Factors impacting unbound vancomycin concentrations in neonates and young infants

  • Anne Smits
  • Steven Pauwels
  • Matthijs Oyaert
  • Nele Peersman
  • Isabel Spriet
  • Veroniek Saegeman
  • Karel Allegaert
Original Article


Vancomycin pharmacokinetic (PK) and pharmacodynamic (PD) data in neonates are based on total concentrations. However, only unbound vancomycin is pharmacologically active. The objective was to determine vancomycin protein binding and the covariates impacting unbound vancomycin concentration in neonates and young infants. In neonates and young infants to whom vancomycin was administered intermittently for medical indications, total and unbound vancomycin plasma concentrations were determined using LC-MS/MS. Sampling occurred randomly during vancomycin exposure, covering a broad range of concentrations. Impact of covariates on unbound vancomycin concentration was determined using linear regression. Significant results of the univariate regressions were entered in a stepwise multiple regression. Passing-Bablok regression and Bland-Altman were used to assess the difference between measured and calculated unbound vancomycin concentration. Thirty-seven samples in 33 patients (median (interquartile range) gestational age 35 (29–39) weeks) were collected. Median total and unbound vancomycin concentrations were 14.2 (7.4–20.6) and 13.6 (7.2–22.5) mg/L, respectively. Median unbound fraction was 0.90 (0.77–0.98). Multiple regression revealed total vancomycin concentration (β = 0.884, p < 0.001) and albumin (β = − 0.323, p = 0.007) as most important covariates of unbound vancomycin concentrations, with an R2 adjusted of 0.953 (p < 0.0001). Mean absolute difference between calculated and measured unbound vancomycin was − 0.008 (95% CI − 0.92–0.91) mg/L. The unbound vancomycin fraction in neonates is higher compared to that in children and adults, and total vancomycin concentration and albumin were the most important covariates of unbound vancomycin concentration. Integration of protein binding in future PK/PD analyses is appropriate to optimize vancomycin dosing and to determine population-specific vancomycin PD targets for neonates.


Neonate Vancomycin Protein binding Unbound concentration 


Funding information

K. Allegaert has been supported by the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen), by a fundamental Clinical Investigatorship (1800214N). The research activities of A. Smits, S. Pauwels, and I. Spriet were supported by the Clinical Research and Education Council of the University Hospitals Leuven. The research was further facilitated by the “Agency for Innovation, Science and Technology in Flanders” (IWT) through the “SAFEDRUG” project (IWT/SBO 130033).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed parental consent was obtained for all included participants.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neonatal Intensive Care UnitUniversity Hospitals LeuvenLeuvenBelgium
  2. 2.Department of Laboratory MedicineUniversity Hospitals LeuvenLeuvenBelgium
  3. 3.Department of Cardiovascular SciencesKU LeuvenLeuvenBelgium
  4. 4.Department of Laboratory MedicineGhent University HospitalGhentBelgium
  5. 5.Department of Pharmaceutical and Pharmacological SciencesKU LeuvenLeuvenBelgium
  6. 6.Department of PharmacyUniversity Hospitals LeuvenLeuvenBelgium
  7. 7.Department of Development and RegenerationKU LeuvenLeuvenBelgium
  8. 8.Division of NeonatologyErasmus MC-Sophia Children’s HospitalRotterdamThe Netherlands
  9. 9.Intensive Care and Department of Pediatric SurgeryErasmus MC-Sophia Children’s HospitalRotterdamThe Netherlands

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