Unseen Drivers of Antimicrobial Resistance: The Role of Industrial Agriculture and Climate Change in This Global Health Crisis

Abstract

Antimicrobial resistance (AMR) is an urgent global health threat with many anthropogenic drivers outside of healthcare. The impacts of modern agriculture on human health are manifold, from the food systems and dietary patterns they support to the less apparent effects of environmental stresses and biodiversity loss in ecosystems. Intensive practices, such as chemical fertilizers, pesticides, and herbicides, induce abiotic stresses that deplete biodiversity and drive AMR in soil and aquatic microbiomes. The overuse of antibiotics in livestock production is another major driver of AMR. Changes in weather patterns due to climate change have the potential to exacerbate these issues as warmer and wetter weather increases the potential for bacterial infection. While practices exist to address healthcare-associated drivers, the impact of agriculture and environmental destruction are not widely appreciated in healthcare and biomedical sciences. It is imperative that healthcare professionals and public health experts understand these connections to properly address the emergent issue of AMR. This review aims to summarize the current data on important agricultural and environmental drivers of AMR for educational purposes, to fill gaps in knowledge, and to improve current practices and stimulate further research.

1. Introduction

Antimicrobial resistance (AMR), namely the emergence of drug-resistant bacteria, is one of the most pressing global health challenges. The rise of AMR in bacteria is of particular concern due to the rapid rate at which they develop resistance [1]. AMR currently causes substantial morbidity and mortality with a recent Global Burden of Disease, Injuries, and Risk Factors Study estimating that 1.14 million deaths were caused directly by resistant bacteria and 4.71 million associated with AMR in 2021 [2]. This study projects that AMR will become a leading cause of mortality, directly causing an estimated 1.91 million deaths and contributing to 8.22 million deaths, by 2050 if current trends in the spread and acquisition of AMR continue [2]. The contributions of antimicrobial use, chiefly antibiotic use, in healthcare settings to AMR are widely appreciated and are the main focus of initiatives to address AMR [3]. The widespread use and misuse of antibiotics clinically exerts selective pressures on the bacterial pathogens they aim to treat and induce resistance [4,5]. The cumulative acquisition of resistance to many antibiotics, resulting in the emergence of so-called “superbugs”, may lead us to a “post-antibiotic era” in which we have limited tools to fight bacterial infections. Nosocomial infections associated with AMR have increased markedly since the beginning of the COVID-19 pandemic, though measures to combat the spread are in place [6].

While initiatives to promote antibiotic stewardship and more judicious use of antibiotics have been implemented in many healthcare settings, these programs do not address other powerful anthropogenic drivers of AMR, such as modern intensive crop and animal agriculture, and global climate change [3,7]. A 2023 study determined that roughly 8% of Escherichia coli strains responsible for causing urinary tract infections in a U.S. population came from livestock and their meat, providing clear evidence that bacteria with acquired AMR from agricultural sources can readily infect people, even distant consumers [8]. Recognition of the contributions of agriculture to the development and spread of AMR through a One Health lens that appreciates the interconnectedness between environmental, animal, and human health [9] is crucial to our success in managing it. It is imperative that healthcare professionals and public health experts understand the environmental and food-related sources of AMR as a consequence of industrial agricultural practices. Medical professionals must understand the key contributors of AMR coming from outside of healthcare settings so that they may appropriately address the growing public health threat AMR poses. Furthermore, veterinarians, public health officials, and policy makers must have a harmonized understanding of the factors driving AMR so that we may develop comprehensive strategies to address it.

In this narrative review, we describe how industrial agricultural practices deplete biodiversity and contribute to the rise of AMR. We discuss how climate change may further accelerate AMR and compromise the productivity of our food systems. We discuss the state of human and veterinary medical education on the topics of antimicrobial stewardship and AMR. Additionally, we present here an example of a medical curriculum that explores the role of food systems as determinants of human health and explores factors in modern industrial agriculture that contribute to AMR. As AMR is a true One Health issue, it will require a concerted effort to promote harmonized education across medical and health fields and transdisciplinary approaches to properly address it. We hope that this review will provide a primer on important drivers of AMR outside of healthcare to help supplement medical education.

2. Background

2.1. The Study of AMR and Importance of Education

The appraisal of factors contributing to AMR and proposed initiatives to address it have historically been siloed to different isolated fields with limited communication or collaboration. The study of AMR has been compartmentalized to the fields of veterinary medicine, microbiology, pharmacology, and public health [3,10]. There has been very little cross communication, with each field working independently. This has led to many fragmented strategies that incompletely address the sources and factors influencing AMR [11]. More recent policy encourages a more holistic One Health approach to work toward more comprehensive measures to address AMR [12,13]. There is growing recognition of AMR as a planetary health issue and increasing research on the influence of environmental factors, including climate change, on its spread from sources [14,15]. The World Health Organization (WHO) acknowledges that agriculture and the widespread use of antibiotics in livestock is a major contributor to AMR. They have formed a quadripartite joint committee with the Food and Agriculture Organization of the United Nations, the UN Environment Program, and the World Organization for Animal Health to appraise the contributions of agriculture and veterinary medicine on AMR [16]. While agriculture is understood to be a major driver of AMR by the WHO and other presiding public health organizations, education about these issues at the level of healthcare and veterinary medical professionals is still lacking.

As prescribers of antibiotics, it is imperative that human and veterinary medical providers are educated on AMR and how their practices contribute to key sources of AMR. The Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB) of the U.S. Department of Health and Human Services issued a report in June 2021 recommending increased efforts to educate human and animal health professionals, as well as the general public, about agricultural sources of AMR in an effort to combat the growing problem [17]. Undergraduate medical education is a particularly important time where future physicians learn the basic sciences, begin to develop clinical reasoning, and form attitudes around different practices. Thus, early education on the various sources of AMR and physicians’ roles in addressing and combating it could have profound impacts on the future generation of physicians.

To date, medical curricula on the emergence of AMR and the practice of antibiotic stewardship in medical training programs are very limited, with few offered during undergraduate medical education [18,19]. Instruction on AMR and antibiotic stewardship is mostly limited to fellowship training in Infectious Diseases, which further perpetuates AMR and antibiotic stewardship as a siloed issue to be addressed by a single medical specialty [18,19,20]. Among these programs, few discuss the origins of resistant bacteria outside of healthcare [21,22]. Similarly, antimicrobial stewardship training and education on the sources and scale of AMR is lacking in veterinary education. A 2021 European study revealed that only 25% of senior veterinary students polled across 30 countries were familiar with the guidelines for antibiotic use [23]. A 2024 survey of veterinary schools in the U.S. and Caribbean revealed that only 50% of programs polled had an antimicrobial stewardship committee and only two programs offered activities on AMR and antimicrobial stewardship [24]. Human and veterinary medical providers must collaborate at the frontline of AMR to ensure a comprehensive approach to combat it.

One course that aims to bridge these gaps in knowledge in undergraduate medical education is Microbiomes Matter: The Path to Regenerative Systems of Farm, Food and Health in the Age of Climate Change, which is offered at the Carle Illinois College of Medicine at the University of Illinois Urbana-Champaign [25]. This truly multidisciplinary course explores agriculture and its myriad large-scale effects on the environment, underscoring its role as a key contributor to AMR.

2.2. Industrial Agricultural Practices and Their Impact on the Environment

Modern industrial agricultural practices, which form the basis of food systems in many wealthy countries, are a leading contributor to loss of global biodiversity and are a major threat to planetary and human health [26]. Large-scale industrial agricultural systems rely on intensive practices to maximize the production of crops and include the use of chemical inputs, such as fertilizers, herbicides, pesticides, the development and planting of genetically-modified disease-resistant plants, large-scale monocropping, intensive tillage of the soils with minimal fallow periods, and large concentrated animal husbandry and feeding operations [27,28]. The rapid expansion of industrial agriculture globally in the past 50 years has destroyed natural vegetation, displaced wildlife, and dramatically reduced insect populations [29]. While the more apparent effects of this loss, such as the destruction of native habitats and endangerment of animal species are appreciated, many unseen perturbations at the level of microbial communities pose emergent threats to human health [30,31]. These threats include depletion of the ecosystems that support the health and productivity of soils and instead enable the spread of drug-resistant bacteria that threaten the health of plants, animals, and humans [16,32].

2.3. Soil Microbiota: The Unseen Ecosystems

Soil is a vast reservoir of microbiota, containing abundant microbial biomass composed of upwards of 50,000 species [33,34]. Generally, bacteria and fungi comprise the majority of soil microbiota [35], and are important members of the ecosystem [36]. Soil microbiota play many important roles in nutrient cycling, shaping the quality of soils, and directly influence the health and productivity of plants through coevolutionary relationships [34,37]. The diversity of soil microbiota determines the metabolic capacity to cycle nutrients, provides functional redundancy, and strengthens resilience of soils to changes in the environment [38]. Thus, the health of soils and their microbiomes is crucial to the health of plants and the sustainability of our food systems.

Soil microbes have evolved mechanisms that enable them to adapt to their environments and resist various stresses, including exposure to antimicrobial agents from competing organisms and anthropogenic activity [5,39]. Microbes can acquire AMR through autogenetic mutation or the acquisition of genes. Bacteria have mechanisms that allow for the rapid exchange of genes, including antibiotic resistance genes (ARG), via horizontal gene transfer of mobile genetic elements, enabling AMR to spread rapidly through soil and other environmental and host organism microbiomes [40,41,42]. The practices used in modern industrial agriculture are recognized as potent drivers of AMR [43,44]. The intensive management of soils through tillage and use of chemical inputs, such as inorganic fertilizers, pesticides, herbicides, fungicides, and manure from animals treated with antibiotics, alter the makeup of soil microbiomes and provide strong pressures that select for resistance traits, accelerating the spread of AMR, as depicted in Figure 1 [7,34,45]. Further, the reduction in soil microbiome diversity caused by intensive agricultural practices [46,47] may permit resistant and pathogenic microbes to proliferate and spread due to lack of competition for resources [7,48].

2.4. Industrial Livestock Production

Industrial animal production is a major contributor to the rise of AMR. The high demand for animal protein in western diets motivates intensive agriculture of feed crops and practices to support high density animal farming, such as concentrated animal feeding operations (CAFOs). Historically, these practices have included the use of antibiotics to prevent and treat infections in livestock, which spread readily in crowded and confined operations, and to promote faster growth [49]. The doses of antibiotics used are often sub-bactericidal and subinhibitory, the chronic application of which favors emergence of resistant microbial strains over more sensitive ones [50]. After recent increases in their use following restrictions on the use of antibiotics in feed in 2017 in the United States (U.S.), the U.S. Food and Drug Administration (FDA) issued regulations that ended over-the-counter access of medically important antibiotics in 2023 [51]. Medically important antibiotics are defined as classes of antibiotics that are used therapeutically in human medicine [52]. The new regulations require veterinarian authorization for the administration of antibiotics in livestock for food production [53]. Prior to these restrictions, farmers could readily purchase a wide array of antibiotics of many medically important classes over the counter, including macrolides, sulfonamides, cephalosporins, tetracyclines, aminoglycosides, fluoroquinolones, and others with very little oversight of their use [49]. While this will hopefully curb some of the pressures inducing AMR in animal agriculture in the U.S., the pervasive use of medically important antibiotics in agriculture remains a global issue and is expected to increase with rising demands for animal protein to feed growing populations [54,55].

In the following review, we explore the mechanisms through which intensive agriculture and livestock production contribute to AMR and discuss global climate change as a driver of AMR. We highlight the effects of chemical pesticides used in intensive agriculture on AMR in pathogenic bacteria, as depicted in Figure 1. We also consider other effects of current industrial food systems on human health.

3. Review of Current Sources and Drivers of AMR in the Environment

3.1. Influence of Industrial Crop Production on Soil Microbial Diversity and AMR

Synthetic fertilizers, insecticides, herbicides, and fungicides that are used widely around the world to support industrial crop production harm biodiversity at multiple levels and drive AMR in soil microbes. Worldwide, nearly 300 million tons of pesticides are used in agriculture [56]. In addition to their adverse effects on human, animal, and plant health, these chemicals are disruptive to the microbial communities present in soils [57,58]. Chemical pesticides induce AMR and the acquisition of ARGs to medically important antibiotics. Pesticides promote many mechanisms of AMR, including efflux pump activation, membrane pore closure, and the induction of gene mutation. They also promote the transfer of AMRs via conjugation by increasing membrane permeability and increasing the proportion of mobile gene elements (Figure 1) [59]. Exposure to typical application levels of the commonly used herbicide, dicamba (2,4-dichlorophenoxyacetic acid) was associated with enhanced tolerance of the bacterial pathogens Salmonella enterica serovar Typhimurium and E. coli to the medically important antibiotics chloramphenicol, ciprofloxacin, and tetracycline. It also enhanced tolerance to ampicillin in S. enterica Typhimurium [60]. The popular herbicide Roundup (glyphosate) induced tolerance to kanamycin in both S. enterica Typhimurium and E. coli [60]. Further, the loss of soil microbial diversity brought on by intensive tillage and chemical inputs may create niches for multidrug-resistant bacteria, or “superbugs”, to proliferate [48,61].

The microbial composition of healthy soils influences our health by shaping the nutrients present in the foods grown in them, which in turn influence our own microbiomes. There is a growing body of evidence that we and the microbiota that inhabit our gut, which we rely on heavily for numerous physiological processes, have evolved with the microbiota in our environment, including many that are found in soils [30,62]. Conventional industrial farming methods are associated with decreased microbial diversity [45,46,63], which may influence the composition of our own gut microbiomes and the quality of the food we eat. Emerging evidence indicates that foods from industrial agricultural practices lack nutritive value compared to foods grown with organic or regenerative agricultural practices, which do not rely as heavily on chemical inputs and support soil health [64,65,66]. Through social and economic factors, industrialized food systems support Western diets high in ultra-processed foods that are high in saturated fats and sugar and lacking micronutrients and fiber [67], which contribute to gut dysbiosis and the rise of non-communicable chronic diseases [25]. Our current food systems that were intended to provide abundant nutrition and promote good health are yielding foods with suboptimal nutritional value, while contributing to health risks, such as gut microbial dysbiosis and AMR.

3.2. Influence of Conventional Livestock Production on AMR

Globally, about 99,000 tons of antibiotics were used in animal agriculture in 2020 and that quantity is expected to increase [55]. Regions with particularly high quantities of antibiotics used relative to total animal weight include China, Brazil, India, the U.S., and Australia. In terms of intensity, the highest users of antibiotics were concentrated in Asia, with China, India, and Thailand accounting for 67% of global hotspots [55]. Outside of Asia, regions with high intensity of antimicrobials included northern Italy, northern Germany, central Poland, the Midwest of the U.S., and Brazil [55]. The adoption of Western diets as countries industrialize has increased the demand for animal protein [68] and consequently increased the scale of animal agriculture and related antibiotic use [54].

Antibiotics have been used in the production of animal foods for the past 80 years. They were initially used to treat and control infections, but over time were less discriminately used as food and water additives for prophylaxis and growth promotion in livestock production and to preserve seafood [69]. Due to concerns about AMR, the U.S. and European Union established regulations to curb the use of antibiotics in agriculture with varying success. The U.S. trails behind the European Union in its efforts to curb antibiotic use in livestock production. A study tracking the trajectory of antibiotic use in agriculture found that the top livestock producing countries in the European Union decreased the intensity of antibiotic use by greater than 50% in the past decade in the wake of policy that focused on prevention of disease through enhanced surveillance and other efforts to promote the health of animals [70]. From 2016 to 2020, including the period after the restriction of the use of medically important antibiotics as feed additives, the U.S. showed reductions in antibiotic use in chickens by 49% but increases in use in cattle by 5.3%, swine by 12.1%, and turkeys by 11.6% [70]. The 2023 US FDA policy ending the over-the-counter sale and requirement of veterinary oversight for medically important antibiotics is an important step toward improving the judicious use of antibiotics in agriculture. Nations that recently adopted industrial livestock production practices continue to perpetuate these issues around indiscriminate antibiotic use in agriculture and are predicted to increase their use with growing populations and higher demands for animal products [54,55]. Livestock production will continue to contribute to AMR on a global scale without concerted international policy.

Even the use of antibiotics that are not directly specified for use in human medicine is a major contributor to the rise of AMR. Historically, the widespread use of tylosin, a macrolide antibiotic as a growth promoter and prophylactic in livestock has driven the emergence of AMR in multiple animal hosts [5,71]. The brief use of avoparcin, an analogue of the medically important antibiotic vancomycin, as a growth promoter in Europe led to the emergence of vancomycin-resistant enterococci, particularly Enterococcus faecium in animals, humans and the environment [5]. This was particularly worrisome, as vancomycin is used as a drug of last resort against multidrug-resistant enterococci and methicillin-resistant Staphylococcus aureus, both of which are common hospital-acquired pathogens. Farmers in China used colistin, polymyxin E, as a feed additive for prophylaxis for nearly three decades prior to the ban of its use in 2017 [72]. Colistin is used sparingly in human medicine due to its adverse effects and is reserved as a last resort option to treat highly resistant Gram-negative infections with Klebsiella pneumoniae, E. coli, Pseudomonas aeruginosa, and Acinetobacter baumannii [5]. The widespread use of colistin as a feed additive has led to the rise of the colistin resistance gene mcr-1, which is plasmid-mediated and readily transmissible via horizontal gene transfer [73]. Disturbingly, this gene has been observed in clinical E. coli isolates, termed MCRPEC, and is attributed to zoonotic transmission [73,74]. The continued persistence of MCRPEC in humans is attributed in part to the continued use of colistin as a feed additive in low- and middle-income countries, including Pakistan, Bangladesh, and Nigeria, despite bans (Figure 2) [74].

Animal derived food products, such as dairy, meat, and eggs, have been demonstrated to carry zoonotic pathogens and associated ARGs [8,75,76,77]. Thus, transmission of zoonotic pathogens with acquired ARGs from plant foods contaminated with animal wastes and animal foods is a growing concern as depicted in Figure 3.

The widespread use of antibiotics in livestock poses consequences for the management and traditional use of their wastes. Manures from conventional livestock agriculture are used as fertilizers for crops around the world and hold promise as a more sustainable source of nutrients compared to industrially-produced synthetic nitrogen fertilizers, which contribute to global greenhouse gas emissions [78,79]. While manures present a good alternative, the high loads of ARGs driven by widespread antibiotic use pose potential hazards (Figure 2). A study from Spain found that manure slurries from local swine farms contained high levels of tetracyclines and fluoroquinolones and moderate levels of sulfonamides. See

Table 1. Antibiotics used in livestock production and their corresponding antibiotic classes used therapeutically in human medicine. Adapted from Revenge of the Microbes [5].

Antibiotic Used in Livestock	Medically Important Antibiotics That It Selects for Resistance to	Use in Human Medicine
Tylosin	Macrolides	Postsurgical infections, sexually transmitted infections, bacterial upper respiratory infections, bacterial pneumonia
	Quinupristin/dalfopristin combination therapy	Multidrug-resistant bacterial infections, postsurgical infection, systemic bacterial infections
Oxytetracycline	Tetracyclines	Bacterial pneumonia, methicillin-resistant Staphylococcus aureus, Lyme disease, intracellular bacterial infections
Sulfamethazine	Sulfonamides	Urinary tract infections, otitis media, used in combination with trimethoprim and as monotherapy
Enrofloxacin	Fluoroquinolones	Urinary tract infections, bacterial enteric infections, sexually transmitted infections, bacterial pneumonia
Avoparcin	Vancomycin	Postsurgical infections, systemic bacterial infections, bacterial pneumonia, bacterial endocarditis
Colistin	Colistin, polymyxin E	Multidrug-resistant Gram-negative infections, bacterial pneumonia, bacterial meningitis

for a summary of medically important antibiotics used in animal agriculture. The bacteria in these swine slurries had high loads of class 1 integron-integrase, a type of mobile genetic element that is associated with the acquisition of ARGs [80], as well as ARGs that confer resistance to tetracyclines, sulfonamides, fluoroquinolones, and beta-lactams [81]. The ARGs that provide resistance to sulfonamides and tetracyclines transferred to crops grown using swine manure fertilizer and were detected in the edible parts of radishes and lettuces [81]. The study demonstrates the potential for transmission of ARGs from agricultural settings to human microbiomes through plant foods (Figure 3).

The antibiotic residues present in these manure fertilizers have the potential to influence soil microbes as well. Antibiotic residues can remain active in soils long after they are introduced, with many medically important antibiotics, including ciprofloxacin and several other fluoroquinolones, persisting for nearly two months. Other relevant antibiotics with the potential to remain in soils include the macrolide erythromycin, the lincosamide clindamycin, the sulfonamide sulfamethazine, and the tetracyclines oxytetracycline and tetracycline [82]. These antibiotics can induce changes in the bacterial composition of soils and lead to the acquisition and spread of ARGs [15], potentially giving rise to dominant multidrug-resistant bacteria [48]. Contamination of land with antibiotic-treated animal wastes and transfer of ARGs to other microbiomes poses another source of AMR in modern industrial agriculture.

Metal additives in animal feed further drive AMR, especially when administered with other antibiotics. The use of zinc, copper, and other metal ions as growth promoting additives in animal feed contributes to the acquisition of metal resistance genes, which may facilitate the co-selection of ARGs [83]. A study evaluated the ARG profiles of bacteria in manure from Chinese swine farms and found ARGs conferring resistance to tetracyclines and macrolides as well as multidrug resistance genes encoding efflux pumps. They found that these ARGs were associated with the levels of metals in the manure, with zinc concentration strongly associated with multidrug resistance genes and chromium associated with the class 1 integron-integrase, intI1 [83]. They observed that intI1 and the ARG tetW, which confers resistance to tetracyclines, were highly associated with metal resistance genes in bacteria from agricultural soils fertilized with the swine manure. ARGs against tetracyclines and macrolides as well as fluoroquinolones were found in sediments in ponds where the treated manure slurry was disposed [83]. This highlights the potential interactions between antibiotics and other anthropogenic changes to soil, such as metal contamination in driving AMR, and the importance of more careful agricultural wastewater management in mitigating spread.

3.3. Effects of Global Climate Change on AMR and Food Systems

Global climate change is projected to exacerbate the development and spread of AMR through multiple mechanisms. Rising temperatures increase the rate of bacterial proliferation and increase the risk of infection, as seen in rising incidence of infection in summer months [84,85]. In addition to the rising temperatures, climate change increases the occurrence of extreme weather events with heavy precipitation and subsequent flooding, which increases waterborne transmission of bacteria and their ARGs [86]. Increases in extreme weather events, including droughts and flooding, undermine the productivity of our agricultural systems [87]. Not surprisingly, the warmer and wetter ambient conditions and increased flooding due to climate change create a breeding ground for drug-resistant bacteria, spreading AMR [88,89,90] and increasing the likelihood of infection while compromising our food systems, collectively spelling disaster (Figure 4).

The escalation in unpredictable weather patterns and rising global temperatures due to global climate change have the potential to exacerbate the already mounting issue of AMR. Increasing temperatures promote the growth of bacteria and increase the risk of certain infections [91,92]. A meta-analysis by Chua and colleagues revealed that each 1 °C increase in average temperature was associated with increased incidence of enteric infection with a 5% increased risk of salmonellosis, 7% for shigellosis, 2% for campylobacteriosis, 5% for cholera, 4% for E. coli enteritis, and 15% for typhoid [93]. The mechanisms by which bacteria develop temperature resistance and AMR are related and support observations that acquisition of AMR and rising temperatures due to global climate change are intimately linked [44,94]. Proposed mechanisms by which increasing temperatures contribute to AMR include increased horizontal gene transfer, increased mutation rates, in addition to changes in the spread of bacteria and ARGs through waterways [44,95]. Hotter temperatures are associated with increased incidence of infection by resistant bacteria. A Chinese study demonstrated that every 1 °C increase in ambient temperature was associated with a 4.7% increase in detection of third generation cephalosporin-resistant K. pneumoniae and a 10.7% increase in carbapenem-resistant K. pneumoniae in patient populations across 31 provinces [90]. A separate Chinese study found similar associations of carbapenem-resistant K. pneumoniae with a 14% increase with every 1 °C increase in annual temperature as well as a 6% increase in carbapenem-resistant P. aeruginosa [89]. These findings are particularly concerning due to current reliance on carbapenems as a last resort antibiotic to treat resistant infections. A study examining the effect of geographical variation in temperature on AMR found that a 10 °C increase in temperature across regions was associated with increases in AMR in E. coli by 4.2%, K. pneumoniae by 2.2%, and Staphylococcus aureus by 2.7% in the U.S. [88]. These findings demonstrate that, in addition to the direct effects of heat on human health, AMR poses a substantial public health threat.

The rising incidence of extreme weather events, such as heavy precipitation from hurricanes and related runoff and flooding, increases the potential for waterborne transmission of pathogens and spread of ARGs in addition to other devastating effects on affected populations [96,97]. The flood waters from tropical storms are known to permit the waterborne spread of bacteria from numerous sources, including sewer systems. A U.S. study found that exposure to tropical storm flood waters was associated with a 48% increase in Shiga toxin-producing E. coli infections 1 week after and a 42% increase in Legionella pneumophila infections 2 weeks after tropical storms [97]. A study demonstrated that the flooding after Hurricane Harvey in Texas, U.S. increased levels of ARGs conferring resistance to beta-lactams and higher loads of human fecal origin bacteria, including E. coli, Enterococcus spp., and Salmonella spp. in coastal sediments, and that elevated loads remained for several months [98]. Flooding following the storm also affected urban soils, causing transient increases in the ARGs tet(E) and bla_CMY-2 and intl1, conferring resistance to tetracyclines, beta-lactams, and class 1 integron-integrase, respectively [99]. The potential for extreme precipitation events to provide opportunities for the mingling and dispersal of bacteria and ARGs in runoff from agricultural fields and waste streams is deeply concerning and could have disastrous effects if not addressed.

The effects of climate change have also influenced the growth of many marine pathogens, such as Vibrio spp. Changes in precipitation patterns and heatwaves alter the salinity, temperature and other properties of marine environments that facilitate bacterial proliferation and the spread of infection [100]. A study that examined the metagenomes of pathogens in the Florida Gulf Coast following Hurricane Ian and a subsequent spike in cases of Vibrio spp. infection found numerous ARGs and mobile genetic elements in Vibrio parahaemolyticus and Vibrio vulnificus [101]. Thus, mitigation of climate change effects must be an important part of the effort to curb the spread of AMR.

Global climate change threatens the productivity of agricultural systems for food production, particularly large monocropping operations. Extremes in weather, particularly heat and drought, threaten the productivity of agricultural operations globally, especially in the developing world and Global South [102]. However, no nation is immune to the effects of climate change indefinitely and industrialized nations experience substantial decreases in productivity with extreme weather [103,104]. Climate change is projected to affect the growing seasons and productivity of major crops, including wheat, maize, rice, and soybean, with a mean projected decrease of 11% without adaptation of appropriate agricultural methods in the next 25 years [105]. Extreme precipitation events and flooding resulting from climate change has led to large crop losses and drastic projected reductions in arable land suitable for growing healthy crops [106]. With the global population projected to grow to 9.8 billion in that time [107], it will be very important to adapt agricultural methods to be more sustainable and tolerant to the effects of climate change. Further expansion of agricultural lands and intensification of practices with increased inputs could provide a temporary boost to productivity, but are ultimately disastrous to already threatened biodiversity and are not sustainable [108].

Expansion of agricultural lands and increased intensification of the practices used not only harm biodiversity but also have the potential to increase the rate and scale of AMR through the mechanisms presented herein [44]. This in concert with other anthropogenic drivers of AMR, including healthcare-associated antimicrobial use and the pollution of environments by wastewater, would lead to an untenable crisis (Figure 5).

4. Future Directions

We offer solution-oriented alternatives to address the current AMR crisis. These include alternative agricultural practices that do not harm biodiversity and do not rely as heavily on chemical inputs, and regulation and policy to improve antimicrobial stewardship and minimize the impacts on environments. Solutions to this crisis must include a multidisciplinary approach involving diverse stakeholders.

At the minimum, efforts to reduce the use of chemical fertilizer and pesticide inputs in crop production and antibiotic use in livestock production are essential to mitigate the spread of AMR. More comprehensive solutions to these challenges require a departure from intensive agricultural practices with its high use of chemical inputs and monoculture cropping. Alternative practices, such as regenerative and organic agricultural practices, do not rely as heavily on chemical inputs and thus do not exert the same pressures driving the emergence and spread of AMR. Studies have demonstrated that organic agricultural practices are associated with lower abundance of ARGs [109,110]. Alternatives to the current large-scale monocropping systems include agroforestry, which is the intentional planting of trees within crop fields, and intercropping, which is the practice of introducing multiple crops or plants in the same field. Agricultural practices, such as agroforestry that establish permaculture with biodiversity, offer more resilience to the effects of climate change by creating wind and temperature-buffered microclimates, as well as more robust root structures that can better tolerate drought and are less dependent on chemical inputs long term [111].

Other plants introduced into the crop field can provide natural pest suppression through natural repellants or as trap plants. For example, the intercropping of oil seeds and cereals with legumes protects the legumes from pathogenic fungi and nematodes [112]. The above ground biodiversity in these systems promote diversity of soil microbiota in part due to the diversity of root systems, plant litters, and microclimates present in agroforestry schemes [113]. These systems have a greater capacity to sequester carbon from the atmosphere and help remediate high atmospheric greenhouse gas levels [114]. Livestock can also be integrated in these farming operations in the practice of silvopasture, which is the management of woodland pasture and forage lands for animals, with mutual benefits to biodiversity and animal health in part by avoiding the crowding and concentrated accumulation of animal wastes that occur in CAFOs (Figure 6) [115]. A shift away from antimicrobials towards other strategies, including vaccination and improved hygiene for livestock disease management, would help reduce the impact of animal agriculture on AMR. In the meantime, waste and wastewater from livestock operations could be managed more carefully to avoid environmental contamination. In addition, research on the transmission of ARGs to commensal enteric bacteria in livestock and environmental microbiota could help identify targets to mitigate the further spread of AMR. Thus, agricultural systems based on biodiverse permaculture offer better sustainability and resilience in the age of climate change and offer the potential to reduce greenhouse gas concentrations while curbing the use of AMR-driving chemical inputs.

Other sources of antibiotic residue contamination in the environment include human wastewater treatment and industrial waste from pharmaceutical factories. The WHO issued a guidance on wastewater and solid waste management from antibiotic manufacturing [116]. They propose guidelines for the management of solid wastes and wastewater, describe technologies to remove antibiotic residues, and outline potential regulatory mechanisms to ensure compliance. Municipal wastewater treatment plants do not effectively remove antibiotics [117]. Enhanced surveillance of antibiotic residues in industrial, municipal, and hospital sewer wastewater will be important to mitigate the further pollution of the environment and spread of ARGs in environmental microbiota. Retrofitting industrial and sewer wastewater systems with systems to more effectively remove antibiotic residues, such as advanced reverse osmosis technology and ozonation, will be crucial next steps in reducing AMR [118].

In addition to curbing resistance to our existing repertoire of antibiotics, we must expand the efforts to develop new antimicrobials. With mounting resistance to existing antimicrobials and limited efforts to curb the perpetuation of AMR, an expanded antimicrobial toolkit is essential. Wilson and Ho discuss avenues for new drug development, including bacterial genome sequencing to identify potential new targets and the use of bacteriophages, viruses that infect and can kill bacteria, as alternative therapeutic agents [5]. Drug discovery is a costly enterprise and industry interest relies on an immediately favorable market to drive profits. Wilson and Ho propose strategies to provide financial incentives to stimulate and maintain industry participation in the typically unprofitable antibiotic market [5]. They suggest that a combination of upfront financial support for drug discovery, known as push incentives, with measures that promise continued revenue, called pull incentives, would be best to draw industry interest in entering the antibiotic market. These incentives could come from government subscription contracts to support industry partners in novel antimicrobial drug development as has been proposed by the U.S. Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Act [5]. International policy that incentivizes the development of new antimicrobials with a combination of push and pull incentives could help stimulate new antimicrobial discovery and development. Patent buyouts, monetary awards, or extension of market exclusivity agreements for other drugs that the company has developed would support antibiotic discovery through development and testing [5]. Judicious use of new antibiotics and alternative methods of prevention and treatment of infections will be necessary to avoid rapid AMR to these new antimicrobials.

AMR is a true planetary health issue and will require a One Health approach in education and policy to effect adequate change. Future efforts to combat AMR and ensure the sustainability of food systems should include interprofessional collaboration and education between a wide range of human and animal medical professionals, agricultural scientists, farmers, and public health officials. Specific One Health curricula on the role of food systems and planetary health as determinants of human health should be implemented in undergraduate medical education worldwide (Figure 7). Existing undergraduate medical curricula on antimicrobial stewardship should be expanded to include education on the specific patterns of AMR induced by agricultural, industrial, and medical activity. The continued assessment and management of healthcare-associated drivers of AMR is crucial, particularly in terms of their interaction with other sources. Policy should promote expanded antimicrobial stewardship education in undergraduate medical education and throughout veterinary and community health education. There should be more emphasis in medical training on the role of physicians as educators of their patients and communities on the proper use and disposal of antibiotics. Healthcare-associated environmental contamination could be mitigated with improved wastewater treatment methods that can more effectively remove antibiotics and other pharmaceuticals from residential and hospital waste streams. Early education on these issues and programs to foster leadership could help inspire future physician leaders to advocate and create policy to limit agricultural contributions to AMR and promote sustainable and judicious practices for food production and infection management.

5. Conclusions

Industrial agriculture has created an outsized and unsustainable system of food and industrial crop and animal production. The practices of monocropping, intensive soil management, and overuse of chemical inputs have simultaneously depleted the microbial biodiversity of soils and thereby have compromised the productivity of land and reduced the quality of the food crops it can support. These practices have also hastened the acquisition of ARGs, which now poses another emergent health threat. Taken together, these unintended consequences of extractive agriculture simultaneously deplete the diversity of soil microbiota and select for antimicrobial resistance, creating niches for these “superbugs” to flourish. The overall outcome threatens the viability of our food production systems and the efficacy of our already compromised tools to fight infection. The future of human health depends on the sustainability and resilience of our food systems to climate change as well as our efforts to combat antibiotic resistance. It is imperative that current and future healthcare providers understand the impacts of AMR drivers within and outside of healthcare so that we may effectively treat and manage the spread of resistant pathogens. Similarly, other stakeholders in other sectors need to have a comprehensive understanding of AMR beyond their area of expertise. There are solutions to this crisis, including regenerative agriculture, wastewater management, antimicrobial drug development and regulation, which require the efforts of a multidisciplinary team. The collaboration between different industries and concerted efforts toward a common goal will provide the best chance to chart a pathway towards a sustainable future for human and planetary health.