Antimicrobial stewardship – can we afford to do without it?

Abstract

Antimicrobial resistance (AMR) is a rapidly developing and alarming global threat which has been highlighted by national governments and public health bodies including the World Health Organization. The spectre of a ‘post-antibiotic era’ is a real possibility unless curtailing the development and spread of these organisms is given high priority. Numerous studies have shown that AMR is associated with worse outcomes for patients and higher healthcare costs. While clinical data from low and middle income countries is lacking, there is increasing evidence that the problem in these areas is as great, or even greater, than in high income nations. Of the many drivers behind the development of AMR, the most significant is selection pressure caused by antibiotic use. Antimicrobial stewardship programmes are a set of interventions that aim to ensure the judicious use of antimicrobials by preventing their unnecessary use, and by providing targeted and limited therapy in situations where they are warranted. The ultimate goal of these programmes is to provide effective antimicrobial therapy whilst safeguarding their effectiveness for future generations. Whilst they do require an initial investment, they have been shown to be an effective way of controlling antimicrobial use, and have been associated with improved patient outcomes and reduced healthcare costs.

Introduction

‘In the absence of urgent corrective and protective actions, the world is heading towards a post-antibiotic era, in which many common infections will no longer have a cure and, once again, kill unabated.’

Dr Margaret Chan, WHO Director-General, 2011

Antimicrobial resistance (AMR) is a rapidly developing and alarming global health problem, which poses difficulties for the management of individual patients and healthcare systems, and for public health policy as a whole. AMR has been shown to result in worse outcomes for patients in terms of morbidity and mortality, as well as increased healthcare costs 1–3, with additional expense estimated as high as US$ 4–5 billion per year in the United States 4 and €9 billion per year in Europe 5. The most recent threat, carbapenem-resistant organisms (CRO), carry resistance determinants known as metallo-β-lactamases. These enzymes confer resistance to almost all β-lactams, and have been found to be disseminated globally 6 (Figure 1). New antimicrobials have been slow to come to the market and there is therefore an urgent need to preserve the efficacy of antimicrobials in the armoury currently available to us 7 (Figure 2). Antimicrobial stewardship programmes are a set of interventions that aim to ensure the judicious use of antimicrobials by preventing their unnecessary use, and by providing targeted and limited therapy in situations where they are warranted. The ultimate goal of these programmes is to provide effective antimicrobial therapy whilst safeguarding their effectiveness for future generations, and they have been shown to be an effective way of controlling antimicrobial use 8–10.

Figure 1.

Worldwide dissemination of different metallo-β-lactamases (Cornaglia et al. 6)

Figure 2.

FDA approvals of new antibiotics by 5 year period (updated from IDSA 7)

There are a number of drivers behind the development of AMR, but the most significant is selection pressure caused by antibiotic use, whether appropriate or inappropriate (Figure 3). The rate at which resistance occurs and the extent to which it spreads can therefore be modified by human behaviour such as management of hygiene, sanitation, infection control policy and, most importantly, antibiotic consumption 11. There is also growing concern about the transmission of resistant bacteria through the food chain, as antimicrobials are used worldwide therapeutically, prophylactically and as growth promoters in animal husbandry 12. This topic, however, is beyond the scope of this article, which focuses on antimicrobial stewardship in humans.

Figure 3.

Drivers behind antimicrobial resistance

There is ample evidence that antibiotic use drives antibiotic resistance. Data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) shows that the frequency of resistance at country level correlates with antibiotic consumption 13. In Canada, an increase in fluoroquinolone prescriptions per capita was found to be associated with an increased frequency of pneumococci with reduced susceptibility to fluoroquinolones in patients aged 15 to 64 years 14. In the UK it has also been shown that exposure to antibiotics in primary care doubles the risk of antibiotic resistance in respiratory and urinary bacteria for up to 12 months after treatment 15,16. There is also clear evidence that antibiotics have been used, and continue to be used, inappropriately. Numerous studies have estimated the level of unnecessary antimicrobial use to be around 50% in the USA 17,18, with similar proportions reported in Europe 19.

Low and middle income countries

There is a paucity of clinical data on antibiotic resistance, and this is particularly the case in resource-poor settings. A review in 2005 found that whilst surveillance of resistance in many low and middle income countries is suboptimal, it appears that there are accelerating rates of resistance due to inappropriate antibiotic use, inadequate infection control and lack of public health policy 20,21. They found a high, and increasing, prevalence of resistance in significant pathogens including Salmonella enterica, non-typhoidal salmonella, Shigella flexneri, Vibrio cholerae, Streptococcus pneumoniae, Mycobacterium tuberculosis and Neisseria gonorrhoeae.

There is evidence that low resource settings have a higher proportion of antibiotic use 22 as well as a higher proportion of inappropriate prescriptions 23. The WHO has reported that in low and middle income countries, less than 40% of patients in the public and 30% in the private sector are treated in accordance with clinical guidelines. Less than 60% of children with acute diarrhoea receive appropriate oral rehydration therapy, but more than 40% receive unnecessary antibiotics. Similarly, only 50–70% of patients with pneumonia are appropriately treated with antibiotics, yet up to 60% of patients with viral upper respiratory tract infections receive unnecessary antibiotics 5. It should be noted that underdosing of antibiotics, due to lack of access or inadequate courses being prescribed or purchased, is also problematic, because it leads to bacterial exposure to subtherapeutic concentrations of antibiotic and drives resistance. In addition, use of an inappropriate antibiotic due to lack of access to appropriate agents will likely lead to a poor clinical outcome as well as selection pressure for resistance in the absence of any clinical benefit.

Low and middle income countries face fewer resources with which to mobilize a systematic approach, as well as differing levels of political will to engage with the problem of antibiotic resistance. They also have a high proportion of antimicrobials being dispensed over the counter (OTC), which further complicates the regulation of antimicrobial use. A recent systematic review of the literature from 1970 to 2009 showed that worldwide, OTC sales accounted for 19%–100% of antimicrobial use outside of northern Europe and North America 24. The dissemination of poor quality and counterfeit antimicrobials is also a massive problem, which disproportionately affects poorer countries 25,26. Limiting the dispensing of antimicrobials only to those with a prescription from a qualified medical professional can be difficult to achieve in many developing countries for a number of reasons, not least because of the need to allow access to medicines in areas where there is a lack of qualified health workers 27. This adds a layer of complexity to the implementation of stewardship programmes in these regions. It should be noted, however, that regulations prohibiting the sale of certain antibiotics without prescription has not always achieved a reduction in overall consumption 28. The reasons for this are unclear but it has been posited that it may be due to a lack of other interventions including education of prescribers and consumers.

Whilst there is a lack of clinical data on AMR from studies in the developing world, travel to developing countries has been shown to be a risk factor for colonization with resistant organisms in areas of low endemicity. A study of Swedish patients published this year found that patients with ESBL-producing E. coli were significantly more likely to have travelled to Asia, Turkey, the Middle East and Egypt than patients who were not ESBL carriers 29. Another study in 2008 found international travel to be a risk factor for developing ESBL-producing E. coli infections in Calgary, Canada 30. ProMED mail recently reported a case of a Dutch male who returned to Holland following a 2 week admission to a hospital in Egypt after he developed appendicitis on holiday. He was found to be colonized with various multi-drug resistant bacterial strains, including an NDM-1-producing Klebsiella pneumoniae. In addition, his family members who had visited him in hospital were found to be colonized with one or more extended-spectrum-beta-lactamase producing strains 31. This raises the suggestion that travellers returning from endemic regions should be screened for resistant enterobacteriaceae on admission to hospital, a practice which has now begun in many hospitals in the UK. It also highlights the fact that AMR does not respect national borders, and that global interventions are necessary.

Aims of antimicrobial stewardship programmes

‘Antimicrobial stewardship refers to coordinated interventions designed to improve and measure the appropriate use of antimicrobial agents by promoting the selection of the optimal antimicrobial drug regimen including dosing, duration of therapy and route of administration. The major objectives of antimicrobial stewardship are to achieve best clinical outcomes related to antimicrobial use while minimizing toxicity and other adverse events, thereby limiting the selective pressure on bacterial populations that drives the emergence of antimicrobial-resistant strains. Antimicrobial stewardship may also reduce excessive costs attributable to suboptimal antimicrobial use.’ 32

Achieving the above, as set out by the Infectious Diseases Society of America in 2012, is no simple task. It involves a coordinated and sustained response with input from a number of different healthcare executives who are invested in clinical governance: infectious disease physicians to provide clinical liaison and lead on education programmes for prescribing physicians, clinical pharmacologists to aid with writing guidelines and provide specialist knowledge about altered effects of pharmacokinetics and pharmacodynamics in hospitalized patients, clinical pharmacists to provide expertise on dosing, toxicity and novel agents and microbiology laboratory staff and hospital epidemiologists to provide input on local resistance patterns. A comprehensive programme will include:

• the development of guidelines for treatment of common infections and empiric regimens based on local microbiology surveillance and resistance patterns

• establishing the correct dosing regimens and duration of therapy

• evaluation of new agents, preferably with a more targeted spectrum of activity, for addition to the formulary, as well as removal of redundant agents

• an antibiotic restriction programme, for example using a system of prior approval by an infection specialist, to prevent excessive use of agents which are broad spectrum, last-line, expensive or particularly toxic

• antibiotic ‘streamlining’ or de-escalation guidance, to facilitate the change from broad to narrow spectrum agents, or intravenous to oral

• an ongoing educational programme

• continuing monitoring and audit of antibiotic usage patterns with feedback to the prescribing clinicians 33.

Each programme must be region-specific and constantly under review given that resistance patterns change, requiring changes to local policy of, for example, empirical antibiotic choice. It will also require financial investment from the institution in which it is located to cover, e.g. additional staffing requirements in the departments of infectious diseases or pharmacy, and technology such as computer-assisted prescribing programs. A number of studies, however, have shown that the cost saving effects of antimicrobial stewardship programmes outweighs the resource allocation to establish and maintain them 8,9,34. It is worth noting however, that any potential cost savings will be dependent on a number of factors in the institution, including baseline antibiotic use and rates of AMR. Depending on the setting, it may be difficult to demonstrate cost-effectiveness in the short to medium term, and there may be situations in which antimicrobial stewardship interventions will carry a financial cost.

In the hospital setting, the main aim should be to reduce unnecessary use of broad spectrum antibiotics 11. Whilst broad spectrum antibiotics are in some cases clearly warranted, evidence suggests that in most hospital patients, the use of narrow spectrum agents which are broadened in cases of clinical failure or confirmed resistance is a reasonable and safe approach to take 35. The UK Department of Health Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infections published guidance on antimicrobial stewardship in November 2011, entitled ‘Start Smart – then Focus’ 36, the key elements of which are shown in Figure 4.

Figure 4.

‘Start Smart – then Focus’, UK DOH 35

The aims of stewardship programmes should not be in opposition to, but complement programmes that promote the rapid identification and treatment of patients with severe infections. For example, in the Surviving Sepsis campaign, set up in 2002 with the aim of reducing deaths from sepsis by 25% in the following 5 years, one of the key components is prompt administration of broad-spectrum antibiotics, within 1 h. in cases of life-threatening sepsis. The hospital setting should also not be our only focus, as studies in primary care have also consistently shown excessive antibiotic use, with one study in the UK demonstrating that the number needed to treat with antibiotics for acute non-specific respiratory infection in order to avoid one admission due to pneumonia was 12 255 37. Given that the majority of patients and antibiotic prescriptions are in primary care, there is a clearly a need to develop programmes in the community setting.

Antibiotic stewardship programmes can and do involve a number of different interventions, which can broadly be described as persuasive or restrictive. Persuasive interventions involve advising physicians how to prescribe or providing feedback on prescriptions. Restrictive interventions limit prescriptions using strategies such as formulary restriction of antimicrobials, prior approval of prescriptions by infection specialists, streamlining of empiric broad spectrum agents to more targeted narrow spectrum ones, and computer-assisted programs to facilitate safe and appropriate prescribing 33. A Cochrane review performed to estimate the impact of antibiotic stewardship interventions on hospital inpatients in 2005 found that restrictive interventions led to a significantly greater change than persuasive interventions in antibiotic prescribing at 1 month and microbial outcomes at 6 months. However, there were no significant differences at 12 or 24 months 38. Restrictive policies are arguably the easiest to enforce, as well as being the easiest to monitor and audit. However, it can be argued that such policies may actually drive resistance by applying unmitigated selection pressure to certain bacteria. Chisholm et al. suggest that such a policy has led to a progressive loss of treatments for Neisseria gonorrhoea – sulphonamides, penicillin and quinolones, with evidence that cephalosporin MICs are now increasing 39. Whilst antibiotic stewardship programmes have been shown to be beneficial, it is unclear which particular intervention is the safest and most effective, and research into this area is sorely needed.

Regardless of the specific strategies employed, education for prescribers is of paramount importance in any antibiotic stewardship programme. A 2004 survey of doctors in a teaching hospital in the USA showed that 90% wanted more education about antibiotics 40. Another study in France and Scotland found that junior doctors considered the availability of guidelines as the most important intervention in promoting appropriate prescribing of antibiotics 41. Given that one of the disadvantages of antibiotic stewardship programmes can be a perceived lack of autonomy by clinicians, it is of vital importance that they are engaged in decisions and kept updated with policy changes, and regular contact in the form of education programmes is an excellent way to do this. In the developing world, educational programmes are typically the most affordable as they can rely on locally sourced staff rather than expensive materials 42. A summary of the findings from educational intervention studies in developing countries, compiled by Management Sciences for Health on behalf of the WHO, found that successful educational programmes for prescribers resulted in improved diagnostic quality, reduction in inappropriate antimicrobial prescriptions and reduced poly-pharmacy among private and public providers, including non-physicians 21,43.

When implemented successfully, there is good evidence that antimicrobial stewardship programmes are successful in reducing antibiotic consumption and reducing AMR. A Cochrane review in 2005 showed that interventions aimed at reducing excessive prescribing were associated with a reduction in colonization or infection with aminoglycoside-or cephalosporin-resistant Gram-negative bacteria, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis 38. Additionally, there was an associated reduction in Clostridium difficile infections. Meta-analysis of clinical outcomes demonstrated that interventions aimed at increasing appropriate prescriptions for pneumonia were associated with a significant reduction in mortality risk, and interventions aimed at decreasing excessive prescriptions were not associated with a significant increase in mortality. Similarly, a 2011 review into the application of antimicrobial stewardship principles to the management of community-acquired pneumonia within hospitals showed an increased level of appropriate antibiotic prescribing, reduced bacterial resistance and improved clinical outcomes for patients. It also demonstrated reduced hospital length of stay, reduced failure rates and reduced healthcare costs 44.

Suggestions for the future

Leadership and responsibility

Whilst infectious diseases physicians and microbiologists must take a leadership role when it comes to antibiotic stewardship, appropriate and responsible prescribing is the responsibility of all clinicians. In the UK the General Medical Council (GMC) and Academy of Royal Colleges have approved a 2012 report published by the National Prescribing Centre on behalf of the National Institute for Health and Care Excellence (NICE) called A single competency framework for all prescribers. Competency 11 is stated as ‘Understands antimicrobial resistance and the roles of infection prevention, control and antimicrobial stewardship measures’ 45. Similarly, the Royal College of Physicians Healthcare Associated Infection Working Group published Effective antibiotic prescribing – top ten tips in 2011 46. Antimicrobial stewardship should be a core component of medical student and junior doctor educational programmes, to ensure that all clinicians understand the basic principles of AMR, and appreciate the role they can play in reducing this for the benefit of their patients and the general public.

Political will and use of the media

The efforts of antimicrobial stewards and physicians in general must be backed up by political will. Professor Dame Sally Davies, UK Chief Medical Officer, has described AMR as ‘a catastrophic threat’ which is ‘as big a risk as terrorism’. Statements such as these garner media attention and therefore public engagement, meaning that AMR has now become a subject that is on the public agenda. In September of this year the UK Department of Health published the UK Antimicrobial Resistance Strategy 47 which outlines steps to improve education around prescribing, improve surveillance, encourage development of new antibiotics and, importantly, provide funding for a new research unit which will focus on AMR and health care associated infections. It remains to be seen what the outcome of these interventions will be, but it is clear that this is the level of support necessary to achieve a sustained response to the problem of AMR. The media could play a vital role in public health campaigns informing specific communities and the population as a whole about the problem of AMR and the need for rational prescribing, and may have an effect on health-seeking behaviour in the longer term.

Research

As mentioned earlier, there is an urgent need for the development of novel antimicrobial agents, and for research into AMR. This is particularly true in the developing world where clinical data are needed to delineate the scale of the problem: risk factors for acquisition, routes of transmission, effectiveness of decolonization strategies as well as health economic impact. Data from such research will aid infection specialists and public health professionals in garnering political engagement, which is necessary to implement strategies to counteract the spread of AMR. Imported cases of infections with resistant bacteria to developed countries highlight the fact that combating resistance in the developing world would be of benefit also to patients in the developed world.

Technology

The use of computer-assisted technology and electronic prescribing has been introduced in a number of hospitals and has shown to improve antibiotic prescribing. They provide clinicians with relevant information about individual patients, antibiotics, drug–drug interactions and drug-related adverse effects 33. With the advent of new technology some hospitals are developing software, which can be used on personal computers and smartphones. This will enable clinicians to access at least some of this information on a mobile device and should also aid in improving prescribing. Electronic prescribing facilitates the monitoring and audit of prescribing data, to department or even individual physician level, allowing a comparison of activity and benchmarking of practice. It also allows for real-time intervention and direct prescriber feedback by antimicrobial stewardship teams, an approach which is already in use in the USA.

Conclusions

We screwed it up, and we ought to say so and apologize. Doctors were handed the wonderful gift of antibiotics but are destroying them through indiscriminate use. We don't need another committee. We know what we should do: we should just use them less.

Dr Norman Simmons, Pan-European Meeting on Antimicrobial Resistance, Copenhagen, 1998

The last few years have seen the return into use of older antimicrobials such as chloramphenicol, colistin and fosfomycin in treating multiresistant infections. However, these agents tend to have high levels of toxicity, and there are now reports of emerging resistance associated with their use 48,49. There have been numerous calls to prioritize the development of novel antimicrobials as a matter of urgency, to combat the rising tide of resistant organisms. However, history tells us that the inevitable consequence of the introduction of a new agent is the development of resistance to it. Preservation of antimicrobials, novel or existing, must be our goal, and achieving this requires a paradigm shift by all doctors and prescribers. The days of antimicrobials being ‘wonderdrugs’ are over and doctors must adjust their practice, and expectations, accordingly. ‘Defensive prescribing’ 11 of broad spectrum agents in the hope that it will cover all eventualities must be a practice of the past. Infection specialists must lead, for example, engaging in stewardship interventions in areas of high antibiotic use such as diabetic foot clinics, intensive care units and emergency departments. Similarly, collaboration between hospital and primary care settings is necessary, as clearly hospital-based interventions will have minimal impact in isolation, given that most antibiotic consumption occurs in the community. Prescribers must all take responsibility for managing patients effectively whilst also safeguarding our precious antimicrobials. Prescribing injudiciously now carries a very real risk of treatment failure in addition to creating an arsenal of obsolete agents for future generations. Responsible educational campaigns and social media are also required to bring about a paradigm shift in public opinion and expectation to be prescribed an antibiotic, even if not appropriate.

Competing Interests

Both authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.