Ciprofloxacin-resistant variants of Listeria monocytogenes EGD-e show increased heat resistance in buffer and milk

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.

Antimicrobial Use and Resistance in Pigs and Chickens: A Review of the Science, Policy and Control Practices from Farm to Slaughter – Executive Summary

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.

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. A in which antibiotics no work is that should As an schemes on antibiotics may also antibiotic development by the pharmaceutical industry or biotechnology for on antibiotics, as further will only the A. Antibiotics in the The New York A. to the from Resistant to the of the United Health at Antibiotic The Centers for Disease A. Antibiotics in the The New York and Antibiotic and – Health Antibiotic and of an Ethical in Health use in Agriculture and in Environmental Health – Health Ethical of Health Health resistance genes from livestock and resistance genes from livestock and resistance genes from livestock and resistance genes from livestock and use in Agriculture and in Environmental Health resistance genes from livestock and use in Agriculture and in Environmental Health on Antibiotic in The Environmental Working at in the A of Environmental and resistance genes from livestock and use in Agriculture and in Environmental Health use in Agriculture and in Environmental Health Antibiotic and use in Agriculture and in Environmental Health Addressing antibiotic resistance from a global will developing nations in and developing rules and enforcement around antibiotic use in humans and animals. 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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.

Resistance to antimicrobial agents develops soon after these life-saving drugs are introduced into human and animal medicine. The role of veterinary and animal use of antimicrobial agents has been debated for years. Frank Aarestrup and colleagues attempt to summarize information concerning this topic in their new book, Antimicrobial Resistance in Bacteria of Animal Origin. This book has 51 contributors, who have written 25 chapters on the public health, clinical, and regulatory importance of antimicrobial drug resistance in bacteria of animal origin. The editor recognizes the complexity of this subject and makes no claims to cover all the issues but rather highlights what he and the contributors believe to be the most important topics. The first 6 chapters highlight modes of action and resistance, history of usage, susceptibility testing, antimicrobial-drug resistance for antimicrobial agents, detection methods, dosing schedules, and mechanisms that lead to the spread of bacterial resistance. These chapters provide the reader with very detailed molecular and genetic information on resistance mechanisms in bacteria of animal origin. Knowing the pharmacodynamics and pharmacokinetics of antimicrobial agents is essential for these drugs to be used correctly, and a good overview of these mechanisms is also provided in these beginning chapters. The book also stresses the urgent need for establishing veterinary-validated breakpoints for species-specific host-pathogen combinations that are clinically relevant. Some of the tables and diagrams in these chapters contain a large amount of material and need to be read carefully to understand the total wealth of information. The 12 middle chapters provide an in-depth review of the known resistance mechanisms found in most of the pathogenic bacteria and bacteria of public health importance in animals. Each chapter takes a closer look at a particular family, genus, or species of bacteria and, when possible, attempts to estimate the prevalence of resistance to key antimicrobial agents. The information provided in these chapters is useful to clinicians, researchers, public health officials, and regulators. For some zoonotic agents, the animal health consequences of resistance are not known. For future editions, expanding on this topic would be helpful. The last 7 chapters attempt to tie all of the previous information together by providing an overview of the licensing and approval procedures for veterinary antimicrobial agents, surveillance systems that monitor resistance and usage, and the use of risk assessments to guide industry and government in decision making. These chapters take a global approach. When possible, side-by-side comparisons of resistance data or surveillance systems are discussed. This book is the first of its kind to provide a comprehensive overview of resistance mechanism in bacteria of animal origin rather than concentrating solely on zoonotic or foodborne bacteria. All uses of antimicrobial agents contribute to resistance, and each use must be examined in an attempt to understand its part in encouraging further dissemination of resistance in bacteria, including bacteria of animal origin. This book will serve as a valuable reference for persons who treat, research, or monitor resistance in bacteria of animal origin.

Antimicrobial resistance in bacteria from animals and the environment

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

EFSA Supporting PublicationsVolume 12, Issue 12 914E Technical reportOpen Access Annual report of the Scientific Network on Microbiological Risk Assessment 2015 European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author First published: 11 December 2015 https://doi.org/10.2903/sp.efsa.2015.EN-914 Published date: 11 December 2015 Question number: EFSA-Q-2015-00739 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References ECDC (European Centre for Disease Prevention and Control), 2015. Best practices in ranking emerging infectious disease threats. Available at: http://ecdc.europa.eu/en/publications/Publications/emerging-infectious-disease-threats-best-practices-ranking.pdf EFSA (European Food Safety Authority), 2013. Analysis of the baseline survey on the prevalence of Listeria monocytogenes in certain ready-to-eat foods in the EU, 2010–2011 Part A: Listeria monocytogenes prevalence estimates. EFSA Journal 2013; 11(6):3241, 75 pp. doi:10.2903/j.efsa.2013.3241 EFSA (European Food Safety Authority), 2014. Analysis of the baseline survey on the prevalence of Listeria monocytogenes in certain ready-to-eat foods in the EU, 2010–2011 Part B: analysis of factors related to prevalence and exploring compliance. EFSA Journal 2014; 12(8):3810, 73 pp. doi:10.2903/j.efsa.2014.3810 EFSA (European Food Safety Authority), 2015a. An update on the risk of transmission of Ebola virus (EBOV) via the food chain – Part 2. EFSA Journal 2015; 13(3):4042, 17 pp. doi:10.2903/j.efsa.2015.4042 EFSA (European Food Safety Authority), 2015b. The European Union summary report on trends and sources of zoonoses, zoonotic agents and food-borne outbreaks in 2013. EFSA Journal 2015; 13(1):3991, 165 pp. doi:10.2903/j.efsa.2015.3991 EFSA (European Food Safety Authority), 2015c. Scientific and technical assistance on the evaluation of the temperature to be applied to pre-packed fishery products at retail level. EFSA Journal 2015; 13(7):4162, 48 pp. doi:10.2903/j.efsa.2015.4162 EFSA (European Food Safety Authority), 2015d. EU Summary Report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2013. EFSA Journal 2015; 13(2):4036, 178 pp. doi:10.2903/j.efsa.2015.4036 EFSA (European Food Safety Authority), 2015e. ECDC/EFSA/EMA first joint report on the integrated analysis of the consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food-producing animals. EFSA Journal 2015; 13(1):4006, 114 pp. doi:10.2903/j.efsa.2015.4006 EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), 2012. Scientific Opinion on the development of a risk ranking framework on biological hazards. EFSA Journal 2012; 10(6):2724, 88 pp. doi:10.2903/j.efsa.2012.2724 EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), 2014. Scientific Opinion on the risk posed by pathogens in food of non-animal origin. Part 2 (Salmonella, Yersinia, Shigella and Norovirus in bulb and stem vegetables, and carrots). EFSA Journal 2014; 12(12):3937, 91 pp. doi:10.2903/j.efsa.2014.3937 EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), 2015a. Scientific Opinion on the development of a risk ranking toolbox for the EFSA BIOHAZ Panel. EFSA Journal 2015; 13(1):3939, 131 pp. doi:10.2903/j.efsa.2015.3939 EFSA BIOHAZ Panel (EFSA Panel on Biological Hazards), 2015b. Scientific Opinion on the public health risks related to the consumption of raw drinking milk. EFSA Journal 2015; 13(1):3940, 95 pp. doi:10.2903/j.efsa.2015.3940 EFSA (European Food Safety Authority) and ECDC (European Centre for Disease Prevention and Control), 2015. Technical report on a fatal human case of Bacillus anthracis infection and bovine meat contamination in Bulgaria. First update, 7 August 2015. EFSA supporting publication 2015:EN-863. 4 pp. EFSA Scientific Committee, 2015. Risk profile related to production and consumption of insects as food and feed. EFSA Journal 2015; 13(10):4257, 60 pp. doi:10.2903/j.efsa.2015.4257 Volume12, Issue12December 2015914E ReferencesRelatedInformation

Antimicrobial resistant zoonotic pathogens present on food constitute a direct risk to public health. Antimicrobial resistance genes in commensal or pathogenic strains form an indirect risk to public health, as they increase the gene pool from which pathogenic bacteria can pick up resistance traits. Food can be contaminated with antimicrobial resistant bacteria and/or antimicrobial resistance genes in several ways. A first way is the presence of antibiotic resistant bacteria on food selected by the use of antibiotics during agricultural production. A second route is the possible presence of resistance genes in bacteria that are intentionally added during the processing of food (starter cultures, probiotics, bioconserving microorganisms and bacteriophages). A last way is through cross-contamination with antimicrobial resistant bacteria during food processing. Raw food products can be consumed without having undergone prior processing or preservation and therefore hold a substantial risk for transfer of antimicrobial resistance to humans, as the eventually present resistant bacteria are not killed. As a consequence, transfer of antimicrobial resistance genes between bacteria after ingestion by humans may occur. Under minimal processing or preservation treatment conditions, sublethally damaged or stressed cells can be maintained in the food, inducing antimicrobial resistance build-up and enhancing the risk of resistance transfer. Food processes that kill bacteria in food products, decrease the risk of transmission of antimicrobial resistance.

The presence of antimicrobial resistant foodborne bacteria is a major food safety challenge for food that is consumed raw. Abuse and overuse of antibiotics in the agriculture sector has been identified as a contributory factor to the rising threat of antibiotic resistance. In many developing countries where milk is marketed and consumed raw through informal channels, the occurrence of bacterial contamination is high and poses a major public health risk. This situation is exacerbated when caused by antimicrobial resistant bacteria. Hence this study was conducted to determine the antimicrobial resistant pattern of bacteria in raw cow milk and milk products retailed in the Northern Region of Ghana. Antibiotic resistance profiles were established for 150 bacteria isolates (Escherichia coli, E. coli O157:H7, Klebsiella pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella spp. Shigella spp. and Proteus spp.) obtained from the culture of raw milk (n=210) and milk products (n=60) retailed within the Northern region of Ghana. Susceptibility to nine antimicrobials commonly used in veterinary and human medical practice was performed on all the isolates using the agar disc diffusion method according to Clinical and Laboratory Standards Institute guidelines. Isolates showed highest resistance to Nalidixic acid followed by Chloramphenicol, Gentamicin, Trimethoprim-sulfamethoxazole and Ceftriaxone but were most susceptible to Ciprofloxacin and Ampicillin. About 25 – 47.6 % of Staphylococcus aureus showed resistance to Cefoxitin. Milk and milk products sold in the northern region of Ghana are contaminated with bacterial pathogens with high levels of antimicrobial resistance. A one health approach is required to curtail the threat of antibacterial resistant bacteria in the food chain.

In recent years, the sudden increase in the prevalence of antimicrobial-resistant bacteria and the emergence of multidrug-resistant bacteria have become serious worldwide problems. Therefore, in 2000, the World Health Organization (WHO) declared antimicrobial resistance to be an international danger, and has been working with its member nations to promote the appropriate use of antimicrobials as a solution to the antimicrobial resistance threat [1]. The recent emergence of New Delhi metallo-β-lactamase carbapenem-resistant Enterobacteriaceae has motivated us to increase our alertness to antimicrobial-resistant organisms [2]. Thus, surveillance of healthcare-associated infection has been enhanced. Surveillance for antimicrobial resistance is being executed mainly in European countries and in the U.S. In Korea, with the enactment of the Infectious Disease Control and Prevention Act in December 2010, infectious diseases caused by 6 types of multidrug-resistant bacteria-vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, methicillin-resistant S. aureus, multidrug-resistant Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae-were legally designated for sentinel surveillance [3]. The prevalence of antimicrobial resistance in bacteria varies substantially from country to country and according to the date of the analysis and the hospital characteristics, because it is influenced significantly by the use of antimicrobial drugs and the degree of success of efforts to control the spread of resistant bacteria. The purposes of an antimicrobial resistance surveillance system (ARSS) are as follows: (1) to detect antimicrobial susceptibility patterns; (2) to monitor the identity, transmission, and expression of antimicrobial-resistance genes; (3) to provide important information on the development of bacterial resistance mechanisms in different regions; and (4) to allow changes in antimicrobial prescription practices and participation of infection control professionals. Well-designed antimicrobial resistance surveillance systems are needed when fighting bacterial resistance. The parameters of an ideal ARSS are as follows: global geography, year-on-year longevity, multiple species selection, centralized methods and test sites, large sample size, monitoring for many antimicrobial drugs, incorporation of epidemiology, and frequent data distribution [4]. Implementation of an ARSS requires 4 components: administrative commitments, system organization (participant, expert, and coordinator), financial support (from government agencies and the pharmaceutical industry), and data analysis and reporting systems (online and offline). The scope of ARSS networks is divided into global, continental, and nationwide. The global representative ARSSs are the Alexander Project, MYSTIC Program, SENTRY Program, PROTEKT System, and WHO Program. The European ARSS (EARSS; EARS-Net) is the surveillance system implemented in Europe, and the ARSSs available in the U.S. are the National Nosocomial Infections Surveillance, Intensive Care Antimicrobial Resistance Epidemiology, National Antimicrobial Resistance Monitoring System, International Surveillance Program for Emerging Antimicrobial Resistance, and Surveillance for Emerging Antimicrobial Resistance Connected to healthcare. In Korea, the nationwide ARSSs are the Korean Nationwide Surveillance of Antimicrobial Resistance (KONSAR), Korean Nosocomial Infections Surveillance System, and Korean Antimicrobial Resistance Monitoring System. Since 1997, the KONSAR program has been collecting data on antimicrobial-resistant bacteria from participating laboratories [5], and has therefore played an integral role in informing interested parties about the current state and severity of domestic antimicrobial resistance in bacteria by analyzing and reporting bacterial antimicrobial susceptibility data. However, the KONSAR program releases all its laboratory data to research papers or newsletters only after analysis; therefore, a web-based system that can analyze data in real time is needed [6]. To create such a system, a knowledge-based rule check system capable of detecting errors by setting the exact data variables as the definition of the specimen, the species identification method, and the antimicrobial susceptibility test methods must be defined. Furthermore, various analysis functions such as data comparison between entire hospitals and participating laboratories, and between peer groups, must be made possible on the internet. According to a recent KONSAR report [7], susceptibility to antimicrobials, including colistin, was analyzed without dividing Acinetobacter spp. into A. baumannii and non-baumannii Acinetobacter. This is a problem that has yet to be resolved. At the government level, blaOXA-23-like or ISAba1-activated blaOXA-51-like gene tests for detecting carbapenem-resistant A. baumannii need to be supported. For manufacturers that supply identification kits and for clinical microbiology laboratories, the development of testing methods that can accurately identify A. baumannii is also needed.

Opportunities and challenges in managing antibiotic resistance in bacteria using plant secondary metabolites

Exposure to antimicrobial resistant (AMR) bacteria is a major public health issue which may, in part, have roots in food production practices that are conducive to the selection of AMR bacteria ultimately impacting the human microbiome through food consumption. Of particular concern is the prophylactic use of antibiotics in animal husbandry, such as the medication of feeds with sulfonamides and other antibiotics not considered clinically relevant, but which may nonetheless co-select for multi-drug resistant (MDR) bacteria harboring resistance to medically important antibiotics. Using a MDR Klebsiella pneumoniae strain exhibiting resistance to sulfonamides and beta-lactams (including carbapenem) as a model, we examined the ability of non-medicated and commercially medicated (sulfonamide) animal feeds to select for the model strain when inoculated at low levels by measuring its recovery along with key AMR markers, sul1(sulfonamide) and blaKPC-3 (meropenem), under different incubation conditions. When non-medicated feeds were supplemented with defined amounts of sulfadiazine the model strain was significantly enriched after incubation in Mueller Hinton Broth at 37°C overnight, or in same at room temperature for a week, with consistent detection of both the sul1 and blaKPC-3 markers as determined by polymerase chain reaction (PCR) techniques to screen colony isolates recovered on plating media. Significant recoveries of the inoculated strain and the sul1 and blaKPC-3 markers were observed with one of three commercially medicated (sulfamethazine) feeds tested under various incubation conditions. These results demonstrate that under certain conditions the prophylactic use of so-called non-priority antibiotics in feeds can potentially lead to co-selection of environmental AMR bacteria with resistance to medically important antibiotics, which may have far-reaching implications for human health.

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.