Isabel Spriet

Background: In critically ill patients with severe infections, beta-lactam antibiotics are frequently underdosed, while studies indicate that shorter treatment durations may be sufficient when adequately dosed. The HIT-HARD trial aims to evaluate whether short-course, high-dose beta-lactam therapy is non-inferior to conventional dosing and duration in critically ill patients with severe infections. A shorter course may reduce the development of antimicrobial resistance and serve a public health benefit. Methods: The HIT-HARD trial (EU ref. 2024-514730-21-00) is a prospective, multicenter, cluster-randomized, cross-over, non-inferiority trial conducted in 14 hospitals (7 in Belgium and 7 in the Netherlands). The study aims to enroll 1,282 patients with organ dysfunction due to common infections (community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, intra-abdominal infection, or bloodstream infection). Patients treated with ceftriaxone, cefuroxime, cefotaxime, piperacillin–tazobactam, or meropenem can be included in the study. Exclusion criteria include prior study-antimicrobial therapy > 12 h for the current infection, absence of adequate source control, and infections requiring prolonged or specific dosing regimens. Participants are allocated to either the HIT-HARD strategy, a high-dose regimen (around 150–200% of standard dosing) for a short course of 3–5 days (72–120 h), or the CONTROL strategy, a conventional dosing regimen for 6–9 days (144–216 h). The primary endpoint is all-cause 90-day mortality. Secondary endpoints include mortality, recurrence of infection, antimicrobial resistance development, toxicity, antimicrobial exposure, clinical cure, resource utilization, health-related quality of life, and cost-effectiveness. Non-inferiority will be assessed using a pre-specified 7% margin by estimating the risk difference between the HIT-HARD and CONTROL groups with an unweighted cluster-level summary regression. Discussion: By determining whether this short-course, high-dose approach is non-inferior to conventional regimens, the trial has the potential to directly inform antibiotic policy and guide an evidence-based approach to safely shorten antimicrobial therapy as part of an ICU stewardship program. Trial registration: 20245147302100 (EUCT), prospective trial registration date 05DEC2024. Protocol version 3.0, protocol date 01JUN2026.

Background and Objectives Vancomycin is a widely used antibiotic with a narrow therapeutic window and considerable pharmacokinetic variability, necessitating accurate and precise dosing. Population pharmacokinetics (popPK) models have become essential for facilitating model-informed precision dosing (MIPD) of vancomycin. We aimed to summarise and compare popPK models of vancomycin and evaluate MIPD software modules incorporating these models. Methods We systematically searched PubMed, EMBASE, and reference lists of relevant articles from inception through 01 January 2026 to identify articles describing the development of compartmental, one-stage parametric popPK models based on data from adult patients (aged ≥ 18 years) receiving intravenous vancomycin. We extracted and summarised key information on study design, patients, vancomycin dosing regimens, sampling strategies, quantification methods, modelling techniques, and covariates. We contacted providers of MIPD software tools and invited them to complete an online questionnaire assessing the features and clinical integration of their vancomycin module. We evaluated the incorporated models and their clinical applicability. Results We identified 99 adult-applicable vancomycin popPK models across 97 articles: 48 (48.5%) were one-compartment, 47 (47.5%) two-compartment models, and 4 (4.0%) three-compartment models. Kidney function estimators and body weight metrics were the most commonly retained covariates on clearance and volume of distribution, respectively. Of 18 identified MIPD software tool providers, 13 (72.2%) completed the questionnaire, confirming the inclusion of vancomycin modules. These tools incorporated a total of 101 vancomycin models, of which 48 were intended for adults. Three tools had been evaluated in prospective non-interventional studies, and two in a prospective interventional trial. Five tools were certified as conforming to European Union (EU) regulatory standards under the Medical Devices Directive and were in the process of obtaining EU conformity under the Medical Device Regulation. Mapping published models to tool implementations revealed partial overlap, limited transparency on model selection and lack of model‑level external validation, underscoring the need for structured evaluation before routine clinical adoption. Conclusion This review presents a comprehensive overview of vancomycin popPK models and MIPD software modules for adult patients. Our findings highlight the diversity among popPK models and the need for standardised reporting, transparent model selection, and prospective evaluation to support clinical implementation of MIPD.

Background: Beta-lactam allergy labels (BLALs), especially penicillin allergy labels, are frequently recorded in hospitalized patients and are associated with increased use of broad-spectrum and second-line antibiotics. Most BLALs are incorrect, but current allergy workups require invasive testing and specialized resources. We recently developed a strictly noninvasive, electronic patient record–embedded clinical decision support tool, the Allergy Fact Checker (AFC), which proactively identifies potentially incorrect BLALs by detecting uneventful re-exposures to the culprit or other beta-lactams since introduction of the BLAL. Objective: This study aims to evaluate the clinical, antimicrobial, and economic impact of the AFC in hospitalized adults with BLALs compared to the standard of care (no AFC). Methods: We are conducting a multicenter, open-label, crossover cluster-controlled study in 9 hospitals in Flanders, Belgium. All hospitalized adults with a BLAL are eligible, excluding patients in palliative care, discharged within 24 hours, or previously enrolled. Each hospital will alternate between intervention (use of the AFC) and control (standard practice) phases, separated by washout periods. The primary endpoint is cumulative guideline-concordant prescribing of first-line and/or narrow-spectrum beta-lactams following local antibiotic treatment guidelines, across predefined care windows up to day 100, expressed as a weighted per-patient proportion. Secondary endpoints include delabeling or refinement rate, beta-lactam tolerance, antibiotic switching, hospital length of stay, in-hospital and 3-month mortality, intensive care unit admission, readmission, multidrug-resistant organism colonization or infection, and costs. Based on prior data, we calculated that a total of 3285 participants are required to achieve 80% power to detect superiority of the intervention (4.6% vs 9.9% appropriate prescribing). Recruitment started in March 2025 and is ongoing. Results: The primary outcome will be analyzed using hierarchical mixed-effect models accounting for hospital-level clustering and period effects. Data collection will continue until 200 days after the last patient is discharged. This trial is expected to conclude in 2026. Ethical approval was obtained from the institutional review board in November 2024. Recruitment started in March 2025 and is ongoing. As of manuscript submission, more than 3000 participants have been enrolled across the participating hospitals. According to the prespecified protocol, an interim assessment of nuisance parameters will be performed in the following month to evaluate the initial design assumptions. Data collection is expected to continue until the end of 2026. The main study results are anticipated to be reported in 2027. Conclusions: This is the first multicenter European study evaluating a strictly noninvasive BLAL delabeling approach. If successful, this AFC tool could improve antimicrobial stewardship, reduce costs, and provide a scalable model for centralized allergy label management.

Vancomycin is frequently used to treat gram‐positive infections in neonates and children. The optimal marker for efficacy and toxicity is the 24‐h area under the concentration‐time curve/minimal inhibitory concentration, which can be estimated using population pharmacokinetic (popPK) models. These models can be integrated into model‐informed precision dosing (MIPD) tools to personalize therapy. This study aimed to systematically review neonatal and paediatric vancomycin popPK models and develop a model selection tool for MIPD. A systematic literature search (December 2025; PubMed, EMBASE, WoS, Scopus, IPA) was conducted following PRISMA guidelines using the concepts ‘neonates/children’, ‘vancomycin’ and ‘popPK model’. Inclusion criteria were age 0–18 years, intravenous vancomycin, and popPK model development. Descriptive statistics summarized tested vs . retained covariates. Based on literature and multidisciplinary expert input, model selection criteria were proposed and applied to the identified models. Across 7915 articles, 112 popPK models were identified (1994–2025; 35 neonatal, 6 infantile, 39 paediatric, 2 adolescent, 30 mixed‐age). Models were built on data from median (range) 114 (6–7167) patients, representing 337 (26–13 372) PK samples. There were 81 one‐ and 30 two‐compartment models. Of 180 covariates tested across models, 47 (26.1%) were retained. Body weight was most frequently tested and retained (101/106, 95.3%). Model selection criteria included matching population, external and internal model evaluation (calibration, discrimination, uncertainty), cohort size, PK sampling schedule. The Chen (2023) model scored highest for both the neonatal and paediatric populations. This review and model selection tool can guide and standardize model selection for MIPD.

In 2019, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) redefined the “I” category from “intermediate susceptibi

Penicillin allergy delabeling strategies are time- and resource-consuming. In this mixed-methods study, we evaluated the ‘Allergy Fact Checker’, a novel clinical decision support system designed to identify patients with uneventful re-exposure to penicillins, enabling delabeling without additional testing. The intervention involved implementation of the tool, pharmacist-led review of alerts, and physician contact. An interrupted time series analysis assessed delabeling outcomes, and physicians were interviewed to explore implementation barriers. The Allergy Fact Checker identified 8.9% (164/1850) of patients with a penicillin allergy label. The delabeling rate increased from 12% to 60% (OR 6.8 (95% CI 1.3–35, P = 0.02)). Addressing one alert took 5 min ( ± 3 min). Reported barriers included workload and limited knowledge of the allergy label removal process. By streamlining the identification process, the Allergy Fact Checker offers a low-resource, scalable solution that significantly improves delabeling and integrates easily into existing clinical workflows.

Background/Objectives: Surgical site infection (SSI) significantly impacts patient outcomes in oncologic head and neck surgery with free flap reconstruction. Perioperative antibiotic prophylaxis (PAP) is widely accepted to prevent SSI. Despite decades of research, infection rates often exceed 40%, and controversies remain regarding antibiotic type and duration. While the literature on general head and neck surgery is abundant, it does not fully address the unique challenges of oncologic patients undergoing complex free flap reconstruction in the head and neck region. This review assesses the evidence for PAP in this population and examines concerns related to antimicrobial resistance (AMR). Methods: We conducted a review of clinical trials, systematic reviews, and relevant literature on PAP in oncologic head and neck surgery with free flap reconstruction. Key aspects included antibiotic type, timing, duration, and impact on SSI rates and patient outcomes. General head and neck surgery literature was considered when procedure-specific data were lacking. Results: PAP reduces SSI rates, but clinical practice varies regarding antibiotic choice and duration. Short-term prophylaxis may suffice for some procedures, whereas prolonged regimens are often used despite limited additional benefit. A multidisciplinary approach considering procedure-specific risks and patient factors improves outcomes. The risk of AMR underscores the need for standardized, evidence-based protocols. Significant gaps remain, particularly concerning optimal PAP regimens for free flap reconstruction. Conclusions: PAP is essential for SSI prevention in head and neck oncologic surgery with free flap reconstruction, yet current practices are heterogeneous. Standardized, procedure-specific protocols are needed to optimize prophylaxis, reduce SSI rates, and limit AMR, ultimately improving patient care and outcomes.