Journal Article

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

De Paepe, Peter, Van der Linden, Dimitri, De Cock, Pieter A., De Pla, Hans, Colman, Roos, Amza, Anca, Vanlanduyt, Lieselot

2024

Overview

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

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adjustment / Anti-Bacterial Agents - administration & dosage / Anti-Bacterial Agents - adverse effects / Anti-Bacterial Agents - pharmacokinetics / Antibiotics / Area Under Curve / Area under the concentration–time curve dosing / Biomedicine / Child / Child, Preschool / Clinical trials / Critical Illness / Critically ill children / Drug dosages / Drug Monitoring - methods / Estimates / Female / Health Sciences / Hospitals / Humans / Hypotheses / Infant / Infant, Newborn / Infection / Infections / Kidneys / Male / Medical care / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Methicillin / Microbial Sensitivity Tests / Model-informed precision dosing / Mortality / Multicenter Studies as Topic / Neonatal intensive care / Patients / Pediatrics / Quality management / Randomized controlled trial / Randomized Controlled Trials as Topic / Sepsis / Statistics for Life Sciences / Study Protocol / Therapeutic drug monitoring / Toxicity / Vancomycin / Vancomycin - administration & dosage / Vancomycin - adverse effects / Vancomycin - pharmacokinetics