NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Anderson M, Clift C, Schulze K, et al. Averting the AMR crisis: What are the avenues for policy action for countries in Europe? [Internet] Copenhagen (Denmark): European Observatory on Health Systems and Policies; 2019. (Policy Brief, No. 32.)
Averting the AMR crisis: What are the avenues for policy action for countries in Europe? [Internet]
Show detailsIntroduction
The discovery of antibiotics 90 years ago has revolutionized the treatment of communicable bacterial diseases and facilitated significant developments in areas of medicine such as surgery, obstetrics and oncology [1,2]. Concerns regarding resistance to antibiotics were raised almost immediately, with Sir Alexander Fleming, the discoverer of penicillin, noting in an interview as early as 1945:
In such cases, the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.
(New York Times, 1945)
AMR is a naturally occurring mechanism by which microorganisms such as bacteria become resistant to antimicrobial medicines. Resistance can be intrinsic1 or acquired and occurs if selective pressure – through the use of antibacterial medicines – kills off susceptible bacteria, while creating a survival advantage for those bacteria with the ability to resist the killing effect of the respective antibiotic(s). We now understand that resistant pathogens can disseminate across the human, animal and environmental sectors, meaning there are wide implications for all aspects of society.
AMR2 increasingly threatens our ability to treat infections and to undertake life-saving treatments such as surgical procedures and chemotherapy. The dangers emerging from this alarming development of increasingly resistant microorganisms have previously been mitigated by the discovery of novel classes of antibiotics. However, for the last 30 years this has not been the case, with very few novel antibiotics discovered [4,5]. To date, rising rates of AMR are already responsible for a significant health and economic burden, which, without swift action, is projected to dramatically increase.
The world community is taking the problem seriously, as demonstrated by a history of increasing efforts to combat AMR (see Figure 3 in ‘Global action to date’). These efforts culminated in the launch of the Global Action Plan on Antimicrobial Resistance, which asked for all countries to develop NAPs by 2017 [6,7]. However, progress has been inconsistent. Also, developing NAPs is only the beginning, and the ability of countries to implement these plans can be challenged by the absence of sufficient human and financial resources, low health system capacity, and weak governance and coordination. The UN Interagency Coordination Group on Antimicrobial Resistance (IACG) recently concluded that the biggest obstacle is not just developing the NAPs but also pursuing their successful implementation, suggesting that governance of AMR policies is a key determinant for success [8].
Aim and scope
The aim of this brief is to present key policy options that can be effective in combating AMR in Europe. The brief is meant to serve as a succinct, accessible overview of the policy avenues necessary to build a national strategy to combat AMR. This document does not supplant the need to look more deeply into the evidence for each of the discussed policy options, nor are the options discussed comprehensive or suitable for every type of setting. It begins with an overview of estimations of the health and economic impacts of AMR as well as an outline of global action to date. What follows is a description of several essential AMR policy areas and priority interventions to consider, and then an exploration of the importance of governance to facilitate the successful implementation of AMR NAPs.
Methods
The selection of policy responses reflects the breadth of objectives and recommendations contained within recent international guidance such as the 2015 WHO Global Action Plan on Antimicrobial Resistance [6], the 2016 World Organisation for Animal Health (OIE) Strategy on Antimicrobial Resistance and the Prudent Use of Antimicrobials [9], and the 2016 Food and Agriculture Organisation (FAO) Action Plan on Antimicrobial Resistance [10]. These plans have overlapping, complementary goals and objectives (see Table 1). They also underscore the need for a holistic and multisectoral ‘One Health’ approach to controlling and preventing AMR, which has been generally accepted since the beginning of this decade.
Table 1
Overview of the objectives of WHO/FAO/OIE action plans and strategies.
The health and economic impact of AMR
AMR prevalence rates have been on the rise in recent years. Between 2007 and 2015, it is estimated that the annual burden of infections with selected antibiotic-resistant bacteria of public health importance more than doubled across European Union/European Economic Area (EU/EEA) countries [11]. If this trend continues, simple infections may no longer be treatable, with extensively drug-resistant strains of bacteria such as tuberculosis (TB) and gonorrhoea already emerging [12,13].
AMR has adverse effects on both health outcomes and the cost of healthcare. Clinicians often decide the type of antibiotic treatment in the absence of microbiological test results. If a resistant infection is present, the chosen treatment may be ineffective, resulting in wasted resource and a delayed commencement of effective treatment [14]. Additional diagnostic tests will often need to be undertaken to identify the appropriate treatment – again, at increased cost. The severity of resistant infections is often greater than that of treatment-susceptible infections, and this can be intensified by the delayed start of effective treatment. The appropriate treatment for resistant strains is often second-line treatment, which is more costly than front-line options. Treatment of resistant infections often also relies on broad-spectrum antibiotics, which can be less safe and less effective than narrow-spectrum counterparts. Increased severity leads to poorer outcomes and an increase in treatment failure and fatality. There is also a higher risk of complications and a greater chance that patients will require (longer) hospital stays, surgery and time in intensive care or isolation [15]. Modelling analysis of the health burden in disability-adjusted life years (DALYs) of selected antibiotic-resistant bacteria of public health importance across the EU/EAA in 2015 showed that the burden was greatest in infants (aged <1 year) and people aged 65+, and was highest in Romania, Italy and Greece (Figure 1).
Figure 1
Estimates of the burden of infections with selected antibiotic-resistant bacteria of public health importance in DALYs per 100 000 population, EU/EEA, 2015. Sources: [11].
These all come at significant cost to patients (including non-monetary costs), healthcare systems and the wider economy. For example, hospital costs of treatment for resistant infection are estimated to be USD10 000–40 000 higher than those for susceptible infection [16–20]. In Europe, about 6% of patients develop HAIs, of which 30–40% may be caused by resistant organisms [21]. In 2007, it was estimated that in 31 European countries there were more than 8000 deaths and €62 million of excess costs caused by Methicillin-resistant Staphylococcus aureus (MRSA) and resistant Escherichia coli [22,23]. The adverse health effects of AMR can also have a serious economic impact by reducing the size of the working population and affecting labour market participation and productivity. Rand Europe [24] estimated that by 2050 a situation of 100% resistance to E.coli, Klebsiella pneumoniae, S.aureus, human immunodeficiency virus (HIV), TB and malaria in OECD countries would lead to a loss of 10.2 million working-age people per year, compared with a loss of 2.1 million per year under current levels of resistance (Figure 2).
Figure 2
Estimated annual working-age population loss in OECD countries in various resistance scenarios. Source: Adapted from World Bank [25]. Note: Resistance rates of E.coli, K. pneumoniae, S. aureus, HIV, TB and malaria.
KPMG estimated that a doubling of infection rates for MRSA, E.coli, K.pneumoniae, HIV and TB due to AMR would lead to 700 million deaths by 2050, at a cumulative cost of $14 trillion to the global economy [26]. Further modelling by the World Bank using two scenarios, a low-impact and a high-impact scenario, again emphasized the cost of inaction but across many dimensions (Box 1).
Box 1
World Bank projections of AMR impact by 2050.
More recently, the OECD has published individual analyses evaluating the impact of AMR on health and healthcare expenditure for 33 OECD and EU/EEA Member countries. The OECD model estimated that, on average, AMR causes around 67 000 deaths per year across the included countries and costs their healthcare systems $3.5 billion annually [27] (see also Box 4).
Global action to date
In 1998, due to concerns regarding the rapid emergence and spread of many human pathogens resistant to available antibiotics, the first WHO resolution on antimicrobial resistance was published [28,29]. Following this, some (mainly OECD) countries began to publish AMR NAPs [7,8].
In 2009, the Swedish EU Presidency made antimicrobial development a priority. High unmet need, as well as potential policies and incentives to promote antimicrobial research, were highlighted as priorities at an expert conference in Stockholm [30]. Following this meeting, the Swedish Prime Minister, Fredrik Reinfeldt, proposed to the US President, Barack Obama, the formation of a Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) between the EU and the United States to encourage global research and address resistance [31]. Slowly, the ‘One Health’ perspective, which includes the imperative to coordinate actions across the human, animal and environmental health sectors to combat AMR, has gained widespread acknowledgement, with one significant milestone being the European Council conclusions on a ‘One Health’ perspective in 2012 [32].
Later in 2014, G73 leaders committed to working with the WHO to develop a global action plan on AMR. To follow this up, the United Kingdom established the independent review on AMR, which in 2016 outlined the severity of the threat AMR poses to health and the global economy, proposing several measures necessary to improve antibiotic stewardship and promote the development of new antibiotics, vaccines and diagnostics [33].
Efforts were renewed with World Health Assembly resolutions in 2014 and 2015, which peaked in the launch of the Global Action Plan on Antimicrobial Resistance, which asked for all countries to develop NAPs by 2017 [6,8,34]. In 2016, a mapping exercise of international initiatives to encourage antibiotic drug discovery commissioned by the Dutch EU presidency noted that, despite progress, there appeared to be a lack of global coordination across all initiatives, which risked duplicated effort, funding gaps in the value chain and overlooking important AMR goals [35]. In 2016, the tripartite collaboration of the WHO, FAO and OIE reported that only 53% (79/149) of countries had developed an AMR NAP. However, results from the second global self-assessment survey on the progress of countries indicate that almost all countries have initiated the process of NAP development and many have adopted their plans: by May 2017, 79 out of 154 countries (51%) reported they had a plan, with a further 50 reporting having a plan under development.
Later in 2016, the UN General Assembly agreed a political declaration on AMR, which accepted the WHO Global Action Plan on Antimicrobial Resistance as a blueprint; recognized and underlined the severity of the AMR threat to health and society in general; and committed to work at national, regional and global levels to develop and implement multisectoral NAPs in accordance with the ‘One Health’ approach [36]. In 2017, leaders of the G20 endorsed actions to combat AMR, including the establishment of a new international R&D Collaboration Hub [37]. Figure 3 summarizes the major WHO, EU and UN AMR key events and policy milestones.
Besides the actions taken by international bodies, many nations have made further concrete steps to restrict the unnecessary use of antibiotics in both humans and animals. New initiatives, such as CARB-X and GARDP, have been started to strengthen the pipeline of new antibiotic drugs urgently needed as resistance grows, and diagnostic development has been stimulated by several schemes, such as the Longitude Prize (see below).
Yet, what has been done so far does not match the scale of actions required to address AMR that have been recommended in recent reports [38]. For example, while there has been some progress in addressing the financing of early-stage research, nothing has been done to implement proposals for incentivizing late-stage research and clinical trials. Much also remains to be done to eliminate inappropriate antibiotic use in both humans and animals. The limited availability of rapid point-of-care diagnostics is a key barrier to reducing inappropriate use, given the natural risk aversion of health professionals. Finally, AMR does not respect borders, and countries in Europe cannot coordinate their actions in isolation from the rest of the global community. They should seek to support other countries in their actions to combat AMR with financial and technical expertise, in particular low- and middle-income countries (LMICs), whose specific contexts have led to the emergence of a disproportionately high prevalence of resistant pathogens (Box 2).
Box 2
Prevalence of AMR in low- and middle-income countries.
What are the options? Essential AMR policies and priority interventions
To date, 23 EU countries report that they have completed an AMR NAP and countries are adopting a broad range of polices to tackle AMR [49]. However, given that the health and economic impact of AMR is potentially huge, recent comparative reviews of AMR NAPs find that the quality and comprehensiveness of AMR NAPs is inconsistent [50]. To aid policy-makers, the following section includes a summary of the essential policy areas and priority interventions to consider when formulating a national strategy to combat AMR. As the drivers of AMR are multifactorial, the response should be multifactorial, and any national strategy to combat AMR should weight these avenues equally. These options have been endorsed by the WHO/FAO/OIE tripartite in their respective AMR action plans (see Table 1).
1. Increasing awareness of AMR
Participation in the European Antibiotic Awareness Day (EAAD) initiated in 2008 and the World Antibiotic Awareness Week (WAAW) initiated in 2015 has been strong, however ongoing and repeated efforts are needed to raise public awareness. Eurobarometer results from 2018 showed that 57% of Europeans were unaware that antibiotics are ineffective against viruses [51]. This is a slight improvement from 2013, when 60% of Europeans were unaware that antibiotics are ineffective against viruses [52]. Therefore, it is essential that any national strategy to combat AMR includes actions to increase awareness of AMR among the public as well as for professionals who may be in a position to prescribe antibiotics.
Patient pressure and expectations in primary care have been identified as a trigger for clinicians to prescribe antibiotics in the absence of a clear indication; therefore, it is not surprising that several countries have experienced a reduction in the number of antibiotic prescriptions following AMR awareness campaigns [53]. Nevertheless, the most effective messages and interventions remain unclear as it is difficult to compare interventions due to variations in measurement [54–56]. It has also been suggested that future AMR campaigns should be multimodal in nature and that their design needs to incorporate behavioural science to consider the messages and modalities that will be most cost-effective in reducing antibiotic prescribing, whilst also maximizing the impact on people’s knowledge, attitudes and behaviour [57]. It is recommended that campaigns should be implemented at national, regional and local levels to ensure widespread coverage and, when possible, involve an integrated evaluation plan.
Increasingly, countries are focusing on educational campaigns within schools, to target the very young. For example, the e-Bug programme led by Public Health England and involving a consortium of 28 international partner countries, provides interactive exercises which educate children on communicable diseases generally as well as infection prevention measures such as handwashing techniques [58]. Another important strategy that has gained momentum is the Antibiotic Guardian movement developed by Public Health England, which asks both the public and professionals to sign up to be advocates of restricting antimicrobial usage [59,60].
For professionals, it is important that they receive dedicated and continuous education on responsible antimicrobial prescribing and IPC, and that there is an environment conducive to using and adopting standards, facilitating control policies, and implementing guidelines sufficiently [54]. Acknowledging the need to provide guidance in this area, WHO recently (2018) published a dedicated Competency Framework for Health Workers’ Education and Training on Antimicrobial Resistance [61].
In the health sector, medical students, physicians, pharmacists, nurses, midwifes, dentists and technicians need to be trained in order to build the capacity required to implement guidelines and objectives [62]. It is equally important for professionals from the animal and environmental health sectors, such as veterinarians, veterinary nurses, farmers, as well as professionals working in sensitive parts of the food industry or environmental agencies, to be trained [63]. Findings from the most recent ‘Global monitoring of country progress on addressing antimicrobial resistance: Self-assessment questionnaire 2017–18’ indicate that there is still room for improvement in Europe: currently 48% of EU/ EEA countries report having fragmented, ad hoc or limited pre- and in-service training for healthcare workers on AMR. The same was reported by 41% of respondents for training activities in the veterinary sector [49]. Results from the latest global survey find that in 38% of EU/EEA countries awareness campaigns on antibiotic resistance in humans are rather limited and/or small-scale in scope and reach; in non-human health sectors this was reported by 44% of respondents [49].
2. Strengthening surveillance and monitoring, and moving towards national ‘One Health’ surveillance systems
Comprehensive surveillance is key during the conception, implementation, monitoring and evaluation of AMR NAPs. Surveillance data is useful initially to establish the extent of AMR and AMU to inform the development phase of an AMR NAP. Thereafter, it is a key element in the feedback and accountability mechanisms for relevant stakeholders which will improve the likelihood of the successful implementation of the NAP. Surveillance is also essential for the ongoing monitoring and evaluation of NAPs as well the effectiveness of specific policies. The importance of AMR surveillance systems cannot be overestimated.
While not always the case currently, countries should aspire towards developing a national AMR surveillance system that adopts a ‘One Health’ approach across animal, human and environmental health [64]. Some countries, such as Denmark, Norway, the United Kingdom, Sweden and Canada, have already begun to publish joint annual AMR surveillance reports, which cover AMR rates of different organisms across both human and animal health, as well as recent data regarding antimicrobial usage [65–69]. Across Europe, many human health surveillance systems are well established and financed, and, due to EU financing and guidance regarding the monitoring of resistant isolates from food animals, national surveillance for animal health is becoming increasingly harmonized [70,71]. Surveillance systems in the environment remain inconsistent, although a recent report from the United Nations Environment Programme (UNEP) provides data sources and exposure pathways for AMR and AMU in the environment, which could be used to identify entry points for integrating environmental surveillance into existing systems [72].
These national surveillance systems must also link into international surveillance systems such as the European Antimicrobial Resistance Surveillance Network (EARS-Net), European Surveillance of Antimicrobial Consumption Network (ESAC-Net), European Surveillance of Veterinary Antimicrobial Consumption (ESVAC), Central Asian and Eastern European Surveillance of Antimicrobial Resistance (CAESAR), WHO Antimicrobial Medicines Consumption (AMC) Network, Healthcare-associated Infections Surveillance Network (HAI-Net) and the Global Antimicrobial Resistance Surveillance System (GLASS). To meet the standards of these systems, the provision of adequate laboratories, equipment and technical expertise, as well as regular external quality assessment, is necessary.
3. Strengthening antimicrobial stewardship in human health
Antibiotic stewardship (ABS) can be defined as ‘the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance [73].’
In 2016, the EU/EEA population-weighted mean consumption of antibiotics for systemic use in the community was 21.9 defined daily doses (DDD) per 1000 inhabitants per day, ranging from 10.4 in the Netherlands to 36.3 in Greece (Figure 5a). In the hospital sector the mean consumption was 2.1 DDD per 1000 inhabitants per day, ranging from 1.0 in the Netherlands to 2.9 in Malta (Figure 5b). Whilst the majority of antimicrobials are prescribed in the community, antimicrobial use in hospital patients tends to be high-volume use by relatively small populations, exerting a higher selection pressure. It has been estimated that on any given day an average of 35% of hospitalized patients in EU/EEA countries receive at least one antibiotic (country range 21–55%) [74].
Figure
a) Consumption in the community Notes: Cyprus and Romania provided total care data, i.e. including the hospital sector; Spain provided reimbursement data, i.e. not including consumption without a prescription and other non-reimbursed courses.
Governments are adopting a broad range of policy approaches to decrease the ineffective use of antimicrobials, usually as part of their NAP. A recent OECD survey (2016) showed that about 60% of OECD countries have produced a strategy to rationalize the use of antimicrobials, while an additional 37% are in the process of developing one [76]. Recent models from the OECD concluded that the implementation of ABS programmes could result in a 51% reduction of deaths from AMR and €2.3 billion saved [76].
Antimicrobial stewardship in the community
In HICs, most antibiotics are prescribed not in hospitals but in primary care in the community; in England, for example, three quarters of antibiotics are prescribed in general practice and just 11% in hospitals [77], with an estimated 8.8–23.1% of antibiotic prescribing in primary care considered to be inappropriate [78]. Common infections, such as throat, urinary, skin or tooth and especially respiratory tract infections (RTI), are responsible for the biggest share of antibiotic prescriptions in non-hospitalized patients. For the majority of RTIs and sore throats, which are caused by viral agents and are self-limiting in nature, antibiotics have only been shown to reduce the length of symptoms by a few hours [79,80].
Stewardship strategies in primary care focus on the use of evidence-based guidelines and algorithms, delayed prescribing, and recommendations to discourage the use of broad-spectrum antibiotics wherever possible when narrower options are available and likely to be effective (e.g. in the case of urinary tract infections; UTIs) [81]. Interventions focusing mainly on changing the prescribing behaviour of clinicians through the use of guidelines, outreach visits, clinical audit, as well as computerized reminders, have all been shown to be effective [82]. A multifaceted approach combining several measures is preferable to focusing on single interventions. Many healthcare systems also utilize financial incentives to encourage appropriate antibiotic use, such as the Antibiotic Quality Premium (AQP) in England in 2015/16, which contributed to a 3% reduction in antibiotic prescribing rates for uncomplicated RTIs [83] (Box 3). Shared decision-making between the clinician and patient, based on the best available evidence and patient preferences, is an essential tool for reducing antibiotic use and has been shown to be highly effective [84]. Shared decision-making can often be utilized in conjunction with delayed prescribing strategies [85,86], although both strategies rely upon good communication and well-informed patients who appreciate the importance of tackling AMR. A further option is to provide patient educational materials during consultation [86].
Effective interventions also focus on rapid, affordable and easy-to-use diagnostic tools. Point-of-care tests, such as for C-reactive protein, can be effective in ruling out viral infections, but appropriate tests are often not available [87]. Evidence on the cost-effectiveness of these strategies is currently limited, due to uncertainties about the impact of reduced antibiotic use on AMR, and of the value that should then be attached to AMR reduction.
Box 3
The United Kingdom Antibiotic Quality Premium (AQP).
Antimicrobial stewardship in the hospital sector
ABS programmes in hospitals primarily focus on changing the prescribing behaviour of healthcare professionals. The strategies can be broadly split into five categories: educational, persuasive, restrictive, environmental restructuring and enablement [93]. Educational techniques involve the use of educational meetings and the dissemination of educational materials, whereas persuasion techniques involve outreach visits to review and recommend actions to stimulate change. Restrictive techniques use rules and guidelines to alter behaviour, whereas structural techniques involve the use of physical reminders or laboratory improvements. Lastly, enablement uses techniques such as audit and feedback, and decision support tools [93]. A recent systematic review found that both enablement and restrictive techniques consistently improve the effectiveness of ABS interventions, although often ABS interventions involved multiple techniques [93]. Overall, it was found that ABS interventions improve hospital antibiotic prescribing, reduce the length of hospital stays and do not affect mortality [93]. However, current evidence on what works and what is cost-effective is often of low quality and more research is needed to build a stronger case for investment in ABS [94,95]. Recent efforts in this area include the cost-effectiveness model developed by the OECD, which aims to assess and compare the health and economic impact of a number of AMR control policies relative to a business-as-usual scenario in which there are no interventions (Box 4).
Box 4
The OECD Strategic Public Health Planning for AMR (SPHeP-AMR) model.
4. Strengthening infection prevention and control (IPC) in human health
Although antibiotic use in hospitals is small relative to total use, the impact of AMR on critically ill patients, the associated extra healthcare costs and the opportunities for cross-infection through patient or caregiver contact mean that the health and economic impacts of AMR in hospitals are disproportionate. Data collected by the HAI-Net indicate that, on any given day, one in 18 patients in a European acute care hospital has a HAI [21]. The excess costs associated with resistant HAIs have not been comprehensively studied, but the available evidence suggests that the major costs arise from extended hospital stays and blocked beds that are needed to isolate infected patients.
Effective IPC requires a combination of actions such as standard hygiene measures (i.e. hand washing), the isolation of infected patients, environmental cleaning, as well as active screening of incoming patients [96]. IPC teams within hospitals should include nurses and physicians, and be supported by laboratory and data analysis [97]. IPC activities can be further broken down into horizontal or vertical measures. Horizontal measures are general approaches across a whole institution, such as hand hygiene campaigns, whereas vertical measures address specific problems, such as catheter-associated bloodstream infections [98]. Although there is no clear consensus over which strategy is the more effective, it is likely that a combination of both should be taken [98]. To encourage consistent implementation of IPC practices across providers, many countries have utilized financial incentives and/or penalties associated with HAI rates. One example from the United States is considered further in Box 5.
Box 5
Hospital-Acquired Condition (HAC) Reduction Program in the United States.
In 2009, WHO published evidence-based guidelines on core components for IPC programmes to support countries and healthcare facilities in developing or strengthening IPC programmes and strategies. Updated guidelines were published in 2016 and cover eight components: (1) IPC programmes; (2) IPC guidelines; (3) IPC education and training; (4) Surveillance; (5) Multimodal strategies; (6) Monitoring/audit of IPC practices and feedback; (7) Workload, staffing and bed occupancy (acute healthcare facilities only); and (8) Built environment, materials and equipment for IPC at the facility level (acute healthcare facilities only). In 2017, 14 HICs in Europe had functioning IPC programmes at national and health facility levels, according to the WHO IPC core component guidelines, as well as a mechanism in place to monitor compliance and evaluate effectiveness [100].
5. Strengthening IPC and reducing inappropriate antibiotic use in animals
The use of antibiotics in the food and animal sector generates resistance in bacteria that may affect both humans and animals. For example, resistance to colistin, which is commonly used as a last-resort antibiotic in humans, has been detected in pigs with E.coli [101]. Even low doses, such as those used for growth promotion, have an impact on AMR. The transmission of pathogens between humans and animals may occur in several ways – by direct contact or by transmission through the environment (see Figure A1 in the Appendix). In the livestock sector, antibiotic use extends beyond therapy to use for prophylactic and growth promotion purposes. Antibiotics have often been used to boost productivity by counteracting the adverse consequences of poor or ‘intensive’ farming conditions, as their benefits far outweigh their costs.
The global use of antibiotics in animal production is excessive. For example, in the US, it has been estimated that food and agriculture production accounts for an estimated 70% of total antimicrobial consumption in the country [102]. A global study estimated that the volume of antimicrobials used in agriculture is expected to increase by 67% by 2030, principally because of increasing demand for food-producing animals and ‘intensive’ farming in countries with growing populations, such as the US, India, China and Brazil [102]. In Europe, on the other hand, an important step has been a ban on the use of antibiotic growth promoters in animal feed for all EU countries since 2006 (Regulation 1831/2003/EC7) [103]. Despite this, there is still significant variation in the sales of veterinary antimicrobials across Europe (Figure 7). Positively, recent trends in Europe across 25 countries have seen an overall decline in sales of veterinary antimicrobials by 20.1% between 2011 and 2016, although in six countries sales increased by more than 5% in this period (a range of 7.9–67.7%) [104].
Strategies to reduce AMU in animals should involve: preventing the use of non-therapeutic antimicrobials; IPC measures such as higher biosecurity; improved husbandry methods; use of vaccination; as well as restricting the use of critically important antimicrobials for human use [105–107]. In some cases, farmers’ attitudes and behaviour, such as the perception that improved husbandry methods and higher biosecurity are costly interventions, can act as barriers to implementation [108,109]. These can be overcome though, and countries such as Norway and Iceland have achieved impressive low sales of veterinary antimicrobials, with both countries recording sales below 5mg/PCU in 2016, compared to an EU/EEA average of 129.4mg/PCU [104]. Norway has cut the antibiotic use in salmon farming (one of the central foods consumed in that country and a principal export good) to almost zero [110], while the Netherlands has shown that antimicrobial use can be reduced (64% between 2011 and 2016) by improved monitoring and husbandry (see Box 6) [104].
Box 6
Vaccinating salmon in Norway and antimicrobial stewardship in livestock in the Netherlands.
6. Limiting the exposure of antimicrobial-resistant pathogens to the environment
The barriers to combatting antimicrobial-resistant infections in the clinical setting have been studied and understood well, which has resulted in AMR NAPs and policies focusing on the clinical setting and lack of emphasis on the environment [56]. Yet, without a comprehensive ‘One Health’ approach, including actions within the environmental health sector, AMR NAPs are not complete and are at potential risk of being ineffective. The research on AMR and the environment has long focused on antibiotics in animal, human and manufacturing waste, without investigating other compounds that affect resistance [114]. Recent research, however, has extended the list of resistance-driving chemicals to three classes. First, antimicrobials consisting of four subclasses (antibiotics, antifungals, antivirals and antiparasitics); second, heavy metals; and third, biocides (e.g. disinfectants and surfactants) [56]. The research also describes three main pathways through which these chemicals can enter the environment: municipal and industrial wastewater; land spreading of animal manure and sewage sludge; and aquaculture (see Figure A2 in the Appendix). The interactions and relationships between these chemicals and pathways contribute to the spread of AMR and should be considered in AMR policy.
One key approach to addressing AMR in the environment is to monitor and regulate the environment and environmentally related activities or products that influence the spread and development of AMR pathogens. The Environmental Agency of England, for example, monitors and regulates wastewater treatment plants (WWTPs); agriculture (i.e. land spreading of manure, sewage sludge, fertilizers, bioaerosols); animal husbandry (i.e. disposal of animal byproducts, slurry and manure); river water quality (i.e. impact of sewage effluent, fresh fish farms); coastal and bathing waters (e.g. impact of aquaculture); and groundwater quality (e.g. content of chemical crop treatments) [115–117]. These different locations can provide effective targets for intervention. For example, as WWTPs are a major pathway for the dissemination of AMR bacteria, treatment of wastewater with ozone, ultraviolet (UV), ultrafiltration or chlorination can drastically reduce their concentrations [114]. Switzerland is one country in Europe that has included targets for WWTPs in its AMR strategy [118]. The goal is to almost entirely remove antibiotics from the upgraded WWTPs (see Box 7). A number of countries, including Germany, France, Sweden and the Netherlands, are also presently looking into similar solutions to upgrade their WWTPs [119].
Box 7
Swiss Strategy on Antibiotic Resistance (StAR): upgrade of wastewater treatment plants.
However, as measures have been suggested to avoid the discharge of AMR pathogens into the wastewater in the first place, such as: reducing antibiotic misuse in human and veterinary use; holding producers and factories accountable, especially in countries with weak local regulatory frameworks; reducing biocide use in personal care and household products; or capture, reuse and recycling of metals within the wastestream [56].
7. Fostering R&D of new antimicrobial therapies, diagnostics and vaccines
Regenerating the antibiotic pipeline
As AMR increases there is a need for new classes of antibiotics to replace those rendered ineffective by resistance [120]. A recent WHO review reports that the current pipeline of antibiotics and biologicals could lead to around 10 new approvals over the next 5 years, given past success rates and development times [121]. However, these new treatments will add little to the already existing arsenal and will not be sufficient to tackle the impending AMR threat. More investment is needed in basic science, drug discovery and clinical development, especially for the critical priority Gram-negative carbapenem-resistant pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobateriaceae. To highlight the need for more R&D, priority lists of pathogens to guide research and development of new antibiotics have been published [122]. Pharmaceutical companies find it less profitable to invest in antibiotic R&D compared to other disease areas (Figure 9). One reason is that a novel class of antibiotics is likely to be restricted in use, for stewardship reasons, reducing its revenue potential and market value.
Some progress has been made in the effort to regenerate the antibiotic pipeline, including new initiatives, particularly to increase funding for early-stage and pre-clinical research. These include CARB-X, a non-profit public–private partnership dedicated to accelerating antibacterial research to tackle the global rising threat of drug-resistant bacteria and GARDP, which aims to develop and deliver new treatments for bacterial infections where drug resistance is present or emerging, or for which inadequate treatment exists [124,125].
But there remains a large gap in funding, notably in the risky and expensive business of taking drug candidates through clinical trials to possible marketing approval [126]. This particularly affects small and medium enterprises (SMEs) that are responsible for developing a large proportion of new drug candidates. Various forms of incentive have been proposed through changes in the regulatory or intellectual property regimes. These include a combination of pull and push incentive strategies, either to boost the return from newly discovered antibiotics or to subsidize the cost of R&D (Table 3). Currently, there is a significant mismatch between funding allocated to push and pull incentives. According to an OECD analysis it is estimated that 95% of current funding for antibiotic R&D consists of push incentives [127].
Figure 9
Number of new classes of antibiotics discovered or patented each decade. Source: [123].
Table 3
Push and pull incentives for antibiotic development.
Recent reports have recommended the introduction of ‘market entry rewards’ (MER) (a pull strategy), which would offer rewards of USD1–2 billion for the successful development of new antibiotics meeting prespecified criteria and would also delink the funding of the R&D from the revenues derived from sales [128,129]. This would remove the incentive for maximizing sales and assist good antibiotic stewardship. The impact of such schemes would be maximized if harmonized amongst countries with innovative potential for antibiotics. The Options Market for Antibiotics (OMA) model postulated by the London School of Economics and Political Science takes the MER one step further by combining the pull-based prize of a MER with push-based R&D funding under one mechanism [130]. The OMA, modelled on the principle of financial call options, allows payers to buy the right, in early stages of development, to purchase antibiotics at a discounted price if they ever make it to market approval. It also allows governments and non-governmental organizations (NGOs) to fund all stages of antibiotic R&D and ensure that successful antibiotics are then purchased at a fair price, rationed appropriately, and distributed equitably. Unlike with MERs, purchasers of options are rewarded with discounted prices for the significant risk they take with financing antibiotic R&D [130,131].
Incentivizing research and development of diagnostics
Diagnostics should play an essential role in facilitating the appropriate use of antibiotics by reducing the unnecessary use of antibiotics for non-bacterial infections. They are necessary for improved patient management and outcomes; effective AMR surveillance; and in mounting clinical trials. To be effective in primary care, diagnostics need to provide a result in 15–20 minutes. However, because of the wide variety of bacterial and other infections that can be responsible for similar symptoms, isolating the exact strain of an infection is difficult. A simple rapid test to distinguish between bacterial and viral infections would be very useful.
However, diagnostic developers face several obstacles to innovation, including regulatory and financial barriers. Approval processes for diagnostics are lengthy, costly and often not transparent, and there is wide variation between countries in their quality. There is an urgent need to harmonize regulatory standards and procedures to reduce duplication of clinical performance studies, to minimize delays and to reduce the costs of meeting regulatory standards. HTAs need to be applied so that the risks and benefits can be better understood by policy-makers as well as regulators and other stakeholders [132].
Diagnostic development has been stimulated by several schemes, such as the Longitude Prize [133]. However, access to finance is also a problem. Public funders do not generally view diagnostics as having a direct effect on health outcomes. There is therefore a need to develop a better business case for investment in diagnostic development to combat AMR, which would identify the health and economic cost of not having effective diagnostics [134].
Stimulating research and development in vaccines to combat AMR
Vaccination can help in reducing the number of infections through herd immunity and the transmission of infections, with a consequent reduction in antibiotic use [135]. It can also reduce the inappropriate use of antibiotics for viral infections and their use to treat secondary bacterial infections often associated with influenza. It has been estimated that in 75 countries universal coverage with pneumococcal conjugate vaccine could halve antibiotic use in young children [136].
Hitherto, the value of vaccines in combatting AMR has not been a factor in decisions on vaccine development and use, which rely on the traditional financial and health benefits of vaccines. In principle, this value should be incorporated in such decisions. But there are difficulties in accurately assessing this value because of the multiple pathways by which vaccines could reduce AMR [137]. Moreover, it is not well understood how reductions in antibiotic use translate into reductions in AMR. Three pathways are important. First, how vaccine use translates into reductions in prescribing. Secondly, the epidemiological pathway that governs the direct impact of vaccine use on AMR. Thirdly, there is the pathway that assigns a value to AMR reduction, which involves developing counterfactual scenarios modelling the future health and economic costs of AMR and here there is a high degree of uncertainty. Thus, in practice, there are considerable challenges in quantifying the undoubted value of vaccines in the fight against AMR.
Research efforts must be coordinated
As AMR has achieved growing attention, research efforts to address the emergence and spread of AMR, as well as to incentivize the development of novel antimicrobials, have accelerated. Due to the complexity of AMR, these research activities are sponsored by multiple funding organizations. There is a need to coordinate the research activities funded by these organizations for many reasons. The very nature of AMR warrants a multidisciplinary and holistic approach to research and, without effective coordination, there is a risk that gaps and/or duplication of effort will occur. On the international level, organizations such as the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) have taken important steps in coordinating research activities. JPIAMR was formed in 2011 and now comprises 26 countries globally. It is funding €65 million of basic and exploratory research across six priority areas (Box 8).
Box 8
JPIAMR priority areas.
A mapping exercise of the 19 countries signed up to JPIAMR demonstrated that approximately half of the research funding for AMR research projects is at EU level and half at national level [139]. Therefore, there is a need also to effectively coordinate AMR research projects nationally. Box 9 shows how the funding of AMR research is coordinated across 20 funding organizations in the UK.
Box 9
Coordinating AMR research in the United Kingdom.
Facilitating successful implementation of ‘One Health’ AMR NAPs: governance is key
In 2018, the UN IACG on Antimicrobial Resistance concluded that developing a national AMR policy is not enough – the main challenge in tackling AMR is not writing the policy but its successful implementation [7]. Strengthening governance is a key strategy for any policy-maker attempting to address this challenge. A review of health system governance frameworks identified common principles of good governance, such as strategic vision, participation, coordination, responsibility, accountability, sustainability, monitoring and evaluation [141]. Although an AMR NAP should cover activities beyond the health system, these governance principles remain just as relevant.
Strategic vision should reflect good leadership, with oversight of the general direction of the national AMR strategy, as well as an awareness of any gaps or failures that need to be addressed. The United Kingdom and Sweden have set clear national targets to reduce AMU (Table 4); this is a positive example of overall strategic direction, which allows stakeholders to converge around a common goal.
Table 4
National antimicrobial usage quantitative targets in the United Kingdom and Sweden.
Effective leadership should also facilitate the inclusive participation and engagement of relevant stakeholders, including ministries, the medical and veterinary professions, research and academic institutions, agricultural organizations, and the food and pharmaceutical industries, during the conception and development of the NAP to maximize its legitimacy. A ‘One Health’ approach means that effective coordination between stakeholders across the human, animal and environmental health sectors during implementation is essential to avoid initiatives and programmes operating in silos. Many countries now use a national intersectoral coordinating mechanism (ICM) for this purpose, which offers a formal platform for coordinating activities during regular meetings (Box 10). These began with the EU Council recommendation of 15 November 2001 on the prudent use of antimicrobial agents in human medicine (2002/77/EC) to establish a national ICM with responsibility for developing a national strategy. Subsequently, ICMs were also utilized to coordinate the implementation and then evaluation of NAPs [144].
Box 10
The importance of intersectoral coordinating mechanisms.
Just as important as coordination between sectors is coordination within sectors. For example, coordinating activities across different levels of the healthcare sector, such as ambulatory, hospital and long-term care is particularly challenging. Sweden’s approach to addressing this has been to develop regional networks known as Strama groups; this is explored further in Box 11.
Box 11
Coordination of AMR policies across the Swedish healthcare system.
Without specific, measurable, achievable, relevant and time-bound (SMART) objectives within AMR NAPs, mechanisms to enforce responsibility and accountability are difficult to implement. Setting SMART objectives should be a by-product of strategic vision and are key to facilitating the monitoring and evaluation phase of a national action plan. Many countries have used this as a framework to structure objectives; one example from the Austrian NAP is showcased below (Table 5). A larger goal has been broken down into more specific measurable objectives, with priorities defined, responsibilities designated and clear deadlines outlined.
Table 5
Implementation plan for Goal 5: ‘Promoting feedback systems for surveillance data’ of the Austrian National Action Plan for Antibiotic Resistance.
To improve the quality of governance of AMR policies, the interlinked nature of these governance principles should be acknowledged. They can form a cyclical process where progress is continuously monitored and evaluated, and priorities are realigned. Ongoing research to review existing and novel policy interventions is essential for this process. Without a thorough understanding of the drivers of AMR and polices in place to limit them, resistance will quickly develop against any potentially new antimicrobials discovered. The cyclical nature of continual improvement is key to improving sustainability, but it is also important that an AMR NAP is linked to a dedicated budget and to a transparent financial strategy. Without engaging with these processes, there is a risk that an AMR NAP will not lead to effective implementation and may become a solely symbolic effort which is not followed up or improved upon.
Discussion
AMR is global in nature and crosses national boundaries; the costs of inaction therefore affect all countries. The costs of action, however, must be carried by individual nations, which may be unwilling to invest in the absence of action by others. Nations also vary widely in their ability to mobilize the resources necessary to combat AMR. Moreover, the costs of action are immediate and more visible than the benefits, which are long-term and difficult to value economically. Several countries (such as the Nordic countries and the Netherlands) have demonstrated that successful action to reduce antibiotic use in both humans and animals is achievable at an affordable cost.
Collective global action critically depends on effective national policies. Without dedicated national efforts to tackle AMR across the entire ‘One Health’ spectrum, national surveillance data collection and sharing, committed funds for AMR research and AMR activities in general, as well as stringent governance of national AMR policies to ensure successful implementation, global collective action will not be able to deliver the desired outcomes – with potentially dire consequences for health and economies. Here, we have outlined key policy options that enable policy-makers both to direct action to addressing AMR nationally and to contribute to the efforts to tackle AMR globally. Ultimately, all these avenues are important and, while some countries may need to prioritize certain avenues initially, all countries should aim towards a comprehensive AMR NAP. The drivers of AMR are multifactorial, so the response to combatting AMR should also be multifactorial.
Footnotes
- 1
The intrinsic antibiotic resistome (antibiotic resistance genes) is a naturally occurring phenomenon that predates antibiotic chemotherapy and is present in all bacterial species [3].
- 2
While this brief will focus on antibacterial resistance (ABR) more specifically, the term AMR will be used throughout, because the strategies discussed here concer n AMR more broadly.
- 3
Canada, France, Germany, Italy, Japan, the United Kingdom and the United States.
- Policy brief - Averting the AMR crisisPolicy brief - Averting the AMR crisis
Your browsing activity is empty.
Activity recording is turned off.
See more...