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. 2024 Oct 10;25(1):669.
doi: 10.1186/s13063-024-08512-z.

A multicentric, randomized, controlled clinical trial to study the impact of bedside model-informed precision dosing of vancomycin in critically ill children-BENEFICIAL trial

Pieter A De Cock  1   2   3 , Roos Colman  4 , Anca Amza  5 , Peter De Paepe  5 , Hans De Pla  6 , Lieselot Vanlanduyt  6 , Dimitri Van der Linden  7 ; Beneficial Trial Consortium
Collaborators, Affiliations

A multicentric, randomized, controlled clinical trial to study the impact of bedside model-informed precision dosing of vancomycin in critically ill children-BENEFICIAL trial

Pieter A De Cock et al. Trials. .

Abstract

Background: Vancomycin is a commonly prescribed antibiotic to treat serious Gram-positive infections in children. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. In most countries, steady-state plasma concentrations are used as a surrogate parameter for this target AUC/MIC, but this practice has some drawbacks. Hence, AUC-based dosing using model-informed precision dosing (MIPD) tools has been proposed for increasing the target attainment rate and reducing vancomycin-related nephrotoxicity. Solid scientific evidence for these claimed benefits is lacking in children. This randomized controlled trial aims to investigate the large-scale utility of MIPD dosing of vancomycin in critically ill children.

Methods: Participants from 14 neonatal intensive care, pediatric intensive care, and pediatric hemo-oncology ward units from 7 hospitals are randomly allocated to the intervention or standard-of-care comparator group. In the intervention group, a MIPD dosing calculator is used for AUC-based dosing, in combination with extra sampling for therapeutic drug monitoring in the first hours of treatment, as compared to standard-of-care. An AUC24h between 400 and 600 is targeted, assuming an MIC of 1 mg/L. Patients in the comparator group receive standard-of-care dosing and monitoring according to institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400-600 between 24 and 48 h after the start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury during vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400-600 between 48 and 72 h after the start of vancomycin treatment, time to clinical cure, ward unit length-of-stay, hospital length-of-stay, and 30-day all-cause mortality.

Discussion: This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children.

Trial registration: Eudract number: 2019-004538-40. Registered on 2020-09-08 ClinicalTrials.gov NCT046666948. Registered on 2020-11-28.

Keywords: Area under the concentration–time curve dosing; Critically ill children; Model-informed precision dosing; Randomized controlled trial; Therapeutic drug monitoring; Vancomycin.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Dose calculation and dose adjustment in the intervention arm. Legend: AUC, area under the concentration–time curve; TDM, therapeutic drug monitoring
Fig. 2
Fig. 2
Study flowchart. Legend: ICF, informed consent; MIPD, model-informed precision dosing
See this image and copyright information in PMC

References

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