Biomarker-guided duration of antibiotic treatment in hospitalised patients with moderate or severe sepsis

Design: Multicentre randomised controlled trial with internal pilot. Progression and success criteria (from pilot to main study) will be assessed on (a) recruitment and (b) protocol adherence. Setting: UK acute NHS hospitals, including adult surgical, medical and critical care services (including high dependency/intensive care units), with a track record of recruitment to sepsis trials. Target population: Hospitalised adults who have been commenced on intravenous antibiotics for sepsis. Inclusion criteria: (a) At least 18 years old; (b) receiving intravenous antibiotics for sepsis; (c) No more than 24 hours of systemic antibiotic treatment for present sepsis episode. Main exclusions: (a) prolonged antimicrobial therapy mandated; (b) severely immunocompromised; (c) where the treating clinician does not expect survival. Health Technology: 3 protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily C-reactive protein (CRP) monitoring; (c) standard care + daily procalcitonin (PCT) monitoring. Standard care will be based on routine sepsis management with associated NHS antibiotic stewardship guidance. We have developed biomarker protocols, based on daily assays, adopting the best evidence from the international guidance for CRP (1) and including NICE guidance (2) for PCT to guide antibiotic discontinuation. Measurement of costs and outcomes: Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; dose of antibiotics; length and level of critical care stay and length of hospital stay. 60-day all-cause mortality rates will also be collected. An assessment of in-trial cost effectiveness will be performed. Sample size: A total sample size of 2760 would be able to detect both a mean of 1-day reduction in antibiotic duration (using a mean antibiotic duration of 7 days, a pooled standard deviation of 6 days, 90% power, a significance level of 5%, with a 5% withdrawals rate) and a non-inferiority safety margin of 5% (using a 1-sided significance level of 2.5%, 90% power and 5% withdrawal rate) assuming 28-day mortality is 15%. Project timetable: Total project 48 months (48/12). Set up (6/12), recruitment (30/12), follow up, analysis and reporting (12/12). Expertise in team: A multi-disciplinary team of international experts in sepsis, infectious diseases, microbiology, antibiotic stewardship, clinical chemistry, pharmacy, methodologists, clinicians and patient representatives with a strong track record in large-scale trials in acutely unwell patients. Our team has the support of the Intensive Care Society (UK) and NIHR CRN delivery leadership in Critical Care.