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WHO guidelines on use of medically important antimicrobials in food-producing animals

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WHO guidelines on use of medically important antimicrobials in foodproducing animals

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WHO guidelines on use of medically important antimicrobials in food-producing animals ISBN 978-92-4-155013-0 Formatted: Left

© World Health Organization 2017 Some rights reserved. This work is available under the Creative Commons AttributionNonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for noncommercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. WHO guidelines on use of medically important antimicrobials in foodproducing animals. Geneva: World Health Organization; 2017. Licence: CC BY-NCSA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout: Blossoming.it Printed in Switzerland 2

Deleted: ¶ ¶ ¶ © World Health Organization 2017¶ Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/bync-sa/3.0/igo). ¶ Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. ¶ Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization.¶ Suggested citation. WHO Guideline on Use of Medically Important Antimicrobials in Food-Producing Animals. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO.¶ Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.¶ Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. ¶ Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user.¶ General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal ...

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Contents Acknowledgements................................................................................................................................. 5 Acronyms and Abbreviations .................................................................................................................. 6 Glossary of Terms.................................................................................................................................... 7 Executive summary ................................................................................................................................. 9 Background ............................................................................................................................................. 9 An important food safety issue ..................................................................................................... 14 Rising public health concern about use of antimicrobials in food-producing animals ................ 15 Response to concern about use of antimicrobials in food-producing animals ............................ 16 The WHO critically important antimicrobial list (WHO CIA List) ................................................... 17 Previous WHO recommendations relevant to these guidelines .................................................. 19 Relevant recommendations by external organizations ................................................................ 20 Rationale for, and objectives of, these guidelines ............................................................................ 21 Who should use these guidelines? ................................................................................................... 22 Methods ................................................................................................................................................ 22 Priority questions .............................................................................................................................. Page number will be updated, once the design22 Identification of critical and important outcomes ........................................................................ 23 elements are incorporated Systematic review search strategies ................................................................................................. 23 Assessment of the evidence ............................................................................................................. 24 Formulation of recommendations .................................................................................................... 25 Setting the strength of the recommendations ............................................................................. 25 Decision-making during GDG meetings ........................................................................................ 26 Peer review and finalization of these guidelines .......................................................................... 26 Best practice statements and recommendations ................................................................................. 26 Recommendations ............................................................................................................................ 27 RECOMMENDATION 1: Overall antimicrobial use ............................................................................ 28 RECOMMENDATION 2: Growth promotion use ............................................................................... 29 RECOMMENDATION 3: Prevention use (in the absence of disease) ................................................ 31 RECOMMENDATION(s) 4: Treatment and control use (in the presence of disease) ........................ 32 Contributors and their role in the development of these guidelines ................................................... 35 WHO Steering Group ........................................................................................................................ 35 Guideline Development Group ......................................................................................................... 35 Systematic review teams .................................................................................................................. 35 Narrative literature reviewers ...................................................................................................... 36 External Review Group ..................................................................................................................... 36 Management of conflicts of interests ............................................................................................... 36 Dissemination and implementation of these guidelines ...................................................................... 36

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21 September 2017 Dissemination ................................................................................................................................... 37 Monitoring and evaluation ............................................................................................................... 37 Research gaps ....................................................................................................................................... 37 Updating these guidelines .................................................................................................................... 38 References ............................................................................................................................................ 39 Annex 1: External experts and WHO staff involved in development of these guidelines .................... 42 Annex 2: Summary and management of declared secondary interests ............................................... 48 Annex 3: Critical and important outcomes for decision-making .......................................................... 52 Annex 4: Summaries of systematic reviews including supplementary report ..................................... 57 Summary of supplementary report of systematic review and Meta-Analysis #3 ............................ 59 Annex 5: Summaries of the narrative literature reviews...................................................................... 63

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Additional Web Annex (available at www.who.int/xxxxxxx) Contents: 1. Evidence-to-Recommendations Tables 2. Evidence Profile Tables 3. Summary of Findings Tables 4. Narrative Evidence Summary of Systematic Reviews

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Acknowledgements WHO would like to thank the many individuals who contributed to these guidelines, especially Hanan Balkhy, Peter Collignon, John Conly, Cindy Friedman, Aidan Hollis, Samuel Kariuki, Hyo-Sun Kwak, Scott McEwen, Gérard Moulin, Antoinette Ngandjio, Bernard Rollin, Flavia Rossi, and David Wallinga who served as members of the Guideline Development Group (GDG); Peter Collignon for serving as Chair at the first GDG meeting in October 2016; and to both Scott McEwen and Peter Collignon for serving as Co-Chairs at the second GDG meeting in March 2017. WHO appreciates the contribution of participants at the February 2016 guideline scoping meeting, including members of the WHO Advisory Group of Integrated Surveillance for Antimicrobial Resistance (AGISAR). Several groups and individuals gathered and presented evidence that the GDG considered in the development of these guidelines. Two research teams, one at Bond University in Australia, led by Chris Del Mar, and the other at the University of Calgary in Canada, led by William Ghali, conducted systematic reviews on the effects of restrictions on the use in food-producing animals of medically important antimicrobials on antimicrobial resistance in bacteria isolated from food-producing animals and humans. Hattie Webb conducted a narrative literature review on transfer of antimicrobial resistance determinants from food-producing animals to humans. Scott McEwen led a narrative literature review on the potential unintended consequences associated with restrictions on antimicrobial use in food-producing animals. Ellen Silbergeld provided a narrative literature review on molecular mechanisms of antimicrobial resistance and associations between antimicrobial use in food-producing animals and human exposures to, and infections by, antimicrobial-resistant pathogens. John Conly and Mauricio Ferri served as Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodologists, and prepared the evidence profiles tables, summary of findings tables, narrative evidence summaries, and the outcomes and ratings questionnaire. Frederick Angulo Additional thanks go to the external review group, which included Saeed Murie Al-Shahrani, Casey Barton Behravesh, Delia Grace, Dik Mevius, Paturkar Ashish Motiram, Hnin Thidar Myint, Langelihle Simela, Linda Tollefson, Jan L. M. Vaarten, Haruo Watanabe, and Khadija Id Sidi Yahia. WHO also acknowledge the contributions of Henk Jan Ormel from the Food and Agriculture Organization of the United Nations and Elisabeth Erlacher-Vindel of the World Organisation for Animal Health, who served as special members of the WHO Steering Group. Assistance and guidance was provided by Susan Norris of the secretariat of the WHO Guideline Review Committee throughout the development and finalization of these Guidelines. Funding The Government of the Netherlands, Government of Japan, Government of the United Kingdom, and the Government of United States of America provided financial support for this work. The views of the funding bodies did not influence the development or content of this guideline. Deleted: this Deleted:

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Acronyms and Abbreviations AFRO: Regional Office for Africa AGISAR: WHO Advisory Group on Integrated Surveillance for Antimicrobial Resistance AMRO: Regional Office for the Americas CINAHL: Cumulative Index to Nursing and Allied Health Literature COI: Conflict of Interest DOI: Declaration of Interest EMBASE: Excerpta Medica database ERG: External Review Group EURO: Regional Office for Europe FAO: Food and Agriculture Organization of the United Nations FERG: Foodborne Diseases Epidemiology Reference Group GDG: Guideline Development Group GRADE: Grading of Recommendations Assessment, Development and Evaluation GREAT: Guideline-driven Research Priorities Evidence Synthesis Application of Evidence Transfer of Knowledge IndMED: Indexing of Indian Medical Journals LILACS: Latin American and Caribbean Health Sciences Literature MEDLINE: Medical Literature Analysis and Retrieval System Online OIE: World Organisation for Animal Health OIE List: OIE List of Antimicrobials of Veterinary Importance PICOTS: Population, intervention, comparison, outcome, time, setting SEARO: Regional Office for South-East Asia UN: United Nations WPRO: Regional Office for the Western Pacific WHO CIA List: WHO list of Critically Important Antimicrobials for Human Medicine

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Glossary of Terms Antimicrobial: A medicine that inhibits the growth of or destroys microorganisms. For the purposes of these guidelines, “antimicrobial” is considered an equivalent term to “antibiotic.” Clinically diagnosed disease: Disease diagnosed by a veterinary professional based upon clinical judgement supported when appropriate by bacteriological testing. For the purposes of these guidelines, appropriate use of bacteriological testing is the use of culture and sensitivity test results to justify the use of a medically important antimicrobial for disease prevention. Food-producing animals: Animals used in production of food. The term ‘food-producing animals’ includes all terrestrial and aquatic animals (that is, includes aquaculture) used to produce food. For the purposes of these guidelines, ‘food-producing animals’ is considered an equivalent term to ‘food animals.’ Medically important antimicrobials: Antimicrobials used in human medicine, and therefore listed on the WHO CIA List. Medically important antimicrobials are categorized on the WHO CIA List, according to specified criteria, as “important”, “highly important” or “critically important” for human medicine. Categorization criteria, definitions for the categories and a complete list of medically important antimicrobials are available on the WHO website1. Critically important antimicrobial: Antimicrobials in an antimicrobial class providing the sole therapy, or one of limited available therapies, to treat serious bacterial infections in humans AND used to treat infections in humans caused by either: (1) bacteria that may be transmitted to humans from nonhuman sources, or (2) bacteria that may acquire resistance genes from nonhuman sources. Several of the antimicrobial classes rated critically important have been further classified as ‘highest priority critically important antimicrobials’. A complete list of critically important antimicrobials is available on the WHO website1. Highest priority critically important antimicrobial: A critically important antimicrobial belonging to an antimicrobial class that meets three criteria. 1. It is used for treating infections in high absolute numbers of humans, or is commonly used in healthcare settings to treat patients with serious bacterial infections for which the antimicrobial class is the sole, or one of few alternatives, to treat serious infections in humans. 2. It is frequently used for any indication in human medicine, or else is commonly used in patients with serious infections in healthcare settings. 3. It is used to treat infections in humans for which there is evidence of transmission of resistant bacteria or resistance genes from non-human sources to humans. A complete list of highest priority critically important antimicrobial is available on the WHO website1. Growth promotion use of antimicrobials in food-producing animals: Growth promotion use of antimicrobials refers to the use of antimicrobials to increase the rate of weight gain and/or the efficiency of feed utilization in animals by other than purely nutritional means. The term does not apply to the use of antimicrobials for the specific purpose of treating, controlling, or preventing infectious diseases, even when an incidental growth response may be obtained2. Disease prevention use (or prophylactic use) of antimicrobials in food-producing animals: Disease prevention use (or prophylactic use) of antimicrobials refers to use of antimicrobials in healthy animals considered to be at risk of infection or prior to the onset of clinical infectious disease. This includes use for control of the dissemination of a clinically diagnosed infectious disease identified 1

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Deleted: is Deleted: Antimicrobials justified by culture and sensitivity results should be used in reverse order to their importance for human health, as listed on the WHO CIA List. Use of critically important antimicrobials should only be considered when recent culture and sensitivity results indicate that the critically important antimicrobial is the only treatment option. Deleted: this

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WHO list of Critically Important Antimicrobials (CIA) http://www.who.int/foodsafety/areas_work/antimicrobial-resistance/cia/en/

21 September 2017 within a group of animals, and prevention of an infectious disease that has not yet been diagnosed clinically2. Treatment use (or therapeutic use) of antimicrobials in food-producing animals: Treatment use (or therapeutic use) of antimicrobials refers to use of antimicrobials for the specific purpose of treating an animal(s) with a clinically diagnosed infectious disease or illness 2.

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Codex Alimentarius, Texts on Foodborne Antimicrobial Resistance, 2015 http://www.fao.org/3/a-i4296t.pdf

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Executive summary In May 2015, the Sixty-eighth World Health Assembly recognized the importance of the public health problem posed by antimicrobial resistance by adopting the global action plan on antimicrobial resistance (‘global action plan’). The global action plan proposes interventions to control antimicrobial resistance, including reducing the unnecessary use of antimicrobials in humans and in animals. The global action plan also emphasizes the need to take a cross-sectoral, ‘One Health’ approach for controlling antimicrobial resistance, involving efforts by actors from many disciplines including human and veterinary medicine. Recognizing the urgent need for cross-sectoral action to address antimicrobial resistance, the assemblies of the Food and Agriculture Organization of the United Nations (FAO) and World Organisation for Animal Health (OIE) also adopted resolutions supporting the global action plan on antimicrobial resistance in 2015. Many antimicrobials used in food-producing animals are identical, or closely related, to antimicrobials used in humans. Most antimicrobials used in plant production, including orchards, are also identical, or closely related, to antimicrobials used in humans. Antimicrobials are used to treat and control bacterial infections in the presence of disease and for disease prevention and growth promotion in the absence of disease. Antimicrobial use in food-producing animals can lead to selection and dissemination of antimicrobial-resistant bacteria in food-producing animals, which can then be transmitted to humans via food and other transmission routes. Why are these guidelines needed? The development of these guidelines were driven by the need to mitigate the adverse human health consequences of use of medically important antimicrobials (i.e. antimicrobials used in humans) in food-producing animals. In 2005, a WHO expert committee was set up to establish criteria for classifying medically important antimicrobials as important, highly important, or critically important for human medicine. These criteria were then used to establish the WHO List of Critically Important Antimicrobials for Human Medicine (WHO CIA List), which has since been updated regularly. WHO published the fifth revision of the WHO CIA List in 2017. These guidelines present evidence-based recommendations on use of medically important antimicrobials in food-producing animals, based on the WHO CIA List. These guidelines aim to help preserve the effectiveness of medically important antimicrobials, particularly those antimicrobials judged to be critically important to human medicine and help preserve the effectiveness of antimicrobials for veterinary medicine , in direct support of the WHO Global Action Plan on Antimicrobial Resistance. How were these guidelines developed? These guidelines were developed using the WHO guideline development process described in the WHO Handbook for Guideline Development (second edition). These included: (i) identification of priority questions and critical outcomes; (ii) retrieval of the evidence in a transparent manner using standard methods for systematic reviews; (iii) narrative literature reviews produced by topic-expert scientists; (iv) assessment and synthesis of the evidence; (v) use of this evidence for the formulation of recommendations; (vi) planning for dissemination, implementation, impact evaluation and future updating of the guideline. The process of the guideline development was managed by the WHO Steering Group, while the Guideline Development Group (GDG) consisting of external experts was responsible for the drafting 9

Deleted: Executive summary¶ ¶ In May 2015, the Sixty-eighth World Health Assembly recognized the importance of the public health problem posed by antimicrobial resistance by adopting the global action plan on antimicrobial resistance (‘global action plan’). The global action plan proposes interventions to control antimicrobial resistance, including reducing the unnecessary use of antimicrobials in humans and in animals. The global action plan also emphasizes the need to take a crosssectoral, ‘One Health’ approach for controlling antimicrobial resistance, involving efforts by actors from many disciplines including human and veterinary medicine. Recognizing the urgent need for cross-sectoral action to address antimicrobial resistance, the assemblies of the Food and Agriculture Organization of the United Nations (FAO) and World Organisation for Animal Health (OIE) also adopted resolutions supporting the global action plan on antimicrobial resistance in 2015.¶ ¶ Many antimicrobials used in foodproducing animals are identical, or closely related, to antimicrobials used in humans. Most antimicrobials used in plant production, including orchards, are also identical, or closely related, to antimicrobials used in humans. Antimicrobials are used to treat and control bacterial infections in the presence of disease and for disease prevention and growth promotion in the absence of disease. Antimicrobial use in food-producing animals can lead to selection and dissemination of antimicrobialresistant bacteria in food-producing animals, which can then be transmitted to humans via food and other transmission routes. ¶ ¶ Why is this guideline needed? ¶ The development of this guideline was driven by the need to mitigate the adverse human health consequences of use of medically important antimicrobials (i.e. antimicrobials used in humans) in food-producing animals. In 2005, a WHO expert committee was set up to establish criteria for classifying medically important antimicrobials as important, highly ...

21 September 2017 of these Guidelines. Priority questions on the effects of limitations of use of medically important antimicrobials in food-producing animals on antimicrobial resistance in human and animal populations, including use overall and specifically for growth promotion, disease prevention, and treatment were agreed by the WHO Steering Group. These questions guided systematic reviews and narrative literature reviews and the evidence identified was summarized in evidence-torecommendation tables to enable the Guideline Development Group (GDG) to use the appropriate evidence to formulate each recommendations. The GRADE (grading of recommendations, assessment, development and evaluation) approach was used to appraise and use the evidence to develop recommendations. The whole process was supervised by the WHO Guideline Review Committee, which approved the final guidelines.

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Recommendations and Best Practice Statements Recommendations RECOMMENDATION 1: Overall antimicrobial use We recommend an overall reduction in use of all classes of medically important antimicrobials in food-producing animals. (Strong recommendation, low-quality evidence).

RECOMMENDATION 2: Growth promotion use We recommend complete restriction of use of all classes of medically important antimicrobials in food-producing animals for growth promotion. Strong recommendation, low quality evidence 10

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Justification The GDG determined that this recommendation should be strong despite the low quality evidence due to the potentially large human health benefits of lowered prevalence of antimicrobial resistance in bacteria isolated from humans resulting from the complete restriction of use of antimicrobials in food-producing animals for growth promotion. Evidence from the systematic reviews and a large body of information on the mechanisms of antimicrobial resistance supports the conclusion that antimicrobial use in food-producing animals, particularly for growth promotion, selects for antimicrobial resistance in bacteria isolated from food-producing animals. Resistant bacteria then spread among food-producing animals, into their environment, and to humans. This conclusion, supported by narrative literature reviews, is based upon consistent evidence from systematic reviews that restriction of growth promotion use of antimicrobials in food-producing animals reduces the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals that are, and can be, transmitted to humans. Furthermore, potential undesirable consequences associated with complete restriction of growth promotion use of antimicrobials in food-producing animals (e.g. increased use of veterinary antimicrobials, adverse effects on animal health, animal welfare, food safety, the environment and animal production, increased costs of animal production, and economic impacts) appear to be relatively small or non-existent (see Annexes 4&5). Finally, many countries have successfully achieved complete restriction of growth promotion use of antimicrobials in food-producing animals, demonstrating the feasibility of this recommendation.

RECOMMENDATION 3: Prevention use (in the absence of disease) We recommend complete restriction of use of all classes of medical important antimicrobials in food-producing animals for prevention of infectious diseases that have not yet been clinically diagnosed. Strong recommendation, low-quality evidence Justification The GDG determined that this recommendation should be strong, despite the low-quality evidence, because complete restriction of all classes of medical important antimicrobials in food-producing animals has potential to confer the large human health benefit of lowered antimicrobial resistance in bacteria isolated from humans. This conclusion is based upon the systematic reviews, narrative reviews and evidence from documented additional observational studies. In particular, a study on the use of third generation cephalosporins for disease prevention in chickens in Canada found evidence that restriction of this use reduced the prevalence of antimicrobial resistance in bacteria transmitted to humans. Extensive research into mechanisms of antimicrobial resistance also supports the conclusion that using antimicrobials in food-producing animals selects for antimicrobial resistance in bacteria isolated from food-producing animals, which then spread among foodproducing animals, into their environment, and to humans. Furthermore, the potential undesirable consequences associated with complete restriction of use of antimicrobials for the prevention of infectious diseases that have not yet been clinically diagnosed in food-producing animals (e.g. adverse effects on animal health and welfare) appear to be relatively small. Finally, several countries have successfully achieved restriction of disease prevention use of antimicrobials in foodproducing animals, demonstrating the feasibility of this recommendation.

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Implementation of these guidelines These guidelines apply universally, regardless of region, income and setting, however, the GDG acknowledged that implementation of these guidelines in low and middle-income countries may require special considerations. These include assistance with animal health management to reduce the need for antimicrobials, including improvements in disease prevention strategies, housing and husbandry practices. Furthermore, many countries may need technical and laboratory capacity building assistance for conducting the recommended bacterial culture and antimicrobial sensitivity testing. FAO and OIE may be able to assist in implementation of these guidelines. Finally, the GDG emphasized the need for countries to conduct surveillance and monitoring of antimicrobial usage in food-producing animals to monitor and evaluate the implementation of these guidelines.

Best practice statements Best practice statements represent recommendations that Guideline Development Group feel are important, but that are not appropriate for formal recommendations with ratings of quality of evidence. Based upon the evidence presented from the systematic reviews and narrative literature reviews, the GDG formulated two best practice statements on use of medically important 12

21 September 2017 antimicrobials in food-producing animals. The rationale for the best practice statements was the need to advise against use in food-producing animals of new antimicrobials developed for use in humans. A second issue was the need to avoid future use in food-producing animals of any antimicrobials currently used in humans. This is because of the evidence of the large human health benefits of lowered antimicrobial resistance in bacteria isolated from humans and limited evidence of harmful or unintended consequences of restrictions on antimicrobial use of medically important antimicrobials in food-producing animals.

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Best practice statement 1. Any new class of antimicrobials or new antimicrobial combination developed for use in humans will be considered critically important for human medicine unless categorized otherwise by WHO.

Best practice statement 2. Medically important antimicrobials that are not currently used in food production should not be used in the future in food production including in food-producing animals or plants*. ________________________________________________________________________________ * Although these guidelines only pertain to use of medically important antimicrobials in food-producing animals, the GDG concluded that this best practice statement ought to apply to all antimicrobial uses in food-producing animals and in plants. All such uses have the potential to select for antimicrobial resistance, which can be subsequently transferred to humans. __________________________________________________________________________________________________

Rationale:  A number of medically important antimicrobials not currently used in food-producing animals are antimicrobials ‘of last resort’ for the treatment of serious and life -threatening infections in humans. Examples include carbapenems, oxazolidinones (e.g. linezolid), and lipopeptides (e.g. daptomycin). Preserving the effectiveness of these antimicrobials for treatment of serious and life-threatening infections in humans must be a best practice.  Development and eventual marketing of new classes of antimicrobials intended for treatment of serious and life-threatening infections in humans is likely.  Since the use in food-producing animals of antimicrobials covered by these best practice statements has not been reviewed for human safety, there are concerns about unauthorized (e.g. extra-label) use in food-producing animals.  It is not possible to obtain direct evidence of the antimicrobial resistance consequences of use of new classes of antimicrobials not currently used in food-producing animals. Therefore, we rely upon experience that includes a large body of evidence from mechanistic studies of antimicrobial resistance.  These best practices are consistent with the OIE statement that “Antimicrobial classes/subclasses used only in human medicine are not on the OIE List of Antimicrobials of Veterinary Importance (OIE List).”

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Background The increase in prevalence of antimicrobial resistance is a worldwide problem. Infection with antimicrobial-resistant bacteria can have more severe consequences for human health than infections with antimicrobial susceptible bacteria. Such consequences include treatment failure, increased or longer hospitalization, and prolonged illness. Although many factors contribute to the rise in antimicrobial resistance in bacteria infecting humans, antimicrobial use in both humans and food-producing animals is an important contributor. There is considerable evidence supporting the need to reduce antimicrobial use in humans and in food-producing animals to prevent and control antimicrobial resistance. In May 2015, the World Health Assembly adopted the global action plan on antimicrobial resistance, which aims to combat the increasing health threat posed by antimicrobial resistance (http://www.who.int/antimicrobialresistance/global-action-plan/en/ ). The global action plan aims to control antimicrobial resistance using a variety of interventions, including reducing use of antimicrobials in humans and animals. The global action plan also emphasizes the need for a cross-sectoral, ‘One Health’ approach for control of antimicrobial resistance with efforts contributed by actors from many disciplines including human and veterinary medicine. Recognizing the urgent need for cross-sectoral action to address antimicrobial resistance, the assemblies of both the Food and Agriculture Organization of the United Nations (FAO) and the World Organisation for Animal Health (OIE) adopted resolutions supporting the global action plan on antimicrobial resistance in 2015. Antimicrobials that are identical, or closely related, to antimicrobials used in humans, are also used in food-producing animals. Antimicrobials used to treat humans are also used in plant production, including in orchards. Antimicrobials are used in food-producing animals for treatment and control of clinical bacterial infections but also for disease prevention and growth promotion in the absence of disease. The apparent growth promotion benefits of antimicrobials were first identified when fermentation byproducts from streptomycin and penicillin production for humans were fed to foodproducing animals in the United States of America during the 1940s. By the 1950s, drug companies were widely marketing and selling antimicrobials for addition to animal feeds for growth promotion. Although the biological mechanism for the purported growth promotion benefits of antimicrobials has not been fully demonstrated, antimicrobials continue to be added to animal feed for growth promotion and disease prevention worldwide. Use of antimicrobials in food-producing animals can lead to selection for, and dissemination of, antimicrobial-resistant bacteria in food-producing animals, their wastes, and their surrounding environment. Prolonged use of antimicrobials in humans or animals increases the risk of multidrug resistance. Furthermore, bacteria that are pathogenic (e.g. Salmonella spp., Campylobacter spp.) and commensal (e.g. Escherichia coli, Enterococcus spp.) in humans, including resistant bacteria, are transmitted from food-producing animals to humans via food and other transmission routes. Finally, infection with antimicrobial-resistant bacteria, including antimicrobial-resistant foodborne bacteria (such as non-typhoidal Salmonella spp., Campylobacter spp., and Escherichia coli) can have more severe consequences for human health than infections with susceptible bacteria. These include treatment failure, increased or longer hospitalization, and prolonged illness.

An important food safety issue The use of antimicrobials in food-producing animals, subsequent antimicrobial resistance in bacteria isolated from food-producing animals, then transfer of those antimicrobial-resistant bacteria from food-producing animals to humans via food, is an important food safety issue. Foodborne diseases 14

21 September 2017 are a major cause of human morbidity and mortality. According to recent estimates from the WHO Foodborne Diseases Epidemiology Reference Group (WHO FERG), foodborne diseases caused 600 million illnesses, 420,000 deaths, and 33 million Disability Adjusted Life Years in 2010 (1). There is considerable variation in the burden of foodborne diseases among populations in certain subregions, with the highest burden of foodborne diseases observed in Africa (1). Foodborne diseases are particularly important in children. According to the WHO FERG estimates, although children 5 years of age and less represent only 9% of the global population, this age group represents 40% of the foodborne disease burden. Food-producing animals are the predominant source of many foodborne diseases, including infections caused by nontyphoidal Salmonella, and Campylobacter (2). According to WHO FERG, nontyphoidal Salmonella caused an estimated 80 million infections and 60,000 deaths, while Campylobacter caused 95 million infections and 21,000 deaths in 2010. The WHO FERG estimates do not include estimates of the human health burden of antimicrobial-resistant foodborne diseases. However, studies including national surveillance studies have found a notable prevalence of antimicrobial resistance in nontyphoidal Salmonella and Campylobacter infections in humans. For example, studies in Asia have found that most Campylobacter isolated from symptomatic humans are resistant to fluoroquinolones, the antimicrobial class commonly used to treat Campylobacter infections in adults (3).

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Rising public health concern about use of antimicrobials in food-producing animals The potential effects of using antimicrobials in food-producing animals have caused public health concern for decades. Early concerns focused mainly on the use of antimicrobials in animal feed for growth promotion. In 1960, government of the United Kingdom of Great Britain and Northern Ireland (UK) established the Netherhorpe Committee to investigate whether use of antimicrobials in animal feeds constituted a danger to humans. This was followed, in 1968, by the UK governmentappointed Swann Committee (Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine) which concluded that administration of antimicrobials to food-producing animals poses hazards to human and animal health because it leads to the emergence of strains of bacteria which are resistant to antimicrobials (4). Concerns about the effects on public health were not limited to Europe. From 1969, onward, scientific, regulatory, and professional organizations in the United States of America (USA) have deliberated on the public health consequences of use of antimicrobials in food-producing animals, particularly in animal feeds. These include the American Academy of Microbiology, the Infectious Disease Society of America, the Institute of Medicine, Food and Drug Administration, the National Academy of Sciences and the Office of Technology Assessment. For example, in 1988, the US Institute of Medicine (part of the National Academy of Sciences) concluded that sparse data showed that resistant Salmonella, which had developed resistance due to use of antimicrobials in foodproducing animals, had been transmitted from food-producing animals to humans through food products and had caused clinical illness in humans (5). In 1994, the American Society of Microbiology concluded that resistant bacteria and genes encoding for resistance could spread from animals to humans, particularly in contaminated food products (6). By the beginning of the 1990s, widespread use of fluoroquinolones and third-generation cephalosporins in food-producing animals, particularly as mass medications, were adding to the concern about the implications for human health. Several governments commissioned plans deliberations on the public health consequences of use of antimicrobials in food-producing animals. 15

21 September 2017 These include Canada in 1997 (National Consensus Conference - Controlling Antimicrobial Resistance: An Integrated Action Plan for Canadians), Australia in 1998 (Joint Expert Advisory Committee on Antibiotic Resistance), and the United Kingdom in 1998 (Ministry of Agriculture, Fisheries and Food).

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Response to concern about use of antimicrobials in food-producing animals In 1997, WHO organized a consultation on the ‘medical impact of the use of antimicrobials in food animals’ in Berlin, Germany. The experts convened at that meeting concluded that use of antimicrobials in food-producing animals leads to selection of antimicrobial resistance. They also concluded that resistant bacteria and resistant determinants are transmitted to humans in food or through direct contact with food-producing animals. Furthermore, the expert group concluded that although the magnitude of the public health impact of use of antimicrobials in food-producing animals was uncertain, there was enough evidence to cause concern (7). In 2000, WHO, recognizing the public health threat posed by use of antimicrobials in food-producing animals, developed with the participation of FAO and OIE, the WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food ( hereon called the ‘Global Principles’ in this document) (8). These Global Principles, which form part of the comprehensive WHO Global Strategy for Containment of Antimicrobial Resistance (9), provided recommendations aimed at reducing the use of antimicrobials in food-producing animals for the protection of human health. Some countries began to use the recommendations from WHO consultations to implement restrictions on the use of selected antimicrobials in food-producing animals. In 1999, Denmark was able to discontinue the use of antimicrobials in food-producing animals for growth promotion by using a combination of regulatory action and voluntary measures by food-producing animal producers. An expert committee convened by WHO in 2002 to evaluate the impact of terminating the use of antimicrobials for growth promotion in Denmark found that this intervention had been accomplished with no major consequences for animal health, nor economic consequences for consumers or producers (10). The experts further concluded that it led to a large reduction in antimicrobial use, reduction in antimicrobial resistance in food-producing animal reservoirs, and reduction in the public health threat of antimicrobial resistance. In 2001, the Executive Committee of the Codex Alimentarius Commission recommended that the public health threat posed by antimicrobial use in food-producing animals should be assessed via consultations convened by FAO, OIE, and WHO (11). The three agencies agreed that these consultations should use a food safety risk analysis approach. This involves holding an initial meeting to assess the human health risks of antimicrobial use in food-producing animals, followed by a meeting to consider the options available for managing the identified human health risks. Accordingly an expert workshop, Non-Human Antimicrobial Usage and Antimicrobial Resistance: Scientific Assessment, was jointly convened in Geneva in 2003 by FAO, OIE, and WHO to perform a scientific assessment of antimicrobial risks arising from non-human usage of antimicrobials and to formulate recommendations for future risk management actions. (12). The expert group concluded that there is clear evidence of adverse human consequences due to resistant organisms resulting from non-human usage of antimicrobials. In 2004, the second stage of the process, an expert workshop on Non-Human Antimicrobial Usage and Antimicrobial Resistance: Management Options, was convened by FAO, OIE and WHO in Oslo, Norway to consider risk management options, given the conclusions of the scientific assessment (13). The workshop recommended that WHO should pursue the concept of “critically important” 16

21 September 2017 classes of antimicrobials for human medicine, while the OIE should develop a list of critically important antimicrobials for veterinary medicine.

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The WHO critically important antimicrobial list (WHO CIA List) In 2005, WHO convened an expert committee in Canberra, Australia, to develop a process for defining and prioritizing medically important antimicrobials (i.e. antimicrobials important to human medicine). The expert committee established the criteria for classification of antimicrobials used in humans as important, highly important, or critically important for human medicine (14). These criteria were then used to establish a WHO CIA List. The expert committee also advised that these criteria, and therefore the WHO CIA List, should be updated at regular intervals. In 2007, WHO convened a multi-disciplinary expert WHO CIA List committee in Copenhagen, Denmark, to update the criteria for classifying antimicrobials used in humans and to revise the WHO CIA List, using the newest information. Such information included the emergence of extendedspectrum beta lactam resistance among Salmonella and Escherichia coli in food-producing animals, and plasmid-mediated fluoroquinolone-resistance determinants (15). In this first revision of the WHO CIA List, the experts provided additional criteria for prioritizing the human health importance of antimicrobials judged critically important for human medicine. These criteria were used to identify the highest priority classes of antimicrobials among the critically important antimicrobials for humans. In 2007, a Joint FAO/WHO/OIE Expert Meeting on Critically Important Antimicrobials was convened in Rome to review the WHO CIA List and the OIE List (16). The OIE List was developed using a survey of veterinarians and categorizes the importance to animal health of antimicrobials used in foodproducing animals. It was adopted in 2006 with contributions from veterinary services and international organizations working with OIE. The experts concluded that because the two lists were developed for different purposes, and only the WHO CIA List considered the human health implications of use of antimicrobials in food-producing animals, it would not be possible to combine them. However, comparison of the two lists and consideration of relevant criteria (e.g. frequency and severity of human infection caused by resistant foodborne bacteria and preferred treatment for the infection) indicated that three classes of antimicrobials - fluoroquinolones, cephalosporins, and macrolides – should be top priority when considering action on use of antimicrobials in foodproducing animals. In 2008, WHO established the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) to support efforts to minimize the public health impact of antimicrobial resistance associated with use of antimicrobials in food-producing animals. WHO AGISAR comprises more than 20 experts in a broad range of disciplines relevant to antimicrobial resistance, including human infectious diseases, animal health, and environmental health, appointed following a public call for advisors and a transparent selection process. In 2009, during the first WHO AGISAR meeting in Copenhagen, Denmark, the expert WHO CIA List committee was also convened to develop the second revision of the WHO CIA List (17). The revision provided recommendations on how the WHO CIA List could be used to prioritize specific risk management strategies for the antimicrobials judged critically important to human medicine, and thereby help to preserve their continued effectiveness in humans. The third and fourth revisions of the WHO CIA List were created, respectively, by the expert WHO CIA List committee during the WHO AGISAR meetings in Oslo, Norway in 2011 (17) and Bogota, Colombia in 2013 (18). At the WHO AGISAR meeting in Oslo, WHO AGISAR provided recommendations on the food-producing animal use of selected antimicrobials, taking into account 17

21 September 2017 the WHO CIA List (18). For example, WHO AGISAR recommended that the antimicrobials classified on the WHO CIA List as critically important for humans that have not been used in food-producing animals yet, should not be used in food-producing animals. The WHO AGISAR meeting in Bogota recommended that WHO develop guidelines on the use of antimicrobials in food-producing animals that would take into account the WHO CIA List (19). Such WHO guidelines could include recommendations on potential restrictions of antimicrobials in foodproducing animals that, taking into account the WHO CIA List and previous recommendations made by earlier WHO expert consultations, could contribute to the preservation of the effectiveness in humans of medically important antimicrobials, particularly antimicrobials judged critically important to human medicine. The fifth revision of the WHO CIA List was created by the expert WHO CIA List committee during the WHO AGISAR meeting in Raleigh, United States of America in 2016 and is available on the WHO website3.

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Previous WHO recommendations relevant to these guidelines Recommendations on use of antimicrobials in food-producing animals from the World Health Assembly and from WHO meetings and consultations include: 1. In 1997, the WHO Consultation on Medical Impact of the Use of Antimicrobials in Food Animals in Berlin recommended that antimicrobials for growth promotion in animals should be terminated if the antimicrobial is used in humans (7). 2. In 1998, the Fifty-first World Health Assembly adopted a resolution (WHA51.17) urging Member States to encourage the reduce use of antimicrobials in food-producing animals (20). 3. In 1998, the WHO consultation on the Use of Quinolones in Food-Producing Animals and Potential Impact on Human Health in Geneva recommended that fluoroquinolones should be used only under the close supervision of a veterinarian and preferably based upon culture and susceptibility testing; and that treatment with other efficacious antimicrobials would be preferable to treatment with fluoroquinolones (21). 4. In 2000, the WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food recommended that (8): a. use of antimicrobials for growth promotion that belong to classes of antimicrobials used in humans should be terminated, b. use of antimicrobials in food-producing animals judged to be essential to human medicine should be restricted and justified by culture and susceptibility results, and c. disease prevention use of antimicrobials in food-producing animals should not be a substitute for good animal health management. 5. In 2003, a joint FAO, OIE, and WHO report, Non-Human Antimicrobial Usage and Antimicrobial Resistance: Scientific Assessment recommended that WHO appoint an expert group of physicians to define the antimicrobials that are considered critically important in humans (12). 6. In 2004, a joint FAO, OIE, and WHO report , Non-Human Antimicrobial Usage and Antimicrobial Resistance: Management Options recommended that WHO should develop a list of antimicrobials critically important for humans with a view to enabling specific resistanceprevention actions for these antimicrobials in the context of non-human use. The workshop also recommended that the OIE should develop a list of critically important antimicrobials in veterinary medicine (13). 7. In 2009, WHO AGISAR recommended that the WHO CIA List should be used for prioritizing specific risk management strategies for medically important antimicrobials, particularly antimicrobials judged to be critically important to human medicine (17). 8. In 2011, WHO AGISAR recommended that the antimicrobials classified on the WHO CIA List as critically important for humans but which have not been used in food-producing animals yet, should not be introduced into food-producing animal usage (18). 9. In 2015, the World Health Assembly adopted the global action plan on antimicrobial resistance which called on Member States to (22): a. develop policies on use of antimicrobials in food-producing animals including implementation of guidelines on use of antimicrobials critically important in humans, b. phase out the use of antimicrobials for growth promotion in food-producing animals, and c. reduce the non-treatment use of antimicrobials in food-producing animals. 10. In 2015, the WHO/FAO Codex Alimentarius published Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance, stating that foodborne antimicrobial resistance risk analysis should consider relevant international documents, including the WHO CIA List (10).

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Relevant recommendations by external organizations A number of external organizations, countries, and private companies have reviewed the human health consequences of use of antimicrobials in food-producing animals. Although the scope and dates of these reviews vary, there is consensus among the scientific community that use of antimicrobials in food-producing animals can cause adverse human health consequences. There is no consensus, however, as to the proportion of antimicrobial resistance in bacteria isolated from humans caused by use of antimicrobials in food-producing animals. Nevertheless, given the public health risk posed by use of antimicrobials in food-producing animals, a number of external organizations have recommended, and a number of countries and private companies have imposed, restrictions on use of antimicrobials in food-producing animals, particularly on antimicrobials important for human medicine. These restrictions and recommendations include: 1. In 1969, the United Kingdom Swann Commission recommended prohibition of the use for animal growth promotion of antimicrobials used in human medicine (4). 2. In 1986, Sweden prohibited the use of antimicrobials for growth promotion in foodproducing animals (23). 3. In 1997, the European Union prohibited the use of avoparcin (a glycopeptide closely related to vancomycin) for growth promotion in food-producing animals (24). 4. In 1997, the United States of America prohibited the extra-label use of fluoroquinolones and glycopeptides in food-producing animals, due to their importance for use in humans (25). 5. In 1998, an expert committee for the Ministry of Agriculture, Fisheries and Food in the United Kingdom recommended that key antimicrobials in humans should be identified, with the aim of reducing the use of such antimicrobials in food-producing animals (26). 6. In 1998, the European Union Chief Medical Officers recommended that the use of antimicrobials in food-producing animals for growth promotion should be stopped whenever there was clear evidence of a significant risk to human health from such usage (27). 7. In 1999, producers in Denmark voluntarily discontinued the growth promotion use of antimicrobials in food-producing animals (11). 8. In 1999, the European Union prohibited the growth promotion use of four classes of antimicrobials in food-producing animals, followed in 2006 by a discontinuation of all growth promotion use of antimicrobials in food-producing animals (24). 9. In 1999, an expert committee for the Ministry of Health in Australia recommended taking a conservative regulatory approach towards approval of antimicrobials in food-producing animals, to enable severe limitations or prohibitions on use in food-producing animal of antimicrobials important for use in humans (28). 10. In 2002, Demark imposed severe limitations on the use of fluoroquinolones in foodproducing animals such that fluoroquinolones were only available for use by veterinarians in food-producing animals following demonstrated need based upon antimicrobial susceptibility testing and following specific approval by national authorities (29). 11. In 2002, the Infectious Disease Society of America recommended a multi-pronged approach to limit the impact of antimicrobial resistance including limits on the use of antimicrobials in food-producing animals (30). 12. In 2002, the Alliance for Prudent Use of Antibiotics recommended that the use of antimicrobials for economic purposes such as growth promotion should be discontinued, and that, because of their critical role in treating human disease, fluoroquinolones and thirdgeneration and fourth-generation cephalosporins should not be used in food-producing animals except to treat refractory infections in individual animals (31). 13. In 2005, the United States of America prohibited the use of fluoroquinolones in poultry (32).

21 September 2017 14. In 2011, the Netherlands used the WHO CIA List to place severe limitations on use in foodproducing animals of antimicrobials listed as critically important for humans (33). For example, use of fluoroquinolones and third and fourth generation cephalosporins in foodproducing animals is only permitted upon demonstrated need based on antimicrobial susceptibility testing and following specific approval by national authorities. Following implementation of this restriction, use of such antimicrobials in food-producing animals fell to almost zero (validated via a national surveillance programme on use of antimicrobials in food-producing animals) and no adverse animal health consequences were identified. 15. In 2012, the United States of America prohibited the extra-label use of third-generation and fourth-generation cephalosporins in food-producing animals, due to their importance for use in humans (25). 16. In 2012, the OIE recommended that antimicrobials listed on the WHO CIA List as critically important for humans should not be used as a first line treatment in food-producing animals unless justified based on the results of bacteriological tests (34). 17. In 2015, a government-commissioned review of antimicrobial resistance in the United Kingdom recommended global restrictions on use of antimicrobials in food-producing animals, particularly antimicrobials important for humans (35). The committee acknowledged the WHO CIA List as an important step towards identifying and prioritizing the antimicrobials that should be more restricted in food-producing animals. 18. In 2015, the McDonalds Corporation announced their endorsement of the WHO CIA List, prohibiting their supplying producers from treating their food-producing animals with antimicrobials listed as critically important to humans on the WHO CIA List and not presently approved for veterinary use, and prohibiting the growth promotion use of any antimicrobial on the WHO CIA List (36).

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Rationale for, and objectives of, these guidelines Minimizing the adverse human health impact of the use of medically important antimicrobials in food-producing animals will require action. WHO facilitated the creation of the WHO CIA list to enable prioritization of public health interventions aimed at preserving the effectiveness of medically important antimicrobials, such as restrictions on some uses of medically important antimicrobials in food-producing animals. Building on the creation of the WHO CIA List, there is a need to develop best practice statements and recommendations on the use of medically important antimicrobials in food-producing animals. A number of groups, including WHO Member States have requested that these guidelines be developed. Some actors interpret the current WHO CIA List as a de facto WHO guidelines, not realizing that there is a need to go through a rigorous, transparent process to search the evidence and use this to make recommendations contained in WHO guidelines. Therefore, there is clear need for, and anticipation of, WHO guidelines on the use of medically important antimicrobials in foodproducing animals that takes into account the WHO CIA List. Deleted: is

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The goal of these guidelines are to help preserve the effectiveness of medically important antimicrobials, particularly those judged to be critically important to human medicine. These guidelines will also help preserve the effectiveness of antimicrobials for veterinary medicine. These goals will be attained when there are reductions in use of medically important antimicrobials in food-producing animals. Such reductions in use of medically important antimicrobials in foodproducing animals will contribute to a reduced prevalence of antimicrobial resistance in bacteria isolated from food-producing animals, and a reduced prevalence of antimicrobial resistance to 21

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21 September 2017 medically important antimicrobials in bacteria isolated from humans. By helping to preserve the effectiveness of antimicrobials used in human medicine, these guidelines support the WHO global action plan on antimicrobial resistance. Specifically, these guidelines present evidence-based recommendations on use in food-producing animals of medically important antimicrobials that should help preserve their effectiveness for human medicine with minimal or no harms (e.g. to animal health, welfare, production, food safety and economy). Taking into account the WHO CIA List, the objective of these WHO guidelines are to provide recommendations for limitations of specific uses of medically important antimicrobials in foodproducing animals, particularly antimicrobials judged to be critically important for humans. These recommendations specifically address the overall use of medically important antimicrobials in foodproducing animals and specific uses for growth promotion, disease prevention, and treatment in food-producing animals.

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Who should use these guidelines? The primary audience of these guidelines is policy makers and regulatory officials overseeing the use of antimicrobials in food-producing animals in WHO Member States. The target audience also includes veterinarians, food-producing animal organizations, food producers, pharmaceutical companies, animal health officials, public health officials, physicians and other healthcare providers, and consumers.

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Methods These guidelines were developed by using methods and procedures described in the WHO Handbook for Guideline Development (Second Edition)4. In summary, the process included: (i) identification of priority questions and critical outcomes; (ii) retrieval of the evidence in a transparent manner using standard methods in systematic reviews; (iii) narrative literature reviews; (iv) assessment and synthesis of the evidence; (v) using the evidence for the formulation of recommendations; and (vi) planning for the dissemination, implementation, impact evaluation and future updating of the guideline. Deleted: i Deleted: as Formatted: Font: (Default) +Body (Calibri), 11 pt, Font color: Black Formatted: Default Paragraph Font, Font: (Default) Whitney, 12 pt, Not Italic, Font color: Black Formatted: Font: Not Italic Formatted: Numbered + Level: 1 + Numbering Style: i, ii, iii, … + Start at: 1 + Alignment: Left + Aligned at: 0.63 cm + Indent at: 1.27 cm Deleted: ¶ ¶ Deleted: y

Priority questions The WHO Steering Group, in consultation with the GDG and GRADE methodologists, formulated two questions using the population, intervention, comparison, outcome, time, setting (PICOTS) format with time [T] being contained within the Intervention [I] and setting [S] into the population [P]). These PICOTS questions were: 1. For human populations of any age in any setting, does a limitation compared to not having that limitation of use of antimicrobial(s) in food-producing animals reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial-resistant ebacteria in human populations?

http://apps.who.int/medicinedocs/en/d/Js22083en/

21 September 2017 2. For food-producing animals of any age in any setting, does a limitation compared to not having that limitation of use of antimicrobial(s) in food-producing animals reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobialresistant bacteria in food-producing animals?

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Identification of critical and important outcomes The WHO Steering Group, with input from the GDG, systematic review teams, and guideline methodologists considered potential outcomes discussed at the first GDG meeting and drafted a list of potentially important outcomes related to use of antimicrobials in food-producing animals. A questionnaire with these potential outcomes was then distributed to GDG members who were asked to rank the relative importance of each potential outcome on a nine-point scale ranging from 1 (least important) to 9 (most important). The median score was calculated for each outcome based on the GDG members’ responses, to determine outcomes that are ‘critical’ (median score ≥7) and ‘important but not critical’ (median score 4–6) for making decisions about the recommendations. To ensure consistency, the WHO Steering Group reviewed the final list of critical and important outcomes for each guideline question (see Annex 3 for the final list of outcomes).

Systematic review search strategies Specific inclusion and exclusion criteria were defined. Systematic review teams searched the following databases with no language restrictions or other limits: Ovid MEDLINE, including In-Process and Other Non-Indexed Citations, 1964 to current; Ovid EMBASE, 1964 to current; CINAHL Plus with Full Text, 1964 to current; and Cochrane Database of Systematic Reviews, 1998 to current. The searches consisted of selected subject headings and keywords related to the use of antimicrobials. The searches also used IndMED, using the same keywords, and LILACS, using a combination of the keywords in English and some of their Spanish and Portuguese equivalents. The searches reviewed reference lists from retrieved articles and journals, conference proceedings and the websites of the US Centers for Disease Control and Prevention, the International Centre for Infectious Diseases, FAO, OIE and WHO. Also searched were proceedings of relevant scientific conferences over the past two years, and unpublished data submitted to the US Food and Drug Administration and the European Medicines Agency as part of drug registration applications. Additionally, review teams performed manual searches of clinicaltrials.gov and the WHO International Clinical Trials Registry Platform to identify studies that have not yet been published but are potentially eligible for inclusion. A WHO information specialist reviewed and endorsed the search strategy to ensure no major procedures had been overlooked. Both systematic review teams addressed both PICOTS questions and worked independently of each other. The WHO Steering Group provided regular guidance and feedback on the protocol for the systematic reviews and the evidence tables. The systematic review team from Bond University provided a narrative report of their findings. The systematic review team from the University of Calgary provided a full quantitative report of their systematic review. This included an assessment of the quality of the primary studies, categorized by study design with the highest quality studies listed first in this order: systematic review, randomized trials, prospective cohort studies, retrospective cohort studies, case-control studies, time series studies, before and after studies, and ecological studies. The systematic review team from the University of Calgary also assessed the quality of each study within each category according to their judgement on likelihood of bias, robustness, and appropriateness of conclusions. Finally, the systematic review team from University of Calgary conducted a meta-analysis of the risk differences for reductions in the prevalence in antimicrobial resistance reported with various restrictions on antimicrobial use in food-producing animals. WHO 23

21 September 2017 then commissioned a supplemental analysis of the University of Calgary systematic review that updated the literature, stratified the findings by types of antimicrobial use in food-producing animals, and summarized the evidence of unintended consequences of restricting antimicrobial use in food-producing animals. Summaries of the systematic review reports, including the supplementary report from the University of Calgary, are available at Annex 4. In addition to the systematic reviews, WHO also commissioned narrative literature reviews by topicexperts on the following: (1) illustrative examples of transfer of antimicrobial resistance determinants from food-producing animals to humans; (2) biological plausibility of associations between use of antimicrobials in food-producing animals and selection for resistance in zoonotic pathogens and commensal bacteria, and transfer of resistance determinants from food-producing animals to humans; and (3) unintended consequences of restrictions on antimicrobial use in food-producing animals. The resulting reviews were presented and discussed at the GDG meetings. Summaries are available at Annex 5.

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Assessment of the evidence The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the evidence and to determine the strength of the recommendations. The GRADE approach defines the quality of the evidence as the extent to which there is confidence that an estimate of effect or association reported in the available evidence is correct. Under the GRADE system, randomized clinical trials are initially ranked as high quality evidence, while observational studies as low quality evidence. Five domains are then considered (study limitations, inconsistency, indirectness, imprecision and publication bias) which may lead to rating down the quality of evidence and three (magnitude of effect, dose-response and effect of plausible residual confounding) to potentially raise the quality assessment.

RATINGS

MEANING The GDG is very confident that the true effect of the intervention is close to the estimate of the effect presented to the group. Evidence with this quality rating provides a very good basis to support a decision for a recommendation. Starting point for randomized clinical trials. The GDG is moderately confident that the true effect of the intervention is close to the estimate of the effect presented to the group. The true effect is likely close, but it could be substantially different. Evidence with this quality rating provides a good basis to support a decision for a recommendation. The GDG has limited confidence that the true effect of the intervention is close to the estimate of the effect presented to the group. The true effect may be substantially different. Starting point for observational studies. The GDG has very little confidence that the true effect of the intervention is close to the estimate of the effect presented to the group.

High

Moderate

Low

Very Low

21 September 2017 It should be noted that GRADE was developed to assess clinical and public health interventions in which quantitative studies are used to measure an effect size. It therefore had to be adapted for use in complex questions regarding environmental exposures and multi-component interventions (such as the prevalence of antimicrobial resistance associated with use of medically important antimicrobials in food-producing animals), which is challenging. Such questions often require the consideration of indirect evidence from intermediary endpoints, mechanistic data and several types of observational studies performed under field conditions. It is not practical, and in some cases not ethical, to conduct randomized clinical trials to investigate the impact of restricting antimicrobial use in food-producing animals on the prevalence of antimicrobial resistance. Therefore, under the GRADE approach a body of evidence in this domain is bound to be rated as ‘low’ given that GRADE mandates an initial rating of all studies that are not randomized controlled trials as ‘low quality’.

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Formulation of recommendations The synthesized evidence was used to formulate each recommendation, using the GRADE approach (as summarized in the evidence profiles, summary of findings tables, and the narrative summaries of the systematic reviews provided in Annex 4 and 5). Evidence to recommendation tables, which include the assessment and judgments on quality of evidence, balance between benefits and harms, values and preferences of affected populations, resource implications, equity, human rights, gender and social determinants of health, and acceptability and feasibility for each outcome, were developed for each question. Draft recommendations, evidence summaries, the corresponding GRADE tables and other related documents were provided to the GDG who were then asked to comment on the document in tracked mode. The GDG members discussed and finalized recommendations at two meetings, one in Raleigh, United States of America, in October, 2016 and the second at WHO headquarters in Geneva, Switzerland, in March 2017.

Determining strength of the recommendations The strength of a recommendation can be either strong or conditional. A strong recommendation is one for which the GDG is confident that the desirable effects of adherence to the recommendation clearly outweigh the undesirable effects. For public health policy, this means that in most situations the recommendation should be adopted as policy. A conditional recommendation is one for which confidence in the evidence supporting the recommendation may be low or may apply only to specific groups or settings. In these cases, the GDG may conclude that the desirable effects of adhering to the recommendation outweigh the undesirable effects, but the trade-offs are not clear in all situations. Furthermore, the determination of the strength of a recommendation also involves considerations of the balance between benefits and harms, the values and preferences of affected populations, resource implications, equity, human rights, gender and social determinants of health, and acceptability and feasibility. The strength of each recommendation was determined by the GDG based upon the quality of the evidence, the balance of benefits versus harms, values and preferences, and resource implications. Information on the values, preferences, acceptability and views of those likely to be affected by the recommendation was not explicitly collected or assessed, rather the knowledge, opinions and experience of GDG members on these matters were relied upon. Cost evaluations were based on reported estimates obtained during the evidence retrieval process as well as the experiences and 25

21 September 2017 opinions of members of the GDG. Evidence-to-recommendation tables were used to note and synthesize these considerations and record the reasons for changes made to the strength of the recommendations. The GDG deliberations are summarized in the evidence-to-recommendations tables (summarized in Annex 6 and available in full in Web Annex5). The evidence profiles, summary of findings tables, and the systematic review narrative evidence summaries, are also available in the Web Annex, respectively.

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Decision-making during GDG meetings GDG meetings were structured to allow participants to discuss each of the drafted recommendations, and where necessary, revise recommendations through group discussion. Agreement on final recommendations was reached by group consensus, which was unanimous for each recommendation. WHO staff, external technical experts involved in the collection and grading of the evidence, and observers did not participate in GDG decisions.

Peer review and finalization of these guidelines Following the evidence to recommendations meetings, the full guideline document was drafted by the guideline writing committee to reflect GDG members’ deliberations and decisions. The draft document was then circulated to all GDG members and the WHO Steering Group for further comments and preliminary approval before it was sent to the External Review Group (ERG) for peer review. The ERG comments were used to revise the document, which was then circulated to GDG members for their final approval.

Best practice statements and recommendations The GDG formulated the following recommendations and best practices using the body of evidence established via the two systematic reviews (including the supplementary report to one of the systematic reviews), the three narrative literature reviews, and other scientific sources.

Best practice statements Best practice statements represent recommendations that guideline panels feel are important, but that are not appropriate for formal recommendations with ratings of quality of evidence. Based upon the evidence presented from the systematic reviews and narrative literature reviews, the GDG formulated two best practice statements on use of medically important antimicrobials in foodproducing animals. The rationale for the best practice statements was the need to avoid use in foodproducing animals of any new antimicrobials that may be developed for use in humans and also to avoid the use of any antimicrobials not used in food-producing animals but currently used in people. This is because of the evidence of the large human health benefits of lowered antimicrobial resistance in bacteria isolated from humans and limited evidence of harmful or unintended consequences of restrictions on antimicrobial use of medically important antimicrobials in foodproducing animals.

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Recommendations The systematic evidence reviews yielded a large number of studies demonstrating a consistent decrease in the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals or humans following restrictions in use of medically important antimicrobials in foodproducing animals. However, the GDG acknowledged that there were limitations to this body of evidence. Chief among these was that the evidence was derived mostly from observational studies which, according to the GRADE approach, meant the quality of evidence for any recommendation in these guidelines will be rated as ‘low’. Additionally, the systematic reviews found few studies that included small-scale food-producing animal operations; almost all of the studies involved moderate or large-scale food-producing animal operations. The reviews also found few studies from low and middle-income countries. Despite these limitations, the GDG determined that there was sufficient evidence to conclude that selection of antimicrobial resistance and transmission to humans will occur with antimicrobial use in all food-producing animal settings, including in small-scale production settings and in low and middle-income countries. Furthermore, the GDG concluded that 27

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21 September 2017 the observed decreases in prevalence of antimicrobial resistance in bacteria isolated from foodproducing animals and humans in reviewed studies would equally be expected to occur in smallscale food-animal production settings and in low or middle-income countries. Therefore, to ensure that people in all countries benefit from effective antimicrobials, the GDG concluded that these recommendations in these guidelines should be applied in all countries and settings, not just largerscale animal production settings or high-income countries. A summary of the evidence, justification, and implementation considerations is provided for each recommendation below. Further detail is provided in Annex 6 and in the Web Annex). Guideline users should refer to these remarks for the basis of any of the recommendations and how best to implement them. To facilitate implementation, derivative products such as policy briefs and other implementations tools will be developed.

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RECOMMENDATION 1: Overall antimicrobial use We recommend an overall reduction in use of all classes of medically important antimicrobials in food-producing animals. (Strong recommendation, low-quality evidence).

Justification The GDG determined that this recommendation should be strong, despite the low-quality evidence, because the beneficial human health benefits (lowered prevalence of antimicrobial resistance in bacteria isolated from humans) strongly outweigh any potentially harmful or undesirable outcomes. The evidence from the systematic reviews and narrative literature reviews shows that restricting use of antimicrobials in food-producing animals reduces the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals that are, and can be, transmitted to humans. Extensive research into mechanisms of antimicrobial resistance, including the important role of horizontal gene transfer of antimicrobial resistance determinants, supports the conclusion that using antimicrobials in food-producing animals selects for antimicrobial resistance in bacteria isolated from food-producing animals, which then spread among food-producing animals, into their environment, and to humans. Furthermore, the systematic reviews concluded that broad restrictions covering all antimicrobial classes appear to be more effective in reducing antimicrobial resistance compared to narrow restrictions of one antimicrobial class or drug, even though there are examples of marked reductions in antimicrobial resistance following restriction of a single antimicrobial. Finally, reduction in use of antimicrobials in food-producing animals is in accordance with the WHO global action plan on antimicrobial resistance. Remarks Reductions of overall use of antimicrobials in food-producing animals may include any level of reduction of use of antimicrobials in food-producing animals, including reductions of a single antimicrobial, reductions of multiple antimicrobials, or combinations of reductions of use of antimicrobials. Such reductions may include complete restriction of use, restriction of selected uses such as growth promotion use, voluntary limitations, and/or limiting use to that done with oversight by a veterinarian. Summary of the evidence Of the two reviews commissioned, one provided narrative review and the other a quantitative metaanalysis with, where appropriate, a supporting supplemental narrative. The quantitative analysis identified 179 studies describing antimicrobial resistance outcomes in animals, of which 80 were included in a meta-analysis measuring reduction in prevalence of antimicrobial resistance in bacteria 28

21 September 2017 isolated from animals following restriction of antimicrobial use. Pooled absolute risk reduction of the prevalence of antimicrobial resistance in bacteria isolated from animals varied across different antimicrobial classes, bacteria, and sample types, but ranged from 0-39%. The prevalence of antimicrobial resistance was 10-20% lower where antibiotic use was restricted (intervention groups) compared to those where it was not (comparator groups). The pooled prevalence of multidrug resistance was 24-32% lower in bacteria isolated from intervention groups. These findings were consistent, regardless of stratification, including stratification by intervention type. Twenty-one studies described antimicrobial resistance outcomes in humans (19 of which also reported antimicrobial resistance in bacteria isolated from animals), of which 13 were meta-analyzed. In humans, the pooled prevalence of antimicrobial resistance was 24% lower in intervention groups (where interventions to reduce antimicrobial use in food-producing animals were implemented) compared to comparator groups. The effect was stronger among humans with direct contact with livestock animals (i.e. farm workers). The results were similar with multiple types of stratification in the systematic review, adding to the robustness of the findings. The narrative literature review supported the conclusions of the systematic reviews, describing evidence of transfer of resistance determinants from food-producing animals to humans. The narrative literature review also described a clear association between antimicrobial use in foodproducing animals and increased risks of human exposures to, and infections by, antimicrobialresistant bacteria. Finally, any adverse consequences of restricting antimicrobial use in foodproducing animals appear to be limited and temporary (see Annexes 4 & 5 for more detail). Implementation considerations A variety of measures can be used to achieve overall reduction of antimicrobial use. These include implementation of all recommendations in these guidelines and adopting measures that reduce the need for antimicrobials. Implementing growth promotion and disease prevention strategies that do not involve use of antimicrobials, including improved hygiene, improved biosecurity, and better use of appropriate vaccines, will enable effective restriction of antimicrobial use in food-producing animals. Several countries have achieved substantial reductions by monitoring the quantities of antimicrobials dispensed by veterinarians and used on farms, then providing incentives to reduce excess use. Other interventions that have been successful include reducing profits for antimicrobial dispensing, removing over-the-counter availability, and altering prescriber behavior. Some countries may need support for implementation. FAO and OIE may assist countries that need support with implementation (e.g. alternatives to use of antimicrobials for growth promotion, governance models, considering needs of smallholders). FAO and OIE may also assist with tools for improving veterinary oversight of antimicrobial use. Countries should monitor antimicrobial use in animals in order to identify overuse and document reduction activities.

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21 September 2017 The GDG determined that this recommendation should be strong despite the low quality evidence due to the potentially large human health benefits of lowered prevalence of antimicrobial resistance in bacteria isolated from humans resulting from the complete restriction of use of antimicrobials in food-producing animals for growth promotion. Evidence from the systematic reviews and a large body of information on the mechanisms of antimicrobial resistance supports the conclusion that antimicrobial use in food-producing animals, particularly for growth promotion, selects for antimicrobial resistance in bacteria isolated from food-producing animals. Resistant bacteria then spread among food-producing animals, into their environment, and to humans. This conclusion, supported by narrative literature reviews, is based upon consistent evidence from systematic reviews that restriction of growth promotion use of antimicrobials in food-producing animals reduces the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals that are, and can be, transmitted to humans. Furthermore, potential undesirable consequences associated with complete restriction of growth promotion use of antimicrobials in food-producing animals (e.g. increased use of veterinary antimicrobials, adverse effects on animal health, animal welfare, food safety, the environment and animal production, increased costs of animal production, and economic impacts) appear to be relatively small or non-existent (see Annexes 4 & 5). Finally, many countries have successfully achieved complete restriction of growth promotion use of antimicrobials in food-producing animals, demonstrating the feasibility of this recommendation. Evidence search question Does complete restriction of classes of antimicrobials on the WHO CIA List used in food-producing animals for purposes of growth promotion, compared to no such restriction, reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance in bacteria isolated from humans? Summary of the evidence The quantitative analysis identified 27 relevant studies. Of these 15 were meta-analyzed to measure the outcome ‘animal resistance’. The pooled absolute risk reduction of prevalence of antimicrobial resistance in bacteria isolated from animals, with interventions that restricted use of antimicrobials for growth promotion ranged from 19-40%. Seven studies described the prevalence of antimicrobial resistance in humans, of which six underwent meta-analysis for the outcome ‘human resistance’. The pooled prevalence of antimicrobial resistance was 6-20% lower in intervention groups (where interventions to restrict use of antimicrobials for growth promotion in food-producing animals were implemented) compared to comparator groups (where no interventions to restrict use of antimicrobials for growth promotion were implemented). The narrative literature reviews supported the conclusions of the systematic reviews. Studies of use of antimicrobials in food-producing animals for growth promotion indicated transfer of resistance determinants from food-producing animals to humans. There was a clear association between antimicrobial use in food-producing animals and increased risks of human exposures to, and infections by, antimicrobial-resistant bacteria. Finally, any adverse consequences of restricting use of antimicrobials for growth promotion in food-producing animals appear to be limited and temporary (see Annexes 4 & 5 for full detail). Implementation considerations Non-antimicrobial options for promoting optimal growth of food-producing animals, including improved hygiene, housing, biosecurity, animal husbandry practices, and better use of appropriate vaccines, should be implemented. Particular care is needed to avoid compensatory increases in antimicrobial use for disease prevention or treatment purposes, especially medically important antimicrobials. Experience gained from prohibition of the use of antimicrobials for growth promotion in Europe should be provided to other regions. A detailed WHO report on the effects of 30

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21 September 2017 the prohibition in Denmark on antimicrobial resistance, animal production, food safety, national economy and other parameters can be found online (10). Developing regions should be assisted with implementation, including implementation and follow-up monitoring in AGISAR country pilot projects (e.g. Bangladesh, India, Kenya, Rwanda, and Tanzania). FAO and OIE may assist countries that need support with implementation (e.g. alternatives to use of antimicrobials for growth promotion, governance models, considering needs of smallholders). FAO and OIE may also assist with tools for improving veterinary oversight of antimicrobial use. National antimicrobial resistance and antimicrobial use surveillance programmes, should evaluate, taking an integrated ‘One Health’ approach, the effects of implementation of prohibition. The quantities of antimicrobials used in food-producing animals for disease prevention and treatment should be monitored to identify trends.

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21 September 2017 the prevalence of antimicrobial resistance in bacteria isolated from animals, with restricted nontherapeutic use of antimicrobials, ranged from 6-11%. The narrative literature reviews supported the conclusions of the systematic reviews, finding evidence of transfer of resistance determinants from food-producing animals to humans and clear association between antimicrobial use in food-producing animals and increased risks of human exposures to, and infections by, antimicrobial-resistant bacteria. The review found that adverse consequences of restricting antimicrobial use in food-producing animals appear to be limited and temporary (see Annexes 4 & 5 for detail). Implementation considerations The GDG acknowledges that, when a veterinary professional judges that there is a high risk of spread of a particular infectious disease, use of antimicrobials for disease prevention is justified, if such a judgement is made on the basis of recent culture and sensitivity testing results. The antimicrobials used should start with those of least importance for human health e.g. start with classes not used in humans, and then as listed on the WHO CIA List (important and then highly important).. Antimicrobials classified as critically important in human medicine on the WHO CIA List should be used only when the most recent culture and sensitivity results of bacteria known to have caused the disease indicate that the critically important antimicrobial is the only treatment option. National antimicrobial resistance and antimicrobial use surveillance programmes should evaluate the effects of implementation.

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RECOMMENDATION(s) 4: Treatment and control use (in the presence of disease) Recommendation 4a We suggest that antimicrobials classified as highest-priority critically important for human medicine should not be used for treatment of food-producing animals with a clinically diagnosed infectious disease. Conditional recommendation, very low-quality evidence Justification The GDG concluded that, based upon evidence from the systematic reviews and additional studies, this recommendation will achieve human health benefits of lowered antimicrobial resistance in bacteria in humans, but should be conditional due to the very low-quality evidence for the outcomes of interest. Evidence from the systematic reviews and extensive research into mechanisms of antimicrobial resistance supports the conclusion that using antimicrobials in food-producing animals selects for antimicrobial resistance in bacteria isolated from food-producing animals, which then spread among food-producing animals, into their environment, and to humans. Furthermore, undesirable consequences associated with such a restriction of use of antimicrobials appear to be relatively small or non-existent. Finally, several countries have successfully accomplished such a restriction of antimicrobials in food-producing animals, demonstrating its feasibility. Remarks To prevent harm to animal health and welfare, exceptions can be made when veterinary professionals judge that culture and sensitivity tests demonstrate that the selected drug is the only treatment option.

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Recommendation 4b. We suggest that antimicrobials classified as critically important for human medicine should not be used for control of the dissemination of a clinically diagnosed infectious disease identified within a group of food-producing animals Conditional recommendation, very low-quality evidence Justification The GDG concluded that, although evidence from the systematic reviews and additional studies, indicates it will achieve the human health benefit of lowered antimicrobial resistance in bacteria, this recommendation should be conditional due to the very low quality of available evidence. Evidence from the systematic reviews and extensive research into mechanisms of antimicrobial resistance supports the conclusion that using antimicrobials in food-producing animals selects for antimicrobial resistance in bacteria isolated from food-producing animals, which then spread among food-producing animals, into their environment, and to humans. Furthermore, the undesirable consequences associated with such a restriction of use of antimicrobials appear to be relatively small or non-existent. Finally, several countries have successfully accomplished such a restriction of antimicrobials in food-producing animals, demonstrating its feasibility. Remarks To prevent harm to animal health and welfare, exceptions can be made when veterinary professionals judge that culture and sensitivity tests demonstrate that the selected drug is the only treatment option. The question and evidence summary provided below pertain to both recommendation 4a and recommendation 4b. Evidence search question Does complete restriction of the critically important antimicrobials on the WHO CIA List for disease control and treatment in food-producing animals, compared to no such restriction; reduce the presence of antimicrobial-resistant bacteria and/or genetic elements in humans? Summary of the evidence Two systematic reviews were performed for this question, one providing a narrative summary of the evidence and the other a quantitative assessment. Both found there was a reduction of resistance transfer from food-producing animals to humans when antimicrobial use was restricted in foodproducing animals. The quantitative analysis found 179 animal studies describing antimicrobial resistance outcomes in animals of which 80 underwent meta-analysis. The pooled absolute risk reduction of prevalence of antimicrobial resistance in bacteria isolated from animals, following interventions that restricted antimicrobial use, ranged from 0% to 39%, varying across different antimicrobial classes, bacteria, and sample types. The prevalence of antimicrobial resistance was 1020% lower in groups with restrictions on antimicrobial use versus groups with no restrictions. The pooled prevalence of multidrug resistance was 24-32% lower in bacteria isolated from groups with restrictions. These findings were consistent through many different levels of stratification including stratification by type of restriction. Twenty-one studies described antimicrobial resistance outcomes in humans (19 of which also reported antimicrobial resistance in bacteria isolated from animals) and 13 of these underwent meta-analysis. In humans, the pooled prevalence of antimicrobial resistance was 24% lower in groups with restrictions on antimicrobial use when compared with groups with no

21 September 2017 restrictions. The effect was stronger in humans with direct contact with livestock animals (i.e. farm workers). The narrative literature reviews supported the conclusions of the systematic reviews. One narrative review described evidence of transfer of resistance determinants from food-producing animals to humans and a clear association between antimicrobial use in food-producing animals and increased risks of human exposures to, and infections by, antimicrobial-resistant bacteria. Finally, another narrative literature showed that any adverse consequences of restricting antimicrobial use in foodproducing animals appear to be limited and temporary (see Annexes 4 & 5). Implementation considerations Antimicrobials classified as critically important in human medicine on the WHO CIA List should only be used when recent culture and sensitivity testing results indicate that the critically important antimicrobial is the only treatment option. Feasibility of this recommendation is therefore dependent on access to culture and sensitivity testing. The obligation to do culture and sensitivity testing has been implemented in some countries including the Netherlands. This requirement may introduce inequity in countries currently lacking the capacity to perform such testing, but this would be marginal compared to the gains. Veterinarians should have access to culture and sensitivity testing. Countries lacking capacity should be assisted with implementation, which could include implementation and follow-up monitoring in AGISAR country pilot projects (e.g. Bangladesh, India, Kenya, Rwanda, and Tanzania). National antimicrobial resistance and antimicrobial use surveillance programmes should evaluate the effect of implementation.

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The GDG acknowledges that, use of critically important antimicrobials for humans might be justified if a veterinary professional judges it necessary, based on recent culture and sensitivity testing results. The antimicrobials used should start with those of least importance for human health e.g. start with classes not used in humans, and then as listed on the WHO CIA List (important and then highly important). Antimicrobials classified as critically important in human medicine on the WHO CIA List should only be used when the most recent culture and sensitivity results of bacteria known to have caused the disease indicate that the critically important antimicrobial is the only possible treatment option. National antimicrobial resistance and antimicrobial use surveillance programmes should evaluate the effects of implementation.

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Contributors and their role in the development of these guidelines WHO Steering Group The WHO Steering Group comprised nine WHO staff members and two special members (a representative each from FAO and OIE). The special members provided comments on these guidelines, but were neither responsible for, nor endorsed, its contents. WHO staff serving on the WHO Steering Group were from five regional offices and from four of the WHO AMR technical work streams at WHO headquarters (Rational Use, National Action Plans and Surveillance, Infection Prevention and Control, and One Health). The WHO Steering Group guided the guideline development process, endorsed the draft of the initial scope of these guidelines, including the key systematic review questions for the systematic review teams, and endorsed the nominations of guideline methodologists, members of the Guideline Development Group and members of the External Review Group. The names of the WHO Steering Group members are provided in Annex 1.

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Guideline Development Group The WHO Steering Group identified thirteen external experts from five WHO regions to constitute the Guideline Development Group (GDG). This was a diverse group of individuals with expertise in clinical human medicine, veterinary medicine, microbiology, antimicrobial resistance, agricultural economics and veterinary ethics. The group included a representative from an organization representing consumers, ensuring the GDG included persons from major groups affected by the recommendations. One member of the GDG was a GRADE methodologist. The GDG members were nominated and selected to achieve geographic representation, gender balance and avoid important conflicts of interest. Once nominated, notice of the proposed membership of the GDG, accompanied by profiles of proposed members, was posted on the WHO website. Declared interests were managed according to processes described in the WHO Handbook for Guideline Development (second edition)6. One GDG member declared a potential conflict that the WHO secretariat assessed and deemed not significant. Members of the GDG provided input into the drafting of the guideline scope and the PICOTS questions, and participated in prioritizing outcomes that guided the evidence reviews. The GDG appraised the evidence from the systematic reviews, advised on the interpretation of this evidence, formulated the final recommendations based on a draft prepared by the WHO Steering Group, and reviewed and approved the final guideline document. GDG members’ names and affiliations are listed in Annex 1.

Systematic review teams During the scoping phase, the WHO Steering Group identified a need for systematic reviews of the evidence on the effectiveness of restrictions on use of antimicrobials in food-producing animals for lowering the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals and humans. Two systematic review teams were chosen by the WHO Steering Group, one of them from Bond University, Queensland, Australia, led by Chris Del Mar and the other, from the University of Calgary, Canada, led by William Ghali. The members of both systematic review teams are listed in Annex 1. Summaries of the systematic reviews are available in Annex 4 and full reports are available online7.

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Narrative literature reviewers The WHO Steering Group also identified topic expert scientists to conduct three narrative literature reviews. Summaries of these reviews, including the list of authors, are available in Annex 5.

External Review Group An External Review Group (ERG) was set up to ensure that the guideline decision-making processes considered and incorporated the contextual values and preferences of potential users of the recommendations, health care professionals and policy-makers. The group was comprised of 11 experts and stakeholders with an interest in use of antimicrobials in food-producing animals. ERG members included veterinarians, microbiologists, and physicians, selected to ensure geographicaland gender-balance. All ERG members were asked to declare potential competing interests and three of them declared interests. The WHO Steering Group reviewed the declared interests and determined that none of them posed serious conflicts precluding participation in the guideline development process. The group reviewed the final guideline document to identify any factual errors and commented on the clarity of the language, contextual issues and implications for implementation. It was not within the group’s remit to change the recommendations formulated by the GDG. Names and affiliations of the ERG are provided in Annex 1.

Management of conflicts of interests All members of the GDG, External Review Group (ERG), systematic review teams, narrative reviewers, and other external contributors were required to submit a completed standard WHO declaration of interest (DOI) form. The WHO Steering Group reviewed all information gathered before finalizing external experts and contributors’ invitations to participate in guideline development. Potential candidates for the GDG underwent a public consultation process whereby the secretariat posted a short biography of each potential GDG member online prior to confirmation of their membership of the panel. In addition, the secretariat performed a focused internet search for each proposed GDG member, to identify any obvious public controversies or interests potentially in conflict with the guideline objectives. When a potential conflict of interest (COI) was identified (for any external expert), the WHO Steering Group assessed the conflict to determine whether it would affect the objectivity of the external expert’s judgment during the guideline development process. The assessment and management of potential conflicts were based on the WHO Office for Compliance, Risk Management and Ethics (CRE) 2014 Guidelines for declaration of interests (WHO experts) and criteria for assessing the severity of COI in the WHO Handbook for Guideline Development (2nd Edition) and were undertaken in consultation with CRE. Where COI were identified but were assessed as not posing a risk to the objectivity of the guideline development process, the external experts were required to disclose these COI at the beginning of the GDG meeting. At each GDG meeting, members were updated with a summary of all identified COI. See annex 2 for a summary of all DOI statements provided by external experts, and an explanation of management of any identified COI.

Dissemination and implementation of these guidelines These guidelines apply universally, regardless of region, income and setting, however, the GDG acknowledged that implementation of these guidelines in low and middle-income countries may require special considerations. These include assistance with animal health management to reduce 36

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21 September 2017 the need for antimicrobials, including improvements in disease prevention strategies, housing and husbandry practices. Furthermore, many countries may need technical and laboratory capacity building assistance for conducting the recommended bacterial culture and antimicrobial sensitivity testing. FAO and OIE may be able to assist in implementation of these guidelines. Finally, the GDG emphasized the need for countries to conduct surveillance and monitoring of antimicrobial usage in food-producing animals to monitor and evaluate the implementation of these guidelines.

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Dissemination The recommendations made in these guidelines will be disseminated through WHO regional and country offices, ministries of health, ministries of agriculture, professional organizations, WHO collaborating centres, other United Nations agencies including FAO, and nongovernmental organizations including OIE. These guidelines will also be available on the public WHO website. To increase awareness of the recommendations, a summary of these guidelines will be published in a peer-reviewed journal. Derivative products of these guidelines, such as policy briefs and implementation tools will be developed by the WHO Department of Food Safety and Zoonoses. These guidelines will also be disseminated during meetings or scientific conferences attended by WHO staff. A summary will be translated into the six official UN languages and disseminated through WHO Regional Offices. Deleted: is

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Monitoring and evaluation The WHO Department of Food Safety and Zoonoses will monitor use and implementation of these guidelines as part of monitoring and evaluation of the WHO global action plan on antimicrobial resistance. The metrics for these monitoring and evaluation efforts are currently being developed by working groups of the WHO global action plan. WHO will utilize AGISAR to assist in the evaluation process on the uptake of these guidelines, placing uptake of these guidelines on the AGISAR annual meeting agenda. Member States will be encouraged to implement antimicrobial usage monitoring to document reductions in antimicrobial use in food-producing animals resulting from implementation of these guidelines. Deleted: i

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Research gaps The GDG identified several research gaps in current evidence concerning use of antimicrobials in food-producing animals. Appropriate research would help identify practical approaches for reducing use of medically important antimicrobials in food-producing animals. Areas needing research identified during the guideline development process include:  Identification of the most effective disease prevention strategies for reducing antimicrobial use in food-producing animals.  Alternatives to antimicrobials, including antimicrobial growth promoters, in food-producing animals.  Identification of the most effective methods for implementing antimicrobial stewardship programmes in food-producing animals, and better understanding of values and preferences of those affected by these programmes.  Cost-effectiveness studies of interventions aimed at reducing antimicrobial use in foodproducing animals.  Effects of restriction of antimicrobial use for disease control and treatment in foodproducing animals on antimicrobial resistance in bacteria isolated from animals and humans.  Development of rapid diagnostic and antimicrobial sensitivity tests. 37

21 September 2017  Effects of restriction of antimicrobial use in food-producing animals in low and middleincome countries on antimicrobial resistance in bacteria isolated from animals and humans, and on unintended consequences.

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Updating these guidelines These guidelines will be updated five years after publication unless significant new evidence emerges, necessitating earlier revision. The WHO Steering Group will continue to follow research development in the area of antimicrobial resistance associated with use of antimicrobials in foodproducing animals, particularly where new recommendations or a change in the published recommendation may be warranted. As these guidelines near the end of its proposed five-year validity period, the WHO secretariat and the WHO Steering Group, will assess the currency of the recommendations and the need for new guidance on the topic. Where there are concerns that new evidence challenges the validity of a particular recommendation, the systematic review addressing the primary question will be updated. Any new questions identified following review at the end of five years will be used to guide evidence search and assessment, applying the WHO guideline development process. WHO welcomes suggestions regarding additional questions to be considered in updated guidelines. Deleted: is

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References 1. WHO estimates of the global burden of foodborne diseases: foodborne disease burden epidemiology reference group 2007-2015. Geneva: World Health Organization; 2015. (http://apps.who.int/iris/bitstream/10665/199350/1/9789241565165_eng.pdf?ua=1, accessed 6 September 2017). 2. Molbak K. Human health consequences of antimicrobial drug-resistant salmonella and other foodborne pathogens. Clinical Infectious Diseases. 2005; 4:1613-1620. 3. Luangtongkum T, Jeon B, Han J, Plummer P, Logue CM, Zhang Q. Antibiotic resistance in campylobacter: emergence, transmission and persistence. Future Microbiology. 2009; 4(2):189– 200. doi: 10.2217/17460913.4.2.189. 4. Swann, M.M., Baxter, K.L., Field, H.I., Howie, J.W., Lucas, I.A.M., Millar, E.L.M., et al. Report of the joint committee on the use of antibiotics in animal husbandry and veterinary medicine. London: Her Majesty’s Stationery Office; 1969. 5. Institute of Medicine. Human health risks with subtherapeutic use of penicillin or tetracyclines in animal feed: A report of a study. National Academy Press. 1998. 6. Report of the ASM Task Force on Antibiotic Resistance. American Society of Microbiology, 1995. 7. World Health Organization. The Medical Impact of the Use of Antimicrobial in Food-producing animals: Report of a WHO Meeting. Berlin, Germany. 13-17 October 1997. (http://www.who.int/foodsafety/publications/antimicrobials-food-animals/en/, accessed 4 August 2017). 8. WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food: Report of a WHO Consultation with the participation of the Food and Agriculture Organization of the United Nations and the Office International des Epizooties. Geneva, Switzerland. 5-9 June, 2000. (http://apps.who.int/iris/handle/10665/68931, accessed 4 August 2017). 9. WHO global strategy for containment of antimicrobial resistance. Geneva: World Health Organization; 2001. (http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdf, accessed 6 September 2017). 10. Guidelines for risk analysis of foodborne antimicrobial resistance. CAC/GL 77-2011. Codex Alimentarius 2015. (http://www.fao.org/food/food-safety-quality/a-z-index/antimicrobial/en/, accessed 4 August 2017). 11. Impacts of Antimicrobial Growth Promoter Termination in Denmark: The WHO international review panel’s evaluation of the termination of the use of antimicrobial growth promoters in Denmark. Foulum, Denmark. 6-9 November, 2002. (http://apps.who.int/iris/handle/10665/68357, accessed 4 August 2017). 12. Joint FAO/OIE/WHO Expert Workshop on Non-human Antimicrobial Usage and Antimicrobial Resistance: Scientific assessment. Geneva, Switzerland. 1-5December 2003. (http://apps.who.int/iris/bitstream/10665/68883/1/WHO_CDS_CPE_ZFK_2004.7.pdf, accessed 4 August 2017). 13. Second Joint FAO/OIE/WHO Expert Workshop on Non-Human Antimicrobial Usage and Antimicrobial Resistance: Management options. Oslo, Norway. 15-18 March, 2004. (http://apps.who.int/iris/bitstream/10665/68701/1/WHO_CDS_CPE_ZFK_2004.8.pdf, accessed 4 August 2017). 14. Critically Important Antibacterial Agents for Human Medicine for Risk Management Strategies of Non-human Use: Report of a WHO working group consultation. Canberra, Australia. 15-18 February 2005. (http://apps.who.int/iris/handle/10665/43330, accessed 4 August 2017). 15. Critically Important Antimicrobials for Human Medicine: First Revision. Geneva: World Health Organization; 2007. (http://www.who.int/foodsafety/areas_work/antimicrobialresistance/cia/en/, accessed 4 August 2017). 39

21 September 2017 16. Joint FAO/WHO/OIE Expert Meeting on Critically Important Antimicrobials: Report of FAO/WHO/OIE Expert Meeting. Rome, Italy. 26-30November 2007. (http://www.fao.org/3/ai0204e.pdf, accessed 4 August 2017). 17. WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance: 1st meeting report. Copenhagen, Denmark. 15-19 June 2009. (http://www.who.int/foodsafety/areas_work/antimicrobial-resistance/agisar/en/, accessed 4 August 2017). 18. WHO advisory group on integrated surveillance of antimicrobial resistance: 3rd meeting repor t. Oslo, Norway. 14-17 June 2011. (http://www.who.int/foodsafety/areas_work/antimicrobialresistance/agisar/en/, accessed 4 August 2017). 19. WHO advisory group on integrated surveillance of antimicrobial resistance: 5th meeting report, Bogota, Colombia. 3-5 September, 2013. (http://www.who.int/foodsafety/areas_work/antimicrobial-resistance/agisar/en/, accessed 4 August 2017). 20. Emerging and other communicable diseases: antimicrobial resistance. In: World Health Assembly Fifty-first session, Geneva, 11-16 May 1998. Agenda item 21.3. Geneva: World Health Organization; 1998. (WHA51.17; http://apps.who.int/iris/handle/10665/79863, accessed 6 September 2017). 21. World Health Organization. Use of Quinolones in Food-producing animals and Potential Impact on Human Health: Report of a WHO Meeting. Geneva, Switzerland. 2-5 June 1998. (http://apps.who.int/iris/bitstream/10665/66401/1/WHO_EMC_ZDI_98.12_(p1-p130).pdf, accessed 4 August 2017). 22. World Health Organization. Global action plan on antimicrobial resistance. World Health Organization 2015. (http://www.who.int/antimicrobial-resistance/global-action-plan/en/, accessed 4 August 2017). 23. Wierup M. The Swedish experience of the 1986 year ban of antimicrobial growth promoters, with special reference to animal health, disease prevention, productivity, and usage of antimicrobials. Microbial Drug Resistance 2001;7(2):183-90. 24. Castanon JIR. History of the Use of Antibiotic as Growth Promoters in European Poultry Feeds. Poultry Science 2007;86:2466–2471. doi:10.3382/ps.2007-00249. 25. US Food and Drug Administration: Extra-label use and antimicrobials. (http://www.fda.gov/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/ucm421527.htm, accessed 25 February 2016). 26. A review of antimicrobial resistance in the food chain: A technical report for MAFF. Ministry of Agriculture, Fisheries and Food. United Kingdom, July 1998. 27. The Copenhagen Recommendations: Report from the Invitational EU Conference on the Microbial Threat. Copenhagen, Denmark. 9-10 September 1998. 28. The Use of Antibiotics in Food-producing Animals: Antibiotic-resistant Bacteria in Animals and Humans. Report of the Joint Expert Advisory Committee on Antibiotic Resistance (JETACAR). Commonwealth of Australia, 1999. (http://www.health.gov.au/internet/main/publishing.nsf/Content/health-pubs-jetacarcnt.htm/%24FILE/jetacar.pdf, accessed 4 August, 2017). 29. DANMAP 2014 - Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food-producing animals, food and humans in Denmark. (http://www.danmap.org/~/media/Projekt%20sites/Danmap/DANMAP%20reports/DANMAP%2 02014/Danmap_2014.ashx, accessed 25 February 2016). 30. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. Infectious Disease Society of America, 2004. 31. The Need to Improve Antimicrobial Use in Agriculture: Ecological and Human Health Consequences. A Report of the Facts about Antibiotics in Animals and the Impact on Resistance (FAIIR) Project. Clinical Infectious Diseases 2002;34 (Suppl 3): S1-S144. 40

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21 September 2017 (http://emerald.tufts.edu/med/apua/news/news---press-release-2012_3_2534592257.pdf, accessed 25 February 2016). Nelson JM, Chiller TM, Powers JH, Angulo FJ. Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story. Clinical Infectious Disease 2007;44(7):977-80. Speksnijder DC1, Mevius DJ, Bruschke CJ, Wagenaar JA. Reduction of veterinary antimicrobial use in the Netherlands. The Dutch success model. Zoonoses Public Health 2015;62 Suppl 1:7987. doi: 10.1111/zph.12167. OIE List of Antimicrobial Agents of Veterinary Importance, May 2015. (http://www.oie.int/fileadmin/Home/eng/Our_scientific_expertise/docs/pdf/Eng_OIE_List_anti microbials_May2015.pdf, accessed 25 February 2016). Antimicrobials in Agriculture and the Environment: Reducing unnecessary use and waste. Chaired by Jim O’Neill. December 2015. (https://amrreview.org/sites/default/files/Antimicrobials%20in%20agriculture%20and%20the%20environme nt%20-%20Reducing%20unnecessary%20use%20and%20waste.pdf, accessed 6 September 2017). McDonald’s Global Vision for Antimicrobial Stewardship in Food-producing animals. (http://www.aboutmcdonalds.com/content/dam/AboutMcDonalds/Sustainability/Antimicrobial _Stewardship_Vision.pdf, accessed 25 February 2016).

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Annex 1: External experts involved in development of these guidelines and the members of the WHO Steering Group and secretariat I. Guideline Development Group Centre for Microbiology Research Kenya Medical Research Institute Nairobi, Republic of Kenya Expertise: Veterinary medicine, veterinary microbiology, tropical medicine Hyo-Sun Kwak Director Division of Enteric Disease Center for Infectious Disease Korea National Institute of Health Osong, Republic of Korea Expertise: Microbiology, food safety Scott McEwen (Co-chair) Professor Department of Population Medicine Ontario Veterinary College University of Guelph Guelph, Canada Expertise: Veterinary medicine, veterinary epidemiology Gérard Moulin Anses-Agence Nationale du Médicament Vétérinaire Fougères, France Expertise: Veterinary medicine, microbiology, veterinary pharmaceutical legislation Antoinette Ngandjio Microbiologist Chef Service Hygiène et Environnement Section Microbiologie Centre Pasteur Cameroun Yaounde, Republic of Cameroon Expertise: Clinical microbiology, tropical infectious diseases Bernard Rollin Professor Department of Philosophy Colorado State University Fort Collins, United States of America Expertise: Animal ethics, animal welfare Flavia Rossi Samuel Kariuki 42

Hanan Balkhy Director WHO Collaborating Center for Infection Control Executive Director, Infection Prevention and Control Department- 2134 King Saud Bin Abdulaziz University for Health Sciences Riyadh, Kingdom of Saudi Arabia Expertise: Medicine, infection prevention and control Peter Collignon (Chair) Executive Director ACT Pathology Canberra Hospital Woden, Australia Expertise: Medicine, infectious diseases, clinical microbiology John Conly Professor of Medicine, Microbiology, Immunology and Infectious Diseases Cumming School of Medicine University of Calgary and Albert Health Services Calgary and Area Calgary, Canada Expertise: Medicine, infectious diseases, GRADE methodology Cindy Friedman Team lead National Antimicrobial Monitoring System Enteric Diseases Epidemiology Branch Centers for Disease Control and Prevention Atlanta, United States of America Expertise: Medicine, infectious diseases, public health, epidemiology Aidan Hollis Professor of Economics University of Calgary Calgary, Canada Expertise: Economics including of pharmaceuticals and antibiotics

21 September 2017 Director Microbiology Laboratory Hospital das Clínicas Pathology Department Faculty of Medicine of the University of São São Paulo, Federation Republic of Brazil Expertise: Clinical microbiology, pathology David Wallinga Senior Health Officer Natural Resources Defense Council San Francisco, United States of America Expertise: Medicine, food agriculture, public health policy, consumer organization Postdoctoral Research Associate Texas Tech University Texas, United States of America Expertise: Animal science, veterinary animal production, veterinary microbiology IV. Systematic Review Teams Bond University Team Mina Bakhit PhD student Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Elaine Beller Associate Professor Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Oyungerel Y. Byambasuren PhD student Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Justin Clark Senior Information Specialist Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Peter Coxeter PhD student Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Chris Del Mar Professor Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia 43

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II. GRADE Methodologists John Conly Professor of Medicine, Microbiology, Immunology, and Infectious Diseases Cumming School of Medicine University of Calgary and Alberta Health Services Calgary and Area Calgary, Canada Mauricio Ferri Critical Care Medicine Health Services Research Princeton, United States of America

III. Technical Resource Persons Frederick J Angulo Associate Director for Science Division of Global Health Protection Center for Global Health Centers for Disease Control and Prevention Atlanta, United States of America Expertise: Veterinary medicine, public health, epidemiology, antimicrobial resistance Ellen Silbergeld Professor Johns Hopkins University Bloomberg School of Public Health Baltimore, United States of America Expertise: Geography, environmental health science Hattie Webb

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Paul Glasziou Professor Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Respati Anggi Ranakusuma PhD student Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Anna M. Scott Senior Research Fellow Centre for Research in Evidence-Based Practice (CREBP) Bond University Gold Coast, Australia Darren Trott Professor Australian Centre for Antimicrobial Resistance Ecology, The University of Adelaide, Roseworthy, Australia University of Calgary Team Herman W. Barkema Professor Epidemiology of Infectious Diseases Faculty of Veterinary Medicine and Cumming School of Medicine University of Calgary Calgary, Canada Niamh P. Caffrey Department of Ecosystem and Public Health Faculty of Veterinary Medicine University of Calgary Calgary, Canada Susan C. Cork Professor Department of Ecosystem and Public Health Faculty of Veterinary Medicine University of Calgary Calgary, Canada

Heather Ganshorn Libraries and Cultural Resources University of Calgary Calgary, Canada William A. Ghali Professor, Department of Medicine Cumming School of Medicine and O’Brien Institute for Public Health University of Calgary Calgary, Canada James D. Kellner Professor, Department of Pediatrics Cumming School of Medicine and O’Brien Institute for Public Health University of Calgary Calgary, Canada Diego B. Nóbrega Department of Production Animal Health Faculty of Veterinary Medicine University of Calgary Calgary, Canada Alicia J. Polachek W21C Research and Innovation Centre Cumming School of Medicine University of Calgary Calgary, Canada Paul E. Ronksley Assistant Professor Department of Community Health Sciences Cumming School of Medicine University of Calgary Calgary, Canada Nishan Sharma W21C Research and Innovation Centre Cumming School of Medicine University of Calgary Calgary, Canada Karen L. Tang Department of Medicine Cumming School of Medicine University of Calgary Calgary, Canada

21 September 2017 Langelihle Simela Business Development Manager Agribusiness Centre of Excellence Barclays Africa Johannesburg, Republic of South Africa Expertise: Animal science, veterinary tropical diseases Linda Tollesfon Rear Admiral (Upper Half) U.S. Public Health Service (Retired) United States of America Expertise: Veterinary medicine, veterinary pharmaceutical legislation, public health Jan L.M. Vaaten Executive Secretary - World Veterinary Association Executive Director – Federation of Veterinarians of Europe Brussels, Kingdom of Belgium Expertise: Veterinary medicine Haruo Watanabe Professor Graduate School, International University of Health and Welfare Tokyo, Japan Expertise: Medicine, clinical microbiology Khadija Id Sidi Yahia Director Direction des Intrants et des Laboratoires Rabat, Kingdom of Morocco Expertise: Veterinary medicine, food safety, antimicrobial resistance

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V. External Review Group Saeed Murie Al-Shahrani Veterinary Pharmacologist Saudi Food and Drug Authority Riyadh, Kingdom of Saudi Arabia Expertise: Veterinary medicine, veterinary pharmacology Casey Barton Behravesh Director, One Health Office National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control and Prevention Atlanta, United States of America Expertise: Veterinary medicine, public health, epidemiology, food safety, one health Delia Grace Programme Leader Animal and Human Health Flagship Leader Food Safety International Livestock Research Institute Nairobi, Republic of Kenya Expertise: Veterinary medicine, veterinary epidemiology, food safety Dik Mevius Head Dutch National Reference Laboratory for Antimicrobial Resistance in Animals Bunnik, Kingdom of the Netherlands Expertise: Veterinary medicine, veterinary infectious diseases, veterinary microbiology Paturkar Ashish Motiram Associate Dean Bombay Veterinary College Mumbai, Republic of India Expertise: Veterinary medicine, veterinary public health Hnin Thidar Myint Deputy Director Livestock Health and Development Section Livestock Breeding and Veterinary Department, Ministry of Agriculture, Livestock and Irrigation Yangon, Republic of the Union of Myanmar Expertise: Veterinary medicine, agricultural sciences 45

VI. WHO Steering Group Awa Aidara-Kane (Lead) Coordinator Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO Geneva, Switzerland WHO AMR One Health work stream Mohamed Sheriff Technical Officer Food Safety WHO Regional Office for Africa (AFRO) Brazzaville, Republic of the Congo

21 September 2017 WHO Regional Office for the Western Pacific (WPRO) Manila, Republic of the Philippines Special Members of the WHO Steering Group* *they contributed to the development of these guidelines but should not be taken responsible for the contents of these guidelines.

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Mohamed Elmi Regional Adviser for Food and Chemical Safety WHO Regional Office for the Eastern Mediterranean (EMRO) Amman, Hashemite Kingdom of Jordan Bernadetta Allegranzi Infection Prevention and Control Global Unit Service Delivery and Safety, Health Systems and Innovation WHO Geneva, Switzerland WHO AMR Infection Prevention and Control work stream Carmem Pessoa AMR Secretariat, Office of the Director General Geneva, Switzerland WHO AMR National Action Plans and Surveillance work stream Nicola Magrini Scientist Secretary of the Expert Committee on the Selection and Use of Essential Medicines Policy, Access and Use Team, Essential Medicines and Health Products WHO Geneva, Switzerland WHO AMR Rational Use work stream Enrique Perez Health Emergency Information and Risk Assessment, Health Emergencies Regional Office for Americas (WHO AMRO) Washington DC, United States of America Gyanendra Gongal Technical Officer Country Health Emergency Preparedness and IHR, World Health Emergency Programme WHO Regional Office for South-East Asia (SEARO) New Delhi, Republic of India Peter Sousa Hoejskov Technical Lead Food Safety Health Security and Emergencies

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Elisabeth Erlacher-Vindel Head Scientific and New Technologies Department World Organisation for Animal Health (OIE) Paris, France Henk Jan Ormel Senior Veterinary Policy Advisor Animal Health Service Food and Agriculture Organization of the United Nations (FAO) Rome, Republic of Italy

VII. WHO secretariat Awa Aidara-Kane Coordinator Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO Geneva, Switzerland Amina Benyahia Chaieb Scientist Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO Geneva, Switzerland Chrystelle Daffara Administrative Assistant Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO Geneva, Switzerland Francoise Fontannaz-Aujoulat Technical Officer Risk Communication and Education Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO 46

21 September 2017 Geneva, Switzerland Jorge R. Matheu Project Officer Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO Geneva, Switzerland Yuki Minato Project Officer Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO Geneva, Switzerland Kazuaki Miyagishima Director Foodborne and Zoonotic Diseases Department of Food Safety and Zoonoses WHO Geneva, Switzerland

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6 August 2017

Annex 2: Summary and management of declared secondary interests Members of the Guideline Development Group Name Hanan BALKHY Peter COLLIGNON (Cochair) John CONLY

Declared interest(s) None declared Travel costs received from his employer (Canberra hospital) to attend a WHO meeting 1) Attendance of a meeting in 2013 on the use of linezolid in humans for nosocomial pneumonia and skin and soft tissue infections. Honorarium and travel costs covered by Pfizer, a pharmaceutical company that produces a wide range of medicines including antimicrobials. 2) Attendance of a meeting in 2014 on monoclonal antibodies (a potential replacement to certain antibiotics) for Clostridium difficile infection in humans. Honorarium and travel costs covered by Merck Canada, a pharmaceutical company that produces a wide range of medicines including antimicrobials. 3) Consulting role by affiliated institution to Sanofi-Pasteur for scoping review of Clostridium difficile infections. Review was ultimately not conducted. Travel costs covered by Sanofi-Pasteur to attend a meeting in 2014. 4) Travel costs covered by BioMerieux for attending a meeting on antimicrobial stewardship in 2015. 5) Attended a meeting as a guest speaker about antibiotic resistance in 2015. Honorarium and travel costs covered by BioMerieux. 6) Affiliated institution, University of Calgary, was commissioned to conduct a multi-centre randomized controlled trial for a Staphylococcus aureus vaccine to prevent post-operative infections in spinal fusion surgery patients. Travel and accommodation costs for work as local investigator covered by Pfizer. 48

Conflicts of interest None Not significant 1) Minor (financial)* 2) Minor (intellectual)* 3) Not significant 4) Not significant 5) Not significant 6) Not significant * One-time engagement in a topic not directly related to the scope of the WHO guidelines (i.e. use of antimicrobials in animals).

Management plan Full participation Full participation Full participation as a Guideline Development Group member and methodologist. In addition to Dr Conly, a second methodologist who is neutral to the subject matter was invited to strengthen the methodological base.

6 August 2017 Cindy FRIEDMAN Aidan HOLLIS None declared 1) Provision of expert testimony to several generic pharmaceutical manufacturers (Teva, Sandoz, Apotex, Cobalt and Mylan) concerning the financial extent of the damages either to the generic company or to the patentee. 2) Consulting reports on the economic effects of tendering for generic drugs in Canada (2013) and the design of damages rules in Canada (2015) provided to the Canadian Generic Pharmaceutical Association. None declared None declared Research grants received by public institution None declared None declared Served as an animal welfare expert in 2005-2008 on the few commissions to study the untoward effects of the industrialized animal agriculture None declared Employee of non-profit, tax-exempt membership organization (Natural Resource Defense Council) based in United States of America that primarily advocates for environmental protections including the messaging to reduce antibiotic use in livestock. No individual grants received. None 1) Not significant 2) Not significant Full participation Full participation

Samuel KARIUKI Hyo-Sun KWAK Scott McEWEN (Co-chair) Gérard MOULIN Antoinette NGANDJIO Bernard ROLLIN

None None Not significant None None Not significant

Full participation Full participation Full participation Full participation Full participation Full participation

Flavia ROSSI David WALLINGA

None Not significant

Full participation Full participation

Methodologists Name Declared Interest(s) Conflicts of Interest Management plan

6 August 2017 John CONLY Mauricio FERRI Same as above 1) Spouse is a Bristol-Myers Squibb employee as a medical scientist at the Immunology Department. 2) Consultancy service provided to the Oxford University not on the related subject matter 3) Consultancy service provided to the WHO Guideline Review Committee since 2016 Same as above 1) Not significant 2) Not significant 3) Not significant Same as above Full participation

Members of the External Review Group Name Delia GRACE Langelihle SIMELA Casey Barton BEHRAVESH Saeed Murie ALSHAHRANI Linda TOLLESFON Khadija Id Sidi YAHIA Jan VAARTEM Dik MEVIUS Paturkar Ashish MOTIRAM Hnin Thidar MYINT Haruo WATANABE

Declared Interest(s) None declared None declared Travel support provided by international non-profit-organization None declared Employed for governmental institution None declared Research grant received by public institution None declared None declared None declared None declared

Conflicts of Interest None None Not significant None Not significant None Not significant None None None None

Management plan Full participation Full participation Full participation Full participation Full participation Full participation Full participation Full participation Full participation Full participation Full participation

6 August 2017

Annex 3: Critical and important outcomes for decision-making Methods The WHO Steering Group, with input from the GDG, systematic review teams, and guideline methodologists considered potential outcomes discussed at the first GDG meeting and drafted a list of potentially important outcomes related to use of antimicrobials in food-producing animals. A questionnaire with these potential outcomes was then distributed to GDG members who were asked to rank the relative importance of each potential outcome on a nine-point scale ranging from 1 (least important) to 9 (most important). ). GDG members were informed that critical outcomes are usually rated from 7-9, important outcomes 4-6, and unimportant 1-3. The median score was calculated for each outcome based on the GDG members’ responses, to determine outcomes that are ‘critical’ (median score ≥7) and ‘important but not critical’ (median score 4–6) for making decisions about the recommendations. To ensure consistency, the WHO Steering Group reviewed the final list of critical and important outcomes for each guideline question (see Annex 3 for the final list of outcomes).

Results The GDG gave very high ratings to desirable outcomes from restrictions on antimicrobial use in animals; it gave the highest value (median 9, with score of 9 judged of “most importance”) to the consideration that when people were infected with antimicrobial-resistant bacteria, this leads to more severe health outcomes. The GDG also gave high ratings to outcomes related to decreases in the prevalence of antimicrobial-resistant bacteria and/or antimicrobial-resistant determinants in food-producing animals (median 8) and humans (median 7-8). Undesirable outcomes were rated of lower importance, including decreases in food-producing animal health and welfare (median 4), decreases in food security (median 2), food safety (median 4), increased antimicrobial treatment use in animals following restrictions on growth promoters (median 4), and increased costs to producers and loss of income to national economies (median 3). However, the GDG did value the need to protect animal welfare by ensuring availability of antimicrobials to treat sick animals.

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Questionnaire of Outcomes (with median and range importance score) General questions

A1. Human infections with antimicrobial-resistant bacteria are associated with more clinically severe human health consequences compared to human infections with antimicrobial-susceptible bacteria 1 2 3 4 5 6 7 8 9 of least importance of most importance

Limited importance important Median: 9, Range: 6-9 Responses 9 9 9 9 9 9 7 9 8 9 9 9

critically

A2. Restrictions on the use of antimicrobial agent(s) in food-producing animals decreases the prevalence of antimicrobial-resistant bacteria and/or antimicrobial-resistant determinants in food-producing animals 1 of least importance 2 3 4 5 6 7 8

9 of most importance

Limited importance important Median: 8, Range: 3-9 Responses 9 8 9 9 3 7 8 7 8 8 9 7

critically

A3. Restrictions on the use of antimicrobial agent(s) in food-producing animals decreases the prevalence of antimicrobial-resistant bacteria and/or antimicrobial-resistant determinants in humans 1 of least importance 2 3 4 5 6 7 8 9 of most importance

Limited importance important Median: 7, Range: 4-9 Responses 7 8 9 9 7 7 7 8 4 8 9 7 6

critically

6 August 2017 Specific questions

B1. Complete restriction of the use of antimicrobials on the WHO CIA list for growth promotion in food-producing animals reduces the presence of antimicrobial-resistant determinants and/or antimicrobial-resistant bacteria in humans. 1 of least importance 2 3 4 5 6 7 8

9 of most importance

Limited importance important Median: 8, Range: 5-9 Responses 6 8 9 9 8 8 8 8 9 8 9 8

critically

B2. Complete restriction of the use of antimicrobials on the WHO CIA list for disease prevention in food-producing animals reduces the presence of antimicrobial-resistant determinants and/or antimicrobial-resistant bacteria in humans. 1 of least importance 2 3 4 5 6 7 8

9 of most importance

Limited importance important Median: 7, Range: 6-8 Responses 6 8 8 6 7 8 7 8 7 8 8 7

critically

B3. Restriction of the highest priority critically important antimicrobials on the WHO CIA list in food-producing animals reduces the presence of antimicrobial-resistant determinants and/or antimicrobial-resistant bacteria in humans. 1 of least importance 2 3 4 5 6 7 8

9 of most importance

Limited importance important Median: 8, Range: 6-9 Responses 9 8 9 8 8 9 6 8 8 8 9 8

critically

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B4. Undesirable outcomes on human health from restriction of antimicrobials from the CIA list used as growth promoters or disease prevention and highest priority antimicrobials from the CIA list in food-producing animals include: Decreases in food-producing animal health and welfare 2 3 4 5 6 7 8

1 of least importance

9 of most importance

Limited importance Median: 4, Range: 2-9 Responses 5 2 5 3 2 2 4 6 7 4 9

critically important

Decreases in food and protein availability to people. 2 3 4 5 6 7 8

1 of least importance

9 of most importance

Limited importance Median: 2, Range: 1-7 Responses 4 1 5 2 2 2 4 1 4 2 6

critically important

Increased transmission of human pathogens (e.g. Salmonella, Campylobacter etc.) because more carrier animals and/or less healthy animals sent to slaughter.

1 of least importance

9 of most importance

Limited importance Median: 4, Range: 1-9 Responses 7 4 4 1 6 3 4 4 4 4 4 9

critically important

6 August 2017

Increased transmission of resistant bacteria from food-producing animals to people (due to increase in antimicrobial treatment use to compensate for loss of growth promoter use) (WHO 2002). 2 3 4 5 6 7 8

1 of least importance

9 of most importance

Limited importance Median: 4, Range: 1-7 Responses 6 2 2 1 4 4 5 4 3

critically important

Increased costs to producers and loss of income to national economies related to decreases in health and productivity in food-producing animals 2 3 4 5 6 7 8

1 of least importance

9 of most importance

Limited importance Median: 3, Range: 1-8 Responses 6 2 2 1 2 4 6 2 4 2 3

critically important

6 August 2017

Annex 4: Summaries of systematic reviews including supplementary report 1. 2. 3. Bond University Team: Systematic Review University of Calgary Team: Systematic review with meta-analysis University of Calgary Team: Supplementary report

Summary of Systematic Review #1 Use in food-producing animals of critically important antimicrobial agents for human medicine: systematic review, May-October 2016 Bond University Team Background The contribution of antimicrobial administration to food-producing animals to antimicrobial resistance in bacteria in humans forms a potential risk to human health. WHO is embarking on guidelines to advise Member States. To support this, it commissioned a systematic review of the scientific literature to address the potential benefits of limiting antimicrobials for this purpose. Questions Do interventions for limiting use of antimicrobials in food-producing animals reduce antimicrobial resistance in bacteria in 1) other animals; and 2) humans? Methods Timeline: This was a rapid systematic review, undertaken in 4½ months. Search strategy: This was built and tested with a validation set of already known relevant studies. Screening: teams of trained personnel screened by title/abstract, and then by full-text; consistency between screeners was tested. Data extraction: experienced teams extracted data into pre-designed and tested forms. Synthesis: two experts undertook a narrative synthesis of the data. Heterogeneity (principally from different animals, settings, antimicrobial classes, interventions and sampling timeframes) precluded meta-analysis. Results One hundred and eleven studies were included in the review. One study provided good evidence that withdrawal of antimicrobial results in a reduction of identifiable resistance in potential pathogens in retail meat food for human consumption, and in humans, with credible effect sizes and time sequences. There is also adequate evidence to conclude that limiting antimicrobial supplementation in food-producing animals feed reduces the burden of antimicrobial resistance in bacteria in animals, but insufficient evidence to quantify this effect (which may be specific to different antimicrobials at different doses, food-producing animals and environments). Administration of one antimicrobial can induce resistance in an antimicrobial from a completely different class. Conclusions Limiting the use of antimicrobial supplementation for food-producing animals is likely to reduce the presence of antimicrobial resistance in bacteria in other food-producing animals and humans. This may extend beyond the antimicrobial used to other antimicrobial classes. More primary studies are necessary to strengthen the research evidence. 57

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Summary of Systematic Review and Meta-Analysis #2 Restriction in the Use of Antibiotics in Food-Producing Animals and Antibiotic Resistance in FoodProducing Animals and Humans: Systematic Review and Meta-Analysis University of Calgary Team Background Antibiotics are the cornerstone of therapy for bacterial infectious diseases in humans and animals. The ‘One Health’ approach recognizes that the health of humans, animals, and the environment are intricately linked, that the use of antibiotics in animals selects for resistant bacteria, and that bacteria and their resistant genetic elements can be transmitted cross-species from animals to humans. The rise in resistance to antibiotics is therefore a threat to public health globally and there is growing recognition that we may need to use antibacterial agents in a more judicious way. In this systematic review and meta-analysis, commissioned by WHO, we sought to summarize the evidence on the effects interventions to reduce antibiotic use in food-producing animals have on the presence of antibiotic resistant bacteria and resistant genetic elements in animals and in humans. Methods We conducted a comprehensive search of electronic databases (including Agricola, AGRIS, BIOSIS Previews, CAB Abstracts, MEDLINE, EMBASE, Global Index Medicus, ProQuest Dissertations, and Science Citation Index) in July 2016. In addition, we reviewed conference proceedings of major scientific meetings on antibiotic resistance and conducted a thorough grey literature search that included governmental websites from a wide range of regions globally. Inclusion criteria were original studies that reported on any interventions that aimed to reduce antibiotic use in foodproducing animals and compared presence of antibiotic resistant bacteria or genetic resistance elements between intervention and comparator groups in food-producing animals or in humans. Analysis was conducted and reported separately for animals and humans. We pooled studies that reported an absolute risk difference in the prevalence of resistance in bacteria isolated from intervention compared to control groups using DerSimonian and Laird random-effects models. Meta-analysis for animals was conducted separately for different antibiotic classes for six different bacteria and sample type combinations, while meta-analysis for humans was not stratified due to smaller numbers of studies. Studies reporting on genetic elements of resistance and studies that could not be meta-analyzed (because they reported on different units of analyses or did not provide risk differences) were described qualitatively. Results A total of 5,835 unique records were identified and screened. Of these, 371 were reviewed at the full-text stage. In total, 177 studies were included in the systematic review. Of these, 175 described antibiotic resistance outcomes in animals, of which 80 were meta-analyzed. Twenty-one studies described antibiotic resistance outcomes in humans (19 of which also reported antibiotic resistance in bacteria isolated from animals), of which 13 were meta-analyzed. The pooled absolute risk reduction of the prevalence of antibiotic resistance in bacteria isolated from animals, with interventions that restricted antibiotic use, varied across different antibiotic classes, bacteria, and sample types, but ranged from 0% to 39%; in general, the prevalence of antibiotic resistance was commonly 10-20% lower in intervention compared to control groups. The pooled prevalence of multidrug resistance was 24-32% lower in bacteria isolated from intervention groups. These findings held through many different layers of stratification including by intervention type. Similarly, for humans, the pooled prevalence of antibiotic resistance was 24% lower in intervention groups (where interventions to reduce antibiotic use in food-producing animals were implemented) compared to 58

6 August 2017 control groups. The effect was similar, albeit weaker, when considering humans without direct contact with livestock animals, compared to farm workers. Conclusion There is a large body of evidence that, when pooled, consistently shows that interventions that restrict the use of antibiotics in food-producing animals are associated with a reduction in the presence of antibiotic resistant bacteria in these animals. Our analysis also suggests that there may be a reduction in the number of antibiotic resistant bacteria in human populations with these interventions, with the greatest effect for those in direct contact with animals. These findings are in keeping with One Health approach and the understanding that animals and humans share the same environment, and they suggest that the effects of restricting antibiotic use in animals on antibiotic resistance may extend beyond the animals themselves.

Summary of supplementary report of systematic review and Meta-Analysis #3

Supplemental Report to: Restriction in the Use of Antibiotics in Food-Producing Animals and Antibiotic Resistance in Food-Producing Animals and Humans: Systematic Review and MetaAnalysis University of Calgary team The full report to the World Health Organization (WHO), titled “Restriction in the use of antibiotics in food-producing animals and antibiotic resistance in bacteria isolated from food-producing animals and humans—a systematic review and meta-analysis” was completed in October 2016. Findings from this completed review were used for development of the WHO guidelines on the use and restriction of antibiotics in food-producing animals. To assist further with development of recommendations, the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) requested further supplemental work. This was: (1) an update of the literature search, to identify studies published since the search strategy was last run in July 2016; (2) stratified analysis of the pooled reduction in antibiotic resistance, by the type of antibiotic use that is restricted or targeted by interventions three; and (3) data extraction of the studies included in the systematic review for unintended consequences or harms from interventions that restrict antibiotic use. This report presents the results of the requested supplemental work. Update of the literature search The search strategy described in the original systematic review was re-run in January 2017 in the following electronic databases, to capture studies published since our July 2016 search: Agricola – Ebsco Platform, AGRIS (http://agris.fao.org), BIOSIS Previews – Web of Knowledge Platform, CAB Abstracts – Ebsco Platform, MEDLINE – Ovid Platform (Epub Ahead of Print, In-Process & Other NonIndexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), EMBASE – Ovid Platform, Global Index Medicus (http://www.globalhealthlibrary.net/): The non-MEDLINE indices included: AIM (AFRO), LILACS (AMRO/PAHO), IMEMR (EMRO), IMSEAR (SEARO), WPRIM (WPRO), WHOLIS (KMS), and SciELO, ProQuest Dissertations – ProQuest Platform, and Science Citation Index – Web of Knowledge Platform. A total of 191 citations were identified. Two authors reviewed all abstracts for potential eligibility for inclusion into the systematic review. Any abstract that (a) reported on original research, (b) described an active intervention that aimed to limit antibiotic use in animals, and (c) described 59

6 August 2017 antibiotic resistance in bacteria isolated from animals or humans were selected for full-text review. Fifteen studies were selected for full-text review, of which four met the pre-specified criteria, as described in the original report, for inclusion into the systematic review. All four were animal studies, only one of which could be included into the main set of meta-analyses. We have updated the systematic review and meta-analysis to include these four studies. A revised full report, dated 7 March 2017, was provided to WHO. The findings and conclusions in the updated report are unchanged from those in the original report. Stratified analysis by type of use To conduct the stratified analysis by use type, it was necessary to classify interventions based on the type of antibiotic use targeted. The following classification scheme was thereby created, with input and feedback from WHO AGISAR: (1) restriction on the use of all antibiotics, (2a) antibiotic classspecific restriction, or restriction on the use of one or more, but not all, classes of antibiotics, for all indications of use, (2b) antibiotic-specific restriction, or restriction on the use of one or more individual antibiotics, for all indications of use, (3) restriction on the use of antibiotics for all nontreatment indications including growth promotion and disease prevention, (4) restriction on the use of antibiotics for the non-treatment indications of growth promotion and disease prevention, (5) restriction on the use of antibiotics for purposes of growth promotion only, and (6) undetermined. Of particular note, every study included into the systematic review assessed an intervention that restricted the use of antibiotics. Studies that did not specify the type of antibiotic use or indication targeted in this restriction were classified as “undetermined”. This included studies, for example, that compared regions or farms using “more” versus “less” antibiotics with no indication that was specifically targeted or described, or studies that assessed the impact of reducing antibiotic use in a jurisdiction without delineating how this was achieved. Each category in the classification scheme is mutually exclusive. If a single study included more than one intervention, then each intervention was classified separately based on the above approach. Of the 179 animal studies included in the systematic review, 69 restricted all uses of antibiotics, 36 studies restricted use of antibiotics for all non-treatment purposes, while 27 restricted the use of antibiotics for growth promotion only. A total of 39 studies could not be classified based on the type of antibiotic use targeted by the intervention. An index of the 179 animal studies, their corresponding references from the original report, and their assigned classifications of interventions is presented in a supplemental table in the appendix to this supplemental report. A table also presents the categorization of interventions by type of antibiotic use being targeted for restriction, for human studies. Of the 21 human studies, five restricted all uses of antibiotics, two restricted antibiotic use for all non-treatment indications, and seven restricted use of antibiotics for growth promotion only. Five studies could not be classified based on the type of antibiotic use targeted by the intervention. An index of the 21 human studies, their corresponding references from the original report, and their assigned classifications of interventions is presented in a supplemental table to this supplemental report. Similar to the stratified analysis conducted in the original systematic review and meta-analysis, stratified meta-analysis was performed for all studies amenable to meta-analysis, ignoring specific bacterial species, sample types, units of analysis, and antibiotic classes. The supplemental report has a table that outlines the results from meta-analysis stratified by the type of antibiotic use targeted by interventions in animal studies. Stratified meta-analysis must be interpreted with some caution, due to the lower numbers of studies that can be included and the overlapping confidence intervals in the pooled estimates across strata. With these caveats in mind, we would propose three high-level observations from the stratified 60

6 August 2017 analysis, which we summarize below, followed by further elaboration: 1) the type of antibiotic use targeted by interventions is not specified in many of the studies identified by our search. This finding underlines the need for better characterization of interventions in future research, and perhaps even more importantly, in the development of future policy and regulations. 2) There is some suggestion that the interventions that target only specific antibiotic classes or specific antibiotic drugs may have less effect on antibiotic resistance than do antibiotic restrictions covering all classes. 3) Among antibiotic restriction interventions that target all classes, there does not seem to be any advantage of complete bans preventing any use relative to restrictions that still permit treatment and disease prevention use. Unintended consequence Data were extracted from the studies included in the systematic review, regarding potential harms stemming from interventions that restrict antibiotic use. Categories of potential harms included: 1) increased use of antibiotics, 2) adverse effects on human health, 3) decrease in food and protein availability, 4) food safety, 5) adverse effects on animal health and welfare, 6) adverse effects on animal production, and 7) economic consequences. Only 48 studies in total (all animal studies, two of which also examined antibiotic resistance in bacteria isolated from humans) reported any data on the presence or absence of potential harms of interventions that restrict antibiotic use. Of these, 32 explicitly had at least one of the aforementioned potential harms as a primary research objective. One study examined animal production consequences as a secondary objective. The other 15 studies reported potential harms in the discussion section without pre-specifying these as objectives. No studies reported adverse effects on human health or on food and protein availability. A table in the report presents a summary of the extent to which information on harms is reported in the identified studies. Of note, a single study could report on more than one potential harm. A. Antibiotic use Five studies reported on potential unintended consequences with regard to the total amount of antibiotics used. One study reported that when one antibiotic growth promoter was banned, there tended to be an increased use of other permitted antibiotic growth promoters until the use of these, too, was restricted. The other four studies reported that when antibiotic use was restricted, this resulted in increased administration of antibiotics to individual animals for treatment purposes, but that the total amount or volume of antibiotics used nevertheless decreased. B. Food safety The most widely reported potential unintended consequence was in the domain of food safety, with 34 studies reporting on this outcome. Of these, 14 (41%) found that interventions that restricted antibiotic use resulted in increased contamination with bacteria (including Salmonella spp., Campylobacter spp., and Enterobacteriaceae) in the retail meats produced. Fifteen of 34 studies (45%) reported no difference in contamination rates between food products from intervention and comparator groups. A smaller percentage of studies (12%) demonstrated either variable results within studies or a lower level of contamination of meats in intervention versus comparator groups. The clinical and public health significance of these findings are unclear, especially as to what extent adequate preparation and cooking can mitigate the risk of bacterial contamination of raw retail meat, and whether higher bacterial contamination translates into increased clinical and zoonotic disease. C. Animal health Only five studies reported potential adverse effects on animal health. Three such studies were specific to dairy herds, showing variable results. Two of the three reported higher prevalence of intra-mammary infections when the use of antibiotics is restricted (though one study indicated that the higher prevalence was significant only at parturition but not the dry-off period), while the third 61

6 August 2017 study showed no difference in the prevalence of mastitis between intervention and comparator groups. Berge et al. reported an increase in respiratory disease but decrease of diarrhoea in calves where antibiotics used for disease prevention and growth promoters were restricted. Lastly, DoradoGarcia et al. reported no difference in mortality or mean mortality age in intervention versus comparator groups. D. Animal production Studies reporting on the effects of antibiotic restriction on animal production again demonstrated variable results. One study indicated that such interventions resulted in greater weight gain (from reduced diarrhoea) in intervention groups,13 while two studies indicated that animal production was adversely affected by antibiotic restriction, with increased feeding time (to achieve a target weight) or increased production cycle duration in intervention groups. There may also be effects on parity and milk yield, with antibiotic restriction being associated with increased parity but lower milk yield in one study. E. Costs and economics Only three studies reported potential economic consequences of antibiotic restriction interventions. One study showed that restriction in antibiotic use, in combination with restrictions in the uses of hormone implants and anti-helminthics, may increase feeding time to reach target weight in animals, leading to increases in the need for land for disposal of waste, and increases in energy consumption for animal food production. It is difficult to disentangle the extent to which these unintended consequences in animal production and costs are attributable to the antibiotic restrictions themselves, versus the co-interventions that were implemented in this study. Other studies show variable economic implications to treatment and veterinary costs, with one study showing an increase while another showing a decrease in such costs. Conclusion The supplemental analysis that has been requested sheds light on various policy-relevant questions. Specifically, in the bacteria studied, broad restrictions covering all antibiotic classes appear to be more effective in reducing antibiotic resistance compared to narrow restrictions of one antibiotic class or drug. Furthermore, complete restrictions on the use of all antibiotics do not seem to be more effective than interventions that allow for appropriate treatment use. Regarding potential unintended consequences, there appears to be a recurring finding of somewhat increased use of treatment antibiotic courses in individual animals (though an overall reduction in the volume of antibiotics used) with interventions that restrict antibiotic use, and possible implications for food safety given the possible higher prevalence of bacterial contaminants in these food products. These findings are likely to be important to explore further as future guidelines and recommendations on antibiotic use are developed.

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Annex 5: Summaries of the narrative literature reviews 1. Illustrative example of probable transfer of resistance determinants from food-producing animals to humans: Streptothricins, Glycopeptides, and Colistin 2. Biological plausibility for associations between antimicrobial use in food-producing animals and increased risks of Human Exposures to, and Infections by, Antimicrobial-Resistant Zoonotic Pathogens 3. Potential Unintended Consequences Associated with Restrictions on Antimicrobial Use in Food-Producing Animals

Summary of Narrative Literature Review #1 Illustrative Example of Probable Transfer of Resistance Determinants from Food-Producing Animals to Humans: Streptothricins, Glycopeptides, and Colistin Hattie E. Webb Postdoctoral Research Associate Texas Tech University Texas, United States of America This review summarized the published evidence of probable transfer of resistance determinants for streptothricins, glycopeptides, and colistin from food-producing animals to humans. Streptothricins Nourseothricin, a streptothricin antimicrobial agent, was widely used as a growth promoter in the swine industry in the former German Democratic Republic from 1981-1988. In contrast, toxicity prevented use of streptothricin antimicrobial agents in humans. Less than one year after the introduction of nourseothricin in swine, a plasmid-borne streptothricin resistance (sat) seemingly emerged in E. coli isolated from swine administered nourseothricin. Subsequently, plasmid-borne streptothricin resistance was detected in the gut flora of humans with direct, indirect, and no contact to pig farms, but living in the same regions. Following reports of the plasmid-mediated streptothricin resistance demonstrates an illustrative example of the detection —and apparent emergence—of streptothricin resistant bacteria in swine as a result of antimicrobial use, and the dissemination of the resistant bacteria and mobile genetic elements conferring resistance to humans. Glycopeptides Avoparcin appears to have been widely used in food-producing animals, particularly in chickens and pigs, in parts of Europe, since before the mid-1970s. Vancomycin use in humans, in contrast, was very limited in Europe until the late 1990s. It appears likely that the use of avoparcin in foodproducing animals selected for the emergence and dissemination of a resistance gene cluster (VanA), which was increasingly identified in animals and healthy people. Molecular subtyping of the VanA gene cluster has identified variants that are more likely to be associated with certain foodproducing animal species. Subsequently, GRE were transmitted and found to colonize healthy humans, presumably via the food chain. Therefore, evaluation of the VanA gene cluster variants provides an illustrative example of the probable emergence and selection of a genetic resistance determinant due to antimicrobial use in food-producing animals, and subsequent dissemination of the resistant bacteria to humans. Colistin 63

6 August 2017 Colistin has been widely used in food-producing animals—particularly poultry and swine—in areas of Europe and Asia for decades, perhaps since the early 1980s or earlier. Colistin use in humans, in contrast, has been extremely limited, at least until recently. It appears highly probable that the use of colistin in food-producing animals has selected for a novel resistance gene (mcr-1), identified as far back as the mid-1980s in chickens in China, which has become increasingly identified in isolates from food-producing animals in many regions of the world since its discovery in 2015. This novel resistance gene has more recently been identified among isolates from humans; however, to date mcr-1 has been more frequently associated with food-producing animal and meat isolates compared to human isolates. These chains of events, despite the data gaps, provide an illustrative example of the probable emergence, selection, and widespread dissemination of a resistance gene due to antimicrobial use in food-producing animals, and subsequent transfer of bacteria harboring that resistant gene to humans. Narrative Literature Review #2 Biological Plausibility for Associations between Antimicrobial Use in Food-Producing Animals and Increased Risks of Human Exposures to, and Infections by, Antimicrobial-Resistant Zoonotic Pathogens: A State of the Science Review Ellen K. Silbergeld Professor Johns Hopkins University Bloomberg School of Public Health Baltimore, United States of America This review summarized the published evidence of the biological plausibility for associations between antimicrobial use in food-producing animals and increased risks of human exposure to and infections by antimicrobial-resistant zoonotic pathogens. Background Antimicrobial use in food-producing animals contributes to antimicrobial resistance in zoonotic pathogens that can be transmitted to humans. To assist in managing this public health risk, the World Health Organization (WHO) commissioned reviews of evidence on the health risks of antimicrobial use in food-producing animals. Our report focuses on the biological plausibility of associations observed between these uses and risks to human health. Methods We reviewed published papers on mechanisms of antimicrobial resistance in general and specifically in the context of antimicrobial use in food-producing animals and dissemination of resistant to humans. We adopted methods used by the US Task Force on Community Preventive Services. We also used a scoping review process to locate recent papers and we searched references for additional sources of information. Findings An extensive literature on molecular mechanisms supports observed associations between agricultural use of antimicrobials and emergence and dissemination of antimicrobial resistance determinants from food-producing animals to human populations. Interpretation This review adds to the evidence in other reviews in this series. In addition to supporting the biological plausibility of these observations, we find that the context and conditions of food64

6 August 2017 producing animal production are highly conducive to amplifying horizontal resistance gene transfer, persistence of resistance, and emergence of multidrug resistance. In addition, mechanistic information highlights the importance of environmental reservoirs and pathways as sources of human exposure.

Narrative Literature Review #3 Potential Unintended Consequences Associated with Restrictions on Antimicrobial Use in FoodProducing Animals Scott A. McEwen Professor Department of Population Medicine Ontario Veterinary College University of Guelph Guelph, Canada

Frederick J. Angulo Associate Director for Science Division of Global Health Protection Center for Global Health Centers for Disease Control and Prevention Atlanta, United States of America Peter J Collignon Executive Director ACT Pathology Canberra Hospital Woden, Australia

John Conly Professor of Medicine, Microbiology, Immunology, and Infectious Diseases Cumming School of Medicine University of Calgary and Alberta Health Services Calgary and Area Calgary, Canada

This review summarized the published evidence that restriction of antimicrobial use in foodproducing animals does or does not have effects (largely unintended) on several non-antimicrobial resistance outcomes. The most thoroughly studied restriction is termination of use of antimicrobial growth promoters (AGPs) in Europe. Antimicrobial use Following the AGP ban in Denmark, antimicrobial treatment use in poultry and cattle was unaffected by the ban, however in weaned pigs there were relative increases in treatment use of some antimicrobials important for use in humans (tetracyclines, penicillins, macrolides, aminoglycosides). Among Salmonella Typhimurium (but not E. coli) isolates from pigs and domestically acquired infections in humans, there was an increase in resistance to tetracyclines that may have been caused by increased tetracycline use in pigs. There was a decrease in macrolide resistance in Campylobacter from pigs. Use of cephalosporins and fluoroquinolones was unaffected by the AGP ban. Experience in other countries varied; treatment use decreased in Norway, was unaffected in Switzerland, and increased in Sweden and the Netherlands following their AGP bans. 65

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Food safety and security AGP termination in Denmark did not affect the incidence of antimicrobial residues in foods, domestically-acquired human salmonellosis, campylobacteriosis or yersiniosis, nor were there effects on contamination of domestic meat and poultry with Salmonella and Campylobacter. From the perspective of global food security, likely decreases in poultry and pork production were estimated to be no more than 2% and average daily protein supply would likely decrease by no more than 0.1 g per person (or 0.2% of total protein intake). Animal health and welfare Some countries experienced temporary problems following their AGP bans, mainly diarrhoea in weaned pigs and necrotic enteritis in poultry. In Denmark, treatments for post-weaning diarrhoea increased from approximately 0.4 to 1.0 treatments per pig-month prior to and after AGP termination in weaners, respectively. Necrotic enteritis diagnoses were made in 25 of 1700 Danish broiler flocks in the year after the ban compared with 1-2 per 1700 flocks annually prior to the ban. Environment No evidence was found in Denmark of adverse environmental effects, including total nitrogen and phosphorus output in animal manure. Animal production Estimates of the magnitude of AGP adverse effects on production, mainly from experimental studies, vary widely, ranging from approximately 0-15%, however there is evidence that beneficial effects have declined over time, and since the early 2000s range from 0-5%. In Denmark, some temporary production losses (two years or less after the ban) were detected in weaned pigs, mainly through mortality (0.6% increase), growth rate (2.6% decrease) and feed efficiency (increase of 1-2% in feed units required per weaner produced). No effects on productivity or feed efficiency in finishers were identified. Production effects in Danish broilers were limited to decreased feed efficiency (-2.3%) that was largely offset by savings in the cost of AGPs. In a large U.S. study, removal of AGPs was associated with reduction in livability of 0.14%-0.2%, an average decrease in body weight of 0.030.04 lb., and an average increase in feed conversion ratio of 0.012-0.016. Economic impacts In Denmark, net costs due to productivity losses from AGP termination were estimated to be 7.75 DKK (1.04 €) per pig produced (1%) and no net cost for poultry. Findings from a general equilibrium model of the Danish economy indicated that AGP termination lowered pig production by about 1.4% per annum and increased poultry production by 0.4% per annum. Impact of AGP termination on the Danish economy was estimated to be a reduction of 0.03% (363 million DKK (48 million €) by 2010 at 1995 prices) in real Gross Domestic Product (GDP). A recent U.S. evaluation estimated that a 1-3% increased cost of production in pigs and broilers would lead to a 1% increase in wholesale prices and drop in output of less than 1%. Another study estimated the potential loss of production and meat value following an AGP ban under two scenarios: 1) effects of AGPs are high (using growth response data from the 1980s), and 2) effects of AGPs are low (using growth response data from the 2000s). They projected that a worldwide ban on AGPs would result in a decrease of global meat production by 1.3% to 3% from its current level (1980s vs. 2000s scenarios). This corresponds to a global loss of between USD 13.5 and USD 44.1 billion in the two scenarios. In 2010, the Danish Veterinary and Food Administration introduced the “Yellow Card” system to place regulatory restrictions on pig farmers that used twice the average quantity of treatment antimicrobials. The impact of the programme on slaughter condemnations in pigs at slaughter was evaluated. There were increases in some lesions, but decreases in others. 66

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The Netherlands recently undertook major reductions in antimicrobial consumption in foodproducing animals, as well as further restrictions on critically important antimicrobials such as fluoroquinolones and cephalosporins. The Dutch Animal Health Service reported some indications of increased disease problems in pigs, but some of the increases may have been related to feed changes. Conclusions Overall, the adverse consequences of AGP bans and other restrictions described in the literature appear to be limited and temporary. Based on European experiences with terminating AGPs, such adverse effects that may be encountered can be reduced by taking steps to minimize disease in vulnerable classes of animals, especially weaner pigs, and supporting producers in making a transition to more targeted, prudent antimicrobial use. Such steps include improvements in veterinary advice, animal housing, non-antimicrobial disease control strategies and antimicrobial use surveillance. For future AGP bans, particular care is needed to avoid compensatory increases in antimicrobial use for disease prevention or treatment purposes, particularly antimicrobials important for therapy in either humans or animals.

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Annex 6: Recommendations and Summary of the Judgments of the Guideline Development Group of the Criteria Related to the Strength of the Recommendations for Each Intervention Recommendation Type of food-producing animal use Intervention 1 Overall use Restriction of medically important antimicrobials in food-producing animals 2 Growth promotion use Complete restriction of medically important antimicrobials for growth promotion in food-producing animals Yes Yes Yes Yes Low No important uncertainty or variability Probably yes Varies Varies 3 Prevention use (in the absence of disease) Complete restriction of routine use of medically important antimicrobials for prevention of infectious diseases that have not yet been clinically diagnosed in food-producing animals Yes Yes Probably yes Probably yes Low Probably no important uncertainty or variability Probably yes Uncertain Probably yes 4 Treatment and control use (in the presence of disease) Restriction of critically important antimicrobials for disease control and treatment in food-producing animals

Is the problem a priority? Are a large number of people affected? Are the desirable anticipated effects large? Are the undesirable anticipated effects small? What is the overall certainty of this evidence? How certain is the relative importance of the desirable and undesirable outcomes? Are the desirable effects large relative to undesirable effects? Are the resources required small? Is the incremental cost small

Yes Yes Yes Yes Low No important uncertainty or variability Yes Varies Varies

Yes Yes Probably yes Probably yes Very low Probably no important uncertainty or variability Probably yes Varies Varies 68

6 August 2017 Recommendation Type of food-producing animal use Intervention 1 Overall use Restriction of medically important antimicrobials in food-producing animals 2 Growth promotion use Complete restriction of medically important antimicrobials for growth promotion in food-producing animals 3 Prevention use (in the absence of disease) Complete restriction of routine use of medically important antimicrobials for prevention of infectious diseases that have not yet been clinically diagnosed in food-producing animals Uncertain Varies Probably yes Desirable consequences clearly outweigh undesirable consequences in most settings Strong recommendation for the intervention We recommend complete restriction of use of all classes of medical important antimicrobials in food-producing animals for prevention of infectious diseases that have not yet been clinically diagnosed 4 Treatment and control use (in the presence of disease) Restriction of critically important antimicrobials for disease control and treatment in food-producing animals

relative to the net benefits? What would be the Impact on health inequalities? Is the option acceptable to key stakeholders? Is the option feasible to implement? Balance of consequences?

Probably reduced Yes Yes Desirable consequences clearly outweigh undesirable consequences in most settings Strong recommendation for the intervention We recommend an overall reduction in use of all classes of medically important antimicrobials in foodproducing animals

Probably reduced Probably yes Yes Desirable consequences clearly outweigh undesirable consequences in most settings Strong recommendation for the intervention We recommend complete restriction of use of all classes of medically important antimicrobials in foodproducing animals for growth promotion

Uncertain Varies Uncertain Desirable consequences probably outweigh undesirable consequences in most settings Conditional recommendation for the intervention a. We suggest that antimicrobials classified as highest-priority critically important for human medicine should not be used for the treatment of food-producing animals with a clinically diagnosed infectious disease b. We suggest that antimicrobials classified as critically important for human medicine should not be used 69

Type of recommendation? Recommendation

for control of the dissemination of clinically diagnosed infectious disease identified within a group of food-producing animals

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1. Evidence to Recommendation table – Overarching

Does a restriction of antimicrobials on the WHO CIA List used in food-producing animals, compared to no such restriction, reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance in bacteria isolated from in humans? Problem: Increasing antimicrobial resistance is resulting in increased morbidity and mortality in humans Option: Restriction of antimicrobials on the WHO CIA List in food animals Comparison: No restriction of antimicrobials on the WHO CIA List in food animals Setting: Food animals production and aquaculture worldwide Background: A systematic review conducted by the WHO in 2014, as part of its Global Surveillance Report, asked the question of whether there were any differences in outcome from infections caused by resistant vs sensitive bacteria found a significantly increased risk of mortality and health care expenditures with antibiotic resistant compared to antibiotic sensitive organisms. Use of antimicrobial agents in food animals results in selection and dissemination of antimicrobial-resistant bacteria and resistant determinants in the intestinal tracts of food animals. Furthermore, pathogenic (e.g., Salmonella, Campylobacter spp.) and commensal (e.g., Escherichia coli, Enterococcus spp.) bacteria, including resistant bacteria with resistant determinants, are transmitted to humans through food. Infections with antimicrobial resistant bacteria, including antimicrobial resistant foodborne bacteria (such as non-typhoidal Salmonella, Campylobacter spp., and Escherichia coli) can contribute to more severe human health consequences, including treatment failures, increased or longer hospitalizations, and prolonged illnesses, compared with infections with susceptible bacteria. Antimicrobials are widely used in food animals for treatment, prophylaxis, and growth promotion. Although the quantity of antimicrobials used in food animals is not reported in many countries, it is clear that the quantity of antimicrobials used in food animals is large. Some recent studies indicate that the economic benefits of certain uses, such as growth promotion, are small. A review of the information on the mechanisms of emergence and dissemination of antimicrobial resistance provides strong support for the plausibility of the observed associations between use of antimicrobials in food animals and increased risks of human exposure to and infection by antimicrobial resistant bacteria originating from food animals. Also, intervention studies have examined the impacts of reducing the amounts of antimicrobials used in food animals and have reported associated reductions in antimicrobial resistance in food animals and in humans. These studies have been undertaken in several countries, particularly in Europe, where there has been reliable monitoring of the quantity of antimicrobials used in food animals. These interventions have not resulted in impacts on food animal productivity or food animal health or welfare. We thus sought to critically review the evidence and all other criteria to assess if a recommendation could be made as to whether there should be a restriction of the use of antimicrobials on the WHO CIA List (whether Important, Highly Important, or Critically Important) in food animals, in order to reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance in food animal populations and in humans.

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1. Evidence to Recommendation table – Overarching

ADDITIONAL INFORMATION

Is the problem a priority?

No Probably Uncertain Probably Yes No Yes X

Antimicrobial resistance has been recognized as a major global public health threat. In the 2014 WHO Antimicrobial Resistance. Global Report on Surveillance, high proportions of resistance were reported in all regions of the world to common treatments for bacteria causing infections in both healthcare settings and in the community. Antibacterial resistance has a negative effect on patient outcomes including both morbidity and mortality and was more costly to the healthcare system .A systematic review published by the WHO in 2014 on the impact of AMR on multiple outcomes including mortality revealed for patients with third-generation cephalosporin resistant (including ESBL) E. coli infections there was a significant twofold increase in all-cause mortality, bacterium-attributable mortality and in 30-day mortality; for patients with fluoroquinolone-resistant E. coli Varies infections there was a significant twofold increase in both all-cause mortality and 30-day mortality; for patients with third-generation cephalosporin resistant K. pneumoniae infections there was: a significant almost two-fold increase in all-cause mortality, bacterium-attributable mortality and 30-day mortality, and in the risk of intensive care unit (ICU) admission; for patients with carbapenem-resistant K. pneumoniae infections there was a significant two-fold increase in both all-cause mortality and 30-day mortality; and for patients with methicillin-resistant S. aureus infections there was a significant increase in allcause mortality, bacterium-attributable mortality and ICU mortality, and septic shock. Treatment options for common infections are limited. Food animals are important reservoirs and / or amplifiers of many bacterial infections of humans, including among others non-typhoidal Salmonella, Campylobacter, and E. coli, as well as opportunistic pathogens including E. coli and Enterococcus spp.

Reference : WHO Antimicrobial Resistance. Global Report on Surveillance 2014 http://www.who.int/drugresistance/documents/surv eillancereport/en

PROBLEM

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Are a large number of people affected?

Probably No

Uncertain

Probably Yes

Yes

Foodborne diseases are a major cause of human morbidity and mortality. According to recent estimates from the WHO Foodborne Diseases Epidemiology Reference Group (WHO FERG), foodborne diseases caused 600 million illnesses, 420,000 deaths, and 33 million Disability Adjusted Life Years (DALYs) in 2010 (1). Foodborne diseases are particularly important in children. According to the WHO FERG estimates, although children <5 years of age represent only 9% of the global population, 40% of the foodborne disease burden is borne by children in this age group. There are also considerable differences in the burden of foodborne diseases among sub-regions with the highest Varies burden of per population observed in Africa. Exact numbers of the global population affected by AROs is difficult to define but in the recent WHO Global Surveillance Report 5 WHO Regions globally had national reports of 50% resistance or more to three of the most commonly reported bacterial strains causing infections in humans. Lord O’Neill, in his recent economic report suggesting the global financial cost of no action would be the loss of 10 million lives a year by 2050 and £69tn ($100tn) a year. Non-typhoidal Salmonella caused an estimated 80 million infections and 60,000 deaths and Campylobacter caused 95 million infections and 21,000 deaths in 2010. Resistance among these infections is common (e.g. 0-49% resistance to fluoroquinolones among non-typhoidal Salmonella infections, depending on region). Summary of findings: Outcome (from PICO Question 1): For food animal populations of any age in any setting, does a restriction compared to not having that restriction of use of antimicrobial agent(s) in food animals reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistant bacteria in food animal populations? Risk Difference (intervention compared to control groups) (n= no. studies) (95%CI) Certainty of the evidence (GRADE)

http://www.who.int/drugresistance/documents/surv eillancereport/en/ Reference: Havelaar AH, Kirk MD, Torgerson P, Gibb HJ, Hald T, Lake RJ, Praet N, Bellinger JD, de Silva NR, Gargouri N, Speybroeck N, Cawthorne A, Mathers C, Stein C, Angulo FJ, Devleesschauwer B. World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010. PLoS Medicine 2015; doi: 10.1371/journal.pmed.1001923

BENEFITS & HARMS

Are the desirable anticipated effects large?

No Probably Uncertai Probably Yes No n Yes X

Varies

Of the two systematic reviews, one was a narrative summary of the findings and the other a quantitative assessment. Both revealed similar findings with respect to the reduction of resistance transfer from food producing animals to human. Within the quantitative analysis, in the animal studies, 179 described antibiotic resistance outcomes in animals, of which 80 were metaanalyzed. The pooled absolute risk reduction of the prevalence of antibiotic resistance in animals, with interventions that restricted antibiotic use, varied across different antibiotic classes, bacteria,

Are the undesirable anticipated effects small?

No Probably Uncertai Probably Yes No n Yes X

Varies

Final - Version 7 31/08/2017 16:05 Quinolone resistance in Enterobacteriaceae Faecal samples (n=16) RD=-0.01 (-0.01, 0.00) Meat samples (n=12) RD=-0.09 (-0.17, -0.02) Quinolone resistance in Campylobacter spp. Faecal samples (n=11) RD= -0.06 (-0.16, 0.05) Meat samples (n=12) RD= -0.08 (-0.17, 0.01) Cephalosporin resistance in Enterobacteriaceae Faecal samples (n=16) RD=-0.01 (-0.04, -0.01) Meat samples (n=11) RD=-0.07 (-0.14, 0.01) What is the overall certainty of this evidence? No included studies Very low Macrolide resistance in Campylobacter spp. Low X Moderate High Faecal samples (n=11) RD=-0.15 (-0.26, -0.04) Meat samples (n=7) RD=-0.04 (-0.17, 0.09) Macrolide resistance in Enterococcus spp. Penicillins resistance in Enterobacteriaceae Faecal samples (n=10) RD= -0.39 (-0.56, -0.23) Faecal samples (n=19) RD= -0.12 (-0.17, -0.06) Meat Samples (n=11) RD= -0.16 (-0.25, -0.08) Penicillins resistance in Enterococcus spp. Tetracyclines resistance in Enterobacteriaceae Faecal samples (n=7). RD= -0.10 (-0.18, -0.02) Faecal samples (n=20) RD= -0.16 (-0.27, -0.04) Meat Samples (n=12) RD= -0.20 (-0.36, -0.03)

1. Evidence to Recommendation table – Overarching

Low

and sample types, but ranged from 0% to 39%; in general, the prevalence of antibiotic resistance was commonly 10-20% lower in intervention compared to control groups. The pooled prevalence of multi-drug resistance was 24-32% lower in bacteria isolated from intervention groups. These findings held through many different layers of stratification including by intervention type. Twenty-one studies described antibiotic resistance outcomes in humans (19 of which also reported antibiotic resistance in animals), of which 13 were meta-analyzed. In humans, the pooled prevalence of antibiotic resistance was 24% lower in intervention groups (where interventions to reduce antibiotic use in food animals were implemented) compared to comparator groups. The effect was similar, albeit weaker, when considering humans without direct contact with livestock animals, compared to farm workers. The results were similar with multiple types of stratification, adding to the robustness of the findings.

Low

Low Low

Final - Version 7 31/08/2017 16:05 Glycopeptide resistance in Enterococcus spp. Multi-drug resistance in Enterobacteriaceae Faecal samples (n=12) RD=-0.22 (-0.32, -0.12) Faecal samples (n=19) RD=-0.24 (-0.32, -0.17) Meat samples (n=14). RD=-0.32 (-0.43, -0.22) Overall antibiotic resistance

1. Evidence to Recommendation table – Overarching

Low

With stronger interventions (n=22) RD=0.22 (95% CI -0.31, -0.13) With weaker interventions (n=62) RD=0.16 (95% CI -0.18, -0.14)

Low

Outcome (from PICO Question 2): Does a restriction compared to not having that restriction of use of antimicrobial agent(s) in food animals reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistant bacteria in human populations? Resistance to any antimicrobial

Risk Difference (intervention compared to control groups) (n= no. studies) (95%CI)

Certainty of the evidence (GRADE)

Pooled absolute risk differences of antibiotic resistance (n=13 studies) RD=-0.24 (-0.42, -0.06) -Stratification by the studied human population Farm workers (n=9)

Low

Final - Version 7 31/08/2017 16:05 RD=-0.29 (-0.54, -0.04) Not farm workers (n=4) RD=-0.09 (-0.13, -0.05)

1. Evidence to Recommendation table – Overarching

-Stratification by stronger versus weaker interventions* Stronger interventions (n=8) RD=-0.14 (95% CI -0.20, 0.08) Weaker interventions (n=5) RD= -0.38 (95% CI -0.83, 0.08) The nature and extent of potential harms will vary depending on the type of antimicrobial use that is restricted and could include one or more of: 1) increased use of antibiotics (such as increased need for antibiotics for treatment purposes) 2) adverse effects on human health, 3) decrease in food and protein availability, 4) food safety, 5) adverse effects on animal health and welfare, 6) adverse effects on animal production, and 7) economic consequences. For details see “Supplemental report to: Restriction in the use of antibiotics in food animals and antibiotic resistance in food animals and humans – a systematic review and metaanalysis” and “Potential unintended consequences associated with restrictions on antimicrobial use in food-producing animals”. The main conclusions of the former state “Regarding potential unintended consequences, there appears to be a recurring finding of somewhat increased use of therapeutic antibiotic courses in individual animals (though an overall reduction in the volume of antibiotics used) with interventions that restrict antibiotic use, and possible implications for food safety given the possible higher prevalence of bacterial contaminants in these food products.” The main conclusions of the latter report state: • Overall, the adverse consequences of AGP bans and other restrictions described in the literature appear to be limited and temporary. • Based on European experiences with terminating AGPs, such adverse effects that may

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1. Evidence to Recommendation table – Overarching

be encountered can be reduced by taking steps to minimize disease in vulnerable classes of animals, especially weaner pigs, and supporting producers in making a transition to more targeted, prudent antimicrobial use. Such steps include improvements in veterinary advice, animal housing, non-antimicrobial disease control strategies and antimicrobial use surveillance. • For future AGP bans, particular care is needed to avoid compensatory increases in antimicrobial use for disease prophylactic or therapeutic purposes, particularly antimicrobials important for therapy in either humans or animals.

CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE

ADDITIONAL INFORMATION Public health concerns about the use of antimicrobial agents in food animals have been expressed for decades. Many groups have concluded that public health concerns warrant placing restrictions on the use of antimicrobial agents in food animals given that: a. antimicrobials agents used in humans are widely used in food animals, b. use of antimicrobial agents results in antimicrobial resistance, c. food animals are an important source of antimicrobial-resistant bacteria for humans, and infections in humans caused by antimicrobialresistant bacteria may have more severe health consequences compared with infections caused by antimicrobial-susceptible bacteria.

How certain is the relative importance of the desirable and undesirable outcomes?

Probably Possibly no No Important important important important uncertainty uncertainty uncertainty uncertainty No known or or or or undesirable variability variability variability variability outcomes X

The GDG gave very high ratings to desirable outcomes from restrictions on antimicrobial use in animals; it gave the highest value (median 9, with score of 9 judged of “most importance”) to the consideration that when people were infected with antimicrobial resistant bacteria, this leads to more severe health outcomes. Also rated highly were desirable outcomes related to decreases in the prevalence of antimicrobial resistant bacteria and/or antimicrobial resistant determinants in food animals (median 8) and humans (median 7-8). Undesirable outcomes were rated of lower importance, including decreases in food animal health and welfare (median 4), decreases in food security (median 2), food safety (median 4), increased therapeutic antimicrobial use in animals following restrictions on growth promoters (median 4), and increased costs to producers and loss of income to national economies (median 3). However, the GDG did give value to the need to protect animal welfare by ensuring availability of antimicrobials to treat sick animals

VALUES

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ADDITIONAL INFORMATION As mentioned in the O’Neil report,: “Undesirable effects poorly quantified and in some cases hypothetical, but probably much smaller than desirable. Desirable effects potentially large”; Lord O’Neill, in his recent economic report suggests the global financial cost of no action would be the loss of 10 million lives a year by 2050 and £69tn ($100tn) a year.

Are the desirable effects large relative to undesirable effects?

Probably No

Uncertain

Probably Yes

Yes X

Varies

CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE In Denmark, net costs due to productivity losses from growth promoter termination were estimated to be 7.75 DKK (1.04 €) per pig produced (1%) and no net cost for poultry. Findings from a general equilibrium model of the Danish economy indicated that AGP termination lowered pig production by about 1.4% per annum and increased poultry production by 0.4% per annum. Impact of AGP termination on the Danish economy was estimated to be a reduction of 0.03% (363 million DKK (48 million €) by 2010 at 1995 prices) in real Gross Domestic Product (GDP). A recent U.S. evaluation estimated that a 1-3% increased cost of production in pigs and broilers would lead to a 1% increase in wholesale prices and drop in output of less than 1%. Another study estimated the potential loss of production and meat value following an AGP ban under two scenarios: 1) effects of AGPs are high (using growth response data from the 1980s), and 2) effects of AGPs are low (using growth response data from the 2000s). They projected that a worldwide ban on AGPs would result in a decrease of global meat production by 1.3% to 3% from its current level (1980s vs. 2000s scenarios). This corresponds to a global loss of between USD 13.5 and USD 44.1 billion in the two scenarios. The costs associated with implementation of the Yellow Card system in Denmark (for reduction in therapeutic / prophylactic use) were estimated to be approximately € 1 million per annum. Variable results from studies examining effects of therapeutic / prophylactic antimicrobial use interventions on animal

ADDITIONAL INFORMATION

RESOURCE USE

Are the resources required small?

No Probably Uncertain Probably Yes No Yes

Varies X

In addition, a study by a major poultry producer reported little effects of removing growth promoter antimicrobials from poultry..

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ADDITIONAL INFORMATION

production, treatment costs, veterinary costs. (For details see above reports).

According to the Lord O’Neill Report, “The value of a delay is potentially enormous”: RAND Europe’s study demonstrated that delaying the development of widespread resistance by just 10 years could save 65 trillion USD of the world’s output between now and 2050” Is the incremental cost small relative to the net benefits? No Probably Uncertain Probably Yes No Yes Varies Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance Chaired by Jim O’Neill December 2014 https://amr-review.org/

The World Bank recently reviewed the economic impacts of failure to control antimicrobial resistance in terms of reductions in national GDP (World Bank Group, Drug-Resistant Infections A Threat to our Economic Future 2016). This analysis indicated large decreases in global economic growth. In contrast to acute economic events such as the 2008-9 financial crisis, these impacts are expected to be prolonged. This analysis indicated substantial inequities in impacts that varied inversely with per capita income such that the poorest countries would experience the greatest decreases in annual economic growth as measured by GDP (figure 3). Overall, under a more optimistic scenario (related to the magnitude of AMR) the losses of world economic output exceeded $1 trillion annually to reach a total of $2 trillion per year by 2050. Under a more pessimistic scenario, these losses were estimated to be #3.4. trillion annually to 2030 and $6.1 trillion annually by 2050. Economic shocks to livestock production were also anticipated due to trade restrictions and consumer fears of food safety. These impacts and associated effects on nutrition and health would also be more severe in low income countries. Health care costs in terms of extra costs associated

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ADDITIONAL INFORMATION with AMR infections would also increase significantly. Because of these disparate economic impacts, poverty is anticipated to increase markedly in low income countries

EQUITY

What would be the impact on health inequities?

Increased Probably Uncertain Probably Reduced Varies increased reduced

In the O’Neill Report, it was indicated that “KPMG looked at what would happen if infection rates doubled and then stayed constant and the analysis suggested an increase in infection rates alone could mean 150 million people dying prematurely and reduce world GDP by 55 trillion USD between now and 2050, just over half the total impact they estimate for AMR.” The impact would be greater on low to middle income countries and thus by acting on our recommendations health inequities would be likely reduced.

Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance Chaired by Jim O’Neill December 2014 https://amr-review.org/ See World Bank statement above.

ACCEPTABILI TY

Is the option acceptable to key stake-holders?

No Probably Uncertain Probably Yes No Yes X

Varies

Key target audience are Governments and regulatory agencies, veterinarians, farmers and other food producers, the food production industry, and consumers. Access to antimicrobials varies between countries.

FEASIBILITY

Is the option feasible to implement

No Probably Uncertain Probably Yes No Yes X

Varies

Reductions in the use of antimicrobials in food producing animals have been undertaken in several countries, particularly in Europe. These reductions in in these countries demonstrates that this option is feasible.

Final - Version 7 31/08/2017 16:05 Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings

1. Evidence to Recommendation table – Overarching

The balance between desirable and undesirable consequences is closely balanced or uncertain

Desirable consequences probably outweigh undesirable consequences in most settings

Desirable consequences clearly outweigh undesirable consequences in most settings X

As of 31/08/2017 4:05 PM 1. Evidence to Recommendation Table - Overarching Reduction of overall use of antimicrobials on the WHO CIA List in food producing animals?

Conclusions Type of recommendation Recommendation

Strong recommendation against the intervention ○

Conditional recommendation against the intervention ○

Conditional recommendation for either the intervention or the comparison ○

Conditional recommendation for the intervention ○

Strong recommendation for the intervention x

We strongly recommend an overall reduction of use of all classes of medically important antimicrobials in food-producing animals. The evidence shows that restricting use of antimicrobials in food-producing animals reduces the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance in humans. The panel determined that this recommendation should be strong despite the low quality evidence due to the large health benefits of lowered antimicrobial resistance. The beneficial human health outcomes are larger than any undesirable outcomes. Furthermore, the systematic review concluded broad restrictions covering all antibiotic classes appear to be more effective in reducing antibiotic resistance compared to narrow restrictions of one antibiotic class or drug and the literature review on mechanisms of resistance supports the biological plausibility of this conclusion.. Reducing use of antimicrobials is in accordance with the Global Action Plan on Antimicrobial Resistance which states that “evidence that antimicrobial resistance is driven by the volume of use of antimicrobial agents is compelling”. To reduce possible undesirable outcomes, non-antimicrobial options for disease prevention in animals should be implemented, including improved hygiene, improved biosecurity, and better use of vaccines. Some countries may need support for implementation. FAO and OIE may assist countries with implementation (e.g. governance models, taking small holders into account). FAO and OIE may assist with tools for veterinary oversight of antimicrobial use.

Justification

Implementation considerations

Countries should implement antimicrobial usage monitoring in order to be able to document reductions in antimicrobial use in animals. Reductions of overall use of antimicrobials in food-producing animals may include any level of reduction of use of antimicrobials in food-producing animals including reductions of a single antimicrobial, reductions of multiple antimicrobials, or combination of reductions of use of antimicrobials. Such reductions may include complete restriction of selected uses as growth promotion use or off-label use, voluntary limitations, or limiting use only to use with oversight by a veterinarian.

Monitoring and evaluation

Quantities of antimicrobials used in food-producing animals should be monitored to determine trends in antimicrobial use in food-producing animals.

Research priorities

While research is compelling concerning the evidence that antimicrobial use selects for antimicrobial resistance, and that reducing antimicrobial use can lead to reduction in antimicrobial resistance, additional research would be helpful to identify the most effective disease prevention strategies for reducing antimicrobial use, alternatives to antimicrobials, and the most effective methods for implementing antimicrobial stewardship programs in food-producing animals.

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2. Evidence to Recommendation Table – Growth Promotion

Does complete restriction of classes of antimicrobials on the WHO CIA List used in food-producing animals for purposes of growth promotion, compared to no such restriction, reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance in bacteria isolated from humans? Problem: Increasing antimicrobial resistance is resulting in increased morbidity and mortality in humans Option: Complete restriction of antimicrobials on the WHO CIA List for growth promotion in food animals Comparison: No restriction of use of antimicrobials on the WHO CIA List for growth promotion in food animals Setting: Food animal production and aquaculture worldwide Background: A systematic review conducted by the WHO in 2014, as part of its Global Surveillance Report, asked the question of whether there were any differences in outcome from infections caused by resistant vs sensitive bacteria found a significantly increased risk of mortality and health care expenditures with antibiotic resistant compared to antibiotic sensitive organisms. Use of antimicrobial agents in food animals results in selection and dissemination of antimicrobial-resistant bacteria and resistant determinants in the intestinal tracts of food animals. Furthermore, pathogenic (e.g., Salmonella, Campylobacter spp.) and commensal (e.g., Escherichia coli, Enterococcus spp.) bacteria, including resistant bacteria with resistant determinants, are transmitted to humans through food. Infections with antimicrobial resistant bacteria, including antimicrobial resistant foodborne bacteria (such as non-typhoidal Salmonella, Campylobacter spp., and Escherichia coli) can contribute to more severe human health consequences, including treatment failures, increased or longer hospitalizations, and prolonged illnesses, compared with infections with susceptible bacteria. The use of antimicrobial agents as growth promoters in animals is concerning because such use exposes large numbers of animals for prolonged periods of time to low doses of antimicrobials for reasons related to production efficiency rather than therapy of sick animals. In some countries, members of classes of antimicrobials important to human health are (or were) used as growth promoters. For example, avoparcin, a glycopeptide antimicrobial, was widely used in Europe, Australia and other countries as a growth promoting feed additive in swine and poultry. Such use selected for resistance in enterococci to vancomycin, a glycopeptide antimicrobial use for treatment of important human infections. In some countries, tetracyclines, penicillins, macrolides, polymixins and other drugs important to human health are use for growth promotion, and have been shown to select for resistance to these and other classes of drugs. We thus sought to critically review the evidence and all other criteria to assess if a recommendation could be made as to whether there should be complete restriction of the use of antimicrobials on the WHO CIA List (whether Important, Highly Important, or Critically Important) for purposes of growth promotion in animals, in order to reduce the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance in food animal populations and in humans.

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CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE

ADDITIONAL INFORMATION

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Is the problem a priority?

Probably No

Uncertain

Probably Yes

Yes X

Antimicrobial resistance has been recognized as a major global public health threat. In the 2014 WHO Antimicrobial Resistance. Global Report on Surveillance, high proportions of resistance were reported in all regions of the world to common treatments for bacteria causing infections in both healthcare settings and in the community. Antibacterial resistance has a negative effect on patient outcomes including both morbidity and mortality and was more costly to the healthcare system .A systematic review published by the WHO in 2014 on the impact of AMR on multiple outcomes including mortality revealed for patients with third-generation cephalosporin resistant (including ESBL) E. coli infections there was a significant twofold increase in all-cause mortality, bacterium-attributable mortality and in 30-day mortality; for patients with fluoroquinolone-resistant E. coli Varies infections there was a significant twofold increase in both all-cause mortality and 30-day mortality; for patients with third-generation cephalosporin resistant K. pneumoniae infections there was: a significant almost two-fold increase in all-cause mortality, bacteriumattributable mortality and 30-day mortality, and in the risk of intensive care unit (ICU) admission; for patients with carbapenem-resistant K. pneumoniae infections there was a significant two-fold increase in both all-cause mortality and 30-day mortality; and for patients with methicillin-resistant S. aureus infections there was a significant increase in all-cause mortality, bacterium-attributable mortality and ICU mortality, and septic shock. Treatment options for common infections are limited. Food animals are important reservoirs and / or amplifiers of many bacterial infections of humans, including among others non-typhoidal Salmonella, Campylobacter, and E. coli, as well as opportunistic pathogens including E. coli and Enterococcus spp. Foodborne diseases are a major cause of human morbidity and mortality. According to recent estimates from the WHO Foodborne Diseases Epidemiology Reference Group (WHO FERG), foodborne diseases caused 600 million illnesses, 420,000 deaths, and 33 million Varies Disability Adjusted Life Years (DALYs) in 2010 (1). Foodborne diseases are particularly important in children. According to the WHO FERG estimates, although children <5 years of age represent only 9% of the global population, 40% of the foodborne disease burden is borne by children in this age group. There are also considerable differences in the burden of foodborne diseases among sub-regions with the highest burden of per population observed in Africa. Exact

Reference : WHO Antimicrobial Resistance. Global Report on Surveillance 2014 http://www.who.int/drugresistance/documents/surveilla ncereport/en/

P RO B LE M

Are a large number of people affected?

Probably No

Uncertain

Probably Yes

Yes

http://www.who.int/drugresistance/documents/surveilla ncereport/en/ Reference: Havelaar AH, Kirk MD, Torgerson P, Gibb HJ, Hald T, Lake RJ, Praet N, Bellinger JD, de Silva NR, Gargouri N, Speybroeck N, Cawthorne A, Mathers C, Stein C, Angulo FJ, Devleesschauwer B. World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010. PLoS Medicine 2015; doi: 10.1371/journal.pmed.1001923

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numbers of the global population affected by AROs is difficult to define but in the recent WHO Global Surveillance Report 5 WHO Regions globally had national reports of 50% resistance or more to three of the most commonly reported bacterial strains causing infections in humans. Lord O’Neill, in his recent economic report suggesting the global financial cost of no action would be the loss of 10 million lives a year by 2050 and £69tn ($100tn) a year. Non-typhoidal Salmonella caused an estimated 80 million infections and 60,000 deaths and Campylobacter caused 95 million infections and 21,000 deaths in 2010. Resistance among these infections is common (e.g. 0-49% resistance to fluoroquinolones among non-typhoidal Salmonella infections, depending on region). CRITERIA Are the desirable anticipated effects large? B E NE F IT S & HA RM S O F T HE O P T IO NS

JUDGEMENTS

RESEARCH EVIDENCE Summary of findings:

Probably No

Uncertain

Probably Yes

Yes X

Varies

Are the undesirable anticipated effects small?

Probably No

Uncertain

Probably Yes

Yes X

Varies

Outcome:Reduction of the presence of antimicrobialresistant bacteria and/or genetic elements in animals and humans with a complete restriction of growth promotion use in food animals of classes of antimicrobials classified as critically important on the WHO CIA list, compared to no such restriction Antimicrobial resistance in animals

Risk Difference (intervention compared to control groups) (n= no. studies) (95%CI)

Certainty of the evidence (GRADE)

RD= -0.29 (-0.40, -0.19) n=27 15 were meta- analysed RD = -0.13 (-0.20, -0.06) n=7 6 were meta- analysed

Low

What is the overall certainty of this evidence?

No included studies

Very low

Low X

Moderate

High

Antimicrobial resistance in humans

Low

Possible harms include adverse effects on: 1) increased use of antibiotics (such as increased need for antibiotics for treatment purposes)

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CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE 2) adverse effects on human health, 3) decrease in food and protein availability, 4) food safety, 5) adverse effects on animal health and welfare, 6) adverse effects on animal production, and 7) economic consequences. For details see “Supplemental report to: Restriction in the use of antibiotics in food animals and antibiotic resistance in food animals and humans – a systematic review and metaanalysis” and “Potential unintended consequences associated with restrictions on antimicrobial use in food-producing animals”. The main conclusions of the former state “Regarding potential unintended consequences, there appears to be a recurring finding of somewhat increased use of therapeutic antibiotic courses in individual animals (though an overall reduction in the volume of antibiotics used) with interventions that restrict antibiotic use, and possible implications for food safety given the possible higher prevalence of bacterial contaminants in these food products.” The main conclusions of the latter report state: • Overall, the adverse consequences of AGP bans and other restrictions described in the literature appear to be limited and temporary. • Based on European experiences with terminating AGPs, such adverse effects that may be encountered can be reduced by taking steps to minimize disease in vulnerable classes of animals, especially weaner pigs, and supporting producers in making a transition to more targeted, prudent antimicrobial use. Such steps include improvements in veterinary advice, animal housing, non-antimicrobial disease control strategies and antimicrobial use surveillance. • For future AGP bans, particular care is needed to avoid compensatory increases in antimicrobial use for disease prophylactic or therapeutic purposes, particularly antimicrobials important for therapy in either humans or animals.

ADDITIONAL INFORMATION

CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE

ADDITIONAL INFORMATION

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2. Evidence to Recommendation Table – Growth Promotion

ADDITIONAL INFORMATION Public health concerns about the use of antimicrobial agents in food animals have been expressed for decades. Many groups have concluded that public health concerns warrant placing restrictions on the use of antimicrobial agents in food animals given that: a. antimicrobials agents used in humans are widely used in food animals, b. use of antimicrobial agents results in antimicrobial resistance, c. food animals are an important source of antimicrobial-resistant bacteria for humans, and infections in humans caused by antimicrobial-resistant bacteria may have more severe health consequences compared with infections caused by antimicrobial-susceptible bacteria.

How certain is the relative importance of the desirable and undesirable outcomes? V A LUE S

Important uncertainty or variability

Possibly important uncertainty or variability

Probably no No important important uncertainty uncertainty No known or or undesirable variability variability outcomes X

Are the desirable effects large relative to undesirable effects?

Probably No

Uncertain

Probably Yes X

Yes

Varies

Effects of the intervention on antimicrobial resistance are large (see a summary of the findings table above), and the undesirable effects are relatively small or nonexistent (See Supplemental report to: Restriction in the use of antibiotics in food animals and antibiotic resistance in food animals and humans – a systematic review and meta-analysis” and “Potential unintended consequences associated with restrictions on antimicrobial use in food-producing animals).

As mentioned in the O’Neil report, desirable effects potentially large; Lord O’Neill, in his recent economic report suggests the global financial cost of no action would be the loss of 10 million lives a year by 2050 and £69tn ($100tn) a year.

CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE

ADDITIONAL INFORMATION

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ADDITIONAL INFORMATION Potential resource costs from prohibition of antimicrobial growth promoters include:  Regulatory changes (transactional costs)  Increased efforts by veterinary services and farming groups to help producers transition away from growth promoters  Added resources for monitoring of antimicrobial use Laxminarayan, R., T. Van Boeckel and A. Teillant (2015), “The Economic Costs of Withdrawing Antimicrobial Growth Promoters from the Livestock Sector”, OECD Food, Agriculture and Fisheries Papers, No. 78, OECD Publishing. http://dx.doi.org/10.1787/5js64kst5wvl-en Stacy Sneeringer, James MacDonald, Nigel Key, William McBride, and Ken Mathews. Economics of Antibiotic Use in U.S. Livestock Production, ERR-200, U.S. Department of Agriculture, Economic Research Service, November 2015. Graham, J.P., Boland, J.J., and Silbergeld, E. (2007). Growth Promoting Antibiotics in Food Animal Production: An Economic Analysis. Public Health Rep. 122 , 79– 87. Taylor, Jirka, Marco Hafner, Erez Yerushalmi, Richard Smith, Jacopo Bellasio, Raffaele Vardavas, Teresa Bienkowska-Gibbs and Jennifer Rubin. Estimating the economic costs of antimicrobial resistance: Model and Results. Santa Monica, CA: RAND Corporation, 2014. http://www.rand.org/pubs/research_reports/RR911.html. The World Bank recently reviewed the economic impacts of failure to control antimicrobial resistance in terms of reductions in national GDP (World Bank Group, Drug-Resistant Infections A Threat to our Economic Future 2016). This analysis indicated large decreases in global economic growth. In contrast to acute economic events such as the 2008-9 financial crisis, these impacts are expected to be prolonged.

RE S O URCE US E

Are the resources required small?

Probably No

Uncertain

Probably Yes

Yes

Varies X

The resources required to reduce [or eliminate] use of antimicrobials in food animals include two general types. Governments may require some resources to direct and monitor food-production facilities, including feedmills, farms and aquaculture facilities. These resources are small. AGPs are thought to provide, in some cases, small improvements in feed efficiency, allowing farmers to reduce total inputs; and possibly to reduce heterogeneity of animal growth, thus reducing production costs. It appears that there has been a reduction in the effectiveness of AGPs over the last 50 years, for reasons that are not well understood (Laxminarayan 2015). The most probable estimate of the loss in production is approximately 1.3% to 3%, or approximately $13.5bn to USD45.1bn annually (Laxminarayan, 2015). However, in many well-designed studies, there appear to be no benefits from AGPs (Graham 2008). It appears that the effects are smallest in countries with high biosecurity and optimized production systems; further, producers can compensate for the withdrawal of AGPs by improved biosecurity, vaccination, etc. There are no estimates of the cost of these alternatives, but the costs of eliminating AGPs are bounded by the anticipated loss in production. Generally, it appears that as production systems are reoptimized, the loss in production declines (USDA 2015). Thus, there are likely to be decreasing costs over time.

Is the incremental cost small relative to the net benefits?

Probably No

Uncertain

Probably Yes

Yes

Varies X

The incremental cost of eliminating the use of AGPs globally, discussed above, appears to be in the range of $20bn per year, but likely declining over time. It is even more challenging to estimate the financial value of the net benefits. One estimate of the value of delaying widespread resistance by ten years is approximately USD65 trillion or approximately one year’s global GDP

Final – Version 10 31/08/2017 16:06 CRITERIA JUDGEMENTS RESEARCH EVIDENCE (RAND 2014). AGPs, of course, are not the only contributor to resistance.

2. Evidence to Recommendation Table – Growth Promotion

ADDITIONAL INFORMATION This analysis indicated substantial inequities in impacts that varied inversely with per capita income such that the poorest countries would experience the greatest decreases in annual economic growth as measured by GDP (figure 3). Overall, under a more optimistic scenario (related to the magnitude of AMR) the losses of world economic output exceeded $1 trillion annually to reach a total of $2 trillion per year by 2050. Under a more pessimistic scenario, these losses were estimated to be $3.4. trillion annually to 2030 and $6.1 trillion annually by 2050. Economic shocks to livestock production were also anticipated due to trade restrictions and consumer fears of food safety. These impacts and associated effects on nutrition and health would also be more severe in low income countries. Health care costs in terms of extra costs associated with AMR infections would also increase significantly. Because of these disparate economic impacts, poverty is anticipated to increase markedly in low income countries

Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance Chaired by Jim O’Neill December 2014 https://amr-review.org/

What would be the impact on health inequities?

E Q UIT Y

Increased Probably Uncertain Probably Reduced Varies increased reduced X

Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance Chaired by Jim O’Neill December 2014 https://amr-review.org/ Also see the WB statement mentioned above.

A CCE P T A B ILIT Y

Is the option acceptable to key stakeholders?

No Probably No

Uncertain Probably Yes X

Yes

Varies

Concerns about possible adverse effects have been raised by farmers and veterinarians. See information above under “Are the resources required small?”.

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ADDITIONAL INFORMATION

Is the option feasible to implement?

Probably No

Uncertain

Probably Yes

Yes X

Varies

Prohibition of use of growth promoters been implemented in all European Union countries and additional countries are planning or recently have)to revoke approvals for antimicrobial growth promoters (i.e. over-the-counter, in-feed “production uses”) by the end of 2016.

F E A S IB ILIT Y

Balance of consequences

Undesirable consequences clearly outweigh desirable consequences in most settings

Undesirable consequences probably outweigh desirable consequences in most settings

The balance between desirable and undesirable consequences is closely balanced or uncertain

Desirable consequences probably outweigh undesirable consequences in most settings

Desirable consequences clearly outweigh undesirable consequences in most settings X

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2. Evidence to Recommendation table – Growth promotion

Complete restriction of use of antimicrobials on the WHO CIA List for growth promotion in animals?

Conclusions Type of recommendation Recommendation

Strong recommendation against the intervention ○

Conditional recommendation against the intervention ○

Conditional recommendation for either the intervention or the comparison ○

Conditional recommendation for the intervention ○

Strong recommendation for the intervention x

We strongly recommend complete restriction of use of all classes of medically important antimicrobials in food-producing animals for growth promotion. The panel determined that this recommendation should be strong despite the low quality evidence due to the potential large health benefits of lowered antimicrobial resistance in humans resulting from the complete restriction of use of antimicrobials for growth promotion. This conclusion is based upon the systematic review that found consistent evidence that restriction of growth promotion use of antimicrobials in food-producing animals reduces the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance that can be transmitted to humans. The review of molecular mechanisms also supports this conclusion since bacteria exposed to lower concentrations, as in growth promotion, have an increased efficiency for emergence and dissemination of antimicrobial resistance. Furthermore, undesirable consequences associated with complete restriction of growth promotion use of antimicrobials in food-producing animals appear to be relatively small or non-existent. Finally, complete restriction of growth promotion use of antimicrobials in food-producing animals has been accomplished successfully in multiple countries demonstrating its feasibility. Reducing use of antimicrobials is in accordance with the WHO Global Action Plan which states that “evidence that antimicrobial resistance is driven by the volume of use of antimicrobial agents is compelling”. To reduce possible undesirable outcomes, non-antimicrobial options for disease prevention in animals should be implemented, including improved hygiene, improved biosecurity, and better use of vaccines. Particular care is needed to avoid compensatory increases in antimicrobial use for disease prophylactic or therapeutic purposes, particularly antimicrobials important for therapy in either humans or animals. Experience gained in prohibition of antimicrobial growth promoters in Europe should be made widely available in other regions. A detailed WHO report of the effects of the prohibition in Denmark on antimicrobial resistance, animal production, food safety, national economy and other parameters, is available (WHO, 2002). Provision should be made to assist developing regions with implementation, which could include implementation and follow-up monitoring in AGISAR country pilot projects (e.g. Bangladesh, India, Kenya, Rwanda, Tanzania). Some countries may need support for implementation. FAO and OIE may assist countries with implementation (e.g. alternatives to growth promoters, governance models, taking small holders into account). FAO and OIE may assist with tools for veterinary oversight of antimicrobial use. Among the antimicrobials not currently used in human medicine, special consideration can be given to ionophores - which are a class of antimicrobial agents widely used in food-producing animals in some countries and which are not used in human medicine.

Justification

Implementation considerations

Monitoring and evaluation Research priorities

National antimicrobial resistance and antimicrobial use surveillance programs, using the integrated One Health approach, should evaluate the effect of implementation of prohibition. Quantities of prophylactic and therapeutic antimicrobials used in food-producing animals should be monitored in food-producing animals to determine trends. Alternatives to antimicrobial growth promoters (e.g. vaccines, probiotics), improved hygiene and animal health.

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3. Evidence to Recommendation Table – Prevention in the absence of disease

Does complete restriction of the routine use of antimicrobials on the WHO CIA List for prevention of infectious diseases that have not yet been clinically diagnosed in food-producing animals, compared to no such restriction, reduce the presence of antimicrobial-resistant bacteria and/or genetic elements in humans? 5 April 2017 Problem: Increasing antimicrobial resistance is resulting in increased morbidity and mortality in humans Option: Complete restriction of routine use of antimicrobials on the WHO CIA List for prevention of infectious diseases that have not yet been clinically diagnosed in food animals Comparison: No such restriction in food producing animals Setting: Food animal production and aquaculture worldwide Background: Antimicrobials important to human health (i.e. all of those on the WHO CIA List, whether Important, Highly Important, or Critically Important) are in many countries approved for use in food animals for disease prevention/prophylactic use, i.e. use of an antimicrobial(s) in healthy animals (individually or in groups) considered to be at risk of infectious diseases but prior to the onset of clinical infectious disease in those animals. More simply, such use constitutes treatment with antimicrobials in the absence of disease. Disease prevention/prophylactic use, particularly when such use is regular or routine, has been shown to select for resistance among human pathogens and commensals. We thus sought to critically review the evidence and all other criteria to assess if a recommendation could be made as to whether complete restriction of the routine use of classes of antimicrobials important to human health (i.e. all those on the WHO CIA list) in healthy animals considered to be at risk of infectious diseases but prior to the onset of clinical infectious disease in those animals, compared to no such restriction, would reduce the presence of antimicrobial-resistant bacteria and/or genetic elements in humans. According to Codex Alimentarius, prophylactic use of antimicrobials in food producing animals is defined as the use of an antimicrobial(s) in a group of healthy animals considered to be at risk of infection or prior to the onset of clinical infectious disease. Prophylaxis in food producing animals therefore includes control of the dissemination of a clinically diagnosed infectious disease identified within a group of animals (disease control), and prevention of an infectious disease in a group of animals that has not yet been clinically diagnose (disease prevention). This restriction option being considered pertains only to the disease prevention type of prophylaxis: the use of antimicrobials in group of healthy food producing animals considered to be at risk of infectious diseases but prior to the onset of clinical infectious disease in those animals. This can also be described as the prevention of infectious diseases that have not yet been clinically diagnosed in food producing animals, or, more simply, prevention in the absence of disease.

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RESEARCH EVIDENCE Antimicrobial resistance has been recognized as a major global public health threat. In the 2014 WHO Antimicrobial Resistance. Global Report on Surveillance, high proportions of resistance were reported in all regions of the world to common treatments for bacteria causing infections in both healthcare settings and in the community. Antibacterial resistance has a negative effect on patient outcomes including both morbidity and mortality and was more costly to the healthcare system .A systematic review published by the WHO in 2014 on the impact of AMR on multiple outcomes including mortality revealed for patients with third-generation cephalosporin resistant (including ESBL) E. coli infections there was a significant twofold increase in all-cause mortality, bacterium-attributable mortality and in 30-day mortality; for patients with fluoroquinolone-resistant E. coli infections there was a significant twofold increase in both all-cause mortality and 30-day mortality; for patients with third-generation cephalosporin resistant K. pneumoniae infections there was: a significant almost two-fold increase in all-cause mortality, bacterium-attributable mortality and 30-day mortality, and in the risk of intensive care unit (ICU) admission; for patients with carbapenem-resistant K. pneumoniae infections there was a significant twofold increase in both all-cause mortality and 30-day mortality; and for patients with methicillin-resistant S. aureus infections there was a significant increase in all-cause mortality, bacterium-attributable mortality and ICU mortality, and septic shock. Treatment options for common infections are limited. Food animals are important reservoirs and / or amplifiers of many bacterial infections of humans, including among others non-typhoidal Salmonella, Campylobacter, and E. coli, as well as opportunistic pathogens including E. coli and Enterococcus spp. Foodborne diseases are a major cause of human morbidity and mortality. According to recent estimates from the WHO Foodborne Diseases Epidemiology Reference Group (WHO FERG), foodborne diseases caused 600 million illnesses, 420,000 deaths, and 33 million Disability Adjusted Life Years (DALYs) in 2010 (1). Foodborne diseases are particularly important in children. According to the WHO FERG estimates, although children <5 years of age represent only 9% of the global population, 40% of the foodborne disease burden is borne by children in this age group. There are also considerable differences in the burden of foodborne diseases among subregions with the highest burden of per population observed in Africa. Exact numbers of the global population affected by AROs is difficult to define but in

ADDITIONAL INFORMATION

Is the problem a priority?

Probably No

Uncertain

Probably Yes

Yes X

Varies

Reference : WHO Antimicrobial Resistance. Global Report on Surveillance 2014 http://www.who.int/drugresistance/documents/surveill ancereport/en/

P RO B LE M

http://www.who.int/drugresistance/documents/surveill ancereport/en/ Reference: Havelaar AH, Kirk MD, Torgerson P, Gibb HJ, Hald T, Lake RJ, Praet N, Bellinger JD, de Silva NR, Gargouri N, Speybroeck N, Cawthorne A, Mathers C, Stein C, Angulo FJ, Devleesschauwer B. World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010. PLoS Medicine 2015; doi:

Are a large number of people affected?

Probably No

Uncertain

Probably Yes

Yes X

Varies

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the recent WHO Global Surveillance Report five WHO Regions globally had national reports of 50% resistance or more to three of the most commonly reported bacterial strains causing infections in humans. Lord O’Neill, in his recent economic report suggested the global financial cost of no action would be the loss of 10 million lives a year by 2050 and £69tn ($100tn) a year. Non-typhoidal Salmonella caused an estimated 80 million infections and 60,000 deaths and Campylobacter caused 95 million infections and 21,000 deaths in 2010. Resistance among these infections is common (e.g. 0-49% resistance to fluoroquinolones among non-typhoidal Salmonella infections, depending on region).

10.1371/journal.pmed.1001923

CRITERIA Are the desirable anticipated effects large? BENEFITS & HARMS OF THE OPTIONS

JUDGEMENTS No Probably Uncertain Probably No Yes X Yes Varies

RESEARCH EVIDENCE Summary of finding:

ADDITIONAL INFORMATION Summary of findings data from the systematic reviews (SR) are provided for antimicrobials that are listed the on the current WHO CIA List. Risk differences reflect uses of these antimicrobials as reported in the papers found and analyzed related to “nontherapeutic” use which would have included prophylaxis referring to use of (an) antimicrobial(s) in healthy animals considered to be at risk of infection or prior to the onset of clinical infectious disease, as well as for control of the dissemination of a clinically diagnosed infectious disease identified within a group of animals, and growth promotion. It was not possible to identify what the percentage use of each of the categories would have been in these studies. A total of 36 studies were identified in the quantitative analysis of which 26 were meta-analyzed for the outcome of animal resistance and 2 studies (Dutil 2010, Huijbers 2015) for human resistance and a RD was determined for both. The two studies could not be combined for a metaanalysis since one uses isolates as the unit

Are the undesirable anticipated effects small?

No Probably Uncertain Probably Yes No Yes X

Varies

What is the overall certainty of this evidence?

No included studies Very low

Outcome:Reduction of the presence of antimicrobialresistant bacteria and/or genetic elements in animals and humans with a complete restriction of prophylactic use in food animals of classes of antimicrobials classified as critically important on the WHO CIA list, compared to no such restriction

Risk Difference or Odds Ratios (intervention compared to control groups) (n= no. studies) (95% CI)

Certainty of the evidence (GRADE)

Low X

Moderate

High Antimicrobial resistance in animals RD = -0.08 (-0.11, -0.06) n=36 (26 were metaanalyzed) Low

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ADDITIONAL INFORMATION n=2 RD = -0.08 (-0.20, 0.04) RD = -0.25 ( -0.34, -0.16) OR 1.17 (0.98-1,39) for antimicrobial use in animals (2 fold increase in unit exposure) for LA-MRSA in humans OR 0.19 (0.07-0.53) for LA-MRSA carriage in intervention arm Low of analysis and the other uses sample as the unit of analysis. Two additional studies from Group 6 where it could be discerned that prophylaxis was used with human resistance outcomes were also included but were not amenable to meta-analysis but had ORs for comparison. Twenty-one studies described antibiotic resistance outcomes in humans (19 of which also reported antibiotic resistance in animals), of which 13 were meta-analyzed. In humans, the pooled prevalence of antibiotic resistance was 24% lower in intervention groups (where interventions to reduce antibiotic use in food animals were implemented) compared to control groups. The effect was similar, albeit weaker, when considering humans without direct contact with livestock animals, compared to farm workers.

Antimicrobial resistance in humans

Possible harms include adverse effects on: 1) increased use of antibiotics (such as increased need for antibiotics for treatment purposes) 2) adverse effects on human health, 3) decrease in food and protein availability, 4) food safety, 5) adverse effects on animal health and welfare, 6) adverse effects on animal production, and 7) economic consequences. In the case of complete restriction of routine prevention/prophylactic use of classes of antimicrobials important to human health (i.e. all those on the WHO CIA list) in healthy animals considered to be at risk of infectious diseases but prior to the onset of clinical infectious disease in those animals, the most relevant possible type of harm is 1) increased use of antibiotics (such as increased need for antibiotics for treatment purposes).

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ADDITIONAL INFORMATION

For details see “Supplemental report to: Restriction in the use of antibiotics in food animals and antibiotic resistance in food animals and humans – a systematic review and metaanalysis” and “Potential unintended consequences associated with restrictions on antimicrobial use in food-producing animals”. The main conclusions of the former state “Regarding potential unintended consequences, there appears to be a recurring finding of somewhat increased use of therapeutic antibiotic courses in individual animals (though an overall reduction in the volume of antibiotics used) with interventions that restrict antibiotic use, and possible implications for food safety given the possible higher prevalence of bacterial contaminants in these food products.” The main conclusions of the latter report that are relevant to prophylaxis state: • Such adverse effects that may be encountered can be reduced by taking steps to minimize disease in vulnerable classes of animals, especially weaner pigs, and supporting producers in making a transition to more targeted, prudent antimicrobial use. Such steps include improvements in veterinary advice, animal housing, non-antimicrobial disease control strategies and antimicrobial use surveillance.

CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE The GDG gave very high ratings to desirable outcomes from restrictions on antimicrobial use in animals; it gave the highest value (median 9, with score of 9 judged of “most importance”) to the consideration that when people were infected with antimicrobial resistant bacteria, this leads to more severe health outcomes. Also rated highly were desirable outcomes related to decreases in the prevalence of antimicrobial resistant bacteria and/or antimicrobial resistant determinants in food animals (median 8) and humans (median 7-8). Undesirable outcomes were rated of lower importance, including decreases in food animal health and welfare (median 4), decreases in food security (median 2), food safety (median 4), increased therapeutic antimicrobial use in animals

How certain is the relative importance of the desirable and undesirable outcomes?

VALUES

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RESEARCH EVIDENCE following restrictions on growth promoters (median 4), and increased costs to producers and loss of income to national economies (median 3).

ADDITIONAL INFORMATION c. food animals are an important source of antimicrobial-resistant bacteria for humans, and infections in humans caused by antimicrobialresistant bacteria may have more severe health consequences compared with infections caused by antimicrobial-susceptible bacteria

Are the desirable effects large relative to undesirable effects?

Probably No

Uncertain

Probably Yes X

Yes

Varies

CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE The resources required to eliminate prophylactic use of antimicrobials in food animals include two general types. Governments may require some resources to direct and monitor food-production facilities, including feedmills, farms and aquaculture facilities. These resources are small. Antibiotic prophylaxis is an alternative to good hygiene practices, vaccination, and biosecurity in food production. Some studies have found that the use of vaccines could substantially replace the prophylactic use of antibiotics in food producing animals, but there is a need for more research in this area

ADDITIONAL INFORMATION Bak H, Rathkjen PH, Reduced Use of Antimicrobials after Vaccination of Pigs Against Porcine Proliferative Enteropathy in a Danish SPF Herd. Acta Veterinaria Scandinavica 2009, 51(1). Allen H K, Levine UY, Looft T, Bandrick M Casey TA, Treatment, Promotion, Commotion: Antibiotic Alternatives in Food-Producing

RE S O URCE US E

Are the resources required small?

Probably No

Uncertain

Probably Yes

Yes

Varies

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RESEARCH EVIDENCE (Bak and Rathkjen, 2009; Allen et al 2009). There are no known estimates of the cost-effectiveness of antibiotic prophylaxis distinct from AGPs and so it is difficult to provide clear estimates of the resources required to stop the use of prophylactic antibiotics. Because of increasing resistance, the value of prophylaxis is declining. The incremental cost of eliminating the use of AGPs globally, discussed above, appears to be in the range of $20bn per year, but likely declining over time. It is even more challenging to estimate the financial value of the net benefits. One estimate of the value of delaying widespread resistance by ten years is approximately USD65 trillion or approximately one year’s global GDP (RAND 2014).

ADDITIONAL INFORMATION Animals. Trends in Microbiology, 2013, 21(3), 114-119.

Is the incremental cost small relative to the net benefits?

Probably No

Uncertain

Probably Yes X

Yes

Varies

Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance Chaired by Jim O’Neill December 2014 https://amr-review.org/

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RESEARCH EVIDENCE

ADDITIONAL INFORMATION The World Bank recently reviewed the economic impacts of failure to control antimicrobial resistance in terms of reductions in national GDP (World Bank Group, Drug-Resistant Infections A Threat to our Economic Future 2016). This analysis indicated large decreases in global economic growth. In contrast to acute economic events such as the 2008-9 financial crisis, these impacts are expected to be prolonged. This analysis indicated substantial inequities in impacts that varied inversely with per capita income such that the poorest countries would experience the greatest decreases in annual economic growth as measured by GDP (figure 3). Overall, under a more optimistic scenario (related to the magnitude of AMR) the losses of world economic output exceeded $1 trillion annually to reach a total of $2 trillion per year by 2050. Under a more pessimistic scenario, these losses were estimated to be #3.4. trillion annually to 2030 and $6.1 trillion annually by 2050. Economic shocks to livestock production were also anticipated due to trade restrictions and consumer fears of food safety. These impacts and associated effects on nutrition and health would also be more severe in low income countries. Health care costs in terms of extra costs associated with AMR infections would also increase significantly. Because of these disparate economic impacts, poverty is anticipated to increase markedly in low income countries

What would be the impact on health inequities?

E Q UIT Y

Increased Probably Uncertain Probably Reduced Varies increased reduced X

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JUDGEMENTS

RESEARCH EVIDENCE

ADDITIONAL INFORMATION

Is the option acceptable to key stakeholders?

Probably No

Uncertain

Probably Yes

Yes

Varies X

Key target audience are Governments and regulatory agencies, veterinarians, farmers and other food producers, the food production industry, and consumers.

Concerns about additional restrictions to antimicrobial prescribing have been raised by veterinarians.

Is the option feasible to implement?

Probably No

Uncertain

Probably Yes X

Yes

Varies

Some countries have implemented programs for substantial reduction of antimicrobial use without many problems. Feasibility of implantation in other countries depends on access to laboratory facilities for culture and sensitivity testing (to enable use when justified) as well as resistance patterns to antimicrobials classified Very Important and Important (more feasible if less resistance). In some situations, administration of antimicrobials to individual animals is not practical, and this may affect feasibility to the intervention.

F E A S IB ILIT Y

Balance of consequences

Undesirable consequences clearly outweigh desirable consequences in most settings

Undesirable consequences probably outweigh desirable consequences in most settings

The balance between desirable and undesirable consequences is closely balanced or uncertain

Desirable consequences probably outweigh undesirable consequences in most settings

Desirable consequences clearly outweigh undesirable consequences in most settings X

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3. Evidence to Recommendation table - Prevention

Does complete restriction of the use in the absence of disease in food animals of classes of antimicrobials classified as critically important on the WHO CIA list, compared to no such restriction, reduce the presence of antimicrobial-resistant bacteria and/or genetic elements in humans?

Conclusions Type of recommendation Recommendation

Strong recommendation against the intervention ○

Conditional recommendation against the intervention ○

Conditional recommendation for either the intervention or the comparison ○

Conditional recommendation for the intervention ○

Strong recommendation for the intervention x

We strongly recommend complete restriction of use of all classes of medically important antimicrobials in food-producing animals for prevention of infectious diseases that have not yet been clinically diagnosed. The panel determined that this recommendation should be strong despite the low quality evidence due to the potential large health benefits of lowered antimicrobial resistance in humans resulting from the complete restriction of the routine use of antimicrobials for disease prevention (i.e., the prevention of infectious diseases that have not yet been clinically diagnosed in foodproducing animals). This conclusion is based upon the systematic review and evidence from documented additional observational studies, particularly the use of third generation cephalosporin for disease prevention in chickens in Canada, that found evidence from that restriction of prophylactic use of antimicrobials in food-producing animals reduces the presence of antimicrobial-resistant genetic elements and/or antimicrobial resistance that can be transmitted to humans. A review of molecular mechanisms of resistance indicated that prolonged treatment as in prophylactic conditions is more efficient for horizontal transfer of resistance genes, and therefore enhances emergence and dissemination of resistance. Furthermore, undesirable consequences associated with complete restriction of use of antimicrobials for the prevention of infectious diseases that have not yet been clinically diagnosed in food-producing animals appear to be relatively small. Finally, restriction of disease prevention use of antimicrobials in food-producing animals has been accomplished successfully in several countries demonstrating its feasibility. Reducing use of antimicrobials is in accordance with the WHO Global Action Plan which states that “evidence that antimicrobia l resistance is driven by the volume of use of antimicrobial agents is compelling”. The panel acknowledges that, when in the professional judgment of a veterinary professional, prophylaxis may be used to address an elevated risk of contraction of a particular disease or infection. If antimicrobials are used for disease prevention, this should be justified on the basis of recent culture and sensitivity testing results, and the types of antimicrobials used should be used in reverse order as their importance for human health (i.e., classes not used in humans, important, and lastly highly important antimicrobials). The use of antimicrobials classified as critically important in human medicine on the WHO CIA List should only be used when justified by culture and sensitivity results of bacteria isolated in the recent past that have caused disease that is associated with the judged elevated risk and the sensitivity results indicate that the critically important antimicrobial is the only treatment option. National antimicrobial resistance and antimicrobial use surveillance programs should evaluate the effect of implementation. Alternative to antimicrobials for prophylaxis, such as vaccines, hygiene, changing diets, probiotics.

Justification

Implementation considerations

Monitoring and evaluation Research priorities

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Does complete restriction of the Critically Important Antimicrobials on the WHO CIA List for disease control and treatment in food-producing animals, compared to no such restriction, reduce the presence of antimicrobial-resistant bacteria and/or genetic elements in humans? 31 March 2017 Problem: Increasing antimicrobial resistance is resulting in increased morbidity and mortality in humans Option: Restriction of the Critically Important Antimicrobials on the WHO CIA List used for disease control and treatment in food animals Comparison: No such restriction in food animals Setting: Food animal production and aquaculture worldwide Background: Antimicrobials deemed to be Critically Important antimicrobials on the WHO CIA List (e.g. fluoroquinolones, 3rd and 4th generation cephalosporins and macrolides) are in many countries approved for use in food animals, many for therapeutic purposes in individual animals and in some cases, groups of animals. Antimicrobials are sometimes administered to an entire group of animals, even when only some of the animals in the group have clinically diagnosed infectious disease. In this situation, the antimicrobial is administered for two reasons; 1) disease treatment/therapy for the animal(s) with the clinically diagnosed infectious disease; and 2) control of the dissemination of the clinically diagnosed infectious disease to the other animals in the group. This is sometimes called “metaphylaxis”. Use of antimicrobials of critical importance to human health in food animals has been shown to select for resistance among human pathogens and commensals. We thus sought to critically review the evidence and all other criteria to assess if a recommendation could be made as to whether complete restriction of the Critically Important Antimicrobials on the WHO CIA List for treatment and control in food animals, compared to no such restriction, would reduce the presence of antimicrobial-resistant bacteria and/or genetic elements in humans. According to Codex Alimentarius, disease control is a type of prophylaxis. Codex Alimentarius defines prophylactic use of antimicrobials in food producing animals as the use of an antimicrobial(s) in a group of healthy animals considered to be at risk of infection or prior to the onset of clinical infectious disease. Prophylaxis in food producing animals therefore includes control of the dissemination of a clinically diagnosed infectious disease identified within a group of animals (disease control), and prevention of an infectious disease in a group of animals that has not yet been clinically diagnose (disease prevention). In terms of prophylactic use of antimicrobials in food producing animals, this restriction option being considered only pertains to the disease control type of prophylaxis in group of animals: the use of antimicrobials in group of food producing animals for the control of dissemination of clinically diagnosed infectious disease.

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CRITERIA

JUDGEMENTS

RESEARCH EVIDENCE Antimicrobial resistance has been recognized as a major global public health threat. In the 2014 WHO Antimicrobial Resistance. Global Report on Surveillance, high proportions of resistance were reported in all regions of the world to common treatments for bacteria causing infections in both healthcare settings and in the community. Antibacterial resistance has a negative effect on patient outcomes including both morbidity and mortality and was more costly to the healthcare system .A systematic review published by the WHO in 2014 on the impact of AMR on multiple outcomes including mortality revealed for patients with third-generation cephalosporin resistant (including ESBL) E. coli infections there was a significant twofold increase in all-cause mortality, bacterium-attributable mortality and in 30-day mortality; for patients with fluoroquinolone-resistant E. coli infections there was a significant twofold increase in both all-cause mortality and 30-day mortality; for patients with third-generation cephalosporin resistant K. pneumoniae infections there was: a significant almost two-fold increase in all-cause mortality, bacteriumattributable mortality and 30-day mortality, and in the risk of intensive care unit (ICU) admission; for patients with carbapenem-resistant K. pneumoniae infections there was a significant two-fold increase in both all-cause mortality and 30-day mortality; and for patients with methicillin-resistant S. aureus infections there was a significant increase in all-cause mortality, bacterium-attributable mortality and ICU mortality, and septic shock. Treatment options for common infections are limited. Food animals are important reservoirs and / or amplifiers of many bacterial infections of humans, including among others nontyphoidal Salmonella, Campylobacter, and E. coli, as well as opportunistic pathogens including E. coli and Enterococcus spp. Foodborne diseases are a major cause of human morbidity and mortality. According to recent estimates from the WHO Foodborne Diseases Epidemiology Reference Group (WHO FERG), foodborne diseases caused 600 million illnesses, 420,000 deaths, and 33 million Disability Adjusted Life Years (DALYs) in 2010 (1). Foodborne diseases are particularly important in children. According to the WHO FERG estimates, although children <5 years of age represent only 9% of the global population, 40% of the foodborne disease burden is borne by children in this age group. There are also considerable differences

ADDITIONAL INFORMATION

Is the problem a priority? P RO B LE M

Probably No

Uncertain

Probably Yes

Yes

Varies

Reference: WHO Antimicrobial Resistance. Global Report on Surveillance 2014 http://www.who.int/drugresistance/documents/surveillancere port/en/

http://www.who.int/drugresistance/documents/surveillancere port/en/ Reference: Havelaar AH, Kirk MD, Torgerson P, Gibb HJ, Hald T, Lake RJ, Praet N, Bellinger JD, de Silva NR, Gargouri N, Speybroeck N, Cawthorne A, Mathers C, Stein C, Angulo FJ, Devleesschauwer B. World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010. PLoS

Are a large number of people affected?

Probably No

Uncertain

Probably Yes

Yes

Varies

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in the burden of foodborne diseases among sub-regions with the highest burden of per population observed in Africa. Exact numbers of the global population affected by AROs is difficult to define but in the recent WHO Global Surveillance Report 5/6 WHO Regions globally had national reports of 50% resistance or more to three of the most commonly reported bacterial strains causing infections in humans. Lord O’Neill, in his recent economic report suggested the global financial cost of no action would be the loss of 10 million lives a year by 2050 and £69tn ($100tn) a year. Non-typhoidal Salmonella caused an estimated 80 million infections and 60,000 deaths and Campylobacter caused 95 million infections and 21,000 deaths in 2010. Resistance among these infections is common (e.g. 0-49% resistance to fluoroquinolones among non-typhoidal Salmonella infections, depending on region). In some countries, fluoroquinolones have been approved for therapeutic treatment of bacterial infections (e.g. E. coli) in poultry. The fluoroquinolone was typically administered to the entire flock through drinking water. This practice has been shown to select for fluoroquinolone resistance in Campylobacter. A quantitative assessment of effects on human health by fluoroquinolone-resistant Campylobacter species associated with the therapeutic use of fluoroquinolones in poultry estimated that 153,580 persons were infected with fluoroquinoloneresistant Campylobacter species in 1999 from chicken consumption and 9261 of these people were estimated to have been treated with a fluoroquinolone. Nelson JM, Chiller TM, Powers JH, Angulo FJ (2007). Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story. Clinical Infectious Disease 44:977-980.

Medicine 2015; doi: 10.1371/journal.pmed.1001923

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ADDITIONAL INFORMATION

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CRITERIA Are the desirable anticipated effects large? Are the undesirable anticipated effects small?

JUDGEMENTS

RESEARCH EVIDENCE Summary of findings: Outcome: Reduction of the presence of antimicrobialresistant bacteria and/or genetic elements in animals and humans with a restriction of the Highest Priority, Critically Important antimicrobials on the WHO CIA List used in food animals for trestment and control compared to no such restriction Quinolone resistance in Enterobacteriaceae Risk Difference (intervention compared to control groups) (n= no. studies) (95% CI) Certainty of the evidence (GRADE)

ADDITIONAL INFORMATION Data from a systematic review (SR) is provided for antimicrobials that are listed among the Highest Priority, Critically Important Antimicrobials on the current WHO CIA List. This data provides indirect evidence related to the designated outcome and hence the overall quality of the evidence is considered very low. An additional study which more directly addresses this outcome is also presented. Risk differences reflect uses of the Highest Priority, Critically Important Antimicrobials as reported in the literature. The effect due to the proposed intervention alone has not been determined. Risk differences for multi-drug resistance in Enterobacteriaceae and overall antimicrobial resistance are also shown, because these antimicrobials may also contribute to these outcomes through direct and co-selection. Of the two SRs one was a narrative summary of the findings and the other a quantitative assessment. Both revealed the same findings with respect to the reduction of resistance transfer from food producing animals to humans when a limitation of antimicrobials were used in the food producing animals.

No Probably Uncertai Probabl Yes n y No Yes X

Varie s

BENEFITS & HARMS OF THE OPTIONS

No Probably Uncertai Probabl Yes n y No Yes X

Varie s

Faecal samples (n=16) RD=-0.01 (-0.01, 0.00) Meat samples (n=12) RD=-0.09 (-0.17, -0.02)

Very Low

Quinolone resistance in Campylobacter spp. What is the overall certainty of this evidence? No include d studies Very low X

Faecal samples (n=11) RD= -0.06 (-0.16, 0.05) Meat samples (n=12) RD= -0.08 (-0.17, 0.01)

Very Low

Low

Moderate

High

Cephalosporin resistance in Enterobacteriaceae

Faecal samples (n=16) RD=-0.01 (-0.04, 0.01) Meat samples (n=11) RD=-0.07 (-0.14, 0.01)

Very Low

Macrolide resistance in Campylobacter spp.

Faecal samples (n=11). RD=-0.15 (-0.26, -0.04) Meat samples (n=7) RD=-0.04 (-0.17, 0.09)

Very Low

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RESEARCH EVIDENCE Macrolide resistance in Enterococcus spp. Multi-drug resistance in Enterobacteriaceae Faecal samples (n=10). RD= -0.39 (-0.56, -0.23) Faecal samples (n=19). RD=-0.24 (-0.32, -0.17) Meat samples (n=14). RD=-0.32 (-0.43, -0.22) Overall antibiotic resistance With stronger interventions (n=22) RD=0.22 (95% CI -0.31, -0.13) With weaker interventions (n=62) RD=0.16 (95% CI -0.18, -0.14) Resistance to any antimicrobial Pooled absolute risk differences of antibiotic resistance (n=13 studies) RD=-0.24 (-0.42, -0.06) -Stratification by the studied human population Farm workers (n=9) RD=-0.29 (-0.54, -0.04) Not farm workers (n=4) RD=-0.09 (-0.13, -0.05) -Stratification by stronger versus weaker interventions* Stronger interventions (n=8) RD=-0.14 (95% CI -0.20, Very Low Very Low Very Low Very Low

ADDITIONAL INFORMATION Within the quantitative analysis, in the animal studies, 179 described antibiotic resistance outcomes in animals, of which 80 were metaanalyzed. The pooled absolute risk reduction of the prevalence of antibiotic resistance in animals, with interventions that restricted antibiotic use, varied across different antibiotic classes, bacteria, and sample types, but ranged from 0% to 39%; in general, the prevalence of antibiotic resistance was commonly 10-20% lower in intervention compared to control groups. The pooled prevalence of multi-drug resistance was 24-32% lower in bacteria isolated from intervention groups. These findings held through many different layers of stratification including by intervention type. Twenty-one studies described antibiotic resistance outcomes in humans (19 of which also reported antibiotic resistance in animals), of which 13 were metaanalyzed. In humans, the pooled prevalence of antibiotic resistance was 24% lower in intervention groups (where interventions to reduce antibiotic use in food animals were implemented) compared to control groups. The effect was similar, albeit weaker, when

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RESEARCH EVIDENCE 0.08) Weaker interventions (n=5) RD= -0.38 (95% CI -0.83, 0.08) In the Netherlands, implementation of a requirement whereby the use of a 3rd generation cephalosporin or fluoroquinolone in food animals is only allowed when culture and susceptibility test results show that this is the only available drug, substantially decreased use of the drug and resistance in bacteria from animals (Mevius, 2013). Complete restriction on the use of Antimicrobials Critically Important for Human Use in food animals could lead to animal health and welfare problems in the case of an infectious disease outbreak where these antimicrobials were the only effective treatment.

ADDITIONAL INFORMATION considering humans without direct contact with livestock animals, compared to farm workers. In some countries, fluoroquinolones have been approved for therapeutic treatment of bacterial infections (e.g. E. coli) in poultry. The fluoroquinolone was typically administered to the entire flock through drinking water. This practice has been shown to select for fluoroquinolone resistance in Campylobacter. In 2005, approval of use of fluoroquinolones for therapeutic treatment of bacterial infections in poultry in the U.S. was withdrawn. Since the withdrawal, fluoroquinolone resistance has persisted in Campylobacter from poultry in the U.S. Nelson JM, Chiller TM, Powers JH, Angulo FJ (2007). Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public. Nannapaneni R, Hanning I, Wiggins KC, Story RP, Ricke SC, Johnson MG. Ciprofloxacin-resistant Campylobacter persists in raw

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ADDITIONAL INFORMATION retail chicken after the fluoroquinolone ban. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2009 Oct;26(10):1348-53. Price LB, Lackey LG, Vailes R, Silbergeld E. The persistence of fluoroquinolone-resistant Campylobacter in poultry production. Environ Health Perspect. 2007 Jul;115(7):1035-9. Complete restriction in use of antimicrobials critically important to human use in food animals could lead to increased resistance to antimicrobials of lesser importance to human health (given a need to treat, the intervention determines which antimicrobial to use). Mevius, D. & Heederik, D. J. Verbr. Lebensm. (2014) 9: 177. doi:10.1007/s00003-014-0874-z. http://link.springer.com/article/10.1 007/s00003-014-0874-z

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4. Evidence to Recommendation Table – Control and Treatment ADDITIONAL INFORMATION Public health concerns about the use of antimicrobial agents in food animals have been expressed for decades. Many groups have concluded that public health concerns warrant placing restrictions on the use of antimicrobial agents in food animals given that: a. antimicrobials agents used in humans are widely used in food animals, b. use of antimicrobial agents results in antimicrobial resistance, c. food animals are an important source of antimicrobial-resistant bacteria for humans, and infections in humans caused by antimicrobialresistant bacteria may have more severe health consequences compared with infections caused by antimicrobial-susceptible bacteria

V A LUE S

How certain is the relative importance of the desirable and undesirable outcomes?

Important uncertainty or variability

Possibly important uncertainty or variability

Probably no important No important No known uncertainty uncertainty undesirable or variability or variability outcomes X

Are the desirable effects large relative to undesirable effects?

No Probably Uncertain Probably Yes No Yes X

Varies

Reduction in resistance to highest priority drugs more desirable than reduction to lower priority drugs.

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ADDITIONAL INFORMATION

Are the resources required small?

No Probably Uncertain Probably Yes No Yes

Varies X

RESOURCE USE

The resources required to limit use of critically important antimicrobials for treatment of disease in food animals include two general types. Governments may require some resources to direct and monitor foodproduction facilities, including feedmills, farms and aquaculture facilities. In addition, governments may require resources to support susceptibility testing facilities. These resources are relatively small. Antibiotic treatment with critically important antibiotics is an alternative to good hygiene practices, vaccination, and biosecurity in food production, as well as treatment with alternative antibiotics. Because there are many alternatives, including treatment with critically important antibiotics when justified, the costs for food production should be small. The main cost involved in reduced therapeutic use of critically important antibiotics relates to supporting an infrastructure for susceptibility testing. The incremental costs are likely in the millions of dollars, but such testing facilities would provide many other benefits. (Incremental costs are likely very small in countries with established facilities.) These costs are much smaller than the net benefits caused by reduced resistance to critically important antibiotics.

Potential resource costs from restriction include laboratory costs (culture and sensitivity testing)

Is the incremental cost small relative to the net benefits?

No Probably Uncertain Probably Yes No Yes

Varies X

Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance Chaired by Jim O’Neill December 2014 https://amr-review.org/

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ADDITIONAL INFORMATION The World Bank recently reviewed the economic impacts of failure to control antimicrobial resistance in terms of reductions in national GDP (World Bank Group, DrugResistant Infections A Threat to our Economic Future 2016). This analysis indicated large decreases in global economic growth. In contrast to acute economic events such as the 2008-9 financial crisis, these impacts are expected to be prolonged. This analysis indicated substantial inequities in impacts that varied inversely with per capita income such that the poorest countries would experience the greatest decreases in annual economic growth as measured by GDP (figure 3). Overall, under a more optimistic scenario (related to the magnitude of AMR) the losses of world economic output exceeded $1 trillion annually to reach a total of $2 trillion per year by 2050. Under a more pessimistic scenario, these losses were estimated to be #3.4. trillion annually to 2030 and $6.1 trillion annually by 2050. Economic shocks to livestock production were also anticipated due to trade restrictions and consumer fears of food safety. These impacts and associated effects on nutrition and health would also be more severe in low income countries. Health care costs in terms of extra costs associated with AMR infections would also increase significantly. Because of theses disparate economic impacts, poverty is anticipated to increase markedly in low income countries

What would be the impact on health inequities?

EQUITY

Increased Probably Uncertain Probably Reduced Varies increased reduced

In the O’Neill Report, it indicated that “KPMG looked at what would happen if infection rates doubled and then stayed constant and the analysis suggested an increase in infection rates alone could mean 150 million people dying prematurely and reduce world GDP by 55 trillion USD between now and 2050, just over half the total impact they estimate for AMR.” The impact would be greater on low to middle income countries and thus by acting on our recommendations health inequities would be likely reduced. Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance Chaired by Jim O’Neill December 2014 https://amr-review.org/

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ADDITIONAL INFORMATION

No Probably Uncertain Probably Yes No Yes

Varies X

Key target audience are Governments and regulatory agencies, veterinarians, farmers and other food producers, the food production industry, and consumers.

Concerns about additional restrictions to antimicrobial prescribing have been raised by veterinarians.

FEASIBILITY

Is the option feasible to implement?

No Probably Uncertain Probably Yes No Yes X

Varies

Feasibility difficulties could arise from the potential problems identified above under “Are the resources required small?”.

Balance of consequences

Undesirable consequences clearly outweigh desirable consequences in most settings

Undesirable consequences probably outweigh desirable consequences in most settings

The balance between desirable and undesirable consequences is closely balanced or uncertain

Desirable consequences probably outweigh undesirable consequences in most settings X

Desirable consequences clearly outweigh undesirable consequences in most settings

As of 01/05/2017 7:55 AM

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Does complete restriction of the Critically Important Antimicrobials on the WHO CIA List for disease treatment and control in food-producing animals, compared to no such restriction, reduce the presence of antimicrobial-resistant bacteria and/or genetic elements in humans?

Conclusions Type of recommendation

Strong recommendation against the intervention ○

Conditional recommendation against the intervention ○

Conditional recommendation for either the intervention or the comparison ○

Conditional recommendation for the intervention X

Strong recommendation for the intervention ○

Recommendation

We suggest that antimicrobials classified as highest-priority critically important for human medicine should not be used for treatment of food-producing animals with a clinically diagnosed infectious disease. We suggest that antimicrobials classified as critically important for human medicine should not be used for control of the dissemination of a clinically diagnosed infectious disease identified within a group of food-producing animals.. The GDG concludes that the recommendation on treatment of individual sick animals should be conditional on susceptibility results demonstrating that the selected drug is the only treatment option, and treatment is given to individual animals. This conclusion is based upon the indirect evidence from the systematic review, evidence from documented additional observational studies, and the review of molecular mechanisms. Furthermore, undesirable consequences associated with such a restriction of use of antimicrobials appear to be relatively small or non-existent. Finally, such a restriction of antimicrobials in food-producing animals has been accomplished successfully in several countries demonstrating its feasibility.

Justification

The GDG also concludes that the recommendation on disease control (prophylaxis in a group of animals in the presence of disease) should also be conditional on susceptibility results demonstrating that the selected drug is the only treatment option. Again, this conclusion is based upon the indirect evidence from the systematic review, evidence from documented additional observational studies, and the review of molecular mechanisms. Furthermore, undesirable consequences associated with such a restriction of use of antimicrobials appear to be relatively small or non-existent. Finally, such a restriction of antimicrobials in food-producing animals has been accomplished successfully in several countries demonstrating its feasibility. These recommendations are in accordance with the WHO Global Action Plan which states that “evidence that antimicrobial resistance is driven by the volume of use of antimicrobial agents is compelling”. The use of antimicrobials classified as critically important in human medicine on the WHO CIA List should only be used when justified by culture and sensitivity results indicate that the critically important antimicrobial is the only treatment option. Feasibility is therefore dependent on access to culture and sensitivity testing. The requirement for culture and sensitivity has been implemented in some countries including the Netherlands. There may be some inequity introduced by requirement for culture and sensitivity testing but would be marginal compared to the gains. Veterinarians should have access to culture and sensitivity testing. Provision should be made to assist developing regions with implementation, which could include implementation and follow-up monitoring in AGISAR country pilot projects (e.g. Bangladesh, India, Kenya, Rwanda, Tanzania). National antimicrobial resistance and antimicrobial use surveillance programs should evaluate the effect of implementation. More research is needed to assess the effectiveness, benefits and costs of the intervention.

Implementation considerations

Monitoring and evaluation Research priorities

Key facts

Organisation World Health Organization (WHO)

Document type Publications

Adoption date September 21, 2017

Source World Health Organization