Optimising antibiotic ‘review and revise’ in acute/general medical inpatients: the Antibiotic Review Kit in Hospitals (ARK-Hospital) research programme including a stepped-wedge cluster-randomised trial

Background Patients who present acutely to hospital are often suspected to have bacterial infections and are prescribed antibiotics rapidly. Emerging diagnostic information then shows many of these prescriptions were, or no longer are, necessary, requiring prescribers to stop antibiotics: but there is little evidence for how to support this. United Kingdom ‘Start Smart then Focus’ guidance promotes early effective antibiotics followed by active ‘review and revision’ 24–72 hours later. However, in 2017 < 10% of antibiotic prescriptions were discontinued at review, despite studies suggesting that 20–30% could be stopped safely but are not, largely because of behavioural and organisational factors. Objectives To develop and comprehensively evaluate a complex digital, organisational and behavioural change intervention (i.e. the Antibiotic Review Kit) designed to reduce antibiotic use among adult acute/general medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review. Design and methods To provide underpinning data to design the intervention, we conducted: (1) an overview of the systematic review evidence for the effectiveness and safety of shorter versus longer antibiotic courses in hospitalised patients; (2) hospital-level and individual-level observational analyses of electronic health records to investigate associations between antibiotic usage and outcomes in inpatients; and (3) qualitative studies with healthcare professionals and patients/carers to deepen understanding of perceptions and experiences of inpatient antibiotic prescribing and to identify amenable barriers to change. We used findings from these studies to develop a multi-component healthcare professional and inpatient/carer intervention to support antibiotic ‘review and revise’, using a theory-, evidence- and person-based approach with iterative stakeholder consultation, and targeting practicality, generalisability and sustainability. We then tested its feasibility in one hospital, evaluated using mixed methods, before evaluating its effectiveness and safety in acute/general medical admissions in a non-randomised internal pilot in three hospitals and then a large randomised stepped-wedge cluster trial in 36 hospitals (randomisation unit) across the United Kingdom. The intervention was implemented in two hospitals per month over approximately 18 months. A further minimum 14-month follow-up in all hospitals assessed sustainability of any intervention effect. Analyses used meta-analytic techniques to combine hospital-specific immediate intervention effects (step-change) and underlying trends pre and post implementation, derived using negative binomial regression models for antibiotic outcomes and logistic regression models for binary outcomes. Process evaluation assessed which intervention components were used/useful. Setting and participants Acute/general medical specialties in acute hospital groups; participants were prescribers and non-prescribers involved in decision-making around stopping antibiotics and the inpatients themselves. Interventions The Antibiotic Review Kit comprised short internet-based training, standardised systems to review patients (the Antibiotic Review Kit decision aid), regular support from pharmacists/infection specialists through audit and feedback and an information leaflet for patients. Main outcome measures Coprimary outcomes were 30-day mortality post-admission (non-inferiority) and defined-daily-doses of antibiotics per acute/general medical admission (superiority). Data sources All outcomes were collected from routine electronic National Health Service databases. Results A key barrier to stopping antibiotics was lack of information about the original prescriber’s rationale for, and degree of certainty about their initial antibiotic prescribing decision. An integral component of the Antibiotic Review Kit was developing and optimising a decision aid to increase transparency around initial prescribing decisions. In the 3 pilot and 36 main trial sites (total = 39) who implemented the intervention between 25 September 2017 and 1 July 2019, adjusted estimates showed an immediate change of –1.0% [(95% confidence interval −4.0 to +2.1); p  = 0.54] in total antibiotic defined daily doses per acute/general medical admission following the intervention and then sustained reductions of −4.8% per year (−9.1 to −0.2) ( p  = 0.042) greater post versus pre implementation. Among 7,160,421 acute/general medical admissions, the Antibiotic Review Kit intervention was associated with weak evidence of an immediate change of −2.7% [(−5.7 to +0.3); p  = 0.079] in adjusted 30-day mortality and a year-on-year post versus pre implementation change of +3.0% per year [(−0.1 to +6.2); p  = 0.060]; the latter was not found after excluding admissions after the COVID-19 pandemic started in March 2020 [year-on-year change −0.9% (−4.0 to + 2.4) ( p  = 0.60)]. Limitations COVID-19 had an important impact during the trial, and necessitated changes to the statistical analysis plan that could not have been foreseen. It also affected our ability to assess cost-effectiveness, since estimates were strongly affected by non-significant mortality excesses which were plausibly due to COVID-19. Conclusions The Antibiotic Review Kit intervention resulted in sustained reductions in antibiotic use among adult acute/general medical inpatients. The weak, inconsistent intervention effects suggesting a possible initial decrease in mortality associated with the intervention, followed by a longer-term increase, are likely due to the COVID-19 pandemic. Hospitals should consider using the Antibiotic Review Kit to reduce antibiotic overuse. Future work Most sites were using paper-based prescribing systems during the trial; implementing the Antibiotic Review Kit in electronic-based prescribing, now used by almost all National Health Service Trusts, can be more complex. Further research is needed to support recommendations for the Antibiotic Review Kit, and antimicrobial stewardship functionality more widely, in electronic prescribing systems. Study registration The overview of systematic reviews was registered with PROSPERO (CRD42016046907). The feasibility, pilot and main cluster-randomised trial was registered with ISRCTN (ISRCTN12674243). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0514-20015) and is published in full in Programme Grants for Applied Research ; Vol. 14, No. 10. See the NIHR Funding and Awards website for further award information.