Interventions Targeting the Beef Feedlot Environment to Control Antimicrobial Resistance: A Mathematical Modelling Study.

The fourth joint inter-agency report on integrated analysis of antimicrobial consumption (AMC) and the occurrence of antimicrobial resistance (AMR) in bacteria from humans and food-producing animals (JIACRA) addressed data obtained by the Agencies' EU-wide surveillance networks for 2019-2021. The analysis also sought to identify whether significant trends in AMR and AMC were concomitant over 2014-2021. AMC in both human and animal sectors, expressed in mg/kg of estimated biomass, was compared at country and European level. In 2021, the total AMC was assessed at 125.0 mg/kg of biomass for humans (28 EU/EEA countries, range 44.3-160.1) and 92.6 mg/kg of biomass for food-producing animals (29 EU/EEA countries, range 2.5-296.5). Between 2014 and 2021, total AMC in food-producing animals decreased by 44%, while in humans, it remained relatively stable. Univariate and multivariate analyses were performed to study associations between AMC and AMR for selected combinations of bacteria and antimicrobials. Positive associations between consumption of certain antimicrobials and resistance to those substances in bacteria from both humans and food-producing animals were observed. For certain combinations of bacteria and antimicrobials, AMR in bacteria from humans was associated with AMR in bacteria from food-producing animals which, in turn, was related to AMC in animals. The relative strength of these associations differed markedly between antimicrobial class, microorganism and sector. For certain antimicrobials, statistically significant decreasing trends in AMC and AMR were concomitant for food-producing animals and humans in several countries over 2014-2021. Similarly, a proportion of countries that significantly reduced total AMC also registered increasing susceptibility to antimicrobials in indicator E. coli from food-producing animals and E. coli originating from human invasive infections (i.e., exhibited 'complete susceptibility' or 'zero resistance' to a harmonised set of antimicrobials). Overall, the findings suggest that measures implemented to reduce AMC in food-producing animals and in humans have been effective in many countries. Nevertheless, these measures need to be reinforced so that reductions in AMC are retained and further continued, where necessary. This also highlights the importance of measures that promote human and animal health, such as vaccination and better hygiene, thereby reducing the need for use of antimicrobials.

Photo by Adam Nieścioruk on Unsplash ABSTRACT Antibiotics are useful to stave off infection, though their misuse can be detrimental by creating drug-resistant infections. It is essential that we closely examine the leading causes of antibiotic resistance and consider the serious clinical and ethical ramifications around the issue. This paper will aim to achieve these goals, as well as to propose practical solutions directed towards combating this looming crisis. INTRODUCTION As drug companies race to develop vaccines and treatments in response to the COVID-19 pandemic, other impending public health threats may easily be forgotten and tucked away for another day. Experts are warning that “the same governmental inaction that helped foster the rapid, worldwide spread of the coronavirus may spur an even deadlier epidemic of drug-resistant infection…”[1] Dr. Jeffrey R. Strich, a researcher at the National Institutes of Health Clinical Center remarked, “If there’s anything that this COVID-19 pandemic has taught the world, it is that being prepared is more cost-effective in the long run.”[2] Antibiotic resistant infections cause an estimated 700,000 annual deaths globally.[3] According to the Centers for Disease Control, in the United States alone, drug resistant infections sicken 2.8 million people annually and are responsible for at least 35,000 deaths each year.[4] The United Nations has suggested that, if the problem is not soon addressed, antibiotic resistant infections could kill up to 10 million people by 2050.[5] The genesis of antibiotic resistance is complex and multifaceted. Successfully combating antibiotic resistance will require a global response. This paper will closely examine the leading causes of antibiotic resistance. It will also devote discussion to the clinical and ethical ramifications of antibiotic use and misuse. Lastly, the paper will propose practical measures that countries, such as the US, should be taking now to help stem this ever-evolving public health emergency. I. Antibiotic misuse Antibiotic resistance develops when bacteria are exposed to antibiotics, and propelled by the forces of evolutionary selection, mutate over time to adapt to the antibiotics.[6] This process is greatly accelerated when bacteria are overexposed to antibiotics.[7] Overexposure occurs in two primary ways – the first is through overuse/misuse of antibiotics in humans and the second is misuse/overuse in animals. A. In humans According to studies, treatment decisions involving antibiotics, including whether to use an antibiotic, which antibiotic to use, and the appropriate duration of such use, are incorrect in 30 percent to 50 percent of cases.[8] Antibiotics may be overprescribed in cases where they are not truly needed, or the wrong type or dosage of antibiotic can be prescribed. These issues can contribute to the problem of antibiotic resistance.[9] In many cases, faulty clinical determinations can be attributed to the lack of available microbial testing. Consequently, healthcare providers are unable to properly identify and classify bacteria, thus impairing their ability to make clinically sound treatment decisions. In one US study involving hospitalized patients suffering from community acquired pneumonia, for example, a pathogen was identified in only 7.6% of cases.[10] There is existing technology, specifically polymerase chain reaction (PCR) and semiquantitative PCR, that accurately identifies pathogens in approximately 89 percent of cases.[11] However, this technology is not widely used. When healthcare providers do use testing, they often rely upon culture testing, which is not rapid response and can delay proper treatment assessments.[12] As a result, providers may substitute inappropriate antibiotics in the interim. Another type of antibiotic misuse among humans occurs when patients stop their antibiotic regimens prematurely, thereby allowing harmless bacteria, not fully eradicated due to the abbreviated treatment, to acquire resistance. This resistance is then genetically transferred to dangerous bacteria.[13] Antibiotic resistance is also an unfortunate, frequent occurrence in developing countries where antibiotics are often available without a prescription and can be accessed through unregulated supply chains.[14] Developing nations also frequently suffer from a dearth of standard antibiotic treatment guidelines, which further precipitates antibiotic overprescribing.[15] B. In animals Approximately half of the world’s consumption of antibiotics is for agricultural purposes.[16] In the US, only 20 percent of antibiotic sales are intended for human use, while the remaining 80 percent is for use in livestock.[17] Despite this gross disparity, only 10 percent of publications discussing antibiotic resistance address the role that misuse of antibiotics in animals plays.[18] Antibiotic misuse in animals contributes to antibiotic resistance. Farmers and agribusinesses widely distribute antibiotics, through feed or water, to healthy animal populations for non-therapeutic purposes -- including for growth promotion and disease prevention.[19] The need for antibiotic use for disease prevention arises when animals’ living quarters are cramped and prone to disease.[20] Low concentrations of antibiotics have routinely been observed in the gastrointestinal tracts of livestock.[21] The presence of sub-therapeutic levels of these drugs fosters the growth of resistant bacteria and antibiotic resistance genes in the animals’ guts.[22] When the animals that have developed these resistant bacteria and genes are used as sources of food, both the bacteria and genes are passed along to the food supply, contaminating milk, meat, and eggs.[23] Because the antibiotics used in animals are those that have critically important human applications, the resistant bacteria and genes that develop in response to these drugs can destroy the prospect of their use as effective treatment options in both animals and humans.[24] According to the Environmental Working Group, supermarket meat and poultry contain extremely high levels of antibiotic resistant bacteria. Specifically, ground turkey was found to contain 79 percent resistant bacteria, pork 71 percent, ground beef 62 percent, and chicken 36 percent.[25] While antibiotic resistant bacteria may be killed with proper levels of heat (from cooking, for instance), antibiotic resistance DNA that accompanies the bacteria is not always eradicated. This resistance can then be transferred to the humans who consume it, conferring resistance upon otherwise benign bacteria in their digestive systems.[26] Resistant bacteria and genes contained in animal waste can also enter the environment as pollutants, settling in the ground, air, and water systems.[27] This further increases the transmissibility of antibiotic resistance from animals to humans and, ultimately, from human to human when a person acquires an antibiotic resistant infection from food and/or the environment and passes it along to others.[28] Another unintended adverse consequence of antibiotic use in animals is that foods like meat, milk, and eggs often contain antibiotic residues.[29] Since up to 90 percent of antibiotics are excreted through an animal’s waste, the drugs may also pollute the ground and groundwater.[30] Unnecessarily prolonged exposure to antibiotics increases the risk of acquiring bacterial resistance and/or an antibiotic resistant infection. The constant exposure to antibiotics can have other adverse health effects, ranging from drug hypersensitivity to carcinogenic effects.[31] II. Ethical considerations and obligations of stakeholders A. Tackling antibiotic resistance created through the healthcare sector First, with respect to antibiotic misuse in humans, there needs to be vastly scaled-up pathogenic testing. This will help ensure that treatment decisions involving antibiotics are made with empirical data, rather than being an exercise in supposition. Increased testing would lead to a reduction in unnecessary antibiotic prescriptions and scripts for the wrong antibiotic. PCR technology should be made widely available, at least until more effective testing is developed. At the most basic level, physicians should seek out this testing to make it available in their practices and hospitals. Third-party payors should be poised to approve the costs associated with these tests, since they may expedite improvements in patients’ health, thereby resulting in an overall cost savings. The pharmaceutical industry should also develop accurate, rapid testing technology. Rapid testing could abbreviate patients’ immediate illnesses, because knowledge provided by testing can help physicians quickly determine proper diagnoses. This will allow them to immediately prescribe the correct antibiotics. Finally, on a global level, countries that lack regulations around antibiotic access and use must implement sufficient restrictions. Addressing antibiotic resistance on a global level is imperative. Like with COVID-19, from a pragmatic and ethical perspective, we must create global solutions to antibiotic resistance to prevent resistant bacteria from spreading.[32] B. Ethical considerations around antibiotic prescriptions for human use Some ethicists have argued that antibiotics are a public good, and their overuse can result in a sort of “tragedy of the commons.”[33] In order to ensure the equitable distribution of antibiotics for all patients, society must create disincentives around antibiotic use. One such proposal involves taxing patients who use antibiotics for “minor and self-limiting” infections.[34] However, patients should not be punished for following their physicians’ recommendations. Things like taxing schemes unjustifiably interfere with the doctor-patient relationship and can result in adverse clinical consequences for patients. Others have asserted that physicians owe a duty of care to both present and future patients. Pursuant to this argument, physicians are ethically justified in increasing the risk of harm to present patients by a “small” amount by denying them antibiotics, if, in doing so, they are decreasing a significant risk of harm to future patients.[35] As per the Hippocratic Oath, physicians have an obligation first and foremost, to their current patients. This duty includes the obligation to act for the good of the patient (with beneficence) and to prevent harm from befalling the patient (non-maleficence). Nowhere in the Oath does it say that “a little” harm is acceptable. Failing to provide a patient with an antibiotic when it is warranted in order to “preserve” the drug for use by future patients is a violation of the physicians’ bioethical obligations to the patient. There are cases where it may be in patients’ best interests to avoid antibiotics, thus decreasing their own risk of antibiotic resistance from superfluous use. However, physicians must make these determinations on a case-by-case basis, relying on clinical evidence, rather than an impermissible ethical imperative to future patients. It is also a breach of the patient’s right of autonomy if the patient believes the physician is acting strictly in his or her best interest and relies on the physician’s treatment recommendations due to this belief. From a clinical perspective, a “small” amount of harm could easily become a “large” amount of harm, depending upon the patient and the infection at issue. A physician could also misjudge the level of risk involved in depriving a patient of an antibiotic, thereby creating an increased risk of morbidity or mortality for the patient. This is not to imply that the physician is never justified in proposing a reasonable waiting period before prescribing an antibiotic in order to determine if the illness is self-limiting and begins to improve on its own. However, again, this decision should be driven strictly by clinical criteria and the best interest of the present patient. In addition, proposals that seek to disincentivize antibiotic use can be clinically and ethically dangerous. Although prudence around antibiotic use is necessary, physicians should not be dissuaded from prescribing them when, in the physicians’ clinical judgements, they are necessary. Without antibiotics, seemingly benign infections can quickly turn deadly. Untreated bronchitis can rapidly progress to pneumonia. Untreated strep throat can lead to heart damage. A lingering urinary tract infection can induce sepsis.[1] III. Combating antibiotic resistance created by the agricultural sector As one scholar aptly observed, “[t]he current debate on the ethics of [antimicrobial resistance] is heavily and disproportionately focused on the use of antibiotics in humans…this focus reflects the traditional discourse in medical ethics…”[36] It seems relevant to note the seeming irrationality of ethicists advocating for withholding antibiotics from people while failing to consider the widespread, indiscriminate, unregulated use of antibiotics in the agricultural sector. The bottom line is that the focus on antibiotic use in humans, while important, cannot overshadow the substantial role that antibiotic use in animals has played in the antibiotic resistance crisis. There are several key stakeholders that are under an ethical obligation to take immediate action. The FDA should create a rule immediately banning the non-therapeutic use of antibiotics in healthy animals. The FDA took a small step in 2017 towards limiting antibiotic use in healthy animals when it finally restricted farms from using medically important drugs as growth promotion agents for animals.[37] This move, however, has been described as grossly insufficient. For one, antibiotics can still be used in healthy animals for purposes other than growth promotion, such as for “preventive health” purposes or in “times of stress,” which the FDA never clearly defines.[38] Therefore, the newly imposed restriction is easy to circumvent. Farms simply can purchase antibiotics for use as a “preventive health” measure rather than for growth promotion purposes.[39] To complicate matters further, at least 30 percent of antibiotics intended for animals have labels that lack any parameters around duration of use, meaning they can be used indefinitely throughout animals’ lives.[40] Farms and pharmaceutical companies are still promoting “growth” as an ancillary benefit of antibiotics, encouraging their unbridled use.[41] The next measure that the FDA must implement is the elimination of crowded, inhumane animal conditions in farms which create the need to administer “preventive” antibiotics. It is well established that “[a]ntibiotics are used at subtherapeutic levels to promote growth and to prevent disease in the extremely crowded conditions that food animals are raised in.”[42] The conditions present in many livestock farms has been compared to crowded hospitals “where everyone is given antibiotics, patients lie in unchanged beds, hygiene is nonexistent, infections and re-infections are rife, waste is thrown out the window, and visitors enter and leave at will.”[43] Eliminating crowded conditions will greatly reduce the need for preventive antibiotics. Finally, the FDA must establish a surveillance and enforcement mechanism to ensure proper compliance with limiting antibiotic use in healthy animals and addressing crowded conditions. Surprisingly, and notwithstanding the documented link between antibiotic use in animals and adverse human health effects, the FDA lacks any means of monitoring farms’ use of antibiotics in animals. The only measure it uses to assess possible antibiotic use is the sale of antibiotics to farms.[44] The pharmaceutical and chemical companies that manufacture the antibiotics are required to provide this information to the FDA.[45] Although reports have indicated that around 80 percent of antibiotics are sold for agricultural purposes, the FDA contends that it cannot discern actual use from these numbers. At the same time, the FDA has failed to create any other rules that would establish an alternative means of monitoring use.[46] As a New York Times investigation revealed, public health investigators are often unable to access the most basic information regarding a farm’s practices.[47] The agricultural industry constructs roadblocks so that the government’s access to farms, and how they are using antibiotics in animals, is hindered.[48] Further complicating the matter are conflicts of interest where livestock industry executives hold high positions on advisory committees for government agencies, such as the US Department of Agriculture (USDA).[49] The USDA does have a monitoring system that studies antibiotic use in the agricultural sector.[50] However, as an expert in a recent Washington Post article opined, “[t]he USDA’s oversight is laissez-faire. They test such a small fraction it can’t even be taken seriously…and they rotate the drugs they are testing for, because they can’t afford to test for all of them. They just don’t have the funds to do it. We raise 9 billion animals, and they test hundreds of cattle, not even thousands.”[51] The USDA’s antibiotic surveillance system also relies upon agricultural industry self-reporting, using voluntary questionnaires,[52] which calls into question the completeness and veracity of the data. In addition to the US government, the pharmaceutical industry must also help reign in imprudent antibiotic use in the agricultural sector. In 2007, legislation was introduced that would have required drug manufacturers to phase out use of antibiotics for healthy animals.[53] The meat and poultry industries, and several major pharmaceutical companies opposed the legislation.[54] It is ethically incumbent upon the pharmaceutical industry to support the fight against antibiotic resistance. The industry creates the products, doing a great deal of good, so some may argue they should not be tasked with overseeing poor uses of their products. But the pharmaceutical industry should encourage measures that ensure the responsible use of their products. It should also refrain from touting the “ancillary benefits” of antibiotics, such as “growth promotion,” which encourages their injudicious and illegal use. Consumers pay the ethical price of all three industries’ actions. People eating animal products have no opportunity to consent to the use of antibiotics. Although they may choose antibiotic-free meat and dairy, or choose not to consume animal products, people do not have the opportunity to consent to the presence of antibiotic residues, antibiotic resistant bacteria, and resistance genes in their food supply, and they may not be aware of the risks. Consumers bear the burden while industries profit. While there are animal food products designated “organic,” and their producers allege that no antibiotics were used in their production use, these foods tend to be significantly more expensive than food that is not organic. Therefore, those in lower socio-economic brackets are forced to buy foods that are detrimental to their health, while those in higher brackets can afford healthier food products. This is a violation of the ethical principle of distributive justice. Industry must work to find innovative ways to level the playing field and make all food safe for consumers, regardless of economic disposition. Simply put, no consumer should have to worry about antibiotics, antibiotic resistant bacteria, or resistance genes in their food supply. IV. Creating incentives around antibiotic development Addressing antibiotic resistance by chipping away at its causes is an important approach, though it is not sufficient to truly win the antibiotic resistance war. Since, even with mitigation of causal factors, resistance is inevitable on some level. Therefore, we must also address the crisis from the tail-end. This involves ensuring that, when resistance does occur, we are prepared for it. In order to do this, new classes of antibiotics that have the potential to treat resistant pathogens must be developed. The current landscape for antibiotic research and development is a barren one. Pharmaceutical companies have largely bailed on this area and biotechnology startups are going bankrupt pursuing this venture. As a recent New York Times piece noted, “[i]n the 1980s, there were 18 major pharmaceutical companies developing new antibiotics; today there are three.”[55] Pharmaceutical companies prefer to focus on the development of drugs for chronic diseases, which ensure long term, continuous profits.[56] Antibiotics, on the other hand, tend to be prescribed on a short-term basis for acute infections. This limits their inherent capacity to generate profits.[57] Finally, physicians tend to be reluctant to use new antibiotics, further limiting companies from recouping their investments.[58] Bioethicist Dr. Ezekiel Emanuel has suggested using for new classes of antibiotics, that “[t]he and of created by such a would make an in research pharmaceutical companies are their and using it to biotechnology companies to developing antibiotics in with the Health The companies that they are creating a billion for The the will be short-term intended to provide an a antibiotics The will to approximately companies on Although the are they are not new antibiotic can cost billion to The of to the research and development of new antibiotics may be a more As an article in the New of in to generate continuous growth to up – high of over There is also to drug Some such as the and the for have to contribute to antibiotic the for will be to raise pharmaceutical such as the with government could be directed antibiotic development Antibiotic resistance is a for everyone around the and the problem focused As the Health has observed, the antibiotic resistance crisis may and compared to the COVID-19 resistance needs more and As one public health expert has all of need an antibiotic. 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Antimicrobial Use and Resistance in Pigs and Chickens: A Review of the Science, Policy and Control Practices from Farm to Slaughter – Executive Summary

Antimicrobial compounds are arguably one of the most powerful discovered drugs in the history of human medicine. However, the success of antimicrobial compounds has ultimately contributed to their own downfall due to the emergence of antimicrobial resistant bacteria. Their use, including too frequent and careless use, has led to the increasing development of antimicrobial resistant bacteria. As a result, treating bacterial infections has become more challenging and can lead to treatment failure. Furthermore, the development of new antimicrobials has also become increasingly difficult, both for scientific and economic reasons. Any use of antimicrobials selects for antimicrobial resistant bacteria. Antimicrobial usage in livestock farming is substantial and it is considered one of the main drivers of antimicrobial resistance. It is estimated that global antimicrobial use in livestock farming is around 100,000 tons per year, while only milligrams to grams per animal are needed for treatment. As a result, a reservoir of antimicrobial resistant bacteria is created. From this reservoir, these antimicrobial resistant bacteria can potentially transmit to the environment or humans through various pathways. These antimicrobial resistant bacteria can eventually cause infections, leading to health problems. It is therefore important to investigate whether the selection for resistant bacteria in livestock farming can be reduced. For this reason, stewardship programs have been introduced to promote more responsible antimicrobial use. In that light, the aim of this thesis is to reconsider the classification of antimicrobials through scientific research on selective concentrations, antimicrobial stability, and the unintended selection of resistance to so-called critically important antimicrobials. In this thesis, studies report that some antimicrobials are very stable and that concentrations of these antimicrobials are able to remain in the farm environment. Even more worrying is that these residues are at concentrations, where selection of antimicrobial resistance still occurs. Furthermore, we modelled the effect of these residues on the occurrence of co-selection and has found that co-selection is increased when persistent antimicrobials are used in an commercial farm environment. Lastly, in this thesis we addressed the problem of cross-resistance, which means that antimicrobials select for the same type of resistance, between antimicrobials belonging to the same class such as flumequine and enrofloxacin. The main conclusion of this thesis is that antimicrobial residues of persistent antimicrobials remain in the farm environment, exerting prolonged selective pressure for antimicrobial resistant bacteria. This effect is shown by the observed increase in non-wildtype bacteria over a longer time following the use of persistent antimicrobials compared to non-persistent antimicrobials. Additionally, the findings suggest that these persistent residues may play a significant role in the development of co-resistance and cross-resistance among bacteria.

The third joint inter‐agency report on integrated analysis of antimicrobial consumption (AMC) and the occurrence of antimicrobial resistance (AMR) in bacteria from humans and food‐producing animals (JIACRA) addressed data obtained by the Agencies' EU‐wide surveillance networks for 2016–2018. AMC in both sectors, expressed in mg/kg of estimated biomass, was compared at country and European level. Substantial variations in AMC between countries were observed in human and food animal sectors. In each year over the period 2016–2018, overall AMC was lower in food‐producing animals (for example in 2017, 108.3 mg/kg, range 3.1–423.1) than in humans (for example in 2017, 130.0 mg/kg; range 52.8–212.6). This is the first time this situation has been reported since JIACRA analyses were initiated on 2011 data. Univariate and multivariate analyses were applied to study associations between AMC and AMR for selected combinations of bacteria and antimicrobials. In both food‐producing animals and humans, associations were generally observed between the consumption of an antimicrobial class and bacterial resistance to the antimicrobials in this class in the same population. The multivariate analysis proved to be a useful approach for assessing the statistical significance and relative strength of associations between the occurrence of AMR in bacteria from humans, AMR in bacteria from food‐producing animals and AMC in both food‐producing animals and humans. For certain combinations of bacteria and antimicrobials, resistance in bacteria from humans was associated with resistance in bacteria from food‐producing animals which, in turn, was related to antimicrobial consumption in animals. The analyses showed that the relative strength of these associations differed markedly depending on antimicrobial class, microorganism and sector. Overall, the findings suggest that further interventions to reduce AMC will have a beneficial impact on AMR, which underlines the need to promote prudent use of antimicrobial agents in conjunction with infection control, prevention of infection and other relevant measures in both humans and foodproducing animals. The high levels of AMC and AMR still being reported in animals and humans from several countries show that these interventions should be reinforced.

There is ongoing debate regarding potential associations between restrictions of antimicrobial use and prevalence of antimicrobial resistance (AMR) in bacteria. To summarize the effects of interventions reducing antimicrobial use in food-producing animals on the prevalence of AMR genes (ARGs) in bacteria from animals and humans. We published a full systematic review of restrictions of antimicrobials in food-producing animals and their associations with AMR in bacteria. Herein, we focus on studies reporting on the association between restricted antimicrobial use and prevalence of ARGs. We used multilevel mixed-effects models and a semi-quantitative approach based on forest plots to summarize findings from studies. A positive effect of intervention [reduction in prevalence or number of ARGs in group(s) with restricted antimicrobial use] was reported from 29 studies for at least one ARG. We detected significant associations between a ban on avoparcin and diminished presence of the vanA gene in samples from animals and humans, whereas for the mecA gene, studies agreed on a positive effect of intervention in samples only from animals. Comparisons involving mcr-1, blaCTX-M, aadA2, vat(E), sul2, dfrA5, dfrA13, tet(E) and tet(P) indicated a reduced prevalence of genes in intervention groups. Conversely, no effects were detected for β-lactamases other than blaCTX-M and the remaining tet genes. The available body of scientific evidence supported that restricted use of antimicrobials in food animals was associated with an either lower or equal presence of ARGs in bacteria, with effects dependent on ARG, host species and restricted drug.

Antimicrobial resistance in bacteria from animals and the environment

The use of antimicrobial agents in the veterinary field affects the emergence, prevalence, and dissemination of antimicrobial resistance in bacteria isolated from food-producing animals. To control the emergence, prevalence, and dissemination of antimicrobial resistance, it is necessary to implement appropriate actions based on scientific evidence. In Japan, the Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM) was established in 1999 to monitor the antimicrobial susceptibility of foodborne and commensal bacteria from food-producing animals. The JVARM showed that the emergence and prevalence of resistant Escherichia coli were likely linked to the therapeutic antimicrobial use in food-producing animals through not only direct selection of the corresponding resistance but also indirect selections via cross-resistance and coresistance. In addition, relevant factors such as host animals and bacterial properties might affect the occurrence and prevalence of antimicrobial-resistant E. coli under the selective pressure from antimicrobial usage. This paper reviews the trends in antimicrobial resistance in E. coli and consumption of antimicrobials agents in Japan and introduces the relationship between antimicrobial usage and prevalence of antimicrobial-resistant bacteria, from food-producing animals under the JVARM program. In this paper, we will provide the underlying information about the significant factors that can help control antimicrobial resistance in bacteria in veterinary medicine.

The second ECDC/EFSA/EMA joint report on the integrated analysis of antimicrobial consumption (AMC) and antimicrobial resistance (AMR) in bacteria from humans and food‐producing animals addressed data obtained by the Agencies’ EU‐wide surveillance networks for 2013–2015. AMC in both sectors, expressed in mg/kg of estimated biomass, were compared at country and European level. Substantial variations between countries were observed in both sectors. Estimated data on AMC for pigs and poultry were used for the first time. Univariate and multivariate analyses were applied to study associations between AMC and AMR. In 2014, the average AMC was higher in animals (152 mg/kg) than in humans (124 mg/kg), but the opposite applied to the median AMC (67 and 118 mg/kg, respectively). In 18 of 28 countries, AMC was lower in animals than in humans. Univariate analysis showed statistically‐significant (p < 0.05) associations between AMC and AMR for fluoroquinolones and Escherichia coli in both sectors, for 3rd‐ and 4th‐generation cephalosporins and E. coli in humans, and tetracyclines and polymyxins and E. coli in animals. In humans, there was a statistically‐significant association between AMC and AMR for carbapenems and polymyxins in Klebsiella pneumoniae. Consumption of macrolides in animals was significantly associated with macrolide resistance in Campylobacter coli in animals and humans. Multivariate analyses provided a unique approach to assess the contributions of AMC in humans and animals and AMR in bacteria from animals to AMR in bacteria from humans. Multivariate analyses demonstrated that 3rd‐ and 4th‐generation cephalosporin and fluoroquinolone resistance in E. coli from humans was associated with corresponding AMC in humans, whereas resistance to fluoroquinolones in Salmonella spp. and Campylobacter spp. from humans was related to consumption of fluoroquinolones in animals. These results suggest that from a ‘One‐health’ perspective, there is potential in both sectors to further develop prudent use of antimicrobials and thereby reduce AMR.

To characterize and compare resistance trends in clinical Escherichia coli isolates from humans, food-producing animals (poultry, cattle and swine) and pets (dogs and cats). Antibiogram results collected between January 2014 and December 2017 by MedQual [the French surveillance network for antimicrobial resistance (AMR) in bacteria isolated from the community] and RESAPATH (the French surveillance network for AMR in bacteria from diseased animals) were analysed, focusing on resistance to antibiotics of common interest to human and veterinary medicine. Resistance dynamics were investigated using generalized additive models. In total, 743 637 antibiograms from humans, 48 170 from food-producing animals and 7750 from pets were analysed. For each antibiotic investigated, the resistance proportions of isolates collected from humans were of the same order of magnitude as those from food-producing animals or pets. However, resistance trends in humans differed from those observed in pets and food-producing animals over the period studied. For example, resistance to third-generation cephalosporins and fluoroquinolones was almost always below 10% for both humans and animals. However, in contrast to the notable decreases in resistance observed in both food-producing animals and pets, resistance in humans decreased only slightly. Despite several potential biases in the data, the resistance trends remain meaningful. The strength of the parallel is based on similar data collection in humans and animals and on a similar statistical methodology. Resistance dynamics seemed specific to each species, reflecting different antibiotic-use practices. These results advocate applying the efforts already being made to reduce antibiotic use to all sectors and all species, both in human and veterinary medicine.

A total of 76 participants attended the Workshop held in Calgary, Alberta, Canada. They came from Canada (39), the USA (14), Belgium (4), Qatar (3), France (3), 2 each from the Netherlands, Portugal, the UK, Ireland, and one each from the Kingdom of Saudi Arabia, Republic of Korea, Switzerland, Israel, and Hong Kong, Of these, 33 were from government, 15 were from academia, 17 were instrument and equipment manufacturers and primary producers, 10 represented industry and one was a retired government official. While the majority of participants were involved in generating the database for risk analysis and risk assessment for the veterinary drugs of interest to this community, a sizeable number of participants were risk managers directly involved in making risk policy and risk management decisions. This Proceedings captures some of the relevant contributions presented at the SASKVAL III Workshop which was organized to assemble experts from the research community and those in the non-scientific policy-forming sector involved in the primary production of agri-food and aquaculture products for which veterinary drugs are used. The goal was to provide a forum for the two groups to gain a better understanding of the underlying issues related to the practice of using these drugs in food animal production and how they impact both human health safety issues and global trade with the expectation that this would enable the development of a firm knowledge base for making sound risk assessment and risk management decisions. In addition, it was expected that the workshop would provide the required forum to assist and inform public debate on current and emerging challenges facing the agri-food industry to help increase face-to-face public debate/discussion between the scientists in the analytical community and experts involved in policy decision-making. In that regard, the workshop was designed to centre on seven themes. One of the papers submitted for publication consideration in this section Effective management tools for moving standards through the Codex Standard Setting Process at the CCRVDF, authored by Jack Kay, described how the CCRVDF develops codes of practice related to veterinary drugs and their associated residues in food of animal origin, agreeing priorities for the assessment of the safety of veterinary drugs by the Joint World Health Organization/Food and Agriculture Organization (WHO/FAO) of the United Nations Expert Committee on Food Additives (JECFA), recommending maximum residue limits (MRLs) for veterinary drugs used in food animal production and considering sampling protocols and methods of analysis for veterinary drugs.1 The next two papers were submitted under Theme 2 – Chemical Residue and Contaminant Testing: Emerging and Alternate Technologies. In today's market economy, many nutritional and health studies recommend a higher consumption of fat composed of polyunsaturated fatty acids (PUFA), mainly n-3 polyunsaturated fatty acids which are abundant in fatty fish the major natural dietary source of long chain n-3 fatty acids. Processors and producers are finding ways to increase the amount of n-3 fatty acids in animal feed by addition of linseed oil or fish oil as a way to increase human intake of those compounds through the consumption of food from animal origin other than fatty fish. Consequently, many products including meat, milk, eggs, and dairy products enriched with n-3 fatty acids can now be found in the market. Unfortunately, this practice can result in the rapid oxidation of these high polyunsaturated fatty acids to potentially cytotoxic and genotoxic aldehydes, including malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), 4-hydroxy-2-hexenal (4-HHE), crotonaldehyde (CRT), benzaldehyde (BNZ), hexanal (HXL), 2,4-nonadienal and 2,4-decadienal. A 2011 safety assessment of MDA, crotonaldehyde and 4-HNE by the Belgian Superior Health Council concluded that these compounds were of major concern for human health. To protect consumers from ingesting potentially toxic compounds, a method authored by Douny et al.2 using the latest liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform technology was validated and used to characterize and measure these aldehydes in food or animal feed to establish their residue profile in consumer products whose labels claim to contain enriched fatty acids. In the second paper submitted under this theme, Akre and Mizuno3 demonstrated how difficult it is to develop a single method for the analysis and detection of natural and synthetic steroids, stilbenes, and resorcylic acid lactones in bovine urine despite recent advances made in the detection capabilities of current platform technologies such as gas chromatography-tandem mass spectrometry (GC-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Most laboratories conducting residue testing for monitoring drug use in the food animal population in support of regulatory requirements use multi-residue methods to increase laboratory efficiencies in sample analysis and to reduce the cost of operating those laboratories. Under Theme 3 – High Throughput Analysis in Labs and Food Production – Berendsen et al.4 presented results of a recent international collaborative laboratory study to revise and update the acceptance criteria for the characteristic operational parameters including retention times, ion ratios, etc., which were previously based on single analyte methods using vintage equipment, none of which is currently available in our regulatory laboratories. In this study, the authors assessed existing criteria in the light of currently applied methodologies and developed new evidence-based criteria applicable to modern and emerging analytical methods applied in the field of veterinary drug residue testing. Datasets were constructed from the analysis of in-house prepared homogeneous materials using relevant and state-of-the-art (front end) analytical instruments, combining chromatographic separation and mass spectrometric detection techniques. These datasets provided the basis for the proposed new/amended criteria. The amended criteria were then validated by a collaborative study employing in-house prepared homogeneous unknown test materials in collaboration with residue testing laboratories from all over the world, to ensure validity of the proposed criteria for confirmatory analysis. The results of this collaborative study will be presented to the next session of the CCRVDF which will meet in October 2016 in the USA to consider how it can incorporate the new acceptance criteria for mass spectrometric detection techniques into the Codex Criteria for the Performance of Analytical Methods Used in Regulatory Monitoring Programs. Urine samples obtained from food animals are used extensively in some regulatory programmes to screen for the presence/absence of veterinary drug residues and contaminants. In North America, regulatory decisions can only be made on analysis performed directly on the edible tissue (not urine) to demonstrate that the concentration of an approved veterinary drug detected in that particular food sample exceeds the MRL defined by the Competent Authority as safe for human consumption. Kaufmann5 reviewed the practice of using advanced analytical technologies like ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC-HRMS) for veterinary drug screening of animal urine where the MRLs of those compounds in organs like muscle, kidney, or liver have been exceeded. He discussed the limitations and possibilities of the technique drawing attention to the most critical point which is the variability of the drug concentration ratio between the tissue and urine and offered strategies to manage the potential for false positive and false negative results. Ramadan et al.6 described a validated LC-MS/MS method for the quantitative analysis and confirmation of 120 pesticide residues in apples and cucumbers based on the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, Safe) approach to sample extraction. The validated method has been used for over two years in the routine analysis of these matrices in Qatar's residue monitoring programme. Matus and Boison7 reported the development and validation of a liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF/MS) method for 17 anticoccidial drugs and ractopamine residues in animal tissues quail liver, bovine kidney, liver, muscle, chicken muscle, and horse muscle. The method which describes a short extraction time of 3 h and short chromatographic run times provides test results in 1 day for 24 samples and has been demonstrated to be suitable for the analysis of an additional 110 veterinary drugs including nitroimidazoles, NSAIDs, corticosteroids, hormones, steroids, β-agonists, tranquilizers, macrolides, desoxycarbadox, phenicols, endectocides, zeranols, estradiols, fluoroquinolones, and sulphonamides. Since food is extensively traded on the world market, it is imperative that all countries involved in global trade respect the basic tenet of the World Trade Organization (WTO) that countries engaged in global trade activities adopt the scientific, risk-based standards established by the Codex Alimentarius Commission that will facilitate trade rather than become barriers to trade. In that same vein, Codex has also recommended that all laboratories providing analytical support services to the residue control programme must be accredited to an international testing standard such the ISO/IEC 1705:2005 and that the methods used in support of that work must be validated in accordance with accepted criteria. Since the EU is a major trading partner in global trade, developments in food safety issues undertaken by the EU will usually have significant implications to the rest of the trading partners. So, under Theme 4 – International Harmonization of Analytical Methods and Processes – McEvoy8 reviewed past food and feed safety crises that have shaped the development of EU food law and showed that the current flexible regulatory framework and support mechanisms underpinning its operation means that the EU is now in a much stronger position to identify and address food and feed safety incidents and prevent their escalation into crises than was the case previously. On the basis of past experience, unexpected or unforeseen events are most likely to trigger food and feed safety crises. Consequently, preparedness for such events will require ongoing investment in active and passive surveillance systems allied with vigilance on the part of all of the players in the feed and food chains, effective communication, sharing of intelligence, and coordination of activities between the member states and the European institutions. Having all of these elements in place, whilst not guaranteeing that there will never be any further food/feed safety incidents in the EU, would nevertheless appear to offer the best hope of preventing the escalation of such incidents into crises. He concluded that in this respect the EU is well placed to face future challenges. Continuing on the theme of international harmonization, van Ginkel and Sterk9 reviewed the current laboratory network system in support of residue monitoring programmes within the EU which formally started in the early 1990s and noted with interest that since then it has evolved and incorporated new techniques and methods for quality assurance and is moving in parallel with the shift at the EU headquarters itself from production-based control to risk-based control. The paradigm shift from production-based to risk-based control now is foreseen in the EU laboratory operations which will have a significant impact on the type of methodologies to be used and subsequently also on the specific roles of EU reference laboratories. In this presentation, van Ginkel and Sterk project how the laboratory operations at the EU Reference Laboratories (EURLs) will look in years to come. With all the recent scandalous events in the UK on the detection of phenylbutazone residues in meat that had intentionally been contaminated with horse meat and not properly labelled, Decloedt et al.10 presented a paper in Theme 5 – “Sports Doping: First Past the Post before Veterinary Drug Abuse –Show Cows and Race Horses” to highlight a situation that might be construed to be cheating as a result of feeding the race horse with mouldy corn (poor feed quality) or a herbal phyto-supplement. In the race-horse industry, all substances that are not allowed to be used in treating a horse in competition including most anabolic-androgenic steroids are clearly listed and posted. As zero-tolerance regulation is enforced, a question arose if the consumption of mouldy corn feed could lead to the excretion of steroids, due to the biotransformation of plant phytosterols to steroids that would lead to the implication of cheating when these are detected in the race horse. The authors used a rapid UHPLC-MS/MS analytical method, previously validated according to the Association of Official Racing Chemists (AORC) and European Commission (EC) guidelines, to measure steroids in different sample types and found that mouldy corn can develop concentrations of up to 3.0 ± 0.4 µg/kg 4-androstenedione. An herbal phyto-supplement was also shown to contain α-testosterone. The authors strongly recommended caution against the consumption of any feed or (herbal) supplement of which the detailed ingredients and quantitative analysis are unknown. Boison et al.11 presented a study which showed that the recovery of phenylbutazone (PBZ) and oxyphenbutazone (OXPBZ) residues from equine tissues are improved with the addition of a β-glucuronidase enzyme hydrolysis step. In the absence of enzymatic hydrolysis, liver tissue obtained from the horse sacrificed 6 days post dose contained the highest concentration of PBZ followed by kidney and muscle. With the additional enzymatic hydrolysis step in the sample preparation procedure, the recovery of PBZ was elevated by about a factor of 1.3 in liver, 1.4 in kidney, and 4.7 times in muscle tissues. The concentration of OXPBZ residues was highest in the kidney followed by liver but it was below the limit of quantification (LOQ) of the method for muscle using their previously published method without enzymatic hydrolysis. The authors, therefore, strongly recommended that methods developed for the analysis of PBZ and its OXPBZ metabolite consider the inclusion of this enzyme hydrolysis step. Talking about the use and monitoring of antimicrobial use in food animals without the issue of antimicrobial resistance is almost impossible. All too often though, we as chemists think we are doing a very good job by being able to measure as low as possible of the residues in the food animal. The microbiologists also believe that they are doing a very good job identifying the end points for assessment of antimicrobial resistance and communicating that information that the development of antimicrobial resistance in bacteria and the human population is on the rise sometimes making claims that this could be contributed by the consumption of low levels of antimicrobials in the foods of animal origin that consumers are exposed to. What we haven't done well yet is for both teams to come together and develop strategies to look at the issue collectively. Also to be included in this exercise is the toxicologists and policy decision-makers. We were very fortunate at this Workshop to have all the relevant groups together. So, under Theme 6 – Antibiotics in the Environment, Food Chain, Aquatic and Food Animal Production: Is There a Link to Antibiotic Resistance? – Cerniglia et al.12 provided the workshop participants with the most current update of the concern that antimicrobial new animal drugs in or on animal-derived food products at residue-level concentrations could disrupt the colonization barrier and/or modify the antimicrobial resistance profile of human intestinal bacteria. Therapeutic doses of antimicrobial drugs have been shown to promote shifts in the intestinal microbiome, and these disruptions promote the emergence of antimicrobial-resistant bacteria. To assess the effects of antimicrobial new animal drug residues in food on human intestinal bacteria, many national regulatory agencies and international committees follow a harmonized process, VICH GL36(R). The authors provide an overview of this current approach as part of the antimicrobial new animal drug approval process in participating countries, insights on the microbiological endpoints used in this safety evaluation, and the availability of new information. Daeseleire et al.13 describe some general aspects of antibiotic resistance such as microbiological versus clinical resistance, intrinsic versus acquired resistance, resistance mechanisms and transfer of resistance are briefly introduced and follow that with a description of a Belgian mission founded in 2012 to collect and analyze all data related to antibiotic use and resistance in animals in Belgium and to communicate these findings in a neutral and objective manner. One of the 10 objectives of the mission was to develop strategies that will result in a 50% reduction in antibiotic consumption in veterinary medicine in Belgium by 2020. The authors report on the achievements of this national project and described in detail the project undertaken by the Belgian Government in order to accomplish this mission. Fish and other aquatic organisms have become an increasingly important source of food for human consumption, and the practice of aquaculture is growing and evolving as is the need to develop safe and effective drugs for treating fish diseases. In order to control diseases and to improve production, farmers use various resources including veterinary drugs, vaccines, immune-stimulants, etc. The challenge of sustainable aquaculture is to contribute to the national objectives for economic development and food security while simultaneously addressing the goals of reducing poverty and increasing environmental protection. The industry has historically depended on the use of veterinary drugs, but in response to the increasing concerns of environmental sustainability and consumer preference for safe food, the sector has begun to realize the potential risk associated with the irresponsible use of these products. Many veterinary drugs are used in both the aquaculture and livestock industries, as well as being available in formulations suitable for human treatments. That the issues of antimicrobial use in food animal production are of global concern is well recognized. In Asian countries, it is common to find fish farms integrated with animal houses and agricultural land which could lead to environmental contamination via unintended residues of drugs or pesticides in foods leading to an increase in antimicrobial resistance. To minimize environmental contamination by the effective use of drugs for aquatic animals, it is important to understand the aquaculture system which includes the life cycle of the aquatic animal, feed, disease and the environment. The study of the fate of a drug in the environment can provide a lot of information which includes dissipation time, the identification of degradation or metabolic products by photolysis, hydrolysis, and microbial degradation, and the distribution related to adsorption onto sediment or soil. An understanding of the fate of veterinary drugs administered to fish in aquatic systems might aid in more effective prevention and treatment of diseases of aquatic animals, for environmental conservation and for food safety. Kwon14 describes a study that was conducted to investigate the fate of erythromycin and oxolinic acid in aquatic systems for the effective use of remedies, prevention of fish diseases and environmental conservation which reflect the marine and fresh water aquaculture systems in Korea. All veterinary drugs used in food animal production have to be subjected to extensive clinical trials and metabolism studies in a number of laboratory animals and the food animal prior to their being registered and licensed for use in food animal production. The studies that need to be completed in the process are very well laid out and in all the studies there is a requirement to use suitably sensitive methods for the studies being conducted. Under Theme 7 – Pharmacokinetics and Depletion Studies – Sanders et al.15 reviewed the general principles and methods for chemical risk assessment described in Environmental Health Criteria 240, Principles and methods for the risk assessment of chemicals in food approaches which the Joint WHO/FAO of the UN Expert Committee on Food Additives (JECFA), follows to conduct risk assessments. Following a request from the CCRVDF, JECFA will assess veterinary drugs which are currently used under national marketing authorization or unregulated compounds which are used as a veterinary treatment (e.g. dyes). The authors described the different pharmacokinetic analysis tools used by JECFA to assess all compounds used as drugs referred to JECFA. Good Laboratory Practice (GLP) is a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. Croubels et al.16 describe the GLP principles applicable for veterinary drug registration and licensing purposes First, a general overview of the GLP requirements is given, followed by a more specific comparison and discussion of the analytical method validation parameters and acceptance criteria of different international guidelines applied in the context of veterinary drug pharmacokinetic and residue depletion studies. Finally, the authors identified some needs with respect to method validation and highlighted some new developments in pharmacokinetic and residue depletion studies. Boison17 described the role validated analytical methods play in the risk assessment evaluations conducted by JECFA and points out that the work of JECFA will never be complete without the availability of suitably validated analytical methods. In the final manuscript Boison et al.18 describe a method that was validated and used for the depletion study of tulathromycin residues in bison and deer sera as well as selected tissues of white-tailed deer.

Poverty and antibiotic misuse: a complex association

Herd-level association between antimicrobial use and antimicrobial resistance in bovine mastitis Staphylococcus aureus isolates on Canadian dairy farms

EFSA's assistance for the 2015 Codex Committee on Residues of Veterinary Drugs in Food (CCRVDF) in relation to rBST

Antimicrobial resistance (AMR) is a global health threat, and antimicrobial use and environmental contamination, particularly in food animal production settings, are important contributors, among many others. We explore the critical role that farm environments play in shaping AMR dynamics, particularly within the rapidly expanding poultry sector, which is growing to meet the increasing global demand for animal protein. Despite the implementation of practices aimed at reducing antimicrobial use in poultry, the continued presence of antimicrobial residues and resistant bacteria in poultry farm environments may still contribute to the persistence and spread of AMR. Current surveillance efforts primarily focus on retail meat and slaughterhouse samples, neglecting environmental reservoirs. Expanding surveillance to include farm environments is crucial to understanding AMR dynamics. We also emphasize the challenges involved in measuring AMR and suggest that integrating multiple methodologies may offer a more comprehensive understanding of AMR dynamics in farm environments. Integrating environmental monitoring into AMR surveillance strategies within the One Health framework can enhance the identification of critical control points in both agricultural and environmental settings that contribute to the spread of AMR and develop more targeted mitigation strategies.