How, why and when are delayed (back-up) antibiotic prescriptions used in primary care? A realist review integrating concepts of uncertainty in healthcare.

BACKGROUND: Antimicrobial resistance is a global patient safety priority and inappropriate antimicrobial use is a key contributing factor. Evidence have shown that delayed (back-up) antibiotic prescriptions (DP) are an effective and safe strategy for reducing unnecessary antibiotic consumption but its use is controversial. METHODS: We conducted a realist review to ask why, how, and in what contexts general practitioners (GPs) use DP. We searched five electronic databases for relevant articles and included DP-related data from interviews with healthcare professionals in a related study. Data were analysed using a realist theory-driven approach - theorising which context(s) influenced (mechanisms) resultant outcome(s) (context-mechanism-outcome-configurations: CMOCs). RESULTS: Data were included from 76 articles and 41 interviews to develop a program theory comprising nine key and 56 related CMOCs. These explain the reasons for GPs' tolerance of risk to different uncertainties and how these may interact with GPs' work environment, self-efficacy and perceived patient concordance to make using DP as a safety-net or social tool more or less likely, at a given time-point. For example, when a GP uses clinical scores or diagnostic tests: a clearly high or low score/test result may mitigate scientific uncertainty and lead to an immediate or no antibiotic decision; an intermediary result may provoke hermeneutic (interpretation-related) uncertainty and lead to DP becoming preferred and used as a safety net. Our program theory explains how DP can be used to mitigate some uncertainties but also provoke or exacerbate others. CONCLUSION: This review explains how, why and in what contexts GPs are more or less likely to use DP, as well as various uncertainties GPs face which DP may mitigate or provoke. We recommend that efforts to plan and implement interventions to optimise antibiotic prescribing in primary care consider these uncertainties and the contexts when DP may be (dis)preferred over other interventions to reduce antibiotic prescribing. We also recommend the following and have included example activities for: (i) reducing demand for immediate antibiotics; (ii) framing DP as an 'active' prescribing option; (iii) documenting the decision-making process around DP; and (iv) facilitating social and system support.

Probability of sepsis after infection consultations in primary care in the United Kingdom in 2002-2017: Population-based cohort study and decision analytic model.

BACKGROUND: Efforts to reduce unnecessary antibiotic prescribing have coincided with increasing awareness of sepsis. We aimed to estimate the probability of sepsis following infection consultations in primary care when antibiotics were or were not prescribed. METHODS AND FINDINGS: We conducted a cohort study including all registered patients at 706 general practices in the United Kingdom Clinical Practice Research Datalink, with 66.2 million person-years of follow-up from 2002 to 2017. There were 35,244 first episodes of sepsis (17,886, 51%, female; median age 71 years, interquartile range 57-82 years). Consultations for respiratory tract infection (RTI), skin or urinary tract infection (UTI), and antibiotic prescriptions were exposures. A Bayesian decision tree was used to estimate the probability (95% uncertainty intervals [UIs]) of sepsis following an infection consultation. Age, gender, and frailty were evaluated as association modifiers. The probability of sepsis was lower if an antibiotic was prescribed, but the number of antibiotic prescriptions required to prevent one episode of sepsis (number needed to treat [NNT]) decreased with age. At 0-4 years old, the NNT was 29,773 (95% UI 18,458-71,091) in boys and 27,014 (16,739-65,709) in girls; over 85 years old, NNT was 262 (236-293) in men and 385 (352-421) in women. Frailty was associated with greater risk of sepsis and lower NNT. For severely frail patients aged 55-64 years, the NNT was 247 (156-459) in men and 343 (234-556) in women. At all ages, the probability of sepsis was greatest for UTI, followed by skin infection, followed by RTI. At 65-74 years, the NNT following RTI was 1,257 (1,112-1,434) in men and 2,278 (1,966-2,686) in women; the NNT following skin infection was 503 (398-646) in men and 784 (602-1,051) in women; following UTI, the NNT was 121 (102-145) in men and 284 (241-342) in women. NNT values were generally smaller for the period from 2014 to 2017, when sepsis was diagnosed more frequently. Lack of random allocation to antibiotic therapy might have biased estimates; patients may sometimes experience sepsis or receive antibiotic prescriptions without these being recorded in primary care; recording of sepsis has increased over the study period. CONCLUSIONS: These stratified estimates of risk help to identify groups in which antibiotic prescribing may be more safely reduced. Risks of sepsis and benefits of antibiotics are more substantial among older adults, persons with more advanced frailty, or following UTIs.

Potential for reducing inappropriate antibiotic prescribing in English primary care.

Objectives: To identify and quantify inappropriate systemic antibiotic prescribing in primary care in England, and ultimately to determine the potential for reduction in prescribing of antibiotics. Methods: Primary care data from 2013-15 recorded in The Health Improvement Network (THIN) database were used. Potentially inappropriate prescribing events in the database were identified by: (i) comparing prescribing events against treatment guidelines; (ii) comparing actual proportions of consultations resulting in prescription for a set of conditions with the ideal proportions derived from expert opinion; and (iii) identifying high prescribers and their number of prescriptions above an age- and body-system-specific benchmark. Results: Applying the most conservative assumptions, 8.8% of all systemic antibiotic prescriptions in English primary care were identified as inappropriate, and in the least conservative scenario 23.1% of prescriptions were inappropriate. All practices had non-zero reduction potentials, ranging from 6.4% to 43.5% in the middle scenario. The four conditions that contributed most to inappropriate prescribing were sore throat (23.0% of identified inappropriate prescriptions), cough (22.2%), sinusitis (7.6%) and acute otitis media (5.7%). One-third of all antibiotic prescriptions lacked an informative diagnostic code. Conclusions: This work demonstrates (i) the existence of substantial inappropriate antibiotic prescribing and (ii) poor diagnostic coding in English primary care. All practices (not just the high prescribers) should engage in efforts to improve antimicrobial stewardship. Better diagnostic coding, more precise prescribing guidelines and a deeper understanding of appropriate long-term uses of antibiotics would allow identification of further potential for reductions.

Effect of Oral Dexamethasone Without Immediate Antibiotics vs Placebo on Acute Sore Throat in Adults: A Randomized Clinical Trial.

Importance: Acute sore throat poses a significant burden on primary care and is a source of inappropriate antibiotic prescribing. Corticosteroids could be an alternative symptomatic treatment. Objective: To assess the clinical effectiveness of oral corticosteroids for acute sore throat in the absence of antibiotics. Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial (April 2013-February 2015; 28-day follow-up completed April 2015) conducted in 42 family practices in South and West England, enrolled 576 adults recruited on the day of presentation to primary care with acute sore throat not requiring immediate antibiotic therapy. Interventions: Single oral dose of 10 mg of dexamethasone (n = 293) or identical placebo (n = 283). Main Outcomes and Measures: Primary: proportion of participants experiencing complete resolution of symptoms at 24 hours. Secondary: complete resolution at 48 hours, duration of moderately bad symptoms (based on a Likert scale, 0, normal; 6, as bad as it could be), visual analog symptom scales (0-100 mm; 0, no symptom to 100, worst imaginable), health care attendance, days missed from work or education, consumption of delayed antibiotics or other medications, adverse events. Results: Among 565 eligible participants who were randomized (median age, 34 years [interquartile range, 26.0-45.5 year]; 75.2% women; 100% completed the intervention), 288 received dexamethasone; 277, placebo. At 24 hours, 65 participants (22.6%) in the dexamethasone group and 49 (17.7%) in the placebo group achieved complete resolution of symptoms, for a risk difference of 4.7% (95% CI, -1.8% to 11.2%) and a relative risk of 1.28 (95% CI; 0.92 to 1.78; P = .14). At 24 hours, participants receiving dexamethasone were not more likely than those receiving placebo to have complete symptom resolution. At 48 hours, 102 participants (35.4%) in the dexamethasone group vs 75 (27.1%) in the placebo group achieved complete resolution of symptoms, for a risk difference of 8.7% (95% CI, 1.2% to 16.2%) and a relative risk of 1.31 (95% CI, 1.02 to 1.68; P = .03). This difference also was observed in participants not offered delayed antibiotic prescription, for a risk difference of 10.3% (95% CI, 0.6% to 20.1%) and a relative risk of 1.37 (95% CI, 1.01 to 1.87; P = .046). There were no significant differences in any other secondary outcomes. Conclusions and Relevance: Among adults presenting to primary care with acute sore throat, a single dose of oral dexamethasone compared with placebo did not increase the proportion of patients with resolution of symptoms at 24 hours. However, there was a significant difference at 48 hours. Trial Registration: isrctn.org Identifier: ISRCTN17435450.

Randomised controlled feasibility trial of a web-based weight management intervention with nurse support for obese patients in primary care.

BACKGROUND: There is a need for cost-effective weight management interventions that primary care can deliver to reduce the morbidity caused by obesity. Automated web-based interventions might provide a solution, but evidence suggests that they may be ineffective without additional human support. The main aim of this study was to carry out a feasibility trial of a web-based weight management intervention in primary care, comparing different levels of nurse support, to determine the optimal combination of web-based and personal support to be tested in a full trial. METHODS: This was an individually randomised four arm parallel non-blinded trial, recruiting obese patients in primary care. Following online registration, patients were randomly allocated by the automated intervention to either usual care, the web-based intervention only, or the web-based intervention with either basic nurse support (3 sessions in 3 months) or regular nurse support (7 sessions in 6 months). The main outcome measure (intended as the primary outcome for the main trial) was weight loss in kg at 12 months. As this was a feasibility trial no statistical analyses were carried out, but we present means, confidence intervals and effect sizes for weight loss in each group, uptake and retention, and completion of intervention components and outcome measures. RESULTS: All randomised patients were included in the weight loss analyses (using Last Observation Carried Forward). At 12 months mean weight loss was: usual care group (n = 43) 2.44 kg; web-based only group (n = 45) 2.30 kg; basic nurse support group (n = 44) 4.31 kg; regular nurse support group (n = 47) 2.50 kg. Intervention effect sizes compared with usual care were: d = 0.01 web-based; d = 0.34 basic nurse support; d = 0.02 regular nurse support. Two practices deviated from protocol by providing considerable weight management support to their usual care patients. CONCLUSIONS: This study demonstrated the feasibility of delivering a web-based weight management intervention supported by practice nurses in primary care, and suggests that the combination of the web-based intervention with basic nurse support could provide an effective solution to weight management support in a primary care context. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31685626.

Electronic health records for intervention research: a cluster randomized trial to reduce antibiotic prescribing in primary care (eCRT study).

PURPOSE: This study aimed to implement a point-of-care cluster randomized trial using electronic health records. We evaluated the effectiveness of electronically delivered decision support tools at reducing antibiotic prescribing for respiratory tract infections in primary care. METHODS: Family practices from England and Scotland participating in the Clinical Practice Research Datalink (CPRD) were included in the trial; 53 family practices were allocated to intervention and 51 practices were allocated to usual care. Patients aged 18 to 59 years consulting for respiratory tract infections were eligible. The intervention was through remotely installed, computer-delivered decision support tools accessed during the consultations. Control practices provided usual care. The primary outcome was the proportion of consultations for respiratory tract infections with an antibiotic prescribed based on electronic health records. Family practice-specific proportions were included in a cluster-level analysis. RESULTS: Data were analyzed for 603,409 patients: 317,717 at intervention practices and 285,692 at control practices. Use of the intervention was less than anticipated, varying among practices. There was a reduction in proportion of consultations with antibiotics prescribed of 1.85% (95% CI, 0.10%-3.59%, P=.038) and in the rate of antibiotic prescribing for respiratory tract infections (9.69%; 95% CI, 0.75%-18.63%, fewer prescriptions per 1,000 patient-years, P=.034). There were no adverse events. CONCLUSIONS: Cluster randomized trials may be implemented efficiently in large samples from routine care settings by using primary care electronic health records. Future studies should develop and test multicomponent methods for remotely delivered intervention.

Recruitment to a large scale randomised controlled clinical trial in primary care: the Helicobacter Eradication Aspirin Trial (HEAT).

BACKGROUND: The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter (H.) pylori eradication reduces hospitalisation for peptic ulcer bleeding. Recruited participants were aged 60 and over and taking aspirin (≤325 mg daily) for at least four months prior to consent. Based on results of a pilot study, a sample size calculation predicted 6600 H. pylori-positive randomised participants would be required, from 33,000 volunteers, recruited from 170,000 invited patients. Methodology was therefore designed for recruitment of large numbers of patients from primary care using a novel electronic search tool, automated mail-out and electronic follow-up. Recruitment started in 2012 and completed in 2017. METHODS: All participants were recruited from GP practices, with assistance from the UK Clinical Research Network (UKCRN). H. pylori-positive participants were randomised to one week of eradication treatment or placebo. Recruitment was managed using a bespoke web-based database that communicated directly with a programmed search tool downloaded at participating practices. The primary endpoint is hospitalisation due to peptic ulcer bleeding. The trial will end when 87 adjudicated events have occurred, identified from searches of GP databases, review of secondary care admission data and mortality data, and reported events from randomised participants and GPs. RESULTS: HEAT has recruited participants from 1208 GP practices across the UK. Of the 188,875 invitation letters sent, 38,771 returned expressions of interest. Of these, 30,166 patients were consented to the trial, of whom 5355 H. pylori-positive participants (17.8% of those consented) were randomised. Mean age at consent was 73.1 ± 6.9 (SD) years and 72.2% of participants were male. Of the randomised (H. pylori-positive) participants, 531 have died (as of 17 Sep 2020); none of the deaths was due to trial treatment. CONCLUSION: The HEAT trial methodology has demonstrated that recruitment of large numbers of patients from primary care is attainable, with the assistance of the UKCRN, and could be applied to other clinical outcomes studies. TRIAL REGISTRATION: ClinicalTrials.gov ; registration number NCT01506986 . Registered on 10 Jan 2012.

Aspirin to target arterial events in chronic kidney disease (ATTACK): study protocol for a multicentre, prospective, randomised, open-label, blinded endpoint, parallel group trial of low-dose aspirin vs. standard care for the primary prevention of cardiovascular disease in people with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a very common long-term condition and powerful risk factor for cardiovascular disease (CVD). Low-dose aspirin is of proven benefit in the secondary prevention of myocardial infarction (MI) and stroke in people with pre-existing CVD. However, in people without CVD, the rates of MI and stroke are much lower, and the benefits of aspirin in the primary prevention of CVD are largely balanced by an increased risk of bleeding. People with CKD are at greatly increased risk of CVD and so the absolute benefits of aspirin are likely to be greater than in lower-risk groups, even if the relative benefits are the same. Post hoc evidence suggests the relative benefits may be greater in the CKD population but the risk of bleeding may also be higher. A definitive study of aspirin for primary prevention in this high-risk group, recommended by the National Institute for Health and Care Excellence (NICE) in 2014, has never been conducted. The question has global significance given the rising burden of CKD worldwide and the low cost of aspirin. METHODS: ATTACK is a pragmatic multicentre, prospective, randomised, open-label, blinded endpoint adjudication superiority trial of aspirin 75 mg daily vs. standard care for the primary prevention of CVD in 25,210 people aged 18 years and over with CKD recruited from UK Primary Care. Participants aged 18 years and over with CKD (GFR category G1-G4) will be identified in Primary Care and followed up using routinely collected data and annual questionnaires for an average of 5 years. The primary outcome is the time to first major vascular event (composite of non-fatal MI, non-fatal stroke and cardiovascular death [excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage]). Deaths from other causes (including fatal bleeding) will be treated as competing events. The study will continue until 1827 major vascular events have occurred. The principal safety outcome is major intracranial and extracranial bleeding; this is hypothesised to be increased in those randomised to take aspirin. The key consideration is then whether and to what extent the benefits of aspirin from the expected reduction in CVD events exceed the risks of major bleeding. DISCUSSION: This will be the first definitive trial of aspirin for primary CVD prevention in CKD patients. The research will be of great interest to clinicians, guideline groups and policy-makers, in the UK and globally, particularly given the high and rising prevalence of CKD that is driven by population ageing and epidemics of obesity and diabetes. The low cost of aspirin means that a positive result would be of relevance to low- and middle-income countries and the impact in the developed world less diluted by any inequalities in health care access. TRIAL REGISTRATION: ISRCTN: ISRCTN40920200 . EudraCT: 2018-000644-26 . CLINICALTRIALS: gov: NCT03796156.

Prevalence and Antimicrobial Resistance of Bacteria in Children With Acute Otitis Media and Ear Discharge: A Systematic Review.

BACKGROUND: Of children with acute otitis media (AOM), 15%-20% present with acute onset ear discharge due to a spontaneous perforation of the tympanic membrane (AOMd). This review aims to quantify the prevalence and antimicrobial resistance (AMR) status of bacteria in children with AOMd in the pneumococcal conjugate vaccine (PCV) era. METHODS: Systematic searches were performed in PubMed, EMBASE and Cochrane Library from inception to June 7, 2019. Two reviewers extracted relevant data and assessed risk of bias independently. All English studies reporting any prevalence and/or AMR data of bacterial middle ear isolates from children with AOMd were included. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal checklist. RESULTS: Of 4088 unique records retrieved, 19 studies (10,560 children) were included. Overall quality was judged good. Streptococcus pneumoniae (median 26.1%, range 9.1%-47.9%), Haemophilus influenzae (median 18.8%, range 3.9%-55.3%), Staphylococcus aureus (median 12.3%, range 2.3%-34.9%) and Streptococcus pyogenes (median 11.8%, range 1.0%-30.9%) were the most prevalent bacteria. In 76.0% (median, range 48.7%-100.0%, 19 studies, 1,429 children) any bacterium was identified. AMR data were sparse and mainly limited to S. pneumoniae. We found no evidence of a clear shift in the prevalence of bacteria and AMR over time. CONCLUSIONS: In children with AOMd, S. pneumoniae and H. influenzae are the 2 predominant bacteria, followed by S. aureus and S. pyogenes in the post-PCV era. AMR data are sparse and no clearly change over time was observed. Ongoing surveillance of the microbiology profile in children with AOMd is warranted to guide antibiotic selection and to assess the impact of children's PCV status.

Topical or oral antibiotics for children with acute otitis media presenting with ear discharge: study protocol of a randomised controlled non-inferiority trial.

BACKGROUND: Around 15%-20% of children with acute otitis media present with ear discharge due to a spontaneous tear or perforation of the eardrum (AOMd). Current guidance recommends clinicians to consider oral antibiotics as first-line treatment in this condition. The opening in the eardrum however should allow topical antibiotics to enter the middle ear directly. Local administration of antibiotics does not expose children to systemic side effects and may put less selective resistance pressure on bacteria. Evidence on the effectiveness of this approach in children with AOMd is lacking. METHODS AND ANALYSIS: A primary care-based, open, individually randomised, controlled, non-inferiority trial. The trial aims to recruit 350 children aged 6 months to 12 years with AOMd and ear pain and/or fever. Participants will be randomised to 7 days of hydrocortisone-bacitracin-colistin eardrops five drops three times daily or amoxicillin oral suspension 50 mg/kg body weight per day, divided over three doses. Parents will keep a daily diary of AOM symptoms, adverse events and complications for 2 weeks. In addition, they will record AOM recurrences, healthcare utilisation and societal costs for 3 months. The primary outcome is the proportion of children without ear pain and fever at day 3. Secondary outcomes include ear pain and fever intensity/severity; days with ear discharge; eardrum perforation at 2 weeks; adverse events during first 2 weeks; costs; and cost effectiveness at 2 weeks and 3 months. The primary analyses will be intention-to-treat and per-protocol analyses will be conducted as well. ETHICS AND DISSEMINATION: The medical research ethics committee Utrecht, The Netherlands has given ethical approval (17-400/G-M). Parents/guardians of participants will provide written informed consent. Study results will be submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings. TRIAL REGISTRATION NUMBER: The Netherlands National Trial Register; NTR6723. Date of registration: 27 November 2017.

Immediate oral versus immediate topical versus delayed oral antibiotics for children with acute otitis media with discharge: the REST three-arm non-inferiority electronic platform-supported RCT.

BACKGROUND: Acute otitis media is a painful infection of the middle ear that is commonly seen in children. In some children, the eardrum spontaneously bursts, discharging visible pus (otorrhoea) into the outer ear. OBJECTIVE: To compare the clinical effectiveness of immediate topical antibiotics or delayed oral antibiotics with the clinical effectiveness of immediate oral antibiotics in reducing symptom duration in children presenting to primary care with acute otitis media with discharge and the economic impact of the alternative strategies. DESIGN: This was a pragmatic, three-arm, individually randomised (stratified by age < 2 vs. ≥ 2 years), non-inferiority, open-label trial, with economic and qualitative evaluations, supported by a health-record-integrated electronic trial platform [TRANSFoRm (Translational Research and Patient Safety in Europe)] with an internal pilot. SETTING: A total of 44 English general practices. PARTICIPANTS: Children aged ≥ 12 months and < 16 years whose parents (or carers) were seeking medical care for unilateral otorrhoea (ear discharge) following recent-onset (≤ 7 days) acute otitis media. INTERVENTIONS: (1) Immediate ciprofloxacin (0.3%) solution, four drops given three times daily for 7 days, or (2) delayed 'dose-by-age' amoxicillin suspension given three times daily (clarithromycin twice daily if the child was penicillin allergic) for 7 days, with structured delaying advice. All parents were given standardised information regarding symptom management (paracetamol/ibuprofen/fluids) and advice to complete the course. COMPARATOR: Immediate 'dose-by-age' oral amoxicillin given three times daily (or clarithromycin given twice daily) for 7 days. Parents received standardised symptom management advice along with advice to complete the course. MAIN OUTCOME MEASURE: Time from randomisation to the first day on which all symptoms (pain, fever, being unwell, sleep disturbance, otorrhoea and episodes of distress/crying) were rated 'no' or 'very slight' problem (without need for analgesia). METHODS: Participants were recruited from routine primary care appointments. The planned sample size was 399 children. Follow-up used parent-completed validated symptom diaries. RESULTS: Delays in software deployment and configuration led to small recruitment numbers and trial closure at the end of the internal pilot. Twenty-two children (median age 5 years; 62% boys) were randomised: five, seven and 10 to immediate oral, delayed oral and immediate topical antibiotics, respectively. All children received prescriptions as randomised. Seven (32%) children fully adhered to the treatment as allocated. Symptom duration data were available for 17 (77%) children. The median (interquartile range) number of days until symptom resolution in the immediate oral, delayed oral and immediate topical antibiotic arms was 6 (4-9), 4 (3-7) and 4 (3-6), respectively. Comparative analyses were not conducted because of small numbers. There were no serious adverse events and six reports of new or worsening symptoms. Qualitative clinician interviews showed that the trial question was important. When the platform functioned as intended, it was liked. However, staff reported malfunctioning software for long periods, resulting in missed recruitment opportunities. Troubleshooting the software placed significant burdens on staff. LIMITATIONS: The over-riding weakness was the failure to recruit enough children. CONCLUSIONS: We were unable to answer the main research question because of a failure to reach the required sample size. Our experience of running an electronic platform-supported trial in primary care has highlighted challenges from which we have drawn recommendations for the National Institute for Health Research (NIHR) and the research community. These should be considered before such a platform is used again. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12873692 and EudraCT 2017-003635-10. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 67. See the NIHR Journals Library website for further project information.

Ear infections are common in childhood. Some are complicated by a burst eardrum, followed by discharge from the ear. The usual treatment for this is a short course of antibiotics taken by mouth. However, alternative treatment using antibiotic drops, or a 'wait and see' policy before starting antibiotics, would result in less antibiotic use and reduce the subsequent risk of antibiotic resistance, which is bad for both patients and the environment. This study set out to see if these alternative treatments were as effective as the usual treatment for children with ear discharge. Although ear infections are common, only one in six children develops ear discharge, so only a few children might be available to take part at each general practice. We planned to use an electronic recruitment system to help us to gather enough patients. The system [called the 'TRANSFoRm' (Translational Research and Patient Safety in Europe) platform] was designed to remind busy general practitioners and nurses about the study and take them through the recruitment process step by step, as well as to support trial processes. Although the TRANSFoRm platform had been developed and tested, it had not been used in general practices before. We were surprised to find that there were many technical problems in setting up the TRANSFoRm platform in general practices, and staff were too busy and/or did not have the skills to overcome the technical issues. As a result, recruiting patients was slow and the study was halted before we had enough children to answer the main research question. In total, we managed to get 44 general practices and 22 children, but this was not enough. We still think that this kind of research and electronic trial platforms are important. We have noted many system and technical issues that need to be solved to enable funders and researchers to use this recruitment approach in the future.

Delayed Antibiotic Prescription by General Practitioners in the UK: A Stated-Choice Study.

Delayed antibiotic prescription in primary care has been shown to reduce antibiotic consumption, without increasing risk of complications, yet is not widely used in the UK. We sought to quantify the relative importance of factors affecting the decision to give a delayed prescription, using a stated-choice survey among UK general practitioners. Respondents were asked whether they would provide a delayed or immediate prescription in fifteen hypothetical consultations, described by eight attributes. They were also asked if they would prefer not to prescribe antibiotics. The most important determinants of choice between immediate and delayed prescription were symptoms, duration of illness, and the presence of multiple comorbidities. Respondents were more likely to choose a delayed prescription if the patient preferred not to have antibiotics, but consultation length had little effect. When given the option, respondents chose not to prescribe antibiotics in 51% of cases, with delayed prescription chosen in 21%. Clinical features remained important. Patient preference did not affect the decision to give no antibiotics. We suggest that broader dissemination of the clinical evidence supporting use of delayed prescription for specific presentations may help increase appropriate use. Establishing patient preferences regarding antibiotics may help to overcome concerns about patient acceptance. Increasing consultation length appears unlikely to affect the use of delayed prescription.

Effectiveness and safety of electronically delivered prescribing feedback and decision support on antibiotic use for respiratory illness in primary care: REDUCE cluster randomised trial.

OBJECTIVES: To evaluate the effectiveness and safety at population scale of electronically delivered prescribing feedback and decision support interventions at reducing antibiotic prescribing for self limiting respiratory tract infections. DESIGN: Open label, two arm, cluster randomised controlled trial. SETTING: UK general practices in the Clinical Practice Research Datalink, randomised between 11 November 2015 and 9 August 2016, with final follow-up on 9 August 2017. PARTICIPANTS: 79 general practices (582 675 patient years) randomised (1:1) to antimicrobial stewardship (AMS) intervention or usual care. INTERVENTIONS: AMS intervention comprised a brief training webinar, automated monthly feedback reports of antibiotic prescribing, and electronic decision support tools to inform appropriate prescribing over 12 months. Intervention components were delivered electronically, supported by a local practice champion nominated for the trial. MAIN OUTCOME MEASURES: Primary outcome was the rate of antibiotic prescriptions for respiratory tract infections from electronic health records. Serious bacterial complications were evaluated for safety. Analysis was by Poisson regression with general practice as a random effect, adjusting for covariates. Prespecified subgroup analyses by age group were reported. RESULTS: The trial included 41 AMS practices (323 155 patient years) and 38 usual care practices (259 520 patient years). Unadjusted and adjusted rate ratios for antibiotic prescribing were 0.89 (95% confidence interval 0.68 to 1.16) and 0.88 (0.78 to 0.99, P=0.04), respectively, with prescribing rates of 98.7 per 1000 patient years for AMS (31 907 prescriptions) and 107.6 per 1000 patient years for usual care (27 923 prescriptions). Antibiotic prescribing was reduced most in adults aged 15-84 years (adjusted rate ratio 0.84, 95% confidence interval 0.75 to 0.95), with one antibiotic prescription per year avoided for every 62 patients (95% confidence interval 40 to 200). There was no evidence of effect for children younger than 15 years (adjusted rate ratio 0.96, 95% confidence interval 0.82 to 1.12) or people aged 85 years and older (0.97, 0.79 to 1.18); there was also no evidence of an increase in serious bacterial complications (0.92, 0.74 to 1.13). CONCLUSIONS: Electronically delivered interventions, integrated into practice workflow, result in moderate reductions of antibiotic prescribing for respiratory tract infections in adults, which are likely to be of importance for public health. Antibiotic prescribing to very young or old patients requires further evaluation. TRIAL REGISTRATION: ISRCTN95232781.

Microbial epidemiology and carriage studies for the evaluation of vaccines.

Respiratory tract infections are responsible for over 2.8 million deaths per year worldwide. Colonization is the first step in the process of microbes occupying the respiratory tract, which may lead to subsequent infection. Carriage, in contrast, is defined as the occupation of microbial species in the respiratory tract. The duration of carriage may be affected by host immunity, the composition and interactions between members of the microbial community, and the characteristics of colonizing bacteria, including physiology associated with being present in a bacterial biofilm. Numerous vaccines have been implemented to control infections caused by bacteria that can colonize and be subsequently carried. Such vaccines are often species-specific and may target a limited number of strains thereby creating a vacant niche in the upper respiratory tract. Epidemiological changes of bacteria found in both carriage and disease have therefore been widely reported, since the vacant niche is filled by other strains or species. In this review, we discuss the use of carriage-prevalence studies in vaccine evaluation and argue that such studies are essential for (1) examining the epidemiology of carriage before and after the introduction of new vaccines, (2) understanding the dynamics of the respiratory tract flora and (3) identifying the disease potential of emerging strains. In an era of increasing antibiotic resistance, bacterial carriage-prevalence studies are essential for monitoring the impact of vaccination programmes.

Anaesthetic-analgesic ear drops to reduce antibiotic consumption in children with acute otitis media: the CEDAR RCT.

BACKGROUND: Acute otitis media (AOM) is a common reason for primary care consultations and antibiotic prescribing in children. Options for improved pain control may influence antibiotic prescribing and consumption. OBJECTIVE: The Children's Ear Pain Study (CEDAR) investigated whether or not providing anaesthetic-analgesic ear drops reduced antibiotic consumption in children with AOM. Secondary objectives included pain control and cost-effectiveness. DESIGN: A multicentre, randomised, parallel-group (two-group initially, then three-group) trial. SETTING: Primary care practices in England and Wales. PARTICIPANTS: 1- to 10-year-old children presenting within 1 week of suspected AOM onset with ear pain during the preceding 24 hours and not requiring immediate antibiotics. Participating children were logged into the study and allocated using a remote randomisation service. INTERVENTIONS: Two-group trial - unblinded comparison of anaesthetic-analgesic ear drops versus usual care. Three-group trial - blinded comparison of anaesthetic-analgesic ear drops versus placebo ear drops and unblinded comparison with usual care. MAIN OUTCOME MEASURES: The primary outcome measure was parent-reported antibiotic use by the child over 8 days following enrolment. Secondary measures included ear pain at day 2 and NHS and societal costs over 8 days. RESULTS: Owing to a delay in provision of the placebo drops, the recruitment period was shortened and most participants were randomly allocated to the two-group study (n = 74) rather than the three-group study (n = 32). Comparing active drops with usual care in the combined two-group and three-group studies, 1 out of 39 (3%) children allocated to the active drops group and 11 out of 38 (29%) children allocated to the usual-care group consumed antibiotics in the 8 days following enrolment [unadjusted odds ratio 0.09, 95% confidence interval (CI) 0.02 to 0.55; p = 0.009; adjusted for delayed prescribing odds ratio 0.15, 95% CI 0.03 to 0.87; p = 0.035]. A total of 43% (3/7) of patients in the placebo drops group consumed antibiotics by day 8, compared with 0% (0/10) of the three-group study active drops groups (p = 0.051). The economic analysis of NHS costs (£12.66 for active drops and £11.36 for usual care) leads to an estimated cost of £5.19 per antibiotic prescription avoided, but with a high degree of uncertainty. A reduction in ear pain at day 2 in the placebo group (n = 7) compared with the active drops group (n = 10) (adjusted difference in means 0.67, 95% CI -1.44 to 2.79; p = 0.51) is consistent with chance. No adverse events were reported in children receiving active drops. LIMITATIONS: Estimated treatment effects are imprecise because the sample size target was not met. It is not clear if delayed prescriptions of an antibiotic were written prior to randomisation. Few children received placebo drops, which hindered the investigation of ear pain. CONCLUSIONS: This study suggests that reduced antibiotic use can be achieved in children with AOM by combining a no or delayed antibiotic prescribing strategy with anaesthetic-analgesic ear drops. Whether or not the active drops relieved ear pain was not established. FUTURE WORK: The observed reduction in antibiotic consumption following the prescription of ear drops requires replication in a larger study. Future work should establish if the effect of ear drops is due to pain relief. TRIAL REGISTRATION: Current Controlled Trials ISRCTN09599764. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 34. See the NIHR Journals Library website for further project information. Alastair D Hay was funded by a NIHR Research Professorship (funding identifier NIHR-RP-02-12-012).

Ear infections are common in children < 10 years of age, with 40% of these children suffering from an ear infection at least once per year. During the infection, germs multiply in the confined space of the middle ear, resulting in a build-up of pressure that pushes on and stretches the ear drum. This causes severe pain and distress to the child, which in turn leads to disrupted family life. Although there is world-class evidence showing that antibiotics do not help, and the National Institute for Health and Care Excellence advises against their use, > 85% of UK children with middle ear infections (acute otitis media) are prescribed an antibiotic, which is a higher percentage than for any other childhood infection. Antibiotics do not treat the child's pain and, in most cases, they do not help to treat the infection (because many ear infections are caused by viruses that do not respond to antibiotics), but they can cause side effects (such as diarrhoea) and increase the problem of antibiotic resistance, which is a major public health concern. The Children's Ear Pain Study (CEDAR) wanted to find out whether or not painkilling ear drops [benzocaine­phenazone otic solution (Auralgan^®) currently manufactured by Pfizer Consumer Healthcare(Pfizer Inc., New York, NY USA)] can, by treating children's ear pain, reduce the number of parents giving their children antibiotics for acute otitis media. Children were given the painkilling drops, placebo (dummy) drops or usual care. The study found that, if the children were given the painkilling drops, significantly fewer of them were given antibiotics. Unfortunately, there were not enough children who took part in the study to change advice on how doctors treat ear infections. However, these results suggest that ear drops help reduce unnecessary antibiotic use and should be investigated in a further larger study.

Findings from a feasibility study to improve GP elicitation of patient concerns in UK general practice consultations.

OBJECTIVES: To establish: a) feasibility of training GPs in a communication intervention to solicit additional patient concerns early in the consultation, using specific lexical formulations ("do you have 'any' vs. 'some' other concerns?") noting the impact on consultation length, and b) whether patients attend with multiple concerns and whether they voiced them in the consultation. METHODS: A mixed-methods three arm RCT feasibility study to assess the feasibility of the communication intervention. RESULTS: Intervention fidelity was high. GPs can be trained to solicit additional concerns early in the consultation (once patients have presented their first concern). Whilst feasible the particular lexical variation of 'any' vs 'some' seemed to have no bearing on the number of patient concerns elicited, on consultation length or on patient satisfaction. The level of missing questionnaire data was low, suggesting patients found completion of questionnaires acceptable. CONCLUSION: GPs can solicit for additional concerns without increasing consultation length, but the particular wording, specifically 'any' vs. 'some' may not be as important as the placement of the GP solicitation. PRACTICE IMPLICATIONS: GPs can solicit early for additional concerns and GPs can establish patients' additional concerns in the opening of the consultation, which can help to plan and prioritise patients multiple concerns.

Ecology and diversity in upper respiratory tract microbial population structures from a cross-sectional community swabbing study.

PURPOSE: Respiratory tract infections (RTIs) are responsible for over 2.8 million deaths per year worldwide with pathobiont carriage a required precursor to infection. We sought to determine carriage epidemiology for both bacterial and viral respiratory pathogens as part of a large population-based cross-sectional carriage study. METHODOLOGY: Nose self-swab samples were collected in two separate time-points, May to August 2012 (late spring/summer) and February to April 2013 (winter/early spring). The presence of six bacterial species: S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, P. aeruginosa and N. meningitidis in addition to respiratory syncytial virus, influenza viruses A and B, rhinovirus/enterovirus, coronavirus, parainfluenza viruses 1-3 and adenovirus was determined using culture and PCR methods.Results/Key findings. Carriage was shown to vary with age, recent RTI and the presence of other species. Spatial structures of microbial communities were more disordered in the 0-4 age group and those with recent RTI. Species frequency distributions were flatter than random expectation in young individuals (X2=20.42, P=0.002), indicating spatial clumping of species consistent with facilitative relationships. Deviations from a neutral model of ecological niches were observed in summer samples and from older individuals but not in the winter or younger individuals (0-4 years), suggesting the presence of seasonal and age-dependent niche processes in respiratory community assembly. CONCLUSION: The application of epidemiological methods and ecological theory to respiratory tract samples has yielded novel insights into the factors that drive microbial community composition.

Yeast-derived ß-1,3/1,6 glucan, upper respiratory tract infection and innate immunity in older adults.

OBJECTIVE: The aims of this study were to test whether yeast-derived ß-1,3/1,6 glucan can prevent the occurrence or reduce the severity of upper respiratory tract infection (URTI) and modulate innate immune responses during winter months in community-dwelling older adults. METHODS: This was a double-blind placebo-controlled trial of community-dwelling adults ages 50 to 70 y randomized to once-daily ß-1,3/1,6 glucan (Wellmune 250 mg/d; n = 50) or identical placebo capsule (n = 50) over 90 d during winter. URTI episodes were medically confirmed. Symptom severity was recorded via self-reported daily Wisconsin Upper Respiratory Tract Infection Score 21. Blood and saliva samples were collected at days 0, 45, and 90 for measurements of innate immune parameters. RESULTS: Forty-nine participants completed the trial in each group. Supplementation was well tolerated. Forty-five URTIs were confirmed: 28 in the placebo group and 17 in the Wellmune group (odds ratio, 0.55; 95% confidence interval, 0.24-1.26; P = 0.149). There was a strong trend for Wellmune to decrease the number of symptom days (P = 0.067). Symptom severity did not differ significantly between groups. Compared with the placebo group, lipopolysaccharide-stimulated blood from participants in the Wellmune group showed an increase in interferon-γ concentration from baseline at day 45 (P = 0.016) and smaller decreases in monokine induced by interferon-γ concentration from baseline at days 45 and 90 (P = 0.032 and 0.046, respectively). No difference was seen in serum or nonstimulated blood cytokines and chemokines or in salivary immunoglobulin A. CONCLUSION: Daily oral ß-1,3/1,6 glucan may protect against URTIs and reduce the duration of URTI symptoms in older individuals once infected. This may be linked to effects on innate immune function. Larger studies are needed to confirm the benefits of ß-1,3/1,6 glucan on URTIs in this older population.

Randomised controlled trial and economic analysis of an internet-based weight management programme: POWeR+ (Positive Online Weight Reduction).

BACKGROUND: Behavioural counselling with intensive follow-up for obesity is effective, but in resource-constrained primary care settings briefer approaches are needed. OBJECTIVES: To estimate the clinical effectiveness and cost-effectiveness of an internet-based behavioural intervention with regular face-to-face or remote support in primary care, compared with brief advice. DESIGN: Individually randomised three-arm parallel trial with health economic evaluation and nested qualitative interviews. SETTING: Primary care general practices in the UK. PARTICIPANTS: Patients with a body mass index of ≥ 30 kg/m2 (or ≥ 28 kg/m2 with risk factors) identified from general practice records, recruited by postal invitation. INTERVENTIONS: Positive Online Weight Reduction (POWeR+) is a 24-session, web-based weight management intervention completed over 6 months. Following online registration, the website randomly allocated participants using computer-generated random numbers to (1) the control intervention (n = 279), which had previously been demonstrated to be clinically effective (brief web-based information that minimised pressure to cut down foods, instead encouraging swaps to healthier choices and increasing fruit and vegetables, plus 6-monthly nurse weighing); (2) POWeR+F (n = 269), POWeR+ supplemented by face-to-face nurse support (up to seven contacts); or (3) POWeR+R (n = 270), POWeR+ supplemented by remote nurse support (up to five e-mails or brief telephone calls). MAIN OUTCOME MEASURES: The primary outcome was a modelled estimate of average weight reduction over 12 months, assessed blind to group where possible, using multiple imputation for missing data. The secondary outcome was the number of participants maintaining a 5% weight reduction at 12 months. RESULTS: A total of 818 eligible individuals were randomised using computer-generated random numbers. Weight change, averaged over 12 months, was documented in 666 out of 818 participants (81%; control, n = 227; POWeR+F, n = 221; POWeR+R, n = 218). The control group maintained nearly 3 kg of weight loss per person (mean weight per person: baseline, 104.4 kg; 6 months, 101.9 kg; 12 months, 101.7 kg). Compared with the control group, the estimated additional weight reduction with POWeR+F was 1.5 kg [95% confidence interval (CI) 0.6 to 2.4 kg; p = 0.001] and with POWeR+R was 1.3 kg (95% CI 0.34 to 2.2 kg; p = 0.007). By 12 months the mean weight loss was not statistically significantly different between groups, but 20.8% of control participants, 29.2% of POWeR+F participants (risk ratio 1.56, 95% CI 0.96 to 2.51; p = 0.070) and 32.4% of POWeR+R participants (risk ratio 1.82, 95% CI 1.31 to 2.74; p = 0.004) maintained a clinically significant 5% weight reduction. The POWeR+R group had fewer individuals who reported doing another activity to help lose weight [control, 47.1% (64/136); POWeR+F, 37.2% (51/137); POWeR+R, 26.7% (40/150)]. The incremental cost to the health service per kilogram weight lost, compared with the control group, was £18 (95% CI -£129 to £195) for POWeR+F and -£25 (95% CI -£268 to £157) for POWeR+R. The probability of being cost-effective at a threshold of £100 per kilogram was 88% and 98% for POWeR+F and POWeR+R, respectively. POWeR+R was dominant compared with the control group. No harms were reported and participants using POWeR+ felt more enabled in managing their weight. The qualitative studies documented that POWeR+ was viewed positively by patients and that health-care professionals generally enjoyed supporting patients using POWeR+. STUDY LIMITATIONS: Maintenance of weight loss after 1 year is unknown. FUTURE WORK: Identifying strategies for longer-term engagement, impact in community settings and increasing physical activity. CONCLUSION: Clinically valuable weight loss (> 5%) is maintained in 20% of individuals using novel written materials with brief follow-up. A web-based behavioural programme and brief support results in greater mean weight loss and 10% more participants maintain valuable weight loss; it achieves greater enablement and fewer participants undertaking other weight-loss activities; and it is likely to be cost-effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN21244703. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 4. See the NIHR Journals Library website for further project information.