Main findings of the intervention development study
The intervention development study led to the refinement of the intervention materials for the trial, including electronically delivered antibiotic-prescribing reports and DSTs, supported by a webinar. The development study also provided insights into the preparedness of health professionals to engage in this antimicrobial stewardship intervention. The analysis revealed two main themes: the perception that the problem of overprescribing is not individually applicable and the perception that the researchers responsible for planning interventions in primary care do not understand how general practices operate.
Participants considered that they were not personally responsible for high levels of antibiotic prescribing, sometimes taking the view that the problem of overprescribing did not apply to them. This is inconsistent with analysis of data from 568 UK general practices contributing to the CPRD, which showed an overall antibiotic-prescribing proportion of between 50% and 60% for RTIs.8 Such rates of prescribing suggest that most UK GPs and NPs prescribe at rates in excess of the current recommendations.17 This perception may result from the ‘better than average effect’72 – a phenomenon in which people perceive themselves as special and feel that a special set of psychological rules apply to them. McKay and Dennett73 have argued that the illusion of superiority is an evolved human trait, serving an adaptive function by motivating adaptive behaviours. This illusion of superiority might be resistant to modification and should be recognised as part of normal human functioning.
A second overarching theme was the perception that researchers do not understand the demands of general practice. Most of the clinicians interviewed considered that clinical uncertainty concerning RTIs was low and were confident in diagnosing RTIs. However, convincing patients that antibiotics are not needed for a RTI episode was time-consuming and frustrating, and this perception was strengthened by the high-pressure working environment. Many participating GPs expressed the view that they have been de-professionalised in the process of achieving targets and pursing financial incentives, to the detriment of patient-centred care. Some GPs perceived certain elements of the intervention as being potentially unhelpful, with frequent audits being inconsistent with patient demands. The small risk of adverse complications representing an important concern in the context of performance review. These factors combined undermine GPs’ sense of professional competency and create anxiety. Therefore, it is possible that the intervention was not perceived as a possible source of support for GPs, resulting in less likelihood of using these tools. Similar barriers have been reported in the implementation literature,74,75 literature on GP morale76,77 and studies exploring the reasons why GPs leave practice early.78
Although participants expressed concerns about the target-driven NHS culture and de-professionalised role of a GP, at the same time a majority of interviewed clinicians considered that funding to incentivise antibiotic reduction initiatives should be provided, as this would demonstrate the importance of reducing antibiotic prescribing to the NHS and would promote engagement.79,80 Although the introduction of the pay-for-performance scheme in the NHS in 2004/2005 was associated with some improvements in quality of care for chronic diseases, evidence also suggest that practices divert their attention to activities associated with incentives.81 It is possible that the scheme has contributed to the paradox reported by clinicians in this study, when they recognise the negative aspects of the target paradigm (i.e. improvements are achieved at the expense of those aspects of care that are not incentivised) and when clinicians are focused on ‘ticking the boxes’ rather than demonstrating empathy towards the patient.
Previous reviews of qualitative data suggest that GPs would welcome interventions that would bring benefits once implemented into general practice.82 One such benefit in the REDUCE trial intervention is decreased workload, as patients who are not prescribed antibiotics for RTIs are less likely to consult in the future.83 However, interviewed clinicians were concerned that involvement would have negative consequences in terms of workload and time. It is possible, therefore, that the tools developed for this study were not successful at conveying the message that the intervention would not disrupt usual daily practice and might bring future benefits in terms of a reduced number of consultations for RTIs.
The results demonstrate the potential limitations of implementing individual-level interventions, even when informed by a substantial understanding of user perspective and grounded in well-established behaviour change theory. A review of interventions to reduce unnecessary antibiotic prescribing found only a modest reduction of 9.7% (interquartile range 6.6–13.7%) in the proportion of patients receiving antibiotics.20 More recent studies have achieved similar reductions, although the GRACE [Genomics to combat Resistance against Antibiotics for Community-acquired lower respiratory tract infection (LRTI) in Europe] trial reported a reduction of 15%.21 Factors identified in this study, such as lack of perception of personal responsibility for changing antibiotic prescribing, might be less amenable to individual-level interventions. Attempts to curtail the clinical autonomy of GPs are likely to be counterproductive and the findings suggest that approaches aligned to the professional values of GPs are likely to be more acceptable.
Limitations of the intervention development study
The intervention development study included a convenience sample of GPs and NPs from non-trial practices. It is possible that those who volunteered for the study could be more motivated by, for example, vocational interest or a sense of professional duty. It is also not known whether the GPs recruited were comparable either with the national GP profile (e.g. representing group vs. single handed practices) or with those who later took part in the trial. The study cannot be sure whether or not intervention development respondents represented a mix of low and high antibiotic prescribers. The results of the interview study might overestimate the importance of individual-level factors and underestimate the importance of patient-level factors, organisational factors and the cultural and social context. Each interview was conducted using the same interview guide, but the differences in interviewing styles might have elicited different responses. Finally, this study asked clinicians about hypothetical, rather than the actual, use of the intervention, reducing the generalisability of our findings. Previous research suggests that initial scepticism and belief that the intervention would not be beneficial diminished over time and with experience in using the intervention that may not have been captured in our study.84
Main findings of the cluster randomised trial
The cluster randomised trial evaluated the effectiveness of a complex electronically delivered intervention including antibiotic-prescribing reports and DSTs, supported by a webinar, at reducing antibiotic prescribing for self-limiting RTIs to people of all ages in primary care. The study provided evidence that these interventions might be associated with lower overall antibiotic prescribing for RTIs in primary care, but, given the size of the trial, this evidence may not be viewed as strong. This might be accounted for, in part, by the wide variations in practice that exist. It was observed that antibiotic utilisation for RTIs is patterned by age, with children accounting for a high proportion of all RTI consultations and antibiotic prescriptions.9 There was no evidence that the intervention was effective at reducing antibiotic prescribing to children or the very old. In the adult population aged 15–84 years, there was evidence that antibiotic utilisation for RTIs was 16% lower in the intervention trial arm. The reduction in antibiotic utilisation was greater at practices that used the trial DSTs more frequently, which suggests a causal association. The study did not find evidence that the secondary outcome of proportion of RTI consultations with antibiotics prescribed was reduced. There was no evidence that the costs of health-care utilisation differed between trial arms over the course of the trial.
The agreed aim of the study, following discussion between the study team and the funders, was to address antibiotic prescribing in people of all ages. The trial general practice prescribing reports presented data aggregated across age groups. This was justified because any effective strategy must be shown to reduce antibiotic utilisation across the whole population. The results of the trial suggest that future interventions should stratify feedback and advice by age group. The trial DSTs specifically addressed common diagnostic concerns in children, including otitis media and cough and bronchitis. Prescribing to the youngest and oldest age groups may be more difficult to modify because safety concerns may be more salient at these ages. More research is needed to evaluate safety outcomes for more vulnerable subgroups of the population.
Strengths and limitations of the cluster randomised trial
The trial was conducted in the context of system-wide efforts to reduce unnecessary antibiotic prescribing in primary care. The NHS introduced an incentive known as the ‘Quality Premium’ to encourage reduced antibiotic utilisation. Antimicrobial stewardship interventions became available from a number of national and local sources. Perhaps as a result of some of these interventions, the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) found that there was a 13% decrease in the number of antibiotic prescriptions dispensed from GP settings between 2012 and 2016. These system-wide interventions will have ‘contaminated’ both trial arms of the study. It is possible that a greater intervention effect might have been observed in their absence.
The intervention materials were successfully delivered into intervention trial arm practices. The DSTs were triggered when a Read code was entered into the general practice system. Thus, there was no control over the exact point during the consultation at which the intervention would be triggered. Practitioners had discretion over whether or not to view the intervention materials; viewing of the materials was not ‘forced’ through active-alerting or ‘pop-ups’ because these have been associated with negative feedback in previous studies. The study included a large sample of general practices. These were drawn from all parts of the UK including England, Scotland, Wales and Northern Ireland, including all registered patients in trial analyses. These features of the study enhanced the external validity of the study. However, it is possible that general practices that agreed to take part in the study might be more motivated to reduce antibiotic prescribing. At the time of the study, data could only be used from CPRD general practices employing the Vision practice system, many of which, during the course of the study, migrated to other practice systems and thus could not provide data to the REDUCE trial. There was a smaller pool of eligible practices than anticipated, the final number of practices included was smaller than originally intended and several practices were unable to continue with the trial before the end of the intervention period because they transferred to a different practice system. It should be noted that since this study was completed, the CPRD has increased its coverage to almost 1000 practices [the majority of which use the EMIS GP software system (EMIS Health, London, UK)] and the CPRD general practice coverage continues to grow. Data from EMIS practices could not be used in this study, but data are planned to be made available for future studies with the CPRD. Additionally, there was very wide variation in antibiotic prescribing, with different general practices prescribing antibiotics at as few as 12% or as many as 78% of RTI consultations. The sample size calculation did not allow for this overdispersion. Interventions might offer little benefit to those practices that had low prescribing rates. Consequently, the effect of intervention was not estimated precisely and there may be a risk of overlooking small effects that could be of clinical or public importance. Based on prespecified subgroup analysis, the study identified effects in adults aged 15–84 years. Interpretation of effects for subgroups carries a risk of false-positive interpretation. However, it was found that utilisation of intervention DSTs was associated with effect size, which points to a causal association. The study analysed data for antibiotic prescriptions issued by trial general practices. Patients may have received antibiotic prescriptions at consultations with walk-in centres and out-of-hours or emergency services; some antibiotic prescriptions may have been issued as delayed or deferred prescriptions but not recorded as such. It is possible that these alternative patterns of antibiotic utilisation differed between the trial arms, potentially contributing to biased assessment of intervention effects. It is also possible that altered diagnostic code selection may have occurred in order to justify antibiotic prescriptions.85 There was necessarily no blinding of general practice staff to the intervention, which included feedback of counts of antibiotic prescriptions that were the outcome for the study. The study employed a hierarchical random-effects model for analysis. This provided estimates that can be interpreted as being conditional on cluster/general practice membership. Marginal population-averaged estimates are sometimes recommended in randomised trials, but Lee and Nelder86 showed that marginal predictions may also be obtained from a conditional model and this will usually have advantages compared with a marginal model. The data obtained from general practices showed evidence of overdispersion, but models were fitted that allow for overdispersion and these provided similar estimates. There was some evidence for regional variation in intervention effects and these could be investigated further, perhaps through qualitative research.
At the design stage of the project, it was concluded, through discussion with a health economist, that attempting a cost-effectiveness analysis would not be appropriate for this project. The study focused on the costs of health-care utilisation on the grounds that decision-makers need to be aware of whether or not an intervention leads to overall increased costs. The study did not identify any difference in health-care utilisation between general practices in the intervention and control trial arms. However, the study did not have access to linked Hospital Episode Statistics data for all trial practices, which would have strengthened the assessment of hospital utilisation. The research was conducted within the set of general practices contributing to the CPRD, which represents an existing research infrastructure. The CPRD draws on a single general practice information system; practices were further selected for this study that used, or were prepared to use, the DXS system. The immediate costs of delivering the intervention comprised the fees paid to the CPRD and DXS for work on the trial and for EHR data, as well as costs of staff time and materials for developing the intervention materials. The resources required to roll out a similar intervention into routine practice in the NHS might differ. On the one hand, economies of scale might reduce the marginal cost of delivering the intervention to a single general practice. On the other hand, there will be significant logistical challenges associated with working across general practices that employ different practice systems, sometimes with no established systems for data collection and analysis. Consequently, further feasibility work to evaluate resource requirements and logistical issues will be required before any possible scaling up of these interventions. Caution is also needed, as the intervention effects estimated in this 12-month trial might not be sustained in the longer term.
Comparison of trial results with other studies
Previous studies of audit and feedback interventions show that these often have only small effects.29 Roshanov et al.29 found that feedback interventions that provide advice to patients as well as physicians are associated with a greater chance of success. This was exemplified in the REDUCE trial DSTs, which offered patient information leaflets that could be viewed online or printed, as well as offering advice to physicians on the recognised indications for giving an antibiotic prescription. A recent trial reported on the outcome of quarterly feedback on antibiotic utilisation over 2 years among 2900 Swiss physicians.87 Over the first and second years of the trial, there was no difference in antibiotic prescribing to all patients. The study found that there was nearly a 5% lower antibiotic utilisation to adults aged 19–65 years in the second year of the study, but not in the first year. The study appeared to identify age-related changes in prescribing that were not consistent over time. However, there are important differences from the present study because the feedback employed by Hemkens et al.87 was less immediate (this study provided monthly rather than quarterly feedback) and because Switzerland already has very low antibiotic prescribing rates.88 A study of dental practices in Scotland, which might account for 10% of community antibiotic prescribing, found that feedback of past antibiotic prescription data were associated with a 5.7% relative reduction in antibiotic prescribing over 12 months.89 Audit and feedback have also been employed successfully to reduce other forms of high-risk prescribing in primary care.90 Antibiotic prescribing to children was investigated by Cabral et al.;91 the authors reported an analysis of four qualitative studies. Their analysis suggested that both parents and clinicians view children as being more vulnerable to the risks associated with RTIs. For parents and for doctors, giving an antibiotic prescription are viewed as safe courses of action. ‘Failing’ to intervene appropriately was anticipated to incur future disapproval from peers.91 Similar considerations may influence the management of very old people. The development of clearer criteria for the prescribing of antibiotics to these more vulnerable groups is desirable.92
Main findings of the cohort study of 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 study used a large data set of EHRs to investigate the safety of reducing unnecessary antibiotic prescribing for RTIs in primary care. The results show that non-trial general practices that prescribe fewer antibiotics for respiratory infections may expect to have a higher incidence of pneumonia and peritonsillar abscess than higher-prescribing general practices. If a general practice, with an average list size of 7000 patients, reduced the proportion of RTI consultations with antibiotics prescribed by 10%, it might encounter about one additional case of pneumonia each year and one additional case of peritonsillar abscess each decade. Changes will be proportionately greater for larger reductions in antibiotic prescribing. These estimates represent averages across general practice populations, but complications might be fewer than expected if GPs are able to effectively stratify antibiotic prescribing on the basis of the level of risk. There was no evidence that diagnoses of mastoiditis, empyema, bacterial meningitis or intracranial abscess might increase. Lemierre syndrome was rare, with about one case per 2 million person-years, but there was no evidence that this was more frequent at low-prescribing practices. This is reassuring in view of recent suggestions that F. necrophorum may often be present in patients with sore throat.36 These estimates must be viewed in the context of quantitatively important declining secular trends in incidence for several infective complications of RTIs, including peritonsillar abscess, mastoiditis and meningitis. Bacterial meningitis from pneumococcal, meningococcal or Haemophilus infection has declined following the introduction of vaccination programmes.93 However, the incidence of pneumonia showed a slight increase over time, consistent with previous studies based on hospital admissions.94,95
Reducing the proportion of RTI consultations with antibiotics prescribed by 10% is expected to be accompanied by some 2000 fewer antibiotic prescriptions per practice over a 10-year period. Benefits to individual patients from avoiding antibiotics include reductions in common adverse reactions to antibiotics (including rashes, vomiting and diarrhoea), which may affect 10% of patients,12 as well as less common side-effects, such as anaphylaxis. Benefits to general practices may include a demedicalisation of RTIs followed by a decline in the consultation rate, as previous observational studies show higher-prescribing general practices attract more consultations for RTIs.83 Trial evidence shows that even one antibiotic prescription increases the likelihood of re-consultation with a new episode of RTI.11 Most of the ‘complications’ identified do not require hospital admission and, currently, respond well to antibiotics, so simply the occurrence of an uncommon complication rates is not in itself a reason to justify more widespread prescribing of antibiotics for initially uncomplicated presentations. There was no evidence for a threshold between ‘safe’ or ‘unsafe’ prescribing levels. Inspection of forest plots suggested some departure from linearity, but the addition of non-linear terms did not improve the goodness of fit of regression models.
Strengths and weaknesses of the cohort study in relation to other studies
Previous studies have consistently demonstrated high levels of unnecessary prescribing of antibiotics for RTIs in primary care.96 Although there has been a declining trend in the consultation rate for RTIs,7 there has been little change in the proportion of consultations with antibiotics prescribed in the UK7 in spite of the efforts of researchers, clinicians and policy-makers to bring about changes. This is in contrast to Sweden, where there has been a long-term decline in antibiotic prescribing for respiratory indications without evidence of increased risk of bacterial complications.97 General practitioners may often be concerned to meet patients’ expectations for antibiotic prescriptions,98 but both patients and prescribers may also have concerns about the safety of non-prescribing strategies.98 Petersen et al.32 provided evidence that antibiotics reduced the risk of pneumonia, mastoiditis and peritonsillar abscess (quinsy), but did not quantify the potential population impact of these complications.
The present results represent averages across general practice populations. There is considerable diversity among the population of patients at risk of RTIs. Current management guidelines for RTIs recommend that specific groups of patients should be considered to have positive indications for antibiotic treatment.12 An immediate antibiotic prescription is recommended if patients are very unwell, or have clinical features suggestive of serious illness or complications,99 or if comorbidity is present, or the patient is very young or very old. Further research is needed to evaluate whether or not the present results will be confirmed when subgroups that may be at higher risk, including older adults, are analysed separately. It is possible that general practices with the same overall level of antibiotic prescribing may differ in the appropriateness of their management of patients with defined markers of vulnerability and this could influence the rate of complications. However, the clinical features of a RTI episode may have only limited predictive value for the future occurrence of complications, and a high proportion of complications may occur in patients who appeared to be at low risk.100 A delayed antibiotic-prescribing strategy, in which a prescription is issued but used only if symptoms fail to improve, is sometimes recommended as a method for reducing antibiotic utilisation in the management of RTIs.27 Delayed antibiotic prescribing may be as effective as immediate use of antibiotics in the prevention of complications of sore throat.101 The development and application of point-of-care testing to guide antibiotic prescribing may have a future role in identifying individuals who may benefit from antibiotic treatment.102,103
Strengths and weaknesses of the cohort study
This study comprised > 600 general practices, with a registered population of > 4 million patients and 45 million person-years of observation. Consequently, the study provided very precise estimates for the more frequent outcomes evaluated. It is acknowledged that there was lower power to evaluate potential changes in less frequent outcomes. It can be concluded that the absolute risks of mastoiditis, empyema, intracranial abscess or Lemierre syndrome remain small even in low-prescribing practices. This study adopted a population perspective, aiming to quantify the outcomes of either high- or low-prescribing strategies in the management of RTIs. Consequently, the study evaluated changes in infective complications at the level of the general practice population. The research did not address variation in prescribing at the level of the individual physician. The research did not show whether or not individual patients who experienced complications received antibiotics. Conclusions might differ if individual-level analyses showed that complications arise in patients who were treated with antibiotics. This study did not evaluate the outcomes of individual patients who were diagnosed with complications. Further research is required to evaluate the severity of complications, such as pneumonia, and their outcomes, including mortality. Future studies might also make use of linked hospital episode data, which are available for selected CPRD practices in England in more recent years, in order to evaluate hospitalised cases in more detail. The risk of complications associated with different classes of antibiotics also merits study. It is acknowledged that there may be other complications, such as a proportion of all cases of septicaemia diagnosed in primary care, which might follow from RTIs. The study acknowledges several sources of misclassification: the study used a sample of the CPRD to estimate consultation and prescribing rates; there is variation among general practices in the use of diagnostic categories;85 general practice populations may vary in their use of out-of-hours and emergency services, whose generally higher antibiotic prescribing may not be captured in the CPRD; and some general practices may use delayed antibiotic-prescribing strategies,101 but these were not distinguished in the analysis of prescriptions issued. It is also possible that use of near-patient testing may have contributed to better diagnosis during the period. These forms of misclassification will generally tend to diminish estimated associations, but might cause bias if effects are differentially distributed across prescribing categories. Diagnostic coding may have a subjective element104 and bias might arise if low-prescribing practices are more likely than high-prescribing practices to code ‘pneumonia’ in order to justify the prescription of an antibiotic. The research utilised non-randomised data, and the data were adjusted for age, gender, region, deprivation category and general practice, but it is possible that unmeasured confounders might have biased the reported associations. Caution is required in the analysis of large data sets; ‘significant’ results must be judged in relation to their clinical importance. Antibiotic prescribing in the UK is high compared with some international comparators, and the study cannot be sure that the associations reported here would also hold at very low antibiotic-prescribing levels.
Conclusions
The study identified a range of views that may influence GPs’ acceptance of an intervention addressing the problem of inappropriate antibiotic prescribing to patients with RTIs. Primary care prescribers may tend to deny personal responsibility for overprescribing and may not engage with the intervention as having relevance for them. Such individual attitudinal barriers might suggest that solutions need to be developed and implemented at an organisational level as well as, or instead of, at the individual practitioner level. It appears likely that barriers to active engagement in research interventions identified in this study might go beyond antibiotic prescribing and this might suggest a need to shift the focus of research towards less individual-based approaches, as well as addressing the possible negative attitudes of individual health professional. These findings might be useful for researchers, professional organisations and guideline developers who engage in designing interventions for primary care.
This research successfully conducted an efficient trial to evaluate the effectiveness of electronically delivered antimicrobial stewardship interventions in a large population. The study included 79 general practices, with a registered population of > 600,000 people. The study found evidence that, overall, general practice antibiotic prescribing for RTI is reduced by these electronically delivered interventions. The imprecise result reflected very wide variations in clinical practice. The study found evidence that antibiotic prescribing might be reduced by 16% in adults aged 15–84 years, but not in children or very old people. This finding is consistent with previous research that shows that parents and doctors may be cautious in their management of children. It can be concluded that future intervention strategies for antimicrobial stewardship should employ stratified interventions that are tailored to the needs and concerns of specific age groups, with reporting of antibiotic utilisation disaggregated by age.
There was no evidence from trial data that any safety outcomes might be increased through interaction with the intervention. The larger cohort study in non-trial practices provides evidence that general practices that prescribe antibiotics less frequently at consultations for RTIs may experience a slight increase in the incidence of pneumonia and peritonsillar abscess, which would be expected to respond to treatment while bacterial pathogens remain sensitive to antibiotics. No increase in mastoiditis, empyema, meningitis, intracranial abscess or Lemierre syndrome is likely. Even a large reduction in antibiotic prescribing was predicted to be associated with only a small increase in numbers of cases observed over a 10-year period, and this would be expected to reduce the risks of antibiotic resistance, the side effects of antibiotics and, the medicalisation of largely self-limiting illnesses. The safety outcomes of no antibiotic-prescribing strategies for RTIs are an important aspect for communication to patients and the public in the context of wider communication strategies to support antimicrobial stewardship.105
Research recommendations
This research provides some evidence to support scaling up the interventions employed in this trial. The research illustrates the value of using EHR data to provide practitioners with detailed feedback on antibiotic prescribing for particular prescribing indications. Any decision to scale up should be made in the context of the changing policy environment, current antibiotic stewardship policies, advances in computerised decision support design, the need for increased patient involvement in design and awareness of the possible waning of effect over time among other considerations. The contributions of pharmacists, microbiologists and health economists with expertise in antimicrobial stewardship will also be essential.
Interventions need to be developed and implemented at an organisational level as well, or instead of, at the individual practitioner level. It appears likely that barriers to active engagement in research interventions identified in this study might go beyond antibiotic prescribing and this might suggest a need to shift the focus of research towards less individual-based approaches.
It is recommended that future research should develop and test age-stratified interventions specifically focusing on antibiotic prescribing for more vulnerable age groups.
Research should further investigate the safety of no prescribing strategies using individual patient data, a more systematic selection of safety outcomes and analyses that specifically address vulnerable groups.