Advertisement

Clinical Pharmacokinetics of Vancomycin in Critically Ill Children

  • Kannan SridharanEmail author
  • Amal Al Daylami
  • Reema Ajjawi
  • Husain Al-Ajooz
  • Sindhan Veeramuthu
Original Research Article
  • 10 Downloads

Abstract

Background and Objective

Critically ill children exhibit altered pharmacokinetic parameters of vancomycin, mainly due to altered renal excretion and volume of distribution (as a result of altered plasma protein concentrations). We assessed the pharmacokinetic parameters of vancomycin in this subpopulation.

Methods

Vancomycin trough concentrations in critically ill children were obtained following first dose and at steady state. Using a one-compartment model, clearance (CL), volume of distribution (Vd), elimination half-life (t1/2), and area under the time–concentration curve for 24 h (AUC0–24) were estimated. Subgroup analyses were carried out, with patients differentiated based on age, renal clearance, outcome, and renal dysfunction. Protein-free vancomycin concentrations were calculated using a previously reported formula.

Results

Twenty-two samples were evaluated for first-dose and 182 for steady-state pharmacokinetics, and similar pharmacokinetic parameter values were observed at first dose and at steady state. Only 36.4% and 47.3% of the samples attained the recommended AUC0–24 (mg·hr/L) of > 400 at first dose and at steady state, while 62.5% of the patients with renal dysfunction achieved this target. Nearly 40% of the patients had augmented renal clearance (ARC), which was associated with higher CL, shorter t1/2, and lower AUC values. Amongst the patients with ARC, none had AUC0–24 (mg·hr/L) > 400 at first dose, while 16% achieved this target at steady state. Volume of distribution was significantly higher in infants and a decreasing trend was observed in toddlers, children, and older children at steady state. Children with renal dysfunction had lower CL, prolonged t1/2, and higher AUC values than patients with normal renal clearance at first dose. A good correlation was observed between trough concentration and AUC0–24, as corroborated by the area under the receiver operating characteristic curve. The median fraction of protein-free vancomycin was around 77%.

Conclusion

Vancomycin dosing strategies in younger children should be revisited, and increased doses should be considered for critically ill children with ARC in order to achieve therapeutic concentrations of AUC0–24.

Notes

Funding

None.

Compliance with Ethical Standards

Funding

No funding was received to conduct this study.

Conflict of Interest

The authors have no conflict of interest.

Ethics approval

The study was carried out after obtaining approval from the relevant ethics committees.

Informed consent

Since it was a retrospective study using anonymised data consent from patients was not required.

References

  1. 1.
    Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis. 2006;42:S35–9.CrossRefGoogle Scholar
  2. 2.
    Álvarez R, López Cortés LE, Molina J, Cisneros JM, Pachón J. Optimizing the clinical use of vancomycin. Antimicrob Agents Chemother. 2016;60:2601–9.CrossRefGoogle Scholar
  3. 3.
    Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, Rybak JM, Talan DA, Chambers HF. Infectious Diseases Society of America. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18–55.Google Scholar
  4. 4.
    Batchelor HK, Marriott JF. Paediatric pharmacokinetics: key considerations. Br J Clin Pharmacol. 2015;79:395–404.CrossRefGoogle Scholar
  5. 5.
    Van Der Heggen T, Dhont E, Peperstraete H, Delanghe JR, Vande Walle J, De Paepe P, De Cock PA. Augmented renal clearance: a common condition in critically ill children. Pediatr Nephrol. 2019;34(6):1099–106.  https://doi.org/10.1007/s00467-019-04205-x.
  6. 6.
    Holford N, Yim D-S. Clearance. Trans Clin Pharmacol. 2015;23:42–5.CrossRefGoogle Scholar
  7. 7.
    Baptista JP, Sousa E, Martins PJ, Pimentel JM. Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents. 2012;39:420–3.CrossRefGoogle Scholar
  8. 8.
    Oyaert M, Spriet I, Allegaert K, Smits A, Vanstraelen K, Peersman N, Wauters J, Verhaegen J, Vermeersch P, Pauwels S. Factors impacting unbound vancomycin concentrations in different patient populations. Antimicrob Agents Chemother. 2015;59:7073–9.CrossRefGoogle Scholar
  9. 9.
    Bakke V, Sporsem H, Von der Lippe E, et al. Vancomycin levels are frequently subtherapeutic in critically ill patients: a prospective observational study. Acta Anaesthesiol Scand. 2017;61:627–35.  https://doi.org/10.1111/aas.12897.CrossRefGoogle Scholar
  10. 10.
    Blot S, Koulenti D, Akova M, et al. Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study. Crit Care. 2014;18:R99.CrossRefGoogle Scholar
  11. 11.
    Sridharan K, Al-Daylami A, Ajjawi R, Ajooz HAA. Vancomycin use in a paediatric intensive care unit of a tertiary care hospital. Paediatr Drugs. 2019.  https://doi.org/10.1007/s40272-019-00343-9.Google Scholar
  12. 12.
    Thakkar N, Salerno S, Hornik CP, Gonzalez D. Clinical pharmacology studies in critically ill children. Pharm Res. 2016;34:7–24.CrossRefGoogle Scholar
  13. 13.
    Shull BC, Haughey D, Koup JR, Baliah T, Li PK. A useful method for predicting creatinine clearance in children. Clin Chem. 1978;24:1167–9.Google Scholar
  14. 14.
    Wu G, Furlanut M. Prediction of serum vancomycin concentrations using one-, two- and three-compartment models with implemented population pharmacokinetic parameters and with the Bayesian method. J Pharm Pharmacol. 1998;50:851–6.CrossRefGoogle Scholar
  15. 15.
    Matzke GR, Kovarik JM, et al. Evaluation of the vancomycin-clearance: creatinine-clearance relationship for predicting vancomycin dosage. Clin Pharm. 1985;4:311–5.Google Scholar
  16. 16.
    RxKinetics. Pharmacokinetic modeling of vancomycin. Plattsburg: RxKinetics; 2017. http://www.rxkinetics.com/vanmodel.html. Accessed on 3 May 2019.
  17. 17.
    Gawronski KM, Goff DA, Brown J, Khadem TM, Bauer KA. A stewardship program’s retrospective evaluation of vancomycin AUC24/MIC and time to microbiological clearance in patients with methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. Clin Ther. 2013;35:772–9.Google Scholar
  18. 18.
    De Cock PA, Desmet S, De Jaeger A, Biarent D, Dhont E, Herck I, Vens D, Colman S, Stove V, Commeyne S, Vande Walle J, De Paepe P. Impact of vancomycin protein binding on target attainment in critically ill children: back to the drawing board? J Antimicrob Chemother. 2017;72:801–4.Google Scholar
  19. 19.
    Mahmoud SH, Shen C. Augmented renal clearance in critical illness: an important consideration in drug dosing. Pharmaceutics. 2017;9:36.CrossRefGoogle Scholar
  20. 20.
    Martin JH, Norris R, Barras M, Roberts J, Morris R, Doogue M, Jones GR. 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. Clin Biochem Rev. 2010;31:21–4.Google Scholar
  21. 21.
    Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37:840–51.CrossRefGoogle Scholar
  22. 22.
    Hanrahan TP, Lipman J, Roberts JA. Antibiotic dosing in obesity: a BIG challenge. Crit Care. 2016;20:240.CrossRefGoogle Scholar
  23. 23.
    Demirjian A, Finkelstein Y, Nava-Ocampo A, Arnold A, Jones S, Monuteaux M, Sandora TJ, Patterson A, Harper MB. A randomized controlled trial of a vancomycin loading dose in children. Pediatr Infect Dis J. 2013;32:1217–23.CrossRefGoogle Scholar
  24. 24.
    Truong J, Levkovich BJ, Padiglione AA. Simple approach to improving vancomycin dosing in intensive care: a standardised loading dose results in earlier therapeutic levels. Intern Med J. 2012;42:23–9.CrossRefGoogle Scholar
  25. 25.
    Albrecht LM, Rybak MJ, Warbasse LH, Edwards DJ. Vancomycin protein binding in patients with infections caused by Staphylococcus aureus. DICP. 1991;25:713–5.Google Scholar
  26. 26.
    Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, Dalovisio JR, Levine DP. 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;66:82–98.Google Scholar
  27. 27.
    Broome L, So TY. An evaluation of initial vancomycin dosing in infants, children, and adolescents. Int J Pediatr. 2011;2011:470364.CrossRefGoogle Scholar
  28. 28.
    Delicourt A, Bussières JF, Lebel D. Pediatric pharmacokinetics of vancomycin: a Canadian perspective. Can J Hosp Pharm. 2011;64:156–7.Google Scholar
  29. 29.
    Balch AH, Constance JE, Thorell EA, et al. Pediatric vancomycin dosing: trends over time and the impact of therapeutic drug monitoring. J Clin Pharmacol. 2014;55:212–20.CrossRefGoogle Scholar
  30. 30.
    Arun A, Swamy S, Jacob K, Sharma R, Kohlhoff SA, Hammerschlag MR. Evaluation of clinical outcome in children and adolescents receiving vancomycin for invasive infections due to methicillin-resistant Staphylococcus aureus: impact of increasing vancomycin MICs. Minerva Pediatr. 2018;70:207–11.Google Scholar
  31. 31.
    Le J, Bradley JS, Murray W, Romanowski GL, Tran TT, Nguyen N, Cho S, Natale S, Bui I, Tran TM, Capparelli EV. Improved vancomycin dosing in children using area under the curve exposure. Pediatr Infect Dis J. 2013;32:e155–63.CrossRefGoogle Scholar
  32. 32.
    De Cock PA, Standing JF, Barker CI, et al. Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children. Antimicrob Agents Chemother. 2015;59:7027–35.CrossRefGoogle Scholar
  33. 33.
    Chu Y, Luo Y, Qu L, Zhao C, Jiang M. Application of vancomycin in patients with varying renal function, especially those with augmented renal clearance. Pharm Biol. 2016;54:2802–6.CrossRefGoogle Scholar
  34. 34.
    Hirai K, Ihara S, Kinae A, Ikegaya K, Suzuki M, Hirano K, Itoh K. Augmented renal clearance in pediatric patients with febrile neutropenia associated with vancomycin clearance. Ther Drug Monit. 2016;38:393–7.CrossRefGoogle Scholar
  35. 35.
    Hahn A, Frenck RW Jr, Allen-Staat M, Zou Y, Vinks AA. Evaluation of target attainment of vancomycin area under the curve in children with methicillin-resistant Staphylococcus aureus bacteremia. Ther Drug Monit. 2015;37:619–25.CrossRefGoogle Scholar
  36. 36.
    Ploessl C, White C, Manasco K. Correlation of a vancomycin pharmacokinetic model and trough serum concentrations in pediatric patients. Pediatr Infect Dis J. 2015;34:e244–7.CrossRefGoogle Scholar
  37. 37.
    Kishk OA, Lardieri AB, Heil EL, Morgan JA. Vancomycin AUC/MIC and corresponding troughs in a pediatric population. J Pediatr Pharmacol Ther. 2017;22:41–7.Google Scholar
  38. 38.
    Ye ZK, Li C, Zhai SD. Guidelines for therapeutic drug monitoring of vancomycin: a systematic review. PLoS One. 2014;9:e99044.CrossRefGoogle Scholar
  39. 39.
    Tkachuk S, Collins K, Ensom MHH. The relationship between vancomycin trough concentrations and AUC/MIC ratios in pediatric patients: a qualitative systematic review. Paediatr Drugs. 2018;20:153–64.Google Scholar
  40. 40.
    Turner RB, Kojiro K, Shephard EA, Won R, Chang E, Chan D, Elbarbry F. Review and validation of Bayesian dose-optimizing software and equations for calculation of the vancomycin area under the curve in critically ill patients. Pharmacotherapy. 2018;38:1174–83.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Therapeutics, College of Medicine and Medical SciencesArabian Gulf UniversityManamaBahrain
  2. 2.Department of Pediatrics, College of Medicine and Medical SciencesArabian Gulf UniversityManamaBahrain
  3. 3.Pediatric Intensive Care UnitSalmaniya Medical Complex, Ministry of HealthManamaBahrain

Personalised recommendations