External Validation of Model-Based Dosing Guidelines for Vancomycin, Gentamicin, and Tobramycin in Critically Ill Neonates and Children: A Pragmatic Two-Center Study

Abstract

Background: The Dutch Pediatric Formulary (DPF) increasingly bases its guidelines on model-based dosing simulations from pharmacokinetic studies. This resulted in nationwide dose changes for vancomycin, gentamicin, and tobramycin in 2015.

Objective: We aimed to evaluate target attainment of these altered, model-based doses in critically ill neonates and children.

Methods: This was a retrospective cohort study in neonatal intensive care unit (NICU) and pediatric ICU (PICU) patients receiving vancomycin, gentamicin, or tobramycin between January 2015 and March 2017 in two university hospitals. The first therapeutic drug monitoring concentration for each patient was collected, as was clinical and dosing information. Vancomycin and tobramycin target trough concentrations were 10-15 and ≤ 1 mg/L, respectively. Target gentamicin trough and peak concentrations were < 1 and 8-12 mg/L, respectively.

Results: In total, 482 patients were included (vancomycin [PICU] n = 62, [NICU] n = 102; gentamicin [NICU] n = 97; tobramycin [NICU] n = 221). Overall, median trough concentrations were within the target range for all cohorts but showed large interindividual variability, causing nontarget attainment. Trough concentrations were outside the target range in 66.1%, 60.8%, 14.7%, and 23.1% of patients in these four cohorts, respectively. Gentamicin peak concentrations were outside the range in 69% of NICU patients (term neonates 87.1%, preterm infants 57.1%). Higher creatinine concentrations were associated with higher vancomycin and tobramycin trough concentrations.

Conclusion: This study illustrates the need to validate model-based dosing advice in the real-world setting as both sub- and supratherapeutic concentrations of vancomycin, gentamicin, and tobramycin were very prevalent. Our data underline the necessity for further individualization by addressing the high interindividual variability to improve target attainment.

Fig. 1

Flowchart indicating the total number of patients, number of exclusions, reason for exclusion, total number of inclusions, and stratification among our four cohorts. ECMO extracorporeal membrane oxygenation, MC medical center, NICU neonatal intensive care unit, PICU pediatric intensive care unit

Fig. 2

Concentrations of vancomycin, gentamicin, and tobramycin in critically ill neonates and children. Overview of (steady-state) concentrations of vancomycin, gentamicin, and tobramycin concentrations in four cohorts. a Vancomycin NICU, b vancomycin PICU, c gentamicin NICU, and d tobramycin NICU cohorts. Upward facing triangles represent patient subgroups for which the dose advice was altered in 2015, open circles represent subgroups for which no alteration in dose or dose interval was made. Blue symbols represent a single-patient trough concentration, red symbols represent gentamicin peak concentrations. Dashed lines indicate the target concentrations. NICU neonatal intensive care unit, PICU pediatric intensive care unit

Fig. 3

Correlation of antibiotics trough concentrations with creatinine concentrations at start of antibiotic treatment and on the day of TDM. Correlation of antibiotic trough concentrations with creatinine concentrations taken within 24 h of start of antibiotic treatment (a–d) or within 24 h of the TDM sample (e–h). Open circles represent single-patient creatinine and antibiotic trough concentrations. The solid line represents the linear regression line. Correlation coefficients, p values, and number of patients are presented in each panel in the corresponding legend box. Number of patients may deviate from total patient cohort because of missing creatinine data. n number of patients, NICU neonatal intensive care unit, PICU pediatric intensive care unit, rho Spearman’s rho correlation coefficient, TDM therapeutic drug monitoring