A complex cyclical One Health pathway drives the emergence and dissemination of antimicrobial resistance

Elizabeth M. Parker Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, OH

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Gregory A. Ballash Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, OH

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Dixie F. Mollenkopf Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, OH

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Thomas E. Wittum Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, OH

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Abstract

Since their commercialization, scientists have known that antimicrobial use kills or inhibits susceptible bacteria while allowing resistant bacteria to survive and expand. Today there is widespread antimicrobial resistance (AMR), even to antimicrobials of last resort such as the carbapenems, which are reserved for use in life-threatening infections. It is often convenient to assign responsibility for this global health crisis to the users and prescribers of antimicrobials. However, we know that animals never treated with antimicrobials carry clinically relevant AMR bacteria and genes. The causal pathway from bacterial susceptibility to resistance is not simple, and dissemination is cyclical rather than linear. Amplification of AMR occurs in healthcare environments and on farms where frequent exposure to antimicrobials selects for resistant bacterial populations. The recipients of antimicrobial therapy release antimicrobial residues, resistant bacteria, and resistance genes in waste products. These are reduced but not removed during wastewater and manure treatment and enter surface waters, soils, recreational parks, wildlife, and fields where animals graze and crops are grown for human and animal consumption. The cycle is complete when a patient carrying AMR bacteria is treated with antimicrobials that amplify the resistant bacterial populations. Reducing the development and spread of AMR requires a One Health approach with the combined commitment of governments, medical and veterinary professionals, agricultural industries, food and feed processors, and environmental scientists. In this review and in the companion Currents in One Health by Ballash et al, JAVMA, April 2024, we highlight just a few of the steps of the complex cyclical causal pathway that leads to the amplification, dissemination, and maintenance of AMR.

Abstract

Since their commercialization, scientists have known that antimicrobial use kills or inhibits susceptible bacteria while allowing resistant bacteria to survive and expand. Today there is widespread antimicrobial resistance (AMR), even to antimicrobials of last resort such as the carbapenems, which are reserved for use in life-threatening infections. It is often convenient to assign responsibility for this global health crisis to the users and prescribers of antimicrobials. However, we know that animals never treated with antimicrobials carry clinically relevant AMR bacteria and genes. The causal pathway from bacterial susceptibility to resistance is not simple, and dissemination is cyclical rather than linear. Amplification of AMR occurs in healthcare environments and on farms where frequent exposure to antimicrobials selects for resistant bacterial populations. The recipients of antimicrobial therapy release antimicrobial residues, resistant bacteria, and resistance genes in waste products. These are reduced but not removed during wastewater and manure treatment and enter surface waters, soils, recreational parks, wildlife, and fields where animals graze and crops are grown for human and animal consumption. The cycle is complete when a patient carrying AMR bacteria is treated with antimicrobials that amplify the resistant bacterial populations. Reducing the development and spread of AMR requires a One Health approach with the combined commitment of governments, medical and veterinary professionals, agricultural industries, food and feed processors, and environmental scientists. In this review and in the companion Currents in One Health by Ballash et al, JAVMA, April 2024, we highlight just a few of the steps of the complex cyclical causal pathway that leads to the amplification, dissemination, and maintenance of AMR.

In 2017, our research laboratory detected carbapenem-resistant species of Enterobacterales (CRE) in environmental samples collected from farrowing and nursery rooms in a US pig farm.1 The gene conferring carbapenem resistance by encoding for a metallo-β-lactamase was blaIMP on an IncQ1 plasmid. This gene-plasmid combination was found in different species of Enterobacterales recovered from the farm including Escherichia coli, Proteus mirabilis, Morganella morganii, Proteus vulgaris, Klebsiella spp, Citrobacter spp, and Providencia spp. This was the first reported detection of plasmid-mediated CRE in US livestock. The carbapenems are considered the antimicrobials of last resort for invasive, life-threatening gram-negative bacterial infections in human patients,2 but in the US, this class of antimicrobials is not allowed for use in food-producing animals.3 In the US, detection of the IMP gene is uncommon, even in healthcare settings, but is the most prevalent carbapenem-resistant gene type in South Pacific and Asian countries.4 This leads to important scientific questions about where this antimicrobial resistance gene (ARG) originated and how it was introduced and amplified in the environment of a pig farm in the US.

Similar questions regarding the origin and routes of ARG dissemination have been discussed by other researchers. For example, why are antimicrobial-resistant bacteria (ARB) and ARGs detected in humans and animals never treated with antimicrobials and on meat products from animals raised “antibiotic free?”5 Sometimes the first appearance of an ARG, such as blaNDM-1, a metallo-β-lactamase gene that confers resistance to carbapenems, in a new location is in a human patient following overseas travel.6 Other times, however, the first appearance of the gene is in food-producing animals or their food products. In 2017, researchers reported the detection of Salmonella enterica serovar Infantis from chicken, cattle, and human sources in the US. The isolates were resistant to extended-spectrum β-lactams and were harboring blaCTX-M-65 on pESI-like megaplasmids. This gene-plasmid combination was previously detected in human and animal bacterial isolates in Italy between 2011 and 2014.7 In another example, the plasmid-mediated colistin resistance gene mcr-1 was detected in an E coli isolate from a human blood sample in Denmark in 2015. Retrospective investigations found the mcr-1 gene in 5 E coli isolates from poultry meat samples in Denmark collected between 2012 and 2014.8 In 2015, the mcr-1 gene was also detected in humans and food animals in China.9 The mcr genes have now been identified in human and animal samples from across the US. The point of origin and the path that these genes followed to enter human and animal populations in the US are still unknown.10

Amplification

When antimicrobial therapy is applied systemically, bacterial populations present in multiple patient organ systems, including the microbe-rich gastrointestinal tract, can experience selection pressure. Susceptible bacterial strains present in the flora will be eliminated, which creates an ecological niche allowing resistant strains to flourish and expand in a process that can be thought of as amplification. Amplification of resistant bacterial strains can occur in the flora of any individual receiving antimicrobial therapy, but when the human or animal patient is an individual in a household, there is little opportunity for the amplified resistant flora to be broadly disseminated. However, when antimicrobials are commonly applied to individuals housed in population-dense environments where there is frequent contact among individuals and movement in and out of the population, then there is an opportunity for amplification to create a reservoir of resistant bacteria and a means of escape from the reservoir. This process commonly occurs in human healthcare environments (Figure 1) and in intensive animal agriculture (Figure 2).

Figure 1
Figure 1

The amplification and dissemination of antimicrobial-resistant bacteria occur in population-dense environments where antimicrobial use is common and there is frequent contact between individuals, such as in human healthcare settings.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

Figure 2
Figure 2

Similar to human healthcare, frequent antimicrobial use and close contact among individuals in animal agriculture can result in the amplification and dissemination of antimicrobial-resistant bacteria.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

The causal pathway describing the amplification and transmission of ARB and ARGs is complex. During antimicrobial treatment, spontaneous mutations in bacteria may confer resistance so that even in the presence of the antimicrobial, bacteria with the mutation survive and multiply.11,12 The threat of spread, however, is greatest when the DNA coding for AMR is moved horizontally between bacteria with the aid of mobile genetic elements (MGEs). Insertion sequences, transposons, and integrons are MGEs that move within DNA molecules, whereas plasmids can be transferred between bacteria.13 Just as computer program files and folders can be shared with a USB, so can DNA codes and gene cassettes be shared on MGEs, between bacteria of the same and different species. Often these MGEs carry DNA sequences that encode for resistance to multiple classes of antimicrobials so that selection for one antimicrobial such as ceftiofur, a third-generation cephalosporin, will also confer resistance to aminoglycosides and fluoroquinolones.14 Antimicrobial susceptibility testing of the US pig farm isolates harboring blaIMP found that most were not only resistant to the extended-spectrum β-lactams, cephalosporins, and carbapenems but were also resistant to other classes of antimicrobials including tetracyclines and aminoglycosides.1

Amplification of antimicrobial-resistant strains occurs primarily in populations, but those resistant can disseminate and have an impact far beyond the source population. The environment, the food supply chain, human and animal clinical environments, and agricultural animal production systems form a complex cyclical web making it difficult to pinpoint the source of AMR so that mitigation measures can be implemented (Figure 3).

Figure 3
Figure 3

The One Health cycle of antimicrobial resistance amplification, dissemination, and maintenance. Antimicrobial-resistant bacteria and the resistance genes they harbor are amplified following exposure to antimicrobials. These then disseminate in clinical and natural environments where they are maintained and spread to new hosts.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

Wastewater

Municipal wastewater flows provide an important mode of reservoir escape for resistant bacterial strains that are amplified in human healthcare environments. These resistant bacteria enter the wastewater treatment process where they are reduced but not eliminated (Figure 4).15 In addition, waste from agricultural animals is commonly spread on agricultural cropland where resistant bacterial strains that originated on the farm can be recovered from soil and may enter nearby surface waters.16

Figure 4
Figure 4

Antimicrobial-resistant bacteria that are amplified in human healthcare environments escape into municipal wastewater flows where they are reduced but not eliminated by treatment processes.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

As much as 70% to 90% of the antimicrobial doses consumed by both humans and animals to treat and prevent disease 17 are excreted, often unchanged, or only slightly transformed.18 Antimicrobial residues present in human and animal waste and the mixing of diverse bacterial species from the gut of humans and animals treated with antimicrobials drive the release, exchange, and selection of ARGs in wastewater treatment plants (WWTPs).19 To better understand the role of the WWTP in the maintenance and dissemination of carbapenemase-producing Enterobacterales, we analyzed effluent and upstream and downstream surface water samples from 50 US WWTPs from both large metropolitan cities and small rural towns.15 Using selective media, we found a diverse mixture of carbapenem resistance genotypes, 66.7% of which were bacteria with known intrinsic resistance. We also detected 30 carbapenem-resistant clinically relevant bacterial species including E coli, Raoultella ornithinolytica, Enterobacter cloacae, Citrobacter freundii, and Klebsiella pneumoniae. The most frequently detected (n = 22) carbapenemase gene was blaKPC-2, also the most prevalent carbapenemase gene reported in US clinical infections at the time of the study.15 This is consistent with a European study20 that found that the AMR profile in WWTPs mirrored the AMR profile in clinical isolates taken from patients in hospitals located in the WWTP catchment. The use of antimicrobials in humans and animals contributes to antimicrobial pollution and the selection and dissemination of ARB and ARGs not only in clinical environments but in the natural environment, soils and waterways, and the farms where plant-based food products are grown (Figure 5).

Figure 5
Figure 5

The dissemination pathway of healthcare-associated antimicrobial-resistant bacteria via surface water into a downstream watershed. Antimicrobial-resistant bacteria enter streams and rivers from hospitals via wastewater treatment plants where surface water utilization, fish and other wildlife, and direct exposure of humans and animals may widely distribute resistant bacteria.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

AMR Dissemination in Food and Feed

Retail food products provide an important mode of reservoir escape for resistant bacterial strains that are amplified in agricultural animal environments. This includes not only fresh meat products that can be directly contaminated with enteric bacteria from the food animals they originated from but also fresh produce that may become contaminated with waste used as fertilizer.

In Ohio, we collected samples of leafy greens from grocery stores and farmers’ markets to test for the presence of extended-spectrum cephalosporin and carbapenem-resistant Enterobacterales. Enterobacterales resistant to carbapenems and extended-spectrum cephalosporins are considered by the WHO as “top priority pathogens.”21 Although resistance to carbapenems was not detected, Enterobacteriaceae expressing resistance to first-, second-, third-, and fourth-generation cephalosporins (both AmpC β-lactamase and ESBL β-lactamase phenotypes), harboring blaCTX-M and blaCMY genes were detected. Other studies22,23 have found similar results. The use of antimicrobials in plant agriculture in the US is low, about 0.4% of the antimicrobials used in animal agriculture, consisting mostly of tetracycline and streptomycin.24 How did these genes enter and persist in the agricultural environment? An important management tool for plant-based agriculture is the use of reclaimed water, sewage effluent, and organic fertilizers such as sludge and manure. These products decrease the competition for potable water providing a reliable source of the water and nutrients necessary for plant growth,25 with the added benefit of reducing the impact of environmental pollution by human and animal waste.26 Wastewater treatment quality standards set by environmental protection agencies prevent the release of heavy metals and microbial hazards such as disease-causing bacteria, viruses, and protozoa27; however, the efficiency of removal of pharmaceuticals such as antimicrobials is variable.28 In addition to the antimicrobial residues in reclaimed water and organic fertilizers, other chemicals used in plant-based agriculture, such as fungicides, pesticides, and herbicides, are thought to enhance the selection of ARB and ARGs.29,30

The use of antimicrobials in livestock selects for and amplifies ARB and ARGs that have the potential to enter the food chain at the time of slaughter. In 2018, we visited 17 grocery stores in west and central Ohio 29 times and purchased 763 packages of fresh and cooked retail ground pork and beef products to estimate the frequency of contamination with foodborne pathogens and ARB including methicillin-resistant Staphylococcus aureus, Salmonella, extended-spectrum cephalosporin-resistant Enterobacteriaceae, and CRE.31 Among the 619 fresh meat products, we detected methicillin-resistant Staphylococcus aureus in 85 (13.7%) of the packages, Salmonella in 19 (3.1%), Enterobacteriaceae expressing an AmpC (blaCMY) resistance genotype in 136 (22.0%), and Enterobacteriaceae expressing an ESBL (blaCTX-M) resistance genotype in 25 (4.0%) of the meat packages.31 Of the 144 packages of cooked meat, only 1 was contaminated with Enterobacteriaceae harboring blaCTX-M-15. We also detected carbapenemase-producing organisms in both fresh and cooked meat products, but these were all ubiquitous environmental Pseudomonas spp with intrinsic resistance to carbapenems that did not harbor transmissible, epidemiologically important genotypes. Pathogenic bacteria, including ARB, may be transferred to humans during handling, cooking, and consumption of animal-based food products31 (Figure 6).

Figure 6
Figure 6

Plant-based food products for human and animal consumption grown in soils amended with sewage effluent, sludge, and manure may be contaminated with antimicrobial-resistant bacteria and resistance genes. Enteric antimicrobial-resistant bacteria and genes selected for and amplified following antimicrobial treatment of food-producing animals also have the potential to enter the food chain at harvest. Antimicrobial-resistant pathogenic and nonpathogenic bacteria have been detected in both plant and animal retail food products.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

In another study, we assessed the prevalence of AMR Salmonella in commercial feed mills in Australia. Of the 453 Salmonella isolates tested, 48 were resistant to 2 or more antimicrobials, 44 were isolated from the processing equipment, 2 from raw feed ingredients, and 2 from finished feed.32 We speculated that exposure to antimicrobials added to feed ingredients during processing selected for AMR Salmonella residing in biofilms on equipment surfaces. Biofilm-forming Salmonella are difficult to remove from feed and food processing environments and have the potential to contaminate the finished product. Animal feeds and feed ingredients are traded within and between countries providing a means of introducing pathogenic bacteria and AMR to new locations.33 We know that some countries do not have stringent regulations surrounding antimicrobial use34,35 and waste management,36 increasing the risk of AMR contamination of food and feed products. A feed safety study37 in India detected Salmonella resistant to extended-spectrum cephalosporins and the carbapenem, imipenem, in beef cattle feed. The detection of carbapenem-resistant Salmonella in animal feed may be associated with the environment in which the raw feed ingredients were grown and processed. The global food and feed trade increases the risk of introducing and disseminating ARB and ARGs.

AMR Dissemination by Humans and Wildlife

In addition to feed and food, the global dissemination of AMR is aided by the movement of humans and domestic and wild animals. Humans are exposed to ARGs and ARB by many different pathways, including participation in outdoor activities, attending recreational parks,38 swimming in waterways,39 close contact with wildlife,40 visiting petting zoos,41 close proximity to companion animals,42 and the consumption of both animal- and plant-based food products.43 Humans can travel vast distances and may be exposed to many different local, interstate, and international environments, animals, and foods, and novel ARB and ARGs can therefore be acquired when these activities are associated with overseas travel.44 These ARGs and ARB are maintained in the healthy human microbiota and have the potential to spread to others in communities and clinical environments45 and farms and food (Figure 7).

Figure 7
Figure 7

Humans may be exposed to antimicrobial-resistant bacteria by participating in outdoor activities, interacting with wild and domestic animals, and consuming animal and plant-based food products. Humans also travel long distances and may both spread and acquire resistant bacteria during international and local travel. There is an increased prevalence of resistant bacteria in wildlife that live near human populations. Wildlife can also travel long distances and can acquire and spread antimicrobial-resistant bacteria during migration.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

Wild animals also have the potential to travel long distances and urban adapted wildlife species are considered good indicators of environmental pollution with antimicrobial residues,46 ARB,47 and ARG.14 Fecal samples from wildlife that live in close proximity to human activity have an increased prevalence of AMR E coli and MGE.48 Many studies14,40,4952 have described the prevalence of ARB in wildlife and the association between AMR prevalence and proximity to humans and livestock. We assessed the role of wild and free-ranging white-tailed deer (Odocoileus virginianus) in the dissemination of AMR. Bacteria recovered from fecal samples from deer living in urban and suburban parks in Ohio carried blaCMY and blaCTX-M and expressed resistance to third- and fourth-generation cephalosporins. Two isolates from 2 separate deer were resistant to carbapenem and carried blaKPC on an IncFII plasmid and blaNDM-5 on an IncFII/FIA plasmid.40 A similar study14 in Australia assessed the AMR profile of the urban-adapted Australian silver gull (Chroicocephalus novaehollandiae), a bird that forages in waste sites near coastal areas. Of 425 E coli isolates from cloacal swabs of silver gull chicks from 3 coastal locations, 170 grew on selective media supplemented with either meropenem, cefotaxime, or ciprofloxacin. Whole genome sequencing of these isolates identified ARGs including blaIMP, blaOXA (conferring carbapenem resistance), blaCTX-M (resistance to first-, third-, and fourth-generation cephalosporins), and qnrS (resistance to quinolones). Wild, free-ranging animals are bystander recipients of ARB and ARGs and have the means to travel long distances and spread AMR to distant sights including internationally,53,54 thus exposing humans and domesticated animals to novel sources of AMR. Wildlife surveillance provides insight into the epidemiology of AMR.

Amplification: Closing the Cycle

How did blaIMP enter, amplify, and disseminate in a US commercial pig farm? There are several possible pathways of entry. The gene may have entered the farm via reclaimed water or even from river water downstream of the WWTP. This is unlikely because the IMP gene was uncommon in the US at the time of the study. Other possible sources of entry include migratory birds visiting the farm,53 farm workers recently returned from overseas,6 or animal feed or feed ingredients.55 Perhaps the raw materials used to make the pig feed were sourced from countries where this gene was the dominant carbapenem resistance gene at the time of the study. After exposure, the novel ARB and ARGs, such as the CRE and blaIMP in this scenario, became part of the diverse microbiota of healthy humans and animals.56 Sometimes, however, healthy individuals get sick, injured, or require surgery and are treated with antimicrobials. Antimicrobials will change the patient’s bacterial population so that the resistant bacteria survive while susceptible bacterial populations decrease. No matter what the source, the transfer of the IMP gene was likely a rare event. However, the blaIMP gene persisted in the nursery and farrowing barn environment and was detected in many different species of Enterobacterales, the spread between species facilitated by the highly mobilizable IncQ plasmid. Although carbapenems are not used in animal agriculture in the US, other β-lactam antimicrobials such as ceftiofur are labeled for use in food-producing animals (Figure 8). In the pig farm we sampled, ceftiofur was administered to all piglets between 0 and 1 day after birth and males received a second dose at castration. Carbapenem-resistant Enterobacterales are also resistant to all or nearly all β-lactams and extended spectrum cephalosporins.57 Therefore, it is likely that the administration of ceftiofur provided selection pressure that amplified the CRE in treated piglets and in the farrowing and nursery barn environments.1,58

Figure 8
Figure 8

Antimicrobial-resistant bacteria and resistance genes enter farms via many different potential pathways such as migratory birds, farm workers, water, animal feed, or imported livestock. The novel antimicrobial-resistant bacteria enter the diverse microbiota of healthy individuals. If livestock are administered antimicrobials for disease treatment or control, the patient’s bacterial population changes so that resistant bacteria survive while susceptible populations decrease.

Citation: American Journal of Veterinary Research 85, 4; 10.2460/ajvr.24.01.0014

Future Directions

Amplification of AMR is directly related to the frequency and quantity of antimicrobials administered to humans, animals, or plants. Antimicrobial stewardship in conjunction with targeted disease prevention interventions can reduce the frequency and quantity of antimicrobial use, reducing the selection pressure that drives resistance. The aim of antimicrobial stewardship is to promote responsible and evidence-based antimicrobial use through prescriber education and guidance. Stewardship can also be facilitated with farm, clinic, hospital, institution, and government policies, developed under the guidance of health experts, that protect antimicrobials and regulate their use. Ongoing scientific research is needed to develop farming systems that decrease the prevalence of common diseases that drive antimicrobial use in animal industries. This includes research that improves animal genetic selection, management, housing, handling, nutrition, vaccination, and the development and implementation of farm-specific biosecurity practices. Mitigation of environmental contamination with antimicrobial residues and ARB requires a better understanding of how AMR is disseminated from farms, clinics, and hospital settings and how AMR is maintained in natural environments.

Conclusion

Our research and that of others highlight the complexity of the causal pathway from antimicrobial susceptibility to resistance. The spread of AMR is not linear but rather cyclical with no defined start or end points. This implies that every step in the causal pathway is an opportunity to reduce the amplification, dissemination, and maintenance of AMR. The responsibility for the AMR global health crisis does not rest on one specific entity. Mitigation of AMR progression will require the combined efforts of governments, environmental scientists, agricultural and horticultural industries, and veterinary and medical health professionals to implement measures to promote the judicious use of antimicrobials, prevent environmental pollution, and educate the public to help preserve the effectiveness of antimicrobials for future generations.

Acknowledgments

None reported.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.

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