Title: Antibiotic Reduction and Conservation in Hospitals (ARK-Hospital)
Funder: Department of Health and Social Care

Abstract: Aims/objectives: To develop feasible, inexpensive interventions to increase prescriber compliance with antibiotic review&revise strategies in acute/general medical inpatients, and patient acceptability of shorter antibiotic therapy durations driven by them To evaluate their safety and cost-effectiveness Background/rationale: Broad-spectrum antibiotics are commonly prescribed for acute/general medical inpatients, because delays in administering effective antibiotics increase mortality risk in those with bacterial infections, and what is wrong with a patient is frequently unclear at admission. Department of Health guidance on antimicrobial stewardship ( Start Smart then Focus ) recommends active review&revision of antibiotics 24-72 hours after initiation, but in practice relatively few prescription changes are made. This is perhaps not surprising given the lack of evidence to inform how review&revise should be implemented. Research plan: The goal of reducing total antibiotic burden in acute/general medical inpatients by at least 15% will be addressed through 6 work-packages. WP1-WP3 will provide underpinning data for design and piloting in WP4 of a review&revise intervention package for inpatients/carers and healthcare professionals WP5 will evaluate its effectiveness and safety WP6 will conduct health-economic evaluations. WP1 is an overview to summarise the systematic review evidence for the effectiveness and safety of short- versus longer antibiotic courses in hospitalised patients across indications, to address concerns that stopping antibiotics early in those who have genuinely had bacterial infections could lead to poorer individual-level outcomes. The overview will draw on methods and search terms used by co-applicants for previous systematic reviews/overviews in Primary Care antibiotic prescribing. WP2 contains two observational analyses investigating antibiotic usage and outcomes in inpatients admitted to acute/general medicine at hospital and speciality level, using Hospital Episode Statistics and data from the University Hospitals Birmingham NHS Trust. Completely adjusting for confounding in such analyses is difficult; the goal is to assess whether there is strong evidence of harm (greater rates of treatment failure/mortality associated with less antibiotic use), when confounding would have lesser impact. WP3 consists of qualitative studies with healthcare professionals and patients/carers to deepen understanding of perceptions and experiences of inpatient antibiotic prescribing (particularly focussing on antibiotic duration, not addressed in qualitative research in hospitals to date), and to identify barriers to change to be addressed in WP4. WP4 will develop a feasible, generalisable and sustainable multi-component healthcare professional and inpatient/carer intervention to support antibiotic review&revise , informed by relevant theory, existing evidence, and WP1-WP3 findings. This will be piloted and evaluated using mixed methods. We envisage the patient/carer intervention will be a simple, generic paper booklet and the patient/healthcare professional intervention will include a personalised internet-based educational module for self-completion and standardised review&revise management/review algorithm and proforma, supported by regular antibiotic stewardship ward rounds/review. WP5 will evaluate this intervention in acute/general medical admissions in 36 NHS Trusts using a hospital-randomised stepped-wedge cluster RCT, where each hospital acts as its own control. The intervention will be implemented in two Trusts per month over 18 months. A further 12 months follow-up in all hospitals will assess sustainability of any intervention effect. Co-primary outcomes will be 30-day mortality post-admission (non-inferiority) and defined-daily-doses of antibiotics per acute/general medical admission (superiority). The intervention will be considered successful only if it significantly reduces antibiotic usage with no evidence of increased mortality. All outcomes will be collected from routine electronic NHS databases. Analyses will use meta-analytic techniques to combine Trust-specific intervention effects and underlying trends pre- and post-implementation, using negative binomial regression models. From simulations, the proposed design has >85% power to exclude small increases in 30-day mortality (non-inferiority margin for the relative risk=1.05) and to detect a 15% relative reduction in antibiotic use associated with the intervention. Antibiotic resistance among gut microflora will be assayed in 2000 discarded faecal samples to objectively measure impact on antibiotic selection pressure. Process evaluation will assess which intervention components were used/useful. WP6 will estimate whether the intervention is cost-effective, and also provide information on how the intervention could be rolled out across the NHS if it is shown to be cost-effective. WP6 will also conduct simulation studies to incorporate plausible associations between antibiotic use now and future resistance leading to loss of antibiotic options. Projected outputs/dissemination plans: Outputs will include the results of the overview, observational analyses, qualitative and quantitative studies; and the review&revise intervention itself. Providing WP5&6 demonstrate effectiveness and value-for-money, the major dissemination route would be through incorporation of the internet-based training module as a mandatory NHS e-learning module and of the standardised management/review algorithm and proforma within mainstream electronic patient record systems. Benefits to patients/the NHS: Plausible benefits from less exposure to antibiotics include less development of resistance in individuals own gut flora, lower risks of antibiotic-associated side-effects and further antibiotic-associated infections, reduced patient-to-patient transmission of antibiotic-resistant micro-organisms, and more antibiotic treatment options in future. The overview of systematic reviews will support local policy-making around recommended antibiotic durations, which will benefit patients by more consistent evidence-based treatment.

Lay abstract: Antibiotics are essential to treat serious infections caused by bacteria. Unfortunately, the more bacteria are exposed to antibiotics, the more likely they are to become resistant. This means that antibiotics stop working. So it is important that antibiotics are only used when they are needed. Whilst antibiotics kill bacteria, they don t cure viral infections. When sick patients arrive at hospital, doctors have to try to work out whether they have a bacterial infection, viral infection, or another illness altogether. This is difficult, because initially the symptoms can be very similar (e.g. cough, temperature). Finding out exactly why a patient is sick takes a while, so it makes sense to give antibiotics initially. However, Department of Health guidance recommends stopping antibiotics when it becomes clear that they aren t needed anymore. This could be because doctors work out that the patient never had a bacterial infection, or because they have got better. Stopping antibiotics when they aren t needed reduces the chances of disease-causing and other gut bacteria becoming resistant to antibiotics. It is also important because antibiotics kill friendly gut bacteria. But stopping antibiotics when they are no longer needed often doesn t happen. Sometimes this is just in case or thinking better safe than sorry , or because of the myth that antibiotic courses must be completed to avoid resistance. But, because gut bacteria, rather than those causing disease, become antibiotic-resistant during treatment, taking more antibiotics than really needed is not a safe strategy for the future. There is no good evidence on how best to encourage doctors to stop giving unnecessary antibiotics in hospitals and changing behaviour is hard. This research will first summarise findings from previous studies of strategies for using fewer antibiotics to make sure this is safe. We will also analyse existing hospital data to check that there is no other evidence that stopping antibiotics could harm patients. We will then ask patients, their relatives and healthcare workers what they think about stopping antibiotics. We will use all this information to develop a package of strategies to help doctors, nurses, pharmacists and patients stop antibiotics in hospital when they are no longer needed. The package will include internet-based education, training, standard systems to help doctors review patients, regular support from pharmacists or infections specialists, and materials for patients themselves. We will test the package in 36 hospitals, comparing what happens before and after its introduction. We aim to reduce overall exposure to antibiotics by >15%. We will assess if patients health is affected at all, to make sure this can be done safely. The research team have experience in this area, and include NHS doctors, health psychologists, behaviour change experts, statisticians/clinical trial specialists, health economists, pharmacists and patient representatives.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION