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Vancomycin, a glycopeptide, is often ad-ministered to treat (suspected) serious gram-positive in-fections caused by Staphylococci, including methicillin-re-sistant Staphylococcus aureus (MRSA) and coagulase-neg-ative Staphylococci (CoNS). Vancomycin pharmacokinetic (PK) and pharmacodynamic (PD) data in neonates are based on total concentrations. However, only unbound vancomycin is pharmacologically active and available for elimination. The objective was to determine vancomycin protein binding and the covariates impacting unbound vancomycin concentration in neonates and young infants.Neonates and young infants, admitted to the neonatal intensive care unit of the University Hospitals Leuven to whom vancomycin was administered inter-mittently for medical indications, were considered for inclusion after parental informed written consent. In our unit, each vancomycin dose (15 mg/kg) is intravenously administered over 60 min. The dosing interval de-pends on postmenstrual age and plasma creatinine.1 Total and unbound vancomycin plasma concentrations were determined using a validated LC-MS/MS method.2 Sampling occurred randomly during vancomycin ex-posure, covering a broad range of vancomycin concen-trations. Impact of covariates on unbound vancomycin concentration was determined using Spearman correla-tion, linear regression or Mann Whitney U test. Significant results of the univariate regression were entered in a mul-tiple regression.Thirty-seven samples in 33 patients [median (in-terquartile range) gestational age 35 (29-39) weeks and postnatal age 14 (8-29) days] were collected. Median total and unbound vancomycin concentrations were 14.3 (7.4–20.6) and 13.6 (7.2–22.5) mg/L, respectively. Median un-bound fraction was 0.90 (0.77–0.98). Multiple regression re-vealed total vancomycin concentration (β=0.88, p<0.001) and albumin (β=−0.32, p=0.007) as most important covari-ates of unbound vancomycin concentrations, resulting in an R² adjusted of 0.95 (p<0.0001). Unbound vancomycin concentration (VAN) can hereby be predicted using the formula: Unbound VAN (mg/L)=0.88 x total VAN (mg/L) – 0.32 human albumin concentration (g/L)+10.61.The unbound vancomycin fraction in neo-nates is higher compared to children and adults and total vancomycin concentration and albumin were the most important covariates of unbound vancomycin concen-tration. Integration of protein binding in future PK/PD analyses is appropriate to optimise vancomycin dosing and to determine population-specific vancomycin PD targets for neonates.