Prospective validation of neonatal vancomycin dosing regimens is urgently needed

Abstract

BackgroundAlthough vancomycin is frequently used to treat neonatal late-onset sepsis, there is no consensus on the optimal dosing regimen. Because many neonates needed dosing adaptation due to suboptimal trough values, the vancomycin dosing regimen in our neonatal department was changed during 2012.ObjectiveWe aimed to document the need for validation of neonatal vancomycin dosing by exploring serum trough levels achieved using 2 published dosing regimens (previous regimen: based on postmenstrual age and serum creatinine and new regimen: based on postmenstrual age and postnatal age) and to identify covariates associated with suboptimal vancomycin trough levels (<10 mg/L).MethodsRoutine therapeutic drug monitoring serum trough levels quantified after initiation of intravenous vancomycin therapy and clinical covariates were retrospectively collected. Median vancomycin trough levels of both dosing regimens were compared using the Mann-Whitney U test. The influence of continuous and dichotomous covariates on achieving a suboptimal trough level was explored using the Van Elteren test (stratified Mann-Whitney U test) and Mantel-Haenszel test (stratified χ2 test), respectively. Covariates significant in monovariate analysis were subsequently included in a logistic regression analysis.ResultsIn total, 294 observations (median current weight 1870 g [range = 420–4863 g] and median postmenstrual age 35.07 weeks [range = 25.14–56.00 weeks]) were included. Using the previous and new dosing regimens, 66.3% and 76.2% of trough levels, respectively, were below 10 mg/L. Overall, suboptimal vancomycin trough values were significantly associated with lower weight (birth weight and current weight) and age (gestational age and postmenstrual age).ConclusionsThe majority of vancomycin trough levels in neonates achieved using 2 published dosing regimens did not reach the target of 10 mg/L. This illustrates the urgent need for prospective validation of neonatal vancomycin dosing regimens. We anticipate that dosing regimens integrating covariates reflecting general physiological maturation and renal maturation, as well as disease characteristics, could improve vancomycin exposure in neonates.

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

“…At this moment, several pediatric pharmacokinetic models of vancomycin have been published (19-34, 36, 54-59), but only few individualized, model-based dosing algorithms are available (25,27,30,34,57,59). In clinical practice, target concentrations and AUC 24 /MIC values are hard to achieve (42)(43)(44)(45)60). Simulations based on two models (22,23), that are now validated internally and externally, showed, indeed, that adapted doses are needed, especially for neonates and young infants.…”

“…The data used for the external validation of the neonatal model consisted of both preterm and term neonates (42), and the model proved to be good in terms of predictive performance for both groups (Fig. 2).…”

“…Tools like PsN, version 4.2.0 (University of Uppsala, Sweden) (50), and R, version 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria), were used to visualize data and evaluate the model. External validation was performed with an external data set containing TDM data which were not used for model development (42). This external data set (42) consisted of both (pre)term neonates and young infants (PNA up to 169 days; n ϭ 206).…”

“…Despite the large number of proposed vancomycin dosing regimens currently available for neonates and infants (10,11,(37)(38)(39)(40)(41), studies reporting on the results of therapeutic drug monitoring show that the target trough concentrations are difficult to attain in clinical practice (42)(43)(44)(45). In accordance with reported clinical practice in adults, continu- Citation Janssen EJH, Välitalo PAJ, Allegaert K, de Cock RFW, Simons SHP, Sherwin CMT, Mouton JW, van den Anker JN, Knibbe CAJ.…”

Neonatal vancomycin trough level audit using British National Formulary for Children dosing

“…Given a binomial distribution, the 95% CI for the percentage of patients within the target range is 6.8%–22.5%. This very low target achievement is even lower than that in other studies using alternative dosing regimens 3. Doses were increased, as per local guidance, in neonates with a level outside the target range and a further level was taken (immediately prior to the third dose).…”