Model-informed precision dosing improves vancomycin target attainment in critically ill children compared to standard therapeutic drug monitoring

BACKGROUND: Vancomycin is widely used to treat serious Gram-positive infections but is difficult to dose given its narrow therapeutic index and risk of acute kidney injury at high doses. We aimed to study whether model-informed precision dosing (MIPD) of vancomycin, compared with standard-of-care therapeutic drug monitoring (TDM), increases pharmacokinetic and pharmacodynamic target attainment, is safe, and reduces vancomycin-associated acute kidney injury in children with severe illness. METHODS: The BENEFICIAL trial is a pragmatic, individually randomised, controlled superiority trial done in 14 paediatric or neonatal intensive care and haemato-oncology units in seven hospitals in Belgium. Critically ill patients younger than 18 years initiating intravenous vancomycin for suspected or confirmed Gram-positive infection were eligible. Key exclusion criteria were extracorporeal support, severe acute kidney injury, chronic kidney disease, and imminent death. The intervention combined the use of an MIPD dosing calculator for starting and follow-up doses, with extra sampling for TDM in the first hours of treatment compared with standard-of-care TDM. Patients were randomly assigned (1:1) to MIPD or standard-of-care TDM of vancomycin using stratified permuted blocks by ward type. Allocation occurred via a secure web interface; patients, families, and the biostatistician were masked, but treating physicians and pharmacist staff were not. The intervention used Bayesian software with early sampling to estimate AUC. The primary outcome was the proportion of patients with a 24-h AUC-to-MIC ratio of 400-600 mg·h/L, assuming a minimum inhibitory concentration of 1 mg/L, 24-48 h after treatment initiation. A key secondary outcome was the proportion of patients with new or worsening acute kidney injury or death. These outcomes were assessed in the intention-to-treat (ITT) population (all randomly assigned patients who provided informed consent). Safety was evaluated in all patients who received at least one dose of vancomycin. This trial is registered with ClinicalTrials.gov (NCT04666948) and the EU Clinical Trials register (EudraCT 2019-004538-40), and is closed to recruitment. FINDINGS: Between Dec 28, 2020, and Dec 14, 2023, 332 patients aged between 1 day and 18 years were randomly assigned, 165 to the standard-of-care group and 167 to the intervention group. 18 participants were excluded from the analysis when their deferred consent was not followed by informed consent; therefore 314 patients (179 male and 135 female) were included in the analysis. Target AUC-to-MIC ratio attainment at 24-48 h was found in 82 (53·9%) of 152 patients with available data in the standard-of-care group and 112 (71·8%) of 156 in the MIPD group (absolute difference 18·9% [1·7 to 34·7]). The proportion of patients with acute kidney injury or all-cause mortality was numerically but not significantly lower in the intervention group (26 [16·9%] of 154 vs 19 [12·4%] of 153; absolute difference -4·5% [95% CI -11·6 to 3·5]). Serious adverse events occurred in eight (5%) of 158 patients in the standard-of-care group and eight (5%) of 156 patients in the intervention group. One patient in the intervention group died due to a serious adverse event at least possibly related to the vancomycin administration method. INTERPRETATION: AUC-based MIPD improves AUC-to-MIC ratio-based target attainment and has a low risk of harm. Given that elevated vancomycin AUC is a well established driver of acute kidney injury, the lower cumulative exposure observed in this trial support the use of MIPD in severely ill children, particularly in those who require long treatment durations or present with additional acute kidney injury risk factors. FUNDING: Belgian Federal Knowledge Centre Trials Programme.