Introduction

Background and rationale

This research was proposed in response to the National Institute for Health Research (NIHR)’s call for proposals on antimicrobial drug resistance (AMR). There is growing concern that the widespread, and sometimes unnecessary, use of antibiotics is leading to the development of AMR.1,2 In economic terms, the antimicrobial effect of drugs may be viewed as a natural resource. Antimicrobial resistance represents a negative externality of antibiotic use. If resistant organisms persist over time, then the resource of antibiotic drugs will be exhaustible.3,4 Reducing inappropriate use of antibiotics, as well as ensuring that antibiotics can be used when they are needed, represents an important component of a strategy to control infectious diseases.5

Governments of all countries need to adopt a stewardship role so as to ensure that effective antimicrobial drugs are available to future generations.1 This should include responding to the requirement to improve governance and standards of clinical practice with respect to antimicrobial drug utilisation. The present research addresses a subject of great public health importance because overutilisation of antibiotics contributes to the emergence of AMR and, consequently, infections that may be very difficult to treat. The review on antimicrobial resistance,2 chaired by Jim O’Neill, identified education and training to reduce inappropriate and unnecessary antibiotic use as key measures to fight AMR. This research specifically aims to address the problem of inappropriate and unnecessary prescribing of antibiotics to patients with self-limiting respiratory tract infections (RTIs) in primary care.

Self-limiting respiratory tract infections in primary care

Self-limiting RTIs, including colds, sore throats, cough, bronchitis, rhinosinusitis and otitis media, represent common reasons for consultation with a general practitioner (GP).6 Each year there are about 200 consultations for RTIs per 1000 registered patients in primary care.7 Antibiotics are prescribed at about 50% of all RTI consultations,8 with RTIs commonly stated to account for about 60% of all antibiotics prescribed in primary care. There are substantial age-related differences in consultations for RTIs, with children < 5 years of age having extremely high consultation rates.9 However, on a per-consultation basis, antibiotic prescribing at RTI consultations generally increases with age.9,10

Most respiratory infections are self-limiting without specific treatment.11 Antibiotic treatment generally offers minimal benefit in terms of duration and severity of symptoms, but may be associated with side effects such as diarrhoea or rashes.12,13 Patients prescribed antibiotics are more likely to believe that this is an effective treatment and are more likely to consult in future.11 The small minority of individuals who may benefit from antibiotics can be positively identified through indicators of severity of illness or comorbidity.6 Patterns of microbial colonisation begin to change soon after antibiotics are started, leading to the emergence of drug-resistant organisms.14

Databases of primary care electronic health records (EHRs), such as the Clinical Practice Research Datalink (CPRD), provide an important resource for understanding the epidemiology and public health impact of respiratory infections and antibiotic prescribing in primary care. Previous research using the CPRD showed that there has been a long-term decline in consultation for RTIs.7 During the 1990s, following the publication of the Standing Medical Advisory Committee’s report, The Path of Least Resistance,15 there was some reduction in the proportion of consultations at which antibiotics were prescribed, but there was little change in antibiotic prescribing for RTIs after 2000.7

Recent CPRD analyses for 2012 from the eCRT (a cluster randomised trial using electronic records)8,16 showed that antibiotics are prescribed for about one-third of consultations with patients presenting with common colds, more than half of consultations with patients presenting with sore throat or otitis media and about 90% of consultations with patients presenting with sinusitis. In the context of treatment recommendations that advise that most acute respiratory infections can be managed without antibiotics, these data clearly indicate an opportunity to make a major impact on unnecessary antibiotic prescribing.

There are striking variations between general practices in the rates of consultation and antibiotic prescribing for RTIs.8 The rate of antibiotic prescribing per 1000 registered patients is always less than the consultation rate for RTIs; this is consistent with an overall prescribing proportion of between 50% and 60%. In the CPRD, in 2012, < 1% of general practices prescribed antibiotics at < 20% of RTI consultations, other general practices prescribed antibiotics at > 80% of RTI consultations, with 89% of general practices prescribing antibiotics at > 40% of RTI consultations. Most general practices are unaware of their pattern of antibiotic prescribing for particular indications, and its standing in relation to their peers, with only aggregated data for all antibiotic prescriptions dispensed being generally available for performance management.8 Some antibiotic-prescribing indicators based on aggregated data for prescriptions dispensed for general practices in England can be viewed through the OpenPrescribing website (https://openprescribing.net; accessed October 2018).

Linder17 observed that nearly all general practices are currently prescribing antibiotics at rates that are ‘way off the mark’ in the context of good practice recommendations, which advise that most RTIs can be managed without the prescription of antibiotics.6 Based on this guidance, most practices might optimally be prescribing antibiotics at considerably fewer RTI consultations. For example, in the Netherlands, antibiotics are prescribed at a little over 20% of RTI consultations.18 These CPRD data suggest that considerable reductions in antibiotic utilisation for RTIs are necessary in UK primary care. The then prime minister, David Cameron, pledged to half inappropriate antibiotic prescribing by 2020. This raises a question concerning how reductions in antibiotic prescribing can be achieved.

Evidence from previous trials and systematic reviews

Strategies to reduce unnecessary antibiotic prescribing have been tested in a number of previously published randomised controlled trials (RCTs). Ranji et al.19,20 performed a systematic review up to 2007. In 30 trials contributing to a quantitative analysis, Ranji et al. found a median reduction of 9.7% [interquartile range (IQR) 6.6–13.7%] in the proportion of participants receiving antibiotics. Most studies employed educational activities aimed at clinicians or patients, an audit of antibiotic prescribing with feedback of results or a combination of these interventions. More recent trials have demonstrated similar reductions in antibiotic utilisation (Table 1), with a reduction in antibiotic prescribing of up to 15%, as reported by Little et al.21 These recent trials have used similar intervention strategies, but have more frequently used electronic media to deliver advice on appropriate prescribing.21,26

Some authors recommend a delayed antibiotic-prescribing strategy, in which a prescription is issued but used only if symptoms fail to improve. This approach is sometimes recommended as a method for reducing antibiotic utilisation in the management of RTIs.27

Systematic reviews28,29 of the wider implementation science literature are also informative in identifying features of audit and feedback or decision support that are associated with greater intervention effects. Ivers et al.28 found that feedback was more effective when performance is suboptimal, when feedback is given in written and verbal formats, and when explicit targets and actions are recommended. Roshanov et al.29 found that clinical decision support systems were more likely to be effective when these required active measures before they could be over-ridden or if patient information was provided in addition to clinician information.

The eCRT

The systematic review and recent trials are important in identifying strategies that may be effective at changing prescribers’ behaviour. However, previous trials required resource-intensive interventions and these intervention techniques have not yet been translated on a wide and sustainable scale into the NHS. For example, the trial by Gonzales et al.23 required clinicians to participate in a half-day training session, triage nurses to provide patients with education leaflets to read before their consultation, a specially designed structured template to be programmed into the practice system to provide an algorithm-based probability of the patient having pneumonia, and ‘order sets’ to be created for group diagnosis and treatment options for different types of RTIs. The challenge now is to take the components of intervention that have been shown to be effective and to find methods to deploy these efficiently into routine practice settings.

The methods of deploying the components of the intervention into routine practice settings have been investigated in the recently completed eCRT, which involved cluster randomisation of general practices that contribute EHRs to a national primary care database, the CPRD.16 The study included 104 general practices in England and Scotland. Decision support tools (DSTs) were delivered remotely to general practices. The effectiveness of the intervention was evaluated by analysing EHRs that are routinely collected into the database. Data were analysed for > 600,000 individual participants, with a financial cost of about 27 pence per participant. Even with a very simple intervention, the trial showed a near 2% reduction in antibiotic prescribing. This eCRT showed that it was feasible to use the CPRD to evaluate interventions that may be readily scaled up to the population level. Feedback received in the eCRT process evaluation,30 together with evidence from other trials cited above, identifies ways to increase engagement in the intervention and increase effect sizes.

Safety outcomes

Material in this section is reproduced from Gulliford et al.31 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/.

The present research also addresses the safety of reducing antibiotic prescribing in primary care. There may be well-grounded clinical concern that reducing antibiotic use might increase the risk of complications following RTIs. Clinical trial evidence suggests that antibiotics may reduce the risk of suppurative complications of RTIs,13 but the more serious complications are generally too rare to evaluate precisely in randomised studies. Petersen et al.32 conducted a cohort study in 162 general practices in the General Practice Research Database (the predecessor of the CPRD) from 1991 to 2001 to evaluate the effect of antibiotic treatment on the incidence of pneumonia after ‘chest infection’, peritonsillar abscess after sore throat, and mastoiditis after otitis media. The results suggested that antibiotic treatment was associated with lower odds of each these complications, but the overall risk of complications was generally small and the number of patients who would have to be treated to avoid one complication was estimated to be in excess of 4000. However, pneumonia following chest infection was more frequent. In people aged < 65 years, it was estimated that there might be one case for every 100 antibiotic prescriptions for chest infection avoided, and one case for every 39 prescriptions avoided in people aged > 65 years. Infections of the middle ear or sinuses may rarely be complicated by intracranial abscess.33 Lemierre syndrome,34 from thrombophlebitis of the internal jugular vein associated with Fusobacterium necrophorum infection, is a rare complication of sore throat,34 but F. necrophorum infections may be frequently detectable in patients with symptoms of sore throat.35,36 The annual number of cases of Lemierre syndrome in England was reported to have increased from 19 in 1997 to 34 in 1999, prompting a reminder from the Chief Medical Officer that some sore throat symptoms may require antibiotic treatment.37 In addition to concerns about complications, medical practitioners may be concerned about the potential consequences of diagnostic misclassification. The initial symptoms of meningitis may sometimes resemble an influenza-like illness.38 Awareness of the possibility of a more serious diagnosis might prompt GPs to issue an antibiotic prescription for conditions in which this is not usually indicated.

These observations raise important questions for a policy to reduce antibiotic prescribing for RTIs in primary care: is there a safe level of antibiotic prescribing for RTIs? What target can general practices safely adopt in reducing the proportion of RTI consultations with antibiotics prescribed? Is there a threshold for antibiotic prescribing below which complications may increase? An additional aim was added to the present research to evaluate the safety of a policy to reduce antibiotic prescribing for RTIs in primary care. The incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess and Lemierre syndrome was evaluated. The study aimed to determine whether or not these complications were more frequent at general practices that prescribe fewer antibiotics for self-limiting RTIs than at higher-prescribing practices. The use of this information was aimed to quantify the potential clinical and public health impact of changes in antibiotic-prescribing practices.

Evidence explaining why this research is needed now

The recent systematic review, together with the additional, more recent, trials, show that interventions to modify prescribing behaviour in primary care can be effective. However, there is a block in the translational pathway because it has not been possible to roll-out this evidence into routine practice; antibiotic prescribing for RTIs remains high outside trial settings. There is a lack of effective interventions that can easily be translated, in a sustained way, into routine practice settings. This research aimed to use the strengths of EHRs to inform, deliver and evaluate an intervention. This will be achieved with a high degree of efficiency by employing at the research environment a database of EHRs accessed through the CPRD.

This research is at a later stage of translation than previous trials. In order to overcome the block in the translational pathway, the study aimed to develop and evaluate more effective complex multicomponent interventions that can be implemented and delivered remotely. Development of the interventions was informed by evidence from recent trials, as well the process evaluation of the eCRT study.30 The research focused on deployment of interventions with potential to be readily scaled up, through remote delivery using electronic media, to large samples of unselected practices. The present research built on previous experience of implementing the eCRT within the CPRD. In the eCRT, the intervention was an educational and DST39 that aimed to support evidence-based antibiotic prescribing for respiratory illness in primary care. The intervention was installed remotely at practices and utilisation of the intervention was monitored.

The approach of utilising the EHRs of the CPRD to provide the environment for delivering and testing the interventions has several advantages:

1. both the interventions and a cluster randomised trial of the interventions can be implemented at a very low cost
2. the sample available for the study is nationally representative for the UK and large sample sizes are expected
3. the sustainability of the effect of the intervention may be evaluated after the end of the trial, because data continue to be collected from trial practices
4. utilisation of the intervention can be routinely monitored through electronic information routinely collected into EHRs
5. a cost-effectiveness analysis may be implemented using data on health-care utilisation, which are collected for all patients in CPRD40
6. translation of the trial results is readily feasible because the interventions are delivered using the practice systems that are employed in delivering routine care within the NHS.

Aim and objectives

Aim

This main aim of this research was to test the effectiveness, in a cluster RCT, of electronically delivered, multicomponent interventions to reduce unnecessary antibiotic prescribing when patients consult for RTIs in primary care.

Objectives

Specific objectives were to:

1. Develop, refine and implement complex multicomponent interventions, but low-cost interventions, to influence GPs’ prescribing of antibiotics when patients consult with RTIs. The intervention comprised:
   1. feedback of monthly updated antibiotic-prescribing information from the CPRD as a major novel component
   2. educational and DSTs, which include a summary of antibiotic-prescribing recommendations, a summary of research evidence concerning no antibiotic-prescribing strategies, information on the definite indications for antibiotic prescription, information and evidence on the risks from non-prescribing and patient information
   3. brief web-based training (a webinar) to introduce, provide training on and promote effective utilisation of the intervention materials.
2. Conduct a parallel-group cluster RCT, with general practices as the unit of allocation, over 12 months to estimate the difference between intervention and control practices in primary outcome (i.e. antibiotic prescription rate per 1000 patients) and secondary outcomes (i.e. proportion of RTI consultations with antibiotics prescribed, RTI consultations, subgroups of age, gender, comorbidity and infection type and intervention utilisation, safety outcomes and costs of health-care utilisation), in an intention-to-treat analysis.
3. Conduct a population-based cohort study in general practices not exposed to trial interventions to determine whether or not the incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess or Lemierre syndrome is higher at general practices that prescribe fewer antibiotics for self-limiting RTIs.