British Journal of Clinical Pharmacology
DOI:10.1111/bcp.12417
Antimicrobial stewardship – can we afford to do without it?
Dr Anna Aryee MRCP DTM&H, Guy’s & St Thomas’ NHS Trust, Department of Infection, 5th floor North Wing, St Thomas Hospital, Westminster Bridge Road, London SE1 7EH, UK. Tel.: +44 207 188 3100 Fax: +44 207 188 3146 E-mail: [email protected]; [email protected] -----------------------------------------------------------------------
Anna Aryee1,2 & Nicholas Price1 1
Correspondence
Keywords
Department of Infection, Guy’s & St Thomas’ NHS Trust, St Thomas’ Hospital, London and 2Centre for
Clinical Infection and Diagnostics Research, King’s College London, St Thomas’ Hospital, London, UK
antibiotic resistance, antibiotic stewardship, antimicrobial resistance, antimicrobial stewardship -----------------------------------------------------------------------
Received 27 January 2014
Accepted 29 April 2014
Accepted Article Published Online 6 May 2014
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 © 2014 The British Pharmacological Society
(CRO), carry resistance determinants known as metallo-βlactamases. 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]. 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 Br J Clin Pharmacol
/ 79:2
/
173–181
/
173
A. Aryee & N. Price
IMP VIM SPM GIM SIM AIM KHM NDM DIM
Figure 1 Worldwide dissemination of different metallo-β-lactamases (Cornaglia et al. [6])
18 16 14 12 10 8 6 4 2 0 1983-87
1988-92
1993-97
1998-02
2003-07
2008-12
Figure 2 FDA approvals of new antibiotics by 5 year period (updated from IDSA [7])
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. There is ample evidence that antibiotic use drives antibiotic resistance. Data from the European Antimicro174
/ 79:2
/
Br J Clin Pharmacol
bial 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
Antimicrobial stewardship – can we afford to do without it?
Transmission of resistant microbes via direct contact (patients/ household contacts/ healthcare staff), environmental surfaces, vater supplies and food Selection pressure from antimicrobial use in humans
Gene mutation and gene transfer under antimicrobial exposure
Antimicrobial Resistance
Figure 3 Drivers behind antimicrobial resistance
significant pathogens including Salmonella enterica, nontyphoidal 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 Br J Clin Pharmacol
/ 79:2
/
175
A. Aryee & N. Price
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 176
/ 79:2
/
Br J Clin Pharmacol
• 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. 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
Antimicrobial stewardship – can we afford to do without it?
Start Smart: ∑ Do not start antibiotics in the absence of clinical evidence of bacterial infection ∑ If there is evidence/suspicion of bacterial infection, use local guidelines to initiate prompt effective antibiotic treatment ∑ Document on drug chart and in medical notes: clinical indication, duration or review date, route and dose ∑ Obtain cultures first ∑ Prescribe single dose antibiotics for surgical prophylaxis; where antibiotics have been shown to be effective then Focus: ∑ Review the clinical diagnosis and the continuing need for antibiotics by 48 hours and make a clear plan of action-the ‘Antimicrobial Prescribing Decision’ ∑ The five Antimicrobial Prescribing Decision options are: Stop, Switch IV to Oral, Change, Continue and Outpatient Parenteral Antibiotic Therapy (OPAT) ∑ It is essential that the review and subsequent decision is clearly documented in the medical notes.
Figure 4 ‘Start Smart – then Focus’, UK DOH [35]
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 Gramnegative 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 Br J Clin Pharmacol
/ 79:2
/
177
A. Aryee & N. Price
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 178
/ 79:2
/
Br J Clin Pharmacol
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
Antimicrobial stewardship – can we afford to do without it?
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.
4 Smolinski MS, Hamburg MA, Lederberg J, eds. Microbial Threats to Health: Emergence, Detection, and Response. Washington: National Academies Press, 2003. 5 World Health Organisation. Medicines: rational use of medicines [online]. WHO Factsheet no 338. Geneva: World Health Organisation, 2010. Available at http://www.who.int/mediacentre/factsheets/fs338/en/ (last accessed 5 December 2013). 6 Cornaglia G, Giamarellou H, Rossolini GM. Metallo-β-lactamases: a last frontier for β-lactams? Lancet Infect Dis 2011; 11: 381–93. 7 Infectious Diseases Society of America (IDSA). Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis 2011; 52 (Suppl. 5): S397–S428. 8 Ohl CA, Dodds Ashley ES. Antimicrobial stewardship programs in community hospitals: the evidence base and case studies. Clin Infect Dis 2011; 53 (Suppl. 1): S23–S28; quiz S29–S30. 9 Bantar C, Sartori B, Vesco E, Heft C, Saúl M, Salamone F, Oliva ME. A hospitalwide intervention program to optimize the quality of antibiotic use: impact on prescribing practice, antibiotic consumption, cost savings, and bacterial resistance. Clin Infect Dis 2003; 37: 180–6. 10 Cheng VC, To KK, Li IW, Tang BS, Chan JF, Kwan S, Mak R, Tai J, Ching P, Ho PL, Seto WH. Antimicrobial stewardship program directed at broad-spectrum intravenous antibiotics prescription in a tertiary hospital. Eur J Clin Microbiol Infect Dis 2009; 28: 1447–56. 11 Hand K. Antibiotic stewardship. Clin Med 2013; 13: 499–503.
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.
REFERENCES 1 Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis 1433; 36: 1433–7. 2 Lee SY, Kotapati S, Kuti JL, Nightingale CH, Nicolau DP. Impact of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species on clinical outcomes and hospital costs: a matched cohort study. Infect Control Hosp Epidemiol 2006; 27: 1226–32. 3 John JF, Fishman NO. Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital. Clin Infect Dis 1997; 24: 471–85.
12 Singer RS, Finch R, Wegener HC, Bywater R, Walters J, Lipsitch M. Antibiotic resistance – the interplay between antibiotic use in animals and human beings. Lancet Infect Dis 2003; 3: 47–51. 13 Van de Sande-Bruinsma N, Grundmann H, Verloo D, Tiemersma E, Monen J, Goossens H, Ferech M. Antimicrobial drug use and resistance in Europe. Emerg Infect Dis 2008; 14: 1722–30. 14 Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 1999; 341: 233–9. 15 Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ 2010; 340: c2096. 16 Duffy M, Hernandez-Santiago V, Orange G, Davey PG, Guthrie B. Trimethoprim prescription and subsequent resistance in childhood urinary infection: multilevel modelling analysis. Br J Gen Pract 2013; 63: e238–43. 17 Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis 2001; 33: 757–62. 18 Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: Br J Clin Pharmacol
/ 79:2
/
179
A. Aryee & N. Price
current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med 2003; 163: 972–8.
ProMED-mail, 2013. Available at http://www .promedmail.org/direct.php?id=20131018.2008610 (last accessed 2 December 2013).
19 Cusini A, Rampini SK, Bansal V, Ledergerber B, Kuster SP, Ruef C, Weber R. Different patterns of inappropriate antimicrobial use in surgical and medical units at a tertiary care hospital in Switzerland: a prevalence survey. PLoS ONE 2010; 5: e14011.
32 Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012; 33: 322–7.
20 Okeke IN, Laxminarayan R, Bhutta ZA, Duse AG, Jenkins P, O’Brien TF, Pablos-Mendez A, Klugman KP. Antimicrobial resistance in developing countries. Part I: recent trends and current status. Lancet Infect Dis 2005; 5: 481–93.
33 Fishman N. Antimicrobial stewardship. Am J Med 2006; 119: S53–S61.
21 Okeke IN, Klugman KP, Bhutta ZA, Duse AG, Jenkins P, O’Brien TF, Pablos-Mendez A, Laxminarayan R. Antimicrobial resistance in developing countries. Part II: strategies for containment. Lancet Infect Dis 2005; 5: 568–80. 22 Country pharmaceutical situations: fact book on WHO level 1 indicators 2007 [online]. Geneva: World Health Organization, 2009. Available at http://apps.who.int/ medicinedocs/index/assoc/s16874e/s16874e.pdf (last accessed 5 December 2013). 23 Medicines use in primary care in developing and transitional countries? Fact book summarizing results from studies reported between 1990 and 2006 [online]. Geneva: World Health Organization, 2009. Available at http://apps.who .int/medicinedocs/documents/s16073e/s16073e.pdf (last accessed 5 December 2013). 24 Morgan DJ, Okeke IN, Laxminarayan R, Perencevich EN, Weisenberg S. Non-prescription antimicrobial use worldwide: a systematic review. Lancet Infect Dis 2011; 11: 692–701. 25 Newton PN, Green MD, Fernández FM, Day NPJ, White NJ. Counterfeit anti-infective drugs. Lancet Infect Dis 2006; 6: 602–13. 26 Kelesidis T, Kelesidis I, Rafailidis PI, Falagas ME. Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence. J Antimicrob Chemother 2007; 60: 214–36. 27 Chapter 3: measures to ensure better use of antibiotics. The evolving threat of antimicrobial resistance: options for action [online]. Geneva: WHO Library Cataloguing-inPublication Data, 2012. Available at http://whqlibdoc .who.int/publications/2012/9789241503181_eng.pdf (last accessed 7 December 2013). 28 Wirtz VJ, Dreser A, Gonzales R. Trends in antibiotic utilization in eight Latin American countries, 1997–2007. Rev Panam Salud Publica 2010; 27: 219–25. 29 Tham J, Odenholt I, Walder M, Andersson L, Melander E. Risk factors for infections with extended-spectrum beta-lactamase-producing Escherichia coli in a county in Southern Sweden. Infect Drug Resist 2013; 6: 93–7. 30 Laupland KB, Church DL, Vidakovich J, Mucenski M, Pitout JDD. Community-onset extended-spectrum beta-lactamase (ESBL) producing Escherichia coli: importance of international travel. J Infect 2008; 57: 441–8. 31 ProMED-mail: PRO/EDR> Antimicrobial resistance – Netherlands ex Egypt: family [online]. Louisiana: 180
/ 79:2
/
Br J Clin Pharmacol
34 White AC, Atmar RL, Wilson J, Cate TR, Stager CE, Greenberg SB. Effects of requiring prior authorization for selected antimicrobials: expenditures, susceptibilities, and clinical outcomes. Clin Infect Dis 1997; 25: 230–9. 35 Corona A, Bertolini G, Lipman J, Wilson AP, Singer M. Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC). J Antimicrob Chemother 2010; 65: 1276–85. 36 UK Department of Health Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infections. Antimicrobial Stewardship: ‘Start Smart – then Focus’. 2011. 37 Meropol SB, Localio AR, Metlay JP. Risks and benefits associated with antibiotic use for acute respiratory infections: a cohort study. Ann Fam Med 2013; 11: 165–72. 38 Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, Holmes A, Ramsay C, Taylor E, Wilcox M, Wiffen P. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2005; 4: CD003543. 39 Chisholm SA, Mouton JW, Lewis DA, Nichols T, Ison CA, Livermore DM. Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink? J Antimicrob Chemother 2010; 65: 2141–8. 40 Srinivasan A, Song X, Richards A, Sinkowitz-Cochran R, Cardo D, Rand C. A survey of knowledge, attitudes, and beliefs of house staff physicians from various specialties concerning antimicrobial use and resistance. Arch Intern Med 2004; 164: 1451–6. 41 Pulcini C, Williams F, Molinari N, Davey P, Nathwani D. Junior doctors’ knowledge and perceptions of antibiotic resistance and prescribing: a survey in France and Scotland. Clin Microbiol Infect 2011; 17: 80–7. 42 Holloway K. Essential drugs monitor 2000 [online]. Geneva: WHO, 2000; 16–8. Available at http://apps.who.int/ medicinedocs/pdf/s2248e/s2248e.pdf (last accessed 12 December 2013). 43 Management Sciences for Health, Arlington VA. Interventions and strategies to improve the use of antimicrobials in developing countries: a review [online]. Geneva: World Health Organization, 2001. Available at http://whqlibdoc.who.int/hq/2001/who_CDS_CSR_DRS_ 2001.9.pdf (last accessed 7 December 2013). 44 Bosso JA, Drew RH. Application of antimicrobial stewardship to optimise management of community acquired pneumonia. Int J Clin Pract 2011; 65: 775–83.
Antimicrobial stewardship – can we afford to do without it?
45 A single competency framework for all prescribers [online]. London: National Prescribing Centre, provided by NICE, 2012. Available at http://www.npc.co.uk/improving_safety/ improving_quality/resources/single_comp_framework.pdf (last accessed 19 December 2013).
48 Oteo J, Orden B, Bautista V, Cuevas O, Arroyo M, Martínez-Ruiz R, Pérez-Vázquez M, Alcaraz M, García-Cobos S, Campos J. CTX-M-15-producing urinary Escherichia coli O25b-ST131-phylogroup B2 has acquired resistance to fosfomycin. J Antimicrob Chemother 2009; 64: 712–7.
46 Effective antibiotic prescribing – top ten tips. Royal College of Physicians Healthcare Associated Infections Working Group. 2011.
49 Oteo J, Orden B, Bautista V, Cuevas O, Arroyo M, Martínez-Ruiz R, Pérez-Vázquez M, Alcaraz M, García-Cobos S, Campos J. CTX-M-15-producing urinary Escherichia coli O25b-ST131-phylogroup B2 has acquired resistance to fosfomycin. J Antimicrob Chemother 2009; 64: 712–7.
47 UK five year antimicrobial resistance strategy 2013 to 2018. London: Department of Health, 2013. Available at https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/244058/20130902_UK_5_year_AMR_ strategy.pdf (last accessed 19 December 2013).
Br J Clin Pharmacol
/ 79:2
/
181
Copyright of British Journal of Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
DOI:10.1111/bcp.12417
Antimicrobial stewardship – can we afford to do without it?
Dr Anna Aryee MRCP DTM&H, Guy’s & St Thomas’ NHS Trust, Department of Infection, 5th floor North Wing, St Thomas Hospital, Westminster Bridge Road, London SE1 7EH, UK. Tel.: +44 207 188 3100 Fax: +44 207 188 3146 E-mail: [email protected]; [email protected] -----------------------------------------------------------------------
Anna Aryee1,2 & Nicholas Price1 1
Correspondence
Keywords
Department of Infection, Guy’s & St Thomas’ NHS Trust, St Thomas’ Hospital, London and 2Centre for
Clinical Infection and Diagnostics Research, King’s College London, St Thomas’ Hospital, London, UK
antibiotic resistance, antibiotic stewardship, antimicrobial resistance, antimicrobial stewardship -----------------------------------------------------------------------
Received 27 January 2014
Accepted 29 April 2014
Accepted Article Published Online 6 May 2014
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 © 2014 The British Pharmacological Society
(CRO), carry resistance determinants known as metallo-βlactamases. 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]. 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 Br J Clin Pharmacol
/ 79:2
/
173–181
/
173
A. Aryee & N. Price
IMP VIM SPM GIM SIM AIM KHM NDM DIM
Figure 1 Worldwide dissemination of different metallo-β-lactamases (Cornaglia et al. [6])
18 16 14 12 10 8 6 4 2 0 1983-87
1988-92
1993-97
1998-02
2003-07
2008-12
Figure 2 FDA approvals of new antibiotics by 5 year period (updated from IDSA [7])
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. There is ample evidence that antibiotic use drives antibiotic resistance. Data from the European Antimicro174
/ 79:2
/
Br J Clin Pharmacol
bial 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
Antimicrobial stewardship – can we afford to do without it?
Transmission of resistant microbes via direct contact (patients/ household contacts/ healthcare staff), environmental surfaces, vater supplies and food Selection pressure from antimicrobial use in humans
Gene mutation and gene transfer under antimicrobial exposure
Antimicrobial Resistance
Figure 3 Drivers behind antimicrobial resistance
significant pathogens including Salmonella enterica, nontyphoidal 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 Br J Clin Pharmacol
/ 79:2
/
175
A. Aryee & N. Price
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 176
/ 79:2
/
Br J Clin Pharmacol
• 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. 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
Antimicrobial stewardship – can we afford to do without it?
Start Smart: ∑ Do not start antibiotics in the absence of clinical evidence of bacterial infection ∑ If there is evidence/suspicion of bacterial infection, use local guidelines to initiate prompt effective antibiotic treatment ∑ Document on drug chart and in medical notes: clinical indication, duration or review date, route and dose ∑ Obtain cultures first ∑ Prescribe single dose antibiotics for surgical prophylaxis; where antibiotics have been shown to be effective then Focus: ∑ Review the clinical diagnosis and the continuing need for antibiotics by 48 hours and make a clear plan of action-the ‘Antimicrobial Prescribing Decision’ ∑ The five Antimicrobial Prescribing Decision options are: Stop, Switch IV to Oral, Change, Continue and Outpatient Parenteral Antibiotic Therapy (OPAT) ∑ It is essential that the review and subsequent decision is clearly documented in the medical notes.
Figure 4 ‘Start Smart – then Focus’, UK DOH [35]
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 Gramnegative 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 Br J Clin Pharmacol
/ 79:2
/
177
A. Aryee & N. Price
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 178
/ 79:2
/
Br J Clin Pharmacol
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
Antimicrobial stewardship – can we afford to do without it?
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.
4 Smolinski MS, Hamburg MA, Lederberg J, eds. Microbial Threats to Health: Emergence, Detection, and Response. Washington: National Academies Press, 2003. 5 World Health Organisation. Medicines: rational use of medicines [online]. WHO Factsheet no 338. Geneva: World Health Organisation, 2010. Available at http://www.who.int/mediacentre/factsheets/fs338/en/ (last accessed 5 December 2013). 6 Cornaglia G, Giamarellou H, Rossolini GM. Metallo-β-lactamases: a last frontier for β-lactams? Lancet Infect Dis 2011; 11: 381–93. 7 Infectious Diseases Society of America (IDSA). Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis 2011; 52 (Suppl. 5): S397–S428. 8 Ohl CA, Dodds Ashley ES. Antimicrobial stewardship programs in community hospitals: the evidence base and case studies. Clin Infect Dis 2011; 53 (Suppl. 1): S23–S28; quiz S29–S30. 9 Bantar C, Sartori B, Vesco E, Heft C, Saúl M, Salamone F, Oliva ME. A hospitalwide intervention program to optimize the quality of antibiotic use: impact on prescribing practice, antibiotic consumption, cost savings, and bacterial resistance. Clin Infect Dis 2003; 37: 180–6. 10 Cheng VC, To KK, Li IW, Tang BS, Chan JF, Kwan S, Mak R, Tai J, Ching P, Ho PL, Seto WH. Antimicrobial stewardship program directed at broad-spectrum intravenous antibiotics prescription in a tertiary hospital. Eur J Clin Microbiol Infect Dis 2009; 28: 1447–56. 11 Hand K. Antibiotic stewardship. Clin Med 2013; 13: 499–503.
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.
REFERENCES 1 Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis 1433; 36: 1433–7. 2 Lee SY, Kotapati S, Kuti JL, Nightingale CH, Nicolau DP. Impact of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species on clinical outcomes and hospital costs: a matched cohort study. Infect Control Hosp Epidemiol 2006; 27: 1226–32. 3 John JF, Fishman NO. Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital. Clin Infect Dis 1997; 24: 471–85.
12 Singer RS, Finch R, Wegener HC, Bywater R, Walters J, Lipsitch M. Antibiotic resistance – the interplay between antibiotic use in animals and human beings. Lancet Infect Dis 2003; 3: 47–51. 13 Van de Sande-Bruinsma N, Grundmann H, Verloo D, Tiemersma E, Monen J, Goossens H, Ferech M. Antimicrobial drug use and resistance in Europe. Emerg Infect Dis 2008; 14: 1722–30. 14 Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 1999; 341: 233–9. 15 Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ 2010; 340: c2096. 16 Duffy M, Hernandez-Santiago V, Orange G, Davey PG, Guthrie B. Trimethoprim prescription and subsequent resistance in childhood urinary infection: multilevel modelling analysis. Br J Gen Pract 2013; 63: e238–43. 17 Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis 2001; 33: 757–62. 18 Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: Br J Clin Pharmacol
/ 79:2
/
179
A. Aryee & N. Price
current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med 2003; 163: 972–8.
ProMED-mail, 2013. Available at http://www .promedmail.org/direct.php?id=20131018.2008610 (last accessed 2 December 2013).
19 Cusini A, Rampini SK, Bansal V, Ledergerber B, Kuster SP, Ruef C, Weber R. Different patterns of inappropriate antimicrobial use in surgical and medical units at a tertiary care hospital in Switzerland: a prevalence survey. PLoS ONE 2010; 5: e14011.
32 Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012; 33: 322–7.
20 Okeke IN, Laxminarayan R, Bhutta ZA, Duse AG, Jenkins P, O’Brien TF, Pablos-Mendez A, Klugman KP. Antimicrobial resistance in developing countries. Part I: recent trends and current status. Lancet Infect Dis 2005; 5: 481–93.
33 Fishman N. Antimicrobial stewardship. Am J Med 2006; 119: S53–S61.
21 Okeke IN, Klugman KP, Bhutta ZA, Duse AG, Jenkins P, O’Brien TF, Pablos-Mendez A, Laxminarayan R. Antimicrobial resistance in developing countries. Part II: strategies for containment. Lancet Infect Dis 2005; 5: 568–80. 22 Country pharmaceutical situations: fact book on WHO level 1 indicators 2007 [online]. Geneva: World Health Organization, 2009. Available at http://apps.who.int/ medicinedocs/index/assoc/s16874e/s16874e.pdf (last accessed 5 December 2013). 23 Medicines use in primary care in developing and transitional countries? Fact book summarizing results from studies reported between 1990 and 2006 [online]. Geneva: World Health Organization, 2009. Available at http://apps.who .int/medicinedocs/documents/s16073e/s16073e.pdf (last accessed 5 December 2013). 24 Morgan DJ, Okeke IN, Laxminarayan R, Perencevich EN, Weisenberg S. Non-prescription antimicrobial use worldwide: a systematic review. Lancet Infect Dis 2011; 11: 692–701. 25 Newton PN, Green MD, Fernández FM, Day NPJ, White NJ. Counterfeit anti-infective drugs. Lancet Infect Dis 2006; 6: 602–13. 26 Kelesidis T, Kelesidis I, Rafailidis PI, Falagas ME. Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence. J Antimicrob Chemother 2007; 60: 214–36. 27 Chapter 3: measures to ensure better use of antibiotics. The evolving threat of antimicrobial resistance: options for action [online]. Geneva: WHO Library Cataloguing-inPublication Data, 2012. Available at http://whqlibdoc .who.int/publications/2012/9789241503181_eng.pdf (last accessed 7 December 2013). 28 Wirtz VJ, Dreser A, Gonzales R. Trends in antibiotic utilization in eight Latin American countries, 1997–2007. Rev Panam Salud Publica 2010; 27: 219–25. 29 Tham J, Odenholt I, Walder M, Andersson L, Melander E. Risk factors for infections with extended-spectrum beta-lactamase-producing Escherichia coli in a county in Southern Sweden. Infect Drug Resist 2013; 6: 93–7. 30 Laupland KB, Church DL, Vidakovich J, Mucenski M, Pitout JDD. Community-onset extended-spectrum beta-lactamase (ESBL) producing Escherichia coli: importance of international travel. J Infect 2008; 57: 441–8. 31 ProMED-mail: PRO/EDR> Antimicrobial resistance – Netherlands ex Egypt: family [online]. Louisiana: 180
/ 79:2
/
Br J Clin Pharmacol
34 White AC, Atmar RL, Wilson J, Cate TR, Stager CE, Greenberg SB. Effects of requiring prior authorization for selected antimicrobials: expenditures, susceptibilities, and clinical outcomes. Clin Infect Dis 1997; 25: 230–9. 35 Corona A, Bertolini G, Lipman J, Wilson AP, Singer M. Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC). J Antimicrob Chemother 2010; 65: 1276–85. 36 UK Department of Health Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infections. Antimicrobial Stewardship: ‘Start Smart – then Focus’. 2011. 37 Meropol SB, Localio AR, Metlay JP. Risks and benefits associated with antibiotic use for acute respiratory infections: a cohort study. Ann Fam Med 2013; 11: 165–72. 38 Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, Holmes A, Ramsay C, Taylor E, Wilcox M, Wiffen P. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2005; 4: CD003543. 39 Chisholm SA, Mouton JW, Lewis DA, Nichols T, Ison CA, Livermore DM. Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink? J Antimicrob Chemother 2010; 65: 2141–8. 40 Srinivasan A, Song X, Richards A, Sinkowitz-Cochran R, Cardo D, Rand C. A survey of knowledge, attitudes, and beliefs of house staff physicians from various specialties concerning antimicrobial use and resistance. Arch Intern Med 2004; 164: 1451–6. 41 Pulcini C, Williams F, Molinari N, Davey P, Nathwani D. Junior doctors’ knowledge and perceptions of antibiotic resistance and prescribing: a survey in France and Scotland. Clin Microbiol Infect 2011; 17: 80–7. 42 Holloway K. Essential drugs monitor 2000 [online]. Geneva: WHO, 2000; 16–8. Available at http://apps.who.int/ medicinedocs/pdf/s2248e/s2248e.pdf (last accessed 12 December 2013). 43 Management Sciences for Health, Arlington VA. Interventions and strategies to improve the use of antimicrobials in developing countries: a review [online]. Geneva: World Health Organization, 2001. Available at http://whqlibdoc.who.int/hq/2001/who_CDS_CSR_DRS_ 2001.9.pdf (last accessed 7 December 2013). 44 Bosso JA, Drew RH. Application of antimicrobial stewardship to optimise management of community acquired pneumonia. Int J Clin Pract 2011; 65: 775–83.
Antimicrobial stewardship – can we afford to do without it?
45 A single competency framework for all prescribers [online]. London: National Prescribing Centre, provided by NICE, 2012. Available at http://www.npc.co.uk/improving_safety/ improving_quality/resources/single_comp_framework.pdf (last accessed 19 December 2013).
48 Oteo J, Orden B, Bautista V, Cuevas O, Arroyo M, Martínez-Ruiz R, Pérez-Vázquez M, Alcaraz M, García-Cobos S, Campos J. CTX-M-15-producing urinary Escherichia coli O25b-ST131-phylogroup B2 has acquired resistance to fosfomycin. J Antimicrob Chemother 2009; 64: 712–7.
46 Effective antibiotic prescribing – top ten tips. Royal College of Physicians Healthcare Associated Infections Working Group. 2011.
49 Oteo J, Orden B, Bautista V, Cuevas O, Arroyo M, Martínez-Ruiz R, Pérez-Vázquez M, Alcaraz M, García-Cobos S, Campos J. CTX-M-15-producing urinary Escherichia coli O25b-ST131-phylogroup B2 has acquired resistance to fosfomycin. J Antimicrob Chemother 2009; 64: 712–7.
47 UK five year antimicrobial resistance strategy 2013 to 2018. London: Department of Health, 2013. Available at https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/244058/20130902_UK_5_year_AMR_ strategy.pdf (last accessed 19 December 2013).
Br J Clin Pharmacol
/ 79:2
/
181
Copyright of British Journal of Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
