Award Title: Biomarker-guided duration of antibiotic treatment in hospitalised patients with moderate or severe sepsis
Funder: Department of Health and Social Care

Abstract: Sepsis is a common life-threatening condition that is triggered by infection. In sepsis, the body’s defence mechanisms (immune system) react excessively, resulting in widespread inflammation and swelling. If not treated quickly, sepsis can result in shutdown of vital organs which can result in death. Each year in the UK, about 200,000 people develop sepsis and up to a quarter will die. Previous research indicates that early recognition of sepsis and rapid antibiotic treatments are the most important factors for patient survival. _x000D_
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While starting antibiotics for sepsis is crucial, the recommended duration of such treatment is uncertain. The lack of research on when to stop treatment safely can lead to an overuse of antibiotics in this condition. Antibiotic overuse is important because it promotes bacteria that are resistant to antibiotics (so-called antimicrobial resistance), which means that sepsis and, indeed, other infections would become difficult to treat in the future. Shorter courses of antibiotics for a patient with sepsis, if given appropriately, may result in less antibiotic use resulting in fewer side effects, less risk of antibiotic resistance and a reduction in costs.  _x000D_
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Chemicals circulating in the blood can indicate the level of an infection and how effective the treatment of an infection is. These chemicals are called biomarkers. The two most well researched circulating biomarkers in sepsis are C-reactive protein (CRP) and procalcitonin (PCT). They are both protein chemicals produced by the human body in response to infection and can be readily measured in blood samples using NHS laboratory equipment. Our proposed research is to determine if the duration of antibiotic treatment given to patients with sepsis can be safely reduced following the close, daily monitoring of these biomarkers.  A number of studies around the world have shown high levels of both CRP and PCT in the blood of patients with sepsis and that they can fall to low levels during a spell of antibiotics. While these studies suggest that these biomarkers could help determine when to stop antibiotics in sepsis, no studies have been performed to test such strategies for NHS patients.  _x000D_
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The proposed research will offer 2760 patients with sepsis an opportunity to take part in our study. Patients with sepsis are usually very ill and many will not have the mental capacity to give their views. Under such circumstances, their next-of-kin will be consulted to determine what the patient’s wishes would be. The study seeks to test and compare 3 possible treatment protocols: standard antibiotic treatment course (usually about 7 days), or treatment courses based on the addition of either daily CRP measurement; or daily PCT measurement. Patients will be allocated to only one of the groups at random. All biomarker measurements will be performed on one extra daily blood sample as part of usual care. The results will help provide advice to the patient’s treating team about when to stop antibiotics. To assure patient safety, the final decision to stop antibiotics will rest entirely with the treating team and an independent Monitoring Committee will scrutinise study progress. The study will run over 4 years to allow enough NHS patients throughout the UK to take part so that there is confidence in the results to ensure that any recommendations regarding the duration of antibiotic treatment for sepsis is safe for patients and can be widely achieved.

Lay Abstract: 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._x000D_
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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._x000D_
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Target population: Hospitalised adults who have been commenced on intravenous antibiotics for sepsis._x000D_
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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._x000D_
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Main exclusions: (a) prolonged antimicrobial therapy mandated; (b) severely immunocompromised; (c) where the treating clinician does not expect survival._x000D_
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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. _x000D_
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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._x000D_
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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%. _x000D_
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Project timetable: Total project 48 months (48/12). Set up (6/12), recruitment (30/12), follow up, analysis and reporting (12/12)._x000D_
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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.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health Categories: INFECTION