Final Report DRUG-RESISTANT INFECTIONS A Threat to Our Economic Future March 2017 © 2017 International Bank for Reconstruction and Development/The World Bank 1818 H Street NW, Washington, DC 20433 Telephone: 202-473-1000; Internet: www.worldbank.org Some rights reserved 1 2 3 4 19 18 17 16 This work is a product of the staff of The World Bank with external contributions. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of The World Bank, its Board of Executive Directors, or the governments they represent. The World Bank does not guarantee the accuracy of the data included in this work. The boundaries, colors, denominations, and other information shown on any map in this work do not imply any judgment on the part of The World Bank concerning the legal status of any territory or the endorsement or acceptance of such boundaries. 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Examples of components can include, but are not limited to, tables, figures, or images. All queries on rights and licenses should be addressed to the Publishing and Knowledge Division, The World Bank, 1818 H Street NW, Washington, DC 20433, USA; fax: 202-522-2625; e-mail: pubrights@worldbank.org. For more information, please visit www.worldbank.org/health. Cover Design: Emily Yahn Typesetting: Shepherd, Inc. Photos: World Bank   n  iii Table of Contents Acknowledgments  vii Abbreviations and Acronyms  ix Glossary of Select Terms  xiii Executive Summary  xv Introduction  1 Part I. Drug-Resistant Infections: A Primer on the AMR Challenge  5 A. What Is AMR?  6 B. A Tragedy of the Commons  6 Incentives to Overuse and Misuse of Antimicrobials  8 Counterfeit and Poor-Quality Drugs   8 Drug-Resistant Infections Are Already Common Worldwide  9 A Human-Made Problem—with Human Solutions  9 Over Reliance on New Miracle Cures Is Unwise—and Immoral  9 C. AMR Containment: A Global Public Good  10 Public-Sector Responsibility in Conserving Antimicrobial Effectiveness  10 D. AMR and Access to Treatment in Developing Countries   11 E. Closing Governance Gaps  11 Surveillance Is Critical, but Systems Are Weak  11 Growing Threats  12 Coordination Is Key  12 Joining Forces to Strengthen Surveillance and Response  12 How International Coordination Can Lower Costs: The Example of Tuberculosis  13 Part II. Economic Impact of AMR  15 A. Rationale and Approach to the Simulations  16 Economic Impacts Considered in the Simulations  16 Direct and Indirect Costs of Disease  17 B. Impacts of AMR on the Global Economy  17 C. Impacts on Select Components of the World Economy  19 International Trade  19 Livestock Production  20 Health Care Expenditures  20 D. Impacts on Poverty  22 E. The Economic Case for Tackling AMR: Focus on the Health Sector  22 iv  n  Table of Contents Part III. What Will It Take to Contain AMR?  25 A. Expert Consensus on Measures to Contain AMR  26 A Bold Agenda: Integrated Public-Health Protection in All Countries  26 AMR-Specific and AMR-Sensitive Measures  27 Can the World Afford AMR Control?  27 B. Two Threats to AMR Containment   27 Support for Human and Veterinary Public-Health Systems: Changing the Paradigm  28 Mitigating Risks of Inadequate and Unpredictable Financing  29 Multiple Gains from One-Health Models  29 C. International Cooperation  30 AMR Containment and the Global Development Agenda  30 Organizing for International Collective Action  31 Distribution of AMR Containment Benefits  31 D. Economic Justification of Investments in AMR Containment  33 E. Turning Evidence into Action  34 Part IV. Directions for Country Action  37 A. Laboratory-Based AMR Surveillance  38 Status of Global AMR Surveillance  38 Benefits and Costs of AMR Surveillance   39 Components of an AMR Surveillance Network  40 East Africa Public Health Laboratory Networking Project  40 Findings from the EAPHLN Network Case Study and Capacity Assessment  41 B. Antimicrobial Use in Human Health Care and AMR  42 Case Study 1—Antibiotic Market Offer  42 Case Study 2—Antibiotic Consumption in the Public Health System  42 Case Study 3—Antimicrobial Availability without Prescription  43 Case Study 4—Hospital-Acquired Infections (HAIs)  43 Case Study 5—Multidrug-Resistant Tuberculosis  44 Countries Can Win the Battle  44 C. Antimicrobial Use in Animals and AMR  44 Use of Antimicrobials in Animal Production: Background  44 Concerns in Low- and Middle-Income Countries  45 AMR Transmission Pathways   45 Measures to Reduce Antimicrobial Usage and Find Alternatives  45 Knowledge Gaps Revealed by Country Case Studies  45 Conclusions   46 D. Recommendations for Country Action  46 Driving AMR Progress from the Health Sector  47 Agriculture: A Critical Frontier for AMR   50 Water, Sanitation, and Hygiene: AMR-Sensitive Development Priorities  52 Table of Contents  n  v Part V. Conclusions  55 A. The Costs of Inaction  56 B. The Rewards of Leadership   56 C. Action at Country Level  56 Partnerships Build Power   57 Support from Multilateral Organizations  57 D. What Will the World Bank Group Do?  57 Creating an Investment Framework for AMR Action   57 An AMR Lens on Development Finance  58 Mobilizing Finance for AMR Innovation across Agriculture and Health  58 Bringing the Private Sector on Board  58 Leveraging UHC Reforms to Reach AMR Objectives  59 AMR and Resilient Health Systems: The Agendas Converge   59 Action Today—To Preserve Tomorrow   60 Annex 1. September 2016 Political Declaration of the United Nations General Assembly on Antimicrobial Resistance, and Statements to the General Assembly by the WHO and OIE Directors-General  61 Annex 2. Top 18 Drug-Resistant Threats to the United States  69 Annex 3. Potential Savings from Using One Health Approaches  71 Targets for Sustainable Development Goal #3: Ensure Healthy Lives and Promote Annex 4.  Well-being for All at All Ages  73 Annex 5. Example of a Budget for AMR Surveillance  75 Example of a Laboratory-Improvement Budget to Perform Antibiotic Susceptibility Annex 6.  Testing (AST)  77 National, Regional, and International Antimicrobial Resistance Surveillance Annex 7.  Networks  81 Laboratory-Based Surveillance of AMR: Summary Report  83 Annex 8.  Annex 9. Antimicrobial Use in Human Health Care and AMR: Summary Report  97 Annex 10. Antimicrobial Use in Animals and AMR: Issues and Options for Low- and Middle- Income Countries: Summary Report  111 World Bank List of Economies (July 2016)  135 References  137 Boxes Box 1. The Basics about Bugs That Cause Disease  7 Box 2. Indicators of Weak Governance of Antimicrobials  8 Box 3.  Pilot Program for an AMR Surveillance Network in Ghana  85 Box 4. Structured Expert Judgment  88 vi  n  Table of Contents Box 5. Main Findings from the Laboratory Capacity Assessments  92 Box 6. Animal Health Management  112 Tables Table 1.  Cost of Measures to Minimize and Contain AMR  28 Table 2.  Cumulative Costs of AMR, Benefits of Containment, and Costs of Measures Cumulative to 2050, Present Discounted Values  34 Table 3.  Sensitivity of Expected Rate of Return to AMR Containment Success (Assuming $9 Billion Annual Investment in AMR Containment)  34 Table 4.  Specific Examples of Benefits of AMR Surveillance  87 Table 5.  Antimicrobials Dispensed without Prescription  103 Table 6.  Proposed List of Potential Country-Level Actions to Contain AMR in Livestock  122 Figures Figure ES1.  Substantial and Protracted Shortfalls in Global Economic Output  xix Figure ES2.  Economic Costs of AMR May Be as Severe as During the Financial Crisis  xix Figure ES3.  High-Income and Upper Middle-Income Economies Stand to Benefit the Most from AMR Containment, Both in Absolute and per Capita Terms  xxi Figure ES4.  Five Objectives of the Global Action Plan on AMR, 2015–19  xxiii Figure 1.  AMR Makes TB Far Costlier to Treat  13 Figure 2.  Substantial and Protracted Shortfalls in Global Economic Output  18 Figure 3.  Economic Costs of AMR May Be as Severe as During the Financial Crisis  19 Figure 4.  AMR Impact on World Trade  20 Figure 5.  Decline in Livestock Production Could Be Substantial and Most Pronounced in Low-Income Countries  21 Figure 6.  Health Care Costs Reach Nearly $1.2 Trillion in the “High-AMR” Case  21 Figure 7.  Most of the People Falling into Extreme Poverty Because of AMR Will Be in Low-Income Countries  22 Figure 8.  The Five Objectives of the WHO Global Action Plan on AMR, 2015–19  26 Figure 9.  Synergies and Tensions with Global Development Goals for 2030  30 Figure 10.  National and International Plans to Tackle AMR: Year of Implementation and Duration  31 Figure 11.  High-Income and Upper Middle-Income Economies Stand to Benefit the Most from AMR Containment, Both in Absolute and per Capita Terms  32 Figure 12.  Global AMR Surveillance Networks  39 Figure 13.  Location of Satellite Laboratories  40 Figure 14.  Top Five Active Ingredients According to Number of Brand Names  42 Figure 15.  Distribution of “Simulated Self-Referred Patient” Visits That Ended with Dispensation of an Antimicrobial, by Country  43 Table of Contents  n  vii Figure A8.1.  Global AMR Surveillance Networks  84 Figure A8.2.  Theoretical Framework for a Cost-Benefit Analysis of Antimicrobial Resistance  89 Figure A8.3.  Location of Satellite Laboratories  90 Figure A9.1.  A Basic “Antimicrobial Use Chain”  99 Figure A9.2.  Single-Compound Antibacterial Products  100 Figure A9.3.  Top Five Active Ingredients According to Number of Brand Names  100 Figure A9.4.  Top Five Antimicrobials Consumed  101 Figure A9.5.  Distribution of “Simulated Self-Referred Patient” Visits That Ended with Dispensation of an Antimicrobial, by Country  102   n  ix Acknowledgments World Bank report team: Olga Jonas (lead author), Alec Irwin (second author/editor), Franck Berthe, Francois Le Gall, Patricio V. Marquez, Irina Nikolic, Caroline Plante, Miriam Schneidman, Donald Shriber, and Alessia Thiebaud, with advice and inputs from Chris McCahan, Brendan McNulty, Richard Seifman, Andreas Seiter, Vadim Solovyov, Elena Sterlin, Juergen Voegele, and Pauline Zwaans. Administrative support was ensured by Akosua Dakwa. Anugraha Dharani Palan and Sheryl Silverman managed communications. Timothy Grant Evans, s, the World Bank Group’s Health, Nutrition, and Population (HNP) Global Practice Senior Director, and Enis Barı¸ HNP Practice Manager in charge, provided substantive input and strategic guidance throughout the preparation of the report, with support from Olusoji O. Adeyi, HNP Global Practice Director. Special Studies Team s Modeling of Economic Impacts: Syud Amer Ahmed, Delfin S. Go, Hans Lofgren, Israel Osorio-Rodarte (World Bank Group, Development Economics Prospects Group) and Karen Thierfelder (U.S. Naval Academy). Laboratory-Based Surveillance: Hellen Gelband, Principal Investigator (Center for Disease Dynamics, Economics & Policy, CDDEP), Iruka N. Okeke (University of Ibadan, Nigeria), Aaron Oladipo Aboderin (Obafemi– Awolowo University Teaching Hospital, Nigeria), Elena Martinez (CDDEP); Martin Matu, Senior Laboratory Specialist (East, Central and Southern Africa Health Community, ECSA-HC), Yoswa Dambisya (ECSA-HC), John Kiiru (Kenya), Henry Kajumbula (Uganda), Claudette Ndayikunda (Burundi), Antony Nsojo (Tanzania) and Aniceth Rucogoza (Rwanda); and Miriam Schneidman (World Bank). Antibiotic Misuse and AMR in Human Health Care: Albert Figueras and Paúl Pérez Vázquez (Catalan Institute of Pharmacology—FICF, Barcelona); Patricio V. Marquez, Jaime Bayona, Sheila Dutta, and Ishani Premaratne (World Bank Group), on the basis of research undertaken with the participation of a multiinstitutional team comprised of local researchers from the case study countries: Richard Leepo (Botswana), August Cesarec (Croatia), Kwabena Asare and Adobea Ohene-Addo (Ghana), Lela Serebryakova (Georgia), Emilce Herrera (Nicaragua), and Germán Rojas (Peru). Contribution and support were also provided by World Bank Group specialists working in case study countries: Amparo Elena Gordillo-Tobar (Nicaragua), Aneesa Arur (Croatia), Nino Moroshkina, and Aparnaa Somanathan (Georgia). Antimicrobial Use in Animals and AMR: Jonathan Rushton (Royal Veterinary College, University of London); Elisabeth Erlacher-Vindel (World Organisation for Animal Health, OIE, Paris); Franck Berthe, Stéphane Forman, Caroline Plante, and François Le Gall (World Bank Group), on the basis of research undertaken with the participation of a team, including Betty Bisdorff and Liz Redmond (Royal Veterinary College, University of London); Gérard Moulin, and Delfy Gochez (OIE Collaborative Centers); Hernán Rojas (Chile), Houda Benanni (Morocco), Ian Patrick (Thailand), and Kevin Queenan (Uganda). Inputs from the FAO ’s Agriculture and Consumer Protection Department and Fisheries and Aquaculture Department. The WHO-OIE-FAO Tripartite  offered expert guidance throughout, including from Suzanne Hill, Carmem Lucia Pessoa-Silva, Marc Sprenger (WHO); Elisabeth Erlacher-Vindel, Jean-Philippe Dop (OIE); and Juan Lubroth, Hendrik Jan Ormel (FAO). Comments and advice from others, including: Amanda Glassman (Center for Global Development); Gunturu Revathi (The Aga Khan University Hospital, Nairobi); Thomas R. Shryock (Antimicrobial Consultants, LLC); John Stelling (Brigham and Women’s Hospital); Benjamin Park, Michael Craig, Rachel Silverman, Robert Douglas Scott II (Centers for Disease Control and Prevention, US CDC); Ramanan Laxminarayan (Center for Disease Dynamics, Economics & Policy, CDDEP); Thea Emmerling (EU Delegation in Washington, DC); Carlos Santos-Burgoa, Laura Rogers (George Washington University); Ok Pannenborg; Michele Cecchini (OECD); John Flanigan (NIH); Graeme Archibald, Charmaine Bene, Kirsten Duke, Krista Hanniman, Christophe Ingeri (Public Health Agency of Canada); Hala Audi, Jeremy Knox (UK Review on AMR); Aidan Hollis (University of Calgary); Anthony D. So (Johns Hopkins Bloomberg School of Public Health); Victoria Fan (University of Hawaii at Maa); Dean Jamison (University of Washington); Kevin Outterson (Boston University); Bruce Gellin, Joe Larsen (U.S. Dep’t of Health & Human Services); Eric Mallard, Timothy Bouley, Andreas Seiter, Ishani Premaratne (World Bank). The governments of Canada, the Netherlands, and the United Kingdom provided vital financial support for the special studies and the report.   n  xi Abbreviations and Acronyms AGAR Australian Group on Antimicrobial Resistance AGP Antimicrobial Growth Promoters AIDS Acquired Immune Deficiency Syndrome AM Antimicrobial (drug or agent designed to kill microbes) AMPs Antimicrobial peptides AMR Antimicrobial resistance (resistance of microbes to antimicrobials) ANSORP Asian Network for Surveillance of Resistant Pathogens API Active pharmaceutical ingredient ARSP Philippines Antimicrobial Resistance Surveillance Program ASP Antibiotic stewardship program AST Antimicrobial susceptibility testing BRICS Large middle-income countries (Brazil, Russia, India, China, South Africa) CAESAR Central Asian and Eastern European Surveillance of Antimicrobial Resistance CIPARS Canadian Integrated Program for Antimicrobial Resistance Surveillance CDC United States Centers for Disease Control and Prevention CDDEP Center for Disease Dynamics, Economics & Policy CHINET China Antimicrobial Resistance Surveillance Study CLSI Clinical and Laboratory Standards Institute CRE Carbapenem-resistant Enterobacteriaceae (type of bacteria) CSF Cerebrospinal fluid DANMAP Danish Integrated Antimicrobial Resistance Monitoring and Research Program DDDs Defined daily doses DUS Drug-utilization studies EAC East African Community EAPHLN East Africa Public Health Laboratory Network EAPHLNP East Africa Public Health Laboratory Networking Project EARS-Net European Antimicrobial Resistance Surveillance Network ECDC European Centre for Disease Prevention and Control ECSA-HC East, Central and Southern Africa Health Community EIP Emerging Infections Program EQA External quality assurance ESAC-Net European Surveillance of Antimicrobial Consumption Network ESBL Extended-spectrum beta-lactamase ESPAUR English Surveillance Programme for Antimicrobial Utilization and Resistance ESR New Zealand Institute of Environmental Science and Research EU European Union EuSCAPE European Survey on Carbapenemase-Producing Enterobacteriaceae FAO Food and Agricultural Organization of the United Nations xii  n  Abbreviations and Acronyms FAOSTAT FAO Statistics FDCs Fixed-dose combinations FINRES-VET Finnish Veterinary AMR Monitoring and Consumption of Antimicrobial Agents FoodNet Foodborne Diseases Active Surveillance Network GAP Global Action Plan GDP Gross domestic product GERM-VET German National Veterinary Antibiotic Resistance Monitoring GHSA Global Health Security Agenda GISP Gonococcal Isolate Surveillance Program GLASS Global Antimicrobial Resistance Surveillance System HAI Hospital-acquired infection HIC High-income country HIV Human immunodeficiency virus HIV/AIDS Human immunodeficiency virus/acquired immune deficiency syndrome ICT Information, Communication, Technology IEG Independent Evaluation Group IHR International Health Regulations IPC Infection prevention and control ITAVARM Italian Veterinary Antimicrobial Resistance Monitoring JANIS Japan Nosocomial Infections Surveillance JVARM Japanese Veterinary Antimicrobial Resistance Monitoring System KARMS Korea Antimicrobial Resistance Surveillance KONSAR Korean Nationwide Surveillance of Antimicrobial Resistance Ksh Kenyan shilling LICs Low-income countries LMIC Low- or middle-income country MDR Multiple-drug resistance MRSA Methicillin-resistant Staphylococcus aureus NAMRU-2 PP United States Naval Medical Research Unit 2 Phnom Penh NARMS National Antimicrobial Resistance Monitoring System NARS-Singapore Singapore Network for Antimicrobial Resistance Surveillance NDM-1 New Delhi Metallo-beta-lactamase 1 NETHMAP/MARAN Consumption of Antimicrobial Agents and AMR among Medically Important Bacteria in the Netherlands/ Monitoring of AMR and Antibiotic Usage in Animals in the Netherlands NHSN National Health Care Safety Network NLN National Laboratory Network NORM/NORMVET Norwegian Surveillance System for Antimicrobial Drug Resistance NPHL National Public Health Laboratory NRL National Reference Laboratories NSAR Malaysia National Surveillance of Antimicrobial Resistance Program NTSS National Tuberculosis Surveillance System Abbreviations and Acronyms  n  xiii OECD Organisation for Economic Co-operation and Development OIE World Organisation for Animal Health ONERBA l’Observatoire National de l’Epidemiologie de la Resistance Bacterienne aux Antibiotiques PCR Polymerase chain reaction (a kind of laboratory test) PCU Population Correction Unit PVS Performance of Veterinary Services QS Quorum sensing R&D Research and development ReLAVRA Latin American Surveillance Network of Antimicrobial Resistance Rif Rifampicin RSN Resistance Surveillance Network SDGs Sustainable Development Goals SEJ Structured expert judgement SLIPTA Stepwise Laboratory Improvement Process Towards Accreditation STAG Strategic and Technical Advisory Group SWEDRES/SVARM Swedish Veterinary Antimicrobial Resistance Monitoring TARGET Treat Antibiotics Responsibly, Guidance, Education, Tools TATFAR Transatlantic Taskforce on Antimicrobial Resistance TB Tuberculosis TSAR Taiwan Surveillance of Antimicrobial Resistance UHC Universal Health Coverage UK United Kingdom UNTRL Uganda National Tuberculosis Reference Laboratory U.S. United States VINARES Vietnam Resistance Project VRE Vancomycin-resistant enterococci VRSA Vancomycin-resistant Staphylococcus aureus VSL Value of a statistical life WAHIS World Animal Health Information System WB World Bank WHO World Health Organization XDR Extensively drug-resistant All dollar amounts in this report are U.S. dollars, unless specified otherwise.   n  xv Glossary of Select Terms Adverse drug events When medical drugs, like antibiotics, have harmful effects; when someone has been harmed by a medication. Antibiotic Type of antimicrobial agent made from a mold or bacterium that kills or slows the growth of other bacteria. Examples include penicillin and streptomycin. Antimicrobial agents A general term for the drugs, chemicals, or other substances that either kill, inactivate, or slow the growth of microbes including bacteria, viruses, fungi and parasites. Antimicrobial resistance Antimicrobial resistance (AMR) is the ability of microbes to grow in the presence of substances specifically designed to kill them. AMR is the result of microbes changing in ways that reduce or eliminate the effectiveness of drugs, chemicals, or other agents to cure or prevent infections they cause. AMR is a natural phenomenon, but human actions may promote avoidable emergence and spread of AMR. These actions include inappropriate use of antimicrobials in health care and in raising crops and animals, poor sanitary practices and conditions, inappropriate food handling (e.g., food not properly stored), disposal of wastes containing antimicrobials, and weak infection prevention and control practices in health care facilities. Antimicrobials Antimicrobials are drugs developed to treat infections. Bacteria Bacteria are microscopic single-celled organisms that thrive in diverse environments. They can live freely nearly anywhere, including in soil, water or plants, animals, and other organisms. Some bacteria help biological functions of their hosts (e.g., digestion), but others can be destructive, causing diseases. Cross-resistance Cross-resistance is the tolerance to a usually toxic substance as a result of exposure to a similarly acting substance. It is a phenomenon affecting e.g., pesticides and antibiotics. As an example rifabutin and rifampin cross-react in the treatment of tuberculosis. Drug resistance Drug resistance is the result of microbes changing in ways that reduce or eliminate the effectiveness of drugs, chemicals, or other agents to cure or prevent infections. Epidemiology The study of the spread of disease, or disease patterns at the population level. First-line antimicrobials First-line drugs are generally inexpensive and widely consumed, and they were developed earlier than second-line drugs, so resistance to first-line drugs is generally higher than to newer drugs. Examples include amoxicillin, ampicillin, pivampicillin, trimethoprim/sulfamethoxazole, and doxycycline. Fungi Single-celled or multicellular organisms. Fungi can be opportunistic pathogens that cause infections in immunocompromised persons, such as cancer patients, transplant recipients, and persons with AIDS. Characteristic fungal diseases of this type include aspergillosis, candidiasis, and cryptococcosis. Some fungal pathogens can cause infections in healthy persons (such as histoplasmosis or coccidioidomycosis). Fungi are also used to develop antibiotics, antitoxins, and other drugs used to control various human diseases. Infection Entry and development or multiplication of an infectious agent (such as pathogenic bacteria or viruses) in the body of humans or animals. Some infections lead to disease. Microbes Organisms so small that a microscope is required to see them. Microbes are also called microorganisms. Multidrug-resistance (MDR) Property of a bacterial pathogen that is resistant to 2 or more antimicrobial agents. Nosocomial Referring to an infection acquired by a patient while in a hospital, or any other health care facility. xvi  n  Glossary of Select Terms One Health “One Health is a framework for enhanced collaboration in areas of common interests (intersections), with initial concentration on zoonotic diseases that will reduce risk, improve public health globally and support poverty alleviation and economic growth in developing countries. This concept involves a better way to deal with risks at the animal-human- environment interfaces.” —World Bank’s operational definition, used since 2007 Organism Any living thing. Organisms include humans, animals, plants, bacteria, protozoa, and fungi. Parasites Any organism that lives in or on another organism without benefiting the host organism; commonly refers to protozoans and helminths. Pathogens Bacteria, viruses, parasites, or fungi that can cause disease. Present value or present Present value is the worth today of a future sum of money. The term is also used for discounting discounted value future sums by using a discount rate. A discount rate is like an interest rate. A specific percentage of a balance is added to the balance. Having $100 in an account that pays interest of 5% per year results in a balance in year 2 of $105. In year 3, the balance will be $110.25 (= 100*1.05*1.05). Discounting answers the question: How much is the $100 that is to be received in year 3 worth today if the discount rate is 5%? The present value is clearly less than $100—given the choice between $100 in year 3 and $100 now, most people will choose $100 now. If the discount rate is 5%, than the present value of $100 in year 3 is exactly $90.70 (= 100/(1.05*1.05). A balance of $90.70 in the account now will grow to $100 in year 3. The higher the discount rate, the smaller is the present value of future amounts. For instance, a low discount rate is used in some studies of the economic impact of climate change and corresponds to a greater concern with the well-being of future generations than a high discount rate. Use of a lower discount rate results in a higher present value of costs of climate change. Second-line antimicrobials Examples of such drugs include amoxicillin/clavulanic acid, macrolides, second-generation or third-generation cephalosporins, and quinolones. Surveillance systems The ongoing systematic collection, collation, and analysis of information related to public health (animal and human), and the timely dissemination of information so that action can be taken. The information is used, for example, in actions that prevent and control an infectious disease. Virus A strand of DNA or RNA in a protein coat that must get inside a living cell to grow and reproduce. Viruses cause many types of illness; for example, varicella virus causes chickenpox, and the human immunodeficiency virus (HIV) causes the acquired immune deficiency syndrome, or AIDS.   n  xvii Executive Summary This report examines the economic and development consequences of antimicrobial resistance (AMR)—the capacity that disease-causing microorganisms acquire to resist the drugs we’ve created to fight them. The report uses World Bank Group economic simulation tools to put a price tag on AMR’s destructive impacts on the global economy from 2017 through 2050, if adequate measures aren’t taken to contain the AMR threat. The report highlights actions low- and middle-income countries and their development partners can take to counter AMR, and estimates the investment required. It shows that putting resources into AMR containment now is one of the highest-yield investments countries can make. What Is AMR? Antimicrobials are drugs that destroy disease-causing microbes, also called pathogens, such as certain bacteria, viruses, parasites, and fungi. The most familiar and important antimicrobials are antibiotics, which treat bacterial infections. Other antimicrobials combat viral and parasitic diseases, such as AIDS and malaria. Since their use began some 70 years ago, antimicrobials have saved hundreds of millions of lives. AMR occurs when pathogens undergo adaptive evolutionary changes that enable them to withstand antimicrobials. People or animals who encounter resistant pathogens may then suffer infections that can’t be treated. The pathogens survive, patients get sicker and may die, the cost of medical care rises, and disease continues to spread. Every use of antimicrobials, even the most prudent, creates opportunities for AMR. However, rigorous management can limit the risks. In recent decades, though, overuse and misuse of antimicrobials have caused avoidable AMR emergence and spread. As a result, antimicrobial drugs are rapidly losing their effectiveness in both developing and developed countries. If this trend continues, humanity may face a reversal of the public-health gains of the past century, and the economic growth, development, and poverty reduction these gains enabled. A Tragedy of the Commons The loss of efficacy of antibiotics and other antimicrobials worldwide can be understood as a “tragedy of the commons.” A tragedy of the commons occurs when people in a community squander a limited, shared resource, as each actor pursues her own short-term self interest by exploiting the resource for private benefit. No one wants the common resource to be exhausted. Yet the group’s collective behavior leads to precisely this result. This concept has been applied, for example, to the collapse of fisheries due to overfishing. The overuse and misuse of antimicrobial drugs worldwide show a similar pattern. Protecting a Global Public Good As effective antimicrobial treatment is part of the global “commons,” containment of AMR is a global public good. All countries can enjoy the benefits of successful AMR containment. Conversely, all countries will be harmed if AMR is not kept in check. The status of AMR containment as a global public good underscores the critical responsibility of public authorities, especially national governments, in protecting this good. xviii  n  Executive Summary This responsibility is all the more crucial, because victory over AMR is never final, since pathogens constantly evolve, and they eventually develop resistance to any medication we discover. However, with wise policies and careful stewardship, the life-saving power of antimicrobials can be greatly extended. The inherent fragility of this public good makes it even more important to defend it well. To date, action on AMR has been dangerously inadequate. Policy and financing choices by governments and development partners have resulted in weak public-health systems across broad regions of the world, enabling the undetected spread of pathogens, including drug-resistant strains. A Threat to the Global Economy What can motivate countries to focus on AMR and deploy the comprehensive response this threat demands? Often, economic interest provides an impetus to political action. In this report, we have used World Bank economic simulation tools to quantify the losses that AMR may inflict on the global economy between now and 2050. Our simulations included two scenarios, corresponding to low AMR impacts and high AMR impacts. AMR impacts were modeled as shocks to labor supply and livestock productivity—a conservative approach that underestimates AMR’s full economic effects. In the optimistic case of low AMR impacts, the simulations found that, by 2050, annual global gross domestic product (GDP) would likely fall by 1.1 percent, relative to a base-case scenario with no AMR effects; the GDP shortfall would exceed $1 trillion annually after 2030. In the high AMR-impact scenario, the world will lose 3.8 percent of its annual GDP by 2050, with an annual shortfall of $3.4 trillion by 2030 (Figure ES1). A Crisis That Won’t Quit During much of the period through 2050, the annual reduction in global GDP caused by AMR could be as large as the losses provoked by the 2008–2009 global financial crisis, at their most severe (Figure ES2). However, the cost impacts of AMR on GDP would be worse than those of the financial crisis in two respects. First, they would be felt during the entire simulation period (through 2050), not just for a couple of very bad years, as was the case in the acute phase of the recent financial crisis. Poorer Countries Will Suffer Most Moreover, with AMR, low-income countries would experience larger drops in economic growth than wealthy countries, so economic inequality between countries would increase. The differential impacts on GDP result from higher infectious disease prevalence and greater dependence on labor incomes in countries with lower per capita incomes. Impacts on International Trade, Livestock Production, and Health Care Costs International trade may be heavily affected if AMR spreads unchecked. By 2050, the volume of global real exports may fall below base-case values by 1.1 percent in the low-AMR scenario and by 3.8 percent in the high-AMR scenario. Output and trade in livestock and livestock products are especially vulnerable to AMR impacts. Livestock production in low-income countries would decline the most, with a possible 11 percent loss by 2050 in the high AMR-impact scenario. Executive Summary  n  xix FIGURE ES1.  Substantial and Protracted Shortfalls in Global Economic Output World Real GDP 101 100 99 Base = 100 98 97 96 95 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 Base Low-AMR High-AMR FIGURE ES2.  Economic Costs of AMR May Be as Severe as During the Financial Crisis AMR could reduce GDP substantially—but unlike in the recent financial crisis, the damage could last longer and affect low-income countries the most (annual costs as % of GDP) GDP growth fell during the 2008–2009 financial crisis, compared to pre-crisis growth in 2001–2007 “Low-AMR” scenario, 2050 “High-AMR” scenario, 2050 1 0.7 0 Percent of GDP (annual) –1 –0.8 –1.2 –1.3 –1.1 –1.4 –2 –1.7 –3 –3.2 –3.1 –4 –3.6 –3.8 –4.1 –4.4 –4.4 –5 –6 –5.6 Country group: Low-income Lower middle-income Upper middle-income High-income World xx  n  Executive Summary Meanwhile, as AMR spreads, health care expenditures, both public and private, will increase in step with the rising disease burden; by 2050 the annual costs may exceed the base-case level by some 25 percent in low-income countries, 15 percent in middle-income countries, and 6 percent in high- income countries. Derailing Global Development Goals Without AMR containment, the Sustainable Development Goals for 2030—such as ending poverty, ending hunger, ensuring healthy lives, reducing inequality, and revitalizing global development partnerships—are less likely to be achieved. The impacts of AMR on poverty are particularly concerning. In the high AMR-impact scenario, an additional 24 million people would be forced into extreme poverty by 2030. Most of the increase would occur in low-income countries. As a result, the World Bank Group goal of eliminating poverty by 2030 would be harder to reach. High-Yield Investments Policy makers may be concerned that the cost of tackling AMR will be excessive. On the contrary, our analysis shows that action on AMR constitutes one of the highest-yield development investments available to countries today. The cost of AMR containment measures is estimated at $9 billion annually in low- and middle-income countries. About half of this amount is for investments in, and operation of, core veterinary and human public-health systems in 139 countries. The recommended investments in AMR containment are justified according to two key economic criteria. The Net Present Value Test First, the test of net present value (NPV) is unambiguously satisfied. This is the case not only globally, but also separately for high-income countries and upper middle-income countries. Assuming that just 50 percent of AMR costs will be avoided by vigorous AMR containment efforts, the expected cumulative global benefits from AMR containment in 2017–2050 range between $10 trillion and $27 trillion, far greater than the investment costs of $0.2 trillion. The net present value is thus between $9.8 trillion and $26.8 trillion. Different countries stand to benefit from AMR control in different ways. Low-income countries will see substantial economic payoffs, relative to the size of their economies. The largest absolute and per capita gains, however, will actually flow to upper middle-income and high-income countries. Assuming, very conservatively, that only 10 percent of the modeled costs were averted through AMR containment measures, high-income countries would still obtain benefits of $0.9 trillion and $2.7 trillion, in the low AMR-impact and high AMR-impact cases, respectively. This is four times and thirteen times more than the global investment cost of $0.2 trillion (Figure ES3). Remarkable Returns The second test of the investment case for AMR control considers the expected economic rate of return (ERR) on the $9 billion annual investment. Assuming that investments would be made for seven years before any benefits materialize, the ERR ranges from 31 percent annually (if only 10 percent of AMR costs can be mitigated) up to 88 percent annually (if 75 percent of AMR costs are avoided). The chance to obtain returns of this magnitude constitutes an exceptional investment opportunity for countries. Executive Summary  n  xxi FIGURE ES3.  High-Income and Upper Middle-Income Economies Stand to Benefit the Most from AMR Containment, Both in Absolute and per Capita Terms Total world population: 7.3 billion Proportion of global AMR containment benefits (population in billions; share of global total) (based on present value of total benefits in 2017–2050) Upper middle-income and high-income countries 1.2; 16% 0.6; 9% will obtain more than 80 percent of the benefits from AMR containment 3% 15% 2.9; 40% 2.6; 35% 51% Country group: 31% Low-income Lower middle-income    Upper middle-income High-income A Bold Agenda: Integrated Public-Health Protection in All Countries We have argued that aggressive action to tackle AMR is needed now. But what exactly must be done? Before we discuss specific recommendations for action on AMR, we need to emphasize a general principle. AMR cannot be managed in isolation. Drug-resistant infectious diseases are a subset of the broader range of microbial threats to human and animal health and welfare. From a public-health and policy-making standpoint, drug-resistant infections have practical similarities to all infectious diseases with pandemic potential. The surveillance, diagnostic, and control capacities needed to deal with AMR are closely related to those required to control diseases like Ebola and Zika. Instead of viewing AMR as a separate issue isolated from other health challenges, it will be more effective and less costly over time to build a common core of permanent capabilities in all countries for managing the full range of infectious threats. As AMR control is part of a wider agenda of infectious disease management, so the response to infectious diseases in turn depends on the robustness of countries’ broader health systems. Competencies for the AMR fight can’t be built independently of the health system’s durable core capacities. Effective AMR action depends, for example, on reliable health information systems, rational procurement and management of drugs, and the presence of a trained and motivated health workforce. Building core human and veterinary public-health and infectious disease surveillance capacities in all countries is the critical step in confronting the AMR threat. Where these capacities exist, AMR can be detected and contained. Where they don’t, it can’t. This is the fundamental fact. When discussing AMR policy measures, we describe them as “AMR-specific” or “AMR-sensitive.” AMR-specific actions are those whose primary purpose is combating AMR (though they may bring other benefits, too). An example is tightening legislation and enforcement on the sale of antimicrobials without a prescription. AMR-sensitive measures are those whose main purpose is not actually AMR- related, but which can be designed and implemented in such a way that they contribute indirectly to AMR containment. Expanding access to clean water and sanitation, thus reducing the incidence of xxii  n  Executive Summary infections, is an example. Both AMR-specific and AMR-sensitive measures are needed now to contain the spread of drug-resistant pathogens. Options for Country Action WHO’s Global Action Plan on AMR (WHO 2015), developed in collaboration with the World Animal Health Organisation (OIE) and the United Nations Food and Agriculture Organization (FAO), defines five broad objectives for the AMR fight (Figure ES4). Building on the global plan, several recent landmark reports have provided additional guidance on national policies and implementation strategies to fight AMR. These publications include the final report from the U.K. Review on AMR (Review on Antimicrobial Resistance 2016) and global plans from OIE (2016) and FAO (2016). Together with the Global Action Plan, these sources have set forth a comprehensive high-level policy agenda for the AMR fight. This also means that we don’t need to “reinvent the wheel” here. Our recommendations concentrate on select areas where opportunities for important advances exist, and where World Bank knowledge, experience, and resources can add value to the country efforts we propose. To implement the Global Action Plan and in particular to understand how it will be financed, it is useful to analyze country options through a sectoral lens. Accordingly, our recommendations for country AMR action are structured by sector, including: (a) health; (b) agriculture; and (c) water, sanitation, and hygiene. Driving AMR Progress from the Health Sector The health sector offers many entry points for AMR control. Our recommendations focus on three topics: (1) universal health coverage reforms as an enabling platform; (2) harnessing the International Health Regulations (IHRs) to accelerate AMR action; and (3) strengthening laboratory-based surveillance, including through regional networks. 1. Universal health coverage (UHC) provides the best enabling framework to tackle AMR. UHC models are diverse, but UHC efforts will generally strengthen AMR containment through the following mechanisms: ❉❉ Expanded coverage. By definition, UHC designs lead to greater breadth and depth in the population coverage of health services. This includes services like vaccination, preventative care, and hygiene measures that lower the need for antimicrobials and thus slow the spread of AMR. Covering the whole population with vaccinations shows one potent way UHC will reduce the incidence of infections, advancing a key objective of the Global Action Plan on AMR. ❉❉ Better oversight and quality of care. UHC models improve oversight in health care practice. Among other benefits, this helps ensure that antimicrobial use conforms to rational standards. UHC strategies promote rational, regulated access to antimicrobials for all patients under the guidance of trained health professionals. Thus, UHC provides a framework for simultaneously expanding the well-regulated use of antimicrobials where they have been lacking, and tackling the overuse and misuse that have accelerated AMR in other settings. UHC strengthens antibiotic stewardship in health facilities, reinforces the use of standard treatment protocols for infections, and can improve procurement, quality control, and other features of antimicrobial management—with the potential for major gains against AMR. These UHC features support another of the five Global Action Plan objectives: optimizing current antimicrobial use. ❉❉ Smarter, fairer financing. The expansion of health systems towards UHC promises more efficient and equitable financing. This will help close existing access gaps for treatable infections. Pooled, prepayment financing also encourages rational purchasing and prescription, supporting the optimization of antimicrobial use and protecting the efficacy of current drugs. Executive Summary  n  xxiii FIGURE ES4.  Five Objectives of the Global Action Plan on AMR, 2015–19 Strengthen Knowledge Reduce the Incidence Optimize Use of Improve Awareness and and Evidence Base of Infection Antimicrobials Understanding of AMR ❉❉ Develop an AMR ❉❉ Implement and ❉❉ Implement a comprehensive ❉❉ Public communication surveillance system for: strengthen hygiene action plan with: targeting human and animal • health care facilities and infection • antibiotics access health audiences as well as and community prevention programs only through qualified schools and public media • animal husbandry • make it part of individuals ❉❉ Establish AMR as element of and agriculture health care and • only quality, safe and effi- professional education • using at least one veterinary training cacious drugs authorized ❉❉ Elevate AMR to priority reference lab • develop and • reimbursement, agenda across government ❉❉ Share information implement promotion and treatment internationally standards of guidelines Make Economic Case ❉❉ Collect and share practice • laboratory capacity to for Investment data on antimicrobial ❉❉ Test and report guide optimal use use (human/animal/ susceptibility of • evidence-based ❉❉ Secure required financing agriculture) hospital-acquired stewardship programs for implementation ❉❉ Consider an AMR infections (HAI) • elimination of financial ❉❉ Engage in international research agenda, ❉❉ Implement prevention incentives to prescribe research collaboration— including: best practices in • effective and enforceable between developed and • responsible use animal health and regulation developing countries • infection prevention agriculture • reduction/phasing out of ❉❉ Public-private partnership • development of novel ❉❉ Promote vaccination of non-therapeutic antibiotic ❉❉ New market models for agents food animals use in agriculture investment and access WHO Global Action Plan on Antimicrobial Resistance, adopted by the World Health Assembly in May 2015. See http://apps.who.int/iris/ bitstream/10665/193736/1/9789241509763_eng.pdf?ua=1. ❉❉ Better information. UHC generally enables improved data collection and management within the health system, at the population, facility, and individual provider levels. By strengthening data systems, UHC approaches may better equip them to support AMR surveillance, monitoring, and response. These features support the Global Action Plan (GAP) objective to strengthen AMR knowledge and the evidence base. ❉❉ Improved stewardship and governance. A robust UHC approach builds systems-governance and coordination capacities that are critical for the AMR fight. Moreover, under UHC models, regulatory capacities tend to be enhanced. Health facility accreditation provides an example. Requirements for improved antimicrobial stewardship can be built into accreditation processes for hospitals and clinics to bolster AMR control at the facility level. AMR training can also be incorporated into the pre-service and in-service education of health providers, advancing the Global Action Plan objective to improve awareness and understanding of AMR. 2. Implementation of the International Health Regulations (IHR) can accelerate AMR action and focus global support. Under the IHR, 196 countries have committed to work together to prevent, detect, report, and manage public health emergencies, such as infectious outbreaks. To meet their IHR implementation requirements, many countries are participating in systems-diagnostic and planning exercises, for example through the Joint External Evaluation (JEE) process, under the Global Health Security Agenda (GHSA). Systems-evaluation exercises provide opportunities for countries to assess their capacities and needs in areas like infectious-disease and AMR surveillance. Among other benefits, such efforts help lay foundations for the AMR Global Action Plan’s five objectives, especially the first, strengthening knowledge and the AMR evidence base.   In order for these exercises to achieve full impact, it is important that each country designate institutions and individuals who will be accountable for following up on the evaluation results. The designated actors will lead a process to translate assessment recommendations into methodical action to build national capacity for surveillance and response. Because each country’s implementation of IHR commitments benefits all other countries by improving detection and response to transborder threats, the international community has an interest in adequately financing this global good. xxiv  n  Executive Summary 3. Countries at all levels of income can build laboratory capacities for AMR surveillance—and create synergistic regional laboratory networks. Strengthening AMR surveillance capacities, including in low- and middle-income countries, is a cornerstone of AMR control, captured in the first objective of the Global Action Plan. The creation of a national AMR surveillance network is becoming technically feasible and affordable for an increasing number of countries. Kenya, for example, is in the process of launching its own national AMR surveillance network at an estimated annual cost of about $160,000. (This figure represents the specific added expense of AMR surveillance, beyond the ongoing costs of operating the country’s clinical laboratory network.)   A background study commissioned for this report examined the East Africa Public Health Laboratory Networking Project (EAPHLN), in which Kenya participates, along with Burundi, Rwanda, Tanzania, and Uganda. The study documented the benefits that can accrue when countries link their laboratory resources into a regional network structure. The EAPHLN has accelerated innovation and fostered new forms of learning and collaboration, including: (1) joint annual peer audits, in which countries assess each other’s laboratories, and (2) cross-border disease surveillance, simulations, and investigations that have enabled swift regional responses to Ebola and Marburg outbreaks. Agriculture: A Critical Frontier for AMR The bulk of antimicrobial use in many countries occurs in the agriculture sector, particularly in livestock. Worldwide, in 2010, livestock consumed at least 63,200 tons of antibiotics and probably far more, exceeding total human consumption. The precise impacts of this heavy use of antimicrobials in animal production continue to spark debate, and data are scarce. However, recent research suggests that AMR is already common in agricultural systems in low- and middle-income countries. 1. All countries can progressively reduce the use of antibiotics in animal production. Systematic reduction and eventual elimination of antibiotic use for livestock growth promotion is critical for long-term AMR control. This goal has drawn increasing consensus among scientific experts and many political leaders. European Union countries have banned the use of antimicrobials as growth promoters since 2006.   Countries’ specific contexts must be taken into account in designing plans and establishing timelines. Countries that currently rely heavily on the use of antibiotic growth-promoters may require more time and support to adapt their production regimes. Some low-income countries may benefit from extensive technical support.   Experts, including the U.K. Review on AMR, have recommended the use of national numerical targets to drive reductions in the use of antibiotics in agriculture. We support this approach. The use of time-bound, quantitative targets can be a powerful motivator.   Solutions for the livestock sector should foster the adaptability of animal productions systems to reduced use of antimicrobials. Recommendations call for an integrated approach, with cycles of innovation and learning: First, developing policies, setting targets, and monitoring antimicrobial use in livestock production; then identifying gaps or problems in current production systems and methods to address them; and finally sharing knowledge on improved management.   We can protect farmers as antimicrobial practices change. Small farmers may be especially vulnerable as changes to established production methods are introduced. Governments and development partners have a fundamental responsibility to accompany small farmers in adapting their modes of animal production, as we act to save a global public good.   Policy action must also take account of global disparities in access to antimicrobials for livestock, mirroring those in human health. The same drugs that may be used excessively in livestock production in some parts of the world remain unavailable in others, where they could have legitimate applications and save lives and livelihoods. 2. An urgent effort is needed to strengthen country surveillance systems for tracking the use of antimicrobials and the spread of AMR in animals. A consistent finding from country case studies commissioned for this report was a deficiency in data needed to analyze antimicrobial use in livestock, in terms of epidemiology and economic impacts.   Each country may commit to develop a system for collecting standard data on animal populations and animal production systems in its territory. Countries should be supported to build basic data collection Executive Summary  n  xxv systems to track both the use of antimicrobials and AMR in animal production. OIE’s current effort to develop a worldwide system for data collection on antimicrobial use in animals merits strong support. 3. New partnerships can spur innovation for AMR control across agriculture, the environmental sciences, and health. Scientists and policy makers increasingly recognize that integrated strategies are needed to tackle the drivers of AMR simultaneously in livestock production, environmental management, and human health. Today, research on integrated strategies and new technologies to fight AMR is slowly gathering momentum. Yet the field remains under-resourced and fragmented.   Evidence-based, consensus directions for priority research have yet to be defined. International coordination and stewardship of AMR knowledge production are urgently needed. In particular, there is a need to inform and incentivize the global innovation agenda to target the points of highest priority and greatest opportunity for the development of new AMR-management technologies. This would include not only new antibiotics, but also new vaccines (both animal and human), the rapid-diagnostics agenda, and policy innovation in areas like compensation or insurance mechanisms for farmers who cut antibiotic use. Targeted learning and innovation in a broad range of sectors, from pharmacology to development finance, must be nurtured simultaneously.   How might this be done? We can point to promising precedents: innovative models of collaboration that have proven effective for other complex, multi-sectorial challenges. One example is CGIAR, a global consortium of agricultural research centers supported by an extensive network of partners, including the World Bank. For some 50 years, CGIAR has generated creative and practice-relevant research on food security, rural poverty reduction, and sustainable resource management. Today, to jumpstart new investment in AMR research and technological innovation, we can learn from CGIAR and other network models for knowledge production.   A hybrid, networked research center might pursue learning and innovation simultaneously in agriculture, animal health, and human health. To our knowledge, no such hybrid research hub currently exists. However, its feasibility could be explored with existing CGIAR network centers, other research consortiums, countries, donors, and other stakeholders. Through such partnership models, countries will tap into networks of innovation to multiply the impact of their individual actions against AMR. Water, Sanitation, and Hygiene: AMR-Sensitive Development Priorities Historically, safe drinking water and sanitation facilities, along with basic hygiene practices such as hand washing with soap and water, were decisive in reducing the spread of infections, even before modern antimicrobials were invented. In the age of AMR, such infection-prevention strategies once again take on salience. The Global Action Plan has incorporated this principle. Reducing the incidence of infections is one of the five objectives. Two complementary facets of the preventative agenda involve: (1) expanding access to water and sanitation; and (2) universalizing basic hygiene practices, particularly in health care facilities. 1. Countries can harness the power of water and sanitation investments to check infections, fight AMR, and support economic growth. Expanding access to sanitation and clean water is among the most powerful AMR-sensitive investments available. Improved access to clean water and sanitation delivers robust public health benefits in its own right. In addition, by preventing infections and reducing the need for antibiotics, these measures also reduce the pressures that drive antimicrobial resistance (Wellcome Trust 2016). The combined health impacts translate into remarkable gains in life expectancy, which imply productivity and economic gains for countries, as well. As leaders weigh the costs and benefits of development investments, it is important to incorporate public-health benefits, including AMR containment effects, in the expected gains from investing in water and sanitation. 2. Hygiene in health facilities: simple tools, strong impacts. The settings where water, sanitation, and hygiene practices can combine to powerfully impact AMR include health facilities. Infection prevention and control (IPC) strategies in health care settings are pillars of the AMR containment agenda, recognized in the infection-prevention objective of the Global Action Plan. xxvi  n  Executive Summary   Basic hand hygiene (hand washing with soap and water or alcohol-based products) has repeatedly been cited as the single most important practice to reduce health care associated infections. Improved hand hygiene has been associated with a sustained decrease in the incidence of AMR infections in health care settings (Rainey and Weinger 2016). Today, in countries at all income levels, these basic tools are not being rigorously applied. While this is alarming, it also represents an opportunity for low-cost, high-yield action against AMR.   WHO, UNICEF, and partners have set out a global agenda for universal access to water, sanitation, and hygiene in health care facilities. By implementing the plan, governments, international organizations, donors, and civil society partners can achieve substantial gains against AMR (Rainey and Weinger 2016). Country Leadership, Global Partnership Today, political momentum for action on AMR is growing. At the United Nations General Assembly (UNGA) special session on AMR, in September 2016, 193 Member States pledged to “develop . . . multi-sectoral national action plans, programmes, and policy initiatives, in line with a One Health approach and the global action plan.” AMR containment will depend on country-led efforts implemented in countries. But effective AMR containment also demands coordinated action across national borders. Adequately resourced multilateral agencies can multiply the impact of country policies. Multilateral organizations mobilize international attention, facilitate cooperation and knowledge sharing, provide technical advice and standards, and catalyze multi-sectorial action. Successful AMR strategies will also engage private firms, research institutions, global and local civil society, and other partners. What Will the World Bank Group Do? The agenda for AMR action outlined in this report implies responsibilities for the World Bank Group. Creating a Global Investment Framework for AMR Action Thanks to the Global Action Plan and the efforts of many partners, substantial consensus exists on the types of policies and interventions needed to contain AMR. Moreover, we now have a reasonable idea of how much AMR containment will cost. The sums are modest by global investment standards, as we’ve seen, and the likely rewards exceptionally high. But the money still has to be put on the table. The World Bank Group will work with countries and partners to develop an investment framework to deliver the objectives of the AMR Global Action Plan. The framework will include rigorous costing of priority AMR interventions at country, regional, and global levels. Costed plans for AMR will be integrated with broader country agendas for emergency preparedness, response, and resilience, which are gaining momentum through the WHO Monitoring and Evaluation Framework, the OIE Performance of Veterinary Services (PVS) pathway, and other mechanisms. The AMR investment framework will be informed by the results of the International Working Group on Financing of Preparedness, whose research is currently in progress, and by experience with the Pandemic Emergency Financing Facility (PEF), created under World Bank leadership following the 2015 Ebola outbreak in Western Africa. The investment framework will emphasize integration of AMR activities and funding into finance mechanisms that will be sustainable over time. In laying foundations for the global investment framework, World Bank experts will work at the country level with policy makers and technical colleagues to develop national AMR financing assessments, aligned with countries’ AMR National Action Plans (NAPs). Country financing assessments will identify Executive Summary  n  xxvii national priorities, needs, gaps, and best-value interventions. They will explore resource mobilization options, looking across sectors and including public and private sources. The global AMR investment framework will then incorporate the results of country planning and costing exercises to develop a comprehensive instrument that can map and quantify needs worldwide and coordinate global investments in AMR action. The framework will be a decision tool for policy makers, planners, development finance institutions, donors, and other partners in the AMR effort, helping ensure that AMR finance flows to where it is most needed and achieves the greatest impact. We consider the creation of a global AMR investment framework as a key step towards the realization of the Global Action Plan and as a logical follow-up to the September 2016 UNGA special session. The World Bank will deliver an initial version of the AMR investment framework by the time of the official AMR progress report to the UN General Assembly in September 2019. An AMR Lens on Development Finance The World Bank Group will review its own investment lending policies and instruments to support the AMR agenda across relevant sectors. We will also strengthen our institutional capacity on the ground in technical areas that can optimize our services to countries as they advance national AMR agendas. Relevant sectors for World Bank Group investing include, but are not limited to, agriculture; water and sanitation; and urban development, in addition to the health, nutrition, and population sector itself. As the Bank Group weighs investment options in dialog with country leaders and partners, we will apply an AMR lens to identify those projects that hold promise for AMR-sensitive impacts. We will design projects to maximize these impacts. The World Bank Group will also progressively incorporate AMR-related gains into the calculations used when assessing likely costs and benefits of projects competing for support. Over time, the systematic inclusion of an AMR perspective in investment conversations may evolve towards the creation of a formal screening instrument similar to the World Bank’s mandatory Climate and Disaster Risk Screening tools. Mobilizing Finance for AMR Innovation across Agriculture and Health Investment in the AMR knowledge agenda must nurture new technologies in both animal and human health. It should also create connections and harness synergies between the two. To foster this kind of innovation, the World Bank will seek to engage existing multidisciplinary research networks, donors, and other partners around the idea of a combined animal and human health research center on AMR. Promising conversations have begun, and may advance to a detailed feasibility study. The effort may develop as a multifaceted collaboration, along the lines of the successful Coalition for Epidemic Preparedness Innovations (CEPI). Bringing the Private Sector on Board The private sector can contribute substantially to tackling AMR, and private-sector capacities and creativity in this area are only just beginning to be tapped. The World Bank Group’s ability to engage national and global business actors is a strong comparative advantage. The International Finance Corporation (IFC) is the arm of the Bank Group that invests in and advises private-sector companies. IFC is active in the animal protein sector through investment and advisory work. In engagement with its clients in animal production, IFC reviews operational practices and provides benchmarking for clients on good industry practices, including the use of veterinary services and antibiotics. IFC will seek to deepen this partnership by developing a more focused advisory offering as part of its animal protein advisory platform. Where government regulations evolve xxviii  n  Executive Summary towards a more focused use of antibiotics, IFC will seek to partner with private producers and their associations to support the transition of the sector through management practices and investment.  IFC is also active in the private health care sector, mainly through the support of health service providers and companies that manufacture or distribute affordable pharmaceuticals or medical devices. IFC has developed a Quality Assessment Tool used to assess health service companies on various clinical governance and patient safety criteria. IFC plans to enhance this tool and, in the process, incorporate best practices for implementing policies, protocols, and training around antimicrobial drug use. A clear opportunity for private-sector engagement in the AMR challenge is for pharmaceutical and biotech firms to pursue development of new antimicrobials and related technologies, such as rapid diagnostic tests that could inform antimicrobial prescribing decisions at the point of care. The complex topic of antimicrobial drug development is well analyzed elsewhere (Review on Antimicrobial Resistance 2015). Here, we note only that the World Bank Group and other development finance institutions might play a role in creating fresh incentives for pharmaceutical companies to engage in antimicrobial research. One approach is “delinking” company profits for any new antimicrobial product from the actual sales volumes, through a number of possible mechanisms. Country policy makers, in particular among the G77, have pressed for the implementation of delinking strategies. Leveraging UHC Reforms to Reach AMR Objectives In the World Bank’s health sector practice, action on AMR containment will mesh with ongoing work programs on (1) health systems strengthening through UHC reforms, and (2) emergency preparedness and resilience. Many countries are currently carrying forward ambitious UHC reforms with World Bank support, and more are poised to adopt UHC goals. As suggested above, countries’ commitment to implement UHC provides multiple opportunities to reinforce AMR containment. The World Bank will work through its policy dialog and technical collaboration around UHC to support countries in leveraging health systems reforms to accelerate progress on AMR. AMR and Resilient Health Systems: The Agendas Converge Currently, the World Bank is financing improvements in core public-health functions in multiple countries, notably for disease surveillance and laboratory strengthening. These investments reflect a broad consensus on the need to strengthen global health security and reinforce preparedness. We have emphasized that AMR is part of a wider spectrum of infectious threats that generate outbreaks with epidemic and pandemic potential. Thus, the AMR and health emergency preparedness agendas are intertwined. The consolidation of core human and animal public-health capacities; the creation of health systems resilient to emergencies; and the AMR fight reflect largely convergent and mutually reinforcing agendas. The World Bank will expand its action to help countries capitalize on these synergies. Action Today—To Preserve Tomorrow Many important aspects of the AMR threat lie beyond the scope of this report. Yet we hope our work can clarify implications of AMR that have been insufficiently understood, and help point the way toward viable solutions. Executive Summary  n  xxix Those who will benefit most do not have a voice. Many of them have not yet been born. AMR is indeed a threat to our economic future, but above all to the future of our children. Bold action today can safeguard the health and prosperity of those who will come after us. References FAO (United Nations Food and Agriculture Organization). 2016. The FAO Action Plan on Antimicrobial Resistance 2016–2020. Rome: FAO. OIE (World Animal Health Organisation). 2016. The OIE Strategy on Antimicrobial Resistance and the Prudent Use of Antimicrobials. Paris: OIE. Rainey R. and Weinger M. 2016. “The role of water, sanitation and hygiene (WASH) in healthcare settings to reduce transmission of antimicrobial resistance.” In World Alliance Against Antibiotic Resistance (WAAAR). AMR Control 2016. Available at: http://resistancecontrol.info/infection-prevention-and-control/the-role- of-water-sanitation-and-hygiene-wash-in-healthcare-settings-to-reduce-transmission-of-antimicrobial- resistance/ Review on Antimicrobial Resistance. 2015. Securing New Drugs for Future Generations: The Pipeline of Antibiotics. London: Wellcome Trust and Government of the United Kingdom. ———. 2016. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. London: Wellcome Trust and Government of the United Kingdom. Wellcome Trust. 2016. Evidence for Action on Antimicrobial Resistance. London: Wellcome Trust. WHO (World Health Organization). 2015. Global Action Plan on Antimicrobial Resistance, 2015–2019. Geneva: WHO. Introduction 2  ■  Drug-Resistant Infections: A Threat to Our Economic Future T his report seeks to enhance understanding of which addressed both economic and health aspects the economic and development consequences (Review on Antimicrobial Resistance 2016). Our of antimicrobial resistance (AMR) and to clarify analysis seeks to complement, rather than duplicate, the economic rationale for investing to contain AMR. these efforts. Many recent AMR publications—for The report aims to build on and add to the political example, key documents issued by the U.S. Centers momentum that informed the landmark September for Disease Control and Prevention (CDC) (2013), the 2016 United Nations General Assembly declaration Center for Disease Dynamics, Economics & Policy on AMR, signed by 193 countries (United Nations (CDDEP) (2015), the Organisation for Economic General Assembly 2016). Co-operation and Development (OECD) (2016a), and others—are largely focused on the health sector— The present report reflects 15 months of work by predominantly human health. These reports are the World Bank Group and its partners. By analyzing addressed mainly to public-health professionals and economic arguments for combating AMR, the report health sector policy makers. In contrast, while health- responds to a key recommendation of the World sector issues and opportunities are also prominent Health Organization (WHO) Global Action Plan on AMR in our report, we hope a key audience for this (WHO 2015a), as well as to WHO’s direct request publication will be policy makers, policy analysts, and to the World Bank to help make the case for AMR development practitioners outside the health domain. investments. This work harnesses the World Bank’s comparative advantage as a global development Further raising awareness of AMR outside the human financial institution, its economic research health sector remains a critical pending task, despite capabilities, and its multi-sectoral breadth. some recent progress. Without the engagement of other sectors, the world will not succeed in At a moment of unprecedented political opportunity, containing AMR and reducing its substantial quantifying the magnitude of the economic threat economic costs. posed by AMR can help catalyze national and global action on the scale the AMR crisis demands. In the Today, when policy makers in ministries of finance, following pages, we use economic simulation tools development, or commerce are aware of AMR, they to put a price tag on the losses that drug-resistant still rarely consider the problem an urgent challenge, infections will inflict on the global economy by 2050. much less a key opportunity for strategic investment. We detail the development and poverty implications Misinformation on AMR remains pervasive, inside of this economic damage, in particular for low- non-health government agencies and among the income countries, which will suffer the worst impacts wider public. The results of a 2015 WHO survey from AMR. of 10,000 respondents are telling: three-quarters (76 percent) of persons surveyed thought that The extensive economic losses foreseen in antibiotic resistance happens when the human our economic simulations can be prevented or body becomes resistant to antibiotics—in fact, it is substantially reduced. We describe an agenda bacteria that become resistant to drugs. Two-thirds for action to put the brakes on AMR. Our (66 percent) said that individuals are not at risk of a recommendations align with the General Assembly drug-resistant infection if they personally take their political declaration, the WHO Global Action Plan, antibiotics as prescribed—in fact, everyone is at risk recent AMR strategies from the United Nations Food of such an infection if they are exposed to drug- and Agriculture Organization (FAO) (2016) and the resistant pathogens (WHO 2015b). World Animal Health Organisation (OIE) (2016), and the contributions of other partners. Our aim is Pervasive misinformation about the clinical aspects to identify measures that low- and middle-income of drug-resistant infections is worrying. But failure to countries, in particular, can consider in national appreciate AMR’s economic consequences may prove action plans to tackle AMR. We show that, in many even more devastating in the long run. This is where instances, these measures are likely to generate we hope our report can make a difference. substantial co-benefits that will improve low- and This report is structured in five parts. Part I presents a middle-income countries’ overall development brief overview of the AMR challenge. It argues that the prospects. present proliferation of drug-resistant infections can A number of major reports and studies on AMR be understood as a “tragedy of the commons” and have recently been published by other institutions: shows that the availability of effective antimicrobial notably the remarkable research papers and final drugs is a global public good. We draw lessons from summary report issued by the U.K. Review on AMR, this conceptual framing for how an appropriate global Introduction  ■  3 response to AMR can be organized. Part II then looks the use of antimicrobials in human health; and (3) the at the economic impacts of declining availability use of antimicrobials in animals. Drawing on the of effective antimicrobials due to AMR. Illustrative background studies and other resources, the second simulations to the year 2050 show possible AMR half of the part presents policy options for countries impacts on global economic output, incomes, health working to tackle AMR. The WHO Global Action Plan care costs, livestock trade, and poverty. While the guides our recommendations. However, where the simulations are not predictions (rather, a range of Global Action Plan is high-level and comprehensive, outcomes that are possible), they highlight potentially this report drills down on a select number of policy substantial impacts on incomes in countries at topics in three key sectors: human health; agriculture different income levels. Part III then discusses the (in particular livestock production); and water and measures and investments in AMR control that sanitation. countries could make as part of their national action Part V of the report then offers concluding messages plans on AMR. We provide order-of-magnitude and describes specific ways the World Bank Group estimates of the impressive economic gains that are will support countries and partners in the AMR fight. likely to be obtained from AMR containment—even if the effort is only partially successful. Links to the This report does not aim to treat the economics of Sustainable Development Goals (SDGs) suggest some drug-resistant infections exhaustively, nor to address entry points for AMR action. all related policy areas. For example, our discussion does not cover important topics like the weak Part IV provides more in-depth information on a pipeline of research and development (R&D) for new series of topics relevant to the choices countries antimicrobial drugs, nor the feeble current incentives face in creating national AMR action plans. The first for development and use of vaccines and better half of this part summarizes the results of three diagnostic tests. Readers will find these subjects well background studies commissioned for this report. analyzed in other settings (for example, Review on They address: (1) laboratory-based AMR surveillance Antimicrobial Resistance 2015). and the power of regional laboratory networks; (2) Part I. Drug-Resistant Infections: A Primer on the AMR Challenge 6  ■  Drug-Resistant Infections: A Threat to Our Economic Future A. What Is AMR? asset, and how long it will last, depend directly on the rate of use. Without better monitoring and Humans live in a permanent arms race with harmful stewardship, antibiotics and other antimicrobials risk microbes.1 Most microbes either aid humans and going down in history as a textbook “tragedy of the animals or cause no great harm, but a limited commons.” number are pathogens, which cause disease and, too often, the premature death of their host. Evolution ensures a constantly shifting balance of power B. A Tragedy of the Commons between microbes and humans. A tragedy of the commons occurs when people Since the middle of the nineteenth century, humans in a community unduly diminish (or even exhaust) have achieved unprecedented advances in their war a limited, shared resource, despite the fact that on pathogens. This has mainly been due to three disappearance of the resource is not in the developments: improved public-health systems to community’s long-term interests (Hardin 1968). promote measures such as hygiene, better sanitation, This concept has been applied, for example, to cleaner water, and disease surveillance and control; environmental problems and to the collapse of the development of vaccines to control the spread fisheries due to overfishing. Individual fishermen, of viruses; and, for the last 70 years, the use of acting in their self-interest, all seek to catch as antibiotics to combat bacterial pathogens. These many fish as they can—till there are no fish left. advances underpinned an enormous reduction in the This tragedy can be averted only if the community incidence of infectious diseases during the twentieth changes fishermen’s incentives and limits individual century, raising hope for a complete victory over rights to catch fish. Lowering the rate of depletion of infectious threats. the fishery lets the fish reproduce. Regulated access Yet a final triumph over harmful microbes did not leads to benefits for the community as a whole occur—and there is no scientific basis for expecting that are higher and more sustainable than under such a victory. In part, this is because of a painful a laissez-faire approach that allows each actor to paradox: antimicrobial drugs, our best weapons pursue short-term private interest without constraint. against pathogens, sow the seeds of their own Antibiotics (and other antimicrobials) are well on permanent inactivation each time they are deployed. their way to becoming an example of a tragedy The science has been settled for more than a of the commons—in this case, on a global scale. hundred years: any use of antimicrobial drugs can The looming post-antibiotic era will be costly for all cause the emergence and spread of antimicrobial countries, because antibiotics have brought such resistance (AMR), understood as certain pathogens’ immense health and economic benefits. There are adaptive capacity to survive exposure to antimicrobial currently no effective substitutes for antibiotic drugs agents (Box 1). in the treatment of bacterial infections. Untreatable Even the appropriate, prudent use of antibiotics and infections will cause excess illness and premature other antimicrobials to treat infections promotes death, both in humans and in their livestock, with AMR. However, in that case the risk is outweighed by devastating effects on individuals, societies, and the health benefits obtained. On the other hand, in economies. recent decades, overuse and misuse of antimicrobials AMR has already diminished the effectiveness of in human medicine, livestock, fisheries, and crop drugs to treat infection, and this trend will continue. production have caused avoidable AMR emergence For some pathogen-drug pairs, drug effectiveness and spread. has unfortunately already vanished. Continuing Because public-health authorities in most uncontrolled emergence and spread of AMR will countries have not monitored the level and trends mean that drug effectiveness will also diminish of antimicrobial use, the exact extent of current for other pathogen-drug pairs. More and more antimicrobial mishandling is unknown. Initiatives from infections will become harder, and eventually even the World Organisation for Animal Health (OIE) and impossible, to treat. Though the global community the World Health Organization (WHO) are under way as a whole will be worse off than if antibiotics and to help improve the information base on the use of other antimicrobials had been conserved and used antimicrobials. It is essential to monitor consumption rationally, the world is continuing to squander the of antimicrobial drugs, because the value of this cure. This is turning back major public-health gains Drug-Resistant Infections: A Primer on the AMR Challenge   ■  7 Box 1. The Basics about Bugs That Cause Disease Microbes. Bacteria, viruses, protozoa, and fungi resistant microbes, even from very different species. are types of microbes. Most are so tiny that millions Whenever microbes are exposed to antimicrobials fit into the eye of a needle. They are the oldest (even for a short period), the selection pressure form of life on Earth. They evolve fast, thanks to a (evolution) inexorably results in the emergence of high reproduction rate: some bacteria double every microbes that are resistant to the antimicrobials. 20 minutes. There are 2–3 billion microbe species. These microbes and their AMR will then spread. Such Microbes comprise over 60 percent of the Earth’s microbes are sometimes called “superbugs” because living matter, which indicates their evolutionary of their resistance to treatment. Emergence and prowess. spread of AMR may take years, but resistance can also appear within days. Pathogens. A small minority, some 1,415 microbe species, are pathogens that induce infectious disease Impact on the host. An antimicrobial cannot patterns in their human, animal, and plant hosts. stop the growth of microbes that have developed This is how pathogens spread and advance their own resistance to it. With the growth of pathogens reproduction. unchecked because of AMR, the human, animal, or plant host can be harmed or even killed by the Antimicrobials. Humans developed antimicrobials infection—the pathogens prevail. Pathogens can to destroy disease-causing microbes, or pathogens. be resistant to several antimicrobials; a multidrug- The best-known antimicrobials are antibiotics, resistant infection is harder to treat because fewer which are designed to kill bacteria and thus treat effective drugs are available. Treatment may even be bacterial infections. Other antimicrobials are impossible. The results are: antivirals, antifungals, and antiparasitics. Examples of ❉❉ People and animals can’t be effectively treated. antimicrobials include tetracycline, an antibiotic that ❉❉ People and animals are ill longer and are at greater is often used to treat common bacterial infections; risk of dying. oseltamivir, also known as Tamiflu, an antiviral that ❉❉ Others are at greater risk of infection—in hospitals treats the flu; mefloquine, also known as Lariam, to and communities within the country, in the region, treat malaria; and terbinafine, also known as Lamisil, and in the world. an antifungal that treats athlete’s foot. ❉❉ Epidemics (in people) and epizootics (in animals) are Antimicrobial resistance (AMR) and superbugs. prolonged and more costly. AMR occurs when microbes resist the effects of antimicrobials. When microbes are resistant, the Drug resistance has been rising rapidly for certain drugs do not work to kill them. Bacteria and other highly prevalent infectious diseases, including microbes can get resistance by mutating or by gonorrhea, malaria, and tuberculosis (TB). See “horizontal” transfer of resistance genes from already Annex 2 for a list of examples of AMR threats. 8  ■  Drug-Resistant Infections: A Threat to Our Economic Future Box 2. Indicators of Weak Governance of Antimicrobials ❉❉ Globally, WHO estimates that only 50 percent of ❉❉ Up to 60 percent of the antimicrobials used in Africa antibiotics are used correctly. and Asia may be substandard; counterfeit drugs ❉❉ Of the 150 million prescriptions for antibiotics have infested markets in these and other regions. written by U.S. doctors every year, fully 50 million ❉❉ Public data on use of, and trade in, antimicrobials were not necessary, according to a study released are lacking or poor, indicating weak governance of a in May 2016 by the U.S. Centers for Disease Control high-value public asset. Estimates of global annual and Prevention (CDC). use in agriculture range considerably, from 63,000 ❉❉ In many countries, antibiotics can be bought over- tons to over 240,000 tons. the-counter from pharmacies, grocery stores, and street vendors. that have enabled broad-based economic growth other antimicrobials low, which gives yet stronger and development for billions of people over the past incentives for overuse, both in livestock and century (Deaton 2013). other agricultural production, and in humans. The pharmaceutical industry can produce many antimicrobials at low cost, and there are no limits Incentives to Overuse and Misuse on production capacity, especially since most of Antimicrobials antimicrobials are long off-patent. The global supply Individual patients, farmers, fishermen, and others of antimicrobials will not be a constraint on the level appear to have had more incentives to overuse and of use. Instead, the availability of drug effectiveness misuse antibiotics and other antimicrobials than to is the real constraint. It is this constraint that is conserve them. The same is true for manufacturers, becoming more and more severe as AMR increases. distributors, doctors, veterinarians, hospitals, and And it is resistance to antibiotics, including medicines clinics. Expanding access to health care, which often for the treatment of devastating diseases like TB, includes antimicrobials, has been an objective of that is most unsettling. The vanishing of effective health programs in many low- and middle-income antibiotics is the greatest and most urgent among the countries, using both domestic and donor funding. AMR risks. Universal access to quality health care promises gains for public health, but greater access to Counterfeit and Poor-Quality Drugs antimicrobials inevitably means heightened risks of AMR. On the other hand, wider availability of Use of counterfeit and substandard antimicrobials diagnostic services may help to restrain overuse and aggravates AMR and also harms patients directly. misuse of antimicrobial drugs. Access to diagnostics Substandard and counterfeit medicines seem to be can promote appropriate use, especially where many widely available in many countries, though data are patients self-medicate because the private-market poor. WHO has estimated that some 10 percent of all supply of antimicrobials without a prescription is the drugs worldwide may be counterfeits, with half of plentiful (Alsan et al. 2015). these factitious medications mimicking antimicrobials (WHO 1999, 2000). Public health in a country Competition among pharmaceutical producers suffers when counterfeits penetrate its market, and keeps prices of many common antibiotics and this damage is even greater when the counterfeits Drug-Resistant Infections: A Primer on the AMR Challenge   ■  9 promote AMR. There are also other cross-border et al. 2016). This vignette is drawn from experience costs, since organized crime, smuggling, tax evasion, in U.S. hospitals, but the higher costs and worse and bribery are often linked to counterfeit drugs. health outcomes are already all too common in all Combatting the insidious traffic in counterfeit and countries. For instance, tests of 1,606 samples substandard drugs would yield significant benefits, from inpatient and outpatient settings in an African including less AMR, but would need to engage country in 2014 indicate seriously diminished drug multiple sectors across countries. effectiveness: 80 percent of the pathogens were resistant to older antibiotics (such as ampicillin Manufacturing of substandard and counterfeit and tetracycline), 50 percent were resistant to drugs appears to be concentrated in India, followed “third-generation” antibiotics (cephalosporins and by China and Thailand (United Nations Office on quinolones), and most were multidrug-resistant Drugs and Crime 2010). Overall, up to 60 percent (CDDEP 2016). of antimicrobials used in Africa and Asia may have low quality, often containing none, or too little, of the active ingredient. One study found that fraudulent A Human-Made Problem— information on drug quality was common (found in with Human Solutions 59 percent of cases), while only 7 percent of sample medicines tested had the standard concentration AMR is driven by microbes’ natural evolutionary of the active drug (WHO 1999, 2000). Widely adaptation to their environment. However, the spread used antibiotics, such as penicillins, amoxicillin, of AMR as we confront it today is mostly a human- and tetracyclines, as well as antimalarials and made problem. Thus, we refer to “anthropogenic” antiretrovirals (used to treat AIDS), appear to be AMR. Drug-resistant infections in humans and commonly counterfeited antimicrobials (Kelesidis and livestock have been hastened and aggravated by Falagas 2015). poor governance, irrational human practices, selfish behaviors, and low understanding. Public health The consequences of using substandard and authorities and governments more broadly have counterfeit antimicrobials are serious. The individuals not handled the precious antimicrobial commons taking the drugs are harmed because they do not with a degree of care commensurate with the high receive the intended treatment, which can result in social value and the fragility of this asset. Efforts to protracted illness, complications, spread of disease minimize emergence of AMR and avert its spread to others, and death. In addition to harming the cannot be one-off or limited to a temporary action patient, use of counterfeits will promote AMR if the plan. Containment of AMR is a core public-sector drugs contain a low level of the active antimicrobial function that needs to be sustained over decades if ingredient; this is common in counterfeit drugs for AMR containment is to be successful and achieved both human and animal use. The drug is not strong efficiently, at least cost. enough to treat the infection, but it contains enough antimicrobial ingredients to contribute to AMR. Over Reliance on New Miracle Drug-Resistant Infections Are Cures Is Unwise—and Immoral Already Common Worldwide When older drugs eventually fail, won’t they always be replaced by newer ones? The short answer is: AMR and the associated drug-resistant infections “No.” New replacement drugs may be developed in are unfortunately not hypothetical problems, but a some cases, but the prospects for such success have real threat for all countries, both developing and always been uncertain, and they have worsened in developed. They impact increasing numbers of recent decades. The research and development (R&D) health care facilities and patients. “Hospital-based pipeline for new antimicrobial drugs has shrunk health care providers see them every day. We daily since the 1980s and is now nearly empty. R&D for encounter infections resistant to first-line antibiotics, antimicrobials is very costly and not as commercially and we not infrequently encounter infections resistant attractive as for other drugs, especially those that to every antibiotic except colistin or tigecycline, two are taken for long periods and can command high antibiotics that are highly undesirable because of prices. The absence of market incentives to R&D for excess toxicity and inadequate efficacy. We are also antimicrobials is an additional, and powerful, reason now seeing pan-resistant infections that are not to conserve the effectiveness of existing drugs by treatable even with colistin or tigecycline” (Spellberg minimizing misuse and overuse. 10  ■  Drug-Resistant Infections: A Threat to Our Economic Future Improved governance of antimicrobial use will prevent Unmonitored waste containing antimicrobials the scarce common resource from being wasted—an is generated by pharmaceutical manufacturers, objective that governments should have pursued hospitals, and livestock producers—all such waste since antibiotics were first marketed over 70 years can promote AMR in microbes in the environment. ago. Sir Alexander Fleming, who won the Nobel Prize When drug-resistant pathogens infect people and for discovering the first antibiotic (penicillin), warned animals, the pathogens and their AMR genes can in 1945: “The microbes are educated to resist continue to spread by human-to-human, animal-to- penicillin . . . In such cases the thoughtless person human, and animal-to-animal pathways; by means playing with penicillin is morally responsible for the of vectors like mosquitoes and rats; and in the death of the man who finally succumbs to infection environment, including in water from aquaculture with the penicillin-resistant organism. I hope this evil farms, sewage, and animal and other wastes from can be averted.” farms and slaughterhouses. In addition to these numerous routes, AMR can spread “horizontally,” because drug-resistant microbes can transfer C. AMR Containment: A Global resistance genes to other microbes, including across microbe species. Public Good As effective antimicrobial treatment is part of the Public-Sector Responsibility global commons, so containment of AMR is a global in Conserving Antimicrobial public good, which will prolong the availability of effective antimicrobials for all countries. Once this Effectiveness public good—AMR containment—is produced, it is Individual households and livestock producers are impossible to exclude anyone from benefiting from not able to prevent the spread of drug-resistant it. All countries can enjoy the benefits of successful contagion on their own. Provision of this public good AMR containment. Conversely, all countries will be is the responsibility of public authorities: in particular, harmed if AMR is not controlled. national governments and the multilateral institutions One difference between AMR containment and other that national governments have created to facilitate major global public goods (such as slowing climate cross-border collaboration. change, generating knowledge, and preventing A strong argument for government leadership on pandemics) is that there is “rivalry” in the “use” of AMR concerns the impact on future generations. AMR containment benefits.2 Once climate change is The threat of AMR transcends today’s historical mitigated or a pandemic is prevented by early and context and invokes the duty of the State to defend effective control of the contagion at the source, all future generations who cannot speak for themselves. countries and their populations reap the benefits Throughout the coming decades, today’s children without diminishing the benefits that other countries will need access to drugs that work to treat life- can obtain. In contrast, use of antimicrobials in threatening disease. However, if current practices any one country exposes pathogens to selective continue, such drugs will not be available to pressure and thus contributes to reversing AMR them, because their parents’ generation will have containment. This will have negative impacts not only squandered drug effectiveness through reckless for that country, but also for all other countries. This handling of antimicrobials. The free or weakly distinctive trait requires that the global public good regulated market has resulted in a “first-come, first- of AMR containment be managed with exceptional served” allocation of the finite stock of antimicrobial vigilance through international cooperation. effectiveness. There is misuse and excessive use Protecting the global antimicrobial commons is today, at the expense of the generations to come made more challenging by the ease with which (Tisdell 1982). drug-resistant pathogens spread. Resistant In reality, access to the scarce antimicrobial resource microbes do not respect borders; they circulate is not even being managed to maximize the welfare through human travel and through trade in livestock of today’s human community. Many current users (including poultry and fish) and livestock products. of antimicrobials actually do not obtain any benefits They can also spread through food products and from them (because they are misusing the drugs) in the environment, for instance in waterways or benefit only to a small extent: for example, when and in migrations of wild birds and other wildlife. some antimicrobials are used for growth promotion Drug-Resistant Infections: A Primer on the AMR Challenge   ■  11 in livestock and when broad-spectrum antibiotics are significant development challenge, because livestock prescribed unnecessarily for human patients. are frequently the main economic asset for poor households, especially in low-income countries. An additional pragmatic argument for government Untreated disease in animals causes negative shocks responsibility on AMR will be discussed in Part II to owners’ incomes and in some cases lasting of this report. It concerns the magnitude of the damage to the welfare of poor households and economic stakes involved in controlling drug- communities. Counterfeit and substandard drugs resistant infections. As we will see, antimicrobial are also a major factor in harming animal health and effectiveness is an asset with an approximate owners’ incomes. worth today between $20 trillion and $54 trillion (in constant 2007 dollars).3 This asset is “too big to This brings us to an idea that will be a recurrent fail.” For government leaders, neglecting to protect motif throughout this report. Wealthy countries would a resource of this magnitude would be a staggering be extremely unwise to regard inadequate treatment abdication of public trust. of infectious diseases in developing countries as “someone else’s problem.” All countries are at risk of importing infections. The risk is higher the D. AMR and Access to greater the interconnectedness and volumes of trade and travel with other countries. Today, the volume Treatment in Developing and diversity of international trade and travel are Countries dramatically higher than just twenty years ago, and global networks continue to expand. Each country Even as there is overuse and misuse of thus benefits increasingly, if all other countries are antimicrobials, some poor populations still lack equipped to effectively treat infectious diseases and access to effective medicines. For example, one adequately manage AMR threats. million children are estimated to die each year from untreated pneumonia and sepsis, which can be effectively managed with antibiotics (Laxminarayan E. Closing Governance Gaps et al. 2016). Weak health care systems, AMR, and the penetration of many countries’ antimicrobials Surveillance Is Critical, markets by substandard and counterfeit drugs— these conditions all contribute to low access to but Systems Are Weak effective antimicrobials. Relatively high prices of the When a drug-resistant disease starts spreading in an more powerful, later-generation, antimicrobial drugs area where local public-health surveillance is weak, are also a factor. The development and marketing of economic and health costs will escalate rapidly. If the these drugs occurred since the first-line, relatively disease is easily transmissible, the rate of escalation inexpensive antimicrobials lost their effectiveness can be exponential. Multiple factors may facilitate because of AMR. High drug prices then squeeze the this escalation, but the most important is the delay in finite health care budgets of governments, charities, detection. and households, resulting in diminished access to Where AMR is present but undetected, humans and treatment, especially for the poor and vulnerable. In animals likely do not receive medical treatment that addition to the effect on individual health outcomes, works against their drug-resistant infection. Uncured shrinking access to effective antimicrobials hinders animals and patients may then spread the disease progress toward universal health coverage (UHC), further, within hospitals or other health facilities a pillar of the Sustainable Development Goals for and in the community at large. The weaker the local 2030.4 We will discuss the potential development surveillance system, the less knowledge health impacts of AMR extensively in Part II. In Part IV, we authorities can gather about the spread of diseases. will show how country action to promote UHC can Critical information becomes available with a delay, simultaneously enable more effective AMR control. if at all. Control measures are then less likely to Antimicrobial access constraints extend beyond succeed in containing the microbial threat, because the human health sector. The dire scarcity of basic they will confront a dramatically higher number of veterinary services in most low-income countries infected people or animals. is associated with lack of access to effective The risks of such outcomes can be significantly antibiotics to treat infections in livestock. This is a reduced by surveillance systems with the capacity 12  ■  Drug-Resistant Infections: A Threat to Our Economic Future to provide timely warning about microbial threats. Coordination Is Key Key components of a functioning surveillance system include: To contain AMR successfully, all countries will need to act in a coordinated way. Prohibiting one ❉❉ Laboratory capacity to detect and characterize kind of antimicrobial misuse in a country may not resistant organisms through antimicrobial be effective unless all countries adopt a similar susceptibility testing (AST) approach. Conversely, coordinated application of ❉❉ Appropriate criteria and mechanisms for reporting even basic measures could have a powerful effect. For example, consistent international labeling of ❉❉ Effective oversight by a reference laboratory. antimicrobial medicines, agreed among all countries, Unfortunately, the policy and financing choices of would already reduce the scope for confusion and governments and their development partners have misuse among prescribers and patients. In the resulted in inadequate infectious disease surveillance absence of international cooperation, drug-resistant capacity across much of the globe. Early warning pathogens will continue to emerge at the weakest about AMR emergence is simply not possible with the links in the worldwide chain of antimicrobial use. existing public-health capacities in most countries, Of course, country strategies and implementation which means that those countries, as well as the plans for action on AMR will not be entirely uniform. rest of the world, will not learn in time about new Timelines for the implementation of new regulations AMR emergence and spread. The infectious disease may need to differ across countries, and low- surveillance “blind spots” extend across most of income countries may require assistance in building Africa and Asia, as well as parts of other regions. implementation capacity. Collaboration remains critical in the AMR fight, Growing Threats because AMR containment can be diminished or even undone by “free riders.” Any one country may The overlap between surveillance “blind spots” and tend to look to other countries to take the measures potential “hot spots” for drug-resistant disease necessary to tackle AMR—and then benefit from emergence is a substantial concern. This menace is the result without investing to contain AMR on its growing today, as the world confronts an expanding own territory. Such tactics would undermine the array of new, old, and re-emergent infections. success of AMR containment, and all countries would Already, multiple-drug resistance (MDR) is spreading eventually suffer the consequences. in several key pathogens. The infections caused by such pathogens have become diseases with no cure. For many of them, no vaccine is available, either. Joining Forces to Strengthen Such diseases join a growing list of infectious threats Surveillance and Response to which we can offer no effective medical response. These include virulent new strains of existing Fortunately, international organizations entrusted with infections, as well as entirely new pathologies, most the governance of global public goods already exist of which are zoonotic (of animal origin). Most are for human public health (WHO), for veterinary public introduced into human populations through people’s health (OIE), and for food production (FAO). As we contact with livestock (including poultry). The novel will see in subsequent parts, AMR containment will and the drug-resistant pathogens spread unchecked bring large benefits to all countries individually and from wherever they first appear, because we have no to the global economy as a whole. This may provide tools to stop them. incentives for sustained cooperation. Because of AMR, even infectious diseases that were In this context, WHO, OIE, and partners are setting up previously considered controlled may once again be a dedicated structure to facilitate AMR collaboration: poised to spread widely—even worldwide. When this the Global Antimicrobial Resistance Surveillance occurs, there may be pandemics (in humans) and System (GLASS), which embeds AMR in the wider panzootics (in animals) of drug-resistant diseases. array of activities that comprise surveillance of This could occur in successive waves as the drugs microbial threats. GLASS promotes consistency lose effectiveness in different drug-pathogen pairs. of approaches (which is critical for maximizing Waves of contagion from different sources could the information value of surveillance data), quality overlap, exacerbating health and economic impacts. assurance, and provision of data to inform global Drug-Resistant Infections: A Primer on the AMR Challenge   ■  13 decision making (see Part IV). Ultimately, surveillance FIGURE 1.  AMR Makes TB Far Costlier to Treat for AMR will be most reliable if the capacity of TB treatments costs rise dramatically due to AMR Treatment costs are much higher in HICs than in LMICs comprehensive surveillance systems is strengthened (e.g., 80x higher for TB—and 20x higher for MDR-TB—in the U.S. than in India in all countries, for better performance in detecting Drug-resistant pathogens know no borders and assessing the full range of threats to veterinary Treatment cost per patient (US$ 000) Treatment cost per patient (US$ 000) 500 8 and human public health. Today, bold new initiatives 450 7 such as the United Kingdom’s Fleming Fund are 400 6 bringing fresh resources and expertise to this global 350 300 5 effort. Cost Cost 250 increase increase 4 200 due to due to 3 150 AMR AMR How International Coordination 100 2 Can Lower Costs: The Example 50 1 – – of Tuberculosis TB MDR-TB XDR-TB TB MDR-TB Infectious disease control has long been considered US (left axis) India (right axis) the quintessential global public good (International TB = Tuberculosis (infectious disease caused by bacteria) Task Force on Global Public Goods 2006; World Bank MDR = Multidrug-resistant XDR = Extensively drug-resistant 2007). The risk of AMR further bolsters the economic case for effective and early control of infectious diseases at their source. As with preventing and fighting fires, reducing risks at their source is invariably more effective and more efficient than MDR TB and XDR TB infections are far more a reactive stance of waiting for a crisis to develop expensive to treat than drug-susceptible TB. Because before responding. of the higher costs and clinical factors, successful treatment of drug-resistant cases is also less likely In Parts II and III, we will analyze the economic case than for drug-susceptible TB strains. Since uncured for AMR action in detail. For now, we focus on a patients will pass the infection to more people, MDR specific aspect of the problem that again underscores TB and XDR TB will spread. the value of international cooperation. This example also shows that, when wealthy countries and low- It is much more expensive to cure infectious diseases or middle-income countries collaborate on AMR, in high-income countries than in low- and middle- economic benefits can accrue on both sides. income countries, because the costs of medical personnel and supplies are much higher. Thus, it Our example concerns drug-resistant and emerging costs 80 times more to treat one TB patient in the infectious diseases that are imported into high- United States than in India, as shown in Figure 1. income countries from countries currently unable to provide effective therapies for these conditions. Such a large cost differential should inform the Promoting treatment of infectious diseases in the allocation of resources for control of TB globally. countries of origin is an option that can be both Reducing the prevalence of TB in low- and middle- more effective and more efficient than for wealthy income countries by treating all cases properly will, countries to import cases and treat them in their own of course, improve health in those countries, but it health systems. will also reduce both AMR and the probability that drug-resistant TB will spread to other countries. The costs of some of the measures that will be For instance, in the United States, two-thirds of TB required to contain AMR vary widely across countries. patients are foreign-born (with India among the top Figure 1 shows one example: the cost differentials source countries). The number of TB patients treated in treating tuberculosis (TB), with and without AMR. in the United States and AMR risks would be lower TB is an infectious disease that can be treated with if effective treatment had been provided to more antimicrobials. Inadequate treatment of TB will not patients in their countries of origin. cure the patient, but it will promote AMR. Multidrug- resistant (MDR) and extensively drug-resistant (XDR) These considerations provide a powerful rationale strains of TB have emerged. for high-income countries and the international 14  ■  Drug-Resistant Infections: A Threat to Our Economic Future community as a whole to invest in the development Endnotes of effective veterinary and human public-health systems—especially in the countries where these 1. Part I of this report is based in part on Brahmbhatt and Jonas (2015). systems are currently weakest. The returns on Non-rivalrous consumption is commonly cited as a requirement for 2.  investment in core public-health functions are the good to be considered a “public” good. It refers to the property of especially high in these countries, and the economic the good’s being inexhaustible. National defense, clean air, and public benefits will flow to high-income countries, as well. health functions are commonly cited as public goods in countries. When consumption of the good is “non-rivalrous,” any one benefiting But how robust is this argument, really? Can it from the good does not reduce the benefits available to others. To extend beyond the specific case of TB to a wider benefit from AMR containment is to use the antimicrobials, but this range of infections where drug-resistant variants promotes AMR to the detriment of all other users. may emerge? Few would deny, as a theoretical These estimates discount future benefits from antimicrobials at 3.  point, the desirability of international collaboration to 3.5 percent annually. Much greater values of the antimicrobial commons result from using a lower discount rate. For instance the tackle infectious health challenges, including AMR. asset value is as high as $85 trillion, if future benefits are discounted In practice, however, are the economic stakes in at 1.4 percent annually; this lower rate was used in the 2007 report on fighting a potentially broad array of drug-resistant climate change impacts by Sir Nicholas Stern. See Part II. infections sufficient to justify the investments that Sustainable Development Goal 3: “Ensure healthy lives and promote 4.  will be required for large-scale, coordinated, global well-being for all at all ages.” This goal has 13 targets, including action? universal health coverage. See Annex 4 and compare: http://www .un.org/sustainabledevelopment/health/ The next part of this report explores the economic case for AMR containment in greater depth. Part II. Economic Impact of AMR 16  ■  Drug-Resistant Infections: A Threat to Our Economic Future A. Rationale and Approach ignored is miniscule. Such a scenario can safely be excluded from evidence-based policy making. to the Simulations In most countries, a host of competing issues place Economic Impacts Considered legitimate claims on scarce public funds. How much in the Simulations of their economic resources should countries be prepared to invest in tackling AMR? The economic costs of AMR can be divided into several categories. For this report, we considered The answer depends on the economic costs costs that are due to AMR impacts on the health of uncontrolled AMR will inflict. Logically, if the expected workers and costs that are due to AMR impacts on costs are high, then the world should be willing to animal health. The report uses “high AMR” to mean spend more on AMR containment to preempt them. “high AMR impact.” Of note, health and economic Part II of this report presents the results of economic impacts are not directly related to the amount of simulations conducted by the World Bank to estimate resistance per se. To illustrate: for a dangerous the costs that AMR is likely to inflict on the global disease with high mortality, even a modest extent of economy in coming decades, if effective action is AMR will have a large impact on population health. not taken. The projection period ends in 2050, or For a less lethal and less transmissible disease, well within the lifetimes of present-day children however, even significant AMR would have a smaller and young people. Impacts by the year 2030 were impact on health. The impact on health depends on calculated as well, because of their relevance to the which pathogen-drug pair is affected by AMR. Sustainable Development Goals. Effective antimicrobials are a highly valuable There are difficulties in estimating costs that will public good that have brought enormous benefits occur in the future, especially when these costs to humanity. The erosion of this good will impose derive from the inherently uncertain pace of AMR correspondingly high costs. When antimicrobials emergence and spread. Weak surveillance yields started to be used widely about 70 years ago, the sparse, low-quality information about AMR and rates of death from infection fell by some 80 percent. pathogens. The impact simulations prepared for this When drugs stop working because of AMR, the report are thus necessarily based on assumptions, rates of death and illness could increase back to the which the World Bank’s Development Economics levels of the pre-antimicrobial era. This would reduce Group grounded in a review of recent simulations economic output because of a lower effective labor by other research groups, information on actual supply. This reduction of gross domestic product impacts of AMR to date, and expectations about its (GDP), modeled as the consequence of “shocks” to spread. With their strengths and limitations, we hope the labor supply, is the standard approach to valuing our simulations will contribute to a more complete the aggregate, macroeconomic impacts of morbidity understanding of the economic implications of AMR and mortality. The value of the reduction in GDP and stimulate further work. from the baseline (a scenario without “shocks”) is Weak and missing data on the use of antimicrobials the strictly economic impact of these alterations in and on AMR trends, especially in low- and middle- population health. income countries, are not reasons for ignoring AMR There would be additional reductions in human in analyses of countries’ economic prospects. To welfare in the scenarios described, but these are not do so implicitly assumes future AMR impacts in the included in the simulations for this report. Individuals country to be zero, meaning that disease outbreaks and their families may experience a greater loss of and pandemics will never occur. The results of the welfare than those calculated in the simulations, simulations of global impacts presented below as research into people’s subjective valuation of may serve as an incentive to prepare country AMR morbidity and mortality suggests. There is empirical cost simulations. Country policy makers and their evidence that most people value their life more highly development partners will probably make superior than the amount of their foregone wages due to choices, especially on investments in the health premature death (Jamison et al. 2013), so a higher sector, if assessments of major risks to economies probability of premature death (which is a direct and public health are routinely considered in the impact of AMR) reduces their welfare in line with formulation of national budgets and economic their subjective valuation of life and not just as wages development programs. The probability that future lost due to premature death. economic costs of AMR will be small enough to be Economic Impact of AMR  ■  17 A second reason that the simulations underestimate including meat, fish, eggs, and milk. The modeling AMR impacts on human welfare is that some medical work carried out for this report ensures that impacts procedures require effective antimicrobials. AMR on prices, factors of production, and sector outputs would render such procedures too risky to undertake are consistently modeled, across sectors, across and thus less available. There would be fewer (or countries, and over time. All sectors will be affected, no) simple and complex surgical procedures such because all sectors employ workers—the effective as, for example, appendectomies, hip replacements, labor force and productivity of workers are key Caesarian deliveries, and removal of tumors, as well determinants of output in different sectors. More as less chemotherapy. Surgeons and others involved labor-intensive sectors would tend to have greater in the provision of these procedures would see their declines in output growth because of AMR than livelihoods diminished. The health and quality of life sectors where production is relatively ­ of patients would be worse, but the economic value capital-intensive. of such impacts is not easily estimated and was not included in the simulations. Our simulations also fail to capture a third reason B. Impacts of AMR that human welfare would worsen with the spread of on the Global Economy AMR. This is the cost of resorting to inferior medical treatment methods. Older, less effective treatments The results of the simulations of AMR impacts on may become the best available option if AMR is global GDP in 2017–2050 are shown in Figure 2, not contained. For instance, gonorrhea, which is a under two scenarios. In the optimistic low-AMR bacterial infection, is already becoming harder to scenario, global economic output is projected to be treat because of AMR. One alternative to treatment 1.0 percent lower by 2030 and 1.1 percent lower with antibiotics could be the decidedly inferior and by 2050 than in the base case.1 In the pessimistic painful methods that were used to treat gonorrhea high-AMR scenario, global economic output would before antibiotics became available: “Mechanical be 3.2 percent lower in 2030 and then fall further, interventions included genital instillation of large so that in 2050, the world would lose 3.8 percent quantities of iodine solution instilled by urethral or of its GDP, relative to the base case (compare KPMG vaginal catheters, or ‘hot boxes’ where a person’s 2014; Review on Antimicrobial Resistance 2014; body was put in a box to 43°C to try to kill off the Taylor et al. 2014). In the low-AMR case, the costs, organism and not the host” (Kupferschmidt 2016). as measured by the reduction of GDP from the base case, will be a significant economic burden, while in the high-AMR scenario, the costs can be considered Direct and Indirect Costs severe, especially since the costly impacts endure of Disease over time. The impacts of AMR on human health will be Given that the simulations for this report were increased morbidity (illness) and mortality. These done using a dynamic, multi-country, multi-sector, give rise to the direct and indirect costs of illness. general equilibrium model with neoclassical growth The direct costs of illness are the resources used features, economies do adjust to price signals caused to treat, or cope with, disease, including costs of by the AMR shocks. These adjustments lead to a hospitalization and medication. When pathogens are reallocation of resources and to new investments drug resistant, such treatment will invariably be more (capital accumulation). These model characteristics costly and produce worse outcomes for patients and explain the flattening of the output trajectories the community. Indirect costs of illness comprise the after 2040 in Figure 2; by this time much of the present and future costs to society from morbidity, adjustment of the world economy to shifts in relative disability, and premature death, in particular the loss prices and reallocation among sectors would have of output caused by a reduced effective labor supply occurred. Thereafter, growth factors coming from (due to lower productivity and deaths of workers). capital accumulation and labor growth start to In livestock production, the impact will also be prevail, resulting in an essentially constant shortfall increased morbidity and mortality; together these relative to the base case during the decade to 2050. lead to lower productivity, lower supply of livestock Different assumptions about the timing and products (both domestically and for exports), and magnitudes of the AMR shocks would alter the shape increased prices for major sources of protein, of the lines in Figure 2. Additional, accelerated AMR 18  ■  Drug-Resistant Infections: A Threat to Our Economic Future FIGURE 2.  Substantial and Protracted Shortfalls in Global Economic Output World Real GDP 101 100 99 Base = 100 98 97 96 95 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 Base Low-AMR High-AMR emergence and spread late in the projection period annually. The difference, a 3.6 percent reduction in (after 2035, when adjustment to the initial shocks global economic growth, is shown in Figure 3 and is nearly complete) would worsen the impacts, for is a measure of the amount of economic output that example, but were not included in the modeling was not produced during the crisis years. Growth in work. As noted, the scenarios prepared for this report low-income countries remained relatively strong: it are not predictions but illustrations of some of the was in fact 0.7 percent higher in 2008–2009 than plausible impact patterns that could materialize. before the crisis. However, growth in high-income and upper middle-income countries plummeted, by Further analysis of the results of the simulations 4.1 percent and 3.2 percent, respectively, compared shows that the costly impacts of AMR are not to the pre-crisis period. The output losses from these distributed equally among countries at different levels shortfalls in growth in 2008–2009 were severe. of per capita income. The negative impact in low- income countries is more pronounced than in high- How do the simulated impacts of AMR compare income countries (Figure 3). The two main reasons to this recent major economic crisis? The annual for this difference are a higher incidence of infectious economic damage from AMR during much of the diseases and a higher dependence on labor incomes projection period could be of the same order of in low-income countries than in high-income magnitude as the impact during the major global countries. The larger impacts in low-income countries financial crisis. In the high-AMR scenario, GDP in than in high-income countries might cancel decades 2050 would be 3.8 percent lower than in the base of progress in global economic convergence. scenario. For low-income countries, the impact is worse: their GDP would be more than 5 percent How large are the potential economic impacts of smaller than in the base case. Similarly substantial AMR? To provide a point of reference, Figure 3 shortfalls in economic output would occur during also shows indicators of the costly consequences the 20 preceding years (see Figure 3). Even in the of the major global financial crisis that started in optimistic low-AMR scenario, the simulated losses of 2008. Whereas global growth averaged 3.7 percent world output exceed $1 trillion annually after 2030 annually before the crisis, it dropped precipitously in and reach $2 trillion annually by 2050.2 In the high- 2008 and 2009, to an average of just 0.1 percent Economic Impact of AMR  ■  19 FIGURE 3.  Economic Costs of AMR May Be as Severe as During the Financial Crisis AMR could reduce GDP substantially—but unlike in the recent financial crisis, the damage could last longer and affect low-income countries the most (annual costs as % of GDP) GDP growth fell during the 2008–2009 financial crisis, compared to pre-crisis growth in 2001–2007 “Low-AMR” scenario, 2050 “High-AMR” scenario, 2050 1 0.7 0 Percent of GDP (annual) –1 –0.8 –1.2 –1.3 –1.1 –1.4 –2 –1.7 –3 –3.2 –3.1 –4 –3.6 –3.8 –4.1 –4.4 –4.4 –5 –6 –5.6 Country group: Low-income Lower middle-income Upper middle-income High-income World AMR scenario, the absolute levels of losses are three which the world economy started to recover in times as high, reaching $3.4 trillion annually by 2030 2010 (though that recovery has been protracted). In and rising further to $6.1 trillion annually by 2050. contrast to cyclical economic downturns, AMR could cause persistent shortfalls in world economic output The global economic impact of AMR would differ throughout the lifetimes of today’s children and from that of the financial crisis in two respects. First, young people. These impacts would be largest in the AMR would be relatively more costly for low-income poorest countries. countries than for high-income countries; impacts on middle-income countries would be in between the two. The simulations point to a growing income gap between low-income and high-income countries. C. Impacts on Select The impacts on middle-income economies would be Components of the substantial (in the high-AMR case) or moderate (in the low-AMR case). In both cases, growth of these World Economy economies would slow, delaying achievement of high- income status (especially in the high-AMR case). International Trade The second difference is that there is little prospect Figure 4 shows the simulated impact of AMR on world for a “cyclical recovery.” Development of new drugs trade (exports). By 2050, the volume of global real and vaccines may take a decade or more (and may exports may be below base-case values by 1.1 percent not succeed). Even if successful, such new products in the low-AMR scenario and by 3.8 percent in the would take time to reach markets in low- and high-AMR scenario. The pattern of the impacts over middle-income countries. The prolonged economic time follows the pattern of impacts of AMR on GDP. impacts would make AMR a more daunting challenge Trade in livestock and livestock products is vulnerable than the relatively short-lived financial crisis, from to AMR impact not only because untreatable disease 20  ■  Drug-Resistant Infections: A Threat to Our Economic Future FIGURE 4.  AMR Impact on World Trade World Real Exports 101 100 99 Base = 100 98 97 96 95 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 Base Low-AMR High-AMR affects productivity, but also because a “fear factor” partners. The “fear factor” would likely contribute to typically provokes trade disruptions (such as bans reductions in livestock production. on imports) in response to disease outbreaks. Livestock production is a small part of the global While microbial threats are underestimated (and economy (about 2 percent of world GDP), so its even ignored) in “peacetime,” politicians, firms, reduced productivity has a minor influence on the and citizens exhibit strong, spontaneous avoidance overall simulation results. The sector is relatively behaviors during disease outbreaks. Such behaviors more important in the economies and exports of are often based on a substantial overestimation of low- and lower middle-income countries than in risks. These reactions tend to sharply reduce and wealthier countries, however. In addition, the sector otherwise disrupt economic activity (Brahmbhatt plays a substantial development role and makes a and Dutta 2008). Predominantly based on fear, major contribution to nutrition, especially for children such responses are especially likely to accompany and women of reproductive age. AMR will worsen outbreaks of drug-resistant diseases, because there animal health, as well as undermine the welfare of will be no cure available. the animals’ owners and others in the sector, both While trade in livestock is particularly sensitive to by increasing the variability of incomes because of these forces, the effects do not materially affect more frequent and severe infections, and by reducing our simulations of trade flows, because of the small income levels as an increased disease burden share of aggregated livestock and livestock products becomes the “new normal” (Figure 5). in world exports. Instead, the effects of broad declines across all economic sectors dominate the simulation results for trade flows. Health Care Expenditures Health care expenditures (both public and private) would increase in tandem with the rising disease Livestock Production burdens. The trends shown in Figure 6 are only The shocks to livestock production were modeled as two of a range of possible outcomes; they are not both a decrease in productivity because of greater projections but simulations of two scenarios to prevalence of untreatable disease and as reductions illustrate the direction and order of magnitude of in exports due to restrictions imposed by trading global AMR impacts. In the high-AMR scenario, Economic Impact of AMR  ■  21 FIGURE 5.  Decline in Livestock Production Could Be Substantial and Most Pronounced in Low-Income Countries “Low-AMR” Scenario “High-AMR” Scenario 100 100 98 98 96 96 Base = 100 Base = 100 94 94 92 92 90 90 88 88 20 8 20 20 2 24 20 6 28 20 0 32 20 4 36 20 8 40 20 2 44 50 20 6 48 20 8 20 20 2 24 20 6 28 20 0 32 20 4 36 20 8 40 20 2 44 50 20 6 48 1 2 2 3 3 3 4 4 1 2 2 3 3 3 4 4 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 Base Low-income Base Low-income Middle-income High-income Middle-income High-income FIGURE 6.  Health Care Costs Reach Nearly $1.2 Trillion in the “High-AMR” Case Extra Health Care Expenditure in Equivalent Additional Household Tax 1,200 1,000 800 In billions of 2007 USD 600 400 200 0 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 Base Low-AMR High-AMR 22  ■  Drug-Resistant Infections: A Threat to Our Economic Future health care expenditures in 2050 would be as much FIGURE 7.  Most of the People Falling into as 25 percent higher than the baseline values for Extreme Poverty Because of AMR Will Be low-income countries, 15 percent higher for middle- in Low-Income Countries income countries, and 6 percent higher for high- Additional people falling into extreme poverty: income countries. Globally, annual expenditures in nearly 8 million by 2030 in the low-AMR case; more then 28 million by 2050 in the high-AMR case 2050 would be 8 percent higher than in the base case. The additional expenditures in 2050 would Increase in number of people living under $1.90/day be $1.2 trillion annually in the high-AMR scenario. 30 In the low-AMR scenario, the additional health care 2.1 (purchasing power parity), in millions expenditure in 2050 would be $0.33 trillion annually. 25 Since our economic modeling stipulates that these 5.4 expenditures are not made unless they are financed, 20 there would be a decline in consumption. This will mean a reduction in other aspects of population 15 well-being, because resources that could have been 26.2 devoted to reduce poverty or pursue other goals will 10 18.7 have to be diverted to financing the extra costs of 0.6 a larger health sector coping with a larger disease 1.5 5 burden. 6.2 6.3 Similar simulations of health care costs under 0 different AMR scenarios at national and subnational 2030 2030 2050 2050 levels could prove useful in raising awareness of AMR Low-AMR High-AMR Low-AMR High-AMR risks in the health sector and among departments involved in managing public expenditures and Simulation scenario and year revenues. In countries where the public sector Low-income countries finances a substantial part of health care costs, Rest of the world (all other countries) the required additional taxes may not be feasible to Source: Simulation results and author’s calculations. implement, or they would severely burden taxpayers, since people would have to reduce their consumption in order to pay the additional taxes. E. The Economic Case D. Impacts on Poverty for Tackling AMR: Focus on the Health Sector The impact of AMR on economic growth will result in a pronounced increase in extreme poverty. The The preceding discussion has shown that unchecked main reason is the disproportionate impact of AMR is likely to inflict heavy losses on the global AMR on the economies of low-income countries economy in the period 2017–2050. However, we (Figure 3). These countries experienced substantial have not yet suggested what can be done to avoid and protracted shortfalls in economic output in the this highly undesirable outcome. Nor have we simulations. Of the additional 28.3 million people explicitly argued that the costs likely to be involved in living in extreme poverty in 2050 in the high-AMR AMR containment will be manageable for individual scenario, the vast majority (26.2 million) would live countries and the global community as a whole. in low-income countries (Figure 7). In the baseline While the costs of uncontrolled AMR will be vast, scenario, the world is broadly on track to eliminate it does not necessarily follow that the costs of extreme poverty by 2030, moving toward the World containing AMR will be much less so. These issues Bank Group’s target of less than 3 percent of people are the focus of Part III. living in extreme poverty (i.e., on less than $1.90/ Here, it will be useful to anticipate the broad direction day) worldwide. Because of AMR, however, the of subsequent arguments by looking specifically at target would be harder to reach: there could be the health sector. an additional 24.1 million extremely poor people by 2030 in the high-AMR scenario, of whom Already by 2030, extra health care expenditures 18.7 million would be in low-income countries. would rise to $0.22 trillion annually in the low-AMR Economic Impact of AMR  ■  23 scenario generated by our economic simulations. projection period of our simulations would be As we will see in Part III, this figure represents thirty $4 trillion. If the high-AMR case is avoided, that times the amount that is likely to be needed in annual figure would reach $11 trillion.3 If the health sector investments to contain AMR worldwide. were to receive all the savings from the avoided extra health care costs, and if the sector were also to pay Thus, the amount of extra health care expenditures all of the investment costs of AMR containment, the in just this one year would suffice to finance all the sector would still enjoy a cumulative total net gain investments in containment of AMR that are required ranging between $3.8 trillion and $10.8 trillion. between now and 2050. Spending $9 billion annually These substantial resources could be invested in on veterinary and human public-health systems improved health care. and the other measures required to contain AMR (see Part III) is already a justified expenditure, even Are these scenarios too optimistic? It is possible that if we consider only the cost savings that would be even strong AMR containment efforts may not be generated for the human health sector—completely fully successful. Let us assume a very poor outcome ignoring the benefits that other sectors would obtain. for illustrative purposes: just 10 percent success for the containment efforts deployed. In this case, the Investing a cumulative $0.1 trillion in AMR health sector could still provide resources for the containment at a steady pace between now and total costs of containment and come out ahead. The 2030 would lower health care expenditures in that health sector’s net gain ranges between $0.2 trillion single year by as much as $0.22 trillion if the low- and $0.9 trillion, thanks to avoiding 10 percent of the AMR case is avoided, and by as much as $0.7 trillion low-AMR and high-AMR cases, respectively. if the high-AMR case is avoided. And there would be savings every year before and after 2030. The magnitude of the health sector’s expected benefits from AMR containment could be considered If the low-AMR case is avoided, the cumulative in prioritizing health sector expenditures. Indeed, savings on extra health care costs over the full 24  ■  Drug-Resistant Infections: A Threat to Our Economic Future it would be sufficient to avoid just 3 percent of occurring, and the associated costs will continue AMR impacts on health care expenditure in the to grow in the future, if the world does not act to high-AMR case to justify spending the full amount contain AMR. Delayed responses will inevitably be required for AMR containment. From the health care more costly. sector’s perspective, spending on AMR containment is an insurance proposition on attractive terms: the expected annual payout is a high multiple of the Endnotes annual premium. Containment of AMR emerges as a highly productive use of public funds to provide an The base case is the standard World Bank long-term projection for the 1.  essential public service for the benefit of humanity, global economy and excludes AMR from the model. and especially today’s children and young people. All absolute amounts from the simulations for this report are in constant 2.  2007 US$ terms. Our calculations confirm the substantial economic Both figures for health care cost savings represent the present values 3.  gains that can be obtained through strategic of extra health care expenditures in the simulations, cumulative investments in AMR control today. We can recall total in 2017–2050, and using a 3.5 percent discount rate. Use of a the commonsense firefighting analogy. Buying a fire discount rate ensures that later amounts have less weight in the total alarm and extinguishing a fire early are always more than earlier amounts. For instance, in the high-AMR case, the extra expenditure is $1.2 trillion in 2050. Because 2050 lies in a relatively efficient ways to reduce risks than waiting for fire distant future, the present value is calculated as $0.35 trillion, which is to engulf the neighborhood before taking measures the amount that is included in the $11 trillion total. to control it. AMR impacts on health are already Part III. What Will It Take to Contain AMR? 26  ■  Drug-Resistant Infections: A Threat to Our Economic Future P art II quantified the damage that drug-resistant OIE, and other partners, a consensus exists among infections can be expected to inflict on global leading experts on the broad directions countries economic performance in the coming decades, can adopt to build effective national AMR strategies. if countries and the international community fail This consensus is captured in the Global Action Plan to counter the threat. The remainder of this report on AMR, whose five objectives are summarized in explains how we can avoid these grim scenarios. Figure 8 (WHO 2015a). We will argue that there are good reasons to believe threatened AMR devastation can be mitigated. More, A Bold Agenda: Integrated Public- we’ll make the case that putting resources into AMR Health Protection in All Countries control will yield large net economic payoffs for all countries—and that the biggest winners may be in Where should country action start? While national unexpected places. contexts and priorities differ, one fundamental point is applicable everywhere. AMR cannot be managed To get started, Part III maps the broad outlines of an in isolation. Drug-resistant infectious diseases are a AMR containment agenda and analyzes its costs and subset of the broader range of microbial threats to benefits. The outcome is a compelling investment human and animal health and welfare. From a public- case for aggressive AMR policies. Then, in Part IV, health and policy-making standpoint, drug-resistant we’ll drill down on a series of specific practical infections have practical similarities to all infectious issues for AMR action in countries. diseases with pandemic potential. The surveillance, diagnostic, and control capacities needed to deal with AMR are closely related to those required to A. Expert Consensus on control infectious diseases like Ebola and Zika. Measures to Contain AMR Instead of viewing AMR as a separate issue isolated from other health challenges, it will be more effective Some threats to global well-being and prosperity and less costly over time to build a common core of leave experts profoundly divided on how to respond. permanent capabilities in all countries for managing This is not the case with AMR. Thanks to sustained the full range of infectious threats. research, consultation, and advocacy by WHO, FAO, FIGURE 8.  The Five Objectives of the WHO Global Action Plan on AMR, 2015–19 Strengthen Knowledge Reduce the Incidence Optimize Use of Improve Awareness and and Evidence Base of Infection Antimicrobials Understanding of AMR ❉❉ Develop an AMR ❉❉ Implement and ❉❉ Implement a comprehensive ❉❉ Public communication surveillance system for: strengthen hygiene action plan with: targeting human and animal • health care facilities and infection • antibiotic access only health audiences as well as and community prevention programs through qualified schools and public media • animal husbandry • make it part of individuals ❉❉ Establish AMR as element of and agriculture health care and • only quality, safe and professional education • using at least one veterinary training efficacious drugs ❉❉ Elevate AMR to priority reference lab • develop and authorized agenda across government ❉❉ Share information implement • reimbursement, internationally standards of promotion and treatment Make Economic Case ❉❉ Collect and share practice guidelines for Investment data on antimicrobial ❉❉ Test and report • laboratory capacity to use (human/animal/ susceptibility of guide optimal use ❉❉ Secure required financing agriculture) hospital-acquired • evidence-based for implementation ❉❉ Consider an AMR infections (HAI) stewardship programs ❉❉ Engage in international research agenda, ❉❉ Implement prevention • elimination of financial research collaboration— including: best practices in incentives to prescribe between developed and • responsible use animal health and • effective and enforceable developing countries • infection prevention agriculture regulation ❉❉ Public-private partnership • development of novel ❉❉ Promote vaccination of • reduction/phasing out of ❉❉ New market models for agents food animals non-therapeutic antibiotic investment and access use in agriculture What Will It Take to Contain AMR?  ■  27 As AMR control is part of a wider agenda of infectious core veterinary and human public-health capacities in disease management, so the response to infectious low- and middle-income countries. In addition to its diseases in turn depends on the robustness of critical importance for controlling AMR, the capacity- countries’ broader health systems. Competencies building agenda will reduce the risks of pandemic for the AMR fight can’t be built independently of infections of all types, increase preparedness, the health system’s core capacities. Thus, the and enhance numerous facets of public health. fundamental priority in AMR containment is to invest Strengthening systems capacities in countries will in human and veterinary public-health systems. improve human and animal health, food safety, food security, livestock keepers’ livelihoods, economic The dependence of AMR action on underlying growth, and resilience. health-systems capacities means there are no simple, quick-fix solutions to the AMR challenge. But A recent example of the dramatic difference core the systems connection also has an upside. Many public-health functions can make was provided by policies that countries may be considering, or already the arrival of an Ebola patient in Lagos, Nigeria, implementing, to strengthen their health systems in August 2014. The patient came from Liberia, and core infrastructure can be crafted so as to yield where the Ebola epidemic was advancing rapidly. benefits for the AMR fight. This underscores that AMR The disease could have spread in the large, densely can and must be addressed in two complementary populated city of Lagos, just as it had in Liberia, ways. with catastrophic consequences. However, Nigeria’s public-health service was prepared, the infection was detected and addressed promptly, and a disaster AMR-Specific and AMR-Sensitive was averted. The savings from the control of Ebola Measures in Nigeria, through swift action at the source, were Policies and actions that work to contain drug- enormous. resistant infections are described as “AMR-specific” or “AMR-sensitive.” B. Two Threats to AMR AMR-specific actions are those whose main purpose is to reduce AMR. For example, a key AMR-specific Containment action is establishing and enforcing regulations to ensure people can only obtain antimicrobial Public-health action to monitor and contain AMR medicines with a valid prescription. AMR-specific is technically challenging. However, the two most measures also include antibiotic stewardship serious threats to successful AMR containment are programs, which are an effective, low-cost method not technical or scientific. They are political. to change behaviors that drive excessive use of The first of these two risks is that policy makers’ antimicrobial drugs in medical facilities. support will not be sustained over the time span of AMR-sensitive measures are those whose primary future decades, which is the appropriate duration of purpose is not AMR control, but which can be efforts to contain the emergence and spread of AMR. designed and delivered in such a way that they Building up functional veterinary and human public- contribute indirectly to combating AMR. Improving health systems takes time and perseverance. It is a access to clean water and sanitation, thereby marathon, not a sprint. reducing the spread of infections, is an important The second risk relates to the deeply ingrained example. Vaccination of humans and livestock historical divisions between institutions, professions, likewise reduces the incidence of infections and is and capacities for human and veterinary public AMR-sensitive. health. Human and veterinary health systems need Both AMR-specific and AMR-sensitive measures are to work together seamlessly to reduce health risks at vital to prevent and contain drug-resistant infections. the animal-human-environment interfaces. However, in most countries at the present time, pathogens still appear to cross these interfaces with far more Can the World Afford AMR Control? ease than highly educated professionals and public- health organizations. The fault line between human Table 1 presents an overview of the costs of key and animal health systems offers uninterrupted measures for AMR containment. The estimated global opportunities for the emergence and spread of AMR. total is $9 billion annually. About half is for building 28  ■  Drug-Resistant Infections: A Threat to Our Economic Future TABLE 1.  Cost of Measures to Minimize and Contain AMR Best Available Cost Estimates, Approximate Interventions and Services US$ Billion per Share of to Implement the Global Action Plan on AMR (2015) Year Total Cost } Capacities required in low- and middle-income countries to contribute to AMR containment and to benefit from it Veterinary and human public-health systems in 139 LMICs (investment in capacity, 3.4 operations, maintenance) Active management of “antimicrobial commons” for effective, efficient, and equitable access As a priority, implement preventative measures to avoid the need for health care and so 1.3 89% reduce suffering and costs. For example, minimize spread of disease in health facilities and resultant harm to patients through: infection prevention and control (IPC) programs in all publicly funded health facilities; improved waste disposal; raising awareness of AMR risks; and other measures. Make better use of existing antimicrobials to extend their effectiveness in treating 2.0 diseases in humans and livestock. Exercise antimicrobial stewardship; strengthen oversight over quality, trade, distribution, and sales, both for human use and use in animals. Roll out existing and new diagnostics and vaccines both for humans and livestock (initial average proportion 30:70) Global and Regional Interventions (Interventions with global primary objective, implemented in countries and at global and regional levels) } Active management of “antimicrobial commons” for effective, efficient, and equitable access (a) Technical support to countries, development of shared standards and interoperable 0.3 systems, and assessments of system performance; (b) Promoting development of new antimicrobials 11% Global Innovation Fund supporting basic and non-commercial research in drugs, 0.4 diagnostics, vaccines, and other tools Global public awareness campaigns 0.1 Total 7.5 Contingency (cost increases, additional measures, and similar needs)—20% of total 1.5 Financing required 9.0 Sources: Estimates of costs of global/regional interventions and in-country costs of diagnostics, vaccines, and active management of antimicrobials are from the final report of the U.K. Review on AMR (Review on Antimicrobial Resistance 2016). Estimates of cost of public-health system capacities in low- and middle-income countries are from World Bank (2012); best available estimates. Because of the importance of these two threats to public-health systems have been neglected for effective, long-term AMR containment in countries, decades. What can motivate countries to reverse that we will take time to examine each. pattern of neglect, and how can they start to take action? Support for Human and Veterinary Underlying this report is the conviction that decision Public-Health Systems: Changing makers who appreciate the true magnitude of economic stakes in AMR control will be motivated to the Paradigm reconsider prior assumptions about financing public- The frustration and powerlessness that many policy health systems. As we have seen, AMR containment makers feel when confronted with the challenges and reducing pandemic risk will generate of AMR containment are primarily a reminder that extraordinarily high economic returns. The lowest What Will It Take to Contain AMR?  ■  29 estimate of benefits from complete AMR containment countries. This recognition could prompt a review of in our economic simulations was $20 trillion. To the global financing institutions that currently operate obtain this benefit, governments need to invest only in the sectors involved (animal health, human health, $0.2 trillion—much of it in public-health systems environment, disaster risk management) to identify strengthening. As governments consider domestic which institutions could be mandated to take the spending priorities and possible contributions to lead in financing systems-strengthening projects as international cooperation, they have reason to a priority. These investments are needed for AMR prioritize the highly productive investments in AMR containment, but also for pandemic risk reduction, containment and related health security objectives. compliance with International Health Regulations (IHR) and OIE standards, and the achievement of In the past, a barrier to meaningful action on health other national health and economic objectives. systems strengthening was that it was hard for policy makers to know where to start—that is, what was Pragmatic modifications of the existing criteria for actually broken in the system and where priority allocating multilateral concessional funds might efforts should focus. Today, robust health systems be one strategy to increase incentives for country diagnostic and performance analyses are changing governments to make these investments, and for that. Consistent use of systems performance development-finance partners to support them. An measures can incentivize governments to protect example of how such incentives might look comes public health and safeguard their economies through from recent efforts to accelerate concessionary developing core public-health systems capacity. lending for regional development, for example Equally important, performance measures can through the International Development Association provide decision makers with clear information on (IDA), the World Bank Group’s fund for the poorest where systems are weak and what is needed to countries. Novel incentive arrangements have fix them. Measurement of system performance is successfully encouraged countries to implement gaining traction today through WHO’s Monitoring and collaborative regional projects, and some experts Evaluation Framework, launched in connection with have recommended adapting these mechanisms to the Global Health Security Agenda (GHSA), as well as incentivize AMR and health-systems investments through the OIE Performance of Veterinary Services (Glassman et al. 2016). Such innovations may help (PVS) pathway. secure durable financing channels for health-systems strengthening. To sustain the focus on strengthening systems over time, such independent assessments of national veterinary and human public-health systems must Multiple Gains from One-Health become a permanent cornerstone of the global Models public-health agenda. AMR containment will be much more likely to succeed if WHO and OIE are supported The second structural threat to AMR containment is to expand their systems-performance evaluations the failure to bridge divisions between human and to more countries, so that more governments and animal public health. Where One-Health perspectives development actors can use the evaluation results to are not operationalized, competition for resources guide investment decisions. between human and veterinary health systems is inevitable. In most low-income countries, veterinary services have been losing those battles, both for Mitigating Risks of Inadequate domestic financing and in donor envelopes. With and Unpredictable Financing One-Health approaches, the world can better succeed in containing AMR, because veterinary Financing modalities for AMR containment must public-health capacities will be built up; it is these be aligned to the characteristics of the effort that capacities that are currently weakest and that is required: global, multi-sectoral, long-term, with engender the greatest risks of AMR and infectious a predictable and adequate capacity, and with pandemics. appropriate sharing of financial burdens. In particular, these funding mechanisms should not be based on The divide between the medical and veterinary short-term, voluntary contributions. domains is a historical, human-made AMR hazard. Since human populations have much more exposure A long-term effort to finance capacity building for to livestock and other animals in low-income core veterinary and human public-health functions countries than in high-income countries, the risks is required in all countries, especially low-income 30  ■  Drug-Resistant Infections: A Threat to Our Economic Future from lack of collaboration are especially high where C. International Cooperation the populations can least afford to cope with them. In addition, infectious diseases that originate in animals Since AMR does not respect borders, international (zoonoses) are the main group of pandemic-potential cooperation is necessary to tackle the problem. diseases, provoking global risks to health, economies, Moreover, as we’ve seen, the impacts of AMR will and societies. Adding AMR to the reasons why fall disproportionately on low- and middle-income One-Health approaches are needed should provide a countries, causing increased poverty and global strong supplemental incentive to the human-health economic inequality. This threat demands a concerted sector to advance One-Health collaboration. global response. In addition to improving disease prevention and control, One-Health models may generate cost AMR Containment and the Global savings, as human and veterinary public-health services can share some functions and tools. For Development Agenda example, the One-Health approach is generating If AMR is not contained, the prospects for large savings in operating costs (estimated at achievement of the Sustainable Development Goals 26 percent annually) at Canada’s national laboratory; for 2030 will diminish. Achievement of a number such efficiencies, as well as greater effectiveness, of goals is particularly at risk (Figure 9), including could be obtained elsewhere (see Annex 3). ending poverty, ending hunger, promoting healthy FIGURE 9.  Synergies and Tensions with Global Development Goals for 2030 Substantial Risk That AMR Will Hinder Progress Toward Goal Substantial Moderate Impact of Progress Toward Goal on AMR Containment Potential *   1  End poverty in all its forms everywhere   2  End hunger, achieve food security and improved nutrition and promote sustainable agriculture   3  Ensure healthy lives and promote well-being for all at all ages   5  Achieve gender equality and empower all women and girls   6  Ensure availability and sustainable management of water and sanitation for all   7  Ensure access to affordable, reliable, sustainable and modern energy for all Promote sustained, inclusive and sustainable economic growth, full and productive employment and   8  decent work for all Reduce inequality within and among countries 10  11  Make cities and human settlements inclusive, safe, resilient and sustainable Protect, restore and promote sustainable use of terrestrial ecosystems, sustainably manage forests, 15  combat desertification, and halt and reverse land degradation and halt biodiversity loss Promote peaceful and inclusive societies, provide access to justice for all and build effective, accountable 16  and inclusive institutions at all levels Strengthen the means of implementation and revitalize the global partnership for sustainable development 17  *= With AMR-sensitive approaches Source for the list of SDGs: Transforming our world: the 2030 Agenda for Sustainable Development. Resolution adopted by the General Assembly on 25 September 2015 (A/70/L.1). What Will It Take to Contain AMR?  ■  31 lives and well-being, and achieving sustained FIGURE 10.  National and International Plans economic growth. Additionally, if the international to Tackle AMR: Year of Implementation community does not mobilize the resources required and Duration to contain AMR and enable all countries to comply USA with the International Health Regulations (IHR), we Italy will have failed to reach the key goal of revitalizing Canada global development partnerships. UK While unchecked emergence and spread of AMR Germany will impair progress on the global development France agenda, there are also a number of entry points for 2000 2005 2010 2015 2020 advancing AMR containment within the Sustainable Development Goals framework. Some of these EU opportunities are indicated on the right side of TATFAR Figure 9. We’ve noted, for example, that water GHSA supply and sanitation measures are AMR-sensitive. WHO They help reduce infectious disease risks, limiting Source: Cecchini et al. (2015), p. 29. the need to deploy antimicrobials and so reinforcing AMR containment. Thus, AMR control is an additional argument for devoting resources to the water and beyond the European Union (EU).1 The Transatlantic sanitation goal. We will explore this link and its policy Taskforce on Antimicrobial Resistance (TATFAR) implications further in Part IV. has engaged both Europe and the United States, while the Global Health Security Agenda (GHSA), Another opportunity for synergy is in the pursuit of launched in January 2014, now extends to more a revitalized global development partnership, which than 60 countries. These international initiatives includes improving emergency and humanitarian and a number of country plans (which also have responses. Such efforts can become AMR-sensitive international components) are currently ongoing if the balance of attention deliberately shifts to favor through 2017 (Figure 10). partnerships for prevention and preparedness. These examples are by no means exhaustive; there will This discussion reminds us that promising vehicles be many additional opportunities in specific country for cross-border collaboration on AMR have been contexts. established. However, delivery of needed actions on the ground has been uneven. International plans to contain AMR have foreseen measures for low- Organizing for International and middle-income countries, but financing and Collective Action implementation capacities have not been sufficiently considered. These concerns were also neglected International cooperation depends on adequately following adoption of the revised International Health funded international organizations. Existing Regulations (IHR) in 2005, with the result that, multilateral agencies, including WHO, OIE, and FAO, in a large number of countries, the public-health have had to struggle with chronically insufficient capacities that are needed for both IHR compliance funding. However, thanks to their continued efforts, and AMR containment have not yet been built. there is growing cumulative experience in global Even as we work to generate fresh momentum collaboration to contain AMR. Such collaboration for coordinated global action on AMR, we must be has progressed over nearly 20 years. A resolution clear that collective action can once again founder adopted by the World Health Assembly in 1998 in the absence of strong international institutions already urged countries to contain the use of and realistic arrangements to support progress in antimicrobials and improve relevant legislation. Early countries with limited resources. WHO guidelines for containment of AMR were issued in 2001. Distribution of AMR In Europe, the European Commission issued a comprehensive AMR action plan in 2011; subsequent Containment Benefits activities in human health have emphasized Improved public-health governance and AMR surveillance systems, research, recommendations, containment can be seen as a single, joint challenge. and guidelines, as well as collaboration within and Both can advance if at least three things happen: risk 32  ■  Drug-Resistant Infections: A Threat to Our Economic Future awareness, international leadership, and adequate, FIGURE 11.  High-Income and Upper Middle-Income stable financing that shares cost burdens fairly. Economies Stand to Benefit the Most from AMR Containment, Both in Absolute and per Capita Terms Clarifying the distribution of economic benefits from AMR containment may help motivate high- Proportion of global AMR containment benefits and middle-income countries to increase their (based on present value of total benefits in 2017–2050) participation in the needed long-term financing Upper middle-income and high-income countries efforts. will obtain more than 80 percent of the benefits from AMR containment As shown in Part II, economic impacts from AMR (measured by percentage shortfalls of GDP relative 3% to the base case) largely depend on the prevalence 15% of infectious diseases and the labor intensity of production in a given country; both are generally higher in low-income countries than high-income countries. Thus, low-income countries will suffer the largest proportional shortfalls in GDP because of 51% AMR impacts. However, absolute economic losses will be much higher in high-income countries, where 31% workers affected by higher mortality and morbidity have much higher productivity and wages than workers in low-income countries. We clearly can’t prescribe what shares different Total world population: 7.3 billion countries should bear in the investments needed (population in billions; share of global total) to contain AMR. What we can do, however, is to 0.6; 9% underscore the magnitude of benefits expected from 1.2; 16% AMR containment and clarify the distribution of these benefits across countries. These results can inform deliberations on financing arrangements for AMR action. If we use a discount rate of 3.5 percent and assume 2.9; 40% 2.6; 35% that containment efforts will succeed in reducing the economic costs of AMR by 50 percent, we find that high-income countries, with a population of 1.2 billion people, would obtain benefits ranging between $4 trillion and $14 trillion in the low- Country group: AMR and high-AMR scenarios, respectively. Even Low-income Lower middle-income efforts that are only 10 percent successful would Upper middle-income High-income bring immense benefits to high-income countries: $0.9 trillion in the low-AMR scenario and $2.7 trillion in the high-AMR scenario. cost of the measures that need to be implemented For upper middle-income countries, which have a between now and 2050. Recall that the estimate of total population of 2.6 billion people, reducing AMR these costs is $9 billion annually. The present value costs by half brings benefits of $3 trillion in the of the cumulative cost of the measures during the low-AMR scenario and $8 trillion in the high-AMR simulation period is $0.2 trillion. scenario. If AMR containment were only 10 percent Importantly, the measures to be deployed have successful, the benefits would be $0.6 trillion and been developed by global experts and are based on $1.6 trillion, respectively. settled science. They have been tested, and their Together, high-income and upper middle-income effectiveness is known in most cases. Thus, we can countries would obtain about 80 percent of the total be relatively confident that adequate investment in global economic benefits from AMR containment these measures and the underlying delivery systems (Figure 11). The expected benefits of even partial will indeed yield economic rewards on the order our AMR containment are clearly far more than the total simulations describe. Nonetheless, should the control What Will It Take to Contain AMR?  ■  33 actions that experts have foreseen prove inadequate international organizations and sustained political at first, and AMR continue to increase even as they support from world leaders, an enormous benefit can are implemented, the magnitude of the expected be had. Importantly, moreover, our estimate of this benefits from AMR containment still offers a wide benefit is not derived subjectively, as in studies on financial margin to develop and deploy additional valuation of life. Instead, our reckoning is based on measures. economic impact simulations that use pure market valuations. In other words, the likely rewards of AMR containment are so great that countries could spend The economic payoff from containment will of course considerably more than is called for in our models depend on what proportion of anticipated costs will and still come out well ahead. However, without be averted. The costs of AMR were calculated in the spending $9 billion annually, no AMR containment simulations as occurring every year between now will occur. High- and upper middle-income countries and 2050, with trajectories of economic impacts can then expect to suffer cumulative losses ranging as shown in the graphs in Part II. The undiscounted from some $15 trillion (if the low-AMR scenario value of cumulative costs of AMR in the World Bank materializes) to $44 trillion (in the high-AMR simulations is $120 trillion (in constant 2007 dollars) scenario). Even a partial success in reducing these in the high-AMR scenario and $40 trillion in the low- costs will require the world’s leading countries AMR scenario. However, because the values arise and relevant financial institutions to make robust in the coming 34 years, they must be discounted. arrangements for investing $0.2 trillion in AMR Discounting of future costs is needed because people containment over the coming 30 years. care less about getting a given benefit in 2040 than about getting it tomorrow. The higher the discount The public-health capacities that would be developed rate, the lower is the value today of amounts in the to contain AMR have very large expected co-benefits. future. For example, the milestone report on the Global co-benefits include reduction of pandemic economic impacts of climate change by Sir Nicholas risk thanks to compliance with IHR and improved Stern (2007) used a discount rate of 1.4 percent. preparedness. The expected value of pandemic Table 2 reports the main outcomes of our AMR impact on the world economy has been estimated simulations, using the 1.4 percent discount rate as to be $60 billion annually (National Academy of well as results with more conventional discount rates Medicine 2016). By itself, this risk is so large that it of 3.5 percent and 5.5 percent. also justifies substantial investments in strengthening veterinary and human public-health systems in low- The results in Table 2 assume that 50 percent of and middle-income countries. In addition, however, the costs of AMR impacts can be averted. Success there will be large national and regional co-benefits in reducing the costs of AMR will be possible only that will come from preventing and controlling if action plans with measures reflecting expert disease outbreaks and from improving the quality consensus are implemented in all countries, by of health care, thanks to better information on capable public-health authorities, and adjusted as pathogens. needed based on performance and evidence. All this will cost money. Will these investments prove worthwhile, given competing uses for the resources? D. Economic Justification Even when discounted, the values of the net of Investments in AMR benefits of AMR containment that reduces costs by 50 percent range from very large in the low-AMR Containment scenario with a high discount rate ($5.8 trillion, discounted at 5.5 percent), to extremely large in We have already begun to explore the impressive the high-AMR scenario with a moderate discount economic gains that countries and the international ($26.8 trillion, discounted at 3.5 percent), to community are likely to derive from systematic, enormous ($42.2 trillion) in the high-AMR scenario coordinated, global action on AMR. Now is the time when the 1.4 percent annual discount rate is to review these arguments, clarify key points, and adopted. By the test of positive net present value, the summarize the investment case for tackling AMR as a investments are unambiguously justified and should national, regional, and global policy priority. be financed as a priority. The bottom line is that investing in AMR containment There are, of course, uncertainties, including on is an exceptionally productive use of resources. For the extent and pace of future AMR emergence and modest investments, accompanied by mandates for 34  ■  Drug-Resistant Infections: A Threat to Our Economic Future TABLE 2.  Cumulative Costs of AMR, Benefits of Containment, and Costs of Measures Cumulative to 2050, Present Discounted Values Under Alternative Social Discount Rates, in $ Trillion (2007 Constant Dollars) Social Discount Rate (Annual) 0% 1.4% 3.5% 5.5% 1. Costs (results of simulations)   Low AMR-impact scenario 40 30 20 13   High AMR-impact scenario 120 85 54 36 2. Benefits if 50% of costs averted   Low AMR-impact scenario 20 15 10 6   High AMR-impact scenario 60 42 27 18 3. Costs AMR action plan (Table 1) 0.3 0.3 0.2 0.2 4. Net benefits (2.–3.)   Low AMR-impact scenario 19.7 14.7 9.8 5.8   High AMR-impact scenario 59.7 42.2 26.8 17.9 Source: Simulation results and authors’ calculations, and Table 1. spread, which pathogen-drug pairs may be affected expected returns on investments in AMR containment (this is important for the impact on health), and, are very high. For the most pessimistic outcome from finally, how much containment may be possible. To containment efforts, where only 10 percent of the examine whether the investment of $9 billion per costs of AMR are avoided, the expected annual rate year in AMR containment is worthwhile, sensitivity of return is 31 percent in the low-AMR scenario and analysis was carried out on the expected rate of 47 percent in the high-AMR scenario. return (Table 3). All other combinations show even higher expected The assumptions were that no benefits from AMR annual rates of return, up to 88 percent in the containment would occur for the first seven years, high-AMR scenario with containment of 75 percent. while investment in containment would start in year 1 This analysis confirms that AMR containment is a and continue to be made until 2050. The benefits “hard-to-resist” investment opportunity for the global of containment would thus occur only starting in community. Investment opportunities with such high year 8. Even under this conservative assumption expected economic returns are extremely rare in (which reduces the rate of return considerably), the the public sector. The results of the analysis of net present values and expected rates of return are a compelling reason to reallocate resources away TABLE 3.  Sensitivity of Expected Rate of Return from less-productive investments toward the highly to AMR Containment Success (Assuming $9 Billion productive investments in containment of AMR. Annual Investment in AMR Containment) Expected Annual Rate of Return E. Turning Evidence Low AMR-Impact Scenario into Action 10% containment achieved 31% 25% containment achieved 45% This part has described high-level priorities for action 50% containment achieved 58% on AMR and clarified the investment case for AMR 75% containment achieved 66% containment. We’ve presented strong arguments for countries at all levels of income to invest in the High AMR-Impact Scenario human and veterinary public-health systems that are 10% containment achieved 47% the engines of the AMR fight. Wealthy countries have Reach low-AMR scenario 84% sound economic reasons to support these efforts in 75% containment achieved 88% countries whose domestic resources are limited. Source: Simulation results and authors’ calculations. What Will It Take to Contain AMR?  ■  35 The measures we’ve discussed face implementation Endnotes challenges. Knowledge gaps persist on how best to translate widely accepted policy principles EU agencies engaged in AMR collaboration have included the European 1.  into country-level results. In the next part, we’ll Centre for Disease Prevention and Control (ECDC), the European summarize the findings from three special field Surveillance of Antimicrobial Consumption Network (ESAC-Net), and studies commissioned for this report, whose purpose the European Antimicrobial Resistance Surveillance Network. European was to help bridge that knowledge gap. Drawing actors have built AMR collaborations with non-European partner countries, including China and Russia. on the results of these studies and other research, we’ll analyze specific pathways for country action to contain AMR. Part IV. Directions for Country Action 38  ■  Drug-Resistant Infections: A Threat to Our Economic Future T he early parts of this report provided for countries committed to moving forward on AMR background on the crisis of drug-resistant control. We focus our discussion of policy options in infections and presented the investment specific areas where the World Bank can add value to case for an aggressive global response. Economic the sound recommendations provided by other recent modeling exercises indicated the magnitude of reports. losses that unchecked AMR will inflict on the Our studies are by no means a comprehensive global economy from 2017 to 2050. Over against treatment of the topics of AMR surveillance, use these threatened losses, we calculated the of antimicrobials in human health care, and use of approximate level of investment required for global antimicrobials in animals. Many important issues AMR containment. Comparing costs and benefits fall outside the scope of our field studies and of this confirmed that controlling AMR, even partially, will part.1 With their recognized limitations, we believe yield exceptional economic rewards. Bold action these original studies nonetheless contribute to on AMR is justified on purely economic grounds, a practical knowledge base countries can use to independent of the ethical and humanitarian advance swiftly in AMR control. arguments that are often in the forefront when the topic is discussed. Ethical perspectives are essential, but for many policy makers they may fail to clarify how AMR is different from other concerns that A. Laboratory-Based compete for attention and funds. AMR Surveillance Our earlier discussion also sketched the broad We now turn to the first of our specific topics. Earlier outlines of containment strategies that countries may parts of this report argued that AMR surveillance is elect to implement, in line with the Global Action an indispensable component of the response to a Plan on AMR. In this part, we will focus on three rising tide of antibiotic resistance worldwide. WHO specific domains of country AMR strategies. While recommends surveillance as part of every national individual countries’ approaches to tackling AMR will AMR action plan. Here, we will discuss the status differ in many respects, all effective strategies will of AMR surveillance globally, the expected benefits involve these three features: (a) laboratory-based and costs of AMR surveillance, the components of AMR surveillance; (b) measures to improve the use surveillance networks, and the main findings from of antimicrobial drugs in human health care; and a capacity assessment of laboratories supported (c) measures to rationalize the use of antimicrobials under the World Bank-funded East Africa Public and contain AMR in livestock production. Health Laboratory Networking Project (EAPHLN). The Our discussion of these topics is based on three assessment sought to document these laboratories’ original research studies commissioned for this readiness to participate in national and, ultimately, report. Each study aimed to: summarize the state regional AMR surveillance.2 of knowledge in its assigned field; identify key data gaps; report and analyze the results of original case studies in selected countries and/or regions; Status of Global AMR Surveillance and offer evidence-based recommendations that In some regions, strong networks exist to track AMR technical experts and policy makers may consider in among a broad set of pathogens, but there are major formulating and implementing national AMR plans. gaps in coverage (Figure 12). Currently, Europe and The complete final reports for all three commissioned the Americas have the best surveillance coverage studies are included as annexes in this report and Sub-Saharan Africa and South and Southeast (Annexes 8, 9, 10). Readers with special interest in Asia the least developed. Creating comprehensive, the respective technical areas are encouraged to effective surveillance systems is more challenging consult these annexes. Each represents a substantive in low- and middle-income countries due to weak contribution to its field. In this part, we briefly laboratory and communications infrastructure; lack of summarize the main findings and recommendations trained laboratory and clinical personnel; and higher from the three special studies. At the end of the prevalence of counterfeit and substandard antibiotics part, drawing on our special studies and other recent and diagnostics (Dar et al. 2016; Opintan et al. research, we present selected recommendations 2015). Directions for Country Action  ■  39 FIGURE 12.  Global AMR Surveillance Networks Benefits and Costs National Public Health Laboratory (NPHL) and eight of AMR Surveillance county or satellite laboratories. The broad benefits of AMR surveillance include Annex 5 outlines the incremental costs—beyond improved availability of data and information on levels the laboratories’ general operating budgets—to and patterns of resistance, and the opportunity to start and operate an AMR surveillance network in introduce evidence-based policies and interventions, Kenya. Expenses include additional personnel to which in turn contribute to reduced disease burden, analyze data and consult on surveillance; training lower treatment costs, and reduced mortality. and strategic planning related to data collection and management; and equipment and supplies. The The cost of AMR surveillance per se will be a Kenyan team estimates that roughly $2.0 million relatively modest add-on to existing laboratory costs, are required to perform antimicrobial susceptibility when built on an established national network of testing at the NPHL and satellite laboratories, well-functioning clinical laboratories. The routine with the bulk representing running costs (see testing carried out by each laboratory forms the raw Annex 6). The $2.0 million are not part of AMR surveillance data. Apart from some additional quality surveillance spending per se, since they fund the control testing, no further laboratory analyses are routine activities that the laboratories must conduct required to support an AMR surveillance network. anyway, regardless of whether they engage in AMR Supplemental costs are largely for information surveillance work. technology, data analysis capacity, personnel time and training, and software. Epidemiologic and general Based on current expenses in Kenya, establishing public-health expertise is also needed to interpret the and running an AMR surveillance network with data for public-policy use. eight county or satellite laboratories will cost about $160,000 annually. Researchers believe that most Currently, Kenya is in the process of constructing low- and middle-income countries aiming to set up a national AMR surveillance network. Kenyan national AMR surveillance networks would initially colleagues have provided the draft implementation plan for a size of operations similar to the proposed plan and associated cost estimates as a reference Kenya network. for this report. Their network will initially include the 40  ■  Drug-Resistant Infections: A Threat to Our Economic Future Components of an AMR data generated by the laboratories for effective Surveillance Network surveillance and response. This involves functions such as data management with specific software In general terms, how does a national AMR packages (including equipment and training), as well surveillance network actually operate, and what as centralized data analysis. components does it need to include? A laboratory-based AMR surveillance network is East Africa Public Health a partnership between clinicians, microbiology laboratories, and a central organizing body. Clinicians Laboratory Networking Project working in hospitals and other health facilities collect The East Africa Public Health Laboratory Networking and send samples to clinical laboratories. In the Project (EAPHLN) offers an example of a regional laboratory, technicians culture the specimens, identify laboratory network that may soon be able to support bacterial isolates, and test isolates for antimicrobial AMR surveillance capabilities. The EAPHLN project susceptibility. Antimicrobial susceptibility testing was launched to tackle the historical neglect (AST) results are then transmitted back to clinicians, of public-health laboratories in the region. The who use them in developing informed treatment $128.66 million project, approved by the World plans for individual patients. Simultaneously, these Bank in May 2010 with a recent extension to 2020, same test results and the patient demographic is establishing a network of efficient, high quality, information form the basis of laboratory-based AMR accessible public-health laboratories in the East surveillance (Blomberg et al. 2004). African Community (EAC) member states (Burundi, Kenya, Rwanda, Tanzania, and Uganda). The project Surveillance data from laboratories can be is: (a) strengthening diagnostic and surveillance aggregated for analysis on the local, national, and capacity; (b) expanding training and capacity regional levels to identify resistance levels and building; and (c) supporting operational research. trends. Data from multiple surveillance networks can also be combined to facilitate research, visualization, The EAPHLN project has supported 32 laboratories in and mapping of global trends in resistance. the participating countries in both capital cities and cross-border areas to become centers of excellence Critical components of laboratory-based AMR and increase access to laboratory services for poor surveillance networks include capacity and and vulnerable populations (Figure 13). To date, the proficiency for antibiotic susceptibility testing in project’s main achievements include: the laboratories; infrastructure; instrumentation; availability of consumables; quality control measures; ❉❉ State-of-the-art laboratories: Renovated/ and the availability and skill level of personnel. In constructed public-health laboratories; rolled out addition to the components of the network itself, molecular technologies, including for diagnosis countries need to have the capacity to actually use FIGURE 13.  Location of Satellite Laboratories Directions for Country Action  ■  41 of drug-resistant tuberculosis, resulting in more Kenya, an EAPHLN country, is in the process of rapid and accurate results. establishing its own national AMR surveillance system. Such systems are increasingly within ❉❉ Regional specialization: Supported Uganda the technical and financial reach of low- and National Tuberculosis Reference Laboratory middle-income countries. Kenya is sharing full to be certified internationally and qualify as documentation on its experience, so that other a WHO Supranational Reference Laboratory, countries can learn from the process. signing agreements with 20 countries to provide specialized services. While Kenya’s efforts are encouraging for all countries, it is clear that the creation of a laboratory- ❉❉ Skilled human resources: Trained over 10,000 based AMR surveillance system faces substantial health personnel in both short- and long-term technical challenges in every setting, and particularly courses; provided mentorship; recruited qualified where capacities and resources have historically personnel; and established an e-learning been limited. The study reports that one of the major platform. stumbling blocks to AMR surveillance in the EAPHLN ❉❉ Technical and managerial innovations: network countries concerns the specific issue of Introduced (a) joint annual peer audits, whereby microbiology laboratory capacity. In these countries’ countries assess each other’s laboratories; laboratories, bacteriology capacity lags behind other (b) performance-based financing, whereby services, a pattern likely repeated in other low- and facilities receive incentive payments based on middle-income settings. progress towards accreditation; and (c) cross- Three key factors appear to contribute to the border disease surveillance, simulations, and weakness in microbiology capacity within EAPHLN. investigations that have enabled swift responses The first is a lack of demand for microbiology-driven to Ebola and Marburg outbreaks. services from frontline clinicians, related to the length ❉❉ Operational research studies: Conducted of time needed to get results (at least two days); lack multi-country studies, including a study on of trust in results; and lack of laboratory capacity for drug resistance patterns to newly prescribed blood cultures, which are needed for many of the antibiotics to deal with key bacterial enteric most serious, life-threatening infections in the clinical pathogens, which found high levels of drug setting. resistance at project-supported facilities. The second factor concerns weak supply chains Building on these initial achievements, and a strong and frequent stock-outs, which constitute a major track record of collaboration, stakeholders in East roadblock to routine antimicrobial susceptibility Africa have come together to explore the feasibility testing. Stock-outs disproportionately affect bacterial of using the project-supported facilities to introduce culture and antimicrobial susceptibility testing, which laboratory-based surveillance of antimicrobial require that all essential components be immediately resistance. available when testing is needed. A third key challenge is some administrators’ failure Findings from the EAPHLN to recognize that microbiology requires dedicated, Network Case Study and trained personnel, leading some facilities and/or ministries of health to rotate staff too frequently. Capacity Assessment Addressing these obstacles will be imperative, A case study and capacity assessment of the as EAPHLN countries move forward to implement EAPHLN were recently conducted by the Center for national and regional laboratory-based AMR Disease Dynamics, Economics & Policy. The learning surveillance. The specific policy and implementation from this exercise will be useful to EAPHLN countries recommendations derived from EAPHLN case themselves, as they continue to work towards study findings are incorporated in the list of establishing functional laboratory-based AMR recommendations for country action at the end of surveillance systems, and for other low- and middle- this part. income countries that want to develop their own AMR surveillance capacities. Here, we have briefly summarized some of the study’s main descriptive and analytic results. 42  ■  Drug-Resistant Infections: A Threat to Our Economic Future B. Antimicrobial Use in the market prevalence of fixed-dose combinations medications (FDCs) containing an antimicrobial Human Health Care and AMR agent. These drugs often create confusion among prescribers and patients and increase the risk of We now take up a second issue of central importance involuntary exposure to antimicrobials. for countries planning practical action on AMR. This The study found significant differences in the six concerns the use of antimicrobial medications in countries regarding the type and number of available human health care. This is the topic of the second antimicrobials. For example, Peru and Botswana major background study commissioned for this have almost twice as many different antimicrobials report.3 on the market as Georgia, Nicaragua, or Croatia. The To generate new evidence on this issue, our variability is explained in part by the high number researchers conducted a literature review and five of bio-equivalent drugs offered as different brand field studies. The case studies were carried out in name drugs containing the same active ingredient six low- and middle-income countries (Botswana, (Figure 14), and also by the multiplicity of “me-too” Croatia, Georgia, Ghana, Nicaragua, and Peru) from or redundant medicines. November 2015 to April 2016. The aim in each case The proportion of brand names per individual was to identify factors in the health system that may antimicrobial varied significantly among countries, contribute to AMR, along with possible interventions being lower in Croatia (3:1) and higher in Peru to promote more prudent use of antimicrobial agents. (7:1). A plethora of products with the same active Here, we briefly summarize the results of the five ingredient causes confusion among prescribers and case studies. Action recommendations based on the users, complicates therapeutic decision making, findings are reflected at the end of this part. and gives more scope to misleading pharmaceutical promotion. There can be little clinical justification for having 27 products containing ceftriaxone in Georgia Case Study 1—Antibiotic or 23 containing levofloxacin in Peru. Market Offer The first study reviewed the antimicrobials authorized Case Study 2—Antibiotic by the ministry of health or equivalent agency in Consumption in the Public the participating countries to analyze drug approval, offers, and marketing processes. Objectives included Health System documenting the presence of antimicrobials that do The second study reviewed expenditure data in the not have proven superiority over already marketed public health system to analyze prescription and products—sometimes referred to as “me-too drugs.” consumption processes at the national level. The market presence of such drugs tends to raise the cost of medicines and increase providers’ and The most-consumed antimicrobials differ among patients’ exposure to promotional messaging that countries. In Botswana, Ghana, and Nicaragua, four may spur irrational behavior and ultimately contribute to six different antimicrobials represented 90 percent to AMR. Researchers were also concerned to assess of the total consumed units, while in Peru and FIGURE 14.  Top Five Active Ingredients According to Number of Brand Names Country 1st (n) 2nd (n) 3rd (n) 4th (n) 5th (n) Botswana Amoxicillin (18) Metronidazole (17) Erythromycin (16) Gentamycin (11) Ciprofloxacin (11) Croatia Cefuroxime (14) Azithromycin (10) Ciprofloxacin (9) Moxifloxacin (9) Metronidazole (8) Georgia Ceftriaxone (27) Azithromycin (27) Chloramphenicol (15) Amoxicillin (13) Amikacin (10) Ghana Ciprofloxacin (38) Cefuroxime (31) Ceftriaxone (26) Azithromycin (23) Metronidazole (22) Nicaragua Ciprofloxacin (33) Azithromycin (18) Metronidazole (16) Amoxicillin (14) Clarithromycin (13) Peru Ciprofloxacin (69) Azithromycin (43) Amoxicillin (32) Clarithromycin (28) Levofloxacin (23) Directions for Country Action  ■  43 Georgia, the same share of total consumed units was for example, the pharmacist did not ask the patient divided across 15 and 19 different antimicrobials, about drug allergies. Such negligence can place respectively. This finding suggests that in the first set patients at severe risk of developing drug-related of countries the public prescription of antimicrobials complications. may be more tightly controlled (either by restricted The pattern of antimicrobial recommendations by drug lists or better adherence to drug guidelines). pharmacists in the different countries reflected Significantly, the list of the most-consumed the prevailing pharmaceutical market offer in antimicrobials in each country was dominated by each country. For example, irrational fixed-dose antimicrobials that are sold under multiple different combinations with phenazopyridine were common brand names. in Peru and Nicaragua. Also, a relationship was observed between some “redundant” products and high sales (for example, cefuroxime with 31 brand Case Study 3—Antimicrobial names in Ghana accounted for 25 percent of sales). Availability without Prescription Researchers aimed to document dispensation Case Study 4—Hospital-Acquired and advice provided to self-referred patients by pharmacists in the six countries. To explore this Infections (HAIs) issue, in each country, a young woman simulating Researchers reviewed medical records or information lower urinary-tract infection symptoms visited provided by health care professionals on patients 20–50 pharmacies. with HAIs to analyze adherence to guidelines, compliance with prophylactic measures, prescription, The study is key, because pharmacists are the first and health care quality-assurance processes. point of contact with the health care system in many countries, and their dispensing practices for self- Health personnel identified a number of factors referred patients often determine how antimicrobials that appeared to contribute to HAIs. These included are actually used. In many low- and middle-income structural deficiencies, such as lack of safe water countries, pharmacists are the de facto prescribers of and basic sanitation systems, and operational most drugs. problems, such as overcrowded wards, lack of cleaning supplies and protective equipment, or poor In more than 60 percent of pharmacy visits by hand hygiene. Adherence to Infection Prevention the study’s simulated patient, antimicrobials were and Control (IPC) protocols was partial overall, and dispensed without a prescription derived from sometimes poor. These findings underscore the need appropriate clinical diagnosis. This pattern was highly to address both structural factors and health care prevalent in five out of six countries, with Croatia as a processes in efforts to reduce the spread of HAIs and notable exception (only one dispensation in 20 visits). resistant microorganisms. (See Figure 15.) In more than 90 percent of the visits, the simulated self-referred patient was not clinically evaluated: FIGURE 15.  Distribution of “Simulated Self-Referred Patient” Visits That Ended with Dispensation of an Antimicrobial, by Country 100% 80% 60% No 40% Yes 20% 0% BWA CRO GEO GH NIC PE 44  ■  Drug-Resistant Infections: A Threat to Our Economic Future Case Study 5—Multidrug-Resistant guidance. Indications for use, type, and dosage of Tuberculosis antimicrobials are issued by the College of General Practitioners (NHG), and these guidelines are To analyze factors influencing patients’ compliance increasingly followed. The Dutch experience also with treatment regimens, a review of the medical reflects a deliberate policy and operational decision records of MDR-TB patients was conducted in one to prioritize AMR control through sustained action on or more hospitals in each country. “Non-adherence hospital infections. to treatment” was frequently noted in these patients’ records. Specific causes of withdrawal The effective application of this array of measures from treatment varied. For example, in Botswana, has helped the Netherlands achieve one of the lowest patients’ inability to tolerate the prescribed medicines levels of AMR in the world. A comprehensive national reportedly contributed to abandoning therapy in three effort to reduce antimicrobial mis- and overuse and out of ten cases. Findings from Peru also highlighted contain AMR can succeed. nonmedical drivers of noncompliance. Some patients quit therapy because they lived far from treatment facilities and could not afford the out-of-pocket C. Antimicrobial Use transportation costs. in Animals and AMR Countries Can Win the Battle We have just noted once again the importance for AMR containment of close collaboration between By providing new country-level data on antimicrobial human and veterinary health systems. Without use in human health, our study has underscored progress in tracking and controlling drug-resistant the complexities involved in attempting to contain infection sources in animal populations, efforts to AMR. However, some countries have already begun contain AMR in human communities cannot achieve to confront antimicrobial-stewardship challenges lasting success. This section summarizes the results systematically, with impressive results. of a study commissioned for this report to document The responsibility for promoting rational use of the use of antimicrobials in livestock and explore antimicrobials clearly includes policy makers, relevant policy strategies to combat AMR.4 pharmaceutical companies, health system The study included a literature review, country case administrators, and health care providers. But studies, and a regional case study. Here, drawing on responsibility for protecting the efficacy of these those inputs, we briefly outline the current state of crucial agents must also be shared by patients knowledge on antimicrobial use in livestock. Then we themselves and the wider public. A society-wide analyze the mechanisms by which antimicrobial use effort is required. in animal production systems may engender AMR In countries where such an inclusive effort has in animals and humans. Finally, we review current been undertaken, remarkable gains have been strategies to reduce antimicrobial use in livestock achieved. A recent study of the experience in the and discuss the obstacles these efforts face. Specific Netherlands (Sheldon 2016) has confirmed that it policy options for low- and middle-income countries is possible to reduce AMR to low levels across a are presented in the final section of this part. national population. According to the study, success is determined by many of the factors we have discussed in this report: for example, coordination Use of Antimicrobials in Animal between the health and agricultural sectors, Production: Background working together under a One-Health approach. Antimicrobials are used to treat clinical and Authorities have also deliberately worked to change subclinical infectious diseases in animals. In some the medical culture and public perceptions around livestock production systems, they are also used to antimicrobials. As a result, the study finds, Dutch prevent diseases, either because of an increased primary care doctors are consistently parsimonious risk of exposure (metaphylactic treatment) or as in prescribing antimicrobials, and Dutch patients part of routine health management. In addition to do not routinely demand them, reflecting a shared these therapeutic uses, antimicrobials may be used culture of “cautious prescribing” built up over as animal growth promoters, based on continuous time. Part of creating this culture has been general delivery of subtherapeutic doses. practitioners’ acceptance of strict professional Directions for Country Action  ■  45 Estimates of total global antibiotic consumption in waste may contain resistant bacteria, and could also livestock vary widely, from around 63,000 to over contain antibiotics that may foster the emergence of 240,000 metric tons per year. With growing human AMR in microbes living outside animals’ bodies— populations and increasing demands for food, including bacteria that may pose a greater risk to the quantities of antimicrobials used in livestock humans. production are expected to rise steadily. Global consumption of antibiotics in agriculture is expected to increase by 67 percent from 2010 to 2030. Measures to Reduce Antimicrobial Consumption in five major emerging economies— Usage and Find Alternatives Brazil, China, India, Russia, and South Africa—could Some countries have already banned the use of grow by 99 percent in the same period. antibiotics for growth promotion. Banning this use A number of medically important antibiotics are in livestock has generally resulted in a substantial administered to animals in agriculture via feed or decrease in antibiotic resistance. Some countries water. Out of the 27 different antimicrobial classes have also enacted policies to limit the therapeutic use used as growth promoters in livestock, only nine of antibiotics in livestock, with subsequent impact on classes are exclusively used in animals. Even some AMR incidence. second-line antibiotics for humans are being used in Some argue that the sudden withdrawal of antibiotics animals. as growth promoters in lower middle-income countries would have major negative consequences. Concerns in Low- and Middle- However, European countries were able to impose a ban on the use of growth promoters without Income Countries excessive, long-term negative impact on productivity, In most low- and middle-income countries, veterinary profitability, animal health, or welfare. antimicrobials, including antibiotics, are sold over One response to AMR in animal production systems the counter without veterinary prescription. There are may be the development of new, alternative essentially no controls on the use of these agents. treatments that might partially replace antimicrobials. Most data sources do not specify whether antibiotics An overview of the current state of research in this are used for growth promotion rather than treatment area is included in Annex 10. At present, however, or prevention of diseases. As a result, it is difficult to there is still a considerable efficacy gap between track antimicrobial use, not only as regards quantities antibiotics and any proposed new alternatives (Cheng and classes, but also the species in which the drugs et al. 2014). We found no studies that assess the are used and the specific purposes of use. cost-effectiveness of such alternative interventions. Several studies suggest that AMR is already common in agricultural systems in low- and middle-income countries. Knowledge Gaps Revealed by Country Case Studies AMR Transmission Pathways Our country case studies were conducted in four countries, ranging in per capita GDP from Resistant bacteria and genetic material conferring approximately $700 to $14,500 ($1700 to resistance in bacteria can be transmitted from $22,000 PPP). animals to humans in multiple ways. Mainly this transfer occurs through the food chain, from close The main finding of the country case studies was or direct contact with animals, and through the a serious deficiency in data required to undertake environment. Whether all three routes of transmission economic analysis of antimicrobial use, AMR impacts, are equally important remains unclear. To date, and the costs and benefits of alternative approaches. public-health measures have tended to focus on In all countries, obtaining data on antimicrobial the food system to ensure that food consumers are manufacture, import/export, and usage was difficult. protected. It was also problematic to achieve standardization and comparability among data that were available. Transmission pathways other than food may be significant, however. A proportion of antibiotics used Country surveillance systems for AMR were poorly in food animals are excreted unmetabolized and developed. There was no surveillance activity at enter sewage systems and water sources. Animal all in the lowest-income country. It was striking 46  ■  Drug-Resistant Infections: A Threat to Our Economic Future that even countries that collect some AMR data in D. Recommendations animal production settings were not willing to share the information, due perhaps to the concern that for Country Action disclosure of worrisome AMR data might compromise export opportunities. While global development institutions, NGOs, private Given the extreme paucity of data now available, firms, and other partners will have important roles countries should be supported to establish the in containing AMR, countries will lead the fight, and building blocks for future analyses as a matter their engagement will determine its success. We now of urgency. The most basic requirement would summarize the key recommendations for country be standardized data collection on the use of AMR action that emerge from our special studies and antimicrobials and AMR. In this light, OIE’s current related analyses. effort to progressively develop a worldwide system The Global Action Plan on AMR, developed by WHO for data collection on antimicrobial use in animals in collaboration with OIE and FAO, has established a merits the strongest support. durable, comprehensive framework for policy making and program implementation in the AMR fight (WHO 2015a). Our recommendations reflect the Global Conclusions Action Plan’s conceptual structure and key objectives. Our research on antimicrobial use in livestock yields Building on the Global Action Plan, several recent the following conclusions: landmark reports have provided additional expert ❉❉ Improved estimates of the use of guidance on national policies and implementation antimicrobials in animals are needed. This approaches to tackle AMR. These publications include could be delivered by the OIE data collection ambitious global strategies from OIE (2016) and FAO system in the future, and must be combined with (2016), along with the background studies and final an appropriate description of livestock production report from the U.K. Review on AMR, among others systems at country levels. These data are (Review on Antimicrobial Resistance 2016).5 These critical for AMR containment, which can only be documents have presented action agendas spanning undertaken with confidence if the estimates are multiple dimensions of the AMR fight. adequate. This could be achieved by collaborative These contributions make it unnecessary for us to efforts to improve the World Animal Health “reinvent the wheel” here. For readers seeking a Information System (WAHIS) at OIE and FAO complete inventory of relevant policy domains and Statistics (FAOSTAT) at FAO. strategies, we suggest directly consulting these ❉❉ Major knowledge gaps must be addressed. excellent sources. Here, we will concentrate on There are major difficulties in low- and middle- selected issues, where the World Bank’s expertise income countries in monitoring antimicrobial enables us to present ideas that may advance and use and residues and in implementing AMR clarify options for country action, beyond what has surveillance. A robust knowledge base would already been exhaustively discussed elsewhere. also encompass multi-method data and analysis To implement the Global Action Plan and in particular on institutional environments and stakeholder to understand how it will be financed, it is useful behavior. to analyze policy options through a sectoral lens. ❉❉ Economic arguments can demonstrate Critical to effective implementation will be mobilizing the benefits of strengthening human and AMR finance in a way that recognizes and draws on veterinary public-health systems. There existing resources in different development sectors is a critical need to reinforce these systems, to support and expand AMR-sensitive interventions. and to do so will require the engagement of Accordingly, our recommendations for country AMR governments, private companies, and individuals action are structured by sector, including: (a) health; involved in livestock production. All these actors (b) agriculture; and (c) water, sanitation, and hygiene. are likely to be sensitive to economic arguments. Clarifying the economic case may help change attitudes and behaviors around the use of antimicrobials among key stakeholders. Directions for Country Action  ■  47 Driving AMR Progress infections. It will also promote better systems from the Health Sector for the appropriate production, purchase, and prescription of antimicrobials. Pooled, The health sector offers numerous entry points for prepayment financing encourages rational AMR control policies. Our recommendations focus purchasing and prescription, supporting the on four select topics: (1) universal health coverage optimization of antimicrobial use and protecting reforms as an enabling platform; (2) harnessing the efficacy of current drugs. the International Health Regulations to accelerate AMR action; (3) strengthening laboratory-based ❉❉ Better information. UHC generally enables surveillance, including through regional networks; improved data collection and management within and (4) the promise of the Global Antimicrobial the health system: at the population, facility, Surveillance System (GLASS). and individual provider levels. By strengthening data systems, UHC approaches may better equip 1. Universal health coverage (UHC) provides them to support AMR surveillance, monitoring, the best enabling framework to tackle AMR. and response. By giving all people access to the Today, a large number of countries are undertaking health system, UHC also helps health authorities UHC reforms, and UHC occupies a prominent place in build a more comprehensive knowledge base on the Sustainable Development Goals. The UHC agenda health patterns and trends across the population, offers a launching platform to accelerate AMR action which can inform efforts against AMR. All these through multiple AMR-sensitive and some AMR- features support the Global Action Plan objective specific measures. UHC models are diverse, but UHC to strengthen AMR knowledge and the evidence efforts will generally strengthen AMR containment base. through the following mechanisms: ❉❉ Improved stewardship and governance. A robust ❉❉ Expanded coverage. By definition, UHC designs UHC approach builds systems-governance and lead to greater breadth and depth in the coordination capacities that are critical for the population coverage of health services. This AMR fight. Under a UHC model, governments can includes services like vaccination, preventative make better informed, more deliberate decisions care, and hygiene measures that lower the need about health investments, including in areas for antimicrobials and thus slow the spread such as vaccination and infection prevention of AMR. Covering the whole population with and control (IPC), that have direct implications vaccinations shows one potent way UHC will for antimicrobial use levels and AMR. Moreover, reduce the incidence of infections, advancing a under UHC models, regulatory capacities tend key objective of the Global Action Plan on AMR. to be enhanced. Health facility accreditation ❉❉ Better oversight and quality of care. UHC models provides just one example. Requirements for improve oversight in care practice. Among other improved antimicrobial stewardship can be benefits, this helps ensure that antimicrobial built into accreditation processes for hospitals use conforms to rational standards. UHC and other care delivery sites to bolster AMR strengthens antibiotic stewardship in health control at the facility level. AMR training can facilities, reinforces the use of standard treatment be incorporated into the preservice and in- protocols for infections, and can improve service education of health providers, advancing procurement, quality control, and other features the Global Action Plan objective to improve of antimicrobial management—with the potential awareness and understanding of AMR. for major gains against AMR. These UHC features With UHC, countries can strengthen AMR support another of the five Global Action Plan containment and expand access to needed objectives: optimizing current antimicrobial use. antimicrobial treatments at the same time. Leaders With UHC, opportunities exist for substantial from G77 nations and other countries, along with improvements in the control of major global civil society voices, have argued that concerns about diseases exacerbated by AMR, including HIV/ AMR must not be allowed to further obstruct poor AIDS, TB, and malaria. and vulnerable populations’ access to lifesaving ❉❉ Smarter, fairer financing. The expansion of medicines. health systems towards UHC promises more AMR containment is compatible with expanded efficient and equitable financing. This will access to appropriate antibiotics and other help close existing access gaps for treatable antimicrobial therapies for populations that have 48  ■  Drug-Resistant Infections: A Threat to Our Economic Future historically been excluded. UHC strategies promote building and AMR action in settings where systems rational, regulated access to antimicrobials for are weak. all patients under the guidance of trained health 3. Countries at all levels of income can build professionals. Thus, UHC provides a framework for laboratory capacities for AMR surveillance— simultaneously expanding the well-regulated use and create synergistic regional laboratory of antimicrobials where they have been lacking, networks. Strengthening AMR surveillance and tackling the overuse and misuse that have capacities, including in low- and middle-income accelerated AMR in other settings. countries, is a cornerstone of AMR control, captured 2. Implementation of the International Health in the first objective of the Global Action Plan. Regulations (IHR) can accelerate AMR action Countries can accelerate the development of and focus global support. Under the IHR, 196 their domestic laboratory-based AMR surveillance countries have committed to work together to capacities by participating in regional laboratory prevent, detect, report, and manage public health networks. emergencies, such as infectious outbreaks. To Our study of regional laboratory collaboration in East meet their IHR implementation requirements, many Africa suggests that the creation of a national AMR countries are participating in systems-diagnostic and surveillance network is becoming technically feasible planning exercises, for example through the WHO and affordable for an increasing number of low- and Joint External Evaluation (JEE) process, under the middle-income countries. Kenya, a member of the Global Health Security Agenda (GHSA). International EAPHLN consortium, expects to operate its national collaboration on the IHR acknowledges countries’ AMR surveillance network at an added annual cost profound interdependence in the face of infectious of approximately $160,000. (These are new costs for threats and other health emergencies that transcend AMR-related activities, beyond the basic expenses borders, including AMR. involved in providing clinical laboratory services for Systems evaluation exercises provide opportunities patient care.) Many countries will want to consider for countries to assess their capacities and needs in such an investment in health security for their people. areas like infectious-disease and AMR surveillance. The East Africa study also showed the benefits that Through self-assessment and evaluation by external can accrue when countries link their laboratory experts, countries diagnose system shortfalls and resources into a regional network structure. develop plans for strengthening capacity. Among Numerous synergies may emerge, even or perhaps other benefits, such efforts help lay foundations especially when countries create a regional for the AMR Global Action Plan’s five objectives, collaborative structure early in the development of especially the first, strengthening knowledge and the their national laboratory systems. AMR evidence base. In the case of the EAPHLN network, evaluators In order for these exercises to achieve full impact, it found that the regional structure has promoted is important that each country designate institutions and disseminated innovations in service delivery, and individuals who will be accountable for following facilitated knowledge sharing among participating up on the evaluation results. The designated countries, and helped foster an evidence-based actors will define and lead a process to translate approach. Each member country takes the lead recommendations from the assessment into in a specific thematic area and provides regional methodical action to build national surveillance and leadership, generating knowledge and then response capacity. Global partners, including the disseminating experiences and lessons to partners. Tripartite agencies and the World Bank, will work with As described above, the network has promoted countries to design technically and politically realistic specific scientific and management innovations, follow-up processes with clear lines of responsibility. including: (a) joint annual peer audits, in which Because each country’s implementation of IHR countries assess each other’s laboratories; commitments benefits all other countries by (b) performance based financing, whereby improving detection and response to transborder facilities receive incentive payments based on threats, the international community has an interest progress against formal, internationally recognized in adequately financing this global good. Wealthy accreditation standards; and (c) cross-border disease countries’ stake in the success of the IHR may be surveillance, simulations, and investigations that have leveraged to bolster financing for country capacity fostered regional public-health collaboration and Directions for Country Action  ■  49 enabled an effective response to recent infectious They would increase understanding of real-world outbreaks in the region. practice in antimicrobial use and facilitate the design of pragmatic interventions. The EAPHLN experiences suggest that early participation in a regional structure can accelerate Information, educational, and communications the development of each country’s laboratory campaigns addressed to both health services capacities and lay the groundwork for future cross- personnel and the general population are another border cooperation in AMR surveillance. key strategy to improve understanding of the AMR challenge and rationalize antimicrobial use. Such Questions persist about how to finance regional campaigns should incorporate behavioral and social surveillance in the long run. The value of regional aspects. disease surveillance networks is indisputable. However, countries and partners are still seeking Finally, countries should look to accelerate their optimal financing models that would engage, for transition to electronic recording of antimicrobial example, reliable national co-financing of these consumption data, and to electronic medical records. regional structures. In addition to their other benefits, these tools will facilitate action on AMR. 4. The Global Antimicrobial Surveillance System (GLASS) holds transformative potential. Governance, regulation, enforcement: A range of If regional laboratory networks are powerful, global regulatory and governance strategies are available to knowledge sharing and collaboration may be countries to counter AMR. For example, a separate even more so. WHO’s leadership in launching the legal and regulatory framework and payment/ GLASS is a key advance in the global AMR fight. reimbursement modalities could be considered As countries develop national surveillance systems, to promote appropriate use of antimicrobials. many will seek participation in the GLASS in order to Such special arrangements already exist in the benefit maximally from added WHO support for AMR pharmaceutical sector for opioids. Whether or not surveillance efforts. this approach is favored, some countries may want to develop new legislation and regulations or revise Meanwhile, it is critical that member governments and update existing rules governing antimicrobial and donors support WHO’s efforts in creating and distribution and use. This could include developing managing the network, along with OIE’s related enforcement capacity to limit or eliminate perverse work to build a global database on the use of financial incentives that prompt individual providers antimicrobials in animals. and institutions to use antimicrobials indiscriminately. Countries may act to strengthen political oversight Options for Specific Actions of the antimicrobial market offer and dispensing Our commissioned study on antimicrobial practices. Two areas where priority adoption of management in human health has generated oversight measures is likely to yield immediate additional specific recommendations for country benefits are: (a) limiting the market offer of fixed- action in major functional areas of the health system. dose combinations and (b) setting limits on the marketing of a single antimicrobial agent under Health information and knowledge sharing: multiple brand names. Progress in these two A systematic effort to collect data and generate areas will help prevent confusion among providers, evidence on antimicrobial use practices is required patients, and payers; improve therapeutic options and at the country level, to inform strategic action. health outcomes; and reduce AMR. Countries can harness a number of proven tools. For example, drug-utilization studies (DUS) can Harm reduction from nonprescription sales of help identify failures in any link of the therapeutic antimicrobials is another priority area for action. chain. Designing and implementing DUS with the In almost all of the countries studied by our participation of frontline health professionals can researchers, it was easy for simulated patients identify antimicrobial management problems and to obtain antimicrobials in pharmacies without a contextually appropriate solutions in local settings. prescription. Training pharmacists on the risks of inappropriate dispensation while strictly enforcing At a higher level, countries may also consider regulations—including through fines and legal the creation of national, regional, and/or global consequences—may help limit harm caused by the observatories of grey literature and local studies. inappropriate sale and use of antimicrobials. These resources would fill a crucial knowledge gap. 50  ■  Drug-Resistant Infections: A Threat to Our Economic Future On this point, our recommendations rejoin those of that antibiotic use for growth promotion should be the U.K. Review on AMR, which urged the adoption phased out worldwide, as has already been achieved in all countries of robust regulations to prevent in a number of countries (Wellcome Trust 2016). the over-the-counter sale of antibiotics and other European Union countries have banned the use of antimicrobials. The U.K. authors rightly stress that antimicrobials as growth promoters since 2006. such policies need to be locally tailored to recognize Countries’ specific contexts and constraints must instances where over-the-counter sales may be some be taken into account in designing plans and people’s only means of accessing antimicrobials. establishing timelines. Countries that currently rely Where this is the case, strengthening the formal heavily on the use of antibiotic growth-promoters health system to promote proper, clinician-led access may require more time and support to adapt their is the long-term answer (Review on Antimicrobial production regimes. Some low-income countries may Resistance 2016). Once again, we see the utility of benefit from extensive technical support. framing AMR action at the country level in terms of UHC. Experts including the authors of the U.K. Review on AMR have recommended the use of national Proven optimization strategies: High-level numerical targets to drive reductions in the excess political leadership can help generalize the use of antibiotics in agriculture. The U.K. Review application in hospitals and other health facilities of authors propose 10-year targets, formulated in tools that we know work to get the best mileage out terms of total agricultural antibiotic use. They argue of existing antimicrobials, while protecting reserve that, with the support of a global body of experts, medications for second-line use. most countries might be able to set targets as Antimicrobial Stewardship Programs (ASPs) have soon as 2018. Targets and milestones would be proven efficacy in controlling AMR by improving defined consistent with countries’ economic and how antimicrobials are used in daily practice. These technical capacities. Interim milestones would be programs are especially effective in cutting down the set to encourage progress on the way to the 10-year unnecessary use of broad-spectrum antimicrobials in goal. U.K. Review researchers have explored how health care facilities—a powerful driver of resistance. governments might use regulation, taxation, and The adoption of ASPs should be vigorously promoted, subsidies for alternatives to lower antibiotic use. including in nonhospital health facilities. Many governments may choose to combine all three (Review on Antimicrobial Resistance 2016). Agriculture: A Critical We support this approach. The use of time-bound, Frontier for AMR quantitative targets can be a powerful motivator. The World Bank Group is prepared to work with The bulk of antimicrobial use in many countries the full range of stakeholders who will be engaged occurs in the agriculture sector, particularly in in defining targets and setting strategies to reach livestock. Worldwide, in 2010, livestock consumed them, including: country governments; the Tripartite at least 63,200 tons of antibiotics and probably agencies; farmers and private industry; civil society far more, substantially exceeding total human organizations; and donors. consumption. Overuse and misuse of antimicrobials in animal production systems are major global drivers Solutions for the livestock sector should foster of AMR. Accordingly, the livestock sector, particularly the adaptability of animal productions systems to in low- and middle-income countries, is a key reduced use of antimicrobials. Recommendations call battleground for AMR containment. for an integrated approach, with cycles of innovation and learning: first, developing policies, setting 1. All countries can progressively reduce targets, and monitoring antimicrobial use in livestock the use of antibiotics in animal production. production; then identifying gaps or problems in Systematic reduction and eventual elimination current production systems and methods to address of antibiotic use for livestock growth promotion them; and finally sharing knowledge on improved is critical for long-term AMR control. This is a management techniques. challenging goal, but it has drawn increasing consensus among scientific experts and many We can protect farmers as antimicrobial practices political leaders. At a 2016 AMR policy summit change. Small farmers may be especially vulnerable convened by the Wellcome Trust, for example, policy as changes to established production methods are makers and scientists from 30 countries agreed introduced. Governments and development partners Directions for Country Action  ■  51 have a fundamental responsibility to accompany under-resourced and fragmented. Clear, evidence- small farmers in adapting their modes of animal based, consensus directions for priority research production. Small farmers’ livelihoods can be have yet to be defined. International coordination preserved, as we act to protect a global public good. and stewardship of AMR knowledge production are urgently needed. In particular, there is a need to Policy action must also take account of global inform and incentivize the global innovation agenda disparities in access to antimicrobials in the to target the points of highest priority and greatest livestock sector, mirroring those in human health. opportunity for the development of new AMR- The same drugs that may be used excessively in management technologies. This would include not livestock production in some parts of the world only the discovery of new antibiotics, but also new remain unavailable in others, where they could have vaccines (both animal and human), the new rapid- legitimate applications and save lives and livelihoods. diagnostics agenda, and policy innovation in areas This creates a dual problem of how to eliminate like compensation or insurance mechanisms for overuse and misuse of antimicrobials while providing farmers who cut antibiotic use. Targeted learning responsible access to those who desperately need and innovation in a broad range of sectors, from them, especially in low-income countries. pharmacology to development finance, must be 2. An urgent effort is needed to strengthen nurtured simultaneously. country surveillance systems for tracking the How might this be done? We can point to promising use of antimicrobials and the spread of AMR precedents: innovative models of collaboration that in animals. A consistent finding from country case have proven effective for other complex, multi- studies commissioned for this report was a deficiency sectorial challenges. Some of these may be adapted in data needed to analyze antimicrobial use in to accelerate learning and action on AMR. livestock, in terms of epidemiology and economic impacts. One example is CGIAR, a global consortium of agricultural research centers supported by an Each country may commit to develop a system for extensive network of partners, including the World collecting standard data on animal populations Bank. For some 50 years, CGIAR has generated and animal production systems in its territory. creative and practice-relevant research on food Without the information such a system can provide, security, rural poverty reduction, and sustainable tracking progress on national targets for antibiotic resource management. Today, to jumpstart new use in agriculture, for example, will be virtually investment in AMR research and technological impossible. Countries should be supported to build innovation, we can learn from CGIAR and other basic data collection systems to track both the use network models. We can picture the emergence of antimicrobials and AMR in animal production. of a networked research center that would be a Countries may also work to develop systems for novel hybrid—pursuing learning and innovation monitoring antimicrobial residues in food originating simultaneously in agriculture, animal health, and from farmed terrestrial and aquatic animals. OIE’s human health. To our knowledge, no such hybrid current effort to develop a worldwide system for data research hub currently exists. However, its feasibility collection on antimicrobial use in animals merits could be explored with existing CGIAR network strong support. centers, other research consortiums, countries, 3. New partnerships can spur innovation donors, and other stakeholders. Through such against AMR across agriculture, the partnership models, countries will tap into networks environmental sciences, and health. Scientists of innovation to multiply the impact of their individual and policy makers increasingly recognize that unified actions against AMR. strategies are needed to tackle the drivers of AMR simultaneously in livestock production, environmental Options for Specific Actions management, and human health. But once we’ve acknowledged the problem, what do we do next? The Within the broad directions just sketched out, proliferation of resistant pathogens is outpacing our our background study has generated a series of knowledge and in particular our capacity to invent specific options on antimicrobial use in livestock that and disseminate solutions. countries may consider. Research on new technologies to fight AMR is Health information and knowledge sharing. slowly gathering momentum. Yet the field remains We’ve noted that each country has an interest in 52  ■  Drug-Resistant Infections: A Threat to Our Economic Future developing a standard data collection system to use. Countries may use resources like the OIE monitor animal populations and livestock production Performance of Veterinary Services (PVS) pathway in its territory. Ultimately, many countries will move to identify gaps and training needs, and create toward the creation of sample collection, testing, and strategies to fill them. data capture systems for national risk-based AMR surveillance in animal production. Water, Sanitation, and Hygiene: Governance, regulation, enforcement. The AMR-Sensitive Development legislative and regulatory sphere offers important levers for country action on antimicrobial use in Priorities livestock. Policy analysts may be tasked to examine The most efficient way to deal with drug-resistant existing legislation and implementation of public infections is to prevent them from happening in and private standards relating to antimicrobials, to the first place. Historically, safe drinking water identify weaknesses in the institutional environment. and sanitation facilities, along with basic hygiene Legislators can then act to strengthen standards practices such as hand washing with soap and along the antimicrobial supply chain concerning water, were decisive in reducing the spread of registration, manufacture, distribution, sales, and use infections, even before modern antimicrobials of these agents, particularly in agricultural contexts. were invented. These tools and practices brought Countries may also act to reinforce legislation and dramatic improvements in the health and productivity implementation applying to animal feed, in particular of human populations. In the age of AMR, such medicated feed. infection-prevention strategies once again take on Optimization strategies. A number of important salience. options are on the table for countries to move The Global Action Plan has incorporated this towards optimizing antimicrobial use in livestock in principle. Reducing the incidence of infections is one the medium and long term. Some of these strategies of the five objectives. Two complementary facets will involve international cooperation in research, of the preventative agenda involve: (1) expanding including implementation science. access to water and sanitation; and (2) universalizing For example, national governments and their basic hygiene practices, particularly in health care technical agencies may undertake applied facilities. research to improve rapid diagnostic methods for 1. Countries can harness the power of water veterinary diseases, which would reduce the use and sanitation investments to check infections, of antimicrobials by establishing the sensitivity of fight AMR, and support economic growth. infectious agents to antimicrobials before treatment Expanding access to sanitation and clean water is starts. Countries with the appropriate research among the most powerful AMR-sensitive investments capacities may also work to develop veterinary available. Improved access to clean water and vaccines and vaccination strategies that will sanitation delivers robust public health benefits in its ultimately reduce reliance on antimicrobials. own right. In addition, by preventing infections and In addition to bench science studies, countries may reducing the need for antibiotics, these measures pursue implementation science research to solve also reduce the pressures that drive antimicrobial the practical challenges of moving new vaccines resistance (Wellcome Trust 2016). The combined and other technologies from the laboratory to health impacts translate into remarkable gains in life actual use in livestock production settings. Tackling expectancy, which imply productivity and economic implementation challenges will involve overcoming gains for countries, as well. As leaders weigh the multiple logistical, economic, technological, and costs and benefits of development investments, it systems-management obstacles, particularly in is important to incorporate public health benefits, resource-constrained settings. As it comes on line, including AMR containment effects, in the expected the hybrid human health-animal health research gains from investing in water and sanitation. center on AMR described above may play a 2. Hygiene in health facilities: simple tools, supportive role. strong impacts. The settings where water, Countries may also choose to invest in strengthening sanitation, and hygiene practices can combine to veterinary education and the role of veterinary powerfully impact AMR include health facilities. professional standards in governing antimicrobial Infection prevention and control (IPC) strategies in health care settings are pillars of the AMR Directions for Country Action  ■  53 containment agenda, recognized in the infection- systems, the use of antimicrobials in the human prevention objective of the Global Action Plan. health sector, and the use of antimicrobials in While infection prevention can be technologically livestock. In each area, we have summarized key sophisticated, its most important ingredients are learning from a background study commissioned simple, beginning with hand washing. for this report. Drawing on our special studies and other sources, we have put forward selected Hand hygiene (hand washing with soap and water or recommendations for country action on AMR. alcohol-based products) has been repeatedly cited as the single most important practice to reduce health Our next and last part will review the major findings care-associated infections. Improved hand hygiene of this report and discuss how the World Bank Group practices have been associated with a sustained will support countries in the AMR fight. decrease in the incidence of AMR infections in health care settings (Rainey and Weinger 2016). This is an area in which relatively simple actions can bring Endnotes powerful results against AMR. The special study on laboratory-based surveillance, for example, 1.  Today, in many settings, and in countries at all sought to analyze how to introduce AMR surveillance into an existing income levels, these basic tools are not being regional public-health laboratory network that is still being developed rigorously applied. Field studies for this report and includes five countries. Extending the analysis to include confirm previous research in finding inconsistent veterinary public-health laboratories was considered, but could not be and often poor observance of hand hygiene and accomplished in the time and with the resources available. Likewise, other basic IPC practices in health facilities in many our investigation of antimicrobial use in human health care is limited to countries. While this is alarming, it also represents the pressing problem of misuse and overuse of antibiotics and does not an opportunity for low-cost, high-yield action against consider other categories of antimicrobials. Finally, our field research on antimicrobial use in livestock did not deal with other agricultural AMR. subsectors, such as crops, that also use antimicrobials, nor did the One of the best ways to prevent a return to the investigators consider companion animals, which have been implicated pre-antibiotic era is to practice hygiene in health as sources of drug-resistant infections in some settings. facilities as if that return had already happened. WHO For a detailed discussion and relevant references, see the full summary 2.  and UNICEF, working with their partners, have set report, Annex 8. 3. The full summary report on this study is presented in Annex 9. out a global agenda for universal access to water, 4. The full summary report is presented in Annex 10. sanitation, and hygiene in health care facilities. Some experts have set out to show in detail how successful AMR- 5.  Leadership and commitment from governments, control practices developed in high-income countries can be adapted international organizations, donors, and civil society by low- and middle-income countries. See for example: https://www can turn the plan into changes in practice and gains .bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/G/ against AMR (Rainey and Weinger 2016). G7/Best-Practices-Broschuere_G7.pdf This part has looked at three domains that will be central to country-led action on AMR: surveillance Part V. Conclusions 56  ■  Drug-Resistant Infections: A Threat to Our Economic Future W e conclude this report by reviewing our key support other countries’ AMR efforts, in addition to arguments and highlighting actions the World strengthening surveillance and response systems Bank Group will take to support countries in within their own borders. All countries will need to the AMR fight. mobilize political will and invest resources. A. The Costs of Inaction C. Action at Country Level This report has attempted to shift the conversation The Global Action Plan on AMR, developed by on drug-resistant infections from health impacts WHO in collaboration with FAO and OIE, provides a on patients and populations to the threat that AMR comprehensive high-level framework for tackling poses to economies. Our main aim has been to put the AMR threat. Taking the Global Action Plan as a a price tag on the damage AMR may inflict on global guiding framework, this report has aimed to deepen economic output in the coming decades. knowledge on select topics that can help countries set policy priorities on AMR. World Bank economic simulations suggest that failure to contain AMR could result in substantial losses to As a foundational point, we have emphasized that the global economy between now and 2050. In an AMR cannot be managed in isolation. Drug-resistant optimistic scenario of comparatively low impacts, infectious diseases are one part of a broad range unchecked AMR will likely reduce annual global GDP of microbial threats to human and animal health. by 1.1 percent by 2050. In the case of high AMR The most efficient and cost-effective answer to impacts, by 2050, drug-resistant infections may cut AMR is to build a core of permanent infectious- annual global GDP by 3.8 percent. disease surveillance and management capabilities in all countries, integrated within functioning human Thus, the reductions in annual global GDP due to and veterinary health systems. The bulk of AMR AMR may be comparable to the losses caused by expenditures called for in this report are directed to the 2008–09 financial crisis. Except that, instead of that purpose. resolving after a couple of hard years, the economic damage inflicted by unchecked AMR would continue We have proposed specific policy recommendations for decades, with low-income countries suffering the for countries in health, agriculture, and the water worst effects. and sanitation sector. In health, we have argued that universal health coverage (UHC) models provide a comprehensive enabling platform for B. The Rewards of Leadership action against AMR. By implementing UHC reforms, countries will accelerate gains against AMR through The threat AMR poses to the global economy and multiple channels, generally including better health to global shared prosperity also means, however, information, more effective prevention of infections, that timely investment in AMR control can bring and more robust antimicrobial stewardship. extraordinary rewards. Putting funds into AMR Countries’ efforts to implement the International control is likely to be among the highest-yield Health Regulations (IHR) on public health emergency investments that countries and partners can make preparedness also provide an opportunity to today. Assuming that 50 percent of AMR costs can be accelerate AMR action and harness financing and avoided by robust containment efforts from 2017 to technical support for AMR progress. 2050, AMR investments of just $0.2 trillion will bring In agriculture, all countries can take steps to cumulative global benefits between $10 trillion and progressively reduce antimicrobial use in livestock $27 trillion during this period. Rates of return on AMR production. Limiting the use of antibiotics as growth control investments through 2050 may range from promoters is the first step. To guide progress and 31 percent annually (if only 10 percent of AMR costs document results, countries need robust monitoring can be mitigated) to as much as 88 percent annually systems that can track the use of antimicrobials and (if 75 percent of AMR costs are avoided). the spread of AMR in the livestock sector. Wealthy Middle-income and high-income countries will derive countries and development partners have an interest the largest economic rewards, in absolute and per- in supporting low- and middle-income countries to capita terms, from successful AMR containment. To build such surveillance capacities. obtain these gains, wealthier nations will need to Conclusions  ■  57 Country action in the water, sanitation, and hygiene D. What Will the World Bank sector will contribute to the Global Action Plan objective of reducing infections—thus lowering Group Do? antimicrobial demand and slowing AMR. Governments weighing spending options in cost-benefit terms The agenda for AMR action outlined in this report should incorporate public-health benefits, including implies responsibilities for the World Bank Group. AMR containment, in the expected rewards from Our task is to support countries and partners in investment in water and sanitation. implementing the Global Action Plan on AMR and the AMR agenda adopted by the United Nations General Assembly in September 2016. The World Partnerships Build Power Bank Group will support the One Health Tripartite’s global leadership on AMR containment and related Managing the AMR threat will require engagement health security agendas. The World Bank Group will from multiple sectors and stakeholders, under also take specific actions to support country progress national government leadership. The strongest on AMR. strategies will involve the business sector, civil society organizations, multilateral agencies, private philanthropies, and research institutions. Creating a Global Investment For example, partnerships among government, Framework for AMR Action development partners, researchers, and farmers’ groups will be needed to protect the livelihoods Thanks to the Global Action Plan and the efforts of of livestock producers in low- and middle-income many partners, substantial consensus exists on the countries, as farmers cut antibiotic use and transition types of policies and interventions needed to fight to more sustainable production models. AMR. Moreover, work by others and research for this report provide a reasonable idea of how much AMR containment will cost. The sums are modest by Support from Multilateral global investment standards and the likely rewards Organizations exceptionally high. But the money still has to be put on the table. AMR control demands coordinated action across national borders. Country efforts can be strengthened The World Bank Group will work with countries by capable and adequately resourced multilateral and partners to develop an investment framework agencies. Multilateral organizations mobilize to deliver the objectives of the Global Action Plan international attention, facilitate knowledge sharing, on AMR. The framework will include rigorous provide technical advice and standards, and catalyze costing of priority AMR interventions at country, action across sectors. International agencies can regional, and global levels. Costed plans for AMR sustain political leadership and support long-term will be integrated with broader country agendas for capacity development during the inevitable periods emergency preparedness, response, and resilience, when national policy makers turn to other issues, and which are gaining momentum today through the AMR containment risks losing ground. WHO Monitoring and Evaluation Framework, the OIE Performance of Veterinary Services (PVS) pathway, The One Health Tripartite agencies—WHO, OIE, and other mechanisms. and FAO—have provided this leadership continuity over decades. Today’s growing global awareness The AMR investment framework will be informed and momentum for action on AMR are substantially by the results of the International Working Group the fruit of their efforts. These agencies must be on Financing of Preparedness, whose research mandated and resourced to pursue their AMR is currently in progress, and by experience with leadership. Other multilateral agencies will also the Pandemic Emergency Financing Facility (PEF), contribute to the AMR fight. The multilateral created under World Bank leadership following the development banks, for example, have financing, 2015 Ebola outbreak in Western Africa. In keeping convening power, and technical capacity to support with the principle that AMR is not an isolated country AMR efforts. phenomenon that can be addressed with one-off measures, the investment framework will emphasize integration of AMR activities and funding into broader health and development finance mechanisms that will be sustainable over time. 58  ■  Drug-Resistant Infections: A Threat to Our Economic Future In laying foundations for the global investment AMR agenda across relevant sectors. We will also framework, World Bank experts will work at country strengthen our institutional capacity on the ground level with policy makers and technical colleagues in technical areas that can optimize our services to to develop national AMR financing assessments, countries as they advance national AMR agendas. aligned with countries’ AMR National Action Plans We’ve seen some of the technical sectors that can (NAPs). Country financing assessments will identify contribute to the AMR fight through AMR-specific national priorities, needs, gaps, and best-value and AMR-sensitive interventions. Relevant sectors interventions. Country assessments will explore for World Bank Group investing include, but are resource mobilization options, looking across sectors not limited to, agriculture; water and sanitation; and including public and private sources. Teams and urban development; in addition to the health, preparing the studies will analyze the best uses of nutrition, and population sector itself. As the Bank donor assistance and plan how to sustain financing Group weighs investment options in dialog with into the future. country leaders and partners, we will apply an AMR The global AMR investment framework will then lens to identify those projects that hold promise for incorporate the results of country planning and AMR-sensitive impacts. We will design projects to costing exercises to develop a comprehensive maximize these impacts. instrument that can map and quantify needs The World Bank Group will also progressively worldwide and coordinate global investments in incorporate AMR-related gains into the calculations AMR action. The framework will be a decision tool used when assessing likely costs and benefits of for policy makers, planners, development finance projects competing for support. Over time, the institutions, donors, and other partners in the AMR systematic inclusion of an AMR perspective in effort, helping ensure that AMR finance flows to investment conversations with countries may evolve where it is most needed and achieves the greatest towards the creation of a formal screening instrument impact. similar to the World Bank’s existing mandatory We consider the creation of a global AMR investment Climate and Disaster Risk Screening tools. Along with framework as a key step towards the realization of its other utilities, an AMR screening tool would help the Global Action Plan and as a logical follow-up identify regional and global spillover benefits. to the September 2016 UNGA special session. The World Bank will deliver an initial version of the AMR investment framework by the time of the official Mobilizing Finance for AMR AMR progress report to the General Assembly in Innovation across Agriculture September 2019. and Health One way for countries to rapidly boost the impact Investment in the AMR knowledge agenda must of their infection-control and AMR investments nurture new technologies in both animal and human is to participate in a formal systems-diagnostic health. It should also create connections and harness exercise like WHO’s Joint External Evaluations synergies between the two. To foster this kind of (JEE) or the OIE PVS pathway. These evaluations innovation, the World Bank will seek to engage show promise to yield substantial gains in systems existing multidisciplinary research networks, donors, performance—if countries act on the findings. and other partners around the idea of a combined Multilateral organizations and bilateral health and animal and human health research center on AMR. development agencies like WHO, OIE, and the U.S. Promising conversations have begun, and may shortly CDC are supporting countries in the technical phase advance to a detailed feasibility study. The effort of the evaluations. The World Bank will reinforce its may develop as a multifaceted collaboration, along work with countries to ensure that costed plans are the lines of the successful Coalition for Epidemic developed to fill the needs that evaluation teams Preparedness Innovations (CEPI). detect, and that appropriate financing sources are identified to turn plans into action. Bringing the Private Sector on Board An AMR Lens on Development Finance The private sector can contribute substantially to tackling AMR, and private-sector capacities and The World Bank Group will review its own investment creativity in this area are only just beginning to be lending policies and instruments to support the Conclusions  ■  59 tapped. The World Bank Group’s ability to engage programs on (1) health systems strengthening national and global business actors is a strong through UHC reforms, and (2) emergency comparative advantage. preparedness and resilience. The International Finance Corporation (IFC) is the Many countries are currently carrying forward arm of the Bank Group that invests in and advises ambitious UHC reforms with World Bank support, and private-sector companies. IFC is active in the animal more are poised to adopt UHC goals. As suggested protein sector through investment and advisory work. above, countries’ commitment to implement UHC In engagement with its clients in animal production, provides multiple opportunities to reinforce AMR IFC reviews operational practices and provides containment. The World Bank will work through its benchmarking for clients on good industry practices, policy dialog and technical collaboration around UHC including the use of veterinary services and to support countries in leveraging health systems antibiotics. IFC will seek to deepen this partnership reforms to accelerate progress against AMR. by developing a more focused advisory offering as Mechanisms include: universal vaccination coverage part of its animal protein advisory platform. Where to reduce the demand for antimicrobials; improved government regulations evolve towards a more antibiotic stewardship in hospitals and other health focused use of antibiotics, IFC will seek to partner care settings; strengthened IPC practices in health with private producers and their associations facilities; more rigorous “gating” to ensure that to support the transition of the sector through people obtain antimicrobials only with a prescription management practices and investment.  and take them under the guidance of a qualified health professional; and better health information. IFC is also active in the private health care sector, mainly through the support of health service providers and companies that manufacture or AMR and Resilient Health Systems: distribute affordable pharmaceuticals or medical The Agendas Converge devices. IFC has developed a Quality Assessment Tool used to assess health service companies on The World Bank’s large work program of studies and various clinical governance and patient safety criteria. policy dialogue with countries on health systems IFC plans to enhance this tool and, in the process, financing has been under way for over two decades. incorporate best practices for implementing policies, In the past, this work has not systematically protocols, and training around antimicrobial drug use. included costing of investments in core public- health functions or analyses of their relative priority. A clear opportunity for private-sector engagement in Currently, however, the World Bank is financing the AMR challenge is for pharmaceutical and biotech improvements of core public-health functions in firms to pursue development of new antimicrobials multiple countries, notably for disease surveillance and related technologies, such as rapid diagnostic and laboratory strengthening. Such investments tests that could inform antimicrobial prescription were also part of the Bank’s contribution to the decisions at the point of care. The complex topic emergency response to recent avian and pandemic of antimicrobial drug development is well analyzed flu threats. These promising investments mark a new elsewhere. Here, we note only that the World Bank direction—spurred by a wide consensus on the need Group and other development finance institutions to strengthen global health security and reinforce might play a role in creating fresh incentives for collective preparedness. pharmaceutical companies to engage in antimicrobial research. One approach is “delinking” company AMR is part of a wider spectrum of infectious threats profits for any new antimicrobial product from the that generate outbreaks with epidemic and pandemic actual sales volumes, through a number of possible potential. Thus, the AMR and health emergency mechanisms. Country policy makers, in particular preparedness agendas are deeply intertwined. among the G77, have pressed for the implementation Multiple opportunities for synergy exist between the of delinking strategies. AMR agenda as set out in the Global Action Plan and the World Bank’s expanding work with countries and partner organizations on emergency preparedness, Leveraging UHC Reforms response, and resilience. to Reach AMR Objectives As the World Bank develops and transforms its health In the World Bank’s health sector practice, action systems work to encompass greater emphasis on on AMR containment will mesh with ongoing work emergency preparedness and systems resilience, 60  ■  Drug-Resistant Infections: A Threat to Our Economic Future in answer to country demand, the Bank is helping as well as across present and future generations, countries build stronger capacities for public-health leadership by the world’s public authorities— functions, such as infectious disease and outbreak international organizations and above all national surveillance. This in turn nurtures many of the same governments—is indispensable to overcome inertia, capacities needed to detect, track, and manage AMR. free-rider behaviors, and the other governance The consolidation of core human and animal public- shortcomings that threaten public goods. The World health capacities; the creation of health systems Bank Group will contribute to the collective effort. resilient to emergencies; and the AMR fight reflect Countries will make AMR containment real. largely convergent and mutually reinforcing agendas. Those who will benefit most do not have a voice. The World Bank will act to help countries capitalize Many of them have not yet been born. We, however, on these potential synergies. have the knowledge, the means, and the opportunity to act in their interest. AMR is indeed a threat to our Action Today—To Preserve economic future, but above all to the future of our Tomorrow children. Bold action today can safeguard the health and prosperity of those who will come after us. Because the benefits of AMR containment are distributed among all individuals and all countries, Annex 1. September 2016 Political Declaration of the United Nations General Assembly on Antimicrobial Resistance, and Statements to the General Assembly by the WHO and OIE Directors-General 62  ■  Drug-Resistant Infections: A Threat to Our Economic Future Political Declaration of the 4. Also acknowledge that, due to antimicrobial resistance, many achievements of the twentieth UN General Assembly on century are being gravely challenged, in Antimicrobial Resistance particular: the reduction in illness and death from infectious diseases achieved through social and economic development; access to health services We, Heads of State and Government and and to quality, safe, efficacious and affordable representatives of States and Governments, meeting medicines; hygiene, safe water and sanitation; at United Nations Headquarters in New York on disease prevention in community and health- 21 September 2016, in accordance with General care settings, including immunization; nutrition Assembly resolution 70/183, in which the Assembly and healthy food; improvements in human and decided to hold a high-level meeting in 2016 on veterinary medicine; and the introduction of new antimicrobial resistance: antimicrobial and other medicines; 1. Reaffirm that the blueprint for tackling 5. Recognize that the above achievements are now antimicrobial resistance is the World Health gravely challenged by antimicrobial resistance, Organization global action plan on antimicrobial including: the development of resilient health resistance and its five overarching strategic systems and progress towards the goal of objectives developed by the World Health universal health coverage; treatment options Organization in collaboration with, and for HIV and sexually transmitted infections, subsequently adopted by, the Food and tuberculosis and malaria, as well as other Agriculture Organization of the United Nations infections acquired in community and health and the World Organization for Animal Health; care settings; gains in infection prevention and 2. Also reaffirm that the 2030 Agenda for control in community and health care settings; Sustainable Development offers a framework to advances in agriculture and animal husbandry ensure healthy lives, and recall commitments to that help to ensure that the quality of food is fight malaria, HIV/AIDS, tuberculosis, hepatitis, preserved; and prevention and treatment options the Ebola virus disease and other communicable for infectious diseases in veterinary medicine; diseases and epidemics, including by addressing 6. Also recognize that, due to antimicrobial growing antimicrobial resistance and neglected resistance, there will be fewer options for diseases affecting developing countries in the protection of people most vulnerable to particular, while reiterating that antimicrobial serious life-threatening infections, especially resistance challenges the sustainability and women giving birth, newborns, patients with effectiveness of the public health response to certain chronic diseases or those undergoing these and other diseases as well as gains in chemotherapy or surgery; health and development and the attainment of the 2030 Agenda; 7. Note with concern that the fulfilment of the right to the enjoyment of the highest attainable 3. Acknowledge that the resistance of bacterial, standard of physical and mental health, as viral, parasitic and fungal microorganisms to well as access for millions of people to health antimicrobial medicines that were previously services and to quality, safe, efficacious and effective for treatment of infections is mainly affordable antimicrobial medicines, food, clean due to: the inappropriate use of antimicrobial water and a healthy environment, remain a medicines in the public health, animal, food, distant goal, especially in developing countries; agriculture and aquaculture sectors; lack of access to health services, including to 8. Also note with concern that while the current diagnostics and laboratory capacity; and lack of access to health services and access to antimicrobial residues into soil, crops and water: antimicrobial medicines in developing countries within the broader context of antimicrobial contributes to more deaths than antimicrobial resistance, resistance to antibiotics, which are resistance, without an effective One Health not like other medicines, including medicines approach and other multi-sectoral cooperation for the treatment of tuberculosis, is the greatest and actions, antimicrobial resistance is projected and most urgent global risk, requiring increased to cause millions of deaths worldwide, with attention and coherence at the international, massive social, economic and global public national and regional levels; health repercussions; September 2016 Political Declaration of the United Nations General Assembly on Antimicrobial Resistance  ■  63 9. Recognize that the keys to tackling antimicrobial evidence-based and guided by the principles resistance are: the prevention and control of of affordability, effectiveness and efficiency infections in humans and animals, including and equity, and should be considered as immunization, monitoring and surveillance of a shared responsibility: in this regard, we antimicrobial resistance; sanitation, safe and acknowledge the importance of delinking clean water and healthy environments; investing the cost of investment in research and in strong health systems capable of providing development on antimicrobial resistance universal health coverage; promoting access from the price and volume of sales so as to to existing and new quality safe, efficacious facilitate equitable and affordable access to and affordable antimicrobial medicines based, new medicines, diagnostic tools, vaccines where available, on diagnostic tests; sustained and other results to be gained through research and development for new antimicrobial research and development, and welcome and alternative medicines; rapid diagnostic tests, innovation and research and development vaccines and other important technologies, models that deliver effective solutions to interventions and therapies; promoting the challenges presented by antimicrobial affordable and accessible health care; and resistance, including those promoting resolving the lack of investment in research and investment in research and development; all development, including through the provision of relevant stakeholders, including Governments, incentives to innovate and improve public health industry, nongovernmental organizations and outcomes, particularly in the field of antibiotics; academics, should continue to explore ways to support innovation models that address 10. Also recognize that the overarching principle the unique set of challenges presented for addressing antimicrobial resistance is the by antimicrobial resistance, including the promotion and protection of human health importance of the appropriate and rational within the framework of a One Health approach, use of antimicrobial medicines, while emphasize that this requires coherent, promoting access to affordable medicines; comprehensive and integrated multi-sectoral action, as human, animal and environmental d. Underline further that affordability and health are interconnected, and in this regard: access to existing and new antimicrobial medicines, vaccines and diagnostics should a. Recognize further that effective antimicrobial be a global priority and should take into medicines and their prudent use represent account the needs of all countries, in line a global public benefit and, for addressing with the World Health Organization global antimicrobial resistance, it is essential to strategy and plan of action on public health, allow people to have access to efficient and innovation and intellectual property, and resilient health systems; as well as to quality, taking into consideration its internationally safe, efficacious and affordable antimicrobial agreed follow-up processes; medicines and other technologies, when they are needed; and healthy food and e. Improve surveillance and monitoring of environments; antimicrobial resistance and the use of antimicrobials to inform policies and work b. Underline that basic and applied innovative with stakeholders from industry, agriculture research and development, including in and aquaculture, local authorities and areas such as microbiology, epidemiology, hospitals to reduce antimicrobial residues in traditional and herbal medicine and social soil, crops and water; and behavioural sciences, as appropriate, are needed in order to better understand f. Enhance capacity-building, technology antimicrobial resistance and to support transfer on mutually agreed terms and research and development on quality, safe, technical assistance and cooperation for efficacious and affordable antimicrobial controlling and preventing antimicrobial medicines, especially new antibiotics resistance, as well as international and alternative therapies, vaccines and cooperation and funding to support the diagnostics; development and implementation of national action plans, including surveillance and c. Underline also that all research and monitoring, the strengthening of health development efforts should be needs-driven, 64  ■  Drug-Resistant Infections: A Threat to Our Economic Future systems and research and regulatory infrastructure, including through engagement capacity, without jeopardizing, in particular with multilateral development banks in the case of low- and middle-income and traditional and voluntary innovative countries, health or posing barriers for financing and investment mechanisms, access to care; based on priorities and local needs set by governments, and ensuring public return on g. Acknowledge that increasing awareness and investment; knowledge on antimicrobial resistance and all of its implications requires the sharing of c. Take steps to ensure that national action good practices and findings, collaboration plans include the development and with the media and national and multi- strengthening, as appropriate, of effective sectoral actors and the provision of sufficient surveillance, monitoring and regulatory financing for these activities across sectors; frameworks on the preservation, use and sale of antimicrobial medicines for humans 11. Recognize that national conditions and priorities and animals that are enforced according should be taken into account at all levels, and to national contexts and consistent with that relevant sectors of government should be international commitments; engaged in the development and implementation of multi-sectoral national action plans, policies, d. Initiate, increase and sustain awareness and regulations and regional initiatives, taking into knowledge-raising activities on antimicrobial account the national context, legislation and resistance in order to engage and encourage jurisdictional responsibilities; behavioural change in different audiences; promote evidence-based prevention, 12. We therefore commit to work at national, infection control and sanitation programmes; regional and global levels to: the optimal use of antimicrobial medicines a. Develop, in line with World Health in humans and animals and appropriate Assembly resolution 68.7 multi-sectoral prescriptions by health professionals; the national action plans, programmes and active engagement of patients, consumers policy initiatives, in line with a One Health and the general public, as well as approach and the global action plan on professionals, in human and animal health; antimicrobial resistance, including its five and professional education, training and overarching strategic objectives, with a certification among health, veterinary and view to implementing national measures agricultural practitioners; and consider, for strengthening appropriate antibiotic as appropriate, innovative approaches use in humans and animals: to support to increase consumer awareness, giving the implementation of such plans, national attention to local conditions and needs; and international collaboration is needed e. Support a multi-sectoral One Health to assess resource needs and to provide approach to address antimicrobial sustained technical and financial investment resistance, including through public in shared research, laboratories and health-driven capacity-building activities regulatory capacities, as well as professional and innovative public-private partnerships education and training, with a view to and incentives and funding initiatives, safeguarding human health, animal health together with relevant stakeholders in and welfare and the environment; civil society, industry, small- and medium- b. Mobilize adequate, predictable and sustained sized enterprises, research institutes and funding and human and financial resources academia, to promote access to quality, safe, and investment through national, bilateral efficacious and affordable new medicines and multilateral channels to support the and vaccines, especially antibiotics, as well development and implementation of national as alternative therapies and medicines to action plans, research and development treatment with antimicrobials, and other on existing and new antimicrobial combined therapies, vaccines and diagnostic medicines, diagnostics, vaccines and other tests; technologies and to strengthen related September 2016 Political Declaration of the United Nations General Assembly on Antimicrobial Resistance  ■  65 13. Call upon the World Health Organization, Statements to the High- together with the Food and Agriculture Organization of the United Nations and the World Level Meeting of the UN Organization for Animal Health, to finalize a General Assembly by the WHO global development and stewardship framework, as requested by the World Health Assembly in and OIE Directors-General, its resolution 68.7, to support the development, 21 September 2016 control, distribution and appropriate use of new antimicrobial medicines, diagnostic tools, vaccines and other interventions, while Address by Dr. Margaret Chan, Director-General of preserving existing antimicrobial medicines, the World Health Organization: and to promote affordable access to existing Excellencies, distinguished delegates, colleagues in and new antimicrobial medicines and diagnostic public health, ladies and gentlemen, antimicrobial tools, taking into account the needs of all resistance is a global crisis—a slow-motion tsunami. countries and in line with the global action plan The situation is bad, and getting worse. on antimicrobial resistance; Last month, an increase in the number of drug- 14. Call upon the World Health Organization, in resistant pathogens forced WHO to revise its collaboration with the Food and Agriculture treatment guidelines for chlamydia, syphilis, and Organization of the United Nations, the World gonorrhoea. On current trends, a common disease Organization for Animal Health, regional and like gonorrhoea may become untreatable. Doctors multilateral development banks, including the facing patients will have to say, “Sorry, there is World Bank, relevant United Nations agencies nothing I can do for you.” and other intergovernmental organizations, as well as civil society and relevant multi-sectoral The crisis can be succinctly summarized. The misuse stakeholders, as appropriate, to support the of antimicrobials, including their underuse and development and implementation of national overuse, is causing these fragile medicines to fail. action plans and antimicrobial resistance The emergence of bacterial resistance is outpacing activities at the national, regional and global the world’s capacity for antibiotic discovery. Over the levels; past half century, only two new classes of antibiotics reached the market. 15. Request the Secretary-General to establish, in consultation with the World Health Organization, With few replacement products in the pipeline, the the Food and Agriculture Organization of the world is heading towards a post-antibiotic era in United Nations and the World Organization which common infections, especially those caused by for Animal Health, an ad hoc interagency gram-negative bacteria, will once again kill. coordination group, co-chaired by the Executive Superbugs, resistant to nearly all currently available Office of the Secretary-General and the World medicines, already haunt hospitals and intensive care Health Organization, drawing, where necessary, units in every region of the world. Nearly all of us on expertise from relevant stakeholders, to know someone who underwent a routine operation provide practical guidance for approaches only to die from a hospital-acquired infection. needed to ensure sustained effective global action to address antimicrobial resistance, and Last year, the World Health Assembly approved also request the Secretary-General to submit a global action plan for combatting antimicrobial a report for consideration by Member States resistance. What we must see now is the action. by the seventy-third session of the General The pharmaceutical industry is reluctant to invest Assembly on the implementation of the present in costly antibacterial discovery. The return on declaration and on further developments and investment is poor, as antibiotics are taken for a short recommendations emanating from the ad hoc time, cure their target disease, and can fail after a interagency group, including on options to brief market life. improve coordination, taking into account the global action plan on antimicrobial resistance. 66  ■  Drug-Resistant Infections: A Threat to Our Economic Future Incentives must be found to re-create the prolific era ❉❉ Here in this room, we all know that research on of antibiotic discovery that took place from 1940 to new molecules needs to be boosted through 1960. Consumers have to stop demanding antibiotics private and public collaboration. when they have a viral infection, like a cold or the flu. But how can we turn this into action in the field? Doctors have to stop prescribing them. With solutions adapted to national specificities, The medical profession needs better diagnostic tests, sectors and activities? Without endangering human so that antibiotics are prescribed only on the basis and animal health sectors and economic activities? of a firm diagnosis. More vaccines are needed to prevent infections in the first place. In short: How can we drive sustainable change into our practices? The food industry needs to reduce its massive use of antibiotics, at subtherapeutic doses, as growth In Animal health, the World Organisation for Animal promoters. Specific antibiotics, listed by WHO as Health has been working on this topic for a long time. critically important for human medicine, should not ❉❉ We have developed international Standards be used in animal husbandry or agriculture. aimed at defining responsible and prudent use of Consumers should make antibiotic-free meat their antimicrobials to control animal diseases under preferred choice. veterinary supervision. All of these actions are urgently needed. ❉❉ We have built a list of antimicrobial agents of veterinary importance. The World Health Organization welcomes this high- level meeting. A global crisis of this magnitude ❉❉ We have defined adequate legislation to control demands attention at the highest political level. their production, circulation and distribution. Thank you for recognizing the importance of this And to help you implement these Standards at your issue. national level, the OIE has developed a process for evaluation and performance improvement of veterinary services named the “PVS Pathway.” Address by Dr. Monique Éloit, Director-General of the World Organisation for Animal Health (OIE): Tools also exist as far as “One Health” is concerned, with the adoption of the WHO Global Action Plan on Your Excellencies, Ministers, Dear Delegates, Antimicrobial resistance, in which both OIE and FAO Dear Colleagues from International Organisations, are closely collaborating, and which directly leads us Honourable participants, here, to this High-level meeting. Superbugs. If someone had told me, when I was a But these tools, standards, recommendations and young vet student, that one day, I would be standing action plans, internationally built by you as UN or in front of you talking about bugs as the major health OIE Member Countries, can only be useful if they threat of the century, I would not have believed it. are reflected and implemented at the national level, But here we are. Talking about bugs becoming and if they are the basis on which we create the resistant to our most precious medicines, necessary sustainable change in the way we use antimicrobials. antibiotics. Here we are, facing the hard reality: if we do not To allow this sustainable change at the national level, act now, protecting not only human health but also we—WHO, FAO and OIE—need your strong and animal health and welfare, food safety and food long-term political commitment in order to: security, this might become tremendously difficult. ❉❉ build tailor-made national action plans based However, this situation is not yet inevitable. on a systemic inter-sectorial and coordinated approach favoring cohesion and collaboration; ❉❉ We all know how prudent use and good practices could decrease the risk of antimicrobial ❉❉ invest in the long-term sustainability of health resistance development. systems, including the strengthening of veterinary services; ❉❉ We all know that alternatives exist and are only waiting to be developed. September 2016 Political Declaration of the United Nations General Assembly on Antimicrobial Resistance  ■  67 ❉❉ and last but not least, we need to gain ❉❉ By endorsing the outcome document of this High support of stakeholders and populations, by Level meeting, I hope that you will show your raising awareness through education and strong commitment to continue in these efforts communication. and command actions required to fight against antimicrobial resistance. *** ❉❉ We all share responsibility for the development In conclusion, of Antimicrobial Resistance. Consequently, if ❉❉ Much work has already been accomplished, but a we successfully tackle this threat, we will share great deal remains to be implemented in order to victory. see tangible results. I thank you all for your attention. Annex 2. Top 18 Drug-Resistant Threats to the United States (Published by U.S. Centers for Disease Control and Prevention in 2013) 70  ■  Drug-Resistant Infections: A Threat to Our Economic Future Urgent Threats in the long line of drugs to which the bacteria have become resistant—a list that includes penicillin, Clostridium difficile (C. difficile) causes life- tetracycline, and fluoroquinolones. Early signs of threatening diarrhea. These infections mostly occur resistance to cephalosporins, the class of antibiotics in people who have had both recent medical care that includes ceftriaxone, are also being monitored. and antibiotics. Often, C. difficile infections are in hospitalized or recently hospitalized patients. A 2015 CDC study found that C. difficile caused almost half a Serious Threats million infections among patients in the United States Multidrug-resistant Acinetobacter in a single year. An estimated 15,000 deaths are directly attributable to C. difficile infections, making it Drug-resistant Campylobacter a substantial cause of infectious disease deaths. Over Fluconazole-resistant Candida (a fungus) 5 years, up to $3.8 million of medical costs are due to C. difficile resistance. Extended spectrum b-lactamase producing Enterobacteriaceae (ESBLs) Carbapenem-resistant Enterobacteriaceae (CRE) bacteria cause untreatable and hard-to-treat Vancomycin-resistant Enterococcus (VRE) infections; they are on the rise in patients in medical Multidrug-resistant Pseudomonas aeruginosa facilities. CRE have become resistant to all, or nearly all, of the antibiotics we have today. Almost half of Drug-resistant Non-typhoidal Salmonella hospital patients who get bloodstream infections from Drug-resistant Salmonella Typhi CRE bacteria die from the infection. Drug-resistant Shigella Neisseria gonorrhoeae causes gonorrhea, a sexually transmitted disease. The bacteria is already resistant Methicillin-resistant Staphylococcus aureus (MRSA) to many drugs. More than 800,000 infections occur Drug-resistant Streptococcus pneumoniae in the United States annually, many go undetected and untreated, and more than 1 in 4 are resistant Drug-resistant tuberculosis to at least one antibiotic. Left untreated, gonorrhea can cause serious problems, particularly for women, including chronic pelvic pain, life-threatening Concerning Threats ectopic pregnancy, and even infertility. Infection also Vancomycin-resistant Staphylococcus aureus (VRSA) increases the risk of contracting and transmitting HIV. Growing resistance to azithromycin, the currently Erythromycin-resistant Group A Streptococcus recommended drug, suggests that it may be next Clindamycin-resistant Group B Streptococcus Annex 3. Potential Savings from Using One Health Approaches 72  ■  Drug-Resistant Infections: A Threat to Our Economic Future SAVINGS IN DELIVERY OF PUBLIC HEALTH FUNCTIONS  Background Analysis for Estimates of Costs of Veterinary and Human Public Health Systems in 60 Low-Income and 79 Middle-Income Countries (139 Countries) Investment/ Recurrent Specific Areas of Savings Task Cost Savings % in Peacetime and Emergency Operations Surveillance Investment 10–30% Joint transport and communication systems, as shown in campaigns to control avian flu and other zoonoses Surveillance Recurrent 20–40% Shared front-line staff, as already has been demonstrated in many countries with para-veterinary systems Bio-security Investment 5–20% Shared border control and abattoir and market inspection in buildings and equipment, as already done in several countries; sharing also possible with plant sanitary service Bio-security Recurrent 10–30% Shared border control and market inspection, with clear agreement on responsibilities. Sharing also possible with plant sanitary service Diagnostics Investment 5–25% Joint facilities and equipment, as already done in a number of countries Diagnostics Recurrent 15–30% Shared support staff, as already done in a number of countries and recommended in other countries Control (vaccinations, Investment 5–15% Shared quarantine of infected areas, as successfully done in campaigns hygiene, and rapid to control highly pathogenic avian influenza response) Control (vaccinations, Recurrent 10–30% Shared staff and hygiene and awareness programs hygiene, and rapid response) Additional costs Training 5–10% Of total budget Research 5–10% Of total budget Assumptions endorsed by expert panel as “reasonable first estimates.” Canada’s National Microbiology Laboratory. A detailed analysis of Canada’s National Microbiology Laboratory found savings of 26% annually in the One Health facility in Winnipeg, which provides both animal and human public health services. Adoption of such One Health approaches is rare, however, suggesting that advocacy is needed to overcome the cemented sectoral and professional silos. The outcome in Canada is a substantial and ongoing saving of taxpayers’ resources. Moreover, such facilities are also more effective, with faster and more accurate diagnoses. In LMICs, a disproportionately high amount of financing has flowed to human health systems (relative to veterinary public health systems), which has inadvertently encouraged development of silos and reduced prospects for highly desirable collaboration (since collaboration requires some capacity in both sectors). Source: World Bank (2012). People, Pathogens and Our Planet. The Economics of One Health. Annex 4. Targets for Sustainable Development Goal #3 Ensure Healthy Lives and Promote Well-being for All at All Ages 74  ■  Drug-Resistant Infections: A Threat to Our Economic Future SDG #3.  Ensure Healthy Lives and Promote Well-being for All at All Ages Targets Global?  1 reduce the global maternal mortality ratio to less than 70 per 100,000 live births No  2 end preventable deaths of newborns and children under five No  3 end the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases and combat hepatitis, Yes water-borne diseases, and other communicable diseases  4 reduce by one-third premature mortality from non-communicable diseases (NCDs) and promote mental No health and well-being  5 strengthen prevention and treatment of substance abuse, incl. narcotic drug abuse and harmful use of No alcohol  6 halve global deaths and injuries from road traffic accidents No  7 ensure universal access to sexual and reproductive health care services No  8 achieve universal health coverage (UHC), including financial risk protection, access to quality No essential health care, and access to safe, effective, quality, and affordable essential medicines and vaccines for all  9 substantially reduce the number of deaths and illnesses from hazardous chemicals and air, water, and soil Partially pollution and contamination 10 implement Framework Convention on Tobacco Control in all countries as appropriate Partially 11 support research and development of vaccines and medicines that primarily affect developing Partially countries; provide access to affordable essential medicines and vaccines 12 increase substantially health financing and health workforce in developing countries, esp. in LDCs and SIDS No 13 strengthen the capacity of all countries, particularly developing countries, for early warning, risk Yes reduction, and management of national and global health risks Global public goods share two qualities. First, their benefits are non-excludable so that once a good is available, everyone in the world can enjoy it. Second, consumption of global public goods is non-rivalrous because consumption by one person does not reduce the availability to others, across nations. Annex 5. Example of a Budget for AMR Surveillance 76  ■  Drug-Resistant Infections: A Threat to Our Economic Future ANNUAL BUDGET FOR AMR SURVEILLANCE IN KENYA AT THE NATIONAL PUBLIC HEALTH LABORATORY AND EIGHT SATELLITE LABORATORIES Item* Total Needed Unit Cost (Ksh) Total Cost (Ksh) NPHL Personnel (Salary and Benefits) Principal investigator/project manager (full-time)** 1 120,000 120,000 Clinical consultant (hourly) 108 8,000 864,000 Data analyst (per session) 5 200,000 1,000,000 Data manager (full-time) 1 600,000 600,000 Subtotal 2,584,000 Training and strategic planning Strategic planning session 1 2,000,000 2,000,000 Training for NPHL microbiologists 1 50,000 5,0000 Training for satellite laboratory microbiologists 8 90,000 720,000 Sensitization of hospital sites 96 80,000 7,680,000 Subtotal 10,450,000 Equipment Printer/scanner 8 25,000 200,000 Desktop computer 24 100,000 2,400,000 Subtotal 2,600,000 Services Internet access*** 0 0 0 Subtotal 0 Office Supplies Printer toners 16 15,000 240,000 Printing paper (carton) 40 3,000 120,000 Printing 1 100,000 100,000 Subtotal 460,000 TOTAL (Ksh) 16,094,000 TOTAL (USD) 159,347 *See Appendix C for item descriptions. **A principal investigator was already present in Kenya and thus not included in their national surveillance budget, but would otherwise be an essential budget item. ***Internet access is currently available in most EAPHLN laboratories, but would be an additional cost if needed. Annex 6. Example of a Laboratory- Improvement Budget to Perform Antibiotic Susceptibility Testing (AST) 78  ■  Drug-Resistant Infections: A Threat to Our Economic Future ANNUAL BUDGET FOR THE KENYA NATIONAL PUBLIC HEALTH LABORATORY AND EIGHT SATELLITE LABORATORIES Item Total Unit Cost (Ksh) Total Cost (Ksh) NPHL Personnel (salary and benefits) Laboratory supervisor (1) 0 0 0 Laboratory technicians (16) 0 0 0 ICT staff (3) 0 0 0 Data manager/statistician (1) 1 50,000 50,000 Procurement officer (1) 0 0 0 Subtotal 50,000 Satellite Laboratory Personnel 0 Laboratory microbiology technicians (2 per lab; 45,000 Ksh/mo.) 2 45,000 90,000 Additional hospital staff (nurses, technicians; 10,000 Ksh/mo.) 64 120,000 7,680,000 Subtotal 7,770,000 Equipment Autoclave (2 per lab) 0 0 0 Water distiller (1 per lab) 0 0 0 Refrigerators/freezers (2 per lab) 0 0 0 Incubators (2 per lab) 0 0 0 Slide dryer (1 per lab) 8 40,000 320,000 Carbon dioxide gas cylinder (2 per lab) 16 20,000 320,000 Temperature data loggers (2 per lab) 16 2,500,000 40,000,000 Cool boxes (4 per hospital, 20 per lab) 288 2,500 720,000 Thermometers (8 per lab) 64 5,000 320,000 Ultra low freezers (3 for NPHL) 1 2,500,000 2,500,000 Bacticinerator (3 per lab) 24 400 9,600 Freezer management system and barcoding licensing (1 per lab) 8 300,000 2,400,000 Freezer management system and barcoding installation (1 per lab) 8 300,000 2,400,000 Subtotal 48,989,600 Services Courier (G4S) External quality assurance for NPHL 3 200,000 600,000 External quality assurance for satellite laboratories 1 2,000,000 2,000,000 Subtotal 2,600,000 Equipment Service VITEK 8 400,000 3,200,000 BACTEC 1 50,000 50,000 PCR machine 2 100,000 200,000 Other basic equipment, including biosafety cabinets 8 300,000 2,400,000 Subtotal 5,850,000 Example of a Laboratory-Improvement Budget to Perform Antibiotic Susceptibility Testing (AST)  ■  79 Item Total Unit Cost (Ksh) Total Cost (Ksh) Reagents API-10 (pack of 20 strips) 80 8,000 640,000 API-20E (pack of 20 strips) 80 8,000 640,000 API-20NE (pack of 20 strips) 80 8,000 640,000 MacConkey agar (bottle of 500g) 5 10,000 50,000 MacConkey agar with sorbitol (bottle of 500g) 5 10,000 50,000 Mueller Hinton agar (bottle of 500g) 5 10,000 50,000 Nutrient agar (bottle of 500g) 5 10,000 50,000 Sheep blood, defibrinated (bottle of 500g) 60 1,000 60,000 Triple sugar iron agar (TSI) (bottle of 500g) 5 10,000 50,000 Tryptone soya agar (TSA) (bottle of 500g) 5 10,000 50,000 Urea agar base (Christensen’s agar base) (bottle of 500g) 5 10,000 50,000 Urea solution, sterile 40% (5mL) 50 10,000 500,000 Xylose lysine desoxycholate agar (XLD) (bottle of 500g) 5 10,000 50,000 Colombia blood agar base (bottle of 500g) 5 10,000 50,000 Cary blair medium (bottle of 500g) 5 10,000 50,000 Amies transport medium (pack of 50 packs) 80 8,000 640,000 Subtotal 3,620,000 Antibiotics Ampicillin, 10µg (5 cartridges per lab) 40 2,500 100,000 Cefotaxime, 30µg (5 cartridges per lab) 40 2,500 100,000 Ciprofloxacin, 5µg (5 cartridges per lab) 40 2,500 100,000 Erythromycin, 15µg (5 cartridges per lab) 40 2,500 100,000 Gentamicin, 10µg (5 cartridges per lab) 40 2,500 100,000 Tobramycin, 10µg (5 cartridges per lab) 40 2,500 100,000 Azithromycin (5 cartridges per lab) 40 2,500 100,000 Clindamycin (5 cartridges per lab) 40 2,500 100,000 Penicillin, 10 units (5 cartridges per lab) 40 2,500 100,000 Cefuroxime, 30µg (5 cartridges per lab) 40 2,500 100,000 Tetracycline, 30µg (5 cartridges per lab) 40 2,500 100,000 Rifampin, 5µg (5 cartridges per lab) 40 2,500 100,000 Norfloxacin, 10µg (5 cartridges per lab) 40 2,500 100,000 Nitrofurantoin, 300µg (5 cartridges per lab) 40 2,500 100,000 Sulfamethoxazole/trimethoprim (5 cartridges per lab) 40 2,500 100,000 Ertapenem (5 cartridges per lab) 40 2,500 100,000 Colistin (5 cartridges per lab) 40 2,500 100,000 Tigecycline (5 cartridges per lab) 40 2,500 100,000 Cefoxitin (5 cartridges per lab) 40 2,500 100,000 Mac Farland standard (2 per lab) 16 5,000 80,000 Sodium chloride (NaCl) (2 per site) 16 7,000 112,000 Glycerol (2 per site) 16 8,000 128,000 Gram stain kits large (12 kits per lab) 96 2,000 192,000 Subtotal 2,412,000 (continued) 80  ■  Drug-Resistant Infections: A Threat to Our Economic Future Item Total Unit Cost (Ksh) Total Cost (Ksh) VITEK Reagents Saline 0.45% (20 per lab) 160 7,500 1,200,000 VITEK 2 GN bacilli identification (21341) (200 per lab) 1,600 15,400 24,640,000 VITEK 2 GP cocci identification (21342) (200 per lab) 1,600 15,400 24,640,000 VITEK 2 AST GN (200 per lab) 1,600 15,400 24,640,000 VITEK 2 BCL GP bacilli identification (21345) (200 per lab) 1,600 15,400 24,640,000 VITEK 2 AST GP (200 per lab) 1,600 15,400 24,640,000 Subtotal 124,400,000 Consumables Blue pipette tips, non-sterile, 100–1000µl (5 packs 40 1,000 40,000 per lab) Yellow pipette tips, non sterile, 1–200µl (5 packs per lab) 40 800 32,000 BACTEC blood culture bottles (100 per lab) 800 1,000 800,000 Petri dishes, 100 x 15mm polysterene (10 cartons per lab) 80 9,000 720,000 Test tubes, beakers, flasks (1 set per lab) 8 80,000 640,000 Cryo vials (20 packs for NHPL) 20 3,000 60,000 Cryovial boxes (50 per lab) 400 1,000 400,000 Aluminium plate holders (10 per lab) 80 8,000 640,000 Graduated wire loops with handle (2 per lab) 16 3,000 48,000 Graduated wire loop replacements (20 per lab) 160 1,000 160,000 Inoculating loops and needles, disposable (100 packs per lab) 8,000 100 800,000 Petri dishes, 9cm (10 box per lab) 80 7,000 560,000 Urine collection containers, sterile (2000 per lab) 16,000 25 400,000 Slides (10 boxes per lab) 80 70 5,600 Slide boxes (20 per lab) 1,600 1,000 1,600,000 Polysterene tubes, 75mm (1 carton per lab) 8 12,000 96,000 Subtotal 7,001,600 Safety and Waste Management supplies Lab coats (2 per person, 240 1,000 240,000 15 people/lab) Gloves (1 box/day/lab) 2,920 100 292,000 Biohazard autoclave bags, polyethylene (pack of 100;10 per lab) 80 1,000 80,000 Hand wash liquid soap (4 per lab) 32 500 16,000 Ethanol (5L bottle, 12 per lab) 96 3,000 288,000 Paper towels (1 carton per lab) 8 4,000 32,000 Bleach (1 bottle per lab) 40 1,000 40,000 Subtotal 988,000 Office Supplies Permanent markers (2 packs per lab) 16 2,000 32,000 Stationery (paper punches, staplers, staples, scissors, etc.) 8 10,000 80,000 Pens (2 packs per lab) 16 500 8,000 Pencils (2 packs per lab) 16 600 9,600 Folders (10 per lab) 80 400 32,000 CLSI guidelines for AST (500 USD) 1 50,500 50,500 Subtotal 212,100 TOTAL (Ksh) 203,893,300 TOTAL (USD) 2,018,746 Annex 7. National, Regional, and International Antimicrobial Resistance Surveillance Networks 82  ■  Drug-Resistant Infections: A Threat to Our Economic Future Country or Region Programs European Union European Antimicrobial Resistance Surveillance System (EARS-Net) European Antimicrobial Consumption Network (ESAC-Net) Latin America Latin American Surveillance Network of Antimicrobial Resistance (ReLAVRA) Asia Asian Network for Surveillance of Resistant Pathogens (ANSORP) Central Asia and Central Asian and Eastern European Surveillance of Antimicrobial Resistance (CAESAR) Eastern Europe Global Global Antimicrobial Resistance Surveillance System (GLASS) Australia Australian Group on Antimicrobial Resistance (AGAR) Cambodia United States Naval Medical Research Unit 2 Phnom Penh (NAMRU-2 PP) Canada Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) Canadian Nosocomial Infection Surveillance Program (CNISP) Both CIPARS and CNISP fall under the Canadian Antimicrobial Resistance Surveillance System (CARSS) China China Antimicrobial Resistance Surveillance Study (CHINET) China, Hong Kong Hong Kong Antibiotic Stewardship Program (ASP) Denmark Danish Integrated Antimicrobial Resistance Monitoring and Research Program (DANMAP) Federated States Federated States of Micronesia Surveillance Network of Micronesia Finland Finnish Veterinary Antimicrobial Resistance Monitoring and Consumption of Antimicrobial Agents (FINRES-VET) France l’Observatoire National de l’Epidemiologie de la Resistance Bacterienne aux Antibiotiques (ONERBA) Germany German National Veterinary Antibiotic Resistance Monitoring (GERM-VET) Italy Italian Veterinary Antimicrobial Resistance Monitoring (ITAVARM) Japan Japan Nosocomial Infections Surveillance (JANIS) Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM) Malaysia National Surveillance of Antimicrobial Resistance Program (NSAR) Mongolia National Laboratory Network Netherlands Consumption of Antimicrobial Agents and Antimicrobial Resistance among Medically Important Bacteria in the Netherlands/ Monitoring of Antimicrobial Resistance and Antibiotic Usage in Animals in the Netherlands (NETHMAP/MARAN) New Zealand New Zealand Institute of Environmental Science and Research (ESR) Antibiotic Reference Laboratory Norway Norwegian Surveillance System for Antimicrobial Drug Resistance (NORM/NORM-VET) Philippines Antimicrobial Resistance Surveillance Program (ARSP) Republic of Korea Korea Antimicrobial Resistance Surveillance Program (KARMS) Korean Nationwide Surveillance of Antimicrobial Resistance (KONSAR) Singapore The Network for Antimicrobial Resistance Surveillance (NARS-Singapore) Sweden Swedish Veterinary Antimicrobial Resistance Monitoring (SWEDRES/SVARM) Taiwan Taiwan Surveillance of Antimicrobial Resistance (TSAR) United Kingdom English Surveillance Programme for Antimicrobial Utilization and Resistance United States National Antimicrobial Resistance Monitoring System (NARMS) Emerging Infections Program (EIP) National Health Care Safety Network (NHSN) Gonococcal Isolate Surveillance Program (GISP) National Tuberculosis Surveillance System (NTSS) Vietnam Viet Nam Resistance Project (VINARES) Annex 8. Laboratory-Based Surveillance of AMR: Summary Report 84  ■  Drug-Resistant Infections: A Threat to Our Economic Future A MR surveillance is an indispensable component that cause tuberculosis, malaria, and gonorrhea— of the response to a rising tide of antibiotic have been tracked to some extent for many years. resistance worldwide. WHO recommends In some regions, strong networks existed to track surveillance as part of every national AMR action AMR among a broad set of pathogens, but there plan. National-level surveillance systems are critical were major gaps in coverage (Figure A8.1). Europe for guiding local and national policy, while regional and the Americas had the best surveillance coverage systems can enhance the value of the data, depicting and Sub-Saharan Africa and South and Southeast larger patterns and trends. Asia the least developed. Creating comprehensive, effective surveillance systems is more challenging In the following pages, we will discuss the status in low- and middle-income countries due to weak of AMR surveillance globally, the expected benefits laboratory and communications infrastructure; lack of and costs of AMR surveillance, the importance of trained laboratory and clinical personnel; and higher surveillance networks, and the main findings from prevalence of counterfeit and substandard antibiotics a capacity assessment of laboratories supported and diagnostics (Dar et al. 2016; Opintan et al. under the World Bank-funded East Africa Public 2015). A six-month surveillance program through Health Laboratory Networking Project (EAPHLNP). The 24 laboratories in Ghana recently demonstrated the assessment sought to document these laboratories’ feasibility of establishing surveillance in this lower readiness to participate in national and, ultimately, middle-income country, producing evidence of higher regional AMR surveillance. The report ends with a set than expected resistance rates (Opintan et al. 2015) of recommendations that are relevant to countries (Box 3). in East Africa and other low- and middle-income countries facing similar challenges. In addition to tracking AMR, it is important to understand the patterns and trends in antimicrobial use. Per capita use is generally highest in high- A. Status of Global income countries, but is increasing most rapidly in low- and middle-income countries (Van Boeckel et al. AMR Surveillance 2014). However, few data have been gathered to indicate the precise extent of antibiotic resistance in WHO defines public-health surveillance as the low- and middle-income countries or to quantify the systematic collection, analysis, interpretation, related health and health care costs (Laxminarayan and dissemination of public-health data. In 2014, et al. 2013). Low- and middle-income countries WHO surveyed its member states about their AMR typically have weaker public-health systems, fewer surveillance efforts. Results indicated that AMR resources, and higher burdens of infectious disease. among some specific pathogens—such as those In these countries, antimicrobial resistance is FIGURE A8.1.  Global AMR Surveillance Networks Laboratory-Based Surveillance of AMR: Summary Report  ■  85 Box 3.  Pilot Program for an AMR Surveillance Network in Ghana In Ghana, data on antimicrobial resistance are settings were submitted. Susceptibility testing scarce, and no continuous surveillance network showed that existing antimicrobials are not as exists. In 2014, a six-month pilot program effective as previously thought. Eighty percent of established a laboratory-based national surveillance isolates were resistant to older antibiotics such network to generate baseline resistance data and as ampicillin, tetracycline, chloramphenicol, and evaluate current capacity. trimethoprim/sulfamethoxazole. In addition, more than 50 percent of isolates were resistant to third- The study included a three-day workshop where generation cephalosporins and quinolones. scientists from 24 laboratories were trained to identify bacterial isolates and perform antimicrobial These results highlighted the need for continued susceptibility testing (AST). During the study period, surveillance of antimicrobial resistance in Ghana and scientists from each laboratory recorded test results corresponding changes in treatment guidelines. The and sent data sheets and isolates to a central study also highlighted the need for capacity building. location each week. A research assistant at the Twenty-five percent of participating laboratories— central laboratory then performed quality control and including two of three participating public-health other tests, and entered data into WHONET (WHO- reference laboratories—did not submit samples due supported database software for management and to poor microbiology facilities, managerial problems, analysis of microbiology data with a special focus on and lack of samples from clinicians. Furthermore, antimicrobial susceptibility test results). none of the participating laboratories had the capacity for anaerobic cultures, which are standard Over the six-month period, 1606 isolates from for resistance surveillance in high-income countries. 18 laboratories serving both inpatient and outpatient 86  ■  Drug-Resistant Infections: A Threat to Our Economic Future common in community-acquired infections such Annex 4 outlines the incremental costs—beyond the as pneumonia, diarrheal disease, tuberculosis, laboratories’ general operating budgets—to start malaria, and sexually transmitted diseases (Gelband and operate an AMR surveillance network in Kenya. et al. 2015). In addition, resistance makes it more Expenses include additional personnel to manage and difficult to treat patients with HIV/AIDS, which has analyze data and consult on surveillance; training a high prevalence in many low- and middle-income and strategic planning related to data collection and countries (Gelband et al. 2015). management; and additional equipment and supplies. In addition, the Kenyan team estimates that roughly $2.0 million are required to perform antimicrobial B. Benefits and Costs susceptibility testing at the NPHL and eight satellite laboratories with the bulk representing running costs of AMR Surveillance (Annex 5). Benefits of AMR Surveillance Based on current expenses in Kenya, establishing and running an AMR surveillance network with The broad benefits of AMR surveillance are eight county or satellite laboratories will cost about improved availability of data and information on $160,000 annually. Some costs scale to the size of levels and patterns of resistance, and introduction the network (for example, personnel and hardware of evidence-based policies and interventions, which at satellite sites) and some would increase in larger in turn contribute to reduced disease burden, lower steps, depending upon how many laboratories would treatment costs, and reduced mortality. Table 4 be supported centrally by core surveillance staff. presents the multiple benefits of an effective AMR We could find no data to establish the breakpoints surveillance system and cites country-specific at which increases would be needed. However, we examples illustrating the value of AMR surveillance believe that most low- and middle-income countries data. would initially plan for a size similar to the proposed Kenya network. Estimates for other countries can be Estimating the Cost of made by applying appropriate national unit costs to the volume of goods and services required. Implementing AMR Surveillance— The Example of Kenya Estimating the Economic The cost of AMR surveillance should be a relatively modest add-on to existing laboratory costs, when and Health Benefits of AMR built on well functioning laboratories that produce Surveillance reliable results. The routine testing carried out by The economic benefits of AMR surveillance networks, the laboratory forms the raw surveillance data. as detailed above, are multifaceted and challenging Apart from some additional quality control testing, to measure and quantify. Some benefits, such as no additional laboratory analyses are required to increased knowledge of trends in antimicrobial support a surveillance network. Additional costs resistance and improved data quality, are not are largely for information technology, data analysis routinely quantified. As many of the other benefits capacity, personnel time and training, and software. of surveillance aim to reduce the prevalence of Epidemiologic and general public-health expertise antimicrobial resistance, the economic benefits can be is also needed to interpret the data for public estimated by assessing the impact of reduced disease policy use. burden. Reductions in antimicrobial resistance will Kenya, one of the EAPHLN Project participating reduce deaths from resistant infections, health care countries, is in the process of constructing a national costs for treating those infections, and productivity AMR surveillance network. Kenyan colleagues losses. Even if changes are observed, attributing have provided the draft implementation plan and all or some of the changes to a surveillance system associated cost estimates as a reference for this is difficult if not impossible, underscoring the report. Their network will initially include the National complexities and challenges of quantifying the Public Health Laboratory (NPHL) and eight county benefits. In fact, even if no changes are seen, the or satellite laboratories, including the five supported system may be keeping the rates from rising. This is under the World Bank-funded project. not to suggest that AMR surveillance is not effective, and in fact, all indications suggest that it is. Laboratory-Based Surveillance of AMR: Summary Report  ■  87 TABLE 4.  Specific Examples of Benefits of AMR Surveillance Benefits Actions Taken Monitor trends and increase knowledge ❉❉ Ghana: 80% of isolates resistant to ampicillin, tetracycline, chloramphenicol, and of antimicrobial resistance trends trimethoprim/sulfamethoxazole ❉❉ South Africa: Emerging fluoroquinolone resistance in Salmonella Typhi and increasing ciprofloxacin resistance in non-typhoidal Salmonella, 2011 ❉❉ United Kingdom: Increase in ciprofloxacin-resistant E. coli, 1993–2007 Establish and evaluate targets for ❉❉ France, South Korea, and Turkey: Set reduction targets AMR reduction ❉❉ United Kingdom: Set target of 50% reduction of MRSA, 2004–2008; 56% reduction achieved Guide epidemiologic studies; modeling; ❉❉ United Kingdom: Increase in MRSA in 1990s attributed to 2 emerging strains; led and set priorities for research and data to further study on related risk factors collection ❉❉ United States: 500 deaths per year attributed to multidrug-resistant Acinetobacter spp. Develop evidence-based public ❉❉ Denmark: Increased CRE in poultry and hogs contributed to growth promoter health policy ban, 1990s; “yellow card” system implemented to force high users to reduce antibiotic use ❉❉ India: Discovery of NDM-1 led to creation of a high-level AMR committee in the Ministry of Health ❉❉ South Africa: Hospital VRE outbreaks in 2012 led to a national AMR strategy framework and early warning and notification system ❉❉ United Kingdom: Increased carbapenem resistance in E. coli and Klebsiella spp. included in national action plan ❉❉ United States: Cephalosporin resistance in Salmonella led to restrictions on use in food animals Design and evaluate public-health ❉❉ India: High resistance rates led to implementation of laboratory-based AMR interventions surveillance ❉❉ Latin America: High carbapenem resistance led to establishment of AMR surveillance programs in Brazil, Argentina, and Colombia ❉❉ United Kingdom: Created the TARGET tool for antimicrobial use in primary care; developed 5-year national action plan for AMR; created national alert system to inform clinicians about emerging types of resistance Update treatment guidelines ❉❉ United Kingdom: Vancomycin added to treatment guidelines for staphylococcal endocarditis due to methicillin resistance; treatment guidelines for gonorrhea updated to address ciprofloxacin resistance Create public-health engagement ❉❉ Europe: EARS-Net provides capacity building for laboratory technicians in campaigns and support training for participating facilities professionals ❉❉ South Africa: National AMR strategy established web-based and in-person AMR training for clinicians ❉❉ United States: FoodNet epidemiologists train local public-health officers to conduct outbreak investigations Influence industry practices ❉❉ Canada: Link between multidrug-resistant Salmonella in humans and ceftiofur use in poultry led to voluntary ban on ceftiofur in Quebec chicken industry ❉❉ Denmark: ESBL in E. coli led to voluntary withdrawal of cephalosporin and new management practices for disease control in the hog industry ❉❉ Japan: Cephalosporin resistant E. coli in broilers led to voluntary withdrawal of ceftiofur in Japanese hatcheries Improve data quality ❉❉ Europe: Regular data reporting for EARS-Net improved data quality and reporting and facilitated development of a standardized definition of resistance 88  ■  Drug-Resistant Infections: A Threat to Our Economic Future Box 4. Structured Expert Judgment One method to estimate the counterfactual rates or mortality—for specific antimicrobial scenario—that is, what would have happened organism combinations without the surveillance if no surveillance system had been in place—is network. Experts then provide a range of percentile through structured expert judgment (SEJ). A recent values to represent an uncertainty distribution Center for Disease Dynamics, Economics & Policy for their prediction. Each expert’s predictions are (CDDEP) study used this method to examine return weighted according to their responses to similar on investment of an environmental health tracking questions for which the answers are known. program in the United States (Colson et al. 2015). Predictions from the group of experts are then SEJ could be used as one input into determining combined and compared to observed surveillance the value of AMR surveillance. In the case of AMR data to estimate the change in resistance that could surveillance, a group of experts would be asked to be attributed to the surveillance network. predict the burden of resistance—through resistance The most likely chain of events through which AMR the best of conditions. However, some estimates can surveillance can lead to health benefits is as follows: be made for each step. Various elements of cost can also be estimated. To estimate the benefits of ❉❉ High and/or increasing rates of resistance to surveillance, it is necessary to predict how much first-line antibiotics by specific pathogens resistance rates would have changed in the absence are confirmed (or susceptibility to cheaper of surveillance, a complicated task that has not antimicrobials is identified) and made known to been satisfactorily carried out anywhere, to the best policy makers. of our knowledge. Box 4 describes the structured ❉❉ Policy makers revise treatment guidelines, expert judgment (SEJ) approach for quantifying changing first-line recommendations to highly this counterfactual scenario. Once the change effective (that is, low-resistance) antibiotics. in resistance rates attributable to surveillance is identified, other methods can be used to estimate the ❉❉ Guidelines are disseminated and clinical health and economic benefits of this change. Various practice changes. techniques are used to value lives lost, which include ❉❉ Deaths are reduced by an amount equal to the both direct and indirect costs.1 excess caused by antibiotic-resistant infections Aside from increasing mortality, antimicrobial (from epidemiologic studies). resistance also increases the cost of treating disease. ❉❉ Treatment costs are reduced by an amount The cost of illness method can be used to estimate corresponding to the decrease in the proportion the direct and indirect costs of health care and of resistant infections from hospital-based lost productivity due to antimicrobial resistance. studies or the decrease in antibiotic costs, This method requires estimates of the total cost of if cheaper antibiotics are found effective or treating resistant infections from previous studies. In effective treatments are instituted promptly to order to reflect treatment costs in East Africa or other avoid treatment failure. low- and middle-income countries, estimates of the direct costs of treatment can be adjusted by health Taking the five-step chain described above as the expenditure per capita and estimates of indirect main route for achieving benefit, the rates at which costs can be adjusted by GDP per capita, adjusted for these steps occur and the extent of change that purchasing-power parity (Springmann et al. 2016).2 eventually ensues cannot be measured easily under Laboratory-Based Surveillance of AMR: Summary Report  ■  89 FIGURE A8.2.  Theoretical Framework for a Cost-Benefit Analysis of Antimicrobial Resistance Reduced disease burden Increased resistance Increased knowledge of of resistance through Benefits information to clinicians and patients + resistance in the surveillance network area + mitigation activities triggered by surveillance data Cost of implementing the Cost of sharing resistance Cost of implementing Costs antimicrobial resistance surveillance network + data from the network with the public health community + mitigation activities triggered by surveillance data Cost-Effectiveness Analysis Antimicrobial susceptibility testing (AST) results are of AMR Surveillance used by clinicians to aid in developing informed patient treatment plans. These same results and the Cost-effectiveness is a tool often used to guide patient demographic information form the basis of public-health decisions in countries at all resource laboratory-based AMR surveillance. levels (Boyce et al. 2015). The public-health and economic benefit of AMR surveillance derives from Surveillance data from laboratories can be the actions triggered by the information gathered, so aggregated for analysis on the local, national, and the cost of these actions must be taken into account regional levels to identify resistance levels and when assessing the value of surveillance networks. trends. Data from multiple surveillance networks can A cost effectiveness analysis of the surveillance also be combined to facilitate research, visualization, network would have to account for the cost of and mapping of global trends in resistance. For implementing the network, as outlined in Annex 4; example, CDDEP’s Resistance Map online tool the cost of sharing surveillance data with the regional summarizes national and subnational antimicrobial and global public-health communities; and the cost use and resistance and is the largest such repository of further actions triggered by surveillance data in existence (ResistanceMap 2016). Users can create (Babo et al. 2015). Further actions could include maps and charts of antibiotic resistance to specific public-health interventions or educational campaigns, combinations of pathogens and antibiotics. targets for reduction in use, or changes in treatment Critical components of laboratory-based AMR guidelines or industry practices (Figure A8.2). surveillance networks include capacity and proficiency for antibiotic susceptibility testing of the laboratories, infrastructure, instrumentation, C. AMR Surveillance availability of consumables, quality control measures, availability and skill level of personnel, and capacities Networks needed to use data generated by the laboratories for surveillance, including: While most AMR surveillance networks are in high- income countries, some low- and middle-income ❉❉ Standardization of procedures and terminology, countries have established or are participating in above what is needed for clinical testing AMR surveillance networks (Annex 6). A laboratory- ❉❉ Computerization of data using specific software based AMR surveillance network is a partnership packages (including equipment and training) between clinicians, microbiology laboratories, and a central organizing body. Clinicians collect and send ❉❉ Centralized data collection (at national and samples to clinical laboratories (Blomberg et al. regional levels) and analysis. 2004). If possible, these samples are annotated The next section looks at the situation on the ground with patient information such as age, gender, with respect to laboratory capacity and antimicrobial specimen type, date, and geographic location. In susceptibility testing practices at a group of public- the laboratory, technicians culture the specimens, health laboratories participating in the World identify bacterial isolates, and test isolates for Bank-funded East Africa Public Health Laboratory antimicrobial susceptibility (Blomberg et al. 2004). Networking Project. 90  ■  Drug-Resistant Infections: A Threat to Our Economic Future D. East Africa Public otherwise available only in the national reference facilities. The main achievements include: Health Laboratory ❉❉ State-of-the-art laboratories: Renovated/ Networking Project constructed public-health laboratories; rolled out molecular technologies, including GeneXpert for The East Africa Public Health Laboratory Networking diagnosis of drug-resistant tuberculosis, resulting Project tackles the historical neglect of public- in more rapid and accurate results. health laboratories. The $128.66 million project, ❉❉ Progress towards accreditation: Attained approved by the World Bank in May 2010 with a substantial quality improvements in the Stepwise recent extension to 2020, is establishing a network Laboratory Quality Improvement Process Towards of efficient, high quality, accessible public-health Accreditation (SLIPTA), with 90 percent of the laboratories in the East African Community member project-supported facilities attaining at least two states (Burundi, Kenya, Rwanda, Tanzania, and stars, in comparison to 20 percent at baseline, Uganda). The project is: (a) strengthening diagnostic and 60 percent reaching at least three stars.3 and surveillance capacity; (b) expanding training and capacity building; and (c) supporting operational ❉❉ Regional specialization: Supported Uganda research. The operation also promotes innovations National Tuberculosis Reference Laboratory in service delivery, facilitates knowledge sharing (UNTRL) to be certified internationally and qualify among participating countries, and fosters an to serve as a WHO Supranational Reference evidence-based approach. Each country takes Laboratory, signing agreements with 20 countries the lead in a specific thematic area and provides to provide specialized services. regional leadership, generating knowledge and ❉❉ Strengthened human resources: Trained over sharing experiences and lessons. The East, Central, 10,000 health personnel in both short- and and Southern Africa Health Community (ECSA-HC) long-term courses; provided mentorship; facilitates knowledge sharing at the regional level, in recruited qualified personnel; and established an collaboration with the East African Community. e-learning platform. The project has been supporting 32 laboratories in ❉❉ Supported innovations, such as: (a) joint annual the participating countries in both capital cities and peer audits, whereby countries assessed cross-border areas to become centers of excellence each other’s laboratories; (b) performance- and increase access to laboratory services for based financing, whereby facilities received poor and vulnerable populations (Figure A8.3). The incentive payments based on progress towards laboratories are expected to provide specialized accreditation; and (c) cross-border disease services to communities in these regions that are surveillance, simulations, and investigations FIGURE A8.3.  Location of Satellite Laboratories Laboratory-Based Surveillance of AMR: Summary Report  ■  91 that have enabled swift responses to Ebola and E. Major Findings and Marburg outbreaks. Recommendations ❉❉ Operational research studies: Conducted multi-country studies, including a study on drug resistance patterns to newly prescribed This section summarizes the major findings antibiotics to deal with key bacterial enteric from the case study, and synthesizes the key pathogens, which found high levels of drug recommendations for the five countries in East Africa resistance at project-supported facilities. and other low- and middle-income countries that may face similar challenges. Building on these initial investments, and a strong track record of collaboration, stakeholders in East Africa came together to explore the feasibility of Surveillance using the project-supported facilities to introduce Laboratory-based AMR surveillance is the laboratory-based surveillance of antimicrobial second consumer of antibiotic susceptibility resistance. test results, after the patient and treating The case study included four key activities: clinician. ❉❉ Carrying out a capacity assessment of ❉❉ The added value of surveillance is not free, but 30 facilities in the five countries, which was led comes at a relatively low cost, assuming well by the East, Central, and Southern Africa Health functioning laboratories that produce reliable Community (East, Central and Southern Africa results, which are needed for the primary, Health Community 2016). patient-level use. Additional costs are largely for information technology, data analysis capacity, ❉❉ Organizing a two-day consultative workshop, personnel time and training, and software at where scientists and policy makers from East the facility and national levels. Beyond that, Africa discussed the findings of the capacity epidemiologic and general public-health expertise assessment in collaboration with regional and is essential for interpreting the data for public global experts (including participants from WHO, policy use. Kenya is in the process of establishing CDC, CDDEP) (CDDEP et al. 2016). a national AMR surveillance system, with an ❉❉ Producing a short film to improve awareness of estimated annual budget of about $160,000. the importance of AMR surveillance. AMR surveillance creates value at the facility, ❉❉ Commissioning a technical report, produced by national, and global levels. Aggregated at each the Center for Disease Dynamics, Economics & level, these include: Policy, that summarizes the status of global ❉❉ Facility level: information to guide antimicrobial AMR surveillance, provides a discussion of treatment when laboratory results are analyzed expected benefits and costs of investing in AMR regularly and communicated to clinical staff; early surveillance, presents the main findings from the detection of outbreaks of particular AMR strains capacity assessment, and includes a detailed set and hospital-acquired infections generally. of recommendations (CDDEP 2016). ❉❉ National level: information to update standard The study found that while substantial funds treatment guidelines and track trends in AMR, have been invested in upgrading laboratories, the including geographic variations. bacteriology capacity lags behind other services. Most laboratories perform relatively few microbiology ❉❉ Global level: promote understanding of AMR in cultures and ASTs. The specific findings with respect each country compared to global patterns; helps to laboratory capacity and antimicrobial susceptibility complete the global picture. testing practices are summarized in Box 5. 92  ■  Drug-Resistant Infections: A Threat to Our Economic Future Box 5. Main Findings from the Laboratory Capacity Assessments Laboratory Capacity: Antimicrobial Susceptibility Testing (AST) ❉❉ Infrastructure and capacity: All laboratories are Practices: performing below capacity in microbiology, though ❉❉ Culture media preparation and specimen processing: a sufficient number of stool, urinary, cerebrospinal Most of the laboratories use brands of media that fluid, and other specimens are cultured to form are certified for diagnostic testing. About half of the basis for robust surveillance. However, the the facilities listed animal blood procurement as a laboratories process few or no blood cultures that key barrier. A reliable and quality-assured supply capture data from severe and invasive systemic of sheep or horse blood is essential to improve bacterial infections, and which are critical for a bacterial isolation and identification. surveillance network in Africa. ❉❉ Bacterial identification: Most laboratories identify ❉❉ Equipment: In contrast to some other resource-poor bacterial isolates biochemically, which is standard settings, equipment is not presently the capacity- for diagnostic laboratories. However, most do not limiting feature of these laboratories. All are have automated systems that are easier to use and equipped to perform susceptibility testing by disc quality assure. diffusion and some have functional VITEK machines, ❉❉ Blood culture: The vast majority of cultures which can be used for both bacterial identification processed are for urinary tract and enteric and susceptibility testing and are easy to quality infections, primarily at sites in Uganda. While assure. physicians value blood cultures, which provide ❉❉ Reagents and supplies: Many of the laboratories lifesaving information for difficult cases, these suffer from stock-outs that can shut down selected services are challenging to set up and maintain. laboratories services and cause temporal biases Only four laboratories can currently perform blood in surveillance results. Many lack adequate cultures, but with ongoing training, select district control organisms for culture, identification, and laboratories will have similar capacity. Automated susceptibility testing quality assurance. There are blood culture is only available in Kenya. also reports of stock-outs, meaning that bacterial ❉❉ Susceptibility testing: All laboratories use disc culture and susceptibility testing might be available diffusion methods that work well for routine testing only intermittently or are only periodically quality and surveillance in resource-constrained settings. assured (Gelband et al. 2015). All laboratories use Clinical Laboratory Standards ❉❉ Staffing capacity and training: All but three of the Institute (CLSI) standards, but some need to laboratories have at least one staff member holding acquire documentation. Data capture, analysis, and a bachelor’s degree or higher, which bodes well dissemination are not carried out systematically. for increasing the activities and responsibilities. There is also insufficient communication between However, qualified clinical pathologists are in short clinicians and laboratories in terms of data sharing. supply. Additional training is needed in bacteriology ❉❉ Quality Assurance: Four of the five national and AMR. reference laboratories are enrolled in external quality assurance schemes. About 65 percent of the satellite laboratories have trouble in procuring proficiency testing. Laboratory-Based Surveillance of AMR: Summary Report  ■  93 Countries should develop national AMR ❉❉ Preventing stock-outs by consolidating and surveillance systems and contribute to regional prioritizing inventories for infectious disease and global surveillance initiatives: management, to ensure optimal use of antimicrobials, conserve expensive reserve drugs, ❉❉ All countries should develop AMR surveillance and work toward the global goal of containing plans that confirm country commitment and AMR. define the structure, scope, and process of establishing national AMR surveillance networks. ❉❉ Addressing human resources constraints by: appointing/recruiting clinical microbiologists ❉❉ Enrollment of all countries in the Global and/or relying on visiting consultants; ensuring Antimicrobial Surveillance System (GLASS) should that laboratory scientists are fully trained for all be facilitated in order to benefit maximally from specialized tasks; conducting joint training for added WHO support for AMR surveillance. clinical and laboratory staff to strengthen core ❉❉ Adequate investments need to be made in competencies and improve understanding of information technology and systems, laboratory AMR; and minimizing staff turnover. equipment and reagents, and continual staff ❉❉ Establishing antibiotic stewardship programs to training. address low demand for microbiology services, while routinely sharing AMR surveillance reports. Microbiology Laboratory Capacity ❉❉ Maintaining the highest standards and practices Bacteriology capacity lags behind in contrast to by: (a) relying on proficiency testing from WHO other services, a pattern that is likely similar to that or other reliable sources to assess antimicrobial found at other laboratories in the region, and possibly testing for surveillance; (b) using National in other low- and middle-income countries, due to Reference Laboratories (NRL) to facilitate three key factors: the provision of standard microorganisms for internal quality control of media, which is critical ❉❉ Lack of demand from clinicians, related to length for validating the accuracy and reliability of of time to get results (at least two days); lack of laboratory test results for patient management trust in results; and lack of laboratory capacity for and surveillance; (c) adopting and maintaining blood cultures, which are needed for many of the up-to-date standards for susceptibility testing; most serious, life-threatening infections. and (d) sourcing animal blood or preparing ❉❉ Weak supply chains and frequent stock- blood agar plates centrally or regionally in order outs are a major roadblock to routine to reliably culture and sensitivity test certain antimicrobial susceptibility testing; stock-outs pathogens from clinical specimens. disproportionately affect bacterial culture and ❉❉ Enrolling laboratories in the Stepwise Laboratory antimicrobial susceptibility testing that require Improvement Process towards Accreditation, as it that all essential components be available when builds quality awareness, improves performance, testing is needed. builds confidence among clients, provides some ❉❉ Lack of recognition that microbiology requires external assurance for laboratories, and boosts dedicated trained personnel, leading some professionalism, skills, and morale among facilities and/or ministries of health to rotate staff laboratory staff. frequently. At the national and facility level, a focus should be placed on: ❉❉ Emphasizing services that clinicians value most strongly (for example, blood and cerebrospinal fluid cultures). 94  ■  Drug-Resistant Infections: A Threat to Our Economic Future Endnotes Center for Disease Dynamics, Economics & Policy. The value of a statistical life (VSL) represents the amount that a society 1.  CDDEP (Center for Disease Dynamics, Economics & is willing to pay to prevent one death. Estimates of this value vary widely; however, a global meta-analysis conducted by the Organisation Policy); ECSA-HC (East, Central and Southern for Economic Co-operation and Development (OECD) in 2012 provides Africa Health Community); World Bank Group. VSL estimates for use in policy analysis based on a compilation 2016. Antimicrobial Drug Resistance in East of stated-preference studies. The OECD estimates that the VSL in Africa: Meeting Report. May 2016. member countries is US$1.5 to 2.5 million (Lindhjem et al. 2012). Colson A., Cohen M., Regmi S., Nandi A., The VSL for countries in East Africa can be estimated by adjusting this OECD-specific estimate by the country’s GDP per capita, adjusted Laxminarayan R., Macauley M. K. 2015. for purchasing power parity (Lindhjem et al. 2012). The VSL is then “Structured expert judgement for informing multiplied by the number of deaths avoided to estimate the value of the return on investment in surveillance: the reduced mortality. case of environmental public health tracking.” 2.  For example, a 2006 study (Cosgrove 2006) provides estimates of (Unpublished manuscript.) the cost of treating methicillin-resistant S. aureus (MRSA), VRE, and penicillin- and cephalosporin-resistant Streptococcus pneumoniae, Cosgrove S. E. 2006. “The relationship between compared to non-resistant strains, in the United States. A 2012 study antimicrobial resistance and patient outcomes: (Neidell et al. 2012) compared the cost of health care through hospital mortality, length of hospital stay, and health charges and length of stay for resistant and susceptible infections in care costs.” Clin Infect Dis. 42(Suppl 2): New York hospitals. S82–9. SLIPTA is a WHO system to measure and evaluate the progress of 3.  laboratories toward international accreditation and identify areas for Coulter S., Merollini K., Roberts J. A., Graves N., improvement. Facilities are awarded a rating of up to five stars based Halton K. 2015. “The need for cost- on an on-site audit of laboratory operating procedures, practices, and effectiveness analyses of antimicrobial performance. stewardship programmes: A structured review.” Int J Antimicrob Agents 46(2): 140–9. Dar O. A., Hasan R., Schlundt J., Harbarth S., References Caleo G., Dar F. K., et al. 2016. “Exploring the evidence base for national and regional policy Babo Martins S., Rushton J., Stärk K. D. 2015. interventions to combat resistance.” Lancet “Economic assessment of zoonoses 387(10015): 285–95. surveillance in a ‘one health’ context: a ECSA-HC (East, Central and Southern Africa conceptual framework.” Zoonoses Public Health Community). Strengthening the Role Health. of Laboratories in Tracking Antimicrobial Blomberg B., Mwakagile D. S., Urassa W. K., Maselle Drug Resistance in East Africa; Capacity S. Y., Mashurano M., Digranes A., et al. 2004. Assessment. East, Central and Southern Africa “Surveillance of antimicrobial resistance at Health Community, June 2016. a tertiary hospital in Tanzania.” BMC Public Gelband H., Miller-Petrie M., Pant S., Gandra S., Health 4: 45. Levinson J., Barter D., et al. 2015. The state of Boyce S. P., Berruti A. A., Connolly H., Schniedman M. the world’s antibiotics. 2015. “Evaluating the economic and health Laxminarayan R., Chaudhury R. R. 2016. “Antibiotic costs of investing in laboratories in East resistance in India: Drivers and opportunities Africa.” Washington, DC: The World Bank. for action.” PLoS Med. 13(3):e1001974. Available from: https://openknowledge .worldbank.org/bitstream/handle/10986/ Laxminarayan R., Duse A., Wattal C., Zaidi A. K., 22056/Evaluating0the0conceptual0framework Wertheim H. F., Sumpradit N., et al. 2013. . pdf;sequence=1. [Accessed 2016 Jun 30.] “Antibiotic resistance—the need for global solutions.” Lancet Infect Dis. 13(12): 1057–98. CDDEP (Center for Disease Dynamics, Economics & Policy). 2016. East Africa Public Health Lindhjem H., Navrud S., Biausque V., Braathen N. A. Laboratory Networking Project: Strengthening 2012. Mortality risk valuation in environment, the Role of Laboratories in Tracking health and transport policies. Organisation Antimicrobial Drug Resistance in East Africa. for Economic Co-operation and Development. Laboratory-Based Surveillance of AMR: Summary Report  ■  95 Available from: http://www.oecd.org/ ResistanceMap [Internet]. 2016. Center for Disease environment/mortalityriskvaluationinenvironment Dynamics, Economics & Policy. Available from: healthandtransportpolicies.htm. [Accessed http://resistancemap.cddep.org. [Accessed 2016 Jun 30.] 2016 Sep 15.] Neidell M. J., Cohen B., Furuya Y., Hill J., Jeon C. Y., Springmann M., Godfray H. C., Rayner M., Glied S., et al. 2012. “Costs of health care- Scarborough P. 2016. “Analysis and valuation and community-associated infections with of the health and climate change cobenefits antimicrobial-resistant versus susceptible of dietary change.” Proc Natl Acad Sci USA organisms.” Clin Infect Dis. 55(6): 807–15. 113(15): 4146–51. Opintan J. A., Newman M. J., Arhin R. E., Donkor E. S., Van Boeckel T. P., Gandra S., Ashok A., Caudron Q., Gyansa-Lutterodt M., Mills-Pappoe W. Grenfell B. T., Levin S. A., et al. 2014. “Global Laboratory-based nationwide surveillance of antibiotic consumption 2000 to 2010: An antimicrobial resistance in Ghana. Infect Drug analysis of national pharmaceutical sales data.” Resist. 2015 Nov 18;8:379–89. Lancet Infect Dis. 14(8): 742–50. Annex 9. Antimicrobial Use in Human Health Care and AMR: Summary Report 98  ■  Drug-Resistant Infections: A Threat to Our Economic Future M isuse of antimicrobials in humans is prevalent resistance to antibacterials. The terms “antibiotic” in both low- and high-income countries. and the more general term “antimicrobial” are used Observers routinely find, for example, serious interchangeably in this report. overuse of antibiotics for viral upper respiratory tract infections—but underuse of appropriate antibiotics for pneumonia; and serious overuse of antibiotics A. Purpose, Rationale, and in acute cases of diarrhea—but underuse of oral rehydration solution (Kathleen 2011). Findings of the Case Studies Multiple studies1 have found that the causes Case Study 1—Antibiotic contributing to the spread of AMR in countries include numerous factors related to the production, Market Offer distribution, and use of antimicrobial agents in Purpose: Review the list of antimicrobials authorized human health care. Among these factors are: by the Ministry of Health or equivalent agency in excessive numbers of antimicrobials in the the participating countries to analyze drug approval, pharmaceutical market, aggressive pharmaceutical offers, and marketing processes. promotion, economic incentives whereby prescribers Rationale: A reasonable antimicrobial offer in the gain income from dispensing or selling the medicines pharmaceutical market could improve the selection they prescribe, over-prescription or irrational of appropriate antimicrobials and how these drugs prescription in primary health care facilities and are prescribed and used. Two specific considerations hospitals, poor adherence to infection prevention were: and control protocols in health facilities, and treatment interruption by patients. In sum, many ❉❉ The introduction of antimicrobials that do not features of antimicrobial use in human health care have proven superiority over already marketed contribute powerfully to AMR. Improving antimicrobial products—sometimes referred to as “me-too stewardship in the human health system is thus a key drugs”—increases the cost of medicines and the objective for all countries pursuing AMR containment. unnecessary exposure to promotional activities This report provides tools that can help countries that contribute to AMR. advance towards that objective. ❉❉ Some fixed-dose combinations (FDCs)2 which Rather than generalizing widely from the specific include an antimicrobial in their formulation country experiences reported in our case studies, this do not offer any clear advantage to the use of report aims above all to demonstrate methods that the components separately. Additionally, they countries can use to diagnose the functioning of their increase the risk of involuntary exposure to own antimicrobial use chain and identify measures antimicrobials because prescribers or users that would improve antimicrobial stewardship are not aware that the product contains an in their specific contexts. Our concluding action antimicrobial. recommendations are geared toward this goal. Findings: To complement the findings from a literature review ❉❉ There were significant differences in the six conducted for this report (Figueras et al. 2016), case countries regarding the type and number of studies in six low- and middle-income countries available antimicrobials (Figure A9.2). Peru and (Botswana, Croatia, Georgia, Ghana, Nicaragua, Botswana have almost twice as many different and Peru) were prepared from November 2015 to antimicrobials as Georgia, Nicaragua, or Croatia. April 2016 to provide a cross-country “snapshot” of factors in the health system that may contribute to ❉❉ The variability is explained in part by the high AMR. In comprehensively examining the antimicrobial number of bio-equivalent drugs offered as use chain, the objective was to identify the weak different brand-name drugs containing the same links and factors that may contribute to misuse or active ingredient (Figure A9.3), and also by the overuse of antimicrobial drugs, along with possible multiplicity of “me-too” or redundant medicines. interventions to promote more prudent use of these ❉❉ The proportion of FDCs, relative to single brand- agents. Figure A9.1 describes the therapeutic chain name products, ranged from less than 20 percent processes reviewed and sources of data collected for (Croatia and Peru) to almost 30 percent (Ghana). generating country comparisons. The case studies carried out focused on bacteria, antibacterials, and Antimicrobial Use in Human Health Care and AMR: Summary Report  ■  99 FIGURE A9.1.  A Basic “Antimicrobial Use Chain” Link/issue Key actors Case studies Counterfeit AM producers Marketing and distributors Marketing offer authorization Big Pharma Case study 1 Regulations Health Authorities Public health expenditure Marketing and Case study 2 promotion Academia Scientific soc. Healthcare-aquired infection Diagnosis and Case study 4 prescription Prescribers Dispensation Pharmacists Multidrug-resistant TB Case study 5 Administration Nurses and other health professionals Dispensation without prescription Use and Case study 3 self-medication Patients ❉❉ The proportion of brand names per individual Case Study 2—Antibiotic antimicrobial also varied significantly among Consumption in the Public countries, being lower in Croatia (3:1) and higher in Peru (7:1). Such a plethora of products with Health System the same ingredients causes confusion among Purpose: Review expenditure data in the public prescribers and users, complicates antimicrobial health system to analyze prescription and selection and therapeutic decision making, consumption processes at the national level. and increases pharmaceutical promotional pressure (useful for the manufacturer, but not Rationale: Consumption data analyses are useful beneficial and indeed often counterproductive to identify potential misuse of antimicrobials in the for prescribers and users). The “ideal minimum” health system. The combination of market offers and of brand names to ensure clinically adequate consumption data is helpful to identify appropriate coverage and maintain prices should be antimicrobial use. encouraged. Findings: ❉❉ Some antimicrobials found in the different ❉❉ Data on consumption of antimicrobials expressed countries are not sold in the United States in units were available in the participant and in European Union countries (for example, countries, although the data were not always sultamicilin, netilmicin, prulifloxacin, or comparable. Harmonizing information about nifuroxazide), and some have been withdrawn antimicrobial consumption in terms of defined from the market due to their toxicity (for example, daily doses (DDDs) helps analyze cross-country fusafungine). This demonstrates the lack of consumption patterns. harmonization in regulatory schemes—where such schemes exist. ❉❉ Consumption in the system tended to be higher, in per capita terms, in countries with higher per capita GDP, although the relationship was not 100  ■  Drug-Resistant Infections: A Threat to Our Economic Future FIGURE A9.2.  Single-Compound Antibacterial Products Brand Names Brand Names/Active Country Active Ingredients* (Products) Ingredient Presentations** Botswana 76 304 4.0 613 Croatia 59 168 2.9 306 Georgia 53 238 4.5 388 Ghana 44 271 6.3 399 Nicaragua 55 274 5.0 396 Peru 77 513 6.7 1,226 *Individual antibacterials; **Different strengths and packages. Peru and Botswana have about twice as many antimicrobial drugs on the market as Georgia, Nicaragua, or Croatia. These are  “me-too” or redundant medicines. T  he average number of different marketed brand names per single antibacterial is almost 2.5 times greater in Peru and Ghana than in Croatia.  hat is the added value of having an average of six different brand names containing the same antimicrobial agent? Besides W confusing the prescriber and user, this may contribute to increased pressure on firms to sell more antimicrobials than their competitors, in order to preserve and/or expand market share. FIGURE A9.3.  Top Five Active Ingredients According to Number of Brand Names Country 1st (n) 2nd (n) 3rd (n) 4th (n) 5th (n) Botswana Amoxicillin (18) Metronidazole (17) Erythromycin (16) Gentamycin (11) Ciprofloxacin (11) Croatia Cefuroxime (14) Azothromycin (10) Ciprofloxacin (9) Moxifloxacin (9) Metronidazole (8) Georgia Ceftriaxone (27) Azithromycin (27) Chloramphenicol (15) Amoxicillin (13) Amikacin (10) Ghana Ciprofloxacin (38) Cefuroxime (31) Ceftriaxone (26) Azithromycin (23) Metronidazole (22) Nicaragua Ciprofloxacin (33) Azithromycin (18) Metronidazole (16) Amoxicillin (14) Clarithromycin (13) Peru Ciprofloxacin (69) Azithromycin (43) Amoxicillin (32) Clarithromycin (28) Levofloxacin (23) Levofloxacin, clarithromycin, and azithromycin are broad-spectrum, second-choice, expensive antimicrobials.  There is no clinical or therapeutic justification for having 27 products containing ceftriaxone in Georgia, 23 containing  levofloxacin in Peru, or 13 containing clarithromycin in Nicaragua.  A redundant market offer increases the risk of irrational or inappropriate use of antimicrobials. statistically significant. The lowest consumption four to six different antimicrobials represented was in Ghana (2015 per capita GDP $1,381) 90 percent of the total consumed units, while and the highest in Botswana (2015 per capita in Peru and Georgia, the same share of total GDP $6,360) and Croatia (2015 per capita GDP consumed units was divided across 15 and $11,535). Consumption data for private health 19 different antimicrobials, respectively. This services providers and self-medication were not finding suggests that in the first set of countries available. the public prescription of antimicrobials may be more tightly controlled (either by restricted drug ❉❉ The most consumed antimicrobials differ among lists or better adherence to drug guidelines). A countries. In Botswana, Ghana, and Nicaragua, comprehensive consumption analysis including Antimicrobial Use in Human Health Care and AMR: Summary Report  ■  101 public and private sectors would help further by observed practices in some of the study assess country patterns. countries. In Croatia, for example, the second antimicrobial in expenditure was azithromycin ❉❉ The list of the most consumed antimicrobials, (AZM), which has unique pharmacokinetic and in units, in each country was dominated by pharmacodynamic characteristics that give it antimicrobials that are sold under different brand unusual clinical properties for an antibiotic. names (Figure A9.4). The specific rankings differed to some extent among countries. The Azithromycin is used to treat or prevent a range observed difference probably does not reflect of common bacterial infections, including upper different disease profiles, because some of and lower respiratory tract infections and certain these antimicrobials are second-line or broad- sexually transmitted diseases. Azithromycin spectrum. The high use of some antimicrobials has become one of the top 15 most prescribed suggests irrational prescription and use. drugs and best-selling antibiotics. However, a (For example, among the most prescribed growing body of evidence derived from post- antimicrobials are azithromycin, imipenem- marketing surveillance, including analysis over cilastatin, dicloxacillin, or cefuroxime). an eight-year period by the U.S. Food and Drug Administration Adverse Event Reporting System ❉❉ Examples of potential inappropriate use of (FAERS), links azithromycin to sudden cardiac antimicrobials that could not be detected by death risk (Giudicessi and Ackerman 2013). careful analyses of macro prescription and Researchers have also noted additional risks expenditure data are nonetheless provided associated with widespread use of azithromycin, FIGURE A9.4.  Top Five Antimicrobials Consumed (Units/1,000 Population; Except in Georgia, Where Data Are in Defined Daily Doses/1,000 Population) SWA PER HRV GHA GEO NIC amoxicillin 134 2,215 268 278 4,607 amoxicillin + 976 1,353 clavulanic Shows broad-spectrum antimicrobial or   azitromycin 565 1,357 antimicrobial used in case of resistance cefalexin 371 ceftriaxone 90 4,130 cefuroxime 344 ciprofloxacin 646 309 132 1,300 1,292 clindamycin 872 cloxacillin 91 co-trimoxazole 182 Shows a relationship between most-   consumed antimicrobials and antimicrobials dicloxacillin 1,046 with most marketed brand names for that active ingredient doxycycline 38 1,326 isoniazide 1,092 metronidazole 129 330 899 nitrofurantoine 2,687 penicillin 160 In all participant countries, a relationship is observed whereby antimicrobials marketed under a larger number of brand names exhibit higher consumption. 102  ■  Drug-Resistant Infections: A Threat to Our Economic Future as the drug is a serious pollutant in the strongly suspected to be caused by susceptible water environment. Accordingly, experts have bacteria. recommended that azithromycin be used only in ❉❉ These country examples highlight the need to situations where well conducted clinical studies closely survey potential problems that can be have demonstrated an indisputable superiority identified from macro consumption data, but that over standard treatment or placebo (Cohen and should be monitored locally, in order to design Grimpel 2013; Gros et al. 2010). the most appropriate interventions. ❉❉ Imipenem + cilastatin (second in Peru) and meropenem (third in Peru and fifth in Croatia) are examples of expensive antimicrobials Case Study 3—Antimicrobial that should be treated as reserve drugs. Availability Without Prescription Although meropenem is an expensive product, Purpose: Document dispensation and advice 79 units/1,000 inhabitants were prescribed provided to self-referred patients after a young in Croatia during the study period, while in woman simulating lower urinary tract infection Peru, 44 units/1,000 inhabitants were sold symptoms visited 20–50 pharmacies. in the same period. In the case of the fixed- dose combination of imipenem + cilastatin, Rationale: Pharmacists are often the first point 30 units/1,000 inhabitants were prescribed in of contact with the health care system in many Peru. While this figure appears relatively low, it is countries, and their dispensing practices for self- important to note that this agent was the second referred patients contribute to rational or irrational most expensive antimicrobial in Peru, according use of antimicrobials. Indeed, in many low- and to our study findings. Beyond the high cost, middle-income countries, pharmacists are the de there is the problem of potential irrational use facto prescribers of the drugs that are sold and of such restricted antimicrobials. Depending on consumed by patients. their availability, these drugs tend to be used as Findings: empirical treatments. ❉❉ In more than 60 percent of pharmacy visits by ❉❉ Although it is difficult to compare the participant the case study’s simulated “self-referred patient” countries, the macro data of the antimicrobial (156 out of 246 visits), antimicrobials were consumption profile in Nicaragua appear more dispensed without a prescription derived from aligned with principles of rational prescribing. appropriate clinical diagnosis. This practice in The only antimicrobial consumed that attracts five of the six countries studied reflects limited attention is dicloxacillin, third in the expenditure or absent enforcement of health regulations that ranking of this country, with a prescription rate prevent dispensing of antimicrobials without of 593 units/1,000 inhabitants. Dicloxacillin is an prescription. Croatia was an exception (only one example of the beta-lactam antimicrobials useful dispensation in 20 visits). See Figure A9.5. in bacteria resistant to penicillinase; for this reason, it is strongly recommended to use it only ❉❉ In more than 90 percent of the visits, the to treat or prevent infections that are proven or simulated self-referred patient was not clinically evaluated: for example, the pharmacist did FIGURE A9.5.  Distribution of “Simulated Self-Referred Patient” Visits That Ended with Dispensation of an Antimicrobial, by Country 100% 80% 60% No 40% Yes 20% 0% BWA CRO GEO GH NIC PE Antimicrobial Use in Human Health Care and AMR: Summary Report  ■  103 TABLE 5.  Antimicrobials Dispensed without Prescription In orange, products with more brand names or irrational fixed-dose combinations, by country Specific Antimicrobials Dispensed Country (number of pharmacies dispensing the antimicrobial) Botswana norfloxacin (11), amoxicillin + clavulanic acid (7), ciprofloxacin (7), metronidazole (2), nalidixic acid (1), nitrofurantoin (1) Croatia amoxicillin + clavulanic acid (1) Georgia ciprofloxacin (11), doxyciclin (2), norfloxacin (1), amoxicillin (1), furacillin (1) Ghana amoxicillin + clavulanic acid (10), cefuroxime (7), ciprofloxacin (5), cefuroxine + tinidazole (4), cefixime (1), fluconazole (1) Nicaragua nalidixic acid + phenazopyridine (9), nitrofurantoin (7), ciprofloxacin (4), cefixime (2), nitrofurantoin + phenazopyridine + ciprofloxacin, cefadroxil, furazolidin, gentamycin, levofloxacin, ofloxacin Peru norfloxacin + phenazopyridine (16), ciprofloxacin + phenazopyridine (14), ciprofloxacin (7), nitrofurantoin (2), levofloxacin (2), amoxicillin + clavulanic acid (1) Source: Case study 3, data from 156 pharmacies that agreed to sell antimicrobial without prescription in the six study countries. not ask the patient about drug allergies. Such Rationale: HAIs are a growing global problem, not negligence can place patients at severe risk of only in terms of associated morbidity, mortality, and developing drug-related complications, including increased health care costs, but because of the drug ineffectiveness, adverse drug effects, growing recognition that most HAIs can be prevented overdosage, underdosage, and multiple-drug (Lobdell et al. 2012). interactions. ❉❉ Some HAIs are avoidable if health professionals ❉❉ The pattern of antimicrobial recommendations by involved in hospital care follow the necessary pharmacists in the different countries reflected prophylactic measures and infection prevention the prevailing pharmaceutical market offer in control norms. each country (Table 5). For example, irrational ❉❉ The problem of HAIs is greatly aggravated by fixed-dose combinations with phenazopyridine the increasing presence of resistant and multi- were common in Peru and Nicaragua. Also, resistant microorganisms and inappropriate a relationship was observed between some antimicrobial use. “redundant” products and high dispensation (for example, cefuroxime with 31 brand ❉❉ Reducing HAIs requires a multifaceted, holistic names in Ghana accounted for 25 percent of response, because the problem involves multiple dispensations). actors and processes in the therapeutic chain. ❉❉ Advice to visit a physician was provided in Findings: 48 out of the 90 simulated cases in which no ❉❉ Health personnel in selected hospitals in the antimicrobial was dispensed (53 percent of study countries recorded a number of factors that cases); the remaining 47 percent of pharmacist appeared to contribute to observed onset of HAIs. interactions with “fake” self-referred patients These included structural deficiencies, such as ended without treatment and without advice to lack of safe water and basic sanitation systems, visit a physician for follow-up consultation. and operational problems, such as overcrowded wards, lack of cleaning supplies and protective Case Study 4—Hospital-Acquired equipment, or poor hand hygiene practices. Infections (HAIs) These findings underscore the need to address both structural factors and health care processes Purpose: Review medical records or information in efforts to reduce the spread of resistant provided by health care providers on patients with microorganisms that cause HAIs. HAIs in one or more hospitals to analyze adherence to guidelines, compliance with prophylactic ❉❉ Adherence to Infection Prevention and Control measures, prescription, and health care quality (IPC) protocols was partial overall, and sometimes assurance processes. 104  ■  Drug-Resistant Infections: A Threat to Our Economic Future poor. Rigorous compliance with IPC protocols is a multiple aspects of AMR. Moreover, problems necessary and highly effective means to prevent in treating TB can indicate a country’s or infection in health care facilities. institution’s readiness (or otherwise) to deal with AMR. ❉❉ Access to patients’ information and data quality were poor. Researchers frequently noted ❉❉ Observation of a number of cases in the study incomplete and improperly recorded information, countries served to identify relevant issues or found hospitals requiring fees to provide data at the level of the individual patient, the end from medical records, despite Ethical Committee user of antimicrobials. Adherence to treatment guidance. is especially difficult for diseases that, once controlled, can be asymptomatic. ❉❉ Urgency sometimes dictates empirical treatment based on the experience and judgment of health Findings: care personnel. For example, a dangerous ❉❉ Multidrug-resistant tuberculosis is a growing infection with an unknown organism may be problem. MDR-TB and XDR-TB depend on genetic treated with a broad-spectrum antibiotic while modifications of the causal TB microorganisms the results of bacterial culture and other tests (M. tuberculosis). To control the spread of are awaited. In some of these cases, reserve disease, it is important to understand the antimicrobials are prescribed, although the mechanisms that contribute to the appearance microbe might be sensitive to a “less strong” of MDR. antimicrobial. For example, in Croatia, all 24 analyzed cases received an antimicrobial ❉❉ Possible causes of AMR in particular patients appropriate to the causal bacteria, but in one- were inferred from their treatment history. “Non- third of patients, the causal organism was adherence to treatment” was a frequent comment ultimately determined to be sensitive to common in the medical reports of patients with MDR-TB. antimicrobials. Knowing the resistance patterns ❉❉ Specific causes of withdrawal from treatment in the microorganisms associated with an HAI is for MDR-TB (and other diseases) vary and are important to improve the precision of empirical important to identify, understand, and address. treatments and avoid an unnecessary switch of antimicrobials later in the treatment course. ❉❉ For example, in Botswana, the appearance Reserve antimicrobials should be prescribed only of MDR-TB was attributed to patients’ non- when need has been demonstrated. adherence to treatment in four of ten cases. Inability to tolerate the prescribed medicines ❉❉ HAIs tend to complicate the recovery of was reported to have contributed to patients’ hospitalized patients. For example, in seven out withdrawal from treatment in three out of ten of nine analyzed cases in Georgia, recovery time cases. varied between 45 and 120 days. Four of nine patients died as a result of HAI complications. ❉❉ Eight MDR-TB patients were identified in two Ghanaian hospitals. For all patients, there was complete information regarding onset dates, Case Study 5—Multidrug-Resistant initial treatment, and changes in the treatment Tuberculosis regime. This allowed researchers to understand Purpose: To analyze treatment compliance, a the temporal sequence between the initial TB review of the medical records of MDR-TB patients in diagnosis and the MDR-TB diagnosis. All patients one or more hospitals was conducted, after health had at least one relapse, but three out of eight professionals helped identify MDR-TB cases. patients had four, three, and two relapses, respectively. Moreover, five of the patients had Rationale: Multidrug-resistant tuberculosis is a failed to come for treatment; they were without growing global public-health problem. Data from treatment for 50, 26, 25, 20, and 14 days, WHO show that, in 2012, there were 450,000 respectively. Lack of adherence to treatment new cases of MDR-TB, and that extensively drug- increases risk of MDR-TB or XDR-TB. Personal, resistant tuberculosis (XDR-TB) has been identified in family, cultural, religious, and financial factors 92 countries. may explain the lack of adherence to treatment. ❉❉ Failures along the therapeutic chain for MDR- ❉❉ Findings from Peru show the diversity of causes TB increase the risk of AMR. MDR-TB exhibits contributing to poor treatment adherence or Antimicrobial Use in Human Health Care and AMR: Summary Report  ■  105 withdrawal from treatment. Nonmedical causes interventions to include in countries’ AMR action for poor adherence included transportation plans. To this end, consideration should be problems linked to financial constraints. Some given to the establishment of global, regional, patients reportedly interrupted or abandoned or national observatories of grey literature and therapy because they lived far from treatment local studies. This would increase understanding facilities, and out-of-pocket transportation costs of real-world practice in antimicrobial use and were unsustainable for patients and families. facilitate the design of pragmatic interventions. More strictly medical causes of non-adherence ❉❉ Better use of information and communications included: the length of the treatment course; technologies (ICT). To improve knowledge difficulties in treating comorbidities; adverse of antimicrobial consumption and related reactions to some medications; and patients’ expenditures, and to detect problems of decisions to seek alternative or traditional antimicrobial overuse or inappropriate use, efforts treatments. should be made to promote the transition to ❉❉ Another observation in Peru was the number of electronic recording of consumption data, and to family members living together who had MDR- electronic medical records. This would require the TB. Up to 23 patients had one or more relatives definition of minimum common information to be diagnosed with TB, including 16 with MDR-TB. included in such systems to facilitate analyses and comparisons. Training in the use of ICT tools would be needed for health professionals, B. Recommendations including health governance authorities. Such training could encompass electronic database research, analysis of results obtained from Overuse and misuse of antimicrobials contribute databases, and awareness of biases that significantly to AMR. On the basis of the literature may arise due to the characteristics of such review and case study findings, some targeted information. or system-oriented approaches were identified to improve rational prescribing and a more prudent use Use of electronic records has the potential to of antimicrobials. They are outlined here. help identify patterns related to antimicrobial misuse by health personnel, health care facilities, and among patients. Electronic records might From Surveillance to also guide the adoption of corrective measures. “Surveillance + Action” Similarly, there may be opportunities to capitalize To address the imbalance of information in the on “big data” research by aggregating data sets health system and counteract the pharmaceutical to generate new knowledge for policy making industry’s often indiscriminate promotion of products and program development. ICT tools could be to prescribers and dispensers, a systematic effort to harnessed to track antimicrobials after their collect data and generate evidence on antimicrobial market introduction to determine their safety and use practices is required. Promising tools and efficacy, and any emergence of adverse effects. approaches include: ❉❉ Antimicrobial Stewardship Programs (ASPs) have ❉❉ Drug-utilization studies (DUS). These can help proven efficacy in controlling AMR by improving identify failures in any link of the therapeutic how antimicrobials are used and in reducing the chain. Designing and developing DUS with use of broad-spectrum antimicrobials in health the active participation of the involved health care facilities. ASPs have a bigger impact if they professionals could help identify problems combine different methods and approaches and and contextually appropriate solutions within are adapted to local culture and peculiarities particular settings. of antimicrobial use. The adoption of these programs should be promoted, and health ❉❉ Knowledge management. Local information professionals should be trained appropriately, regarding the use and misuse of medicines is including those working in nonhospital health not published in indexed medical journals and facilities. Antimicrobial stewardship is critical for remains as “grey” medical literature. Easy access improving patient outcomes, reducing adverse to this source of knowledge would help policy events, decreasing health care costs, and makers identify appropriate context-specific preventing spread of AMR. 106  ■  Drug-Resistant Infections: A Threat to Our Economic Future Various definitions and models of ASPs exist. Prevention of Antimicrobial Misuse According to the U.S. CDC, core elements of hospital at All Levels ASPs may include: ❉❉ Governance arrangements. AMR is aggravated ❉❉ Leadership commitment: Dedicating necessary by antimicrobial misuse. This problem is made human, financial, and information technology worse by the absence of effective legislation resources. and regulations that influence prescribing ❉❉ Accountability: Appointing a single leader through restrictions and requirements, including responsible for program outcomes and pharmaceutical registration, limited medicine accountable to an executive-level or quality- lists, prescribing restrictions, and dispensing focused hospital committee. Experience with restrictions. Given the special nature of successful programs shows that a physician or antimicrobials, a separate legal and regulatory pharmacist leader is effective. framework and payment/reimbursement modalities could be adopted to promote ❉❉ Drug expertise: Appointing a single pharmacist appropriate use of these drugs. Such special leader responsible for working to improve arrangements already exist in the pharmaceutical antibiotic use. sector for opioids. ❉❉ Action: Implementing at least one recommended ❉❉ Legislation and regulations. Countries may action, such as systemic evaluation of ongoing strengthen their capacity to control AMR by treatment need after a set period of initial developing new legislation and regulations treatment (antibiotic “time-out”). or revising existing ones. This could include ❉❉ Tracking: Monitoring antibiotic use and developing enforcement capacity to control and/or resistance; process measures (for example, remove any financial incentives to individual adherence to facility-specific guidelines, time providers and institutions to use antimicrobials to initiation or de-escalation); and impact on indiscriminately. Deliberate managerial patients (for example, antibiotic-related adverse strategies can strengthen the capacity of effects or emergence of Clostridium difficile national authorities to institute and enforce legal infections). measures in the health system for promoting and ensuring rational antimicrobial use. The ❉❉ Reporting: Regular reporting of information deployment of such strategies merits priority related to these condition to doctors, nurses, and attention from governments. Adequate oversight relevant staff. of both supply and demand in the antimicrobial ❉❉ Education: Clinicians can be educated about market also requires effective coordination with disease state management, resistance, and non-health sector entities (for example, in trade optimal prescribing. Training can also encompass and customs, finance, veterinary, and specialized adoption, adaptation, promotion, and adherence international agencies). monitoring for treatment protocols and guidelines. ❉❉ Oversight of offer and prescribing. The spread of Training on prudent use of antimicrobials and AMR, simultaneous lack of access to effective clear information about common diseases that antimicrobials in many poor communities, and should not be routinely or preventively treated evidence of rampant misuse of these drugs with antimicrobials is a paramount concern. in the health system reinforce the need for ❉❉ Incentives: The adoption and implementation political commitment to strengthen oversight of the above measures could be promoted by of antimicrobial market offer and dispensing positive financial incentives, while removing practices. perverse incentives for prescribers. Measures Two areas where priority adoption of oversight could include changes in how health care measures is likely to yield immediate benefits providers are reimbursed, and prohibiting are limitations on the market offer of fixed-dose antimicrobial sales by prescribers to remove the combinations and reduction in the number of financial incentive for overprescribing (U.S. CDC “uniquely-named” products. Progress in these 2014). two areas will help prevent confusion among providers, patients, and payers, and improve therapeutic options and health outcomes. Antimicrobial Use in Human Health Care and AMR: Summary Report  ■  107 The formulation, adoption, and adaptation our literature review and country cases studies of clinical guidelines advising against using confirmed. or unnecessarily prescribing antibiotics for ❉❉ Information, educational, and communications common problems should also be reinforced with campaigns that incorporate behavioral and dedicated training, supervision, and monitoring social aspects and address both health services and evaluation of prescription patterns in health personnel and the general public are also facilities, pharmacies, and among individual essential. This effort should include the provision doctors. Measures toward effectively combating of accurate, evidence-based information counterfeit/substandard antimicrobials and grounded in actual clinical practice and not only increasing compliance with “by prescription only” on data from clinical trials. labeling are also critical actions to be pursued. Authorities may launch national and local ❉❉ Harm reduction from nonprescription sales campaigns to raise public awareness of the need of antimicrobials is another priority area for to avoid demanding and unnecessarily using action. Obtaining antimicrobials in pharmacies antibiotics for common conditions. Children and without a prescription was a common practice adolescents, in particular, should be the focus in the studied countries. Widespread training to of well-designed and innovative campaigns to explain the risks of inappropriate dispensation, promote the appropriate use of medicines in strict enforcement of norms and regulations, general and antimicrobials in particular. While accompanied by fines and legal consequences doctors should not overprescribe antimicrobials, it may help prevent harm caused by inappropriate is also important that patients not indiscriminately use of antimicrobials. Croatia is the only country demand them, under the influence of manipulative among the six studied that can serve as an drug advertising. The country case studies example of good practice. found many examples of such supplier-induced ❉❉ Decreasing the risk of hospital-acquired antimicrobial use. infections is very important, both because of the vulnerability of immunocompromised hospital patients and because of the high risk of AMR Countries Can Win the Battle emergence and spread in health care facilities. By providing frontline data on antimicrobial use in By spreading disease in settings where patients human health in six countries, our discussion has come for healing, HAIs fundamentally undermine underscored the multiple complexities involved in the mission of hospitals and other health attempting to contain AMR. Moreover, our analysis facilities. Unfortunately, hospitals and health has not yet touched the question of antimicrobial facilities are also the places where multidrug- management in veterinary health. Thus, the overall resistant diseases are most likely to emerge. picture emerging from our discussion may appear Many structural and care-process factors discouraging. However, as we conclude this report, involved in the prevention of HAIs need to be we want to emphasize that some countries have addressed, including: availability of safe water already begun to confront antimicrobial stewardship and basic sanitation services in health care challenges systematically, with impressive results. facilities; medical waste management systems Progress is possible. It’s already happening. and provision of related training to health Clearly, to reduce growing AMR risks, antimicrobials personnel; unbroken availability of cleaning must no longer be considered as “just another drug.” supplies; deployment of infection prevention These are unique products that have the potential, and control measures; and adherence to clinical if well handled, to save vast numbers of lives and guidelines and recommendations for the proper significantly improve population health. However, use of antimicrobials and reserve drugs. unlike most other medicines, antimicrobial agents ❉❉ Non-adherence to treatment regimens is can lose their efficacy for whole human populations another factor to control since the emergence of with disconcerting speed, if their use is poorly numerous cases of drug-resistant pathogens can managed. Promotion of the prudent use of medicines be traced to this source. Treatment compliance in general and antimicrobials in particular should is important for infectious diseases generally, be at the core of efforts to prevent AMR in health but it is vital in severe conditions such as TB, as systems. Programs and interventions to ensure rational use of antimicrobials should be seen as 108  ■  Drug-Resistant Infections: A Threat to Our Economic Future an integral part of continuous quality-assurance The Netherlands program demonstrates that a processes for improving the delivery of safe, effective comprehensive national effort to reduce antimicrobial health and medical care services for all. mis- and overuse and contain AMR can succeed. The responsibility for promoting rational use of antimicrobials clearly includes policy makers, pharmaceutical companies, health system Endnotes administrators, and health services providers. But this To assess the state of knowledge about AMR in the health system, 1.  is just the beginning. Responsibility for protecting the a PubMed literature search was undertaken for this report using efficacy of these crucial agents must also be shared “antibiotic,” “utilization,” and “resistance” as keywords. The search by patients themselves, and the wider public. What is covering the 2013–2015 period retrieved 981 references, which were required is a society-wide effort, based on scientific reviewed and summarized. References were retrieved, organized and evidence, to act in all settings where antimicrobials analyzed by Ishani Premaratne (WB) and Paul Pérez (FICF). Albert are used. Figueras, with input from Patricio V. Marquez, prepared a summary note “Antimicrobial Use and Resistance: Initial Observations from Reviewed In countries where such a society-wide effort has Literature,” March 8, 2016, used for this report. been undertaken, remarkable gains have been A combination drug is a fixed-dose combination (FDC) that includes two 2.  achieved. A recent study of the experience in or more active pharmaceutical ingredients (APIs) combined in a single the Netherlands has confirmed that it is possible dosage form, which is manufactured and distributed in fixed doses to reduce AMR to low levels across a national (Collier 2012). population (Sheldon 2016). To do so requires active promotion and effective coordination between the health and agricultural sectors, working together References under a One Health approach. But success also demands implementing policy and operational Arnold, K. E., Brown, A. R., Ankley, G. T., & Sumpter, measures in the health system to create a different J. P. 2014. “Medicating the environment: medical culture. For example, in the Netherlands, Assessing risks of pharmaceuticals to wildlife antibiotics are supplied only on prescription at and ecosystems.” Philosophical Transactions the primary care level, which serves an effective of the Royal Society B: Biological Sciences gatekeeper function in the health system. The study 369(1656), 20130569. http://doi.org/10.1098/ documents that Dutch doctors do not overprescribe rstb.2013.0569. antimicrobials, and Dutch patients do not routinely demand them, reflecting a culture of “cautious Chung The, H., Rabaa, M. A., Pham Thanh, D., prescribing” built up over time. et al. 2016. “South Asia as a Reservoir for the Global Spread of Ciprofloxacin- Part of creating this culture has been general Resistant Shigella sonnei: A Cross-Sectional practitioners’ acceptance of strict professional Study.” PLOS Medicine | DOI:10.1371/ guidance. Indications for use, type, and dosage of journal. pmed.1002055 (Publ. August 2, antimicrobials are issued by the College of General 2016). Available at: http://journals.plos.org/ Practitioners (NHG), and these guidelines are plosmedicine/article?id=10.1371/journal increasingly followed. A 6 percent decrease in daily .pmed.1002055. doses of antibiotics dispensed by pharmacies was recorded between 2011 and 2014 alone. Cohen, R., and Grimpel, E. 2013. “Rational and irrational azithromycin use.” Arch Pediatr 2013 The Dutch experience also reflects a deliberate (Nov; Suppl 3): S104-7. doi: 10.1016/S0929- policy and operational decision to prioritize control of 693X(13)71418-0. AMR through sustained work on hospital infections. This effort has been coordinated through the Collier, R. 2012. “Reducing the pill burden.” CMAJ national Prevention Working Group, while prudent 184 (2). doi: 10.1503/cmaj.109-4076. antimicrobial use has also been promoted through Dutch Working Party on Antibiotic Policy website. a Working Group on Antibiotic Policy. The effective Accessed at: http://www.swab.nl/english, on application of these measures has helped the September 2, 2016. Netherlands achieve one of the lowest levels of AMR in the world. Figueras, A., and Marquez, P. V. 2016. “Antimicrobial Use and Resistance: Initial Observations from Antimicrobial Use in Human Health Care and AMR: Summary Report  ■  109 Reviewed Literature.” Summary note prepared Marquez, P. V. 2014. “Antimicrobial Resistance: A as an input for this report. new global public health ‘ticking bomb’?” World Bank Group Blogs, July 28, 2014. Figueras, A., Premaratne, I., Pérez, P., and Marquez, Available at: http://blogs.worldbank.org/health/ P. V. 2016. “Approach to Antibiotic Misuse and antimicrobial-resistance-new-global-public- Resistance in 6 Countries: A Comprehensive healthticking-bomb. Series of Case Studies.” Report prepared as a background paper for this report. Premaratne, I., and Pérez, P. 2016. “PubMed Literature Search on Antimicrobial Use and Giudicessi, J. R., and Ackerman, M. J. 2013. Resistance.” References retrieved, organized “Azithromycin and risk of sudden cardiac and analyzed using “antibiotic,” “utilization,” death: Guilty as charged or falsely accused?” and “resistance” as keywords. Search Cleveland Clinic Journal of Medicine 80(9): covered the 2013–2015 period and retrieved 539–44. 981 references, which were reviewed and Gros, M., Petrovi´c, M., Ginebreda, A., and Barceló, D. summarized for the preparation of this report. 2010. “Removal of pharmaceuticals during Sheldon, T. 2016. “Saving antibiotics for when wastewater treatment and environmental they are really needed: The Dutch example.” risk assessment using hazard indexes.” Br Med J 354:i4192 (Publ. August 3, 2016). Environment International 36: 15–26. U.S. CDC. 2014. Core Elements of Hospital Antibiotic Kathleen, A. H. 2011. “Promoting the rational use of Stewardship Programs. Atlanta, GA: US antibiotics.” Regional Health Forum 15 (1). Department of Health and Human Services, Lobdell, K. W., et al. 2012. “Hospital-acquired CDC. Available at http://www.cdc.gov/getsmart/ infections.” Surg Clin N Am 92: 65–77. healthcare/. Annex 10. Antimicrobial Use in Animals and AMR Issues and Options for Low- and Middle-Income Countries: Summary Report 112  ■  Drug-Resistant Infections: A Threat to Our Economic Future W ithout progress in tracking and controlling or as part of routine health management. In addition drug-resistant infection sources in animal to these therapeutic uses, antimicrobials may also populations, efforts to contain AMR in human be used as animal growth promoters, based on communities cannot achieve lasting success. This continuous delivery of sub-therapeutic doses. report seeks to clarify what we know and don’t about Overall, the use of antimicrobials currently translates antimicrobial use and AMR in livestock today, with a into more stable and, in some cases, higher incomes view to informing policy makers’ decisions on how for farmers. Antimicrobials benefit consumers, best to engage the livestock production sector in as well, by enabling greater animal-source food country efforts on AMR. production, leading to more accessibly priced The discussion draws on sources including a livestock products. However, the use of antimicrobials literature review, country case studies, and a regional also creates evolutionary pressures that allow the case study. We first summarize what is currently selection and spread of resistant microorganisms. known about the use of antimicrobials in animal Excessive and inappropriate use of antimicrobials production systems, the reasons producers use accelerates the emergence of resistance (see Box 1). these drugs, and the limited available data on usage Increasing emergence and spread of AMR will affect trends over time. Next, we analyze the mechanisms the capacity to treat animal infectious diseases. by which antimicrobial use in animal production Ultimately, this will undermine current livestock systems may engender AMR in animals and humans. production practices and create uncertainties in food The report then reviews current strategies to reduce production systems. antimicrobial use in livestock and the obstacles these Livestock species and animal production systems efforts face. The closing pages describe specific vary by regions, countries, and areas within actions countries can take to limit antimicrobial use countries. The roles of the veterinary profession in livestock and contain the AMR threat in animal and government veterinary services in antimicrobial production. The options proposed align with the WHO distribution, use, regulation, and enforcement also Global Action Plan, the FAO Action Plan, and the OIE vary.2 Surveillance, monitoring, and regulatory strategy on AMR. infrastructure to address antimicrobial use in animals creates costs for countries. However, such infrastructure can also generate significant benefits Background and Research by regulating the use of antimicrobials, limiting Questions overuse and misuse, and reducing AMR risk. The research summarized in this annex has focused Antimicrobial use in livestock1 is an important on the following four issues: component of health management as defined by the 1. The costs of antimicrobial use in livestock, in OIE Terrestrial Code (Box 6). Antimicrobials are used terms of financial costs at the farm level and to treat clinical and subclinical infectious diseases the costs of registration, manufacture, and in animals. In some production systems, they are distribution by the pharmaceutical industry; also used to prevent diseases, either because of an increased risk of exposure (metaphylactic treatment) Box 6. Animal Health Management Animal health management is “a system designed affecting the individual animal and herd, including the to optimise the physical and behavioural health recording of illness, injuries, mortalities, and medical and welfare of animals. It includes the prevention, treatments where appropriate.” treatment and control of diseases and conditions Source: OIE Antimicrobial Use in Animals and AMR   ■  113 2. Benefits from the use of antimicrobials in been made and a suggestion that future estimates livestock, in terms of animal health and food be based on more systematic, comprehensive data production; collection. 3. The impact of AMR on productivity and production costs in livestock, with the collection of data, where possible, on any linkages to human and B. Use and Role environmental health; of Antimicrobials 4. The costs that would be involved in controlling in Animal Production antimicrobial use in animals so as to minimize AMR: including the costs associated with A number of authors have attempted to compare the monitoring use, authorization, regulation, and overall amount of antibiotic used in humans versus in enforcement, and the cost of implementing animals worldwide. One global study concluded that alternative approaches to livestock production quantitatively, by weight of active ingredient, more and animal-health management that may be antimicrobials are now used in food production than indicated to limit AMR. in humans. This relationship varies by region and country, however. A. Literature Review In livestock, antimicrobials are not only used for therapeutic purposes (to treat and prevent infectious and Gaps in Knowledge diseases); they are also used for nontherapeutic purposes. Not long after antibiotics were first used There have been a number of extensive reviews in human medicine, in the 1950s, it was discovered of antimicrobial use in livestock and animals with that they had the effect of promoting more rapid regard to the emergence and spread of AMR (Grace growth when given to farm animals at low doses, 2015; Landers et al. 2012; Rushton et al. 2014; Van helping the animals reach full market weight more Boeckel et al. 2015). Of note, much of the literature quickly. Subtherapeutic quantities of some antibiotics is focused exclusively on antibiotics, since these (for example, procaine, penicillin, and tetracycline), are the medicines about which there is currently delivered to animals in feed, can enhance the feed- most concern regarding the impact of resistance to-weight ratio for poultry, swine, and beef cattle. on human health. The term “antimicrobial” is often The purpose of using antimicrobials in animal used to mean only antibiotics, rather than including production systems is not only to contribute to anthelmintics, antifungals, antivirals, antiseptics, and animal health and welfare, but also indirectly to disinfectants. Similarly, AMR in this context often contribute to human welfare by improving food refers specifically to drug-resistant bacteria. security, food safety, and producer livelihoods. As it A review commissioned by the OECD, supported by potentially increases producers’ earnings through a global estimate of antimicrobial use (Van Boeckel greater livestock productivity, the use of antibiotics et al. 2015), indicates that much is known about in livestock also indirectly contributes to poverty the biology of resistance mechanisms. However, the alleviation. epidemiology of AMR in livestock and its impact on human and animal health have not been studied in detail. Little concrete information has been Quantifying the Use of generated on this topic, beyond the observation of Antimicrobials Globally an association between the use of antimicrobials in There is wide variation in estimates of the total animals and an increase in the levels of resistance annual global antibiotic consumption in livestock, found in those animal production systems (Bisdorff ranging from around 63,000 to over 240,000 metric et al. 2012; van Cleef et al. 2015). Of note, most tons. With growing human populations and increasing reviews to date have relied on antimicrobial usage demands for food, the quantities of antimicrobials data from a limited number of countries, with used in livestock production are expected to rise estimates of usage in other parts of the world steadily as well. It is suggested that the global based on modeling of livestock populations and consumption of antibiotics in agriculture will extrapolation of usage from countries with data. increase by 67 percent from 2010 to 2030, and that There are concerns about how these estimates have consumption of antibiotics in the five major emerging 114  ■  Drug-Resistant Infections: A Threat to Our Economic Future national economies, Brazil, China, India, Russia, and example livestock-associated methicillin-resistant South Africa, could increase by 99 percent in the Staphylococcus aureus (MRSA). In such scenarios, same period. the economic impacts of AMR will likely be greatest in low- and middle-income countries, with the It is, however, difficult to obtain exact figures on poorest regions of the world disproportionally the use of antimicrobials. Causes include weak affected. capacity among veterinary services to collect data at the country level. It is especially difficult to obtain figures in low- and middle-income countries, Antimicrobial Use in Livestock where the majority of livestock animals are kept on and AMR in Low- and Middle- smallholdings and where antimicrobials are often sold without prescription. In these countries, official Income Countries controls on the manufacture, importation, distribution, Effective livestock health management requires sale, and use of antimicrobials tend to be weak. knowledge of current antibiotic use in local animal In addition, as discussed earlier in this report, there production systems, the purposes of such use, and is growing concern over parallel markets, based the factors influencing livestock owners’ decisions on the production, distribution, and use of illegal, to deploy antibiotics or refrain from doing so. This counterfeit, or suboptimal drugs. The share of such information is also crucial for effective antibiotic markets in some regions could be substantial. stewardship. However, as noted, in most low- and middle-income countries, veterinary antimicrobials including C. Emergence and Impact antibiotics are sold over-the-counter without veterinary prescription. These agents are essentially of AMR in Livestock available without restriction. Most sources of information do not specify whether antibiotics are A number of medically important antibiotics are also used for growth promotion rather than treatment or administered to animals in agriculture via feed or prevention of diseases. As a result, it is difficult to water. Out of the 27 different antimicrobial classes track antimicrobial use, not only as regards quantities used as growth promoters in livestock, only nine and classes, but also the species in which these classes are exclusively used in animals. Even some drugs are used and the specific purposes of use. second-line antibiotics for humans are being used in animals, with no replacements for these agents in What appears certain is that the current increase in human use as yet in view. demand for animal-source food is fueling an increase in antimicrobial use. This increase in demand reflects Very little information is available about the impacts rising populations in developing countries, alongside of AMR on the productivity of livestock production increasing wealth, urbanization, and changing dietary systems. The lack of data or data aggregation means preferences. These factors are driving a change in that the health and economic costs related to AMR dietary practices, in which consumption of eggs, are also difficult to estimate. It is known that the milk, meat, and farmed fish is increasing much more consequences of AMR in both high-income countries rapidly than the consumption of staples or pulses. and low- and middle-income countries would include failure to successfully treat infections, leading to This in turn is spurring changes in how animals are more prolonged illness, production losses, death, farmed. Poultry, pig, and fish production is increasing and negative consequences for livelihoods and food fastest, and ever more animals are kept in high input/ security. Among other consequences, if medicines high output intensive systems. In some instances, used to prevent and cure diseases no longer work, this development has been based on genetically then animals would be less productive and potentially improved breeds or lines, some of them poorly die prematurely. adapted to local conditions, either from the point of view of basic physiology and animal performance, As discussed in detail in Part II, AMR could also or from the standpoint of health and susceptibility impact trade in livestock and livestock products. to infectious diseases. Rising animal numbers and Food consumers may be increasingly concerned changes in farming systems, against a background about contamination risks from imported products, of endemic and epidemic diseases, are expected to while producers may worry about importing animals increase the use of antibiotics in low- and middle- which might carry resistant microorganisms, for Antimicrobial Use in Animals and AMR   ■  115 income countries’ animal production systems—with result in antimicrobial residues in tissues, milk, or a corresponding rise in the risk of AMR. eggs. These residues are usually present in very small amounts and most of them do not create Indeed, several studies suggest that AMR is already public-health problems, as long as their toxicological common in agricultural systems in low- and middle- significance is below a predetermined threshold. income countries. Resistance primarily appears to However, if present in high concentrations, the concern first-line antibiotics. However, there is a residues can have important public-health and high level of uncertainty on the available figures, economic implications, such as: allergic reactions, either because of the methodology used to produce selection of resistant pathogenic and nonpathogenic them, or because of the partial representativity of the bacteria, toxicity, and carcinogenicity of certain food underlying studies. products. The most important cause for the occurrence of Transmission Pathways for AMR antimicrobial residues in animal tissues is insufficient Any use of antimicrobials (in human, animal, plant, time for the drug to be eliminated from the body or environment) creates evolutionary pressures that of the animal before slaughter or harvesting of can generate AMR. Resistant bacteria and genetic food, such that the persisting residue exceeds the material conferring resistance in bacteria can then maximum residue limit. Maximum residue limits be transmitted from animals to humans in multiple for residues of veterinary drugs are the maximum ways. Mainly this transfer occurs through the food concentrations of residues legally permitted in or on a chain, from close or direct contact with animals, and food, as determined by the internationally recognized through the environment. Whether all three routes of standards of the Codex Alimentarius Commission. transmission are equally important remains unclear. It is important that veterinarians, producers, and To date, public-health measures have tended to focus farmers respect the prescribed withdrawal times primarily on the food system to ensure that food prior to slaughter or harvesting of food products. consumers are not affected. This minimizes the risk of AMR emerging through consumption of animal-source food products. Transmission pathways other than food may be significant, however. A proportion of antibiotics used in food animals are excreted unmetabolized and enter sewage systems and water sources. Animal D. Measures to Reduce waste may contain resistant bacteria, and could Antimicrobial Usage also contain antibiotics that could then foster the emergence of AMR beyond those in an animal’s and Find Alternatives gut—including bacteria that may pose a greater risk to humans. Manure from farm animals is often used Some countries have already banned the use of on crops as fertilizer. This has been shown to create antibiotics for growth promotion. Banning this use resistance in soil organisms. Such mechanisms need in livestock has generally resulted in a substantial further specific exploration to document precise decrease in antibiotic resistance. Other countries transmission pathways and environmental impacts. have also engaged in voluntary re-labeling of antibiotics to reduce their use as growth promoters The OIE Terrestrial and Aquatic Codes provide and help tackle at source the problem of AMR arising guidance on how to assess AMR risk arising from the in livestock. Some countries have also put in place use of antimicrobials in animals.3 The antimicrobial policies for drastic reductions of therapeutic uses, compounds used and how they were used, microbial with subsequent impact on the incidence of AMR. co-selection, fitness and persistence mechanisms, host lifestyle, and food treatment conditions are Given poor or nonexistent monitoring of the use of among factors that influence the antibiotic resistance antimicrobials in livestock and the associated impacts cycle. on production, public health, and environmental health, it can be a challenge to generate the interest among decision makers that is required to bring Significance of Antimicrobial about positive change. This applies particularly to Residues lower middle-income countries. An incentive for the creation of national monitoring systems could The administration of antimicrobials to farm animals, be that the economic impact of an eventual global both therapeutically and for growth promotion, may 116  ■  Drug-Resistant Infections: A Threat to Our Economic Future ban on antimicrobial use for growth promotion promotion (Cheng et al. 2014). Currently, only a small would be more severe in lower-income countries number of bacterial diseases can be prevented and because of less optimized production systems. A controlled by the use of vaccines, although antiviral further incentive to raise awareness and encourage vaccines can help to maintain general health and the fight against AMR might be to compare benefits reduce antibiotic use to treat secondary infections, or from antimicrobial use in animals against both viral infections having similar clinical manifestations. their financial cost and the risks of antimicrobial Other approaches including immunomodulators resistance. This approach can make the problem and feed enzymes mainly preserve the health of less abstract and encourage livestock producers to animals, but do not directly kill or inhibit bacteria. change the way they use antimicrobial medicines. In Bacteriophages are currently only used in food, and developing countries, where the burden of infectious their safety is still questionable. The composition diseases remains high, successful interventions have of plant extracts and probiotics is complex and been based on either educating farmers or training the quality in terms of stability is poor, resulting in veterinary auxiliaries, who in turn explain to farmers varying effects and safety risks. the potentially negative consequences of using Inhibitors targeting quorum sensing (QS) and antimicrobials. virulence of bacteria are still in research with no Some argue that, given production systems’ lack of approved products, and most inhibitors are also resilience, the sudden withdrawal of antibiotics as toxic to eukaryotic cells. Biofilm inhibitors show growth promoters in lower middle-income countries good results only when used in combination with would have major negative consequences. However, antibiotics. Although antimicrobial peptides (AMPs) European countries were able to impose a ban on the can treat bacterial infections, the high cost and use of growth promoters without excessive, long-term narrow antibacterial spectrum restrict their use, negative impacts on productivity, profitability, animal and they can still induce bacterial resistance. health, or welfare. The feed industry developed Meanwhile, proteinaceous compounds, for example, alternative approaches to growth promotion, and feed enzymes and AMPs that have been put on good practices were adopted to ensure healthy herds the market, as well as bacteriophage lysins, QS and flocks. This level of resilience to growth-promoter quenching enzymes and enzymatic biofilm inhibitors or prophylactic use bans may not exist among under development, are naturally unstable and easily farmers in developing countries, where such a ban degraded in the digestive tract. could lead to the use of (poor-quality) antimicrobials No information could be found on the actual costs obtained on the black market—exacerbating the of these alternative therapies. The economic problem—or to a considerable increase in disease, impacts of such alternative interventions will vary with consequent losses due to livestock mortality across producers, depending on location, farm size, and morbidity. Of note, the ban on antimicrobials for contracting arrangements, production variables, growth promotion in the European Union in 2006 management, and existing health and sanitation resulted in an initial increase of disinfectants and processes. Again, the economic effects of a complete therapeutic use of antibiotics in animals, probably ban of antimicrobials will be more strongly felt in due to an increased incidence of infectious diseases. countries where animal management and hygiene One response to AMR applicable to animal production practices are suboptimal. There is little economic systems may be the development of new, alternative research on preventive strategies such as enhanced treatments that might partially replace antimicrobials. farm biosecurity and better animal hygiene. No Several alternatives that could substitute for studies were found that assess cost-effectiveness of antibiotics in targeting bacterial infections have these different interventions. been proposed, including: antibacterial vaccines, A set of alternatives to the use of antimicrobial immunomodulatory agents, bacteriophages and agents in pig production were ranked by an expert their lysins, antimicrobial peptides, pro-, pre-, and knowledge elicitation process (Postma et al. 2015a). synbiotics, plant extracts, inhibitors for bacterial The ranking was based on perceived effectiveness, quorum sensing, biofilm and virulence, and feed feasibility, and return on investment. The top five enzymes. measures in terms of perceived effectiveness were: There is still a considerable gap between antibiotics improved internal biosecurity, improved external and these proposed alternatives, in terms of biosecurity, improved climate/environmental effectiveness in disease prevention and growth conditions, high health/specific pathogen free/ Antimicrobial Use in Animals and AMR   ■  117 disease eradication, and improved water quality. ❉❉ Lack of understanding of the drivers and needs The top five measures in terms of perceived for the use of antimicrobials in animal production feasibility were: increased vaccination, increased systems remains a strong obstacle to positive use of anti-inflammatory products, improved water change. quality, feed quality/optimization and use of zinc/ ❉❉ There is no or limited information on the cost of metals. The top five measures in terms of perceived alternatives to antimicrobials. return of investment were: improved internal biosecurity, zinc/metals, diagnostics/action plan, ❉❉ Performance of national veterinary public-health feed quality/optimization, and climate/environmental systems and resilience of animal production improvements. This study showed that with rather systems will be key factors in successfully simple and inexpensive measures, pig investments reducing reliance on antimicrobials. could be increased. Improvements in biosecurity In light of this stocktaking of knowledge on AMR in seemed to rank high in almost all cases, with higher livestock production, our research has proceeded biosecurity resulting in healthier animals. The to examine the nature and characteristics of findings of this study highlighted the benefits of an antimicrobial use in livestock in order to illustrate the improved internal and external biosecurity status at magnitude of the potential AMR problem in low- and the farm. These results appear relevant to efforts middle-income countries. Our research has used four to keep animals healthy while reducing need for sources of information: antimicrobials. No study of a similar kind in lower middle-income countries was identified, but it can be ❉❉ Country case studies—An assessment of the assumed that findings would be similar. level of antimicrobial use in the livestock sector was made for Morocco, Chile, Thailand, and Uganda.4 The costs and benefits of antimicrobial E. Summary of What We Know usage were estimated, and weaknesses in the systems of manufacture, marketing authorization, and Major Knowledge Gaps distribution, storage, prescription, and end-use of antimicrobials identified. The study looked for Prudent and responsible use of antibiotics and trade-offs between the benefits of use and the continuous development of alternatives to antibiotics associated costs, including emergence of AMR. are needed to ensure the long-term, sustainable The importance of the institutional environment development of animal production systems. Key was also considered. results from our survey of the relevant literature can ❉❉ OIE global survey—The OIE conducted a survey be summarized as follows: of its member countries in late 2015, as a part of ❉❉ The use of antimicrobials in animal production the OIE’s program to develop a system for data systems covers therapeutic and nontherapeutic collection on antimicrobial (specifically antibiotic) purposes, including growth promotion. use in animals at a global level. Our analysis primarily used the survey data from lower middle- ❉❉ Antimicrobials are an important component of income countries. animal health management, and the impact of AMR goes far beyond public health. ❉❉ Regional case study—The use of antimicrobials should be related to the animal ❉❉ There is a general lack of data on the use of population it is intended for. Data should be antimicrobials in animal production systems, presented per population correction unit, which particularly in low- and middle-income countries. requires that the livestock sector be properly ❉❉ There is a link between the use of antimicrobials described and data made available. Our study in animals and the emergence of AMR in included a regional case for description and humans; the pathways for transmission of AMR presentation of animal production systems. The are not limited to the food chain, and are poorly region chosen was South America. documented. ❉❉ Other sources of information—Our study ❉❉ While it is difficult to quantify the use of has also included other sources of information antimicrobials in animal production systems, it is identified in the course of the literature review. projected that this use will increase significantly in some parts of the world. 118  ■  Drug-Resistant Infections: A Threat to Our Economic Future Key Considerations for Each of the Studies ❉❉ In the case of the lowest-income country, there were clear capacity issues, particularly in Country Case Studies the control over end-usage of antibiotics and ❉❉ The country case studies were conducted in in surveillance for AMR. Residue monitoring four countries, ranging in per capita GDP from was also lacking, and was more likely to be approximately $700 to $14,500 (PPP $1700 to developed where export markets were more $22,000) (World Bank, 2015 data). significant. Whilst it is recognized that residue monitoring does not relate to antimicrobial ❉❉ The main finding of the case studies was a use overall, if such monitoring is linked to serious deficiency in data required to undertake market access for products, then it provides economic analysis of antimicrobial use, the pressure for more nuanced and informed use of impact of AMR, and the costs and benefits of veterinary medicines, including antimicrobials. alternative approaches. In all countries, obtaining The latter point indicates that it is possible to data on antimicrobial manufacture, import/ manage antimicrobial use at the latter stages of export, and usage across species was difficult. production, and to be truly effective this needs to It was also problematic to achieve any sort be linked to markets that have a mechanism to of standardization or comparability between convey this need across the food animal system data that were available. Areas of divergence to the producers. This is more likely to apply included: the time period to which the different in countries with export markets, which drive datasets pertained (both within country and standards. between countries), whether data related to all antimicrobials or only antibiotics, how the weight ❉❉ Systems for collecting data on antimicrobial of active ingredient had been calculated, and sales and use in animals need to be improved whether all animal species were included or only in most cases. This accords with the findings of terrestrial species. Most of the AMR information the OIE surveys of 2012 and 2015, though some in the case study countries comes from research progress has been observed. Countries have studies, but is not comparable or consistent made efforts to improve, with one-off exercises in methodology and not linked to the use of to allow completion of the OIE 2015 survey and, antimicrobials. in one case, a significant program planned to establish ongoing monitoring systems. Country ❉❉ In all cases, the use of antibiotics as growth surveillance systems for AMR were found to promoters was either banned or in the process be poorly developed. In all countries, there had of being banned, and in the latter cases it was been studies of AMR in bacteria from animals, not possible to distinguish the quantity used for but passive surveillance was not observed in the prophylactic purposes versus growth promotion lower middle-income countries studied, while purposes. active surveillance programs were only just being ❉❉ In all countries, it was possible to establish the implemented and were largely export driven. size of the livestock sectors at a national level There was no surveillance activity in the lowest and to characterize the production systems, income country. although the way data were presented nationally ❉❉ The lowest income country in the group was varied between countries. Farm level information the only country where no significant national was, however, almost completely absent, and changes were yet ongoing, though there were data on the output of livestock products each detailed studies being run by universities, as year were inconsistent, with different data well as one supported by WHO. This country sources sometimes contradicting each other. study also reported the least control over the ❉❉ All countries had in place some structures and dispensing of antibiotics for animal use, and the institutions of government and industry for lowest level of surveillance for AMR, and this controlling the manufacture, import, distribution, coincided with much less intensive systems of sale, and use of animal medicines, including livestock production. Where export markets exist antimicrobials. All countries had facilities for for animal products, much greater efforts and laboratory testing to isolate bacteria and test investment are being made to establish control antibiotic sensitivity. However, the robustness and systems. There is a noticeable increase in activity effectiveness of these structures and institutions in this area very recently. varied greatly. Antimicrobial Use in Animals and AMR   ■  119 ❉❉ Data on pricing were not available in most ❉❉ It is clear that the building blocks for future cases, and in no case was the government analyses need to be put in place as a matter involved in setting or controlling prices of of urgency, along with policy initiatives which veterinary medicines. There appear to be no give countries confidence to take a transparent specific fiscal policies with regards to the use of approach. The most basic requirements for future antimicrobials in the livestock sector. Although analysis would be standardized data collection on some data were available on the overall value of the use of antimicrobials and AMR. As mentioned the pharmaceutical sector, farm-level medicine earlier, OIE is developing a system for data costs which would be necessary to evaluate collection that will be refined and enhanced over alternatives to antibiotic use were only available time. Absolute quantity data need to be matched in the high-income countries studied and were by data on the animal populations, levels of presented mainly as total animal health costs, production, and production systems to which rather than being disaggregated to allow specific this usage relates, in order to develop a robust understanding of antimicrobial costs. and standardized denominator. Work to establish a global denominator is under way at the OIE. ❉❉ A major question raised by the case studies Publication of guidelines and frameworks, based concerns the relative importance, in terms of on intergovernmental standards adopted by OIE risk related to AMR, of uncontrolled usage in member countries, could assist countries in extensive systems versus the higher levels of setting up harmonized systems and methodology usage in intensive systems even in the presence for data collection on the use of antimicrobials, of greater control. The data available through the AMR, population, and production. case studies would not allow any assessment of whether uncontrolled usage of antibiotics in OIE Survey extensive systems poses a threat in terms of ❉❉ OIE conducted a survey of its member states in AMR development, or the extent of the threat late 2015 with a response rate of 131 countries presented by the use of antibiotics in intensive out of 180. Nearly three-quarters of low- and systems supplying export markets. In order to middle-income countries provided information. inform the prioritization of future investments, it However, there are regional variations. would be helpful to analyze whether countries with extensive systems and weak control over ❉❉ Of those low- and middle-income countries antimicrobial use have reason to worry in terms that reported data on the use of antimicrobials, of AMR emergence, or whether control efforts are approximately one-half provided qualitative data best focused on exporting countries where any and a further half the basic level of information mismanagement of antibiotics could have much around quantitative data. Only four out of 74 wider impacts globally. low- and middle-income countries provided fully detailed data on the use of antimicrobials under ❉❉ The case studies provide a stark illustration of the highest-level reporting option (which had the deficiencies in data that currently exist in been mainly used by EU countries, for example). both lower middle-income countries and high- income countries (though these were more acute ❉❉ Eighty percent of reporting low- and middle- in the lower middle-income countries studied), as income countries stated that their official system well as the sensitivities that surround such data. authorized the use of antimicrobials for growth It was not possible in any of the case country promotion in 2015. The main antimicrobial studies to undertake detailed economic analysis classes used for growth promotion are: of antimicrobial use and the impacts of AMR, aminoglycosides, amphenicols, cephalosporins or to assess the economics of alternatives to (all generations), fluoroquinolones, the use of antimicrobials. In many cases, there glycophospholipids, lincosamides, macrolides, was a genuine lack of capacity to collect and nitrofurans, penicillins, polypeptides, analyze these data nationally. In other cases, quinoxalines, streptogramins, sulfonamides it was evident the countries were not willing to (including trimethoprim), and tetracyclines. This share data, due perhaps to the comparatively list is based on a very low level of responses and high profile of the AMR debate and the potential should be treated with caution. sensitivities of countries’ trading partners. 120  ■  Drug-Resistant Infections: A Threat to Our Economic Future ❉❉ At this stage of the OIE program of data collection cattle, chickens, and pigs would use 45, 148 and on the use of antimicrobials in animals, there is 172 mg/PCU, respectively. These three species insufficient data available on the quantities of account for 88 percent of the world’s terrestrial antimicrobials used to perform an analysis at the meat production and produce a majority of the global level. milk and eggs consumed by humans. These three species also represent 80 percent of the Regional Case Study—South America domesticated terrestrial animal biomass and are ❉❉ The key consideration from the South American the species that tend to be kept in intensive and case study is the need to improve livestock semi-intensive systems where antimicrobials information systems in countries and make are used for growth promotion, prophylaxis, the information obtained intelligible and widely metaphylactic and therapeutic treatments. available. ❉❉ Of interest in the calculations of antimicrobial ❉❉ The benefit of such systems is the provision of use is a specific estimate from a country in timely data for politicians and decision makers Asia regarding small-scale poultry fattening whose role is to support and facilitate the operations. The total amount of antimicrobial sustainable growth of their countries’ livestock used for relatively long-lived birds was between sectors. In turn, such growth will benefit livestock 52–276 mg per kilogram of live chicken producers, owners of livestock processing production; a high proportion of this amount industries, consumers, and the stability of stemmed from antimicrobials placed in the feed economies that are heavily reliant on the livestock (Carrique-Mas et al. 2013). sector. ❉❉ The 2015 analysis suggests that the benefits ❉❉ Detailed analysis of livestock populations needs from the use of antimicrobials for growth to be matched by detailed data on the use of promotion have become less pronounced since antimicrobials in these populations, in order to they were first introduced in the 1950s (Van assess impact. Boeckal et al. 2015). ❉❉ To date this has not been done for most ❉❉ The analysis also concludes that the use of countries. these growth promoters could be stopped with little or no impact on productivity or other ❉❉ It would be recommendable to update the economic effects. However, the analysis makes estimates of livestock population and production little or no reference to how the hygiene and data for South America and provide a similar production systems found in low- and middle- estimate for Africa and Asia. To estimate demand, income countries differ, compared to the this information would need to be combined with systems where growth promotion effects have likely antimicrobial use by species, system, and been calculated. The authors of this work have product. The supply data could be provided by also not necessarily compared like with like, as information on antimicrobial manufacture and the pigs and poultry and their feed and water the balance of imports and exports. This process systems pre- and post-2000 are not comparable. will probably highlight where gaps exist and The researchers’ arguments on the potential to raise questions on how these will be filled in eliminate antimicrobials for growth promotion and future interventions. By asking questions about perhaps for prophylaxis across low- and middle- livestock, production systems, and antimicrobial income countries need more careful thought, use, this research will ultimately promote critical if protection is to be provided for smallholder thinking on how best to harness antimicrobials in farmers, small-scale traders, and of course the livestock while protecting the drugs’ efficacy and urban and rural consumers in these countries, safeguarding animal and human health. the majority of whom are poor. Other Sources of Information ❉❉ Promising targets for early action to scale back ❉❉ A previous study (Van Boeckal et al. 2015) antimicrobial use in animals might include the calculated antimicrobials per population large, well-organized multinational companies correction unit (PCU), using a Bayesian logistic whose activities span both high-income contexts regression model, and incorporating data from and low- and middle-income settings. These 32 countries that have monitoring systems for corporations have the resources and technical antimicrobial use. Researchers estimated that capacities to rapidly bring production systems Antimicrobial Use in Animals and AMR   ■  121 to a standard where reliance on antimicrobials F. Conclusions and can be reduced. A high proportion of pig and poultry farmers currently working in such systems Recommendations were ignorant of whether they were using antimicrobials or not (Sneeringer et al. 2015). In Overuse and misuse of antimicrobials in animal this context, reducing the use of antimicrobials production systems can be a source of emergence for growth promotion would likely bring only and spread of AMR. This also signifies, however, minor changes in production and productivity. that the livestock sectors in low- and middle-income This would suggest, as has been demonstrated countries could contribute to the effective and in Europe, that current levels of antimicrobial use sustained containment of AMR. in livestock are well beyond a technical optimum and almost certainly beyond an economic Research commissioned for this report set out optimum, if there is stability in prices and health to examine the nature and characteristics of status. antimicrobial use in animals, in order to help to illustrate the magnitude of the AMR problem Potential Interventions and Their Impacts in low- and middle-income countries and ❉❉ The paucity of data and information on the use prepare a comprehensive set of evidence-based of antimicrobials in terms of quantity, class, and recommendations. The research yields the following species-specific use in the large majority of conclusions and recommendations: countries indicates that the basis for making an ❉❉ Improved estimates of the use of estimate of total use and the impact of use is antimicrobials in animals are needed. This lacking, and any such estimates have so far been could be delivered by the OIE data collection guesswork. system in the future, and must be combined ❉❉ More particularly, it is impossible to estimate the with an appropriate description of the livestock financial costs of farm-level use. The necessary production systems at country levels. These data are likewise unavailable to estimate data are critical for AMR containment, which overall benefits in terms of additional livestock can only be undertaken with confidence if the production, which might lead to: (1) producer estimates are adequate. This could be achieved surplus, due to an improvement in productivity; by the collaborative efforts to improve the World and (2) consumer surplus, due to a greater supply Animal Health Information System (WAHIS) at at a lower price. OIE and FAO Statistics (FAOSTAT) at FAO. Both international organizations participate in the ❉❉ The only conclusive cost that can be dismissed Tripartite and have networks and opportunities to at this moment is the research and development inform technical services that are responsible for costs of the most commonly available data collection and analysis in member countries. antimicrobials, since all are now of such age that patent periods have passed. ❉❉ Major knowledge gaps must still be addressed. This includes knowledge on ❉❉ This leads to a further problem: If the current specific interventions and individual countries. antimicrobial use cannot be described with An adequate knowledge base would encompass accuracy, how can the interventions be described understanding of institutional environments, and evaluated to change antimicrobial usage, human behavior, and communication. There are either in terms of reducing or simply optimizing also major difficulties in low- and middle-income use? Therefore the actions themselves are countries in monitoring the use of antimicrobials difficult to prescribe and their impacts in terms of and their residues and in implementing AMR costs, livelihoods and risks even further from the surveillance. piece. In an attempt to indicate what is possible, Table 6 presents a descriptive assessment of ❉❉ Economic arguments can demonstrate the interventions that could be carried out at the the benefits of strengthening human and country level. veterinary public-health systems. There 122  ■  Drug-Resistant Infections: A Threat to Our Economic Future TABLE 6.  Proposed List of Potential Country-Level Actions to Contain AMR in Livestock Estimated Costs, General Impact, Impact on Livelihoods, and Levels of Risk (Authors’ Assessment) Action Cost Impact Livelihood Risks Monitoring Data collection, database No initial impact Short-term low No risks Antimicrobial development and maintenance, Would allow analysis of productivity change Mid-term low Manufacture data analysis and report writing, to medium feedback Monitoring Data collection, database Knowledge and increased control of the Short-term low No risks Antimicrobial development and maintenance, distribution chain Mid-term low Distribution, data analysis and report writing, Would allow evaluation of management options to medium Including feedback analysis of productivity change Importation Monitoring Data collection, database Raise awareness amongst prescribers and Low impact Could be Antimicrobial development and maintenance, data livestock owners risks for the Sales and Use analysis and report writing, feedback Information on human behavior, and the businesses institutional environment that depend on Refinement of policy making antimicrobial sales Monitoring Laboratory equipment and training, Potentially an immediate impact of raising Low impact Could be risks Residues reagents and maintenance, database awareness across the farming system to farmers with development, analysis and report little access to writing, feedback information Surveillance Laboratory equipment and training, Raising awareness Medium to Risks of of AMR reagents and maintenance, study Needs to be linked to policy and private standard high impact creating food design and data collection, database change that is informed by evidence on the links scares development, analysis and report between AMU and the management of AMR writing, feedback Interest for treatment guidance Removal of Potentially low production, Potentially Predicted in developed countries to have little Low to Potential risk Antimicrobial lower farm level productivity, impact on food supply and farm incomes medium of reducing Growth investments in farm infrastructure Yet unknown if these assumptions are impact livestock Promoters (?), investments in farm-level water transferable to other less well supported setting product food quality (?), investments in feed mills with different levels of management supply (?), extension and farm-level support Will require investments and training across the input and farm-level parts of the livestock sector It may improve productivity Reduction and/ Greater risks of disease, lower Lowers costs of antimicrobials Introduces Low to or Change of production and productivity in Lower AMR risks additional risks medium Antimicrobials general, potentially risks to humans Greater disease risk to incomes for Prophylaxis with zoonoses, farm level training on Potential reduction in productivity with impacts management practices, reduction in on food supply practices that cause animal stress Reduction and/ Greater risks of disease, lower Lowers costs of antimicrobials Introduces Low to or Change in production and productivity in Lower AMR risks additional risks medium Therapeutic general, potentially risks to humans Greater disease risk to incomes Use of with zoonoses, farm level training on Potential reduction in productivity with impacts Antimicrobials management practices, reduction on food supply in practices that cause animal May greatly increase zoonotic disease risks stress, may undermine entire farm management practices, need for research to support change Improved Data Data collection, database Medium- to long-term impact to allow the Low to Minimal to low and Information development, analysis and report assessment of productivity change medium risk on Livestock writing, information sharing Improved estimates of the denominator used for Sector Trends AMU Refinement of vaccination strategies These changes can be linked to AMU and AMR changes to guide public policy and private standards and practices Antimicrobial Use in Animals and AMR   ■  123 is a critical need to reinforce these systems, • Couple monitoring and surveillance with and to do so will require the engagement of adequate capacity to assess risks governments, private companies, and individuals related to any detected emergence of involved in livestock production. All these actors AMR. are likely to be sensitive to economic arguments. ❉❉ National targets for the reduction Clarifying the economic case may help change of antimicrobial use attitudes and behaviors around the use of antimicrobials among key stakeholders. • Establish national targets for substantial reductions in the use of antimicrobials in livestock, prioritizing Options for Action at Country Level reductions in nontherapeutic usages. In addition to the broad conclusions just sketched • Establish intersectoral collaboration to out, our research suggests specific policy jointly report national data on the use recommendations, addressed primarily to low- and of antimicrobials, residue monitoring, and middle-income countries. These recommendations AMR. fall under three headings: (1) mitigation options to • Produce annual reports on progress reduce antimicrobial use in animals; (2) strategies against national AMR targets to be to help production systems adapt to reduced submitted to the Tripartite. antimicrobial use; and (3) optimization options to promote responsible and prudent use, given that ❉❉ National standards on antimicrobials, the use of antimicrobials in livestock production will residues, and AMR continue, even if at lower levels. • Analyze legislation and implementation of public and private 1. Mitigation options to reduce the use of standards at the country level, to antimicrobials identify weaknesses in the institutional ❉❉ Monitoring and surveillance at the environment. national level • Strengthen public and private • Design and implement data collection and standards along the antimicrobial supply capture systems to generate national chain for registration, manufacture, data on the use of antimicrobials, distribution, sales, and use of including uses in animals. Data can antimicrobials. be gathered at multiple levels of the • Strengthen implementation of antimicrobial production, supply, and legislation and standards applying distribution chain. to the manufacture and distribution of • Develop a system to collect standard animal feed, in particular medicated feed. data on animal populations, • Establish enforcement systems that production, and production systems. will be activated when inappropriate use This is required to enable standardized of antimicrobials, use of suboptimal or calculations of antimicrobial use in counterfeit antimicrobials, or residues are livestock for each country, using detected; investigate how enforcement internationally accepted units of measure, can be strengthened in resource- such as milligrams of antimicrobials per constrained environments to target areas kilogram of animal mass. of highest risk. • Develop systems to monitor 2. Adaptation of animal production systems to antimicrobial residues in food reduced use of antimicrobials originating from farmed terrestrial and aquatic animals. ❉❉ Resilient animal production systems • Design and implement sample collection, • Identify animal production testing, and data-capture systems for systems that are heavily reliant on risk-based national surveillance of antimicrobials and critical points in AMR in animal production systems. animal life cycles where antimicrobial use is highest and where interventions 124  ■  Drug-Resistant Infections: A Threat to Our Economic Future would have greatest impact in reducing education on potential alternatives to antimicrobial use. antimicrobials. • Engage large private-sector actors, 3. Optimization options towards responsible for example animal feed companies, and prudent use of antimicrobials to develop and test alternatives to antimicrobial use. For example, feed ❉❉ Rationalization of antimicrobial use companies could be incentivized to • Undertake applied research to improve explore alternative approaches to rapid diagnostic methods, which growth promotion. This might include would reduce the use of antimicrobials by development of innovative techniques and establishing the sensitivity of infectious rations to maintain animals’ gut health, agents to antimicrobials before treatment immune systems, and respiratory health. is begun. • Undertake applied research • Investigate the relative AMR risk of on alternatives to the use of poorly controlled use of antimicrobials in antimicrobials under field conditions, extensive systems versus the higher for example, through systems redesign levels of use in better controlled intensive that would reduce the need for systems which have much larger markets antimicrobials. Measures to test might and therefore exposure potential. include improved livestock housing, • Develop appropriate vaccines and genetic selection, vaccination strategies, vaccination strategies to reduce the dietary adjustments, improved hygiene use of antimicrobials in livestock. procedures, and staff training. ❉❉ Education, training, and communication • Undertake research to identify where at national and global levels current levels of antimicrobial use may unnecessarily increase • Educate professionals and livestock production costs, to the detriment of owners on the importance of veterinary producers and consumers. oversight, the need for responsible and prudent use of antibiotics, and the value • Communicate recommended of adhering to prescriptions, including interventions clearly to decision makers. dose rates and withholding periods. • Manage any changes in livestock • Develop advocacy messages on the production practices so as to reduce importance of AMR that will convey disease without compromising food evidence-based guidance on potential supply or animal health and welfare. individual actions; for example, such For instance, developing insurance messages could highlight the financial against livestock diseases for farmers feasibility of alternatives to antimicrobial who do not use antibiotics is impossible use through improved animal husbandry in the current state of veterinary services. and infection prevention in livestock ❉❉ Behavioral and cultural aspects production systems. • Undertake social science research to • Strengthen veterinary education understand how people manage livestock and the role of veterinary professional health at the farm level, including how standards in governing antimicrobial and why they use antimicrobials. use—the extent to which prescribing is Apply knowledge of actors’ motivations required and the veterinarian is involved and decision-making processes to analyze in treatment decisions (when to treat, how their behavior could be influenced to dose, duration). reduce reliance on antimicrobials. • Use OIE Performance of Veterinary • Raise awareness and educate Services (PVS) pathway to identify gaps professionals and livestock owners to and training needs in low- and middle- better understand how antibiotics function income countries, to direct and prioritize and the potential adverse consequences currently available funding, and to help of inappropriate use (including negative low- and middle-income countries impacts on their own health); provide attract additional funding. Antimicrobial Use in Animals and AMR   ■  125 Endnotes .cdc.gov/drugresistance/about.html (accessed May 2015). This term includes poultry and farmed aquatic species. This report 1.  Cheng, G., Hao, H., Xie, S., Wang, X., Dai, M., does not address companion or sporting animals. This report does not address usage of antimicrobials in agriculture other than livestock. Huang, L., Yuan, Z. 2014. “Antibiotic 2. D  efined by OIE as “the governmental and nongovernmental alternatives: The Substitution of Antibiotics in organisations that implement animal health and welfare measures and Animal Husbandry?” Front. Microbiol. 5:217 other standards and recommendations in the Terrestrial Code and the 10.3389/fmicb.2014.00217. OIE Aquatic Animal Health Code in the territory. The Veterinary Services Davies, S., Verde, E., et al. 2013. Antimicrobial are under the overall control and direction of the Veterinary Authority. Private sector organisations, veterinarians, veterinary paraprofessionals Resistance: In Search of a Collaborative or aquatic animal health professionals are normally accredited or Solution. WISH, QATAR Foundation AMR Report. approved by the Veterinary Authority to deliver the delegated functions.” http://www.wish-qatar.org/app/media/385 3. S  ee “Risk assessment for antimicrobial resistance arising from the use (accessed May 2016). of antimicrobials in animals” (Chapter 6.10 of the Terrestrial code). Durso, L. M., Miller, D. N., Wienhold, B. J. The selection of countries aimed for geographic representativeness 4.  and attempted to include at least one lower-income country; the 2012. “Distribution and Quantification of selection was highly constrained by data availability (data availability Antibiotic Resistant Genes and Bacteria even in these four countries was disappointing), budget, and short time across Agricultural and Non-Agricultural available for the study. 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April 2003. www.worldbank.org/data/ dataquery.html.   ■  135 World Bank List of Economies (July 2016) Low-Income Lower Middle-Income Upper Middle-Income High-Income Afghanistan Armenia Albania Andorra Benin Bangladesh Algeria Antigua and Barbuda Burkina Faso Bhutan American Samoa Aruba Burundi Bolivia Angola Australia Central African Republic Cabo Verde Azerbaijan Austria Chad Cambodia Belarus Bahamas, The Comoros Cameroon Belize Bahrain Congo, Dem. Rep. Congo, Rep. Bosnia and Herzegovina Barbados Eritrea Côte d’Ivoire Botswana Belgium Ethiopia Djibouti Brazil Bermuda Gambia, The Egypt, Arab Rep. Bulgaria British Virgin Islands Guinea El Salvador China Brunei Darussalam Guinea-Bissau Ghana Colombia Canada Haiti Guatemala Costa Rica Cayman Islands Korea, Dem. People’s Rep. Honduras Cuba Channel Islands Liberia India Dominica Chile Madagascar Indonesia Dominican Republic Croatia Malawi Kenya Ecuador Curacao Mali Kiribati Equatorial Guinea Cyprus Mozambique Kosovo Fiji Czech Republic Nepal Kyrgyz Republic Gabon Denmark Niger Lao PDR Georgia Estonia Rwanda Lesotho Grenada Faroe Islands Senegal Mauritania Guyana Finland Sierra Leone Micronesia, Fed. Sts. Iran, Islamic Rep. France Somalia Moldova Iraq French Polynesia South Sudan Mongolia Jamaica Germany Tanzania Morocco Jordan Gibraltar Togo Myanmar Kazakhstan Greece Uganda Nicaragua Lebanon Greenland Zimbabwe Nigeria Libya Guam Pakistan Macedonia, FYR Hong Kong SAR, China Papua Malaysia Hungary New Guinea Maldives Iceland Philippines Marshall Islands Ireland Samoa Mauritius Isle of Man Sao Tome and Principe Mexico Israel Solomon Islands Montenegro Italy Sri Lanka Namibia Japan Sudan Palau Korea, Rep. Swaziland Panama Kuwait Syrian Arab Republic Paraguay Latvia Tajikistan Peru Liechtenstein Timor-Leste Romania Lithuania Tonga Russian Federation Luxembourg Tunisia Serbia Macao SAR, China Ukraine South Africa Malta Uzbekistan St. Lucia Monaco Vanuatu St. Vincent and the Grenadines Nauru Vietnam Suriname Netherlands West Bank and Gaza Thailand New Caledonia Yemen, Rep. Turkey New Zealand Zambia Turkmenistan Northern Mariana Islands Tuvalu Norway Venezuela, RB Oman Poland (continued ) 136  ■  Drug-Resistant Infections: A Threat to Our Economic Future Low-Income Lower Middle-Income Upper Middle-Income High-Income Portugal Puerto Rico Qatar San Marino Saudi Arabia Seychelles Singapore Sint Maarten (Dutch part) Slovak Republic Slovenia Spain St. Kitts and Nevis St. Martin (French part) Sweden Switzerland Taiwan, China Trinidad and Tobago Turks and Caicos Islands United Arab Emirates United Kingdom United States Uruguay Virgin Islands (U.S.) Argentina, which was classified as a high-income economy in 2015, is temporarily unclassified pending the expected release of revised national accounts statistics. ■  137 References Ahmed, S. A., M. Cruz, D. S. Go, M. Maliszewska, and I. 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While AMR has long preoccupied the health sector, this report expands the conversation from medicine and public health to economics. The report uses World Bank Group economic simulation tools to put a price tag on AMR’s destructive impacts on the global economy from 2017 through 2050. It shows that, unchecked, drug-resistant infections will severely reduce global economic output and hobble development progress in the decades ahead. But these destructive effects can be avoided. The report highlights actions low- and middle-income countries and their development partners can take to counter AMR, and estimates the investment required. Analyzing costs and benefits under multiple outcome scenarios, the report shows that putting resources into AMR containment now is one of the highest-yield investments countries can make. By investing in the fight against drug resistance, low-, middle-, and high-income countries will all reap exceptional economic rewards. www.worldbank.org