Title: Penicillin allergy status and its effect on antimicrobial prescribing, patient outcomes, and antimicrobial resistance. Short title: ALABAMA: Allergy AntiBiotics And Microbial resistAnce
Funder: Department of Health and Social Care

Abstract: 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: &ldquo;conserve and steward the effectiveness of existing treatments.&rdquo;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 contemporary behaviour change theory and qualitative research following MRC guidelines; and, 2) undertake a feasibility trial to assess safety, acceptability and practicality of delivering a PAAP trial of the PAAP intervention. STOP/GO DECISION TO PROCEED TO WORKSTREAM-2 Criteria to be pre-agreed and reviewed by AlaBAMA-TSC/Advisory Board with the NIHR. WORKSTREAM-2:-EVALUATION AND IMPLEMENATION OF PAAP This workstream will:1) deliver a RCT to evaluate effectiveness, safety and cost-effectiveness of the PAAP intervention versus usual clinical care on health outcomes, antimicrobial prescribing and AMR; 2) conduct a process evaluation to assess implementation of the PAAP intervention and produce recommendations for wider NHS uptake. Outputs and dissemination plans PAAP-intervention for NHS implementation (see Appendix-2:-Tables 3&4). Dissemination: We will work closely with our AlaBAMA Advisory Board: Allergy UK, British Society for Allergy and Clinical Immunology(BACSI), commissioners and GP eHR system providers to inform policy on wider adoption of PAAP and improved integration of pen-allergy test results into patients eHR to maximize impact on patients and antimicrobial stewardship. Publications/Conferences: We plan: Open-access Gold, high impact, publications from workstreams1&2 and additional green open-access publications e.g. for the AlaBAMA Trial protocol [see:-Appendix-2:-Table 4]. Each workstream will deliver presentations at international/national conferences. A final dissemination event for patients/public key stakeholders, Advisory Board and participating sites to include wider NHS implementation/adoption guidance. Benefits to patients, society and the NHS Potential patients benefits: if pen-allergy status is changed, first-line penicillin treatment for many infections can resume. Potential societal benefits: changes in antimicrobial prescribing/reduced AMR. Potential NHS benefits: reduced cost from improved outcomes, fewer GP visits, altered antimicrobial use.

Lay abstract: Background Antibiotics are important medicines for fighting infections caused by bacteria. Their widespread use has caused a worrying rise in antibiotic resistant bacteria, which are bacteria that are harder to control or kill with antibiotics. Patients with infections caused by antibiotic resistant bacteria are often ill for longer and have an increased risk of death. We can slow the spread of resistant bacteria by using antibiotics more carefully. Penicillins are an important group of antibiotics that are recommended treatment for many infections. About 1 in 10 people think they are allergic to penicillin, often because they once developed a rash while ill and taking penicillin. Rashes are common with infections and are often mistaken for allergy. It is usual for a &ldquo;penicillin allergy label&rdquo; in primary care electronic health records (eHR) to alert doctors to avoid penicillins and prescribe different types of antibiotics for their patients. We are concerned that these different types of antibiotics may not work as well as penicillins, may cause more side-effects (including killing more of the body s &ldquo;helpful&rdquo; bacteria), and may be more expensive. Recent research has also found that patients with a penicillin-allergy label may have a higher risk of infection with resistant bacteria and may not do as well as people without this label. However, about 9 out of 10 people who believe they are penicillin-allergic are found not to be when tested, and so could safely take penicillins. These patients may be receiving less effective antibiotic treatments with additional long-term health risks. Aim To find out if people with a penicillin-allergy label in their GP health records really do have an allergy by specialist testing, and to see if we can reduce the number of patients wrongly labelled as penicillin allergic. We will find out if this results in better use of antibiotics and fewer days of symptoms, when patients are prescribed antibiotics for infection. Design and methods &bull; To design a &ldquo;penicillin allergy assessment pathway(PAAP)&rdquo; that offers a complete penicillin-allergy testing method for use in the NHS that includes ways to change how patients and doctors behave towards allergy testing. &bull; To find out what problems we might have using PAAP in a clinical trial. &bull; To test the benefits and safety of PAAP compared to usual patient care in a clinical trial. &bull; To understand how best to use PAAP in the NHS. Patient and public involvement(PPI) and patient benefits. PPI has helped us design a trial which aims to: 1) improve access to penicillin-allergy testing; 2) improve patient outcomes related to infection e.g. fewer days of symptoms; 3) reduce antibiotic prescriptions and reduce resistant bacteria; 4) benefit the NHS by saving GP time and improving value for money.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION