The Need for Global Antimicrobial Stewardship

Since resistance of microbes to antimicrobials is a global concern and is amplified by global antimicrobial use (AMU), addressing the problem calls for stewardship on a global scale. The Baas Becking hypothesis, proposed by its namesake Dutch microbiologist in 1934, states that “everything is everywhere but the environment selects.” Modern molecular analyses confirm the role of environmental conditions in shaping the population diversity and distribution of microorganisms present in specific habitats, including the enrichment of bacterial communities harboring specific antimicrobial resistance (AMR) traits. Habitats may be defined by geospatial reference points or by ecological niches, such as water, soils, on plants or in an animal or human host.

In today’s world of frequent and rapid international travel and trade in animals and food products, barriers that previously slowed geographic dissemination of microorganisms have all but disappeared. Microorganisms spread globally, often at a rapid pace, as evidenced by worldwide distribution of indistinguishable clonal strains of many pathogens, including viruses, bacteria, and fungi; just a few examples include COVID‐19, extended‐spectrum beta‐lactamase‐producing Escherichia coli, and azole‐resistant Candida auris. A striking example, reported in 2012, involved cases of salmonellosis that were traced to a single manufacturer/distributor of a food ingredient, galactooligosaccharide, a type of sugar often included in infant formula that was manufactured in the Republic of Korea and shipped around the globe (Figure 21.1) (WHO and FAO, 2013).

A further example is the global spread of a particular gene, bla_NDM‐1, among bacteria of the order Enterobacterales. This gene encodes a metalloproteinase enzyme capable of hydrolyzing almost all beta‐lactam antimicrobials. It is most frequently carried on plasmids that also carry multiple antimicrobial resistance genes (ARGs), making infections with organisms harboring bla_NDM‐1 resistant to a very broad range of antimicrobials commonly used in veterinary and human medicine. The gene was reported first from a hospitalized patient in Sweden, although the patient likely acquired the infection from travel abroad. Assuming, however, that the gene first appeared at the time of its first report is as absurd, as the veterinary epidemiologist Dale Hancock always reminded his students, as concluding that oxygen originated in England in 1774, just because Joseph Priestley was the first to describe it there and then. The gene, and subsequently multiple variants of it, was subsequently reported from most countries around the world in quick succession. Organisms harboring bla_NDM‐1 have been recovered from humans, food and companion animals, wildlife, feeds, soils, and water.

There are many more examples of AMR described in a multitude of animal species on every continent. For example, the textbook by Schwartz et al. (2018) includes descriptions of more than 500 discrete resistances. A global approach to antimicrobial stewardship (AMS) is clearly a critically important need.

The One Health Paradigm Helps to Understand the Problem

In addition to the extreme mobility of ARGs, the bacteria that harbor them, and the hosts and vehicles that transport them around the world, the blurring or sharing of ecological niches is also important to consider in the control of AMR. The One Health paradigm, also discussed in Chapter 20, captures this concept, asserting that humans, animals, and plants are intimately interconnected through their shared environment. This relationship results in the spread of food‐borne, water‐borne and other environmental and zoonotically acquired infectious diseases.

The human and animal gastrointestinal tracts are populated with microbes acquired from food, water, and the environment. Foods and feeds of both animal and plant origin are increasingly identified as contaminated with antimicrobial‐resistant organisms. Likewise, these organisms can be readily found in the built and natural environments, including veterinary clinics and hospitals, airplanes, orbiting spacecraft and other forms of transportation, the food production environment, farms, soils, and waters. Thus, even without selective pressure, animals, plants, and humans can all acquire antimicrobial‐resistant microbes. AMR is ancient (having evolved billions of years ago), and present wherever microbial populations thrive, with soil a well‐described reservoir of ARGs. Indeed, we should be surprised if AMR is not present in any microbial sample.

The sharing of habitats not only provides a pathway for transmission of microorganisms but also a common ecosystem where, at the molecular level, ARGs can be exchanged between bacteria (Chapter 3). For example, the ARGs present in the most common animal and human pathogens have an evolutionary origin from soil microorganisms (Forsberg et al., 2012). Of continued concern is the transfer of resistance genes from commensal organisms to pathogenic organisms within an individual host’s gastrointestinal tract. Genetic sequencing of antimicrobial‐resistant organisms demonstrates that such genetic exchanges are not restricted to single bacterial genera and exchanges may occur, for example, readily between E. coli and Salmonella, and even between Gram‐positive and Gram‐negative species (Courvalin, 1994) (Chapter 3). Moreover, genetic exchanges are not limited to an individual host; bacteria may acquire individual genes or other mobile genetic elements (MGE) from many different sources (Chapter 3). One such plasmid which epitomizes One Health at the molecular level was reported in a bacterium isolated from a hospitalized human that contained virulence and ARGs from bacteria of human, animal (fish), plant, and environmental origin (Tauch et al., 2000) (Figure 21.2).

Collectively, the continued uninhibited mobility and dispersal of bacteria and their ability to populate diverse habitats and hosts dictate that the most successful approaches to prevent and mitigate the adverse impacts of AMR must take One Health principles into account. These efforts must be applied on the global scale, irrespective of geopolitical boundaries or levels of economic development, and must be simultaneously implemented from multiple directions across all sectors, including in agriculture, the environment, and human health.

The Global Burden of Antimicrobial Resistance

The global impact of AMR is far more than a problem faced by clinicians vainly treating human or animal infectious diseases with antimicrobial drugs whose effectiveness is compromised by AMR. On the global scale, AMR impedes progress towards the United Nations’ plan to achieve a better and more sustainable future for all people and for the planet. It threatens progress to meet many of the 17 Sustainable Development Goals (WHO and UNEP, 2021), most notably the battles against poverty, hunger, disease, and the enhancement of economic growth and protection of the environment. Although AMR is a global problem, it is communities in low‐ and middle‐income countries (LMIC) that will suffer the largest burden of the many negative consequences.

The government of the United Kingdom commissioned a report in 2014 to assess the growing problem of AMR. That report, authored by Lord O’Neill and sponsored jointly by the UK Department of Health and the Wellcome Trust, painted a dark picture of the world if action to curb the problem of AMR is not taken immediately. From a public health perspective, if left unaddressed, infections with antimicrobial‐resistant organisms were predicted by 2050 to take the lives of 10 million people a year (O’Neill, 2016). These deaths will largely be attributable to human diseases without animal reservoirs of infection, such as malaria, HIV, and tuberculosis caused by M. tuberculosis. However, a portion of these infections will be caused by antimicrobial‐resistant pathogens that are transmitted to people through direct contact with companion, draft, food‐ and fiber‐producing animals, wildlife, their environment, and via food. The problem is exacerbated in LMIC, where most of the deaths attributable to AMR occur, as not only are there antimicrobial‐resistant pathogens but there are additional burdens of other diseases, high rates of poverty and hunger, and less developed systems for medical care (Murray et al., 2022).

Increased mortality and morbidity result in increased healthcare costs and decreases in economic productivity. The cumulative economic losses from 2016 to 2050 attributable to AMR have been estimated to be over US$ 100 trillion (O’Neill, 2016). Resistant infections that limit the ability of an individual to work and produce goods for sale have been predicted to drive an additional 25 million people into poverty by mid‐century. The gross domestic product (GDP) is also predicted to contract, by 3.8% in high‐income settings but by as much as 5.6% in low‐income countries.

Beyond these anticipated adverse human health and economic impacts, AMR will have direct adverse effects on animals and agriculture (Chapters 22, 23). Failure of antimicrobials to treat infectious disease in animals will result in increased morbidity and mortality, resulting in decreased food production. The World Bank (2017) estimates that food animal production could drop as much as 11% in low‐income countries between 2018 and 2050 due to the impacts of AMR. This decrease in food production will exacerbate the gap in food production and the need for more food to meet a growing global population. Moreover, in both food‐producing and companion animals, treatment failures risk exacerbating animal welfare issues.

Fecal waste from humans and animals treated with antimicrobials, if discharged or applied without adequate treatment, is a major source of resistant bacteria and of ARGs that can be spread via the environment to water, soil, and foods. An additional concern as drivers of resistance from the environmental perspective is that some antimicrobials are excreted into the environment in the feces and urine of treated humans and animals as the largely unmetabolized parent drug or as metabolites that retain antimicrobial properties for extended periods after excretion.

Some veterinary antimicrobial agents used in veterinary and human medicine (e.g., azole antifungals, oxolinic acid, streptomycin, tetracyclines) are also used to treat diseases of plants by spray application and directly contaminate the environment. Antimicrobial residues in the environment can cause bacterial and fungal population changes in soils and water, resulting in disruption or alterations in important ecosystem services (e.g., nutrient cycling, pollutant degradation), with ensuing plant health problems and productivity losses, and may be the source of infectious agents in humans and animals that are antimicrobial resistant (UNEP, 2022). The size and diversity of the environmental reservoir of antimicrobial‐resistant bacteria and fungi, and their potential to result in human and animal exposure through contact or drinking water, or indirectly from foods (e.g., grazing, vegetable consumption), are influenced by numerous factors not directly associated with AMU, including such things as chemical fertilizer application and severe weather events associated with climate change (UNEP, 2023).

Global Hotspots of Antimicrobial Resistance

The extent of the global problem of antimicrobial‐resistant organisms in the veterinary, agricultural, and food sectors, and the presence of antimicrobial residues in foods, is not precisely known. In many high‐income countries (HICs), estimates of AMR are informed by reports of systematic or integrated monitoring programs (e.g., CIPARS, Canada; DANMAP, Denmark; JVARM, Japan; NARMS, USA; VARSS, UK). These reports are supplemented by papers published in the scientific literature. Private entities such as food companies and veterinary diagnostic laboratories may also collect data on AMR, only some of which is made public.

Many factors contribute to the increased or elevated emergence, increased transmission, or high prevalence of AMR (“hotspots”) in specific niches, environments, or locations. The primary driver of resistance emergence is AMU, whether it is considered appropriate and necessary or less judicious. Exposure to antimicrobials drives exchange of genetic elements and selection for antimicrobial‐resistant microbial populations, a process that can occur at concentrations of antimicrobials well below the minimum inhibitory concentration. Hence, it is desirable to reduce overall AMU in favor of preventing and controlling animal disease through improved husbandry and other nonpharmaceutical interventions.

Among countries in the European Union, where there are common regulations for antimicrobial use in agriculture, wide variation consumption is observed, with several countries in the south (e.g., Cyprus, Italy, Portugal, Spain) and in the East (e.g., Bulgaria, Hungary, Poland) consuming more antimicrobials than their neighboring countries. The causes of this disparity are unknown but may be attributed to differences in animal disease burden, agricultural practices or infrastructure in these countries. Understanding and intervening at this and other “hotspots” within animal populations provides both a target and an opportunity to mitigate the negative impacts of AMR emerging from food, agricultural, and companion animals.

Published reports describing AMR and AMU are also available from LMICs; however, these are far less frequent than in HICs, especially in companion animal species. A database of survey results of such studies of AMR in food animals is available at www.resistancebank.org. However, the developers of that database point to limitations that should be considered when viewing and interpreting the data presented, notably variability in the quality and collection methods in the surveys reported and differences in sampling frameworks. Importantly, data are only reported where resources were available to conduct surveys. Caution should be used when interpreting data from scoping reviews, metaanalyses, and other databases because the factors influencing the emergence and prevalence of AMR can be greatly affected by the particular antimicrobial stewardship practices, or lack thereof, in the study population.

On the global scale, the exact quantity of antimicrobials used in animals is unknown, is highly debated, and is likely also highly variable among countries and animal species within countries. Limitations in the collection and reporting of AMU data in different animal species complicate the process of prioritizing and monitoring antimicrobial stewardship efforts. Presently, information on AMU on the global scale is primarily derived from two sources: the World Organization for Animal Health (WOAH) initiated an annual self‐reporting survey of global AMU in animals in 2015. The WOAH Fifth Annual Report (2021) indicated a gradual decrease in total global antimicrobial usage, adjusted by animal biomass, from 2017 to 2019. On the other hand, models of AMU based on livestock populations and expected agriculture intensification predict significant increases in antimicrobial usage in agriculture, specifically in LMICs that are intensifying and increasing their food animal production industries to meet their growing demand for animal protein (Tiseo et al., 2020). The latter predicted a total, or gross, 11% increase in global AMU in agriculture by 2030, with the highest estimated AMU occurring in China, Brazil, the United States, and Thailand (Tiseo et al., 2020).

Global Coordination and Response to the Resistance Crisis

The call to action to fight AMR has been longstanding, including a call by the World Health Assembly (WHA), the governing body of the World Health Organization (WHO), in 1998 (Figure 21.3). But it was only in the decade of 2010 that such pleas started to garner broader worldwide public attention and concerted action, including that of intergovernmental organizations, notably the Food and Agriculture Organization of the United Nations (FAO), WHO, and the WOAH. These three organizations have a long history of working together. In 2010, recognizing the need to better coordinate global activities addressing challenges at animal–human–ecosystems interfaces, they signed an agreement to strengthen collaboration and further promote multisectoral cooperation. This FAO‐WOAH‐WHO collaboration was dubbed “The Tripartite” (2021).

In 2014, the delegates of the WHA requested the Director General of the WHO to draft an updated plan to address the growing crisis of AMR. A year later, in 2015, the Global Action Plan (GAP) on Antimicrobial Resistance was launched (WHO, 2016). The GAP has five principal strategic objectives related to AMR, AMU and AMS: (1) stimulating investment and research; (2) evidence gathering, including surveillance; (3) awareness raising; (4) governance; and (5) promoting AMU and AMS to encourage the adoption of best practices to prevent the development and spread of AMR (Figure 21.4). This plan was endorsed by the governing bodies of the FAO and WOAH and outlined actions that should be taken by countries to combat AMR. Importantly, the five objectives outlined in the GAP are applicable not only at the national and international scale, but should also be met at the regional, subnational, and local levels.

The concern about AMR reached the highest level of international political attention in 2016 when the countries of the United Nations General Assembly (UNGA) unanimously endorsed a political resolution acknowledging the gravity of the situation and the need for immediate action. This was only the fourth time in its entire history that the UNGA has taken up health‐related issues, the other times being resolutions on HIV, noncommunicable diseases, and Ebola. What was particularly unique in this action was that it represented the first time that the Assembly had called for veterinarians and human medical professionals to work collaboratively, across disciplinary borders, with other practitioners in agriculture – public health on a global scale. The resolution called for all countries to develop their own One Health National Action Plans (NAPs) to address the problem of AMR. These action plans were meant to be tailored to the country‐specific AMR context but still achieve the objectives of the GAP. In addition, the resolution put in place the establishment of an international group, the Interagency Coordination Group on AMR (IACG), to provide practical guidance for approaches needed to ensure sustained effective global action to address AMR (Figure 21.5).

Although the UNGA was the highest‐level political endorsement of the challenge of AMR, it is not the only international activity to address AMR. In 2017, the World Bank issued a report describing the consequence of AMR on the global economy and the world’s sustainable development efforts (World Bank, 2017

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