Research paper
Published 8 October 2019
Updated 3 April 2024
ISBN: 978 1 78413 368 9
A startling lack of progress on critical recommendations to tackle antimicrobial resistance is highlighted in this new global progress report, as well as opportunities for further action and key obstacles that need to be overcome.
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While resources have flowed into awareness campaigns, as recommended by the Review, there is very limited evidence regarding their impact on antibiotic use, in countries at all levels of development. How to tailor messages to local circumstances, and the appropriate content of those messages, is not well established. More resources are needed to assess impact. There should be a clearer focus on the factors that influence the behaviour of potential and actual patients, doctors and other prescribers, and on what interventions could cause changes in behaviours that lead to inappropriate use. People (including health professionals, veterinarians and farmers) need suggestions about specific things they can do to achieve impact.15
Achieving sustainable change requires the involvement of groups in civil society (including, for example, consumers, professional societies and investors) to create the demand and pressure for change. Incorporating more guidance on AMR in general and professional education is also very important for sustainable impact.
The Review also recommended robust regulations, properly enforced, to prevent antibiotic sales without a prescription. The realities of living conditions and access to healthcare in most low- and middle-income countries (LMICs) makes the enforcement of regulations on prescribing, and the translation of awareness into behaviour change, highly problematic.16 One reason is the inadequacy of healthcare systems for much of the population and the consequent incentives for patients and sellers of antibiotics to go outside the system. Another is that antibiotics are often used as a ‘quick fix’ in the absence of effective measures to resolve underlying structural problems in healthcare systems, housing, water and sanitation, and agriculture that contribute to infections.17
It is not simply a question of regulating inappropriate use but also recognizing that the lack of access to quality antibiotics is a major concern responsible for millions of deaths annually. Regulation is therefore important, but it is necessary to address the inadequacies in healthcare systems and the social and economic circumstances that predispose to infection to bring about sustainable change in appropriate use and access. Providing quality healthcare to all and moving towards universal health coverage would be crucial in addressing the problems of adequate access to antibiotics and in restricting non-prescription sales.18
The Review recommended that healthcare systems embed infection prevention and control (IPC) as a top priority at all levels; that studies on effectiveness of interventions and inducing positive behaviour change in healthcare workers be supported; and that investment in water and sanitation in LMICs be encouraged.
Measures to improve IPC need to be viewed in terms of their importance for public health rather than just through an AMR lens. Compliance with IPC measures is often low, even in well-resourced settings and there is also a lack of good quality evidence on the effectiveness and cost-effectiveness of different IPC interventions.19 IPC is often ignored for a variety of reasons, including pressures on health professionals and the absence of basic facilities such as clean water and sanitation.20 This is particularly the case in LMICs. IPC is not an issue just for healthcare facilities but also for the wider community, where the absence of adequate water, sanitation and housing is a primary driver of the spread of infectious diseases and hence antibiotic use.21 As a result, there is a need for a multi-sectoral approach. At the roundtable, participants discussed whether funders such as the IMF and World Bank should lend their weight to the cause of IPC by integrating public health concerns, including combatting AMR, in their agendas and dialogue with countries. Such a dialogue should include investment in water and sanitation.
The Review recommended that surveillance of antibiotic use and resistance be urgently improved, and that steps be taken to reduce unnecessary antibiotic use in animals by setting targets at the country level, beginning in 2018.
In several high-income countries, particularly in Europe, there has been considerable success in reducing antibiotic use in agriculture.22 The evidence suggests that, with the right policies, the costs to producers of transitioning to low antibiotic use can be relatively small or negligible if compensated by improvements in animal hygiene, herd management and biosecurity.23 The situation is different in LMICs. In less-regulated environments, producers are inclined to resort to antibiotics as they move to more intensive farming methods. Moreover, there is a lack of accurate information on antibiotic use and the level of AMR in animals. One study, based on this inadequate data base, projected that global antimicrobial consumption in agriculture will rise by 67 per cent by 2030, and will nearly double in Brazil, Russia, India, China and South Africa.24 Because of the diversity of livestock development business models in LMICs, identifying solutions for cost-effectively reducing antibiotic use is difficult. More research, as advocated by the Review, could certainly open up new policy options relevant to LMICs.
The Review’s emphasis on aggregate target-setting was criticized by some participants at the roundtable because it failed to take account of the diversity of animal species and of antibiotic use in different species. Moreover, the proposed timescale, with country targets being established in 2018, failed to recognize the lack of data on use, on AMR levels and indeed on production systems in LMICs. Nevertheless, the fact that targets have played a significant role in the successful reduction strategies in a number of European countries suggests they could be an important element in strategies elsewhere.
A major gap in developing effective strategies to reduce unnecessary use in agriculture is the lack of accurate data on antibiotic use and on AMR, without which target-setting is redundant.25 Therefore, as the Review recommended, a priority must be to improve surveillance systems and undertake more research, including on how to promote the transition to lower antibiotic use in LMICs.
Consumer groups and others have played an important role in addressing unnecessary antibiotic use in the food chain. Where voluntary approaches are inadequate to promote changes on the scale required, governments could play a greater role by setting mandatory standards for antibiotic use in agriculture. However, standards are only as effective as the enforcement system. The OIE reports that many LMICs have insufficient or non-existent regulatory systems to address antibiotic use in agriculture.26 For those LMICs that are exporters of animal products, regimes in importing countries can be an important influence on production practices and antibiotic use. Namibia, a major beef exporter, banned the use of hormones and antibiotics for growth promotion in the beef industry as long ago as 1991, presumably to bolster its export credentials.27
The Review recognized the potential impact of the circulation of antibiotics and resistant genes in the environment as a result of animal, human and manufacturing waste. The Review decided to confine its recommendations to discharges from pharmaceutical manufacturing. It proposed that regulators should set enforceable targets for discharges and companies should improve monitoring of emissions and reduce discharges and support voluntary and transparent commitments to that end.
There is little evidence that governments or regulators have sought to introduce measures to enforce limits on discharges of antibiotics by pharmaceutical companies. Environmental pollution does not currently feature in regulations relating to Good Manufacturing Practice (GMP) for pharmaceuticals. WHO and others have made efforts to introduce such provisions but these have yet to come to fruition.28 The EU considered introducing such regulations in 2018 but appears to have pulled back following pressure from the pharmaceutical industry.29 Revising the GMP framework to incorporate emission targets is worth pursuing but it would likely be a slow process.
Early in 2018, the AMR Industry Alliance agreed on a voluntary framework that promotes responsible antibiotic manufacturing and, in September 2018, published a list of discharge targets to guide environmental risk assessments for the manufacture of antibiotics.30
There has therefore been considerable progress in addressing pharmaceutical discharges on a voluntary basis. A review by the Access to Medicines Foundation in 2018 found that, while 15 out of 18 companies had some form of environmental risk-management strategy, only eight applied limits on factory discharges and none of them made data available on actual discharges. Moreover, only four firms extended these limits to third-party manufacturers (e.g. of active pharmaceutical ingredients (APIs)). Nor are monitoring data made public. There was a lack of transparency about the measures the industry took in their supply chains.31 In the absence of government regulation, one avenue would be to reward firms with good environmental practices in procurement processes.
There is much uncertainty about the impact of antibiotic-resistant bacteria and genes in the environment, the relationship with the development of AMR and therefore the priorities for addressing the problem in ways that would maximize the impact on AMR. Moreover, there is a lack of proven technologies that are known to be feasible and cost-effective in preventing the entry of antibiotics into the environment, and in their removal from the environment.32 In such circumstances, it is probably most effective to promote measures that address known hotspots, such as hospitals or manufacturing plants, and to continue to investigate the complexities of the environmental spread of AMR with a view to identifying the priorities and cost-effective mechanisms for mitigating the threat.
The Review asked WHO to provide global leadership to improve surveillance of drug-resistant infections and governments and other stakeholders to promote data sharing between public and private organizations.
As part of its Global Action Plan on AMR, WHO has established the Global Antimicrobial Resistance Surveillance System (GLASS).33 There has been substantial progress, but the experience has demonstrated the significant challenges in building up effective surveillance systems (for both humans and animals) that provide data relevant to clinical practice and research, particularly in LMICs but even in high-income countries.34 Such efforts need to continue. Surveillance is critical to the fight against AMR – without surveillance, efforts to combat AMR are essentially flying blind. Effective surveillance systems are needed to provide the evidence base upon which treatment guidelines and national, regional and global strategies can be developed. It is also through these systems that the impact of interventions can be measured. Much more effort and funding are needed to address root causes of ineffective surveillance systems, such as the shortage of laboratory professionals and technicians to increase coverage, the lack of quality assurance systems to ensure proficiency, and insufficient use of digital technologies and artificial intelligence to translate surveillance data into clinical decision-support tools for patient management.
Alongside this there is a need to strengthen systems for monitoring use in humans and animals. Several monitoring programmes on human antibiotic consumption have been launched in high-income countries and LMICs, by the European Centre for Disease Prevention and Control (ECDC), the Centers for Disease Control and Prevention (CDC) and WHO, but different numerators and denominators are used to express antibiotic use in outpatients and inpatients, and standardization of the methods and indicators is needed. There is much more work to be done in generating data on antibiotic use and resistance in agriculture in LMICs. There is also much to be done on surveillance and understanding of the spread of AMR in the wider environment.
The Review recommended that high-income countries support point-of-care rapid diagnostics, including measures to make their use mandatory, where they are available, by 2020. For LMICs it advocated a subsidy to manufacturers to promote development and use.
In spite of a number of initiatives to stimulate the development of diagnostics, such as prizes offered in Europe,35 the UK36 and the US,37 a multitude of barriers limit the use of diagnostics in clinical practice and hinder the development of new ones. This applies in countries at all income levels but is particularly acute in LMICs. Even existing rapid diagnostic tests, such as that for detecting levels of C-reactive protein, are underutilized in clinical practice for reasons that include mistrust of results, risk aversion, time pressure and cost.38 There is no diagnostic test that meets the desirable target product profile that would enable prescribers to avoid empirical prescribing.39
An important overriding barrier in development is the lack of a viable prospective market, partly as a result of barriers to the use of diagnostic tests in clinical practice. The current access pathway from diagnostics R&D through regulatory approval and policy development for implementation of novel diagnostics is complex and lengthy in many countries. Regulatory systems for approval of diagnostic tests are complex, lack clarity and are not harmonized, unlike what has happened to some extent in the regulation of medicines. The problem therefore has to be addressed on several different levels if new diagnostics are to be developed and used. Following the model of Gavi or the Global Fund, organizations such as UNITAID, which already works to stimulate the development of diagnostics for tuberculosis and HIV, could extend work to cover other antimicrobials and antibiotics and help create markets.
The Review recommended promoting the uptake of existing vaccines for humans and animals more widely and initiating ‘pull’ funding schemes to promote uptake and development.
There has been considerable activity directed at enhancing the role of vaccines in combatting AMR. These include a Chatham House workshop,40 a Wellcome report,41 the formation of a working group at WHO (VAC-AMR)42 as well as contributions from academics and industry.43 Gavi, the Vaccine Alliance, has incorporated the impact on AMR as a criterion in compiling its latest investment strategy.44 Vaccines that might have a particular impact on AMR by averting future antibiotic treatment include those for seasonal influenza45 and typhoid,46 as well as respiratory syncytial virus47 and Group A streptococcus.48 They might be particularly important for diseases such as gonorrhoea where treatment options are now extremely limited.49 While it is self-evident that vaccination should help to reduce AMR, it is a challenge to demonstrate the magnitude and value in ways that would convince policymakers that AMR is a reason to assign a much higher priority to vaccine use and development than they already do.
As with diagnostics, a fundamental issue, alongside scientific challenges in vaccine development, is the absence of an effective market that provides incentives for the development of vaccines relevant to fighting AMR. WHO is already working towards establishing a list of priorities to guide R&D along the lines of the list it developed to guide R&D on antibiotic development. It should also develop target product profiles for priority vaccines. Such an effort would need to be supported by funding agencies in order to help create a viable market. The current Global Vaccine Action Plan, which runs from 2011 to 2020, does not mention the role of vaccines in combatting AMR – this highlights the need for international bodies (such as WHO’s Strategic Advisory Group of Experts (SAGE) on Immunization) as well as national advisory committees to mainstream AMR as a factor in their decision-making.
The Review recommended expanding funding and training opportunities for healthcare workers and scientists and improving their pay, recognition and standing.
Much would be achieved in improving research capacity if the current enhanced level of push funding directed at early-stage research were maintained or further enhanced and if effective pull mechanisms could be implemented to draw resources into late-stage product development, where there is currently the biggest bottleneck. Market forces, as modified by public intervention, would naturally improve the numbers, pay and recognition of researchers in the area. Regarding clinicians and other health workers, the need is for the incorporation of AMR-relevant training at all levels of professional education and for creating paths for career progression in those specialisms most relevant to stewardship of antibiotics.
The Review recommended establishing a Global Innovation Fund for this purpose, with an endowment of $2 billion over five years.
While a fund, as such, has not been established there has been a proliferation of new funding initiatives and new institutions in recent years. Prominent among these are:
These new initiatives and institutions have contributed to positive developments in the funding of early-stage research and significantly more funding from a variety of sources, almost on a par with what the Review called for. However, there is limited evidence that the pipeline of products in development has significantly improved, particularly with respect to new classes of antibiotics needed to address identified priority pathogens.50 Moreover, there remains a massive problem in financing later-stage development, and in bringing promising products to marketing approval and beyond.
The Review called for the design and implementation of a global system of ‘market entry rewards’ to incentivize developers of new antibiotics to meet a specified unmet medical need. It also called for the harmonization of regulatory pathways for antibiotics and the strengthening of clinical trial networks to streamline the process and reduce the time and cost of antibiotic development. It estimated the cost of a market entry reward system at $16 billion over 10 years.
The ideas in the Review have been elaborated by subsequent reports such as that of the BCG and the DRIVE-AB consortium.51 Recent announcements in the UK52 and the US53 have indicated a willingness to reform the way antibiotics are paid for to delink payments from sales volume and to increase the rewards available for delivering new antibiotics. However, on the key issue of a global scheme of market entry rewards on the scale considered necessary by the Review it is now becoming clear, following the recent G20 meeting in Osaka, that there is little, if any, progress being made towards a substantive outcome.54
Meanwhile, the market for antibiotics continues to deteriorate, as illustrated by the demise of Achaogen55 and the difficulties in other biopharmaceutical companies.56 This applies equally to vaccines and diagnostics, for which companies face similar challenges.
That being the case, there is a need to look for and develop alternative ways to address the problem of insufficient investment in R&D.
The Review recommended that the G20 take the leadership role, particularly in developing and implementing new incentive models for new antibiotics, diagnostics and vaccines. It recommended that rapid work be undertaken to consider global coordinated structures to develop and implement financial support for development and use of products to combat AMR. It also called for work to identify ways to finance a long-term global response to AMR, including innovative mechanisms such as hypothecated taxes on antibiotics and/or healthcare products.
Possibly influenced by the Review, the 2016 UN political declaration on AMR called for an interagency coordination group ‘to provide practical guidance for approaches needed to ensure sustained effective global action to address antimicrobial resistance’. The Interagency Coordination Group (IACG) published its report in 2019.57 Its main recommendation was the urgent establishment of a ‘One Health Global Leadership Group on Antimicrobial Resistance’ supported by a small secretariat. The suggested group would consist of past and present political leaders, heads of UN and international agencies and the regional banks and other prominent global leaders in relevant fields. This group would be complemented by an Independent Panel on Evidence for Action against Antimicrobial Resistance, along the lines of the Intergovernmental Panel on Climate Change (IPCC). Finally, it recommended that work on the Global Development and Stewardship Framework to Combat Antimicrobial Resistance, which had been called for in the 2015 World Health Assembly resolution adopting the Global Action Plan and reiterated by the 2016 UN Political Declaration, be expedited.
The UN secretary-general has thus far not responded publicly to the recommendations of the IACG report. One possible concern is that both the new bodies proposed – the Leadership Group and the Independent Panel – sound, as described, rather unwieldy. There is a danger that they might become a forum for more talk rather than action. It is also not encouraging that discussions on the Global Development and Stewardship Framework58 have so far been inconclusive. Furthermore, the Global AMR R&D Hub, the only concrete innovation in global AMR governance, appears to have failed as yet to find an effective role.
However, there are signs that the Tripartite agencies are mobilizing. A secretariat has been formally established based in WHO but including staff designated by the FAO and OIE in Rome and Paris. The hope is that it can become the driving force for converting words into action and have a much greater operational role and impact than hitherto.
