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Published on: October 25, 2013
Age-Related Changes in Vancomycin Protein Binding: Is It Time to Take It Seriously?
Jessica Gadsby1, Lucy Stachow1, Hussain Mulla2
1Department of Pharmacy, University Hospitals of Leicester, Leicester, United Kingdom; and.
Insights
Free vancomycin concentrations (EFVC) differ significantly in neonates and children compared to adults. Relying on total vancomycin concentrations can lead to inaccurate dosing and potentially toxic levels in pediatric patients.
Area of Science:
- Pharmacology
- Clinical Pharmacy
- Drug Monitoring
Background:
- Vancomycin (VAN) protein binding varies with patient age and illness severity.
- Dosing vancomycin based on total drug concentrations can be unreliable due to altered protein binding.
- Free vancomycin concentrations are more indicative of pharmacological activity.
Purpose of the Study:
- To compare model-estimated free vancomycin concentrations (EFVC) with assumed free vancomycin concentrations (AFVC).
- To evaluate the accuracy of standard vancomycin dosing assumptions across different patient populations (neonates, children, adults).
- To assess the impact of age and critical illness on vancomycin protein binding and free concentrations.
Main Methods:
- Retrospective analysis of patient data from electronic health records.
- Identification of patient cohorts including neonates, children, and adults in intensive care and on dialysis.
- Calculation of EFVC using six established pharmacokinetic models and AFVC based on a 50% binding assumption.
- Analysis of predictors for EFVC including albumin, total protein, and dialysis status.
Main Results:
- In adults, EFVC and AFVC showed insignificant differences.
- Significant differences between EFVC and AFVC were observed in pediatric intensive care unit patients.
- Neonates exhibited substantial discrepancies between EFVC and AFVC, with higher percentages of supratherapeutic free concentrations.
- The percentage of free vancomycin within the therapeutic range was considerably lower in neonates and children than assumed.
Conclusions:
- The unbound fraction of vancomycin is higher in critically ill neonates and children than in adults.
- Total vancomycin concentrations do not reliably reflect pharmacologically active free concentrations in pediatric populations.
- Standard vancomycin dosing adjustments targeting adult therapeutic ranges may lead to supratherapeutic and potentially toxic levels in neonates and children.
Background:
Vancomycin (VAN) protein binding in plasma is influenced by illness and age; hence, doses titrated according to total concentrations are fraught. In this study, model-estimated free VAN concentrations (EFVC) were compared with assumed free VAN concentrations (AFVC) in neonates, children, and adults in the intensive care unit and those on dialysis.
Methods:
Patient cohorts were identified from the hospital database. Demographics, clinical characteristics, total VAN concentrations, and laboratory variables were obtained from electronic health records. EFVC was derived from 6 models identified in the literature. For all models, total VAN concentration was the most important predictor; other predictors included albumin, total protein, and dialysis status. The AFVC was calculated as 50% of the total concentration (ie, assumption of 50% bound).
Results:
Differences between EFVC and AFVC in adults were insignificant; however, differences in pediatric intensive care unit patients, according to 2 different models, were significant: mean ± SD = 4.1 ± 1.58 mg/L and 4.7 ± 2.46 mg/L ( P < 0.001); the percentages within the free VAN trough range = 30.4% versus 55.1% and 30% versus 55.1%; and the supratherapeutic percentages = 65.2% versus 31.9% and 66.7% versus 31.9%, respectively. In neonates, the difference between EFVC and AFVC was mean ± SD = 6.9 ± 1.95 mg/L ( P < 0.001); the percentages within the free VAN trough range for continuous and intermediate dosing were 0% versus 81.3% and 14.3% versus 71.4%, and the supratherapeutic percentages were 100% versus 6.25% and 71.4% versus 0%, respectively.
Conclusions:
The fraction of free unbound VAN is higher in sick children and neonates than in adults. Therefore, total VAN concentrations do not correlate with the pharmacologically active free VAN concentrations in the same manner as in adults. Adjusting VAN doses in neonates and children to target the same total VAN concentration as the recommended therapeutic range for adults may result in toxicfree concentrations.
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