Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study

Nguyen TA 1 , Kirubakaran R 2 , Schultz HB 3 , Wong S 3 , Reuter SE 3 , McMullan B 4 Show all authors , Bolisetty S 5 , Campbell C 6 , Horvath AR 5 , Stocker SL 1

Affiliations 

  • 1 School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  • 2 School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  • 3 UniSA: Clinical & Health Sciences, University of South Australia, Adelaide, SA, Australia
  • 4 Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, NSW, Australia
  • 5 Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  • 6 NSW Health Pathology, Department of Chemical Pathology, Prince of Wales Hospital, Sydney, NSW, Australia
Clin Chem, 2023 Jun 01;69(6):637-648.
PMID: 37116191 DOI: 10.1093/clinchem/hvad036

Abstract

BACKGROUND: Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations.

METHODS: Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration-time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing.

RESULTS: Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3-12.1% (amikacin), 16.2-19.0% (tobramycin), 12.2-45.8% (gentamicin), and 9.6-19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin).

CONCLUSIONS: Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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