positive infections and the influence of infectious disease type. J Clin Pharm Ther 34:473–483CrossRefGoogle Scholar
  20. 20.
    Tsai D, Stewart PC, Hewagama S, Krishnaswamy S, Wallis SC, Lipman J, Roberts JA (2018) Optimised dosing of vancomycin in critically ill indigenous Australian patients with severe sepsis. Anaesth Intensive Care 46:374–380CrossRefGoogle Scholar
  21. 21.
    Staatz CE, Byrne C, Thomson AH (2006) Population pharmacokinetic modelling of gentamicin and vancomycin in patients with unstable renal function following cardiothoracic surgery. Br J Clin Pharmacol 61:164–176CrossRefGoogle Scholar
  22. 22.
    Revilla N, Martin-Suarez A, Perez MP, Gonzalez FM, de Gatta MDF (2010) Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulation. Br J Clin Pharmacol 70:201–212CrossRefGoogle Scholar
  23. 23.
    Adane ED, Herald M, Koura F (2015) Pharmacokinetics of vancomycin in extremely obese patients with suspected or confirmed Staphylococcus aureus infections. Pharmacotherapy 35:127–139CrossRefGoogle Scholar
  24. 24.
    Lodise TP, Lomaestro B, Graves J, Drusano GL (2008) Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 52:1330–1336CrossRefGoogle Scholar
  25. 25.
    van Hal SJ, Paterson DL, Lodise TP (2013) Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother 57:734–744CrossRefGoogle Scholar
  26. 26.
    Tam VH, Kabbara S, Yeh RF, Leary RH (2006) Impact of sample size on the performance of multiple-model pharmacokinetic simulations. Antimicrob Agents Chemother 50:3950–3952CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Centre for Translational Anti-Infective Pharmacodynamics, School of PharmacyThe University of QueenslandBrisbaneAustralia
  2. 2.School of MedicineGriffith UniversityGold CoastAustralia
  3. 3.Department of Intensive Care MedicineUniversidade Estadual de Maringá HospitalMaringáBrazil
  4. 4.University of Queensland Centre for Clinical Research, Faculty of MedicineThe University of QueenslandHerstonAustralia
  5. 5.Pharmacy Department and Department of Intensive Care MedicineRoyal Brisbane and Women’s HospitalBrisbaneAustralia

Personalised recommendations