Skip to main content
SpringerLink
Log in

Optimization of Pediatric Antibiotic Dosing Through Therapeutic Drug Monitoring

  • Pediatric Infectious Disease (M Mitchell and F Zhu, Section Editors)
  • Published:
Current Treatment Options in Pediatrics Aims and scope Submit manuscript

Abstract

Purpose of review

Review data and provide recommendations on the optimization of antibiotic dosing in pediatrics through therapeutic drug monitoring (TDM).

Recent findings

Due to physiological alterations, there is growing evidence current weight-based antibiotic dosing regimens are inadequate in obese and critically ill children. Utilization of known PK/PD indices as TDM targets for certain antibiotics (aminoglycosides, vancomycin, β-lactams) in these patients has led to improved clinical results in adults, but pediatric literature remains significantly limited.

Summary

There are significant potential clinical benefits to expansion of TDM from current use (vancomycin, aminoglycosides) to include β-lactams, particularly in the critically ill. The clinical benefits of linezolid and fluoroquinolone TDM remain unclear. There is significant potential for further optimization of TDM based dosing through use of population PK software with Bayesian modeling.

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 and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Roberts J, et al. Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol. 2012;73(1):27–36. Provides an excellent review of TDM of multiple antimicrobial agents.

  2. Barker CIS, et al. Pharmacokinetic studies in children: recommendations for practice and research. Arch Dis Child. 2018;103(7):695–702.

    Google Scholar 

  3. •• Abdulla A, et al. Model-informed precision dosing of antibiotics in pediatric patients: a narrative review. Front Pediatr. 2021;9:624639. Excellent review of the increasing use of pediatric population PK modeling and effectiveness in optimization of dosing/TDM.

  4. Upreti VV, Wahlstrom JL. Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling. J Clin Pharmacol. 2016;56(3):266–83.

    Article  CAS  Google Scholar 

  5. Gritz EC, Bhandari V. The human neonatal gut microbiome: a brief review. Front Pediatr. 2015;3:17.

    Google Scholar 

  6. Lim SY, Pettit RS. Pharmacokinetic considerations in pediatric pharmacotherapy. Am J Health Syst Pharm. 2019;76(19):1472–80.

    Article  Google Scholar 

  7. Cies JJ, et al. Beta-lactam therapeutic drug management in the PICU. Crit Care Med. 2018;46(2):272–9.

    Article  CAS  Google Scholar 

  8. Bernier SP, Surette MG. Concentration-dependent activity of antibiotics in natural environments. Front Microbiol. 2013;4:20.

    Article  Google Scholar 

  9. Jumbe N, et al. Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy. J Clin Invest. 2003;112(2):275–85.

    Article  CAS  Google Scholar 

  10. Barcelo-Vidal J, Rodriguez-Garcia E, Grau S. Extremely high levels of vancomycin can cause severe renal toxicity. Infect Drug Resist. 2018;11:1027–30.

    Article  Google Scholar 

  11. Imani S, et al. Too much of a good thing: a retrospective study of beta-lactam concentration-toxicity relationships. J Antimicrob Chemother. 2017;72(10):2891–7.

    Article  CAS  Google Scholar 

  12. Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009;24(1):1–10.

    Article  Google Scholar 

  13. Rodriguez W, et al. Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics. 2008;121(3):530–9.

    Article  Google Scholar 

  14. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840–51; quiz 859.

  15. Zuppa AF, Barrett JS. Pharmacokinetics and pharmacodynamics in the critically ill child. Pediatr Clin North Am. 2008;55(3):735–55, xii.

  16. • Roberts JA, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072–83. Description of inadequate β-lactam fT > MIC in critically ill adults resulted in worse clinical outcomes.

  17. Abdul-Aziz MH, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother. 2016;71(1):196–207.

    Article  CAS  Google Scholar 

  18. Cheng V, et al. Optimising drug dosing in patients receiving extracorporeal membrane oxygenation. J Thorac Dis. 2018;10(Suppl 5):S629–41.

    Article  Google Scholar 

  19. Wells JC, et al. Body composition in normal weight, overweight and obese children: matched case-control analyses of total and regional tissue masses, and body composition trends in relation to relative weight. Int J Obes (Lond). 2006;30(10):1506–13.

    Article  CAS  Google Scholar 

  20. Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis. 2012;25(6):634–49.

    Article  CAS  Google Scholar 

  21. Harskamp-van Ginkel MW, et al. Drug dosing and pharmacokinetics in children with obesity: a systematic review. JAMA Pediatr. 2015;169(7):678–85.

    Article  Google Scholar 

  22. Hales CM, et al. Prevalence of obesity among adults and youth: United States, 2015–2016. NCHS Data Brief. 2017;288:1–8.

    Google Scholar 

  23. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient–concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014;77:3–11.

    Article  CAS  Google Scholar 

  24. Kirkpatrick CM, Duffull SB, Begg EJ. Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. Br J Clin Pharmacol. 1999;47(6):637–43.

    Article  CAS  Google Scholar 

  25. Rea RS, et al. Suboptimal aminoglycoside dosing in critically ill patients. Ther Drug Monit. 2008;30(6):674–81.

    Article  CAS  Google Scholar 

  26. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1–10; quiz 11–2.

  27. • van Lent-Evers NA, et al. Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Ther Drug Monit. 1999;21(1):63–73. Demonstrated the clinical benefits of active TDM of aminoglycosides utilizing an individualized dosing regimen via model-based PK dosing.

  28. Lim WXS, et al. A retrospective review of the efficiency of first-dose therapeutic drug monitoring of gentamicin, amikacin, and vancomycin in the pediatric population. J Clin Pharmacol. 2020;60(1):7–15.

    Article  CAS  Google Scholar 

  29. Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012;56(6):2795–805.

    Article  CAS  Google Scholar 

  30. Moise-Broder PA, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925–42.

    Article  CAS  Google Scholar 

  31. Holmes NE, et al. Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2013;57(4):1654–63.

    Article  CAS  Google Scholar 

  32. •• Rybak MJ, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by 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. Am J Health Syst Pharm. 2020;77(11):835–864. Most recent IDSA guidelines for TDM of vancomycin in MRSA infections.

  33. • Al-Sulaiti FK, et al. Clinical and pharmacokinetic outcomes of peak-trough-based versus trough-based vancomycin therapeutic drug monitoring approaches: a pragmatic randomized controlled trial. Eur J Drug Metab Pharmacokinet. 2019;44(5):639–652. Demonstrated the benefits of peak-trough-based vancomycin dosing vs trough-based dosing alone.

  34. Kishk OA, et al. Vancomycin AUC/MIC and corresponding troughs in a pediatric population. J Pediatr Pharmacol Ther. 2017;22(1):41–7.

    Google Scholar 

  35. • Le J, et al. Improved vancomycin dosing in children using area under the curve exposure. Pediatr Infect Dis J. 2013;32(4):e155–63. Demonstrated that lower vancomycin troughs in pediatrics were associated with adequate AUC0–24/MIC.

  36. Frymoyer A, Guglielmo BJ, Hersh AL. Desired vancomycin trough serum concentration for treating invasive methicillin-resistant Staphylococcal infections. Pediatr Infect Dis J. 2013;32(10):1077–9.

    Article  Google Scholar 

  37. Rhodin MM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24(1):67–76.

    Article  Google Scholar 

  38. Zhao W, et al. Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring. Arch Dis Child. 2013;98(6):449–53.

    Article  Google Scholar 

  39. Bush K, Bradford PA. Beta-lactams and beta-lactamase inhibitors: an overview. Cold Spring Harb Perspect Med. 2016;6(8).

  40. Lodise TP, et al. Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on beta-lactam antibiotics: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2006;26(9):1320–32.

    Article  CAS  Google Scholar 

  41. Guilhaumou R, et al. Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Societe Francaise de Pharmacologie et Therapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Societe Francaise d’Anesthesie et Reanimation-SFAR). Crit Care. 2019;23(1):104.

    Article  Google Scholar 

  42. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31(4):345–51.

    Article  CAS  Google Scholar 

  43. Abdul-Aziz MH, et al. Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development. Semin Respir Crit Care Med. 2015;36(1):136–53.

    Article  Google Scholar 

  44. De Waele JJ, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial. Intensive Care Med. 2014;40(3):380–7.

    Article  Google Scholar 

  45. Scharf C, et al. The higher the better? Defining the optimal beta-lactam target for critically ill patients to reach infection resolution and improve outcome. J Intensive Care. 2020;8(1):86.

    Article  Google Scholar 

  46. Marsot A. Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children? J Pharm Pharm Sci. 2020;23:470–85.

    Article  CAS  Google Scholar 

  47. •• Fratoni AJ, Nicolau DP, Kuti JL. A guide to therapeutic drug monitoring of beta-lactam antibiotics. Pharmacotherapy. 2021;41(2):220–233. Excellent overview of utilization/implementation of TDM of β-lactam antibiotics.

  48. Roberts JA, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498–509.

    Article  Google Scholar 

  49. Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis. 1998;27(1):10–22.

    Article  CAS  Google Scholar 

  50. van den Elsen SH, et al. Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study. BMJ Open. 2020;10(6):e035350.

    Article  Google Scholar 

  51. Pea F, Cojutti PG, Baraldo M. A 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a hospital-wide population of patients receiving conventional dosing: is there enough evidence for suggesting TDM in the majority of patients? Basic Clin Pharmacol Toxicol. 2017;121(4):303–8.

    Article  CAS  Google Scholar 

  52. • Galar A, et al. Systematic therapeutic drug monitoring for linezolid: variability and clinical impact. Antimicrob Agents Chemother. 2017;61(10). Overview of linezolid TDM that found signficant fluctuaion in levels without correlation with adverse events, mortality, or poor outcome.

  53. Bolhuis MS, et al. Linezolid-based regimens for multidrug-resistant tuberculosis (TB): a systematic review to establish or revise the current recommended dose for TB treatment. Clin Infect Dis. 2018;67(suppl_3):S327-S335.

  54. • Li SC, et al. Population pharmacokinetics and dosing optimization of linezolid in pediatric patients. Antimicrob Agents Chemother. 2019;63(4). Overview which found significant possibility of underdoseing children with linezolid with MIC ≥ 2.

  55. Rao GG, et al. Therapeutic drug monitoring can improve linezolid dosing regimens in current clinical practice: a review of linezolid pharmacokinetics and pharmacodynamics. Ther Drug Monit. 2020;42(1):83–92.

    Article  Google Scholar 

  56. Rayner CR, et al. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin Pharmacokinet. 2003;42(15):1411–23.

    Article  CAS  Google Scholar 

  57. Alsultan A. Determining therapeutic trough ranges for linezolid. Saudi Pharm J. 2019;27(8):1061–3.

    Article  CAS  Google Scholar 

  58. Holford N. Pharmacodynamic principles and target concentration intervention. Transl Clin Pharmacol. 2018;26(4):150–4.

    Article  Google Scholar 

  59. Leroux S, et al. Clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. Antimicrob Agents Chemother. 2016;60(4):2039–42.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Infectious Diseases, Pediatric Infectious Diseases, Medical College of Wisconsin, Suite 450C, 999 North 92nd Street, Wauwatosa, WI, 53226, USA

    Frank Zhu MD

Authors
  1. Frank Zhu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Zhu MD.

Ethics declarations

Conflict of Interest

Dr. Frank Zhu declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Pediatric Infectious Disease

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, F. Optimization of Pediatric Antibiotic Dosing Through Therapeutic Drug Monitoring. Curr Treat Options Peds 8, 382–394 (2022). https://doi.org/10.1007/s40746-022-00259-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40746-022-00259-6

Keywords

Search

Navigation