Penicillin allergy status and its effect on antimicrobial prescribing, patient outcomes, and antimicrobial resistance. Short title: ALABAMA: Allergy AntiBiotics And Microbial resistAnce

Aim To determine whether a complex intervention for verifying penicillin-allergy labels in primary care electronic health records(eHR) can safely reduce the proportion of patients labelled as pen-allergic and lead to improved (safe/appropriate) prescribing of recommended first line antimicrobials, thereby improving patient health outcomes. Objectives We plan an integrated programme of work to address our principal objectives: 1A:-To design an evidence-based complex intervention, following MRC guidelines, to support and provide a pen-allergy assessment pathway(PAAP) for evaluation of primary care patients with a record of pen-allergy. 1B:-To undertake a feasibility trial to assess safety, acceptability and practicality of delivering a PAAP intervention trial. 2A:-To conduct a RCT of the PAAP intervention versus usual clinical care to evaluate impact on health outcomes, antimicrobial prescribing and AMR, with a nested pilot. 2B:-To determine whether the PAAP intervention is cost effective. 2C:-To conduct a process evaluation of the main trial to assess implementation of the PAAP intervention and to produce recommendations for wider adoption in the NHS. Background and rationale The importance of AMR and the need to reduce its impact is well recognised.3 This proposal addresses one of the aims of the UK five-year AMR strategy: "conserve and steward the effectiveness of existing treatments."4 This can be achieved by identifying and removing barriers to optimal antimicrobial prescribing. Penicillins are the most commonly prescribed antimicrobials5,6 and remain first-line therapy for many common infections but a record of pen-allergy is common and has marked effects on antimicrobial prescribing.7-9 About 10% of the UK population self-report a pen-allergy but, importantly, fewer than 10% of these patients are truly allergic;1,10,11 consequently a significant proportion(~9%) of the population are potentially restricted access to highly effective penicillins. Pen-allergy records are associated with AMR; preliminary evidence from the US suggests that patients with a pen-allergy record are more likely to acquire multi-drug resistant bacteria, including MRSA.12,13 In preparation for this application, our preliminary investigation of 2million adult primary care patients(Appendix4) found that a lack of response to treatment and MRSA were significantly more common in patients with a pen-allergy record. The focus of AlaBAMA is false positive records of pen-allergy, how these affect prescribing and if a complex intervention aimed at verifying these records is clinically/cost effective. Patients with a pen-allergy are usually not prescribed penicillins10 but receive alternative, broad-spectrum antimicrobials14 which may lead to sub-optimal therapy, be associated with poorer longer term outcomes, and contribute to AMR.11,15 Our preliminary research found macrolide, tetracycline, cephalosporin, quinolone and clindamycin prescribing were all more common in patients with a record of pen-allergy compared to those without (Appendix4), and that antimicrobial prescriptions were almost twice as frequent in patients with a penicillin-allergy record. These differences were not explained by age, sex, or comorbidity. Limited evidence from USA suggests that antimicrobial-allergies affect health outcomes; increasing mortality, length of stay and costs.11 The large discrepancy between reported and true allergy rates suggests that introducing a pre-emptive pen-allergy assessment pathway(PAAP) for patients who are more likely to receive antimicrobials, could impact upon antimicrobial prescribing, yield patient benefits, limit AMR/Healthcare associated infection(HCAI) and deliver NHS cost savings.17-24 Research plan WORKSTREAM-1:-COMPLEX INTERVENTION DEVELOPMENT AND FEASIBILITY This workstream will:1) undertake design of a complex intervention to support and provide a PAAP for patients with a record of pen-allergy using contempo