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Success stories of implementation of antimicrobial stewardship: a narrative review
REVIEW
10.1111/1469-0691.12803
Success stories of implementation of antimicrobial stewardship: a narrative review B. Huttner1, S. Harbarth1, D. Nathwani2 and on behalf of the ESCMID Study Group for Antibiotic Policies (ESGAP) 1) Infection Control Programme and Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland and 2) Infection Unit, Ninewells Hospital & Medical School, Dundee, UK
Abstract It has been increasingly recognized that antimicrobial stewardship (AMS) has to be a key component of any efforts that aim to mitigate the current global antimicrobial resistance (AMR) crisis. It has also become evident that AMR is a problem that cannot be tackled by single institutions or physicians, but needs concerted actions at regional, national and supra-national levels. However, it is easy to become discouraged, given the problems that are often encountered when implementing AMS. The aim of this review is to highlight some of the success stories of AMS strategies, and to describe the actions that have been taken, the outcomes that have been obtained, and the obstacles that have been met. Although the best approach to effective AMS remains elusive and may vary significantly among settings, these diverse examples from a range of healthcare contexts demonstrate that effective AMS is possible. Such examples will inform others and encourage them to formally evaluate and share their results with the global stewardship community. Keywords: antibiotic policy, antibiotic stewardship, antibiotic use, antimicrobial resistance, unintended consequences Article published online: 8 October 2014 Clin Microbiol Infect
Corresponding author: B. Huttner, Infection Control Programme, Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland E-mail: [email protected]
Introduction Antimicrobial resistance (AMR) is a problem requiring global solutions; antimicrobial stewardship (AMS) is a key component in addressing this issue [1]. However, many hospitals across the globe still lack AMS programmes, primarily because of a lack of funding (Howard, 2013 23rd ECCMID, Abstract O475). The results from published surveys suggesting that approximately half of all hospitals have AMS programmes very likely represent an overestimation of the true prevalence of AMS activities, owing to significant non-response bias and the use of rather broad definitions of what constitutes an AMS programme. This low level of activity is a concern, given that there is now good evidence that AMS programmes in hospitals can reduce overall antibiotic use and have a positive impact on the incidence of Clostridium difficile infection (CDI) and possibly also on AMR and clinical outcomes [2,3].
All too often, discussions about AMS are restricted to the inpatient setting, where there is high antibiotic use, a vulnerable patient population, and ‘ideal’ conditions for the transmission of multidrug-resistant organisms (MDROs). Most antibiotic use, however, occurs in the community, and often involves antibiotics for self-limiting viral infections in otherwise healthy people [4]. However, in the community setting, there have been many large-scale antibiotic awareness campaigns conducted at regional and national levels, and some have been ‘successful’ in reducing outpatient antibiotic use [5,6]. This narrative review aims to illustrate some of the ‘success stories’ of AMS—defined as any intervention aimed at improving the use of antimicrobials—implemented on a larger scale. Obviously, this leads to the question of how ‘success’ should be defined in the context of AMS: a reduction in overall antibiotic use and by what measure, a reduction in the use of specific antibiotic classes, a reduction in key outcomes such as
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases
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the incidence of infections with MDROs or CDI, or even changes in mortality. The metrics for measuring these outcomes remain challenging to define, obtain, and interpret, but are crucial if we are to convince healthcare managers and policy-makers to invest increasingly scarce resource in AMS [7]. Ultimately, ‘success’ is, however, in the eye of the beholder, and in this review we did not tie our perception of ‘success’ to specific outcomes, as these are often not available, and the implementation of AMS activities alone in a large setting can already sometimes represent a ‘success’ story, given the many obstacles. It is important to keep in mind that this review is not aimed to be a comprehensive, systematic description of worldwide AMS activities. It is rather aimed at providing a broad description of some encouraging AMS stories from a convenience sample of case stories and experiences around the world (Fig. 1).
Success stories Australia
Fluoroquinolones are known as an antibiotic class with a particularly detrimental impact on the selection and spread of AMR [8,9]. In Australia, this was recognized earlier than elsewhere, and the use of this antibiotic class has long been restricted by guidelines favouring alternative options, and the limitation of prescription subsidies for this antibiotic class by the Pharmaceutical Benefits Scheme to very specific indications recognized by the guidelines [10]. As a consequence, Australia is one of the lowest overall users of fluoroquinolones among high-income countries (less than 0.6 defined daily doses/1000 inhabitants per day, whereas most European countries are well above one defined daily dose/1000 inhabitants per day), and, despite relatively high overall antibiotic use in the community, rates of resistance to fluoroquinolones are low as compared with many European countries (in 2010, 5.2% of Escherichia coli isolates from community-acquired infections were fluoroquinolone-resistant in Australia, whereas for most European countries this proportion is well above 15%) (EARS-Net: http://www.ecdc.europa.eu/en/healthtopics/anti microbial_resistance/database/Pages/database.aspx (accessed 16 October 2014)) [10–12]. Australia has also been active in inpatient AMS. The Australian Commission on Safety and Quality in Health Care —a government agency—has made surveillance of AMR and antibiotic usage a priority, and since 2013 AMS has become a criterion for accreditation of health services. In particular, hospitals are required to have an AMS programme in place, provide treatment guidelines, and monitor antibiotic use. The
recent introduction of measurable clinical standards for stewardship in Australian hospitals will enhance the pivotal place of stewardship in everyday clinical practice. The impact of this is awaited with interest. Chile
Dispensing of antibiotics without a medical prescription is a problem in many low-income and middle-income countries, where regulations are either non-existent or insufficiently enforced [13,14]. In 1999, Chile implemented a policy enforcing a ban of over-the-counter use of antibiotics without prescription [15]. The policy, also accompanied by a public campaign, was associated with a rapid 30% decrease in overall antibiotic use during the first years after its implementation [16,17]. Unfortunately, antibiotic use increased again between 2003 and 2008, but remains below that in the pre-intervention period [15]. Although the reasons for the increase are unclear (the lack of monitoring of compliance with the measures and the absence of additional interventions are mentioned in the literature), it illustrates that the long-term sustainability and associated cost/benefit ratio of AMS interventions need to be considered [15]. China
Like other countries, China has seen a rapid increase in MDROs over the last decade, and overprescribing of antibiotics is common in all settings, as is self-medication with antibiotics in the general population [18–21]. The Chinese Ministry of Health has recognized the dire situation, and launched a national campaign in 2011 to promote AMS in healthcare settings by establishing mandatory administrative strategies for the rational use of antimicrobials with fixed targets and audits [22]. Long-term data on the impact of these actions are lacking, but preliminary analyses suggest that there may have been a reduction in antibiotic use in the outpatient and inpatient settings between 2011 and 2012 (the proportion of patients prescribed an antimicrobial decreased from 68% to 58% for the inpatient setting, and from 25% to 15% for the outpatient setting) [22,23]. Although it is encouraging that the world’s most populous country is taking the problem of antibiotic misuse seriously, it is unclear whether predefined government targets for antibiotic use really constitute the best approach to ensure appropriate use for all patients. France
France has one of the highest levels of outpatient antibiotic use in Europe [24]. Over the last decade, France implemented three national action plans (2001–2005, 2007–2010, and 2011– 2016) to preserve the effectiveness of antibiotics. As part of the action plans, an intensive yearly public campaign called
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Antibiotic stewardship success stories
Country
Interventions
Success and failures
Australia
Restriction of fluoroquinolone use
Low fluoroquinolone use and low proportion of fluoroquinolone-resistant Escherichia coli
Chile
China
France
Scotland
South Africa
Very high overall antibiotic use Enforcement of a sales restriction Decrease in antibiotic consumption from for antibiotics (‘prescription only’) DID in 1999 to 8.5 DID in 2000 in 1999 in combination with a public campaign Overall antibiotic use has been increasing again since then Implementation of a comprehensive campaign to promote rational antibiotic use in 2011 : • audit and inspection • requirement for hospitals to have an antibiotic administrative group • formulary restrictions • clear targets for antibiotic use (less of 60%/20% of patients prescribed an tibiotic in the inpatient/ outpatient setting; less than 40 DDD/100 patientdays in the inpatient setting) Yearly national antibiotic campaign since 2001
National antibiotic stewardship programme since 2008 • Avoidance of cephalosporins, ciprofloxacin, fluoroquinolones, coamoxiclav and clindamycin (target: CDI) Implementation of an AMS programme in a private network of hospitals since 2010
South Korea
National policy change in 2000 • Separation of prescribing and dispensing of antibiotics
Sweden
National programme to contain antibiotic resistance (Strama) involving all stakeholders • Elaboration of guidelines • Identification and filling of knowledge gaps Implementation of a policy restricting reimbursement for antimicrobials in ambulatory patients with upper respiratory infections to situations where evidence of bacterial involvement is provided in 2001 Public campaign since 1995
Taiwan
USA Vietnam
Vietnam Resistance (VINARES) project : • promotion of prudent antibiotic use • strengthening of laboratory and surveillance activities
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Selected references [10]
[15—17]
Proportion of patients prescribed an antimicrobial [19,22,23] decreased from 68% to 58% for the inpatient setting and from 25% to 15% for the outpatient setting between 2011 and 2012 Fixed targets for antibiotic use seem problematic (impact on patient outcomes ?)
Overall outpatient antibiotic prescriptions per 100 inhabitants decreased by 26.5% over the first few campaign winters
[25,26,28]
Overall antibiotic use remains high as compared with other European countries and has been increasing in recent years [3,29,30] Net decrease in the incidence of CDI between 2008 and 2013 Increase in nephrotoxicity resulting from aminoglycoside use. Unclear how much of the decrease in CDI is attributable to antibiotic stewardship or attributable to concomitant interventions
Net decrease in overall antibiotic use (Fig. 3) Overall antibiotic use remains high. programme limited to the private setting Net decrease in antibiotic prescribing for patients with [35] presumed viral illness between 2000 and 2001 (from 80.8% to 72.8%) Long-term impact unclear. Overall antibiotic use for respiratory tract infections remains high. Low overall antibiotic use and low resistance levels
[39,42,44]
Increase in hospital antibiotic use over the last decade
Net decrease in antimicrobial use for respiratory infections (from DID in 1999 to 10.0 DID in 2001)
[36,37]
Long-term impact unclear
Decrease in outpatient antibiotic use Overall antibiotic use remains high. Too early to judge
[50]
[54]
FIG. 1. Global success stories of antimicrobial stewardship (AMS) mentioned in this review. CDI, Clostridium difficile infection; DDD, defined daily doses; DID, defined daily doses/1000 inhabitants per day; Strama, Swedish Strategic Programme Against Antibiotic Resistance. ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI
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European Centres for Disease Prevention and Control European Antibiotic Awareness Day to further coordinate efforts to educate the public about appropriate antibiotic use (Transatlantic Taskforce on Antimicrobial Resistance—Progress report 2014; http://www.cdc.gov/drugresistance/pdf/ TATFAR-Progress_report_2014.pdf (accessed 16 October 2014)) [49]. Recently, the CDC has also turned its attention to the inpatient setting, with the ‘Get Smart for Healthcare’ programme. A strategy for monitoring inpatient antimicrobial use among hospitals is currently being implemented [50]. The Veterans Health Administration, the largest integrated healthcare system in the USA, has recently also become very active in the context of AMS, with mandatory implementation of AMS at all Veterans Health Administration medical facilities by mid-2014. The availability of a common electronic health record with detailed patient-level data will make it interesting to follow the impact of this policy. Vietnam
In 2013, a report analysed the situation with regard to antibiotic use and resistance in Vietnam [51]. The report draws a rather dire picture, with frequent antibiotic misuse in all settings, and proposes some policy priorities to address the problem, among them being the development of AMS programmes [52,53]. In order to assist local healthcare professionals with the task of strengthening AMS and infection control, the Vietnam Resistance (VINARES) project was initiated [54]. The project has a comprehensive approach, and aims to meet the policy priorities proposed by the WHO in 2011 as a ‘policy package’ to combat AMR that includes both the promotion of prudent antibiotic use and also the strengthening of laboratory and surveillance activities [55]. A recently published paper described the implementation of the project and the challenges that it has met so far [54]. Although it is too early to judge whether VINARES really is a ‘success story’, it is certainly promising, and may be an example to follow for other low-income and middle-income countries.
Discussion With the emergence and spread of multiresistant Gram-negative ‘superbugs’, the need for effective AMS has been recognized in most settings as a key strategy to counter this threat. In this review, we have presented some examples illustrating that AMS activities can be successfully implemented in a variety of geographical and socio-economic settings. There certainly are more success stories in other countries (e.g. Belgium, Slovenia, and Thailand), not to mention in individual hospitals and practices, that are not included in this review
[56–58]. In general, antibiotic stewards around the world should be encouraged to share more often their real-life experiences in medical journals. A recent booklet on hospital stewardship sponsored by a diagnostic company provides further pragmatic good-practice examples of stewardship in action (http://bsac.org.uk/wp-content/uploads/2013/07/Stewardship-Booklet-Practical-Guide-toAntimicrobial-Stewardship-in-Hospitals.pdf (accessed 16 October 2014)). It is evident that AMS is just one element in the quest to combat AMR and that a comprehensive approach, including control of use in animal husbandry and horticulture, is needed, but this is beyond the remit of this review [1]. Many questions about AMS in humans remain. Uncertainty persists about the definition, measurement and interpretation of outcomes. Often, AMS programmes evaluate their success with surrogate measures, such as overall antibiotic use density. The best way to measure antibiotic use and what benchmarks to choose are, however, far from clear [59]. Adjustment for differences in the case mix of the patient populations seen by different institutions or practitioners is another area of uncertainty [60]. Things become even murkier when we move from a quantitative to a qualitative perspective and try to define ‘appropriate’ and responsible antibiotic use (in the context of the Innovative Medicines Initiative, a joint undertaking between the European Union and the pharmaceutical industry association EFPIA, the DRIVE-AB, project will try to address this issue http://drive-ab.eu/ (accessed 16 October 2014)). The only straightforward, universally agreed issue may be avoiding antibiotics altogether when they are not needed. The recommendation to avoid certain ‘high-risk’ antibiotics, such as fluoroquinolones and cephalosporins, is questioned by some experts, as the long-term impact of replacing these antibiotics with other agents is unclear [61]. Other cherished strategies, such as de-escalation, individualized dosing, and reduced duration of therapy, still have to prove their value in curbing AMR. The role and value of rapid diagnostics and biomarkers in stewardship also require further evaluation [62,63]. Antibiotic campaigns have traditionally been focused on children, as they contribute a high percentage of antibiotic prescriptions. Recent analyses from the USA and France suggest, however, that older adults may also constitute a worthwhile target [4,26]. The impact of public campaigns on AMR is also far from evident, as illustrated by a recent simulation study, illustrating the knowledge gaps regarding the emergence and spread of resistance in individuals and populations [64]. The experience that we share here illustrates that there is still much to be learned with regard to AMS. Our review reveals that there remains a poor evidence base for the
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Ltd) has responded to the threat posed by carbapenemase-producing enterobacteria by establishing an AMS programme, which has been progressively implemented in its 55 hospitals since 2010 [31]. The program adopted the Institute for Healthcare Improvement breakthrough series collaborative approach, involving multidisciplinary teams containing pharmacists, infection control practitioners, microbiologists, and other clinicians [32]. Data collection for surveillance was automated, specific outcome measures and deliverables were established (with ranking of the hospitals according to their implementation of AMS), workshops and teleconferences were organized, and guidelines were developed. Preliminary data suggest that the programme was associated with a 12.1% reduction in defined daily doses per 100 patient-days by the first trimester of 2014 (Fig. 3) (D. van den Bergh, personal communication). Although the overall level of antibiotic use remains high, at approximately 82 defined daily doses per 100 patient-days, these results are certainly encouraging, and provide an example to follow for other hospital networks in Africa and elsewhere.
reduction in antibiotic use and an increase in the quality of antibiotic prescribing [35]. Taiwan implemented a similar policy in the 1990s [36]. In addition, in 2001, the national health insurance in Taiwan implemented a policy stopping reimbursement for acute upper respiratory tract infections unless proof of bacterial aetiology was provided. In the first year, this policy was associated with a > 50% reduction in antibiotic use for upper respiratory tract infections [37,38].
South Korea and Taiwan
Certain regulatory frameworks can create economic incentives that counteract the prudent use of medications in general and of antibiotics in particular [33]. The failure to separate prescribing and dispensing of medications in some regions of Switzerland has, for example, been shown to be associated with higher levels of antibiotic use [34]. In South Korea, this problem was recognized, and a pharmaceutical policy reform was implemented in 2000, prohibiting physicians from dispensing drugs [35]. This policy change was associated with both a
Antibiotic stewardship success stories
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Sweden
Sweden was one of the first countries to adopt a universal, national strategy for AMS in all settings (including the veterinary sector). The Swedish Strategic Programme Against Antibiotic Resistance (Strama), which started as an informal network in 1995, was institutionalized as an independent governmental body in 2006 [39]. Local Strama groups cooperate with hospital stewardship programmes to develop guidelines [40]. At the national level, one of the key accomplishments of Strama is the initiation of trials addressing key knowledge gaps in AMS, such as the recently published randomized controlled trial confirming the non-inferiority of 7-day vs. 14-day treatment in women with acute pyelonephritis [41]. Although hospital antibiotic use in Sweden appears to have increased in recent years, it still remains comparatively low, and the level of antibiotic use in the outpatient setting is among the lowest in Europe [24,42]. In that context, it is remarkable that Strama also dedicated efforts to assess potential negative consequences of reduced antibiotic use in the community, an aspect that is often neglected [43,44]. Demonstrating that a decrease in antibiotic use (from an already very low level) is not associated with an increase in complications such as mastoiditis and quinsy constitutes extremely valuable information for other countries [43,44]. USA
FIG. 3. Impact on antibiotic consumption following implementation of an an antimicrobial stewardship programme across a group of 54 private hospitals in South Africa (D. van den Bergh, personal communication; with permission of author). DID, defined daily doses/1000 inhabitants per day.
The USA was among the first high-income countries to implement an antibiotic campaign to educate the public, in 1995, with the CDC ‘Get Smart’ programme. As the USA has somewhat lagged behind Europe with regard to the surveillance of antimicrobial use, it is, however, difficult to assess the impact of the campaign [5,45]. Fortunately, more data have become available recently [46–48]. It seems that outpatient antibiotic prescriptions have been somewhat decreasing since the turn of the century, at least for some subgroups, such as children and adolescents [4]. Unnecessary use of antibiotics for acute respiratory tract infections and the use of antibiotics with an unnecessarily broad spectrum, such as macrolides and fluoroquinolones, remain common [4]. It is promising that there are plans for the CDC’s Get Smart campaign and the
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European Centres for Disease Prevention and Control European Antibiotic Awareness Day to further coordinate efforts to educate the public about appropriate antibiotic use (Transatlantic Taskforce on Antimicrobial Resistance—Progress report 2014; http://www.cdc.gov/drugresistance/pdf/ TATFAR-Progress_report_2014.pdf (accessed 16 October 2014)) [49]. Recently, the CDC has also turned its attention to the inpatient setting, with the ‘Get Smart for Healthcare’ programme. A strategy for monitoring inpatient antimicrobial use among hospitals is currently being implemented [50]. The Veterans Health Administration, the largest integrated healthcare system in the USA, has recently also become very active in the context of AMS, with mandatory implementation of AMS at all Veterans Health Administration medical facilities by mid-2014. The availability of a common electronic health record with detailed patient-level data will make it interesting to follow the impact of this policy. Vietnam
In 2013, a report analysed the situation with regard to antibiotic use and resistance in Vietnam [51]. The report draws a rather dire picture, with frequent antibiotic misuse in all settings, and proposes some policy priorities to address the problem, among them being the development of AMS programmes [52,53]. In order to assist local healthcare professionals with the task of strengthening AMS and infection control, the Vietnam Resistance (VINARES) project was initiated [54]. The project has a comprehensive approach, and aims to meet the policy priorities proposed by the WHO in 2011 as a ‘policy package’ to combat AMR that includes both the promotion of prudent antibiotic use and also the strengthening of laboratory and surveillance activities [55]. A recently published paper described the implementation of the project and the challenges that it has met so far [54]. Although it is too early to judge whether VINARES really is a ‘success story’, it is certainly promising, and may be an example to follow for other low-income and middle-income countries.
Discussion With the emergence and spread of multiresistant Gram-negative ‘superbugs’, the need for effective AMS has been recognized in most settings as a key strategy to counter this threat. In this review, we have presented some examples illustrating that AMS activities can be successfully implemented in a variety of geographical and socio-economic settings. There certainly are more success stories in other countries (e.g. Belgium, Slovenia, and Thailand), not to mention in individual hospitals and practices, that are not included in this review
[56–58]. In general, antibiotic stewards around the world should be encouraged to share more often their real-life experiences in medical journals. A recent booklet on hospital stewardship sponsored by a diagnostic company provides further pragmatic good-practice examples of stewardship in action (http://bsac.org.uk/wp-content/uploads/2013/07/Stewardship-Booklet-Practical-Guide-toAntimicrobial-Stewardship-in-Hospitals.pdf (accessed 16 October 2014)). It is evident that AMS is just one element in the quest to combat AMR and that a comprehensive approach, including control of use in animal husbandry and horticulture, is needed, but this is beyond the remit of this review [1]. Many questions about AMS in humans remain. Uncertainty persists about the definition, measurement and interpretation of outcomes. Often, AMS programmes evaluate their success with surrogate measures, such as overall antibiotic use density. The best way to measure antibiotic use and what benchmarks to choose are, however, far from clear [59]. Adjustment for differences in the case mix of the patient populations seen by different institutions or practitioners is another area of uncertainty [60]. Things become even murkier when we move from a quantitative to a qualitative perspective and try to define ‘appropriate’ and responsible antibiotic use (in the context of the Innovative Medicines Initiative, a joint undertaking between the European Union and the pharmaceutical industry association EFPIA, the DRIVE-AB, project will try to address this issue http://drive-ab.eu/ (accessed 16 October 2014)). The only straightforward, universally agreed issue may be avoiding antibiotics altogether when they are not needed. The recommendation to avoid certain ‘high-risk’ antibiotics, such as fluoroquinolones and cephalosporins, is questioned by some experts, as the long-term impact of replacing these antibiotics with other agents is unclear [61]. Other cherished strategies, such as de-escalation, individualized dosing, and reduced duration of therapy, still have to prove their value in curbing AMR. The role and value of rapid diagnostics and biomarkers in stewardship also require further evaluation [62,63]. Antibiotic campaigns have traditionally been focused on children, as they contribute a high percentage of antibiotic prescriptions. Recent analyses from the USA and France suggest, however, that older adults may also constitute a worthwhile target [4,26]. The impact of public campaigns on AMR is also far from evident, as illustrated by a recent simulation study, illustrating the knowledge gaps regarding the emergence and spread of resistance in individuals and populations [64]. The experience that we share here illustrates that there is still much to be learned with regard to AMS. Our review reveals that there remains a poor evidence base for the
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effectiveness of the myriad of AMS policies that have been implemented across various countries. Even where policies have demonstrated clear benefit in reducing antimicrobial misuse, a full evaluation of the successful policy has often been lacking, with little available information on critical aspects such as cost-effectiveness, and inadequate descriptions of the technical and regulatory environment necessary for implementation and regulatory changes. Unfortunately, we will not have time to wait for solid scientific evidence for all aspects of AMS, as by then it may be too late to avert or mitigate the escalation of the emerging AMR crisis. In our opinion, the examples mentioned in this review illustrate that it is crucial to understand this problem in detail in each country and develop interventions tailored for each setting (e.g. regarding how much public ignorance contributes to antibiotic overuse). A common theme of successful AMS interventions around the globe is that they have been tailored to local conditions, incorporated the advice of opinion leaders, provided a well-developed rationale for change, and received strong support from governmental agencies and/or professional societies of the concerned country. Furthermore, regulatory interventions have been crucial in changing antibiotic prescribing practices and policies, as shown in diverse countries such as Australia, South Korea, Scotland, and Chile. It is evident that changing behaviour with regard to antibiotic prescribing has to be a long-term goal. This should be supported not only by improving knowledge through education, but also by a better understanding of prescribing ‘etiquette’, human factors, and systems of care delivery [65]. In the Scottish example, the ‘goal-oriented’ or ‘target-oriented’ approach combined with explicit feedback of data and a requirement for action has led to some sustained success over a 6-year period. This approach is supported by emerging evidence that audit and feedback of prescribing data can be highly effective if it is provided by a supervisor or colleagues, is repeated several times, is delivered both orally and in writing, and is combined with a specific target and action plan [66]. The long-term evaluation of sustainability should be a component of any intervention to improve antibiotic use. We need more high-quality randomized trials to improve the evidence base, particularly in relation to factors that provide sustained success (or a lack thereof) in a range of diverse resource and healthcare settings, but sharing our experiences with ‘real-life’ AMS practitioners and learning from the failures and successes of others may be just as important. The words of Winston Churchill may provide some consolation for discouraged antibiotic stewards: ‘success is not final, failure is not fatal: it is the courage to continue that counts’.
Acknowledgments
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We would like to thank D. van den Bergh (Director: Quality Leadership, Netcare Group (Pty) Ltd, South Africa) for sharing her experience with AMS in South Africa. We also thank P. Charles (Melbourne) for careful reading of the manuscript.
Funding B. Huttner is supported by funding from the European Community’s 7th Framework Programme (R-Gnosis grant agreement no. 282512).
Transparency Declarations S. Harbarth reports having received a peer-reviewed research grant funded by Pfizer; he is also a member of the speakers’ bureau for bioMerieux and a member of the advisory board of Destiny Pharma, bioMerieux. D. Nathwani received funds for the production of the bioMerieux booklet and has been invited to the bioMerieux-funded World HAI forum. B. Huttner has no conflicts of interest to declare in relation to the contents of this manuscript.
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based data from a large hospital and its surrounding community. J Antimicrob Chemother 2011; 66: 928–935. Cheng AC, Turnidge J, Collignon P, Looke D, Barton M, Gottlieb T. Control of fluoroquinolone resistance through successful regulation, Australia. Emerg Infect Dis 2012; 18: 1453–1460. Adriaenssens N, Coenen S, Versporten A et al. European surveillance of antimicrobial consumption (ESAC): outpatient quinolone use in Europe (1997–2009). J Antimicrob Chemother 2011; 66(suppl 6): vi47– vi56. Van Boeckel TP, Gandra S, Ashok A et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14: 742–750. Puspitasari HP, Faturrohmah A, Hermansyah A. Do Indonesian community pharmacy workers respond to antibiotics requests appropriately? Trop Med Int Health 2011; 16: 840–846. Nga do TT, Chuc NT, Hoa NP et al. Antibiotic sales in rural and urban pharmacies in northern Vietnam: an observational study. BMC Pharmacol Toxicol 2014; 15: 6. doi: 10.1186/2050-6511-15-6. Bavestrello FL, Cabello MA. [Community antibiotic consumption in Chile, 2000–2008]. Rev Chilena Infectol 2011; 28: 107–112. Bavestrello L, Cabello A, Casanova D. [Impact of regulatory measures in the trends of community consumption of antibiotics in Chile]. Rev Med Chil 2002; 130: 1265–1272. Wirtz VJ, Herrera-Patino JJ, Santa-Ana-Tellez Y, Dreser A, Elseviers M, Vander Stichele RH. Analysing policy interventions to prohibit over-the-counter antibiotic sales in four Latin American countries. Trop Med Int Health 2013; 18: 665–673. Jones RN, Castanheira M, Hu B et al. Update of contemporary antimicrobial resistance rates across China: reference testing results for 12 medical centers (2011). Diagn Microbiol Infect Dis 2013; 77: 258– 266. Yin X, Song F, Gong Y et al. A systematic review of antibiotic utilization in China. J Antimicrob Chemother 2013; 68: 2445–2452. Ou Y, Jing BQ, Guo FF et al. Audits of the quality of perioperative antibiotic prophylaxis in Shandong province, China, 2006 to 2011. Am J Infect Control 2014; 42: 516–520. Lv B, Zhou Z, Xu G et al. Knowledge, attitudes and practices concerning self-medication with antibiotics among university students in western China. Trop Med Int Health 2014; 19: 769–779. Xiao Y, Zhang J, Zheng B, Zhao L, Li S, Li L. Changes in Chinese policies to promote the rational use of antibiotics. PLoS Med 2013; 10: e1001556. Zou XX, Fang Z, Min R et al. Is nationwide special campaign on antibiotic stewardship program effective on ameliorating irrational antibiotic use in China? Study on the antibiotic use of specialized hospitals in China in 2011–2012. J Huazhong Univ Sci Technolog Med Sci 2014; 34: 456–463. Adriaenssens N, Coenen S, Versporten A et al. European surveillance of antimicrobial consumption (ESAC): outpatient antibiotic use in Europe (1997–2009). J Antimicrob Chemother 2011; 66(suppl 6): vi3– vi12. Sabuncu E, David J, Bernede-Bauduin C et al. Significant reduction of antibiotic use in the community after a nationwide campaign in France, 2002–2007. PLoS Med 2009; 6: e1000084. Bernier A, Delarocque-Astagneau E, Ligier C, Vibet MA, Guillemot D, Watier L. Outpatient antibiotic use in France between 2000 and 2010: after the nationwide campaign, it is time to focus on the elderly. Antimicrob Agents Chemother 2014; 58: 71–77. Chahwakilian P, Huttner B, Schlemmer B, Harbarth S. Impact of the French campaign to reduce inappropriate ambulatory antibiotic use on the prescription and consultation rates for respiratory tract infections. J Antimicrob Chemother 2011; 66: 2872–2879. Humphreys G. Are antibiotics still ‘automatic’ in France? Bull World Health Organ 2011; 89: 8–9.
29. Nathwani D, Sneddon J, Malcolm W et al. Scottish antimicrobial prescribing group (SAPG): development and impact of the Scottish national antimicrobial stewardship programme. Int J Antimicrob Agents 2011; 38: 16–26. 30. Bell S, Davey P, Nathwani D et al. Risk of AKI with gentamicin as surgical prophylaxis. J Am Soc Nephrol 2014. 2014 May 29 [Epub ahead of print] 31. Mendelson M, Whitelaw A, Nicol M, Brink A. Wake up South Africa! The antibiotic ‘horse’ has bolted. S Afr Med J 2012; 102: 607–608. 32. Institute for Healthcare Improvement. The Breakthrough Series: IHI’s collaborative model for achieving breakthrough improvement. IHI Innovation Series white paper. Boston: Institute for Healthcare Improvement, 2003. 33. Harbarth S, Samore MH. Antimicrobial resistance determinants and future control. Emerg Infect Dis 2005; 11: 794–801. 34. Filippini M, Masiero G, Moschetti K. Physician dispensing and antibiotic prescriptions. Quaderno N. 09-08. Decanato della Facolta di Scienze economiche. 2009; 9. Available at: https://doc.rero.ch/record/13030/ files/wp0908.pdf (accessed 12 August 2014). 35. Park S, Soumerai SB, Adams AS, Finkelstein JA, Jang S, Ross-Degnan D. Antibiotic use following a Korean national policy to prohibit medication dispensing by physicians. Health Policy Plan 2005; 20: 302–309. 36. Chou YJ, Yip WC, Lee CH, Huang N, Sun YP, Chang HJ. Impact of separating drug prescribing and dispensing on provider behaviour: Taiwan’s experience. Health Policy Plan 2003; 18: 316–329. 37. Ho M, Hsiung CA, Yu HT, Chi CL, Chang HJ. Changes before and after a policy to restrict antimicrobial usage in upper respiratory infections in Taiwan. Int J Antimicrob Agents 2004; 23: 438–445. 38. Hsueh PR, Shyr JM, Wu JJ. Decreased erythromycin use after antimicrobial reimbursement restriction for undocumented bacterial upper respiratory tract infections significantly reduced erythromycin resistance in Streptococcus pyogenes in Taiwan. Clin Infect Dis 2005; 40: 903–905. 39. Molstad S, Cars O, Struwe J. Strama—a Swedish working model for containment of antibiotic resistance. Euro Surveill 2008; 13: pii: 19041. 40. Tangden T, Eriksson BM, Melhus A, Svennblad B, Cars O. Radical reduction of cephalosporin use at a tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. J Antimicrob Chemother 2011; 66: 1161–1167. 41. Sandberg T, Skoog G, Hermansson AB et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet 2012; 380: 484–490. 42. Hanberger H, Skoog G, Ternhag A, Giske CG. Antibiotic consumption and antibiotic stewardship in Swedish hospitals. Ups J Med Sci 2014; 119: 154–161. 43. Groth A, Enoksson F, Hermansson A, Hultcrantz M, Stalfors J, Stenfeldt K. Acute mastoiditis in children in Sweden 1993–2007—no increase after new guidelines. Int J Pediatr Otorhinolaryngol 2011; 75: 1496–1501. 44. Molstad S, Erntell M, Hanberger H et al. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme. Lancet Infect Dis 2008; 8: 125–132. 45. Huttner B, Samore M. Outpatient antibiotic use in the United States: time to ‘get smarter’. Clin Infect Dis 2011; 53: 640–643. 46. Hicks LA, Taylor TH Jr, Hunkler RJ. More on US outpatient antibiotic prescribing, 2010. N Engl J Med 2013; 369: 1175–1176. 47. Suda KJ, Hicks LA, Roberts RM, Hunkler RJ, Danziger LH. A national evaluation of antibiotic expenditures by healthcare setting in the United States, 2009. J Antimicrob Chemother 2013; 68: 715–718. 48. Suda KJ, Hicks LA, Roberts RM, Hunkler RJ, Taylor TH. Trends and seasonal variation in outpatient antibiotic prescription rates in the United States, 2006 to 2010. Antimicrob Agents Chemother 2014; 58: 2763–2766. 49. Earnshaw S, Monnet DL, Duncan B, O’Toole J, Ekdahl K, Goossens H. European antibiotic awareness day, 2008—the first Europe-wide public
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59. Coenen S, Gielen B, Blommaert A, Beutels P, Hens N, Goossens H. Appropriate international measures for outpatient antibiotic prescribing and consumption: recommendations from a national data comparison of different measures. J Antimicrob Chemother 2014; 69: 529–534. 60. Ibrahim OM, Polk RE. Antimicrobial use metrics and benchmarking to improve stewardship outcomes: methodology, opportunities, and challenges. Infect Dis Clin North Am 2014; 28: 195–214. 61. Livermore DM. Of stewardship, motherhood and apple pie. Int J Antimicrob Agents 2014; 43: 319–322. 62. Afshari A, Schrenzel J, Ieven M, Harbarth S. Bench-to-bedside review: rapid molecular diagnostics for bloodstream infection—a new frontier? Crit Care 2012; 16: 222. doi: 10.1186/cc11202. 63. Agarwal R, Schwartz DN. Procalcitonin to guide duration of antimicrobial therapy in intensive care units: a systematic review. Clin Infect Dis 2011; 53: 379–387. 64. Kardas-Sloma L, Boelle PY, Opatowski L, Guillemot D, Temime L. Antibiotic reduction campaigns do not necessarily decrease bacterial resistance: the example of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2013; 57: 4410–4416. 65. Mattick K, Kelly N, Rees C. A window into the lives of junior doctors: narrative interviews exploring antimicrobial prescribing experiences. J Antimicrob Chemother 2014; 69: 2274–2283. 66. Ivers N, Jamtvedt G, Flottorp S et al. Audit and feedback: effects on professional practice and healthcare outcomes. Cochrane Database Syst Rev 2012; 6: CD000259.
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Success stories of implementation of antimicrobial stewardship: a narrative review B. Huttner1, S. Harbarth1, D. Nathwani2 and on behalf of the ESCMID Study Group for Antibiotic Policies (ESGAP) 1) Infection Control Programme and Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland and 2) Infection Unit, Ninewells Hospital & Medical School, Dundee, UK
Abstract It has been increasingly recognized that antimicrobial stewardship (AMS) has to be a key component of any efforts that aim to mitigate the current global antimicrobial resistance (AMR) crisis. It has also become evident that AMR is a problem that cannot be tackled by single institutions or physicians, but needs concerted actions at regional, national and supra-national levels. However, it is easy to become discouraged, given the problems that are often encountered when implementing AMS. The aim of this review is to highlight some of the success stories of AMS strategies, and to describe the actions that have been taken, the outcomes that have been obtained, and the obstacles that have been met. Although the best approach to effective AMS remains elusive and may vary significantly among settings, these diverse examples from a range of healthcare contexts demonstrate that effective AMS is possible. Such examples will inform others and encourage them to formally evaluate and share their results with the global stewardship community. Keywords: antibiotic policy, antibiotic stewardship, antibiotic use, antimicrobial resistance, unintended consequences Article published online: 8 October 2014 Clin Microbiol Infect
Corresponding author: B. Huttner, Infection Control Programme, Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland E-mail: [email protected]
Introduction Antimicrobial resistance (AMR) is a problem requiring global solutions; antimicrobial stewardship (AMS) is a key component in addressing this issue [1]. However, many hospitals across the globe still lack AMS programmes, primarily because of a lack of funding (Howard, 2013 23rd ECCMID, Abstract O475). The results from published surveys suggesting that approximately half of all hospitals have AMS programmes very likely represent an overestimation of the true prevalence of AMS activities, owing to significant non-response bias and the use of rather broad definitions of what constitutes an AMS programme. This low level of activity is a concern, given that there is now good evidence that AMS programmes in hospitals can reduce overall antibiotic use and have a positive impact on the incidence of Clostridium difficile infection (CDI) and possibly also on AMR and clinical outcomes [2,3].
All too often, discussions about AMS are restricted to the inpatient setting, where there is high antibiotic use, a vulnerable patient population, and ‘ideal’ conditions for the transmission of multidrug-resistant organisms (MDROs). Most antibiotic use, however, occurs in the community, and often involves antibiotics for self-limiting viral infections in otherwise healthy people [4]. However, in the community setting, there have been many large-scale antibiotic awareness campaigns conducted at regional and national levels, and some have been ‘successful’ in reducing outpatient antibiotic use [5,6]. This narrative review aims to illustrate some of the ‘success stories’ of AMS—defined as any intervention aimed at improving the use of antimicrobials—implemented on a larger scale. Obviously, this leads to the question of how ‘success’ should be defined in the context of AMS: a reduction in overall antibiotic use and by what measure, a reduction in the use of specific antibiotic classes, a reduction in key outcomes such as
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the incidence of infections with MDROs or CDI, or even changes in mortality. The metrics for measuring these outcomes remain challenging to define, obtain, and interpret, but are crucial if we are to convince healthcare managers and policy-makers to invest increasingly scarce resource in AMS [7]. Ultimately, ‘success’ is, however, in the eye of the beholder, and in this review we did not tie our perception of ‘success’ to specific outcomes, as these are often not available, and the implementation of AMS activities alone in a large setting can already sometimes represent a ‘success’ story, given the many obstacles. It is important to keep in mind that this review is not aimed to be a comprehensive, systematic description of worldwide AMS activities. It is rather aimed at providing a broad description of some encouraging AMS stories from a convenience sample of case stories and experiences around the world (Fig. 1).
Success stories Australia
Fluoroquinolones are known as an antibiotic class with a particularly detrimental impact on the selection and spread of AMR [8,9]. In Australia, this was recognized earlier than elsewhere, and the use of this antibiotic class has long been restricted by guidelines favouring alternative options, and the limitation of prescription subsidies for this antibiotic class by the Pharmaceutical Benefits Scheme to very specific indications recognized by the guidelines [10]. As a consequence, Australia is one of the lowest overall users of fluoroquinolones among high-income countries (less than 0.6 defined daily doses/1000 inhabitants per day, whereas most European countries are well above one defined daily dose/1000 inhabitants per day), and, despite relatively high overall antibiotic use in the community, rates of resistance to fluoroquinolones are low as compared with many European countries (in 2010, 5.2% of Escherichia coli isolates from community-acquired infections were fluoroquinolone-resistant in Australia, whereas for most European countries this proportion is well above 15%) (EARS-Net: http://www.ecdc.europa.eu/en/healthtopics/anti microbial_resistance/database/Pages/database.aspx (accessed 16 October 2014)) [10–12]. Australia has also been active in inpatient AMS. The Australian Commission on Safety and Quality in Health Care —a government agency—has made surveillance of AMR and antibiotic usage a priority, and since 2013 AMS has become a criterion for accreditation of health services. In particular, hospitals are required to have an AMS programme in place, provide treatment guidelines, and monitor antibiotic use. The
recent introduction of measurable clinical standards for stewardship in Australian hospitals will enhance the pivotal place of stewardship in everyday clinical practice. The impact of this is awaited with interest. Chile
Dispensing of antibiotics without a medical prescription is a problem in many low-income and middle-income countries, where regulations are either non-existent or insufficiently enforced [13,14]. In 1999, Chile implemented a policy enforcing a ban of over-the-counter use of antibiotics without prescription [15]. The policy, also accompanied by a public campaign, was associated with a rapid 30% decrease in overall antibiotic use during the first years after its implementation [16,17]. Unfortunately, antibiotic use increased again between 2003 and 2008, but remains below that in the pre-intervention period [15]. Although the reasons for the increase are unclear (the lack of monitoring of compliance with the measures and the absence of additional interventions are mentioned in the literature), it illustrates that the long-term sustainability and associated cost/benefit ratio of AMS interventions need to be considered [15]. China
Like other countries, China has seen a rapid increase in MDROs over the last decade, and overprescribing of antibiotics is common in all settings, as is self-medication with antibiotics in the general population [18–21]. The Chinese Ministry of Health has recognized the dire situation, and launched a national campaign in 2011 to promote AMS in healthcare settings by establishing mandatory administrative strategies for the rational use of antimicrobials with fixed targets and audits [22]. Long-term data on the impact of these actions are lacking, but preliminary analyses suggest that there may have been a reduction in antibiotic use in the outpatient and inpatient settings between 2011 and 2012 (the proportion of patients prescribed an antimicrobial decreased from 68% to 58% for the inpatient setting, and from 25% to 15% for the outpatient setting) [22,23]. Although it is encouraging that the world’s most populous country is taking the problem of antibiotic misuse seriously, it is unclear whether predefined government targets for antibiotic use really constitute the best approach to ensure appropriate use for all patients. France
France has one of the highest levels of outpatient antibiotic use in Europe [24]. Over the last decade, France implemented three national action plans (2001–2005, 2007–2010, and 2011– 2016) to preserve the effectiveness of antibiotics. As part of the action plans, an intensive yearly public campaign called
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Antibiotic stewardship success stories
Country
Interventions
Success and failures
Australia
Restriction of fluoroquinolone use
Low fluoroquinolone use and low proportion of fluoroquinolone-resistant Escherichia coli
Chile
China
France
Scotland
South Africa
Very high overall antibiotic use Enforcement of a sales restriction Decrease in antibiotic consumption from for antibiotics (‘prescription only’) DID in 1999 to 8.5 DID in 2000 in 1999 in combination with a public campaign Overall antibiotic use has been increasing again since then Implementation of a comprehensive campaign to promote rational antibiotic use in 2011 : • audit and inspection • requirement for hospitals to have an antibiotic administrative group • formulary restrictions • clear targets for antibiotic use (less of 60%/20% of patients prescribed an tibiotic in the inpatient/ outpatient setting; less than 40 DDD/100 patientdays in the inpatient setting) Yearly national antibiotic campaign since 2001
National antibiotic stewardship programme since 2008 • Avoidance of cephalosporins, ciprofloxacin, fluoroquinolones, coamoxiclav and clindamycin (target: CDI) Implementation of an AMS programme in a private network of hospitals since 2010
South Korea
National policy change in 2000 • Separation of prescribing and dispensing of antibiotics
Sweden
National programme to contain antibiotic resistance (Strama) involving all stakeholders • Elaboration of guidelines • Identification and filling of knowledge gaps Implementation of a policy restricting reimbursement for antimicrobials in ambulatory patients with upper respiratory infections to situations where evidence of bacterial involvement is provided in 2001 Public campaign since 1995
Taiwan
USA Vietnam
Vietnam Resistance (VINARES) project : • promotion of prudent antibiotic use • strengthening of laboratory and surveillance activities
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Selected references [10]
[15—17]
Proportion of patients prescribed an antimicrobial [19,22,23] decreased from 68% to 58% for the inpatient setting and from 25% to 15% for the outpatient setting between 2011 and 2012 Fixed targets for antibiotic use seem problematic (impact on patient outcomes ?)
Overall outpatient antibiotic prescriptions per 100 inhabitants decreased by 26.5% over the first few campaign winters
[25,26,28]
Overall antibiotic use remains high as compared with other European countries and has been increasing in recent years [3,29,30] Net decrease in the incidence of CDI between 2008 and 2013 Increase in nephrotoxicity resulting from aminoglycoside use. Unclear how much of the decrease in CDI is attributable to antibiotic stewardship or attributable to concomitant interventions
Net decrease in overall antibiotic use (Fig. 3) Overall antibiotic use remains high. programme limited to the private setting Net decrease in antibiotic prescribing for patients with [35] presumed viral illness between 2000 and 2001 (from 80.8% to 72.8%) Long-term impact unclear. Overall antibiotic use for respiratory tract infections remains high. Low overall antibiotic use and low resistance levels
[39,42,44]
Increase in hospital antibiotic use over the last decade
Net decrease in antimicrobial use for respiratory infections (from DID in 1999 to 10.0 DID in 2001)
[36,37]
Long-term impact unclear
Decrease in outpatient antibiotic use Overall antibiotic use remains high. Too early to judge
[50]
[54]
FIG. 1. Global success stories of antimicrobial stewardship (AMS) mentioned in this review. CDI, Clostridium difficile infection; DDD, defined daily doses; DID, defined daily doses/1000 inhabitants per day; Strama, Swedish Strategic Programme Against Antibiotic Resistance. ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI
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European Centres for Disease Prevention and Control European Antibiotic Awareness Day to further coordinate efforts to educate the public about appropriate antibiotic use (Transatlantic Taskforce on Antimicrobial Resistance—Progress report 2014; http://www.cdc.gov/drugresistance/pdf/ TATFAR-Progress_report_2014.pdf (accessed 16 October 2014)) [49]. Recently, the CDC has also turned its attention to the inpatient setting, with the ‘Get Smart for Healthcare’ programme. A strategy for monitoring inpatient antimicrobial use among hospitals is currently being implemented [50]. The Veterans Health Administration, the largest integrated healthcare system in the USA, has recently also become very active in the context of AMS, with mandatory implementation of AMS at all Veterans Health Administration medical facilities by mid-2014. The availability of a common electronic health record with detailed patient-level data will make it interesting to follow the impact of this policy. Vietnam
In 2013, a report analysed the situation with regard to antibiotic use and resistance in Vietnam [51]. The report draws a rather dire picture, with frequent antibiotic misuse in all settings, and proposes some policy priorities to address the problem, among them being the development of AMS programmes [52,53]. In order to assist local healthcare professionals with the task of strengthening AMS and infection control, the Vietnam Resistance (VINARES) project was initiated [54]. The project has a comprehensive approach, and aims to meet the policy priorities proposed by the WHO in 2011 as a ‘policy package’ to combat AMR that includes both the promotion of prudent antibiotic use and also the strengthening of laboratory and surveillance activities [55]. A recently published paper described the implementation of the project and the challenges that it has met so far [54]. Although it is too early to judge whether VINARES really is a ‘success story’, it is certainly promising, and may be an example to follow for other low-income and middle-income countries.
Discussion With the emergence and spread of multiresistant Gram-negative ‘superbugs’, the need for effective AMS has been recognized in most settings as a key strategy to counter this threat. In this review, we have presented some examples illustrating that AMS activities can be successfully implemented in a variety of geographical and socio-economic settings. There certainly are more success stories in other countries (e.g. Belgium, Slovenia, and Thailand), not to mention in individual hospitals and practices, that are not included in this review
[56–58]. In general, antibiotic stewards around the world should be encouraged to share more often their real-life experiences in medical journals. A recent booklet on hospital stewardship sponsored by a diagnostic company provides further pragmatic good-practice examples of stewardship in action (http://bsac.org.uk/wp-content/uploads/2013/07/Stewardship-Booklet-Practical-Guide-toAntimicrobial-Stewardship-in-Hospitals.pdf (accessed 16 October 2014)). It is evident that AMS is just one element in the quest to combat AMR and that a comprehensive approach, including control of use in animal husbandry and horticulture, is needed, but this is beyond the remit of this review [1]. Many questions about AMS in humans remain. Uncertainty persists about the definition, measurement and interpretation of outcomes. Often, AMS programmes evaluate their success with surrogate measures, such as overall antibiotic use density. The best way to measure antibiotic use and what benchmarks to choose are, however, far from clear [59]. Adjustment for differences in the case mix of the patient populations seen by different institutions or practitioners is another area of uncertainty [60]. Things become even murkier when we move from a quantitative to a qualitative perspective and try to define ‘appropriate’ and responsible antibiotic use (in the context of the Innovative Medicines Initiative, a joint undertaking between the European Union and the pharmaceutical industry association EFPIA, the DRIVE-AB, project will try to address this issue http://drive-ab.eu/ (accessed 16 October 2014)). The only straightforward, universally agreed issue may be avoiding antibiotics altogether when they are not needed. The recommendation to avoid certain ‘high-risk’ antibiotics, such as fluoroquinolones and cephalosporins, is questioned by some experts, as the long-term impact of replacing these antibiotics with other agents is unclear [61]. Other cherished strategies, such as de-escalation, individualized dosing, and reduced duration of therapy, still have to prove their value in curbing AMR. The role and value of rapid diagnostics and biomarkers in stewardship also require further evaluation [62,63]. Antibiotic campaigns have traditionally been focused on children, as they contribute a high percentage of antibiotic prescriptions. Recent analyses from the USA and France suggest, however, that older adults may also constitute a worthwhile target [4,26]. The impact of public campaigns on AMR is also far from evident, as illustrated by a recent simulation study, illustrating the knowledge gaps regarding the emergence and spread of resistance in individuals and populations [64]. The experience that we share here illustrates that there is still much to be learned with regard to AMS. Our review reveals that there remains a poor evidence base for the
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Ltd) has responded to the threat posed by carbapenemase-producing enterobacteria by establishing an AMS programme, which has been progressively implemented in its 55 hospitals since 2010 [31]. The program adopted the Institute for Healthcare Improvement breakthrough series collaborative approach, involving multidisciplinary teams containing pharmacists, infection control practitioners, microbiologists, and other clinicians [32]. Data collection for surveillance was automated, specific outcome measures and deliverables were established (with ranking of the hospitals according to their implementation of AMS), workshops and teleconferences were organized, and guidelines were developed. Preliminary data suggest that the programme was associated with a 12.1% reduction in defined daily doses per 100 patient-days by the first trimester of 2014 (Fig. 3) (D. van den Bergh, personal communication). Although the overall level of antibiotic use remains high, at approximately 82 defined daily doses per 100 patient-days, these results are certainly encouraging, and provide an example to follow for other hospital networks in Africa and elsewhere.
reduction in antibiotic use and an increase in the quality of antibiotic prescribing [35]. Taiwan implemented a similar policy in the 1990s [36]. In addition, in 2001, the national health insurance in Taiwan implemented a policy stopping reimbursement for acute upper respiratory tract infections unless proof of bacterial aetiology was provided. In the first year, this policy was associated with a > 50% reduction in antibiotic use for upper respiratory tract infections [37,38].
South Korea and Taiwan
Certain regulatory frameworks can create economic incentives that counteract the prudent use of medications in general and of antibiotics in particular [33]. The failure to separate prescribing and dispensing of medications in some regions of Switzerland has, for example, been shown to be associated with higher levels of antibiotic use [34]. In South Korea, this problem was recognized, and a pharmaceutical policy reform was implemented in 2000, prohibiting physicians from dispensing drugs [35]. This policy change was associated with both a
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Sweden
Sweden was one of the first countries to adopt a universal, national strategy for AMS in all settings (including the veterinary sector). The Swedish Strategic Programme Against Antibiotic Resistance (Strama), which started as an informal network in 1995, was institutionalized as an independent governmental body in 2006 [39]. Local Strama groups cooperate with hospital stewardship programmes to develop guidelines [40]. At the national level, one of the key accomplishments of Strama is the initiation of trials addressing key knowledge gaps in AMS, such as the recently published randomized controlled trial confirming the non-inferiority of 7-day vs. 14-day treatment in women with acute pyelonephritis [41]. Although hospital antibiotic use in Sweden appears to have increased in recent years, it still remains comparatively low, and the level of antibiotic use in the outpatient setting is among the lowest in Europe [24,42]. In that context, it is remarkable that Strama also dedicated efforts to assess potential negative consequences of reduced antibiotic use in the community, an aspect that is often neglected [43,44]. Demonstrating that a decrease in antibiotic use (from an already very low level) is not associated with an increase in complications such as mastoiditis and quinsy constitutes extremely valuable information for other countries [43,44]. USA
FIG. 3. Impact on antibiotic consumption following implementation of an an antimicrobial stewardship programme across a group of 54 private hospitals in South Africa (D. van den Bergh, personal communication; with permission of author). DID, defined daily doses/1000 inhabitants per day.
The USA was among the first high-income countries to implement an antibiotic campaign to educate the public, in 1995, with the CDC ‘Get Smart’ programme. As the USA has somewhat lagged behind Europe with regard to the surveillance of antimicrobial use, it is, however, difficult to assess the impact of the campaign [5,45]. Fortunately, more data have become available recently [46–48]. It seems that outpatient antibiotic prescriptions have been somewhat decreasing since the turn of the century, at least for some subgroups, such as children and adolescents [4]. Unnecessary use of antibiotics for acute respiratory tract infections and the use of antibiotics with an unnecessarily broad spectrum, such as macrolides and fluoroquinolones, remain common [4]. It is promising that there are plans for the CDC’s Get Smart campaign and the
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European Centres for Disease Prevention and Control European Antibiotic Awareness Day to further coordinate efforts to educate the public about appropriate antibiotic use (Transatlantic Taskforce on Antimicrobial Resistance—Progress report 2014; http://www.cdc.gov/drugresistance/pdf/ TATFAR-Progress_report_2014.pdf (accessed 16 October 2014)) [49]. Recently, the CDC has also turned its attention to the inpatient setting, with the ‘Get Smart for Healthcare’ programme. A strategy for monitoring inpatient antimicrobial use among hospitals is currently being implemented [50]. The Veterans Health Administration, the largest integrated healthcare system in the USA, has recently also become very active in the context of AMS, with mandatory implementation of AMS at all Veterans Health Administration medical facilities by mid-2014. The availability of a common electronic health record with detailed patient-level data will make it interesting to follow the impact of this policy. Vietnam
In 2013, a report analysed the situation with regard to antibiotic use and resistance in Vietnam [51]. The report draws a rather dire picture, with frequent antibiotic misuse in all settings, and proposes some policy priorities to address the problem, among them being the development of AMS programmes [52,53]. In order to assist local healthcare professionals with the task of strengthening AMS and infection control, the Vietnam Resistance (VINARES) project was initiated [54]. The project has a comprehensive approach, and aims to meet the policy priorities proposed by the WHO in 2011 as a ‘policy package’ to combat AMR that includes both the promotion of prudent antibiotic use and also the strengthening of laboratory and surveillance activities [55]. A recently published paper described the implementation of the project and the challenges that it has met so far [54]. Although it is too early to judge whether VINARES really is a ‘success story’, it is certainly promising, and may be an example to follow for other low-income and middle-income countries.
Discussion With the emergence and spread of multiresistant Gram-negative ‘superbugs’, the need for effective AMS has been recognized in most settings as a key strategy to counter this threat. In this review, we have presented some examples illustrating that AMS activities can be successfully implemented in a variety of geographical and socio-economic settings. There certainly are more success stories in other countries (e.g. Belgium, Slovenia, and Thailand), not to mention in individual hospitals and practices, that are not included in this review
[56–58]. In general, antibiotic stewards around the world should be encouraged to share more often their real-life experiences in medical journals. A recent booklet on hospital stewardship sponsored by a diagnostic company provides further pragmatic good-practice examples of stewardship in action (http://bsac.org.uk/wp-content/uploads/2013/07/Stewardship-Booklet-Practical-Guide-toAntimicrobial-Stewardship-in-Hospitals.pdf (accessed 16 October 2014)). It is evident that AMS is just one element in the quest to combat AMR and that a comprehensive approach, including control of use in animal husbandry and horticulture, is needed, but this is beyond the remit of this review [1]. Many questions about AMS in humans remain. Uncertainty persists about the definition, measurement and interpretation of outcomes. Often, AMS programmes evaluate their success with surrogate measures, such as overall antibiotic use density. The best way to measure antibiotic use and what benchmarks to choose are, however, far from clear [59]. Adjustment for differences in the case mix of the patient populations seen by different institutions or practitioners is another area of uncertainty [60]. Things become even murkier when we move from a quantitative to a qualitative perspective and try to define ‘appropriate’ and responsible antibiotic use (in the context of the Innovative Medicines Initiative, a joint undertaking between the European Union and the pharmaceutical industry association EFPIA, the DRIVE-AB, project will try to address this issue http://drive-ab.eu/ (accessed 16 October 2014)). The only straightforward, universally agreed issue may be avoiding antibiotics altogether when they are not needed. The recommendation to avoid certain ‘high-risk’ antibiotics, such as fluoroquinolones and cephalosporins, is questioned by some experts, as the long-term impact of replacing these antibiotics with other agents is unclear [61]. Other cherished strategies, such as de-escalation, individualized dosing, and reduced duration of therapy, still have to prove their value in curbing AMR. The role and value of rapid diagnostics and biomarkers in stewardship also require further evaluation [62,63]. Antibiotic campaigns have traditionally been focused on children, as they contribute a high percentage of antibiotic prescriptions. Recent analyses from the USA and France suggest, however, that older adults may also constitute a worthwhile target [4,26]. The impact of public campaigns on AMR is also far from evident, as illustrated by a recent simulation study, illustrating the knowledge gaps regarding the emergence and spread of resistance in individuals and populations [64]. The experience that we share here illustrates that there is still much to be learned with regard to AMS. Our review reveals that there remains a poor evidence base for the
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effectiveness of the myriad of AMS policies that have been implemented across various countries. Even where policies have demonstrated clear benefit in reducing antimicrobial misuse, a full evaluation of the successful policy has often been lacking, with little available information on critical aspects such as cost-effectiveness, and inadequate descriptions of the technical and regulatory environment necessary for implementation and regulatory changes. Unfortunately, we will not have time to wait for solid scientific evidence for all aspects of AMS, as by then it may be too late to avert or mitigate the escalation of the emerging AMR crisis. In our opinion, the examples mentioned in this review illustrate that it is crucial to understand this problem in detail in each country and develop interventions tailored for each setting (e.g. regarding how much public ignorance contributes to antibiotic overuse). A common theme of successful AMS interventions around the globe is that they have been tailored to local conditions, incorporated the advice of opinion leaders, provided a well-developed rationale for change, and received strong support from governmental agencies and/or professional societies of the concerned country. Furthermore, regulatory interventions have been crucial in changing antibiotic prescribing practices and policies, as shown in diverse countries such as Australia, South Korea, Scotland, and Chile. It is evident that changing behaviour with regard to antibiotic prescribing has to be a long-term goal. This should be supported not only by improving knowledge through education, but also by a better understanding of prescribing ‘etiquette’, human factors, and systems of care delivery [65]. In the Scottish example, the ‘goal-oriented’ or ‘target-oriented’ approach combined with explicit feedback of data and a requirement for action has led to some sustained success over a 6-year period. This approach is supported by emerging evidence that audit and feedback of prescribing data can be highly effective if it is provided by a supervisor or colleagues, is repeated several times, is delivered both orally and in writing, and is combined with a specific target and action plan [66]. The long-term evaluation of sustainability should be a component of any intervention to improve antibiotic use. We need more high-quality randomized trials to improve the evidence base, particularly in relation to factors that provide sustained success (or a lack thereof) in a range of diverse resource and healthcare settings, but sharing our experiences with ‘real-life’ AMS practitioners and learning from the failures and successes of others may be just as important. The words of Winston Churchill may provide some consolation for discouraged antibiotic stewards: ‘success is not final, failure is not fatal: it is the courage to continue that counts’.
Acknowledgments
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We would like to thank D. van den Bergh (Director: Quality Leadership, Netcare Group (Pty) Ltd, South Africa) for sharing her experience with AMS in South Africa. We also thank P. Charles (Melbourne) for careful reading of the manuscript.
Funding B. Huttner is supported by funding from the European Community’s 7th Framework Programme (R-Gnosis grant agreement no. 282512).
Transparency Declarations S. Harbarth reports having received a peer-reviewed research grant funded by Pfizer; he is also a member of the speakers’ bureau for bioMerieux and a member of the advisory board of Destiny Pharma, bioMerieux. D. Nathwani received funds for the production of the bioMerieux booklet and has been invited to the bioMerieux-funded World HAI forum. B. Huttner has no conflicts of interest to declare in relation to the contents of this manuscript.
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