Short-course, high-dose beta-lactam therapy versus conventional dose and duration in critically ill patients: the HIT-HARD trial protocol for a phase III multicenter, cluster randomized, cross-over, non-inferiority trial

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.