Skip to main content
SpringerLink
Log in

An Update on Population Pharmacokinetic Analyses of Vancomycin, Part I: In Adults

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Despite the wide clinical use of vancomycin, controversy remains regarding its optimal dosage regimens. This can be attributed to the large between- and within-subject variability in the pharmacokinetics of vancomycin. This review aimed at providing a synthesis of population pharmacokinetic models of vancomycin in adults, determining the most reported pharmacokinetic models, and identifying various sources of variability in different special subpopulations to better inform vancomycin dosing. We searched PubMed and EMBASE for population pharmacokinetic studies of vancomycin published from January 2011 to May 2019. Inspection of the relevant lists of references was conducted, as well. This search resulted in a total of 30 eligible studies, which were included. One-, two-, and three-compartments models were reported to best describe vancomycin population pharmacokinetics in 13, 14, and 3 studies, respectively. Three-compartment models were implemented in three studies to account for an additional cerebrospinal fluid compartment. The most common predictors were creatinine clearance and bodyweight, in 20 and 13 studies, respectively. Estimated values of vancomycin clearance and total volume of distribution varied widely from 0.334 to 8.75 L/h (0.0054–0.1279 L/h/kg) and from 7.12 to 501.8 L (0.097–6.97 L/kg), respectively. Almost all studies implemented an exponential interindividual variability model, and the highest variability on clearance was 99.2%. In conclusion, this review highlights the wide ranges and the high variability of estimated population pharmacokinetic parameters. This information can help guide dosing in different subpopulations. Yet, additional analyses with pooled subpopulations might be needed to confirm the necessity of modified dosage regimens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Marsot A, Boulamery A, Bruguerolle B, Simon N. Vancomycin: a review of population pharmacokinetic analyses. Clin Pharmacokinet. 2012;51(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  2. Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, et al. 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. 2009;66(1):82–988.

    Article  CAS  PubMed  Google Scholar 

  3. Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of vancomycin. Clin Pharmacol Ther. 2017;102(3):459–54646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Heil EL, Claeys KC, Mynatt RP, Hopkins TL, Brade K, Watt I, et al. Making the change to area under the curve-based vancomycin dosing. Am J Health Syst Pharm. 2018;75(24):1986–95.

    Article  PubMed  Google Scholar 

  5. Rybak M, Le J, Lodise TP, Levine DP, Bradley, JS, Liu, C, et al. Therapeutic monitoring of vancomycin: a revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists. 2019.

  6. Neely MN, Youn G, Jones B, Jelliffe RW, Drusano GL, Rodvold KA, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother. 2014;58(1):309–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis. 2009;49(4):507–14.

    Article  CAS  PubMed  Google Scholar 

  8. Aljefri DM, Avedissian SN, Rhodes NJ, Postelnick MJ, Nguyen K, Scheetz MH. Vancomycin area under the curve and acute kidney injury: a meta-analysis. Clin Infect Dis. 2019;69(11):1881–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Suzuki Y, Kawasaki K, Sato Y, Tokimatsu I, Itoh H, Hiramatsu K, et al. Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin-resistant Staphylococcus aureus pneumonia. Chemotherapy. 2012;58(4):308–12.

    Article  CAS  PubMed  Google Scholar 

  10. Neely MN, Kato L, Youn G, Kraler L, Bayard D, van Guilder M, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother. 2018;62(2):e02042–e2117.

    PubMed  PubMed Central  Google Scholar 

  11. Zasowski EJ, Murray KP, Trinh TD, Finch NA, Pogue JM, Mynatt RP, et al. Identification of vancomycin exposure-toxicity thresholds in hospitalized patients receiving intravenous vancomycin. Antimicrob Agents Chemother. 2018;62(1):e01684–e1717.

    PubMed  Google Scholar 

  12. Escobar L, Andresen M, Downey P, Gai MN, Regueira T, Bórquez T, et al. Population pharmacokinetics and dose simulation of vancomycin in critically ill patients during high-volume haemofiltration. Int J Antimicrob Agents. 2014;44(2):163–7.

    Article  CAS  PubMed  Google Scholar 

  13. Goti V, Chaturvedula A, Fossler MJ, Mok S, Jacob JT. Hospitalized patients with and without hemodialysis have markedly different vancomycin pharmacokinetics: a population pharmacokinetic model-based analysis. Ther Drug Monit. 2018;40(2):212–21.

    Article  CAS  PubMed  Google Scholar 

  14. Adane ED, Herald M, Koura F. Pharmacokinetics of vancomycin in extremely obese patients with suspected or confirmed Staphylococcus aureus infections. Pharmacotherapy. 2015;35(2):127–39.

    Article  CAS  PubMed  Google Scholar 

  15. Moore J, Healy J, Thoma B, Peahota M, Ahamadi M, Schmidt L, et al. A population pharmacokinetic model for vancomycin in adult patients receiving extracorporeal membrane oxygenation therapy. CPT Pharmacomet Syst Pharmacol. 2016;5(9):495–502.

    Article  CAS  Google Scholar 

  16. Donadello K, Roberts JA, Cristallini S, Beumier M, Shekar K, Jacobs F, et al. Vancomycin population pharmacokinetics during extracorporeal membrane oxygenation therapy: a matched cohort study. Crit Care. 2014;18(6):632.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wu C-C, Shen L-J, Hsu L-F, Ko W-J, Wu F-LL. Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation. J Formosan Med Assoc. 2016;115(7):560–70.

  18. Alqahtani SA, Alsultan AS, Alqattan HM, Eldemerdash A, Albacker TB. Population pharmacokinetic model for vancomycin used in open heart surgery: model-based evaluation of standard dosing regimens. Antimicrob Agents Chemother. 2018;62(7):e00088–e118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li X, Sun S, Ling X, Chen K, Wang Q, Zhao Z. Plasma and cerebrospinal fluid population pharmacokinetics of vancomycin in postoperative neurosurgical patients after combined intravenous and intraventricular administration. Eur J Clin Pharmacol. 2017;73(12):1599–607.

    Article  CAS  PubMed  Google Scholar 

  20. Li X, Wu Y, Sun S, Mei S, Wang J, Wang Q, et al. Population pharmacokinetics of vancomycin in postoperative neurosurgical patients. J Pharm Sci. 2015;104(11):3960–7.

    Article  CAS  PubMed  Google Scholar 

  21. Li X, Wu Y, Sun S, Zhao Z, Wang Q. Population pharmacokinetics of vancomycin in postoperative neurosurgical patients and the application in dosing recommendation. J Pharm Sci. 2016;105(11):3425–31.

    Article  CAS  PubMed  Google Scholar 

  22. Lim HS, Chong YP, Noh YH, Jung JA, Kim YS. Exploration of optimal dosing regimens of vancomycin in patients infected with methicillin-resistant Staphylococcus aureus by modeling and simulation. J Clin Pharm Ther. 2014;39(2):196–203.

    Article  CAS  PubMed  Google Scholar 

  23. Mangin O, Urien S, Mainardi J-L, Fagon J-Y, Faisy C. Vancomycin pharmacokinetic and pharmacodynamic models for critically ill patients with post-sternotomy mediastinitis. Clin Pharmacokinet. 2014;53(9):849–61.

    Article  CAS  PubMed  Google Scholar 

  24. Chung J-Y, Jin S-J, Yoon J-H, Song Y-G. Serum cystatin C is a major predictor of vancomycin clearance in a population pharmacokinetic analysis of patients with normal serum creatinine concentrations. J Korean Med Sci. 2013;28(1):48–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ji XW, Ji SM, He XR, Zhu X, Chen R, Lu W. Influences of renal function descriptors on population pharmacokinetic modeling of vancomycin in Chinese adult patients. Acta Pharmacol Sin. 2018;39(2):286–93.

    Article  CAS  PubMed  Google Scholar 

  26. Liu Tt, Pang Hm, Jing L, Wei Wx, Qin Xl, Guo Q, et al. A population pharmacokinetic model of vancomycin for dose individualization based on serum cystatin C as a marker of renal function. J Pharm Pharmacol. 2019;71(6):945–55.

  27. Purwonugroho TA, Chulavatnatol S, Preechagoon Y, Chindavijak B, Malathum K, Bunuparadah P. Population pharmacokinetics of vancomycin in Thai patients. Sci World J. 2012;2012:762649.

    Article  CAS  Google Scholar 

  28. Usman M, Fobker M, Hempel G. Investigation of the age dependency of vancomycin clearance by population pharmacokinetic modeling. Int J Clin Pharmacol Ther. 2018;56(2):56–63.

    Article  CAS  PubMed  Google Scholar 

  29. Deng C, Liu T, Zhou T, Lu H, Cheng D, Zhong X, et al. Initial dosage regimens of vancomycin for Chinese adult patients based on population pharmacokinetic analysis. Int J Clin Pharmacol Ther. 2013;51(5):407–15.

    Article  CAS  PubMed  Google Scholar 

  30. Kim AJ, Lee J-Y, Choi SA, Shin WG. Comparison of the pharmacokinetics of vancomycin in neurosurgical and non-neurosurgical patients. Int J Antimicrob Agents. 2016;48(4):381–7.

    Article  CAS  PubMed  Google Scholar 

  31. Zaric RZ, Milovanovic J, Rosic N, Milovanovic D, Zecevic DR, Folic M, et al. Pharmacokinetics of vancomycin in patients with different renal function levels. Open Med (Wars). 2018;13:512–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lin WW, Wu W, Jiao Z, Lin RF, Jiang CZ, Huang PF, et al. Population pharmacokinetics of vancomycin in adult Chinese patients with post-craniotomy meningitis and its application in individualised dosage regimens. Eur J Clin Pharmacol. 2016;72(1):29–37.

    Article  CAS  PubMed  Google Scholar 

  33. Roberts JA, Taccone FS, Udy AA, Vincent J-L, Jacobs F, Lipman J. Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother. 2011;55(6):2704–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Medellín-Garibay SE, Romano-Moreno S, Tejedor-Prado P, Rubio-Álvaro N, Rueda-Naharro A, Blasco-Navalpotro MA, et al. Influence of mechanical ventilation on the pharmacokinetics of vancomycin administered by continuous infusion in critically ill patients. Antimicrob Agents Chemother. 2017;61(12):e01249–e1317.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Okada A, Kariya M, Irie K, Okada Y, Hiramoto N, Hashimoto H, et al. Population pharmacokinetics of vancomycin in patients undergoing allogeneic hematopoietic stem-cell transplantation. J Clin Pharmacol. 2018;58(9):1140–9.

    Article  CAS  PubMed  Google Scholar 

  36. Zhou Y, Gao F, Chen C, Ma L, Yang T, Liu X, et al. Development of a population pharmacokinetic model of vancomycin and its application in Chinese geriatric patients with pulmonary infections. Eur J Drug Metab Pharmacokinet. 2019;44(3):361–70.

    Article  CAS  PubMed  Google Scholar 

  37. Bury D, ter Heine R, van de Garde EM, Nijziel MR, Grouls RJ, Deenen MJ. The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults. Eur J Clin Pharmacol. 2019;75(7):921–8.

    Article  CAS  PubMed  Google Scholar 

  38. Hui K, Patel K, Nalder M, Nelson C, Buising K, Pedagogos E, et al. Optimizing vancomycin dosage regimens in relation to high-flux haemodialysis. J Antimicrob Chemother. 2018;74(1):130–4.

    Google Scholar 

  39. Bae SH, Yim D-S, Lee H, Park A-R, Kwon J-E, Sumiko H, et al. Application of pharmacometrics in pharmacotherapy: open-source software for vancomycin therapeutic drug management. Pharmaceutics. 2019;11(5):E224.

    Article  CAS  PubMed  Google Scholar 

  40. Medellín-Garibay SE, Ortiz-Martín B, Rueda-Naharro A, García B, Romano-Moreno S, Barcia E. Pharmacokinetics of vancomycin and dosing recommendations for trauma patients. J Antimicrob Chemother. 2015;71(2):471–9.

    Article  CAS  PubMed  Google Scholar 

  41. Udy AA, Covajes C, Taccone FS, Jacobs F, Vincent J-L, Lipman J, et al. Can population pharmacokinetic modelling guide vancomycin dosing during continuous renal replacement therapy in critically ill patients? Int J Antimicrob Agents. 2013;41(6):564–8.

    Article  CAS  PubMed  Google Scholar 

  42. Udy AA, Roberts JA, Lipman J. Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol. 2011;7(9):539–43.

    Article  CAS  PubMed  Google Scholar 

  43. Roberts DM, Roberts JA, Roberts MS, Liu X, Nair P, Cole L, et al. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. Crit Care Med. 2012;40(5):1523–8.

    Article  CAS  PubMed  Google Scholar 

  44. Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care. 2012;27(6):741.e9–18.

    Article  CAS  Google Scholar 

  45. Buck ML. Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy. 1998;18(5):1082–6.

    CAS  PubMed  Google Scholar 

  46. Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet. 2003;42(5):403–17.

    Article  CAS  PubMed  Google Scholar 

  47. Mousavi S, Levcovich B, Mojtahedzadeh M. A systematic review on pharmacokinetic changes in critically ill patients: role of extracorporeal membrane oxygenation. Daru. 2011;19(5):312–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shekar K, Roberts JA, McDonald CI, Fisquet S, Barnett AG, Mullany DV, et al. Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care. 2012;16(5):R194.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Shekar K, Roberts JA, McDonald CI, Ghassabian S, Anstey C, Wallis SC, et al. Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. Crit Care. 2015;19:164.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Shekar K, Roberts JA, Mullany DV, Corley A, Fisquet S, Bull TN, et al. Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth Intensive Care. 2012;40(4):648–55.

    Article  CAS  PubMed  Google Scholar 

  51. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother. 2008;52(4):1330–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Colin PJ, Allegaert K, Thomson AH, Touw DJ, Dolton M, de Hoog M, et al. Vancomycin pharmacokinetics throughout life: results from a pooled population analysis and evaluation of current dosing recommendations. Clin Pharmacokinet. 2019;58(6):767–80.

    Article  CAS  PubMed  Google Scholar 

  53. Cook AM, Arora S, Davis J, Pittman T. Augmented renal clearance of vancomycin and levetiracetam in a traumatic brain injury patient. Neurocrit Care. 2013;19(2):210–4.

    Article  CAS  PubMed  Google Scholar 

  54. Pujal M, Soy D, Codina C, Ribas J. Are higher vancomycin doses needed in ventricle-external shunted patients? Pharm World Sci. 2006;28(4):215–21.

    Article  CAS  PubMed  Google Scholar 

  55. Wu F-LL, Liu S-S, Yang T-Y, Win M-F, Lin S-W, Huang C-F, et al. A larger dose of vancomycin is required in adult neurosurgical intensive care unit patients due to augmented clearance. Ther Drug Monit. 2015;37(5):609–18.

  56. Campassi ML, Gonzalez MC, Masevicius FD, Vazquez AR, Moseinco M, Navarro NC, et al. Augmented renal clearance in critically ill patients: incidence, associated factors and effects on vancomycin treatment. Rev Bras Ter Intensiv. 2014;26(1):13–20.

    Article  Google Scholar 

  57. Sette LHBC, Lopes EPDA. The reduction of serum aminotransferase levels is proportional to the decline of the glomerular filtration rate in patients with chronic kidney disease. Clinics. 2015;70(5):346–9.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank our summer interns (Aniss Mesli and Ibrahim El-Haffaf) for their great work and help in screening the literature, retaining relevant articles, and filling the tables. We also thank Dr. Frederique Fenneteau for her comments, and Augusto Dos Santos Latge for his help formatting the tables.

Funding

Abdullah Aljutayli received a scholarship from Qassim University in Saudi Arabia. Fahima Nekka acknowledges support provided by NSERC-Industrial Chair in Pharmacometrics, co-funded by Novartis, Pfizer, and Syneos, as well as FRQNT Projet d´equipe.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Université de Montréal, Pavillon Jean-Coutu, 2940 chemin de Polytechnique, Montréal, QC, H3T 1J4, Canada

    Abdullah Aljutayli, Amélie Marsot & Fahima Nekka

  2. Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada

    Amélie Marsot

  3. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada

    Amélie Marsot

  4. Laboratoire de Pharmacométrie, Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada

    Fahima Nekka

  5. Centre de Recherches Mathématiques, Université de Montréal, Montréal, QC, Canada

    Fahima Nekka

Authors
  1. Abdullah Aljutayli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amélie Marsot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fahima Nekka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amélie Marsot.

Ethics declarations

Conflict of Interest

Abdullah Aljutayli, Amélie Marsot, and Fahima Nekka have no conflicts of interest that are directly relevant to the content of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aljutayli, A., Marsot, A. & Nekka, F. An Update on Population Pharmacokinetic Analyses of Vancomycin, Part I: In Adults. Clin Pharmacokinet 59, 671–698 (2020). https://doi.org/10.1007/s40262-020-00866-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-020-00866-2

Search

Navigation