The following post is the result of a classroom writing assignment by Dr. Erika Martin at the University at Albany-SUNY who required students to write a commentary on a health-related topic of interest, explaining some of the complexities of solving the problem and offering recommendations. Here, student Alessia Caputo examines antimicrobial resistance in the US, EU, and Canada.

Antimicrobial resistance (AMR) is becoming a major global burden on both low-middle- and high-income countries. Recent projections claim that the cumulative loss in economic output in OECD countries will total between $20 and $35 trillion by 2050 (O’Neill, 2014). An estimate by the World Bank Group (2017) suggests that, in the worst-case scenario, the global Gross domestic Product (GDP) growth fall due to AMR could be comparable to the 2008-2009 financial crisis (Figure 1).

Figure 1 – Economic Costs of AMR compared to 2008-2009 financial crisis

Source: World Bank Group, 2017.

Furthermore, societal costs will be as severe. Data highlight that AMR is associated with approximately 23,000 deaths and 2 million infections in the United States each year (Hampton, 2015), 25,000 deaths per year in the European Union (Uchil, Kohli, Katekhaye, & Swami, 2014), and 14,000 deaths in Canada in 2018 (Council of Canadian Academies, 2019). By 2050, the death toll will amount to 10 million deaths globally (European Commission, 2016), with peaks in developing countries. Moreover, antibiotic overuse during the 2019 COVID pandemic could further exacerbate the problem (Kuehn, 2020).

Figure 2 – Deaths Attributable to AMR every year by 2050

Source: O’ Neill, 2014.

What has contributed to the increase in antimicrobial resistance? 

Although the adaptive process of microorganisms to drugs is a natural evolutionary phenomenon, recently AMR has seen an exponential growth rate. Among the drivers:

• Patient misuse of antimicrobial medicines. Universal access to health care contributed to health gains, but it also determined a higher risk of AMR, especially in those contexts where patients can self-medicate, relying on the private-market supply of antimicrobials without prescription (World Bank Group, 2017). Usage of counterfeit medications exacerbates the problem. The overuse of antibiotics, as well as patients’ poor adherence to treatment, such as the failure to complete a full cycle of antimicrobial treatment, promotes the development of AMR.
• Inappropriate diagnosis and prescription by clinicians, such as unnecessary treatment of viral or noninfectious diseases with antibiotics (Kesselheim, Outterson, 2010).
• Insufficient regulatory controls on the quality, prescribing, and use of antimicrobials. For example, over one-third of English-language online antibiotics sellers in the United Kingdom, Canada, and the United States were found not to require a medical prescription (Keown, Wartburton, Davies, & Dazi, 2014).
• Market pressure. High competition among pharmaceutical companies on antimicrobial treatments contributes to lowering the price, rendering the drugs affordable and therefore widely used. Conversely, given the low profitability of antibiotics and antimicrobial drugs in general, producers have steadily reduced the investments in research and development (R&D) to benefit other areas with higher commercial returns (Figure 3).

Figure 3 – Discovery of new classes of antibiotics

Source: European Centre for Disease Prevention and Control (ECDC)/ European Medicines Agency (EMEA), 2009.

• Low amount of government funding and venture capital for R&D on new antibiotics. For instance, the US National Institutes of Health (NIH) earmarked only 1.2% of its annual budget $30 billion budget to this field of research between 2009 and 2014 (O’Neill, 2016). However, governments and institutions are trying to reverse this trend. Indeed, in 2019, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, allocated $102.5 million in funding over seven years for the Antibacterial Resistance Leadership Group (ARLG) (The National Institutes of Health (NIH), 2019).
• Inadequate attention to the prevention and control of infection, poor sanitation, and lack of hygienic practices, especially in developing countries. Additionally, globalization propelled the transfer and spread of new resistant bacteria between high- and low-income countries (Keown, Wartburton, Davies, & Dazi, 2014).
• Overuse of antimicrobial medicines in agriculture. The dependence of modern livestock on antibiotics is related to their usage in fighting diseases as well as growth promoters in ordinary production (Jensen, Nielsen, & Fynbo, 2018). The Food and Agriculture Organization of the United Nations (FAO) estimated that around 66% of the rise in antimicrobial consumption will be due to animal production (Food and Agriculture Organization of the United Nations (FAO), 2011). Additionally, more than 70% of antimicrobial is consumed in agricultural industries, 75% of which is employed to promote animal growth at low cost (Keown, Warburton, Davies, & Darzi, 2014).

Due to the multidimensional nature of the problem of antimicrobial resistance, policy makers have taken different approaches. The United States, European Union, and Canada have each adopted an underlying principle of “One Health,” which acknowledges that humans, animals, and the environment are intertwined (Centers for Disease Control and Prevention, n.d.).

How are countries addressing the multidimensional problem of antibiotic resistance?

The European Union is a key player in the fight against AMR. It has become a “best practice” region when it comes to promoting prudent use of antimicrobials in humans and animals. This approach, named “antimicrobial stewardship,” resulted in regulations and guidelines for the prudent use of antibiotics in veterinary medicine. For instance, in May 2020, the European Commission approved the Farm to Fork Strategy, which aims at reducing by 50% the overall EU sales of antimicrobials for farmed animals and in aquaculture by 2030 (European Commission, 2020). Various regulations will complement this strategy, providing a wide range of tools to promote the responsible use of antimicrobials in livestock. The EU is committed to introducing a “comprehensive, collaborative and coordinated collection and analysis of data from multiple domains,” a more integrated surveillance system that will be at the basis of future regulations (European Commission, 2017).

The European Union has also invested massively in R&D, providing economic incentives for pharmaceutical companies to develop new antimicrobials, novel diagnoses, and new preventive vaccines (European Commission, 2017).

Since the EU is a network of actors by its very nature, its main asset is to build connections with different stakeholders. In the fight against AMR, it directly engaged the pharmaceutical industry; various international organizations like the World Health Organization (WHO), the World Organization for Animal Health (OIE), the Food and Agriculture Organization (FAO); strengthened bilateral partnerships; and advocated for a global agenda (European Commission, 2017).

The United States has implemented a plethora of strategies to combat antimicrobial resistance. Financial incentives are one of the key tools the government has adopted to stimulate greater investments by pharmaceutical companies and other institutions. For instance, the Obama Administration issued a $20 million prize to promote the development of point-of-care diagnostic tests to easily detect resistant bacterial infections (Hampton, 2015).

In 2015, the US government released the National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB), allocating $160 million for AR solution initiatives. Among them, strengthening National One-Health surveillance programs, advancing development and use of rapid and innovative diagnostic tests, employing incentivizes for R&D, and improving international cooperation (US White House, 2014). The US is committed to monitoring the progress in the fights against AMR, creating a five-year action plan, CARB, run by a joint task force that engages various departments and institutions.

Canada created the Canadian Antimicrobial Resistance Surveillance System (CARSS) to monitor AMR and antimicrobial use. Alongside surveillance systems, the government has adopted prevention and control measures to reduce infections, especially in hospitals, investing in training courses for medical staff and education campaigns for the public. Stewardship initiatives, embedded in the One-Health framework, have already led to a substantial reduction in the use of antibiotics in agriculture. Among the strategies, the government has mandated that all antimicrobials used for animals have a veterinary prescription (Council of Canadian Academies, 2019). Finally, the government is committed to boosting R&D, especially in what concerns alternative therapies such as vaccines, phage therapy, lysins, and antimicrobial adjuvants (Council of Canadian Academies, 2019).

What strategies have been successful and what gaps remain?

It is still too early to determine the effects of the actions that countries and international organizations have put into place to tackle antimicrobial resistance. It is challenging to a draw firm, robust conclusion on the effectiveness of the policies. Furthermore, given the multi-sectoral nature of the issue, it is complex to detect the impact of each action in a portfolio of coordinated interventions. However, this section will provide some useful insights based on the data that have been collected and processed so far. Indeed, some strategies are already bearing fruits. For instance, the CDC claims that in 2019 the number of deaths due to antimicrobial resistance decreased by 18% compared to 2013 (Centers for Disease Control and Prevention, 2019). This success might be due to the massive efforts to prevent infections in the first place and to diminish overprescribing by doctors. For instance, the recommendation of vaccines by family doctors has contributed to the reduction of pneumococcal infections (Azar and Redfield, 2019).

It is common knowledge that strategies targeting prevention, early detection, reduction of infectivity, and hygiene achieve successful results. They might reduce the incidence of antimicrobial resistance in the United States and EU by 6 million patients (Cecchini, Langer, & Slawomirski, 2015). Also, a study projected that care bundles for the prevention of central line bacteraemia could save 18,000 lives and $1.8 billion per annum in the US alone (Cecchini, Langer, & Slawomirski, 2015).

Early detection usually takes the form of diagnostic and surveillance systems. The introduction of new technological systems allowing early detection of AMR enables a response tailored to the patient and favors a rapid response to the emergence of trends common to the whole society. For instance, Canada implemented a surveillance and monitoring system to reduce the incidence of gonorrhea that proved to be successful in the first years of its implementation. The country issued updated guidelines on therapy, which resulted in a sharp decrease in resistant gonorrhea isolates from 7.6% to 3.7% between 2011 and 2013 (Government of Canada, 2012). However, over the years, the country lost some capacity to track resistant gonorrhea. Indeed, a study concluded that data are available for approximately only one-fifth gonococcal infections in Canada (Bodie, et al., 2019). This case tells us that efforts cannot be limited to short-term successes. Subsequent investments to improve monitoring systems and introduce new technologies are necessary. Also, a cost-benefit analysis might be adopted to evaluate the efficiency of targeted diagnostic approaches (Cecchini, Langer, & Slawomirski, 2015).

Hygiene measures are horizontal since they target every type of pathogen. However, compliance rates with hand hygiene practices and clinical guidelines tend to be low. Indeed, both in Europe and in the United States hand hygiene compliance in hospital settings averaged below 50% (Cecchini, Langer, & Slawomirski, 2015). Boosting hand washing in health care facilities is a cost-saving intervention (Cecchini, Langer, & Slawomirski, 2015) that could result in savings due to a reduction of infection of about $40,000 per year in a facility of 200 beds (Cummings & al., 2010).

The incentives for R&D and the investment in surveillance systems have the potential to be among the most successful strategies for all entities. For instance, the EU funded some successful initiatives like RAPID, a gene-based test for Klebsiella pneumonia, or PNEUMOSIP, which created a state-of-the-art device to analyze AMR and speed up pneumonia diagnosis (CORDIS | European Commission, 2021).

Also, in 2012, the European Union launched the New Drugs for Bad Bugs (ND4BB) program to trigger the development of new antibiotics “along the value chain from basic science to new business models and created conditions for open data sharing” (European Commission, 2016). This initiative is a public-private partnership that brought the pharma sector back to the field of research and development for AMR. Indeed, the initiative counts 11 pharmaceutical companies, compared to the 4 that got involved when the project was launched (European Commission, 2016).

Nevertheless, economic incentives mainly focus on the early stages of R&D, while there is limited funding for the late-stage clinical development (Simpkin, Renwick, Kelly, R., et al., 2017), negatively impacting the commitment of pharma companies to develop new medicines and technologies.

The efficacy and effectiveness of stewardship programs are still under debate. Some studies have questioned them, concluding that they do not contribute to the outcomes as they were supposed to (Bertollo, Lutkemeyer, & Levin, 2018). Indeed, the analysis by Bertollo, Lutkemeyer, & Levin (2018) found no statistically significant correlation between stewardship programs and reduction in AMR.

Conversely, Cecchini, Langer, & Slawomirski (2015) claim that there is a large body of evidence in support of stewardship programs in health care settings. They note in their paper that Epson (2015) argues that a California flagship program that entailed antimicrobial stewardship accomplished a 9.4% reduction in MRSA rates over 3 years. Nationwide programs have the potential to achieve sustainable results with stewardship interventions targeting prescribers. For instance, France adopted a multifaced plan from 2002 to 2007 that resulted in a 26% reduction in antibiotic prescription (Cecchini, Langer, & Slawomirski, 2015).

Furthermore, the initiatives that regulated the adoption of antibiotics in agriculture and livestock in EU countries achieved mild results between 2011 and 2016. This limited result is due to the lack of funding that the Member States have collected and allocated to the fights against AMR (OECD, 2019). It is agreed, though, that the Action Plan by the EU managed to harmonize the monitoring of the veterinary systems among the various countries, therefore allowing for better coordination (European Commission, 2016). Nevertheless, although the sales of veterinary antimicrobials have shrunk between 2011 and 2013, there is still variation between countries (Figure 4). The European Medicine Agency (EMA) suggests that these differences might be due to variation in the level of awareness about AMR, the eventual presence of national campaigns for the judicious use of antimicrobial medicines, and shifts in animal demographics (European Commission, 2016).

Conversely, Canada is struggling in the adoption of different feed alternatives in the agriculture field because “Canadian farmers don’t have access to the products that are available in Europe or even in the United States. An example of this would be probiotics” (Casey, 2018).

Figure 4 – Sales, in tons of active ingredients, of veterinary antimicrobials for food-producing animals between 2010 and 2013

Source: European Commission, 2016.

Ultimately, Countries and international agencies across the globe have conducted antibiotic awareness campaigns to engage the general public in the fight against AMR through factsheets, posters, videos, social media, and interactive games (Ahmed & al., 2020). Using a range of formats is fundamental to engage different targets of people.

Earnshaw, et al. (2014) analyzed the impacts of the European Antibiotic Awareness Day (EAAD), concluding that the number of participating countries grew from 32 in 2008 to 43 in 2013. Also, in a survey administered by the ECDC, 22 countries claimed that the EAAD resulted in some national behavioral changes (European Commission, 2016).

However, a study conducted by the European Commission concluded that the knowledge of the general public about the use of antimicrobials remained pretty stable between 2010 and 2016, with a slight decrease in the percentage of people that are aware that antibiotics are ineffective against colds and flu (56% in 2013 against 47% in 2010) (European Commission, 2016).

Despite the Eurobarometer showing mild improvements, some countries managed to adopt effective awareness campaigns. Indeed, France and Belgium experienced a sharp decrease in antibiotic use thanks to education campaigns (Wallinga, 2015) based on TV, radio, and newspaper ads; folders and brochures provided to patients in health care facilities; information leaflets; and Internet campaigns (Figure 5).

Figure 5 – Outpatient antibiotic use in Belgium in packages per 1,000 inhabitants per day – July-June

Source: Goossens, 2011.

What are the most promising directions to address antimicrobial resistance?

Further efforts are needed to properly address the issue, especially when it comes to international cooperation. The recent pandemic taught us the importance of engaging international actors when dealing with global matters. Since AMR is a worldwide issue that is hitting developing countries to a greater extent, a common strategy is needed to prevent the escalation of AMR. The main threat is indeed the lack of action by low- and middle-income countries (LMICs) to the fight, due to a scarcity of resources (Hart, Kariuki, 1998), the lack of administrative capacity to coordinate intersectoral programs (Ayukekbong, Ntemgwa, Atabe, 2017), and the persistence of other health problems that are putting a strain on those societies (Merson, Black, Mills, 2020).

Moreover, many countries have introduced monitoring and surveillance systems for AMC and AMR. However, further investment is needed for these systems to become an integral part of national health care systems. Additionally, there is insufficient evidence on what are the most effective and cost-effective measures to combat AMR. Further efforts must therefore be taken in this direction.

A crucial theme is to foster the antibiotic pipeline which has been constrained for too many years. As such, evaluations of economic and financial incentives are needed to define which are the best measures to adopt.

Related Reading in the Journal of Public Health Management and Practice:

• Outbreak Response Capacity Assessments and Improvements Among Public Health Department Health Care–Associated Infection Programs—United States, 2015-2017
• Liaison Public Health Nurse Project: Innovative Public Health Approach to Combat Infectious Disease in Hospitals
• The Role of Community Pharmacists as Antimicrobial Stewards

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