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Designer: Maggie Powell Editor: Robert Livernash Contents Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi A slow-motion tsunami . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Knowledge and implementation gaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x Not just a complex issue; a wicked problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Piecing the AMR puzzle together . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii Taking a new look at an old challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 An endless race . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Time to broaden the tent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 Antimicrobials in modern systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 AMR at the crossroads of economic development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 For drivers of AMR, context matters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 AMR and sustainable development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Tensions surrounding antimicrobials, beyond the way we use them . . . . . . . . . . . . . . . . . . . 14 Access to quality medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Understanding our approaches to date . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Taking a country standpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Antimicrobial pollution in the environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Establishing an enabling environment for AMR control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Smart use of antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Reducing the need for antimicrobial use (adaptation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Interventions involve many steps and many actors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Limiting use of antimicrobials (mitigation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Key knowledge and implementation gaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Mapping knowledge gaps in a research landscape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 When AMR is an inconspicuous issue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Tailoring a research agenda to country needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 The pivot of cobenefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 A primer on AMR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Glossary of selected terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72   iii Foreword Imagine a world rife with infectious diseases that are It also lays out an agenda for the research community impossible to cure, even with powerful antibiotics. Or by identifying knowledge and implementation gaps. In living with the threat of virulent new strains of malaria and particular, implementation research, which focuses on tuberculosis that are resistant to tried and tested medical improving the effectiveness of interventions through poli- interventions. For millions of people, especially newborns cies, programs and practices, will be key in moving AMR and the elderly, this is becoming a terrifying reality. knowledge from laboratory settings into the real world. It is vital that all stakeholders know what works in diverse Anti-microbial resistance (AMR), which reduces our abi- and challenging development contexts and tailor solu- lity to treat infectious diseases and breeds ‘superbugs’ tions to specific country circumstances. that are difficult to stop, has emerged in the last decade as a growing threat to public health. This silent pande- Finally, the report urges the development community to mic is already leading to 700,000 deaths per year. If not go beyond technical solutions that focus exclusively on the addressed, AMR could cost millions more lives — or misuse of antimicrobials. We need to redirect development as many as 10 million deaths annually by 2050, which efforts more broadly, so that they become “AMR-smart.” is higher than the death rate for cancer, currently the This means being more conscious of how investments second leading cause of death globally. People living can affect AMR and using available financing more astu- in developing countries and those affected by fragility, tely. This will require applying a rigorous and imaginative conflict and violence are particularly vulnerable. AMR lens to all investments. AMR is not just a health problem, it’s a development pro- In addition to interventions specifically aimed at AMR, a blem. Unchecked, it will impact people’s health and life diverse set of actions across multiple sectors — such as prospects, and ultimately, countries’ human capital. It will improving public health systems, increasing access to also hamper progress towards the 2030 Sustainable Deve- clean water and sanitation, building resilient agriculture lopment Goals and harm economies. If unabated, AMR’s and food systems, educating younger generations on economic impact is projected at more than US$ 1 trillion AMR, or designing urbanization and infrastructure to stop annually after 2030. contamination — will be part of the effort to curb the rise What can we do to put people everywhere on a safer path? of AMR. This report finds that countries can make AMR-related There is no simple cure-all for the AMR challenge, but a investments more efficient and cost-effective by impro- more holistic approach will help ensure that everyone can ving technical capacity and data quality, enhancing inter- look forward to a healthier future. agency coordination and building public awareness of the AMR challenge. Annette Dixon Laura Tuck Vice President Vice President Human Development Sustainable Development iv  Pulling Together to Beat Superbugs Acknowledgments The World Bank team was supported by the External Timothy Grant Evans, senior director of the World Bank Group of Experts, including Evelyn Wesangula (Ministry Group’s Health, Nutrition, and Population (HNP) Global of Health, Kenya), Tim Jinks (Wellcome Trust, United King- Practice, and Juergen Voegele, senior director of the World dom), Suerie Moon (Graduate Institute of International Bank Group’s Food and Agriculture (AGR) Global Prac- and Development Studies, Switzerland), Jaana Husu-Kallio tice, provided substantive input and strategic guidance (Ministry of Agriculture and Forestry, Finland), Frank Moller throughout the preparation of the report, with support Aarestrup (DTU, Denmark), Vincent Lepinay (SciencesPo, from Olusoji O. Adeyi, director of the HNP Global Practice, France), Dieter Schillinger (ILRI/CGIAR, Kenya), Jeff Waage and Martien Van Nieuwkoop, director of the AGR Global (London School of Hygiene and Tropical Medicine, United Practice. Kingdom), Keiji Fukuda (University of Hong Kong), and The case studies were kindly reviewed by Anil Dayakar representatives of the Tripartite [Elizabeth Tayler (WHO), (Gamana, India), Assiongbon Teko-Agbo (EIESMV, Senegal), Elisabeth Erlacher-Vindel (OIE), Ben Davies (OIE), and Philip Amoah (IWMI/CGIAR, Ghana), Daouda Kassie (Institut Suzanne Eckford (FAO)]. Pasteur, Madagascar), Esben Larsen (World Resources Insti- World Bank team: Franck Berthe (lead author), Jonathan tute, USA), Juan Carrique-Mas (Oxford University, Vietnam), Wadsworth (second author/editor), Alessia Thiebaud, Jyoti Joshi (CDDEP, India), Christoph Lübbert (Leipzig Uni- Patricio V. Marquez, and Enis Baris, HNP practice manager versity Hospital, Germany), Marion Bordier (CIRAD, Vietnam), in charge, with advice and inputs from Yoshini Naomi Manuelle Miller (AVSF, France), Nelson Godfried Agyemang Rupasinghe, Timothy Bouley, Manon Hamon, Netsanet (Coalition of Farmers, Ghana), Hung Nguyen (ILRI/CGIAR, Workie, Abigail Goodnow Dalton, Varun Gauri, Richard Vietnam), Nithima Sumpradit (Ministry of Public Health, Damania, Edna Massay Kallon, Robert John Hatton, Robert Thailand), and Suriya Wongkongkathep (formerly Ministry Walter Scherpbier, Aissatou Diack, Luis Alberto Andres, of Public Health, Thailand). Maria Angelica Sotomayor, Richard Seifman, Lilian Puech, The draft report was reviewed by Catherine Machalaba Son Vo, Sara Halstead Hersey, Claire Chase, and Michael (EcoHealth Alliance), Sabiha Essack (University of KwaZu- Morris. lu-Natal), Clare Chandler (London School of Hygiene & Tro- Akosua Dakwa and Zinaida Korableva provided admi- pical Medicine), Lori Sloate (United Nations Foundation), nistrative support. Flore Martinant de Preneuf managed and Olga Jonas (Harvard University). communications. Annie Wang, Melissa Barber, and Geor- The governments of Canada and Norway provided vital gina Neve performed the original bibliographic reviews. financial support for the report. Melissa Barber, Simon Leger, and Kanya Long prepared the case studies.   v Executive summary Antimicrobial drugs such as antibiotics have revolutionized days of penicillin. Scientists have long been aware that the medicine and saved hundreds of millions of lives since their misuse of antimicrobial drugs could accelerate the evolution discovery some 70 years ago. People no longer fear that a of resistant microbes. Over the past three decades, the public simple graze or cut will become septic and that they could health and agriculture communities recognized AMR to be die as a result, and most people now have the freedom to an economic and health problem caused by inappropriate routinely undergo life-enhancing surgery previously thought and excessive use of antibiotics, exacerbated in turn by the impossible due to the high risk of untreatable infections. dwindling supply of new, more effective drugs coming onto the market. At the same time, the AMR literature has grown The rise of antimicrobial resistance (AMR), if not stopped, exponentially from less than 2,000 scientific journal articles threatens to plunge humanity back into an era of health per year in 1990 to over 11,000 in 2018. This report’s exten- uncertainty few people alive today can remember. AMR sive bibliographic review found a broad spectrum of inter- does not follow national borders; its consequences affect ventions to control AMR across three main action areas: (1) the lives of everyone on the planet and blight the pros- establishing and maintaining an enabling environment for pects of future generations. Yet with the right approach AMR control through agenda setting, regulation, legislation, and intelligent investment, the AMR tide can be turned. and surveillance and monitoring; (2) reducing the need for This report sets out a fresh way to look at the AMR crisis. antimicrobial usage through measures to prevent infection It uses a new narrative to identify areas where knowledge such as better hygiene, vaccination, and improved livestock gaps exist and further investigation is needed. It suggests husbandry; and (3) limiting the use of antimicrobials by that too much effort is spent searching for the right solu- means of economic incentives and disincentives, as well as tions in the wrong places, and proposes ways of “pulling education and awareness raising of prescribers and users. together” across traditional institutional and disciplinary boundaries to contain and reduce AMR. The vast majority of published knowledge and evidence covers AMR from the perspective of high-income coun- Antibiotics and other antimicrobials have become an tries (HIC) across a narrow range of subjects. While pro- essential infrastructure of modern society. They are gress on abating AMR has been achieved in some HIC ingrained in our health systems, in our food systems, and situations, there remains a significant gap between pro- in our relaxed approach to risks of minor ailments and posed technical solutions and the reality of implementing injuries. Modern societies are totally reliant on antimicro- them in practice. This implementation gap is even more bials and their continued effectiveness. From a broader acute in low- and middle-income countries (LMICs), which perspective, humanity’s relationship with antimicrobials will bear the greatest burden of AMR’s rising social and can be considered in terms of (a) norms and behaviors— economic impacts. our assumptions, beliefs, and attitudes to antimicrobials Through several country-based case studies, this report in areas such as human medicine, agriculture, livestock, illustrates factors that either enable or block interventions and the environment; (b) use and governance—the roles for controlling AMR in specific LMIC contexts. The report and responsibilities of different actors, industries, insti- identifies knowledge and implementation gaps that merit tutions, and countries; and (c) external trends beyond research attention, together with actionable interventions the system of antimicrobials—such as global population that can be applied now. It particularly focuses attention growth, urbanization, globalization, climate change, and on the importance of local context in carrying out imple- conflicts—that create the conditions for the rapid emer- mentation actions by proposing a typology of countries gence and spread of AMR worldwide. in terms of the interventions likely to provide the greatest The threat of AMR is not new. It is a natural phenomenon benefits. An international summit of AMR experts conve- that Alexander Fleming publicly warned about in the early ned by the Wellcome Trust (2016) agreed: “…even if some vi  Pulling Together to Beat Superbugs evidence gaps remain, meaningful actions need to be aimed at reducing the unnecessary use of and overre- taken immediately to counter AMR, with individual coun- liance on antimicrobials. tries tailoring implementation according to their particular Curbing the rise of AMR demands that it be refocused as national circumstances.” a development problem. Addressing AMR is necessary to In contrast to HIC nations, countries at lower levels of attain many of the sustainable development goals (SDGs), economic development tend to be more exposed to key and it is likewise true that making progress on several contextual risk factors that exacerbate the spread of AMR. SDGs and their specific targets also will contribute to Given the significance of AMR risk factors that increase the tackling AMR. This virtuous synergy should be recognized transmission of AMR in LMICs—such as poor sanitation, lack more widely and exploited more fully. of access to clean water, poor governance, insufficient public Knowledge gaps exist, but they are overshadowed by a health-care expenditures, or poorly regulated private health “doing” gap. Efforts to address AMR are seriously compro- services—efforts to promote prudent and responsible use of mised by the low level of implementation, the fragmen- antimicrobials, while desirable, are not enough for controlling tation of interventions, their poor sequencing in time and the spread of AMR, particularly at lower levels of economic geography, and their deployment in environments that development. In LMIC contexts, interventions that act indi- are not conducive to the AMR control measures selected. rectly on AMR such as water and sanitation improvements, Abundant knowledge exists, yet people do not seem termed AMR-sensitive actions, may have greater impact and to know what to do, or how to do it. This calls for major be more cost-effective in controlling AMR than direct inter- efforts in the field of implementation research to bridge ventions such as banning antibiotics in animal feeds, termed knowledge and actions in real-world settings. AMR-specific interventions. To this effect, it is paramount to build research agendas Two intertwined findings of this report are that (1) AMR in the specific contexts of countries to bridge the imple- needs to be reframed as a global development issue that mentation gap and overcome the shortcomings of best cannot be solved with technical solutions alone; and (2) practice approaches. Out of twenty-three key knowledge AMR-sensitive interventions are often the most cost-effec- and implementation gaps identified in the course of this tive way, especially in LMICs, to overcome the underlying study, one stands out: It is our limited capacity to identify weaknesses in establishing an enabling environment and measure potential cobenefits across a broad array of for successful application of AMR-specific interventions AMR-sensitive interventions in country-specific contexts.   vii Introduction A SLOW-MOTION TSUNAMI You wake up one morning, reach over and grab your Imagine a world where a simple graze or cut could be phone. Your heart sinks when you read a message explai- life-threatening. In addition, simple surgery—not to men- ning that one of your dearest friends is in critical condition tion organ transplantation—could only be conducted at after pulmonary infection and is heading into intensive an unacceptable risk. care. You hope she will come through the experience The report aims to reach a broad audience, beyond those and you might assume that the antibiotics she needs will conversant in AMR. For those unfamiliar with antimicrobial work. It’s exactly that assumption that many of us take for resistance, a primer on AMR is an annex to the report. granted. Every day people across the world rely on antibio- tics; they’ve done so for decades. They are used to treating In April 2016, addressing a high-level dialogue on AMR life-threatening bacterial infections in organ transplants, with UN member countries, Dr. Margaret Chan, at the time chemotherapy, and caesarean sections, as well as to control director-general of the World Health Organization (WHO), diseases and pests in agricultural crops and livestock pro- described antimicrobial resistance as “a slow-motion tsu- duction. Antibiotics and other antimicrobials have become nami.” It may be a slow-moving crisis, but it is nonetheless ingrained in our health systems, our food systems, and our a global crisis that must be managed with the utmost societies. We are now heavily reliant on their effectiveness. urgency, since we know that it is already with us and the costs and consequences will only increase with time. That reality is now disappearing as the emergence and spread of antimicrobial resistance (AMR) threatens the The burden of infections with antibiotic-resistant bacteria health and well-being of people across the world. A in the European Economic Area (EEA) already appears world without effective antibiotics is a problem on many substantial (Cassini et al. 2019). There are increasing fronts. It has been estimated that AMR already costs up reports of patients with infections caused by drug-re- to 700,000 lives per year (O’Neill 2016), although the true sistant bacteria associated with increased risk of worse burden of resistant infections remains uncertain. The clinical outcomes and death, and consuming more number of deaths caused by multidrug-resistant orga- health-care resources than patients infected with suscep- nisms (MDROs) could be more than six times higher than tible strains of the same bacteria. For example, an unpre- the widely cited figures (Burnham et al. 2019). And the cedented epidemic of typhoid caused by a multidrug-re- actual number of treatment failures is probably much lar- sistant (MDR) clone of the bacterium, known as H58, has ger, since there is a strong focus on consequences of resis- rolled across parts of Asia and Africa (Wong et al. 2015; tance to last-resort antibiotics, while the likely much larger Klemm et al. 2018). An outbreak occurred in the Sindh number of treatment failures due to resistance to first-line Province in Pakistan between 2016 and 2018 with 5,274 drugs is virtually unknown. people reported to be affected by extensively drug-resis- tant typhoid (WHO 2018f ). MDR enteric fevers increase AMR stands to take millions more lives; unaddressed, it the cost of treatment and lead to more complications could inflict an economic impact in excess of $1 trillion (Azmatullah et al. 2015). annually after 2030 (World Bank 2017a). Moreover, AMR will disproportionately affect those in low- and middle-in- Globally, resistance in tuberculosis (TB) would by itself come countries (LMICs), making the issue an important account for a third of the AMR burden. In a recent study development challenge. Far beyond public health, AMR following a large multicentered cohort of patients who and the rise of superbugs threaten to undermine seve- were diagnosed with TB between 2013 and 2016, drug ral of the development gains made in the 20th century. susceptibility testing revealed that 62 percent of strains   ix © DOMINIC SANSONI / WORLD BANK were pan-susceptible, 7 percent were resistant to only percent (CDC 2018). Meanwhile, some strains of the cau- one antibiotic, 26 percent were multidrug-resistant (MDR), sative agent of gonorrhea (Neisseria gonorrhoeae) have and 5 percent were pre-extensively or extensively drug developed resistance to all but one recommended drug resistant (XDR). Mortality ranged from 6 percent among combination treatment. patients with pan-susceptible (PDR) TB to 57 percent for In general, resistance is already high in many countries, patients with resistant TB who were undertreated (Zürcher but it is projected to grow even more rapidly, particularly et al. 2019). in LMICs (World Bank 2017a). In Brazil, Indonesia, and Rus- Gonorrhea is another example of infection where MDR sia, for example, 40 to 60 percent of infections are already is a threat (ECDC 2018). The number of gonorrhea cases caused by drug-resistant bacteria, compared to an average is rising worldwide, and an increasing proportion of of 17 percent in OECD countries (OECD 2018). In these cases are multidrug-resistant. WHO reports that about countries, the growth rates of AMR between now and 2050 78 million people are infected with gonorrhea each could be four to seven times higher than in other OECD year around the world. Ninety-seven percent of the countries. There are already inequalities among countries. countries surveyed reported the presence of drug-re- For example, the average resistance proportions in Turkey, sistant gonorrhea strains, and 66 percent—particularly South Korea, and Greece are about seven to eight times in high-income countries, where surveillance is best— higher than in Iceland, the Netherlands and Nordic coun- reported the emergence of resistance to last-resort drug tries (Norway, Sweden, Finland, and Denmark), which have treatments for the infection (Wi et al. 2017; Alirol et al. the lowest proportions (OECD 2018). In this study, inequa- 2017). In the United States between 2009 and 2017, the lities in AMR risk are also related to age, with children and number of reported gonorrhea cases increased by 75.2 the elderly being most vulnerable. x  Pulling Together to Beat Superbugs Different population groups can be at higher risk. AMR KNOWLEDGE AND adds to the devastation of conflict by increasing medical costs, blocking hospital beds because patients need care IMPLEMENTATION GAPS for a longer time, by reducing productivity and earning The current global political agenda on AMR has been potential, and by leaving more people with life-long shaped by a small number of countries. Among these disabilities (Jakovljevic et al. 2018). Fragility, conflict, and countries, the UK, Nordic countries, and several other violence can be factors of emergence (locally) and spread EU member states have been champions. They have (locally and beyond) of resistance (de Smalen et al. 2017; worked through the European institutions, the G7 and Aro and Kantele 2018). G20 forums, as well as the United Nations (UN) and its technical agencies (such as WHO, FAO, and more recently AMR is a catchall term that encompasses a diversity of UNEP) and OIE, embracing a broad spectrum of the issue’s resistance determinants, emergence, and spread mecha- multiple facets. For example, Mexico, Ghana, and Thailand nisms. Discussions about AMR often oversimplify this have taken an active role on AMR. Countries from around biological complexity. A recent study in the EEA shows the globe have participated in regional and global coor- that different types of resistance vary in terms of the dination of AMR efforts through various constituencies of number of cases and the number of attributable deaths the UN system, and 193 countries supported the adop- (Cassini et al. 2019). AMR also is a dynamic process. It is a tion of a political declaration in September 2016. A great function of time and use: the larger the quantity of anti- number of these countries have prepared national action microbials consumed and the longer the time for which plans (NAPs), which provide a framework to assign res- they are consumed, the greater the selection pressure ponsibilities to institutions and sectors. Mainstream media for resistance. First-line antimicrobials change as AMR have reported on the AMR issue, often covering specific evolves, as illustrated by ceftriaxone, which is now a aspects such as the role of livestock or conditions of first-line treatment for gonorrhea, although it was deve- health wards in conflict zones. Since 2010, the world has loped as a third-generation cephalosporin. The levels moved to some AMR awareness, but the implementation of resistance to first-line treatments can be expected to gap remains huge (IACG 2019a and b). increase with time; however, the rates of resistance to second- and third-line antibiotics could increase even In April 2016 the Wellcome Trust organized an interna- more rapidly. A recent study estimates rates will be 70 tional multidisciplinary summit, bringing together policy percent higher in 2030 compared to 2005 for the same makers and researchers from more than 30 countries and antibiotic-bacterium combinations (OECD 2018). 14 multilateral institutions to discuss the evidence under- pinning a range of AMR policy interventions. The summit Beyond resistance to antibiotics and the rise of resistant concluded that, even if some evidence gaps remain, mea- bacterial infections, there is rising concern about resis- ningful actions need to be taken immediately to counter tance to (a) antiviral drugs, such as HIV/AIDS drugs; (b) AMR, with individual countries tailoring implementation antifungal drugs, such as treatment for infections with according to their particular national circumstances Candida auris; and (c) anti-parasitic drugs, such as first-line (Wellcome Trust 2016). treatment for malaria (artemisinin-based combination therapies, also known as ACTs). This report focuses on There is a substantial and rapidly growing body of evidence AMR, primarily understood as resistance to antibiotics. It on AMR. A bibliometric analysis of global scientific research also focuses on AMR as the mechanism by which infec- on carbapenem resistance over the period from 1986 to tions become difficult or impossible to treat. Superbugs 2015 shows a significant increase in the number of publi- is a popular name for multidrug resistant bacteria making cations in the past few years (Sweileh et al. 2016). Such an AMR a global threat. increase in publications is occurring in many areas of the AMR issue. A PubMed search using “antimicrobial resis- The antimicrobial resistance wave has already hit and tance” [performed on March 18, 2019] resulted in 219,113 many are suffering in the flood. hits (including 51,138 for the past 5 years), showing that more than 9,000 peer-reviewed scientific papers have been   xi published in English every year since 2012 (with a record of NOT JUST A COMPLEX ISSUE; 11,158 in 2017). Despite existing knowledge, the challenge posed by AMR remains formidable. Efforts to address A WICKED PROBLEM AMR—particularly in low- and middle- income countries Although the probability of AMR becoming a problem (LMICs)—have been complicated and are compromised was first raised before the beginning of the modern anti- by the low level of implementation, the fragmentation of biotic era, and the emergence of AMR was recognized interventions, their poor sequencing in time and geogra- as a real problem in the 1970s, only much later has AMR phy, and their deployment in difficult environments for started to be defined as falling into the “wicked problem” AMR control measures to be effective. category (Hutchinson 2017). By the end of May 2019, 127 countries had a NAP. In most The term “wicked problem” was first used by Rittel and countries, however, the challenge is not about writing a Webber (1973) with reference to the complicated social plan; it is about implementing the plan once it has been issues affecting urban design and planning, in which “... written. According to the ad hoc Interagency Coordination the search for scientific bases for confronting problems Group (IACG), six factors in particular have made implemen- of social policy is bound to fail, because of the nature ting NAPs a challenge: awareness, political will, coordina- of these problems. They are ‘wicked’ problems, whereas tion, monitoring, data quality, and technical capacity (IACG science has developed to deal with ‘tame’ problems.” 2018 b). There is insufficient knowledge regarding the Understanding the true nature of wicked problems may local (or national) nature and extent of the problem, which not only help to explain the relatively slow pace achieved interventions to implement, and the ability to predict the so far in dealing with AMR, but also provide new insights positive effects of perhaps costly interventions. into how to approach and implement actions that will There is an urgent need to address these knowledge and accelerate progress in its containment. implementation gaps, to facilitate local implementation of Rittel and Webber (1973) proposed ten characteristics of policy interventions, and to support the development of wickedness associated with social or cultural problems that longer term solutions. Important evidence gaps will conti- are difficult or impossible to solve. Of relevance to AMR are nue to exist, but there is abundant evidence to support issues—such as incomplete or contradictory knowledge; immediate action, and the risks justify action even in areas difficulty in clearly defining the problem and solution; the of scientific uncertainty. Further research can provide a number and social diversity of people and opinions invol- clearer picture, supporting prioritization as well as the ved; the large economic burden of the problem; and the development of more targeted AMR countermeasures. intertwined nature of the problem with other problems— In addition, “learning from doing” and sharing knowledge that are particularly significant features of AMR. and experience of implementation in different contexts will provide further evidence to support national efforts Approaching AMR as a wicked problem—and accepting to combat this very real threat to human development that success can only be measured in terms of “better versus (Wellcome Trust 2016). worse” outcomes, rather than “true or false” options—will help identify and understand the need for new social com- pacts, the inadequacy of the existing fragmented disciplinary approach to AMR, the importance of context, and the cur- rent lack of consensus among global, regional, and national actors on the most effective way to address the issue. Fur- thermore, given that wicked problems have no definitive problem statement, being characterized as an evolving set of intertwined questions and constraints, the linear process of first understanding and only then solving is doomed to fail. xii  Pulling Together to Beat Superbugs Coming to grips with real world wicked problems—such mon interventions designed to establish and maintain an as AMR, climate change, or child stunting—requires not enabling environment for AMR control, those designed to only research to develop successful interventions, but reduce the need for antimicrobial usage, and those self-li- more importantly greater efforts to understand how miting the use of antimicrobials. We also examine how to implement these interventions effectively in diverse interventions have played out in practice. real-world contexts. Implementation research (Peters et Chapter 3 aims to assess and organize key knowledge and al. 2014) is a powerful—yet largely neglected—tool for implementation gaps. The focus of this chapter is the criti- interdisciplinary investigation of the multiple interactions cal knowledge that is needed—in particular contexts—to between what can be achieved in theory and what hap- support countries, more particularly LMICs, in better pens in practice in an iterative way with a much greater understanding and addressing AMR. The report identifies emphasis on social sciences than is currently the case. areas where needs exist for further translational, imple- mentation, and policy research. Furthermore, it offers a framework to support national decision making and PIECING THE AMR PUZZLE action. Much of the action on AMR to date has focused on TOGETHER the use, overuse, and misuse of antimicrobials. However, This report aims to identify and organize critical gaps in a country’s risk profile in terms of AMR also is determined knowledge and implementation in relation to AMR. It by context. Building on this understanding, we propose a brings pieces of knowledge and experience together to typology for countries to better understand risk related to document these knowledge and implementation gaps, AMR, preparedness, susceptibility, and needs for research. not as pure academic gnosis but as meaningful areas This report has a strong focus on country-level actions where there is some prospect to better address the AMR and options. It offers a selection of case studies that illus- challenge. By bringing those puzzle pieces together, the trate AMR issues in specific contexts. The case studies report highlights areas of need for further research. It also highlight interventions along with key factors that enable explores the gap between the technical solutions that we or block their success. The case studies have been selec- know can address AMR and the reality that they are often ted to represent a number of AMR issues across different not adapted or well implemented in the places where national contexts, spanning low-, middle-, and high-in- they are most needed. come countries to enrich the analysis and provide illus- Chapter 1 takes a new look at the old challenge of AMR. trations to the reader. The case studies are by no means It builds a cross-disciplinary evidence-based narrative. In country case studies, nor are they remotely comprehen- many cases the use of antimicrobials is a substitute for sive. They have been developed through literature reviews imperfect infrastructures and failing systems, a starting followed by consultation with first-hand observers and point to expanding the horizon of what can be done to national stakeholders. Hence the possibility of bias in address the challenge. We reframe AMR as a global sus- the data collected and subjectivity in the observations tainable development challenge; one that requires both reported here may not be ruled out. a technical and adaptive approach, and an approach that We have used a hashtag [#KKIG] to flag key knowledge acknowledges how and why the use of antimicrobials has and implementation gaps as they are identified become ingrained in our societies. throughout the report. All #KKIGs have also been collated Chapter 2 aims at reviewing approaches used to date to into Table 1, so that the reader can easily refer to this control AMR and further explores knowledge and imple- synopsis of gaps, either as they appear in the text, or later, mentation gaps. Much has been done to understand and as they are collectively discussed in chapter 3. address AMR. Here we survey and categorize most com-   xiii TAKING A NEW LOOK AT AN OLD CHALLENGE ©CHHOR SOKUNTHEA / WORLD BANK xiv  Pulling Together to Beat Superbugs Cha pter 1 Taking a new look at an old challenge In this chapter we build a cross-disciplinary evidence-based narrative on AMR, emphasizing that, in many instances, the use of antimicrobials is a substitute for failing systems and infrastructures. We propose to reframe AMR as a global development challenge; a challenge that requires both a technical and adaptive approach, as well as an approach that acknowledges how and why the use of antimicrobials has become ingrained in many societies. Appreciating the tensions around antimicrobials—the way we think about them as socio-technical objects, the way we use them, and external factors—can be the starting point to expand the horizon of what can be done to address AMR. AN ENDLESS RACE Antimicrobial resistance (AMR) is not a new phenome- necessarily mean drug obsolescence; in many instances, non. Antibiotic-producing organisms have existed on drugs continue to be used despite resistance being earth for millions of years. Due to the process of evolution known to occur because not all microorganisms develop by natural selection, however, microbes also have been resistance to these drugs, everywhere and at the same developing resistance for millions of years. Scientists have time. now detected functional antibiotic-resistant genes in microorganisms found in ancient permafrost (Kashuba WHO has developed and applied criteria to rank anti- et al. 2017) and even caves isolated from the earth’s sur- microbials according to their relative importance in face for 4 million years (Bhullar et al. 2012), supporting human medicine. This list (updated in 2018) is essentially our understanding that AMR is natural, ancient, and hard intended to contribute to risk management of AMR due wired in the microbial nature of things. Hence the origin to non-human use of antimicrobials. In 2018, an OECD of AMR long predates the use of modern antibiotics, but analysis focused on the following antibiotic-bacterium its existence was previously inconspicuous due to lower combinations: third-generation cephalosporin-resistant selection pressure. E. coli, fluoroquinolones-resistant E. coli, penicillin-resis- tant S. pneumoniae, meticillin-resistant S. aureus (MRSA), Alexander Fleming warned the public that microbes were carbapenem-resistant K. pneumoniae, third-generation capable of accelerating their development of resistance cephalosporin-resistant K. pneumoniae, carbapenem-re- under the increased selection pressure of widespread sistant P. aeruginosa, and vancomycin-resistant E. facealis use of antibiotics and other antimicrobials (see Fleming’s and E. faecium (OECD 2018). The significance of a specific discourse to the Nobel Academy). Indeed, resistance to resistance determinant, and how this translates in terms penicillin was formally demonstrated already in 1940 of treatment options—or drug obsolescence—should be (Rammelkamp and Maxon 1942). Ever since then, a vicious better understood and communicated in order to focus cycle has emerged; as drug discoveries have added new on priority questions (#KKIG 1). molecules to the arsenal against infectious diseases, so resistance occurred as predicted. Figure 1 illustrates the Figure 1 also shows that the pace of new molecules timeline of successive discovery, clinical introduction in being discovered has dramatically slowed down since the the United States, and [subsequent] detection of resis- 1980s. The discovery pipeline has currently largely dried tance for antimicrobial drugs over the past 70 years. In up as pharmaceutical companies exit this unprofitable many instances, resistance was known before the drugs race, faced with high development costs and the short were even clinically introduced. Resistance itself does not useful life of any new drugs they do bring to market (Nel- Taking a New Look at an Old Challenge  1 FIGURE 1 FIGURE 1 Timeframe of Antimicrobial Deployment to Antimicrobial Resistance Timeline of antibiotic discovery (D), clinical introduction (CI), and [subsequent] detection of antibiotic Note: Resistance to many naturally-derived antibiotics existed in nature before the antibiotic was discovered. resistance (RF) Note: Resistance is not necessarily synonymous with obsolescence. Sources: Nelson and Levy 2011; CDC 2013. 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 RF CI Diarylquinolines CIRF Ketolides D CI RF Glycylcycline D CIRF Monobactams D RFCI Fluoroquinolones D CIRF Oxazolidinones D CI RF Carbapenems D CI RF Mupirocin D CI RF Fosfomycin D CI RF Rifampicin D CI RF Trimethoprim D CI RF Nitroimizadoless D CI RF Quinolones D CI RF Lincosamides D CI RF Fusidic Acid D CI RF Glycopeptides D RF CI Novobiocin D RF CI Cycloserine D RF CI Streptogramins D CI RF Macrolides D RF CI Pleuromutilins D CI RF Amphenicols D CI RF Tetracyclines D RF CI Cephalosphorins D CI RF Bacitracin D CI Nitrofurans D CI RF D = Discovered Aminoglycosides CI = Clinically Introduced/ FDA approved D CI RF Sulfonamides RF = Resistance Found D RF CI Penicillins 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2  Pulling Together to Beat Superbugs son 2003; Burki 2017)—or even what could become the analysis 2017). In this report, we mainly focus on the imperative of not putting on the market newly discove- increasing influence of factors that predispose the emer- red drugs. Furthermore, there have been no new classes gence and spread of AMR, hence slowing down this arms of antibiotics since the 1970s. New drugs on offer are race between superbugs and humans. now dominated by derivatives of established classes of antimicrobials, and most candidate molecules for further development display limited innovation (WHO 2017e; TIME TO BROADEN THE TENT Theuretzbacher et al. 2018). New antimicrobial drugs wit- hout preexisting cross-resistance are in very short supply, The AMR conversation has largely been carried out within despite being still urgently needed, especially for certain a circle of technical professions and experts focused on geographical areas and infections. the science of AMR. With the exception of economists, who have recently studied the costs and benefits of AMR containment and investigated market failures in the phar- What is the significance of a specific resistance maceutical development and distribution system, rela- determinant? How to translate this in terms of risk of tively little space has been created for social scientists to absence of treatment options or drug obsolescence? join the global conversation (Roope et al. 2019). This has How can this help to focus on priority resistance led to an exaggerated sense that AMR is a purely technical determinants?  — #KKIG 1 problem that will eventually be solved through technical solutions, ignoring that science’s solutions can become science’s problems (Beck 1992). This may have created a A traditional approach to combating AMR—inventing and mistaken belief in science as our savior by disregarding producing new antimicrobial compounds, which in the human, social, and cultural elements that are intimately past may have been a lucrative business model— sowed involved in driving the “wicked” rise of AMR. the seeds of its own demise and has now burned itself out. It has essentially resulted in a “treadmill” or arms race Social scientists have studied medicines and the ways in between new drugs and constantly evolving resistant which humans relate to them for many years (Smith 2015). microbes. The rise of AMR has proven to be an endless This body of work has generated valuable insights of rele- race between microbes and humans, which we are losing vance to AMR, such as how the role of antimicrobials has and cannot win in the absence of a clear understanding influenced health and healthcare practices over a range of the fundamental drivers of resistance emergence and of regions, cultures, social worlds, stages of development, spread. infrastructure, and governance arrangements. Not only can this knowledge be used to understand diverse socie- Drug discovery has a crucial role to play in maintaining ties’ reliance on antimicrobials and their reactions to redu- our ability to successfully treat infections, but without cing them, but also the consequences—intended and addressing the underlying causes of the AMR crisis we will unintended—of doing so. In some societies and cultures, remain on the same broken treadmill, constantly reliving medicines, including antibiotics, have been found to take a self-fulfilling prophesy. Furthermore, it can be expected on other meanings and roles far beyond their purely bio- that we will eventually run out of finding new targets in logical effects (Chandler et al. 2016). Moreover, they take bacteria that are sufficiently different from those in euka- on practical roles that enable them to become a quick ryotic cells to allow for use without damaging effects on fix for the challenges of everyday life in modern societies the animal or vegetal patient. Not to mention that new (Denyer Willis 2019), and social research can explicate how drugs will be reserved, hence having a very limited mar- antibiotics are connected to multiple strands and scales ket, if any access to market. of modern globalized life—for example, understanding New drug development is in itself a large and complex antibiotics as infrastructure (Chandler 2019). Such findings issue, which has been well discussed and analyzed and approaches are highly relevant for understanding the elsewhere (McKenna 2019; see also relevant sections of social compacts around antimicrobials, interpreting how the UK review in O’Neill 2016 and World Bank economic they are used, prescribed, marketed, and integrated into Taking a New Look at an Old Challenge  3 people’s lives across a broad spectrum of actors, including scarce life-saving substances in limited supply into widely patients, livestock keepers, prescribers, pharmaceutical available medicines. This, combined with the availability companies, governments, and regional and global bodies. of vaccines, has led to the misconception that infectious Moreover, pharmaco-epidemiologists, social scientists and diseases would no longer be a challenge; that is, a false humanities scholars are equipped with toolkits for explo- sense of security that the world had entered a post-infec- ring the current architecture of AMR science and policy, tious era. Nevertheless, globally, outbreaks of infectious and can thereby open up alternative framings for action diseases have actually risen (Smith et al. 2014). And while (Landecker 2016 and 2019; Podolsky 2015). the number of people dying from different types of infec- tions has decreased over the long term (although the Behavioral and social sciences—which include but are not trend varies markedly by socioeconomic levels), infectious limited to psychology, anthropology, sociology, econo- diseases remain an important cause of death globally. mics, and political science—are all pertinent to AMR and the understanding of how this knowledge can contribute Antibiotic consumption in humans shows a steady to the conscious suspension of sectoral interests for the growth trend. Between 2000 and 2015, antibiotic good of public health (#KKIG 2). consumption in humans is believed to have increased 65 percent from 21.1 billion to 34.8 billion DDDs (Klein et al. What areas of the AMR problem would behavioral 2018). This increase was greatest in low- and middle-in- come countries (LMICs), where rising consumption was and social sciences be most effective and impactful? correlated with increasing GDP per capita. In high-income How should AMR research and implementation countries (HICs), overall consumption increased much less activities best incorporate the social sciences to and showed no correlation with GDP. If current policies add value and improve progress? What proportion remain unchanged, projections of worldwide human anti- of overall AMR control effort should be devoted to biotic consumption to 2030 indicate an expected tripling social science research? — #KKIG 2 of 2015 levels. Quantitative information on use patterns in animals—inclu- The AMR global dialogue now needs to open up to a ding species, antimicrobial agents or class of antimicrobial broader range of stakeholders, including the develop- agents, route of administration, and type of use—should ment community, civil society, and the public at large be collected by OIE member countries in order to eva- (IACG 2018 d and f; 2019 b). There is an obvious parallel luate antimicrobial exposure in food-producing animals between AMR and the climate change issue, which was (OIE 2019). This applies to veterinary medical use (to treat, hidden from public awareness and engagement in a control or prevent infectious disease) or non-medical shroud of scientific discourse for far too long, only gaining use (including growth promotion). It is widely accepted real traction internationally once ordinary citizens became that—in absolute tonnage—use in animals far exceeds engaged (Gough and Shackley 2002). that in humans. In the United States, for example, the total annual use of antimicrobials rose sixteen-fold from 1950 to 1978 (Black 1984). Over the same period, antibiotic use as ANTIMICROBIALS IN MODERN a livestock feed additive increased from 16 percent to 48 percent of total use, representing a fifty-fold rise in their use SYSTEMS for growth promotion in animal rations. Studies estimated The discovery of arsanilic acid, sulfa drugs, and penicil- the global consumption of antimicrobials by livestock will lin—and the initial recognition of their therapeutic poten- continue to increase by 67 percent between 2010 and 2030 tial in the first half of the 20th century—has been one of (Van Boekel et al. 2015). About a third of this increase will be the greatest advances in fighting infectious diseases and due to intensification of farming systems in middle-income in the evolution of modern medical practice (Aminov countries. In some countries—such as Brazil, Russia, India, 2010; Landecker 2019). The large-scale production of China, and South Africa—the increase in antimicrobial these drugs enabled a transition from dependence on consumption by livestock is projected to double. 4  Pulling Together to Beat Superbugs Global estimates of the total antibiotic use and trends Although antibiotic consumption rates in most LMICs are not currently available (#KKIG 3), not least because remain lower than in HICs despite higher bacterial disease use in humans and animals are quantified in different burdens, human consumption in LMICs is rapidly increa- ways, or figures carry a high level of uncertainty. Other sing (Klein et al. 2018). It is now evident that antimicrobials factors explaining why consumption has been hard to have largely been used as a substitute for good quality measure—and why this remains a gap—include the lack public health systems with the necessary and sustainable of reporting requirements at the national level (or repor- practices to prevent and control infection. Still, the lack of ting limited to specific antimicrobial class), and the lack access to affordable and quality antimicrobials for many of transparency from different sectors. However, better people is a greater problem, and has currently more fata- knowledge of the use, the purpose for use, and where it is lities, than the effects of AMR. Globally, 5.7 million people deemed necessary in the value chains is critical to target die each year from treatable infections due to lack of interventions and change practices. access to antibiotics (Daulaire et al. 2015). Strategies are needed to simultaneously address the double burden of access and excess (#KKIG 4). In some settings, antimicro- What is the current level of consumption (use) of bials may simply not be available, while in other settings— antimicrobials in humans and animals? How can this such as urban and peri-urban informal settlements—anti- be reliably quantified in practice? How this can be microbials are there and cheap but people cannot afford used to set targets and monitor progress on reducing them, prioritizing food rather than a full course of anti- the use of antimicrobials?  — #KKIG 3 biotics. The question of access is not limited to LMICs and raises the broader question of social connectedness. Raising poultry in Colombia Adriana Banderas raises poultry as part of Bank-sup- ported producer’s alliance in La Eugenia, Valle de Cauca, Colombia. Photo: © Charlotte Kesl / World Bank Photo ID: CK-CO077 World Bank Taking a New Look at an Old Challenge  5 © CHARLOTTE KESL / WORLD BANK The discovery of antimicrobials—and their mass produc- What would be the most cost-efficient relative tion—has been rapidly integrated into societies’ approach distribution of AMR-related investments across to health in both human and veterinary medical domains. countries and regions and between intervention It has created space for the notion that infectious diseases types (research, implementation, AMR-specific, AMR were a thing of the past. In many respects antimicrobials have been used as substitutes for preventive health sys- sensitive etc.)? How could this help prioritize where tems and sustainable agricultural practices (Chandler et al. and how funding should be used for the greatest 2016; Kirchhelle 2018), masking development deficiencies global benefit?  — #KKIG 5 in many sectors and areas. From this perspective, antimi- crobial resistance can be viewed as an extremely relevant OECD recently has advanced an ensemble of modeling development issue. techniques to provide support for policy action on AMR (OECD 2018). This mainly covers the human health sector; other sectors should be included in the near future. OECD How to adequately capture the issue of access, has reviewed public health interventions that would especially in the context of acute and chronic provide affordable and cost-effective packages in the poverty? What strategies can be developed to fight against AMR. These packages include: (a) in hospi- simultaneously address the double burden of access tals, improved hand hygiene, stewardship programs, and and excess?  — #KKIG 4 enhanced environmental hygiene in healthcare settings; (b) in community settings, delayed prescriptions when Progress against infectious diseases started well before there is no objective clinical emergency, mass media the antibiotic era. While the discovery of antimicrobials campaigns, and use of rapid diagnostic tests; and (c) has been one of the greatest advances in fighting infec- mixed interventions, stewardship programs, enhanced tious diseases and in the evolution of modern medical environmental hygiene, mass media campaigns, and use practice, another great advance has been introducing of rapid diagnostic tests. These packages would reduce washing hands and hygiene habits at the end of the 19th the burden of infectious diseases, improve how anti- century. For example, a rapid decrease of maternal morta- biotics are used, and consequentially reduce AMR rates lity occurred in England after doctors started to wash their by, respectively, 85 percent, 23 percent, and 73 percent hands before helping deliver a child, following the exa- (OECD 2018) while producing savings of USD purchasing mple of nurses (Chamberlain 2006). Figure 2 shows that power parity 4.1, 0.9 and 3 per capita per year. According progress in mortality rates from tuberculosis and other to this study, the mixed intervention package would save microbial respiratory diseases made great progress well 47,000 lives each year across the 33 participating coun- before the beginning of the antibiotic era in the United tries, and millions of people would avoid AMR-related States. Such progress in the US and other similar HICs was complications and health problems. AMR-sensitive inter- essentially achieved through improved infection control ventions—although they are designed and implemented and sanitation. As shown in Figure 2, some countries have for various reasons—also can have AMR impacts (benefits) not yet reached the death rate level of a high-income while addressing other important rationales (e.g., related country such as the US at the beginning of the antibiotic to objectives of development, sustainability, and equity). era (arbitrarily dated in 1945), or struggle to bring it down More AMR-sensitive interventions should be included in to the current level in the US. Part of the AMR challenge this type of analysis and their expected contributions to is to address the underlying development weaknesses AMR (cobenefits) should be determined. Furthermore, to AMR and identify the most cost-effective AMR invest- these packages of interventions should be assessed for ments across contexts and interventions to be able to national contexts, and a frame of multisectoral accounting prioritize where and how funding should be used for the for costs and benefits may be used for galvanizing politi- greatest global benefit (#KKIG 5). cal support in line with the SDGs (#KKIG 5). It is widely accepted that antimicrobials have been a game changer for the food sector and animal production 6  Pulling Together to Beat Superbugs FIGURE 2 Rate of death from tuberculosis and other respiratory infections in the United States before and after the beginning of the antibiotic (AB) era, compared with selected countries in different regions of the world, 1989–2017 Sources: Adapted FIGURE 2 from Hall, McDonnell, and O’Neill (2018). Authors’ calculations using Center for Disease Control (death rate by tuberculosis, pneumonia and influenza) for United States (before 1990) and Institute for Health Metrics and Evaluation (death rate by Deaths by Tuberculosis and Respiratory Infections respiratory infections and tuberculosis) for all countries from 1990 onward. 800 700 600 Deaths per 100,000 500 Beginning of United States AB era 400 Central African Republic 300 South Sudan 200 Philippines Papua New Guinea Tajikistan 100 Argentina 0 1900 1908 1916 1927 1935 1943 1951 1961 1969 1977 1985 1993 2001 2009 2017 United States Rate at Beginning of Antibiotic Era in particular (including aquaculture). Since the early 1960s, food-producing sector in response to the increasing meat consumption has grown significantly; currently, the appetite for animal-sourced foods in a growing global total biomass of animals raised for food by far outweighs population. Transformations include the systematic use of that of humans. Livestock is one of the fastest growing antimicrobials, a substantial proportion of which is used sectors in agriculture, and based on projected increases at subtherapeutic doses for growth promotion purposes in demand for animal source food, consumption is likely (Van Boeckel et al. 2015). Another part of the antimicrobial to maintain this growth trend for the foreseeable future, usage in livestock is prophylactic use to overcome the particularly in middle-income countries where demand shortfalls of poor husbandry and animal management is expected to increase significantly. This situation has systems. However, taking the perspective of historically been accompanied by profound transformations of the situated animal health concerns, rather than present-day Taking a New Look at an Old Challenge  7 MARIA FLEISCHMANN / WORLD BANK public health concerns, sheds a different light on antibio- tion, and pathogens in the production of animal diseases, tics in the landscape of disease prevention and control suggesting multiple possible points of intervention, inclu- (Woods 2019). In the course of industrializing animal ding antibiotics. Similarly to progress against infectious production, farmers and veterinarians recognized the diseases before the antibiotic era, industrialization of ani- roles played by housing, husbandry, vaccination, nutri- mal production did not rely solely on antibiotics. 8  Pulling Together to Beat Superbugs CASE STUDY 1: AMR AT THE CROSSROADS OF ECONOMIC DEVELOPMENT In Vietnam, the production of meat—including pork, has responded by developing public advertisements beef, and chicken—increased by 90 percent from 2002 on food safety (Nguyen-Viet et al. 2017), establishing a to 2012 (FAO 2018). At present, most meat is produced modernized policy that promotes a shift from traditional on small farms, but the scale of production is increasing. informal (wet) markets to supermarkets (Viet 2014), Aquaculture is also an important sector, producing and addressing food safety risks at the farm level (Dang 4.15 million tons of fish and shellfish in 2018. This and Nguyen 2017). A 2010 food safety law charged the intensification, along with expanding human population Ministries of Health, Agriculture and Rural Development, density in urban and peri-urban areas and the demand and Industry and Trade with control of antimicrobial use, for inexpensive food products, has increased the threat with each ministry assigned control of specific products of infectious diseases and the use of antibiotics to limit with a value chain. Although the Ministry of Health, their impact. through the Vietnam Food Administration, maintains A lack of information about appropriate antibiotic use overall responsibility for regulation of antimicrobials, contributes to the overuse and misuse of antibiotics. In the dispersal of control through several ministries may the animal sector, they are mainly used prophylactically: be an impediment to implementing comprehensive the amount used to raise chickens in the Mekong Delta measures to ensure food safety. For example, within the is estimated to be six times that used in many European Ministry of Agriculture and Rural Development, the use countries, expressed in quantities per unit of livestock of antimicrobials in the animal sector is regulated not (Carrique-Mas et al. 2015). The use of tetracycline and only by the Department of Animal Health but also the tylosin is common in pig and poultry farming (CDDEP Department of Livestock Production, with oversight of 2010). Quinolones and sulfonamides are also common in agriproduct quality by the National Agroforestry-Fisheries fish, shrimp, and crab production, and antibiotic residues Quality Assurance Department (NAFIQAD). are found in many livestock and aquaculture-derived food The World Bank Livestock Competitiveness and products. This in turn can lead to antibiotic residues in Food Safety (LIFSAP) project in Vietnam supports food the environment, in the food chain, and to a subsequent safety protection and a reduction in AMR by promoting rise in AMR. Implementing good husbandry practices, good animal husbandry practices in the agriculture and increasing routine monitoring of animal food products, livestock sectors and increased monitoring of animal food and supporting consumer education on food safety can products for antimicrobial residues. Previous projects to limit risk associated with antibiotic use. limit the risk of avian influenza had provided a proof of National Action Plans on Drug Resistance issued concept for a model of cooperation among government by the Ministry of health (for 2013–20) and by the agencies, and a 2017 World Bank report recommends a Ministry of Agriculture (for 2017–20) were introduced in risk-based approach to food safety in Vietnam that relies Vietnam to control AMR by promoting responsible use of on intersectoral collaboration and input from the private antimicrobials, including antibiotics, in the human and sector to reduce antimicrobial residues in agriproducts in the plant and livestock sectors, respectively, as well as that inhibit their sale in international and domestic to strengthen surveillance for AMR (Dang and Nguyen markets (World Bank 2017b). Bridging the various 2017; MARD 2017). These plans, however, face challenges ministries and departments with responsibilities for AMR in implementation as demonstrated by the occurrence will require similar strong leadership and the coordination of residues of nonauthorized molecules in the food of good practices across sectors. Recently, the academic chain (such as e.g., chloramphenicol, nitrofurans, and sector also has played a role in promoting good animal ivermectin in aquaculture products). husbandry: the Oxford Clinical Research Unit has Food safety is widely perceived by consumers, partnered with the government of Vietnam to implement agro-business operators and government to be a major randomized controlled trials of the development of farm problem in Vietnam (Wertheim-Heck et al. 2016; Nguyen- health plans, training of farmers to raise healthier meat Viet et al. 2017; World Bank 2017b). The government with less antibiotic use, and diagnostic support for 91 Taking a New Look at an Old Challenge  9 farms (IACG 2019 a). Finally, as civil society organizations the continuing gap between awareness about how AMR have become increasingly important in the debate about develops and the appropriate use of antimicrobials; food safety, with a focus on “clean meat” and the absence compartmentalization of food safety oversight into of chemical residues in food products, a greater emphasis different ministries; a growing market for cheap food on AMR could contribute substantially to raising in response to an expanding urban population; and the awareness of appropriate antimicrobial use. informal food system, which predominates in this context. This case study, focusing on Vietnam, provides an This case study shows that laws and regulations regarding example of economic growth of the food sector as a driver food products and antimicrobial use are unlikely to for the use of antimicrobials. It illustrates how they are an address the problem on their own, and that alignment of important component of this growth and the challenge food safety concerns in civil society with concerns over of governing their use requires addressing multiple the emergence and spread of resistant infections are a issues. These issues include a culture of self-medication; potential avenue to advance the national AMR agenda. FOR DRIVERS OF AMR, human waste, and intensive livestock facilities. These are just snapshots of the wide range of everyday human CONTEXT MATTERS activities that are leading to continued exposure to The 2016 Wellcome Trust Summit identified three specific antibiotics, biocides, chemical preservatives, and metals areas of meaningful actions: (1) reduce antibiotic use in in different settings and may result in the emergence agriculture; (2) improve local understanding of antibiotic of resistance. Chemicals with antimicrobial properties use and resistance levels in human and animal medicine are widely used in domestic cleaning products, cosme- and agriculture; and (3) optimize antibiotic use in public tics, plastics, and building materials. Such chemicals health systems (Wellcome Trust 2016). The rise of AMR leave long-lasting residues, yet their effect on indoor has often been seen primarily in terms of use and misuse, resistome dynamics is little known or understood. Even including overuse of antimicrobials. less is known about how they relate to the transmis- sion of latent and infectious drug-resistant pathogens The inappropriate, indiscriminate, and unregulated use to humans, though the threat has been demonstrated of antimicrobials—both for human health and for rai- (Fahimipour et al. 2019). sing crops and animals—is widespread in many parts of the world, although we are far from knowing the entire What are the multiple applications of range of uses (#KKIG 6). In many settings across medicine and agriculture, antimicrobials have become substitutes antimicrobials—including their disposal—and for poor and fragmented systems. This reliance on anti- their contextual drivers in anthropogenic activities? microbials has crept into our systems and become a How do we assess their relevance to the AMR part of the way much of our world operates, with most threat?  — #KKIG 6 of us not giving this pause for thought. However, with their efficacy beginning to fade, we begin to see how Baker et al. (2018) have used whole-genome sequencing significant their roles are in maintaining the systems we to study the temporal and spatial evolution of AMR in currently operate. This reliance has made it difficult to bacterial pathogens. It leads to thinking about AMR in govern their prudent and responsible use. Farmers use terms of emergence and spread. Exposure of susceptible a low dosage of antibiotics to boost the growth of their bacteria to antimicrobials will result in the local emer- livestock, while patients seek antibiotics for viral infec- gence of resistant mutants. This happens continuously, tions that do not require antibiotics. Antimicrobials are as a genetically diverse pool of bacteria are exposed to injected into the trunks of fruit trees and are used by the a range of different compounds at different concentra- clothing industry. Aquatic ecosystems are being conta- tions. Once a resistant clone is locally successfully esta- minated by effluents from production plants, hospitals, 10  Pulling Together to Beat Superbugs FLORE DE PRENEUF/ WORLD BANK blished, opportunities may come for further expansion, What factors contribute to the spread of AMR? How such as broader geographical dissemination or spillo- can their importance be assessed, in locally and ver into another host population. Such opportunities regionally specific contexts (e.g. urban vs rural; rich depend, among other factors, on the mode of trans- vs poor, community vs hospital)?  — #KKIG 7 mission of the bacteria (Baker et al. 2018). At a broad level, antimicrobial use (AMU) has a bearing on the emergence of resistance, but the spread of resistance, Emergence is only one part of the story. AMU can explain sometimes referred to as “contagion,” is understood to only some of the variation in resistance levels across coun- be driven by biological factors along with a number of tries and regions (Hendriksen et al. 2015). Reducing antibiotic socioeconomic conditions, depending on the local and consumption alone will not curb the rise of AMR because the national context (Hendriksen et al. 2019; Collignon et al. spread of resistance is also determined by other contextual 2018). Clarifying the relationship between use and other factors (Hendriksen et al. 2019; Collignon et al. 2018). contextual drivers, and the distinction between the The spread of resistance is associated with a range of emergence and spread of AMR, may be crucial to optimi- socioeconomic, health, and environmental risk factors, zing interventions to curb resistance (#KKIG 7). Further- articulated by recent country-level analyses. There is good more, in some cases, targeting the context rather than understanding about the spread of infectious diseases, and the use might be easier, cheaper, and more effective. there may be very few aspects that are specific about the spread of resistance determinants. But knowledge gaps exist regarding how changes in drivers of spread—such as the lack of adequate sanitation infrastructure, inappropriate Taking a New Look at an Old Challenge  11 waste management, low expenditures on health per capita, AMR AND SUSTAINABLE low public shares of total health expenditure, weak gover- nance, and corruption—might impact AMR, and how to DEVELOPMENT make these changes with maximum impact (#KKIG 8). AMR could bring economic consequences more severe than the 2008–09 financial crisis with a disproportionate Poor sanitation infrastructure is consistently associated and lasting impact on LMICs because (1) losses would be with higher levels of infectious diseases, part of which sustained over a long period, up to 2050 and probably are caused by bacteria resistant to antimicrobials. Where beyond; and (2) the impacts would likely be worse for sanitation and waste disposal infrastructures are lacking, LMICs (World Bank 2017a). A follow-up question, though, or inadequate, antibiotic residues, resistant bacteria, and is to know how this translates into impact for particular resistance genes are more likely to be released directly countries; decision makers need more granular localized into the environment, with higher potential for human evidence to act. contagion (WHO 2014). Country health expenditure levels also are inversely correlated with antimicrobial resistance The threat of drug-resistant infections compromises some levels. In countries where financial protection against of the most significant health achievements of the 20th out-of-pocket health costs is low, utilization of preventive century and poses a serious development challenge. If health care services is lower, and self-medication is more AMR is not contained, prospects for achievement of a common (Ocan et al. 2015). This may ultimately lead to number of the sustainable development goals (SDGs) by increased demand for and consumption of antimicrobials 2030 are particularly at risk. Drug-resistant infections jeo- in instances where they would normally not have been pardize the prospect of ending extreme poverty and pro- needed, and suboptimal use even if they were. A third moting shared prosperity, the World Bank’s twin goals. The example relates to weak governance and corruption. intersection of SDGs with AMR has been acknowledged Lower scores on governance and corruption indexes in several reports (World Bank 2017a; IACG 2019 a and have been shown to be associated with higher levels of b), including ending poverty, ending hunger, promoting antibiotic resistance (Collignon et al. 2015). Countries with healthy lives and well-being, and achieving sustained eco- stronger, more transparent governance systems and lower nomic growth (Figure 3a). levels of corruption might be better able to introduce The emergence and spread of AMR will impede progress regulations limiting the misuse and overuse of antimicro- toward the 2030 agenda, yet there are a number of SDGs bials and mandating their safe disposal, and succeed at that will contribute to containing AMR (Figure 3b). For enforcing those regulations. Weak governance also might example, ensuring the availability and sustainable mana- be associated with increased diffusion of substandard and gement of water and sanitation for all will help reduce falsified antimicrobials on the market. infectious disease risks, hence limiting the need for anti- microbials and reinforcing AMR control. Water supply and How might changes in drivers of spread—such sanitation measures are typical examples of AMR-sensitive as the lack of adequate sanitation infrastructure, interventions that indirectly impact AMR and provide cobenefits. inappropriate waste management, low expenditure on health per capita, low public share of total health In addition to economic inequities between countries, expenditure, weak governance, and corruption— unabated AMR will increase gender inequality. Women impact AMR?  — #KKIG 8 and girls already commit significantly more time than men to unpaid care giving, which AMR would exacerbate. This heavy and unequal responsibility, which affects the equality of women worldwide, will only get worse with AMR (WHO 2018d). For example, worldwide nearly 70–80 percent of the impaired elderly are cared for at home by their family members. While estimates vary across coun- tries, they indicate that 57–81 percent of caregivers of 12  Pulling Together to Beat Superbugs FIGURE 3a FIGURE 3A Risk that AMR will Hinder Progress toward Sustainable Development Goals The emergence and spread of AMR will impede progress toward the 2030 agenda SDGs 1, 2, 3, 8, 11, and 17 are particularly at risk FIGURE 3B FIGURE 3b Impact of Progress toward Sustainable Development Goals on AMR Progress made on some SDGs will contribute to containing AMR SDGs 2, 6, 10,14, 15, 16, and 17 are particularly relevant to AMR Taking a New Look at an Old Challenge  13 the elderly alone are women (Sharma et al. 2016). AMR exacerbates gender inequality because women and girls, who provide care for family members with prolonged illnesses related to AMR, would face a greater burden. In addition, AMR will increase women and girls’ risk of exposure to drug-resistant infections during pregnancy, miscarriage, and childbirth, especially as these events may take place in healthcare settings without safe or hygienic © IMAL HASHEMI / TAIMANI FILMS / WORLD BANK conditions. AMR also can lead to complications in infec- tions that disproportionately affect women, such as sepsis or the much most common urinary tract infections. To reduce the global threat of AMR, AMR-sensitive inter- ventions are necessary. These include increasing access to clean water, investing in education and infrastructure, and ensuring good governance, as well as increasing public health care expenditures and better regulating the private health sector. The global effort to contain AMR could be undermined by neglecting the development dimension of AMR (Figure 3b). TENSIONS SURROUNDING © CHARLOTTE KESL / WORLD BANK ANTIMICROBIALS, BEYOND THE WAY WE USE THEM A gap exists between the technical solutions that we know can address AMR and the reality that they are often not adapted and implemented adequately, or not at all, in the places where they are most needed. The human and animal health communities have long been aware of AMR as a scientific certainty, and, for more than two decades, have recognized it to be a serious problem with far-reaching and severe consequences of no available treatment options for infectious diseases. Despite the voluminous and ever-growing body of scientific knowledge on the subject, we are still far from © SIMONE D. MCCOURTIE / WORLD BANK bridging the gap between knowledge and the ability to reliably contain and reduce AMR as a risk. To replicate achievements of the few successful countries that have made progress on reducing use, and to a certain extent on abating AMR, we must learn more about the persistent problem of converting knowledge into realistic policy and practices, especially in LMIC environments. 14  Pulling Together to Beat Superbugs © ARNE HOEL / WORLD BANK Advances can be made through technical approaches.  Use and governance of antimicrobials across These include improving guidelines and incentives to different sectors, industries, institutions, and prevent the emergence and spread of infection, impro- countries, which refers to their respective roles and ving global surveillance of antimicrobial use and resis- responsibilities. Standards and protocols on the tance, promoting new diagnostics to prevent unnecessary sustainable use of antimicrobials exist with different use, developing new vaccines and antimicrobials, and levels of effective implementation, regulation, improving incentives to promote investment in new and enforcement. The challenge of governing drugs. Relying on technical approaches alone, however, antimicrobials is about the way we use antimicrobials. will not solve the problem in a replicable and reliable  External trends beyond the system of way across the globe. Encouraging people, societies, and antimicrobials such as population growth, nations to change their norms, behaviors, and use of anti- migration, urbanization, climate change, organic and microbials presents an adaptive challenge. inorganic pollution, and loss of biodiversity. These Adaptive challenges can be understood as challenges have contributed to conditions for the emergence and that are underpinned by a difference between values and further spread of antimicrobial resistance. These factors circumstances (Heifetz 1998). People might easily say they can influence tensions around antimicrobials, and value antibiotics and want to preserve them, but the way contribute to optimizing conditions for emergence or societies are deploying them is contrary to that reality. the spread of resistance. Addressing this gap requires changes in values, roles, Multiple factors influence the rise of AMR across these and relationships at all levels within and across societies. three broad areas. As a result, the problems and challen- It requires engagement with people across multiple ges of addressing AMR are becoming more and more different sectors and regions (renewing social compacts). complex, they are difficult or impossible to solve. As men- It requires change in numerous places and across orga- tioned earlier in this report, incomplete or contradictory nizational boundaries (suspending sectoral interests). knowledge, the difficulty of clearly defining the problem Solutions may require experiments and new discoveries. and solution, the number and social diversity of people For example, several countries have had standards and and opinions involved, the large economic burden of the awareness campaigns on the sustainable use of antibio- problem, and the intertwined nature of the problem with tics. These standards and protocols are well known, but other problems are among the most significant features are difficult to implement in countries where perceptions of AMR as a wicked problem. of the quality of medical care are entwined with receiving antibiotics at any routine medical appointment, irrespec- Figure 4 represents the three areas described above as a tive of need. Guidelines—and technical solutions—alone conceptual model to AMR. The way we think about anti- will not be sufficient to change those behaviors. microbials, the way we use them, and the broader factors influencing this system constitute three areas of influence, As discussed earlier, because antimicrobials are now which interact with each other in diverse ways. socially, politically, and economically ingrained in our societies, antimicrobials and their roles need to be rende- The first and central area in Figure 4 can be viewed as the red visible in terms of: system of how we currently use antimicrobials. It pertains to antimicrobials themselves, understood as socio-tech-  Norms and behaviors related to antimicrobials, nological objects, their discovery, and the rules that which refers to people’s assumptions, beliefs, and govern access to them across different sectors, industries, attitudes in life and livelihoods around antimicrobials in institutions, and countries. Standards and protocols on the domains such as human medicine and agriculture and sustainable use of antimicrobials exist with different levels imperatives for progress. These have also developed of effective implementation, regulation, and enforcement. and solidified in the context of a broader modernity, Already authorized products contain antimicrobials, some including social, economic, and political norms. of them at low dosages or in irrational combinations with other non-antibiotic products, are available on the phar- maceutical market. Taking a New Look at an Old Challenge  15 This first area is influenced by a second area—norms and established norm, often facilitated by the lack of regulation behaviors—regarding how we think about antimicrobials. and poor enforcement of prescription guidelines. As a This second area includes, for example, the view that result, antibiotics are increasingly available over the counter antimicrobials are modern panaceas that mark the “end of and are being overly used in situations where they could be infectious diseases” and characterize times of biosecurity having no effect at all and where they are not necessarily and control. indicated. As noted above, the interaction between norms and behavioral and governance drivers can be thought For example, in many LMIC and HIC settings drugs can still of within the antimicrobial system. In this conceptual be purchased without a prescription. Examining the pur- model, the issue of excess—as opposed to prudent and chase of antimicrobials in Manila drugstores, 66.3 percent of responsible use—clearly appears as subjective rather than the transactions were made without prescription (Lansang objective. et al. 1990). In a more recent study, 60 percent of pharmacy visits by a simulated patient led to antimicrobials being A parallel could be drawn with vaccines and vaccine dispensed without prescription (World Bank 2017a). Anti- hesitancy, defined as a delay in acceptance or refusal of microbial availability without prescription is becoming an vaccines despite availability of vaccination services. The FIGURE 4 FIGURE 4 Tensions around antimicrobials: the way we think antimicrobials (norms and behaviors), the way we Three Thethem use Spheres (use of Influence and governance), andthat Create external Tension Around Addressing AMRs factors h • g l oba l i w t za r o tio g • panacea on n• s on • use • di ti s pre s on •popula e i •m zero infect sco ce • exc s s u r e on r e s odernity • very • ac NORMS AND ANTI- EXTERNAL MICROBIALS BEHAVIORS FACTORS an rn ces i s • gove • t l a s o ec urity contr iz o n • u b r ce r s• •u cl im ng e ate cha 16  Pulling Together to Beat Superbugs © DOMINIC CHAVEZ/WORLD BANK trend has been reported in many countries worldwide, parallel of vaccine hesitancy illustrates the potential prompting WHO to declare it one of the biggest threats influence of “norms and behaviors” on “usage.” to global health. For example, lower levels of immuniza- The third area in Figure 4 represents a wider context, and tion are believed to have resulted in a 30 percent rise in drivers outside the antimicrobial system itself that may measles cases globally, even in countries where measles have an influence on antimicrobials and the rise of AMR. had been previously eradicated. A recent Eurobarometer This area includes, among others, the growth of human study on attitudes of EU citizens toward vaccination indi- populations, urbanization, globalization, increased pres- cates that 85 percent of responders believe vaccination sure on natural resources, and climate change, as well as is an effective way to prevent infectious diseases, protec- systemic factors that affect behaviors, such as the way ting themselves and the others (European Commission hospital and health workers are paid or reimbursed, who 2019). Herd immunity is crucial, particularly when one provides education and training, etc. This third area does has a compromised immune system and cannot be influence the first two, namely norms and behaviors as vaccinated. Children who survive cancer, for example, well as governance. should not be put at risk because their peers are not vaccinated. The Eurobarometer also shows that approxi- Following up on the previous example of country settings mately half of EU citizens have been vaccinated in the where drugs can be purchased without a prescription, this last five years. While 79 percent consult and trust health- established norm may be facilitated by the lack of regula- care professionals to get information about vaccinations, tion and enforcement of prescription guidelines, self-me- 48 percent believe that vaccines can often produce dication as a way to avoid paying a doctor consultation, severe side effects and even 38 percent think vaccines as well as increasing demand by a growing population of can cause the diseases against which they protect. The urban dwellers. Taking a New Look at an Old Challenge  17 Fragility, conflicts, and violence are another example of good veterinary and good agricultural practice (OIE of an external factor that can drive a particularly fertile 2019). From a user standpoint, however, what constitutes breeding ground for AMR because of worn-down health “prudent” and “responsible” use can be a matter of judg- systems and a shortage of antibiotic supply (Arie 2013; ment (#KKIG 9). Practically, it probably combines a triad of Abbara et al. 2018; Jakovljevic et al. 2018). Even though knowledge at hand, cost for the user, as well as a form of doctors know the right technical protocols to prevent signaling (i.e., tacit or explicit code of what is expected to AMR, the situation means they cannot always follow be done or not to be done). Such a combination is subject them. Patients take incomplete courses of antibiotics or to huge variations among individuals and communities. are prescribed an inappropriate mix because the right The use of this knowledge, cost, and signaling triad could medicine is not available; in some cases, because they prove powerful in implementation research. The COM-B do not have enough money to afford the complete model has been proposed to address capability, oppor- course. Other shortages—water; power and fuel for tunity, and motivation in behavioral or organizational generators; gloves and gowns; and chlorine tablets for changes (Essack and Sartorius 2018). This model identifies disinfecting water—mean doctors cannot always meet three preconditions for behavior change: capability (i.e., basic hygiene standards, making it easier for any drug-re- knowledge and skills), opportunity (physical and social), sistant infection to spread. One of the consequences of and motivation (Michie et al. 2011; 2014). The model conflicts, violence and fragility in states is the displace- covers the behavioral and social sciences, which include ment of refugees and asylum seekers, which seems to psychology, anthropology, sociology, economics, and play a role in the spread of AMR (de Smalen et al. 2017; political science. Behavioral and social influences should Aro and Kantele 2018). be given more consideration in the design and evaluation of interventions to improve prudent and responsible use External trends—beyond the system of antimicrobial of antimicrobials (Lorencatto et al. 2018). use—are of critical importance as a wider context to AMR. The link between climate change or biodiversity loss and AMR may not be readily understood. There could How can “prudent and responsible” be better be more exposure to pathogens from geographical defined? What factors determine individuals’ expansion of vector ranges, resulting in increased disease adoption of the “prudent and responsible” incidence and more demand for antimicrobial treatment. principle?  — #KKIG 9 In addition, there may be more frequent interruptions to healthcare services from extreme weather events that limit access to antimicrobials, or changes in vegetation In the first case study (Vietnam and AMR at the crossroads leading to soil erosion that facilitates runoff and dissemi- of economic development), we have identified drivers nation of antimicrobial-contaminated effluent. These are belonging to (a) norms and behaviors, such as antimicro- context-specific illustrations of the links that are not com- bials being needed to produce food, and a perception monly made but potentially critical for optimizing cobe- of residues being invisible; (b) governance, such as easy nefits and reducing trade-offs in achieving the SDGs. access to antimicrobials, or the lack of enforcement of the regulation; and (c) external factors, such as urbanization, Many reports, studies, papers, consultation meetings, demand for animal-sourced food, and economic growth. and workshops have extensively described the techni- cal aspects of interventions that can be undertaken to Our second case study, below, will provide another illus- address the threat of AMR (WHO 2015a; World Bank 2017; tration of how this conceptual model applies to address IACG 2019 a). According to OIE, responsible and prudent persistent and multiple AMR-related questions. use is determined taking into account the specifications in the marketing authorization and their implementation when antimicrobials are administered to animals as part 18  Pulling Together to Beat Superbugs CASE STUDY 2: ACCESS TO QUALITY MEDICINAL PRODUCTS Senegal is actively engaged in addressing the issue of of land to graze or access to markets. Traffickers, including of substandard and falsified (SF) veterinary medicinal products substandard and falsified VMPs, take advantage of this ease (VMPs). These SF drugs may have limited effect or even lead of movement to distribute products to farmers and herders to adverse health outcomes. Because they may contain (Didier 1986; Vallée 2006). adulterated or insufficient active ingredients, they can also Pressed by droughts in the 1980s, agricultural traders contribute to the emergence of AMR. Circulation of such and seasonal migrants increasingly settled in cities in products is a threat to animal health and disease control, and Senegal in search of stable incomes (Didier 1986). Sales Senegal has set a national target to eliminate them by 2023. of medicines offered an economic opportunity for these Since 2006 Senegal—with other member states of the migrants. In the absence of a strong private veterinary Union Economique et Monétaire Ouest Africaine (UEMOA)— medicine sector, many filled this role as informal and has been working to develop a common approach to unregulated purveyors of VMPs and began diagnosing regulation of VMPs, including registration and authorization and counseling herders on the best treatment for their of antimicrobials. This harmonization is recognized as livestock. Medicines for sale in this unregulated market essential to controlling the quality of antimicrobials and are obtained from two primary sources: (1) hijacking of other medicinal products in the region. In 2006 a UEMOA products bound for public sector outlets, and (2) smuggling Minister’s Counsel was established, supported by fees from of drugs from neighboring countries (Didier 1986). new drugs entering the market. In addition, a network of Consumers drive this informal market because of the lower laboratories was established across the region to monitor cost of drugs here than in pharmacies. Others value the the quality of available drugs (UEMOA 2006a and b). knowledge, accessibility, and flexible arrangements of A substantial share of VMP sales occur outside formal informal sellers or consider it unnecessary to visit a licensed markets in the country (Tchao 2000; Abiola et al. 2005; veterinary specialist for “easy-to-treat” conditions. Absent Walbadet 2007). From 1979 to 1997, many public services recognition of the value of licensed providers of veterinary in Senegal, including veterinary services, were shifted medicines, consumer demand for informal markets has to the private sector (Gobbers et al. 2000). However, been persisting. the private sector has been slow to take over and is still Senegal’s experience illustrates that ensuring access insufficiently developed to deliver the needed animal to quality VMPs will require a more effective system— health services at scale. This has left gaps in service such as an established list of authorized VMPs, better provision. SF VPMs have become freely available in local laws and regulations, and changes to a sectoral structure informal markets, making it difficult to track their origin, that allows various players to provide veterinary services, control quality, control trade, monitor the effects of these along with changes in norms and behaviors such as a drugs (either in individuals or the animal population at cultural preference for informal markets and lack of large), and assess the likely impact on AMR. appreciation of veterinarians and pharmacists—to Reducing the market for these drugs will require limit substandard and falsified VMPs. Our analysis has focusing on veterinary pharmacies, veterinarians and animal identified regional regulations established by UEMOA, health professionals, and farmers and herders, as well as strong laboratory capacity to conduct quality control, addressing the culture in which the systems developed. political awareness, and outspoken support by senior By themselves, communication campaigns, regulation of members of government as important to addressing VMPs, and increased laboratory capacity for quality control the issue of substandard and falsified VMPs and key do not sufficiently address all the issues associated with contributions to the national and regional AMR agendas. substandard and falsified products. Much of Senegal’s Applying our conceptual model to this case, we have livestock sector is based on pastoralism. Borders between also identified major drivers of AMR in the areas of Senegal and neighboring Mauritania, Mali, Guinea, Guinea- governance, norms and behaviors as well as the existence Bissau, and the Gambia are porous, in part because of the of external factors in action, such as the pastoral and seasonal movement of herders and their livestock in search cross-border movements of livestock and herders. Taking a New Look at an Old Challenge  19 UNDERSTANDING OUR APPROACHES TO DATE © NARENDRA SHRESTHA/ WORLD BANK 20  Pulling Together to Beat Superbugs Cha pter 2 Understanding our approaches to date This chapter examines our most common approaches to understand and address AMR. More specifically, we review interventions establishing and maintaining an enabling environment for AMR control, those reducing the need for antimicrobial usage (adaptation), and those limiting the use of antimicrobials (mitigation). We also examine these interventions, to document key knowledge and implementation gaps. The efforts have mainly focused on use of antimicrobials, broadly ignoring the underlying causes of emergence and spread of AMR such as imperfect infrastructures and failing systems. TAKING A COUNTRY STANDPOINT shing and maintaining an enabling environment for AMR control through agenda setting, regulation, legislation, AMR is a wicked problem; it cannot be solved, but it can and surveillance actions. Another focuses on reducing the be managed. It requires interventions by many actors need for antimicrobial usage through measures to prevent across many sectors. Efforts to address AMR are often infection such as vaccination, better hygiene, and improved compromised by the low level of implementation and livestock husbandry. A third family relates to self-limiting the lack of coordination. The fragmentation of interventions, use of antimicrobials by means of economic incentives and their poor sequencing in time and geography, and their disincentives, as well as education and awareness-raising deployment in non-enabling environments for AMR among users. These proposed action families cut across sec- control measures often compound progress. tors and are equally applicable to diverse national contexts, A number of technical solutions to contain risks related broadly encompassing public health, animal health, and to AMR have been proposed. They have been essentially environmental health in a way that removes discipline designed as technical solutions to be implemented by silos around the AMR question and enabling “One Health” the human and animal health sectors, focusing on use approaches to its containment (Robinson et al. 2016). of antimicrobials. In this chapter, we review a number of Interventions need to be context-specific and the “best interventions that seek to reduce the emergence and practice” approach is likely to fail, especially when direc- spread of AMR. tly translating success stories in high-income countries These interventions have been identified in papers and into the context of low- and middle-income countries reports published over the past few years. They are essen- without adaptation. This observation is not solely related tially the IACG discussion papers and reports (IACG 2018a to resources; it also encompasses cultural, social, and to f, and 2019a and b), the World Bank (World Bank 2017a), environmental dimensions. Our review of interventions Wellcome Trust (2016), and UK (O’Neill 2016) reports, and emphasizes the predominance of AMR-specific interven- the global action plan on Antimicrobial Resistance (WHO tions in national agendas. We observe that AMR-sensi- 2015a). A second body of literature was then used to fur- tive interventions are vastly overlooked. This is a missed ther extract interventions, drawing on published literature, opportunity in view of their expected capacity to contri- studies, comments, and review articles. bute to the battle against AMR. Interventions have been organized into three functional groupings or “action families.” One family deals with establi- Understanding Our Approaches To Date  21 CASE STUDY 3: ANTIMICROBIAL POLLUTION IN THE ENVIRONMENT In India there are over 8,000 pharmaceutical Another challenge is the lack of defined standards— manufacturing plants. The release of pharmaceutical either globally or nationally—for the allowable level of waste products into the environment—particularly water antimicrobial residues in the environment. There are no systems—is believed to be a driver of AMR (Bengtsson- specific laws aimed at reducing antibiotics in wastewater Palme et al. 2018). The potential routes of exposure to in order to limit AMR in India (Bengtsson-Palme and resistant bacteria from environmental pollution include Larsson 2016). India’s Central Pollution Control Board dependence on natural water bodies—for irrigation, (CPCB) sets standards for pharmaceutical effluents, water for livestock, bathing, drinking water in the absence but these standards do not include antibiotic residues. of safe water sources in many parts of the country—as Consequently, antibiotic residues are not monitored as well as dispersion during seasonal flooding. The issue part of other effluent monitoring activities (Gandra et al. of pharmaceutical waste products into the environment 2017). India intends to regulate antibiotic discharges in its is also globally regarded as critical (Lübbert et al. 2017; National Action Plan 2017–21. The Review on Antimicrobial Resistance 2015; Changing The government of India seeks to improve Markets Foundation 2016). Perhaps nowhere is this manufacturing standards, with multiple initiatives aimed problem more pronounced than in India. Industrial at strengthening good manufacturing practices (GMP). effluent treatment plants are frequently overloaded The government recently attained a high “maturity with more effluent than they can effectively process. In level” grading from the WHO Global Benchmarking Tool addition, only part of all pharmaceutical waste in India for its regulation of vaccine manufacturing (WHO 2017 is thought to reach treatment plants, and a significant c). A draft of India’s pharmaceutical policy released portion is illegally dumped into bodies of water. in 2017 suggests the state will procure antibiotics The two regions with the highest concentration and pharmaceuticals only from GMP-compliant of pharmaceutical manufacturing plant effluent are manufacturing units (Government of India 2017). Hyderabad and Visakhaptanam. Hyderabad was declared However, enforcement remains a challenge. Proposed a “critically polluted area” in 2009 by the Central Pollution GMPs for environmental conditions might include proof Control Board (CPCB). Similar problems may exist in of monitoring discharge or proof of implementation of many other areas, given the large number of antibiotic adequate cleaning technologies for effluent. As part of manufacturers in the country (Gandra et al. 2017). this, policy instruments could include shifting part of the A number of challenges exist to regulate and responsibility for ensuring diligent waste processing at monitor manufacturing effluents and limit them as a effluent treatment plants onto the manufacturer. pathway for the emergence of AMR. These challenges The government also has provided substantial include providing sufficient resources for a strong and subsidies to support the manufacture of common independent regulatory authority (or authorities), effluent treatment plants (Kaur et al. 2017). Given reports including a budget, mechanisms to ensure that existing that such plants are chronically overwhelmed by high regulatory agencies in different ministries/departments volumes of waste, it may be that even more plants need work closer together, human resources capacity, and to be constructed, properly maintained, and include an confidentiality in reporting. For example, there may be additional clarification stage such as ozone treatment conflicts of interest between departments—such as or activated carbon filtration. In parallel, resources and environment and industry—that may have diverging political will must be deployed to ensure that existing agendas within the government. Furthermore, the infrastructure is maintained and functioning as expected. private sector may challenge the governmental authority, The adoption of voluntary standards—such as the when for example, a lobbying group representing a AMR Industry Alliance’s Common Antibiotic Manufacturing large number of India’s pharmaceutical manufacturers Framework (AMR Industry Alliance 2018)—benefits from disputed reports of pollution, claiming that foreign clients strong industry buy-in (depending on what proportion regularly audit plants (Siddiqui 2016). of manufacturers sign onto the standard), potentially 22  Pulling Together to Beat Superbugs speedy roll-out compared to other avenues for standard- involved in AMR surveillance (Das et al. 2017) for human setting, and a low administrative burden on governments. health, and the INFAAR network for AMR surveillance Aside from obvious concerns about conflicts of interest, in animal health has only recently been established. voluntary enforcement may be hampered by limited Insufficient data have created uncertainty in the precise expertise both in AMR and in the environmental impact of contribution of water treatment, including proper pharmaceuticals, the high cost of current technology, and handling of industrial effluent, to reducing AMR. This lack relatively few low-cost alternatives. of comprehensive surveillance—along with the lack of When registering a new pharmaceutical product an implementation and monitoring framework for one to take to the market, companies in many countries are health in the country to track AMU and dissemination in required to report to a government agency regarding humans, animals, and the environment—means the true where and by whom the active pharmaceutical ingredient burden of AMR in India remains unknown. is produced. Often, countries are aware of where medicines Establishing an enabling environment for AMR control and their active pharmaceutical ingredients are produced, is our first family of interventions, including agenda but they are not necessarily aware of the environmental setting, regulation and legislation, and surveillance impact of pharmaceutical effluents. Similarly, consumers (discussed in the next section). In this case study, we are usually not aware of the environmental impact of have illustrated the complexity of addressing AMR issues effluents where the pharmaceuticals were produced. In in contexts of conflicting interests and poor capacity of India this is complicated by the lack of central procurement underlying systems. Opportunities to address the particular of antimicrobials. The government, as well as private issue of waste disposal from the manufacturing sector in hospitals and other countries, can leverage buying power India include the following: (1) government support and to support manufacturers that are able to demonstrate enforcement; (2) implementation of good manufacturing adherence to high manufacturing and waste disposal practices (GMP); (3) preferential procurement from high- standards, while ensuring that this does not lead to greater standard manufacturers; and (4) comprehensive AMR economic inequity or access to antimicrobials by effectively surveillance that includes the environmental sector. All limiting the ability of smaller manufacturers to participate. four can contribute to create an enabling environment to Poor infrastructure is associated with higher levels reduce AMR. The case study also illustrates challenges and of AMR (Collignon et al. 2018). Only a few laboratories— difficulties to address AMR issues across sectors and the given the size of the country—are reported to be need to roll out suites of interventions. Understanding Our Approaches To Date  23 ESTABLISHING AN ENABLING partly due to organizational and staffing deficiencies, and lack of substantial amounts of government funding. ENVIRONMENT FOR AMR CONTROL Links with other Agendas Agenda Setting Universal health coverage means that all people and com- Agenda setting refers to the shaping of policies and munities can use the preventive, curative, rehabilitative, country-level plans to address threats posed by AMR. and palliative health services they need, of sufficient quality National action plans require governance structures, inclu- to be effective, while also ensuring that the use of these ding targets and lines of accountability, to turn political services does not expose the user to financial hardship will into action effectively. (Kieny et al. 2018). As acknowledged in the 2017 World Bank report, expanding healthcare coverage, improving National Action plans oversight and quality of care, and smarter and fairer finan- National action plans (NAPs) are important in agenda set- cing all contribute to AMR containment in hospitals and ting because the implementation of AMR interventions community settings (World Bank 2017a). The AMR-sensitive requires long-term vision and investments in areas such nature of universal health coverage (UHC) has potential to as surveillance, research, laboratories, health systems, strengthen AMR containment through expanding health institutions, and professional education. WHO developed coverage to all citizens. a manual (in collaboration with FAO and OIE) to assist countries in preparing or refining their national action At least half of the world’s population still does not have plans (WHO 2016). Birgand et al. (2018) explored different full coverage of essential health services. UHC provides governance approaches by three European governments an enabling framework to tackle AMR because AMR in and suggested that a decentralized bottom-up approach many ways reflects the weaknesses in existing health sys- in the development of a NAP is more effective, since it tems. Moving toward UHC requires strengthening health allows for flexibility and modification as needed and deve- systems and robust financing structures. A robust UHC lops a sense of accountability and ownership in commu- approach builds coordination and governance structures nities and across the governance structure. that are critical for AMR containment, as well as enhanced regulatory capacities (Kieny et al. 2017). One example The scope of a NAP should include a “One Health” is health facility accreditation, where requirements for approach to bring all sectors on board and align respec- improved antimicrobial stewardship can be built into tive contributions to a common set of targets. For exa- accreditation processes for hospitals and clinics. mple, 10-year targets to reduce unnecessary antibiotic use in agriculture should be consistent with a country’s Chapter 1 shows the strong relation between the sustai- economic development and availability of funding. nable development goals and AMR. Here as well, we can connect AMR with various development agendas. Better understanding of the specific contributions of SDGs and How to increase the level of implementation of other relevant agendas to AMR, and ability to quantify NAPs?  — #KKIG 10 these contributions (cobenefits) in different local contexts would be critical (#KKIG 11). Countries fall into four broad categories in terms of their Another important agenda addresses water, sanitation, progress so far with NAPs: (1) countries with no plan or and hygiene (WASH). The WHO WASH Strategy (2018) strategy on AMR (including very fragile and very small responds to a member-state resolution and the broader states); (2) countries preparing a plan or in the process of SDGs. It also recognizes the human right to safe drinking approving a plan; (3) countries with a plan but experien- water and sanitation, adopted by the UN General Assem- cing difficulty in implementation; and (4) countries with a bly in July 2010. Evidence suggests that improving access plan or strategy that is being implemented (IACG 2018b). to safely managed drinking water and sanitation (indica- Many LMICs fall into the third category (#KKIG 10); this is tors for SDG 6.1 and 6.2)—such as regulated piped water 24  Pulling Together to Beat Superbugs 016 El Renacimiento School in Villa Nueva Guatemala Children listen to their teacher in their classroom in El Renacimiento school, in Villa Nueva, Guatemala. Photo: ©Maria Fleischmann / World Bank ©MARIA FLEISCHMANN / WORLD BANK or connections to sewers with wastewater treatment— not have access to safely managed sanitation—that is, can dramatically improve health through improved to a system that safely conveys, treats, and disposes of hygiene and reduced diarrheal disease deaths. Studies household waste. Given that over a third of the world’s also demonstrate how WASH interventions significantly population still has no access to safe sanitation, most reduce the emergence and transmission of antimicrobial development agencies, national governments, NGOs, resistant organisms. and other civil society groups are currently involved in the WASH agenda in some way. This creates a very signi- The WHO WASH Strategy (WHO 2018c) aims to empower ficant opportunity for strong links to the AMR agenda for countries through (a) multisectoral technical cooperation, synergy and greater impact. advice, and capacity building to governments, practitio- ners, and partners regarding sector capacities; (b) public Overall, there are several agendas that can connect to health oversight roles; (c) national policies and regulatory AMR. The global health security agenda (GHSA) is another frameworks; (d) national systems for water quality and example of an AMR-sensitivity, since preparedness for disease surveillance; (e) national systems for WASH moni- pandemics holds many synergies with AMR (International toring; and (f ) national WASH target-setting. Every dollar Working Group on Financing Preparedness 2017). One invested in WASH is expected to yield $3 in economic pillar of GHSA is AMR. A number of other pillars— such benefits. The integration of WASH with AMR initiatives will as legislation and laboratory capacity—include AMR, yield additional cobenefits in health and economic gains making this agenda both specific and sensitive. The GHSA over and above the direct outcomes of WASH programs is a voluntary consortium of countries that not all WHO alone. It is estimated that 2.3 billion people around the members have adopted. Nonetheless, the GHSA includes world still lack access to toilets and 4.5 billion people do a dedicated action package on AMR, and, more broadly, Understanding Our Approaches To Date  25 it also can be leveraged for AMR-sensitive interventions. quences of excessive use in agriculture, animal and plant For example, some countries still lack adequate diagnostic production. capabilities, including for common bacterial infections, Antimicrobials are used in agriculture principally in the and GHSA can help strengthen overall systems for better livestock and aquaculture sectors for three purposes: (1) diagnosis of known and novel infections and can build in growth promotion, (2) prevention of infection based on capabilities for AMR testing in the context of overall labo- known risk of exposure (prophylaxis and metaphylaxis), ratory capacity strengthening. and (3) treatment of clinical infection. Experience suggests that improved husbandry practices often can replace the What are the specific contributions of the Global use of antibiotics for growth promotion and disease pre- Agenda for Sustainable Development and vention (OECD 2015). other relevant agendas to AMR? How can these To reduce the amount of antimicrobials employed in lives- be quantified for AMR-sensitive interventions tock farming, some countries have banned or restricted (cobenefits) in different contexts?  — #KKIG 11 their use for growth promotion. According to a survey conducted by OIE (2017), 86 out of 146 (59 percent) respon- ding countries did not authorize any antimicrobial agents Regulation and legislation for growth promotion in animals in their countries as of 2016. The 60 remaining countries (41 percent) reported use Effective legislation and regulation enable responsible of antimicrobials for growth promotion, either with direct production, distribution, and usage of antimicrobials authorization of some compounds, or because the country across the food production, health, and pharmaceutical had no regulatory framework on this issue. Where countries dispensing systems. Regulation is aimed at ensuring have only banned antimicrobial use for growth promotion, access and reducing excess in the use of antimicrobials total antimicrobial use may not have declined, since usage and their disposal into the environment. The goal of regu- may have simply been reclassified as prophylactic. Coun- lating antibiotic use is to focus on the end-to-end supply tries that have banned use of antimicrobials as growth pro- chain leading up to the dispensing point, as well as the motors may experience a transitory increase in therapeutic operations of the dispensing points. Regulating antibiotic use. use can vary from strict bans to restrictions or “gating,” with the ultimate goal of optimizing the use of antibiotics Specific antibiotics, listed by WHO as highest priority in public health and agriculture. critically important for human medicine, should not be used in animal husbandry or agriculture to lower risks While regulation and legislation are necessary, they are of resistance emergence (WHO 2017d); however, not all not sufficient to impact the AMR problem without the countries have introduced or enforced their prohibition in necessary level of enforcement and substantive punitive livestock, aquaculture, and agriculture regulation. measures for lack of compliance (see case studies 1, 2, 3 and 4). This is a major impediment in many countries There are examples of successful antibiotic bans—or where enforcement is weak and corruption is rife at all restrictions of some classes of antibiotics—in several Euro- levels due to factors such as the highly lucrative trade pean countries, particularly in the use of antibiotics in spe- in antimicrobials spanning the whole supply chain from cific animal species when accompanied with other mea- international imports to local street markets. Collignon et sures (see case study 5). However, some of these coun- al. (2015 and 2018) found a positive correlation between tries, while having achieved excellent results in reducing indices of good governance and levels of AMR. antibiotic use, also have introduced alternatives—such as zinc oxide in Denmark—that have turned into a problem Agriculture and food (Jensen et al. 2018). Improved husbandry and food processing requirements Enforcement of regulations and voluntary uptake of can balance the need for access to antibiotics and conse- recommended standards can be greatly enhanced by the provision of support measures, such as advisory services 26  Pulling Together to Beat Superbugs to farmers and insurance schemes that protect farmers be sold without prescription. Tanzania provides an exa- from financial hardship while phasing out the use of mple of a successful antibiotic gating intervention. The antibiotics. This is particularly relevant in LMICs, where government and its Pharmacy Council and Management the withdrawal of antibiotics in food production, a low Sciences for Health have set up a national network of margin industry, is likely to have greater negative financial 12,000 accredited drug dispensing outlets, which sell impacts compared to HICs, where management practices appropriate antibiotics and educate people on the pru- are generally better (Laxminarayan et al. 2015). dent use of ABs and AMR risks (Wellcome Trust 2018). Regrettably, many countries still report no regulatory Last but not least, a revision of the products containing framework for the manufacture, registration, distribution, antimicrobials marketed in countries is needed, as there commercialization, and pharmacovigilance of veterinary are still many pharmaceutical products containing anti- medicinal products (OIE 2017; World Bank 2017c). In many microbials at dosages lower than those effective, and LMICs, there are essentially no controls over the veterinary fixed-dose combinations of antimicrobials with other use of antimicrobials. These are generally available over drugs, without evidence of efficacy in clinical practice, the counter without prescription, as well as in pharma- but which contribute to the presence of antibiotics in cies, general stores, and informal markets, with serious the environment. concerns over quality of VMPs (see case study 2). They are routinely added to commercially produced animal feeds Labeling as standard ingredients. Implementing targeted interven- Labeling and transparency requirements can affect indus- tions thus remains difficult in many LMICs. try norms in both food supply chains and medicine sup- ply chains involving antibiotic use. The AB supply chain The information provided on the packaging (i.e., a bottle Banning or restricting certain classes of antibiotics must label, package leaflet, and outer carton) is critical to be carefully enforced throughout the entire drug supply ensure the correct and safe use of the product. Standards chain. and regulation on how medicines and food are labe- Legislation to enhance “gating” of antibiotics will ensure led can empower users and consumers to make better that their use is exclusively routed through trained health- informed decisions and recognize the unique nature of care professionals rather than over the counter by unqua- antibiotics. Standard labeling requirements can empha- lified sales people. In addition, restrictions can be placed size the “protected” status of certain antibiotics, support on certain types of highly critical antibiotics such as last- tracking mechanisms to ensure drug quality, and inform line antibiotics that are reserved for tertiary care facilities. customers when antibiotics are included in products like Recently WHO proposed the AWaRe classification for anti- animal feed (Wellcome Trust 2016). microbials in three categories: Access, Watch, and Reserve More importantly, labeling can set industry norms around (Hsia et al. 2019). Strict regulation for at least Reserve anti- appropriate antibiotic use. Labeling of products containing biotics is critical. antibiotics may increase awareness of antibiotic usage at The levels of resistance to second- and third-line antibio- all levels of supply chains and is a potential tool to reduce tics is expected to increase rapidly (70 percent higher in the circulation of substandard and falsified drugs. The UK 2030 compared to 2005 for the same antibiotic-bacterium AMR Review has called on governments and international combinations) compared to first-line antibiotics (OECD health organizations to agree to global labeling standards 2018). Removal of second- and third-line antibiotics from for antibiotics (O’Neill 2016). general and online sale can be an intervention where In India, the “Red Line Campaign” for antibiotic packaging indiscriminate over-the-counter sale of antibiotics is was intended to draw attention to antibiotics as a special widely seen as a primary driver of AMR. According to the type of medicine, targeting consumers and other actors WHO AWaRe classification, efforts should be focused on throughout the supply chain. If distinctive labeling were Watch or Reserve antimicrobials, which never should widely adopted, common labeling standards could become Understanding Our Approaches To Date  27 © DOMINIC CHAVEZ/WORLD BANK a condition of sale of antibiotics. Another option would be labeling standards, they are still only regulated through to include information that is in a relevant local language so voluntary guidelines (FAO and WHO 2015). that people can understand when they can use a medicine A number of interventions can contribute to creating an and how. Consistent international labeling of antimicrobials, enabling environment (including surveillance, which is agreed among all countries, has the potential to reduce exis- discussed in the following section); however, the question ting confusion and misuse among prescribers and users. remains regarding what constitutes an enabling environ- No such international standards are currently in force, ment for local context (#KKIG 12). and each country can interpret existing guidance in its own way. As for VMPs, not all countries follow “good practices” on labeling. A recent survey indicated that What are the essential characteristics of an enabling only 18 of the 57 countries require that precautions on environment for AMR control? How should countries disposal of unused or waste materials are included in prioritize efforts toward establishing an enabling labeling (World Bank 2017c). In the United States, for environment within their contexts?  — #KKIG 12 example, The Pew Charitable Trusts (2016) found that labeling measures to be introduced by FDA in 2017 would result in a third of all antimicrobials intended for livestock use not fully meeting judicious use standards Surveillance after implementation of FDA policy. This parallels the Country surveillance systems to track antimicrobial use situation regarding agricultural pesticides, where after (AMU) and AMR in humans, animals, and the environment 40 years of efforts to establish and enforce international are an important component of AMR containment and 28  Pulling Together to Beat Superbugs are captured in the second objective of the Global Action The technical design and data collection standards of Plan (WHO 2015a). Surveillance and monitoring provide a country surveillance systems should be informed by glo- clear picture of the local situation, which over time builds bal guidance so that data is comparable between coun- a knowledge base to assess the impact of other interven- tries and contexts. The Clinical and Laboratory Standards tions. Surveillance priorities for countries will depend on Institute (CLSI) and the European Committee on Anti- national technical, economic, and human resource capa- microbial Susceptibility Testing (EUCAST) provide global cities, as well as governance and the general socioecono- standardized methods for determining susceptibility to mic context. antimicrobial agents among clinical pathogens. Standardized data collection and systems integration is Resources and guidelines available to LMICs in develo- the key to surveillance of drug resistance and antimicro- ping their laboratory facilities include FAO’s assessment bial consumption. tool for laboratory and antimicrobial resistance surveil- lance systems (ATLASS), which provides recommenda- tions for improving laboratories and ensuring use of What are the critical data and data models for standardized data collection methods. The OIE Manual meaningful surveillance and monitoring of priority of Diagnostic Tests and Vaccines for Terrestrial Animals AMR determinants? How can they be incorporated provides standards on laboratory methods for bacterial into facility and population surveillance, monitoring, antimicrobial susceptibility testing, and the Terrestrial and reporting systems?  — #KKIG 13 and Aquatic codes provide guidance on AMR and AMU surveillance and monitoring. WHO’s Global Antimicro- bial Resistance Surveillance System (GLASS) provides While there is consensus regarding some key principles epidemiological standards for surveillance in humans, of data collection and integration, many LMICs still lack and additional guidance on analysis and sharing of the basic capacity to establish and maintain surveillance data on AMR. As of June 2019, seventy-one countries systems. It is important to focus on how to integrate AMR had enrolled in GLASS, including eleven lower-middle- surveillance into existing data collection systems, which income countries and six low-income countries (WHO will maximize the efficiency of resource use and provide 2018 b). In 2017, the WHO Advisory Group on Inte- more complete data. Other suggested practices (IACG grated Surveillance of Antimicrobial Resistance (AGISAR) 2018c) include: updated its guidance on integrated surveillance of anti-  Shared data platforms enable countries to analyze microbial resistance in foodborne bacteria (WHO 2017e). information on AMU in different sectors and locations In other sectors—like plants and the environment—there (e.g. public hospitals and private hospitals) and assess are few, if any, international guidelines and standards for the prevalence of resistance in humans and animals. surveillance of AMR and AMU. The Tripartite Integrated Sur-  Surveillance of the quality of medicines can help veillance System for AMR/AMU (TISSA) is working toward minimize and contain AMR. harmonizing data from different AMR and AMU surveillance systems (IACG 2018 c). This remains an important gap in  Data collected by local and national monitoring terms of knowledge and implementation (#KKIG 13). systems should be incorporated into regional and global surveillance systems. Microbiology laboratory facilities are important because improving antimicrobial susceptibility testing is key to  Implementation of point prevalence surveys (PPS) enabling the overall surveillance system. Not all countries from a few sentinel sites in remote regions can provide may be able to reach the same antimicrobial susceptibi- a relatively quick assessment that is less resource lity testing capability, but shared regional infrastructure intensive than continuous surveillance. can be effective in both human health and veterinary  Collecting quantitative data will enable tracking of health. The key for LMICs is the cost, portability, and relia- progress and accountability for AMR interventions. bility of equipment. Thus, the technologies employed in HIC contexts may not be directly transferable to lower Understanding Our Approaches To Date  29 resource settings. The development of laboratory capabili- AMR. This includes the use of NGS for analyzing single iso- ties also requires human capital planning and the collabo- lates (Zankari et al. 2013), as well as using the technology ration of technical training institutions. directly on samples and quantifying the entire resistome by using the metagenomics approach (Munk et al. 2018; Most surveillance focuses on phenotypes, while resistance Hendriksen et al. 2019). There are new real-time detection determinants require genotyping. New developments in of antibiotic resistant genes with portable and geo-tag- the use of next-generation sequencing (NGS) may change ged systems, which could allow surveillance even in the ability to perform comparable global surveillance of remote places without microbiology laboratories. CASE STUDY 4: SMART USE OF ANTIBIOTICS Thailand has had a strong political commitment to tackle non-infectious diarrhea in a 14-month-old child. The AMR in the last decade and is following through with results showed that, of 91 pharmacies visited in Khon practical actions. In 2016 the cabinet endorsed a five- Kaen Province, 7.7 percent provided oral rehydration salt year National Strategic Plan on Antimicrobial Resistance solution according to guidelines, whereas 68.1 percent for 2017 to 2021. Understanding the complex network dispensed antibiotics inappropriately (Jaisue et al. of stakeholders was essential in developing the national 2017). These continuing challenges have suggested the strategic plan. Prior to approval of the strategic plan, need to directly address existing norms and behaviors there were roughly 24 committees, subcommittees, and that underlie prescriptions and the use of antibiotics. In working groups under the Ministry of Public Health and Thailand, both physicians and pharmacists are allowed the Ministry of Agriculture and Cooperatives that were to prescribe and dispense controlled-class antibiotics related to AMR. These were consolidated under the new to consumers and they receive either direct or indirect plan, and the participatory approach to implementation benefits for doing so. Other antibiotics—those classified of the plan has given legitimacy and raised public as cautionary in Thailand, such as ciprofloxacin and awareness about AMR efforts. The National Health cotrimoxazole—can be dispensed without a prescription Assembly—which brings together representatives from (Jaisue et al. 2017). In rural areas, many more antibiotics government, academia, the private sector, and civil can be purchased illegally (WHO 2015b). The Thai Food society from all 77 provinces—adopted a resolution on and Drug Administration is working to reclassify drugs AMR that incorporated various actions for the Ministries to limit those in the cautionary class, hence reducing of Public Health, Agriculture, and Education, other access to certain antibiotics (Sommanustweechai et al. governmental agencies, national and provincial health 2018). Thailand aims to reduce antibiotic consumption in assemblies, local governments, civil society organizations, the human health sector by 20 percent and in veterinary and the private sector (Sumpradit et al. 2017). medicine by 30 percent by 2021, as outlined in its Thailand has been grappling with the overuse of National Strategic Plan on Antimicrobial Resistance antibiotics for at least the last decade. A 2010 study (Sommanustweechai et al. 2018). on the health impacts of AMR in Thailand found that This case study describes an initiative to encourage 87,751 hospitalizations led to antibiotic-resistant the smart use of antibiotics in clinical settings as a infections with one of five major bacteria (Escherichia primary approach to limiting AMR in Thailand. The coli, Klebsiella pneumoniae, Acinetobacter baumannii, Antibiotic Smart Use (ASU) program aims to both reduce Pseudomonas aeruginosa, and MRSA), accounting for patient demand and educate providers on appropriate 3.24 million additional days of hospitalization and 38,381 use of antibiotics in clinical care. The ASU program is deaths (Pumart 2012). Norms and behaviors around a collaboration between the Ministry of Health and antibiotic prescriptions and use have contributed to universities in educating consumers and providers on the this problem. In a study published in 2017, simulated appropriate use of antibiotics for respiratory infections, patients visited community pharmacies and reported 30  Pulling Together to Beat Superbugs diarrhea, and simple wounds with the ultimate goal to the norms and behaviors associated with antibiotic use. change social norms (Sumpradit 2012a). For providers, this means, in part, reducing the incentives The ASU program has been rolled out in three phases to overprescribe (e.g., direct fees) and rewarding (Sumpradit 2012a; So 2014). In 2007–08, education appropriate use of antibiotics. For consumers, this means and training reforms were piloted in Saraburi Province, reporting about the ineffectiveness of antibiotics for with Phra Nakhon Si Ayutthaya Province serving as a some illnesses, as well as the direct and indirect harms of control to measure effectiveness. Training included inappropriate use (e.g., clinical consequences). Because educating prescribers and providing posters and videos norms and behaviors (e.g., rural vs. urban purchasing for patient waiting areas, posters with treatment habits) are likely to differ across the country, the flexibility guidelines for clinicians, and white light illuminators for built into implementation of the ASU program may patients’ visualization of their own throat infections (So allow Thailand to contend with diverse underlying 2014). Seed money was given to hospitals to support drivers of excessive and inappropriate antibiotic use. implementation and evaluation. Overall, phase I resulted As effectiveness of the campaign is assessed across the in an 18–46 percent decrease in use across hospitals 15 provinces, lessons on what messages and education (Sumpradit 2012b). In 2008–09, this pilot program methods scale best and change critical norms and was scaled up to 44 hospitals and 621 primary health behaviors of antibiotic use may become apparent. centers in three provinces, including one public and one This case study addresses the norms and behaviors private hospital network. Within the program, a pay- that determine antibiotic use. The program certainly for-performance scheme was initiated by the National benefits from an existing nationwide enabling Health Security Office. There was no single package of environment. It shows how a pilot is currently being interventions. Examples of innovative methods to reduce scaled up to meet the needs of the country. It will benefit antimicrobial use included the use of concave mirrors from enablers such as a decentralized network of AMR with photos of bacterial infections so patients could interventions with potential for innovation, regulation compare clinical signs for themselves; the provision of of controlled-class antimicrobials, and training and other herbal medicines as alternatives to antibiotics (ReAct incentives for appropriate antimicrobial use for clinical 2016); and the availability of materials that addressed practitioners. The case study also highlights how all common misconceptions related to antibiotics, such as elements that will allow scale-up from discrete successes their ability to reduce inflammation (Sumpradit 2012 to an integrated functioning system are not yet identified. a). In 2010, Thailand began scaling up this program to Finally, we note the recurring issue of illegal medicines in 15 of the 77 provinces in the country, and the payment informal markets. mechanism to limit prescription of antibiotics remains This case study emphasizes the importance of sustained. The sustainability and success of this phase is addressing key issues around antimicrobials—that still to be evaluated. is, the way they are situated in our health and other The ASU program addresses the drivers of architectures, the way we use them, as well as external inappropriate antibiotic use that can contribute to AMR. factors to the system. Finally, it showcases an array of Specifically, this program aims to provide education to interventions that benefit from an enabling environment both providers and consumers—both of whom have and seek to reduce the need for and use of antimicrobials. been implicated in the misuse antibiotics—to change Understanding Our Approaches To Date  31 REDUCING THE NEED Successful AMR interventions highlight the need to monitor compliance (Mölstad et al. 2017). Studies show FOR ANTIMICROBIAL USE that adherence to hand washing protocols is frequently (ADAPTATION) suboptimal. Other IPC measures, such as patient scree- ning and isolation, can play an important role in AMR Rather than being afraid of a world without antibiotics containment. All may not be able to implement these with the advent of AMR, we can prepare for this by buil- measures given their cost (Wellcome Trust 2016). Beyond ding our systems and structures in ways that antibiotics cost, factors such as fragility, conflict, and violence (see are less needed. Prevention of infections that require the chapter 1) may also hamper implementation. A better use of antimicrobials to treat them is fundamental to understanding of these obstacles and how to overcome reducing the emergence and spread of AMR. One of the them is needed (#KKIG 14). five objectives of the Global Action Plan for controlling AMR is to reduce the incidence of infections by infection prevention and control (IPC). Other objectives, which also What are the major obstacles in implementing contribute to infection prevention, include reducing risk effective hygiene, infection prevention, and at the human-animal-environment interfaces, expanding control in specific contexts? How can we overcome access to clean water and sanitation, and access and use them?  — #KKIG 14 of basic hygiene practices. Preventing infections in the first place is one of the most efficient ways to address AMR (World Bank 2017a). IPC practices apply to both In the agriculture and food setting, effective preventive human health and animal health. Good hygiene and sani- AMR interventions can be applied to basic infrastructure tation have been highlighted as one of the most powerful such as building design, drainage, and effluent manage- intervention tools in combating AMR, yet basic steps are ment at all stages of the food chain from primary pro- often lacking: across the world today, 2.1 billion people duction to processing and retail outlets. The consistent lack reliable access to safely managed drinking water application of good animal husbandry practices (GAHP) services and 4.5 billion lack safely managed sanitation for livestock rearing with higher biosecurity—like the services. simple act of showering, changing clothes, and shoes before entering a livestock facility—can significantly Hygiene, infection prevention and control reduce the risk of introducing infectious agents and Although IPC practices are often seen as basic or even the subsequent need for antimicrobial use in livestock taken for granted, good hygiene—in the hospital, (Lhermie et al. 2017). This is important with regard to community, and at home—is at the root of preventing risks related to the food chain and to pollution of the infection and must be addressed explicitly as with other, environment. seemingly more complex interventions. Studies show that Food safety remains a challenge in many LMICs. For exa- most healthcare-associated infections can be prevented mple, a study from Ethiopia found that abattoirs were through good hygiene (WHO 2014). High standards of lacking in basic amenities such as soap, hot water, and hygiene—personal hygiene as well as hygiene in hospital, even bathroom facilities for staff (Dulo et al. 2015). Globally, community, and home environments—to reduce the productivity losses associated with foodborne diseases in presence and survival of microbes in the environment and LMICs are estimated to cost $95.2 billion per year, and the reduce human and animal exposure usually correlates annual cost of treating foodborne illnesses is estimated at with conditions and practices that maintain health and $15 billion (Jaffee et al. 2019). Measures to improve food prevent the spread of diseases. safety will have an indirect positive impact on AMU and In the human healthcare setting, the importance of good consequently AMR control (World Bank 2017a). The food hygiene—particularly cleaning the facilities, and good and agriculture sector can do more to limit consumer hand hygiene through hand washing with clean water exposure to drug-resistant microbes. For example, regula- and soap or alcohol-based products—is well established. tions on surface cleansing methods in food processing set- 32  Pulling Together to Beat Superbugs ©MAHMUD RAHMAN / WORLD BANK tings are not employed in all countries, but could reduce What are the major obstacles in accessing clean the spread of bacteria (Wellcome Trust 2016). water and sanitation? How can we overcome A better understanding of obstacles in implementing them?  — #KKIG 16 good practices in agriculture, biosecurity, and food safety and how to overcome them is needed (#KKIG 15). Poor water safety and sanitation is particularly pre- valent in LMICs and accounts for a disproportionately What are the major obstacles in implementing high burden of diarrheal illness through transmission of microbes between people and between people and good agriculture practices, biosecurity, and food their environments. The same applies to AMR conta- safety in specific contexts? How can we overcome gion, which is aggravated due to the inability of current them?  — #KKIG 15 water treatment techniques, including chlorination and UV radiation, to effectively control AMR. This is because antimicrobial resistance genes are able to survive and Water and sanitation pass into treated effluents, thus reinforcing the reservoir Every year, 361,000 children under 5 years of age die due to of antibiotic resistance genes in treated water (Lood et diarrhea related to poor sanitation and contaminated water, al. 2017). which are also linked to transmission of diseases such as There is no organized or functional system for AMR cholera, dysentery, hepatitis A, and typhoid. Improving surveillance specific to the environmental sector, specifi- access to clean water and sanitation is consistent with the cally water, soil, and air (Wuijts et al. 2017). Governments sustainable development goals. It would reduce the inci- that are assessing investments on a cost-benefit basis dence of infections, and therefore reduce the need for anti- should incorporate the public health benefits including microbials and spread of infections with resistant microbes. AMR containment, as part of the expected returns from Although this intervention is not specific to AMR, it consti- improving access to clean water and sanitation (O’Neill tutes a vital step toward better health and fewer infections 2016). and is an AMR-sensitive intervention (#KKIG 16). Understanding Our Approaches To Date  33 Nurse prepares to vaccinate children Jestina Wright a nurse (hands in far left) prepares to vacci- nate children at Redemption Hospital in Monrovia, Libe- ria on March 2, 2015. Photo © Dominic Chavez/World Bank For more information: www. worldbank.org/ebola/ Photo ID: World_Bank_Fi- nal_Hard_Edit_0010 © DOMINIC CHAVEZ/WORLD BANK Vaccination and innovative drugs (Hoelzer et al. 2019). However, vac- cines optimally fulfill their potential when used as part of Vaccination is known to prevent disease transmission and an overall program of infection prevention and control engenders protection against infection by building herd as described above. Much of the first line treatments by immunity in humans and animals, though people and far- farmers or veterinarians is empirical, based on experience mers may lack willingness to adopt vaccination practices and in response to syndromic indications (OIE 2015). for many reasons, including cost. Reduction of syndromic indications through better targe- Vaccination of humans and livestock can prevent infec- ted, potentially multivalent vaccines has the potential to tions and lower demand for antimicrobials (World Bank reduce the need for use of antibiotics (#KKIG 17). 2017a). Higher vaccination rates against viruses can be an effective way to limit AMR through also reducing the need for antibiotics and subsequent selection pressure for What are the priority vaccines that could be the development of resistance. developed for reduction of antimicrobials? What are their projected effects on reducing consumption of The effectiveness of bacterial as well as viral vaccines in reducing the need and use of antibiotics in animal agricul- antimicrobials?  — #KKIG 17 ture has been documented (Murphy et al. 2017). Vaccines are usually considered as part of alternative products, Vaccine-preventable diseases cause approximately which can help minimize the need for antibiotics along 15 percent of disability-adjusted life years (DALYs) in with microbial-derived products, non-nutritive phytoche- Sub-Saharan Africa (Philips et al. 2017). Yet, vaccination micals, immune-related products, chemicals, enzymes, rates are low in LMICs—for many reasons (Restrepo-Mén- 34  Pulling Together to Beat Superbugs dez 2016)—in contrast to others where vaccination pro- Livestock kept under optimal farm environments with grams are successful. For example, 90 percent of children high-quality hygiene, biosecurity, and animal manage- in India are now being fully vaccinated as per the child- ment practices require much lower antimicrobial use hood immunization schedule (Harbarth et al. 2015). Delay (Stevens et al. 2007) due to lower infection rates and in acceptance or refusal of vaccines despite their availabi- reduced need for treatment (Postma et al. 2015), indica- lity has been increasingly reported (see chapter 1). ting the feasibility of preventive approaches to reducing the need for antimicrobial use. Animal vaccination rates remain low with a trend to using antibiotics prophylactically instead, despite WHO guidelines A review performed for OECD (Laxminarayan et al. 2015) that antimicrobials should not be used to prevent disease of the economic costs of banning antimicrobials for in healthy animals (WHO 2017a and d). Studies show far- growth promotion use found that it is possible for pig and mers generally lack understanding and willingness to adopt poultry producers to maintain production levels without vaccination practices, largely citing concerns about the antimicrobials through preventive management such as costs, accessibility, and reliability of vaccines (Coyne et al. vaccination, segregation of animals by age, sanitary proto- 2014). Finally, the need for cold chain—maintaining a pro- cols, good ventilation systems, adjustment in feed rations, duct at a specified low-temperature range from production and physical external and internal biosecurity measures. to consumption—often remains a limitation for vaccination Additional costs of production would be minor at around in many countries. 1–2 percent in well-managed optimized livestock farms with up-to-date infrastructure. USDA concluded that The OIE has prioritized diseases in animals for which the because the efficacy of antibiotics in increasing farm-le- availability of vaccines could reduce antimicrobial use, vel productivity has decreased in the past 20 years, their underscoring the potential of vaccines as alternatives to removal would have limited effects on farm production antimicrobials for controlling animal diseases. This also and prices by less than 1 percent over time (Sneeringer et should guide research on vaccine development in pigs, al. 2015). Hence the economic impacts of moving to pre- poultry, farmed fish, cattle, sheep, and goats. ventive management in HICs are likely to be insignificant. The same cannot be said for the situation in most LMICs, What measures can be taken to improve uptake and where hygiene and husbandry methods are less industria- use of vaccines in specific contexts?  — #KKIG 18 lized. In the absence of efforts to introduce good animal husbandry and management, antimicrobials are poised to become the major driver allowing the country to meet Husbandry and management the projected livestock demand in these countries (Del- The rise of intensive systems of livestock production to gado et al. 2001). Demand for dairy, pig, and poultry pro- reduce costs has led to misuse, including overuse, of anti- ducts is set to grow fastest, with a concomitant increase biotics in livestock farming. In other words, antibiotics have in the use of antimicrobials for livestock of 66 percent by been a short-cut solution to achieving high levels of pro- 2030. ductivity and profitability, while at the same time making meat cheaply available for a growing world population, What strategies can be developed to transition the albeit at a high cost in terms of AMR proliferation. But there is increasing evidence that continual improvement in animal livestock sector to become not only independent of husbandry—such as genetics, vaccines, nutrition, housing, antimicrobials as growth promoters but also less biosecurity, animal management practices, and animal wel- dependent on antimicrobials for prophylactic and fare—have now obviated the need for antibiotics for growth metaphylactic use?  — #KKIG 19 promotion and prophylaxis (Van Boekel et al. 2015). In-depth surveys of farmers and veterinary professionals in HICs found that the key to good husbandry is highly skilled staff (Coyne et al. 2016; Coleman et al. 1998). Understanding Our Approaches To Date  35 Power of consumer preference tion, recently outlined its goals for antibiotic stewardship (McDonald’s 2017). The company intends to reduce the Even in the absence of effective regulation and enfor- need for antibiotics by ensuring its suppliers use appro- cement, the private sector livestock, processing, supply, priate farming practices, including the responsible use of and marketing industry can have a major influence on antibiotics. antimicrobial use on farms. Driven by consumer demand, supermarkets are starting to develop policies and enforce Several public interest nonprofit organizations working standards regarding antibiotic use by their meat suppliers. to eliminate the routine use of antibiotics in food animals Most large food retailers already offer—although most now monitor the implementation of food industry com- often ill-defined and misleading—antibiotic-free, organic, mitments, some of which are more restrictive than required and high-animal-welfare certified products. In the United by government legislation, and publish annual findings States, this is still only a small market share at 5 percent of (Friends of the Earth et al. 2018). There is encouraging evi- all meat marketed. But it is growing at 20 percent annually dence that strengthened consumer preferences, awareness, on average, with antibiotic-free poultry sales growing at 34 and transparency can influence the food industry in positive percent (DNV GL AS 2016), as factory-farming-produced ways for better antibiotic stewardship. meat demand declines. Heightened consumer awareness also is increasingly How can we accelerate adoption of high farm and affecting the sourcing policies of many major global food industry antimicrobial stewardship through fast-food companies, which are increasingly focused on market forces and consumer preferences, awareness, antibiotic-free ingredients. For example, the McDonald’s and transparency?  — #KKIG 20 chain, which buys over 2 percent of global beef produc- 36  Pulling Together to Beat Superbugs CASE STUDY 5: INTERVENTIONS INVOLVE MANY STEPS AND MANY ACTORS Denmark has a highly efficient meat production industry amounts and prices of antimicrobials that veterinarians with significant export of meat products. Agricultural could sell and restricted further antibiotic treatment to that growth promoters (AGPs) have been used to increase obtained from a pharmacy by prescription only (FAO and production in this industry since the early 1950s (FAO and Ministry of Environment and Food of Denmark 2019). In Ministry of Environment and Food of Denmark 2019). turn, farms were subjected to monthly veterinarian visits International concern about this practice was raised as early to maintain the health of animals without use of AGPs. as 1969 in testimony from the Joint Committee on the Use This shift in income source—from sale of antimicrobials of Antibiotics in Animal Husbandry and Medicine before to increased advisory services—allowed livelihoods the British Parliament (Swann Report 1969). In the 1990s, of veterinarians to be maintained while changing outbreaks of Salmonella infection brought local attention to veterinarians’ roles in the food production industry (Kovács food safety issues, including the potential for antibiotic use 2011). In addition, in 2000 a database of all purchased and in animals to contribute to antimicrobial resistance (Kovács prescribed antimicrobials (the Danish Veterinary Medicines 2011), leading to scrutiny of AGP use in Denmark. Statistics Program, or VetStat) increased accountability Following English and German studies on vancomycin- in the profession and provided data to determine the resistant enterococci in the 1990s, the Danish Veterinary association between antimicrobial use and the appearance Laboratory examined poultry samples and identified of antimicrobial resistance. VetStat data support the avoparcin—an antimicrobial closely related to vancomycin— Danish Integrated Antimicrobial Resistance Monitoring as a potential driver of vancomycin resistance in the Danish and Research Programme (DANMAP), which was launched food system (Aarestrup et al. 2000). Appealing to the food in the mid-1990s as a collaboration among the veterinary, safety concerns of Danish citizens, use of avoparcin was food, and human health sectors (FAO and Ministry of banned as an AGP in Denmark in 1995 (FAO and Ministry Environment and Food of Denmark 2019). Based on the of Environment and Food of Denmark 2019). In 1996, “farm-to-fork” concept (Kovács 2011)—the keystone in an FAO/WHO expert panel met to discuss the issue and, responding to Salmonella outbreaks in the 1990s—and spurred further by the appearance of bovine spongiform implicating all stakeholders in the supply chain, DANMAP encephalopathy in Britain that same year, the food production tracks the use of antimicrobials and appearance of industry in Europe began to implement risk analysis principles resistance in livestock. and separated the responsibility for assessment from Based on early DANMAP data, the European Food responsibility for management (EU Food Law) for a proactive Safety Authority recognized Denmark as a country with approach to ensuring food safety. In 1997, the EU also banned a low incidence of antimicrobial resistance relative to its use. Scrutiny of the AGP virginiamycin followed shortly other countries in the EU (Kovács 2011). Between 1994 thereafter, with its use prohibited in Denmark in 1998 and and 2001, Denmark experienced a 54.2 percent decrease the EU in 1999. Use of bacitracin, tylosin, and spiramycin in antimicrobial use (Dibner 2005). A later analysis of were subsequently also banned in Denmark. Further, the antimicrobial consumption and swine productivity Danish poultry industry voluntarily stopped use of all AGPs in in Denmark from 1992 to 2008 indicated that, while broiler poultry by 1998, as did the swine industry in finishing consumption of AGPs decreased, productivity did not pigs in 1998 and all swine by 2000. Supported with data decline following the change in veterinary prescriptions collected by Danish and Swedish scientists and following the and ban on AGPs (Kovács 2011). Other changes—such as 1998 Copenhagen Recommendations—which outlined a improving farm environments, increasing the weaning framework for surveillance, monitoring, and good practice age, and modifying the diets of animals—likely played a use of antimicrobials (Andersen and Hald 2017)—the use role in maintaining this productivity. The pork industry, of all AGPs in the EU was phased out by 2006 (European specifically, expanded substantially—from 18.4 million Commission 2005). hogs annually in 1992 to 28 million in 2010—during Danish veterinarians shared the concerns of policy this period (Kovács 2011). Although antibiotics used for makers and industry and, in 1994, placed limits on the treatment did increase steadily from 1999 to 2007 due to Understanding Our Approaches To Date  37 an increase in production, use was further curbed with and universities. Policy decisions could be made based implementation of a “yellow card” (a dynamic tool that on data available in VetStat and DANMAP and then limits acceptable antibiotic consumption) warning to compared with those of other countries in the EU for farms found to be overusing antimicrobials (Andersen evidence-based decisions. Another important success and Hald 2017). Denmark has continued to promote factor has been the cooperative model of Denmark’s innovations to reduce antimicrobial consumption: in meat production industry, which enabled farmers to 2013, taxation of antimicrobials was scaled to promote collectively decide to implement the precautionary use of narrow-spectrum over broad-spectrum drugs and principle and voluntarily ban AGPs. The role of civil society an annual laboratory diagnosis was required for group has been key as well; opposition from the pharmaceutical treatment of animals (Andersen and Hald 2017). industry increased public awareness of the food safety Limiting use of antimicrobials is our third family risk debate in Denmark, and civil society’s engagement of interventions. In this case study we looked at how created an opportunity for change. The support of Denmark managed to phase out antimicrobial growth veterinarians, including their acceptance of a shift in their promoters in the meat production industry. The Danish practices and willingness to address economic incentives experience in reducing AGP use has been held as a model for the profession, led to a system that benefited both for other countries to emulate. It shows that multiple veterinarians and farmers and decreased the use of steps were needed with the involvement of multiple antimicrobials. Finally, the food chain approach, also actors. The alliance between government and research known as “farm-to-fork,” provided a comprehensive partners was pivotal in this process. There is a long and broadly understandable approach to banning AGPs tradition of cooperation among stakeholders in the area and reducing the use of antimicrobials to prevent the of animal production. The Danish approach has included emergence of resistant bacteria in the food system. This cooperation among organizations representing farmers experience blends interventions aiming at reducing the and industry, veterinarians, government authorities, need for and use of antimicrobials. LIMITING USE OF mitigating the risk of income loss while phasing out AGPs. Even with improved husbandry practices, phasing out ANTIMICROBIALS (MITIGATION) AGPs in livestock feed could affect the profitability of food production, especially in LMICs (Laxminarayan et al. 2015). Economic incentives and disincentives Access programs and insurance schemes for farmers can The market for antibiotics involves drug companies, promote appropriate antibiotic use while protecting far- wholesale suppliers, and distributers that have the profit mers against market risks. incentive to maximize unit sales rather than act in the To help farmers manage this market risk, countries or regions best interests of antibiotic stewardship. There is also a could create pooled procurement programs to improve parallel market of counterfeit and substandard medical access to a sustainable supply of good-quality antimicrobials products, including antimicrobials. On the demand side, for therapeutic purposes, with reduced transaction costs. users of antimicrobials often pay high transaction costs to Demand planning and leveraging consumption data for intermediaries in the medicine supply chain, and farmers these procurement programs also would lead to uninter- may be unprotected from potential financial loss when rupted supply and the strengthening of distribution, which phasing out the use of antibiotics. This section discusses would boost efficiencies across the supply chain. interventions to alter the market dynamics of a “tragedy of Another approach under consideration is for countries to the commons” scenario. develop insurance schemes to mitigate the risk of income Farmers and food producers invariably operate under loss among producers during the phaseout of antibiotics, uncertainty and risk. Market interventions can be effec- or provide insurance against livestock diseases for farmers tive at improving access to antibiotics for treatment and who don’t use antibiotics. The EU ban on antimicrobials 38  Pulling Together to Beat Superbugs for growth promotion in 2006 may have resulted in an tionalized, and moreover that they still do not necessa- increased incidence of infectious diseases, based on the rily translate to improved health care and can have other observation that the phaseout was associated with a unintended consequences (Beisel et al. 2016). short-term increase of disinfectants and therapeutic use of antibiotics in livestock (World Bank 2017a). What are the priority diagnostic tools that could This type of intervention may be challenging for govern- be developed to reduce use of antimicrobials? ments that don’t have the institutional capacity to provide What is their projected effect of reducing livestock insurance, but there could be opportunities to antimicrobial consumption in different country develop public-private partnerships such as those pro- viding index-based insurance for pastoralists in Kenya contexts?  — #KKIG 22 to introduce husbandry interventions for improved household resilience under erratic rainfall conditions (Johnson et al. 2018). Education, awareness, and behavior of professionals The importance of educating healthcare professionals has What financial incentive schemes can be devised long been recognized (WHO 2013) and the organization to reduce farmer risk in adopting good AM recently developed a competency framework for health practices?  — #KKIG 21 workers’ education and training on antimicrobial resis- tance (WHO 2018e). The 2013 guidelines on transforming and scaling up health professionals’ education and trai- Precision use of antimicrobials ning emphasize the importance of linking education to Better diagnostic tools are needed to prevent empirical population need and moving away from education that is prescribing, particularly in LMICs. Microscopy, culture, segregated into silos (WHO 2013). As an issue that affects DNA or protein-based tests, and sensitivity testing can every member of the human race, everyone should be all help to identify individual pathogens so that a spe- aware of AMR, its threat to humanity, and their individual cific, targeted antibiotic treatment can be given. Lack role in avoiding the risks it poses to themselves and to of access, high cost, and lengthy wait times to obtain others. results of such diagnostic tests means antibiotics are often used empirically and “to be on the safe side.” Empi- Despite AMR being recognized as one of the greatest rical prescribing is particularly prevalent in LMICs, where global healthcare challenges of our time, coverage of the diagnostic tools are even less available or less effective. topic in medical education curricula is limited. The “We It often includes the unnecessary combination of two or need you” communication campaign by OIE is probably three individual antibiotics, each potentially contributing the first global campaign dedicated to raising awareness to the emergence of resistance. One challenge lies in of antimicrobial resistance in the animal health sector. The producing tools that are cheap, portable, and provide a campaign, focused on the careful handling of antibiotics, quick result. “Point of care testing” and “pen side testing” was used to develop a toolkit for national veterinary ser- are still relatively rare—even in HIC settings—and it is vices, policy makers, veterinarians, veterinary students, likely to be some time before this translates to the LMIC farmers, the pharmaceutical industry, wholesale and retail setting. For example, in the UK GPs are faced with the distributors, and animal feed manufacturers. dilemma of doing a sensitivity test, which would delay treatment and incur three times the cost of empirically Knowledge and awareness prescribing immediate treatment (House of Commons Educating healthcare professionals about AMR is a vital 2018). We already know from experience with the step in trying to tackle AMR, yet the focus of educational introduction of rapid diagnostic tests for malaria, that interventions to address AMR varies widely among coun- these “simple and mobile” devices often require more tries in all income-level groups. For example, outcomes of infrastructure than they circumvent in order to be opera- effective education programs include a change in prescri- Understanding Our Approaches To Date  39 bing principles and behavior, incorporating AMR discus- What is the long-term impact of interventions to sions into the consultation model, or automatically giving change behaviors and social norms regarding out leaflets with each antibiotic prescription. antimicrobials? What interventions will engender Studies have shown that many healthcare professionals sustainable change in behaviors and social norms are lacking in knowledge and understanding of AMR and regarding antimicrobials?  — #KKIG 23 that gaps exist in the undergraduate healthcare curri- culum (Pereira et al. 2017). For example, in an Ethiopian study of paramedical staff, very few had received any for- Behavior of professionals mal training on antibiotic prescribing and were lacking in The highest rates of antimicrobial prescribing occur in knowledge of AMR (Tafa et al. 2017). the community setting and thus are a priority area for Some research suggests the need for greater emphasis AMR research. In 2014 in the UK, for example, 74 percent in public messages for understanding how resistance is of antimicrobials were prescribed by GPs (Public Health spreading, rather than an active focus on why and what England 2016). can be done to reduce it. They recommend that educatio- Numerous elements of stewardship efforts have been nal interventions should focus on meaning and purpose associated with decreased levels of antimicrobial prescri- (Tsai et al. 2017). The example of AMR is well suited to this bing, including provider and/or patient education, provi- school of thought, as knowing why we need to tackle AMR der feedback, formal guidelines, delayed prescribing, com- is key to sustainable implementation of interventions. munication skills training of providers, drug restrictions, Van Katwyk et al. (2018) reviewed AMR education provider decision support systems, and financial incen- methods available globally and found that many organi- tives (Drekonja et al. 2015). However, more large-scale zations were working on educational resources for AMR studies that assess the effect of outpatient antimicrobial control. They identified some areas for improvement, stewardship on antimicrobial resistance are needed, in including increased student engagement, improved diverse contextual situations, to inform and prioritize resource-sharing, and the need to recognize the impor- interventions as a part of individual national action plans. tance of AMR learning in continuing medical education; One UK study targeted the highest prescribing GP prac- those elements have been integrated into the WHO tices to try and alter prescribing rates. The study utilized competency framework for health workers’ education and “social norm” information, involved a high-profile figure training on AMR (WHO 2018e). to “champion” the initiative, and provided behavioral ins- The importance of recognizing and acknowledging AMR truction, with the intended outcome to lower the rate of in education cannot be underestimated. A recent survey antimicrobial prescription by GPs (Hallsworth et al. 2016). showed that the problem of AMR was often externalized, Social norm feedback was effective in encouraging out- being perceived to be “someone else’s fault” (Zhuo et al. liers to adjust their prescribing levels. However, other 2018). Other researchers have identified this attitude in studies have found the effect to be short-lived (Cairns et other sectors; for example, veterinarians tend to “blame” al. 2013), so long-term follow-up of efficacy is needed. the intensive farming industry for AMR and not their Punitive mechanisms may be effective but short-li- own practices (Hardefeldt et al. 2018). Incorporating ved, whereas self-determined behavioral change may shared responsibility and a “one health” approach into achieve better outcomes in the long term (Sikkens et al. medical and veterinary curriculums, or including this in 2017). The authors conclude that future antimicrobial mandatory departmental induction alongside regular stewardship efforts in hospitals should use behavioral professional updating, would be a good starting point in theory to improve intervention effectiveness in various most organizations. clinical settings. Some interventions focusing on behavioral change and social norms have been successful, yet data on long-term follow-up and sustainability are not available. 40  Pulling Together to Beat Superbugs © SIMONE D. MCCOURTIE / WORLD BANK Professional Culture science and learning theory, and shaped though input Cultures that influence prescribing appear to exist both from patients and practitioners.\nResults: By synthesizing within human healthcare and animal healthcare. A nega- data from 131 articles, the review highlights the complex tive intrinsic hierarchy exists within the medical profes- social and professional dynamics underlying antimicrobial sion, leaving junior doctors reluctant to challenge their prescribing decisions of doctors-in-training. The analy- seniors and so inappropriate prescribing persists. Within sis shows how doctors-in-training often operate within the veterinary sector, financial pressures and client pres- challenging contexts (hierarchical relationships, powerful sures also impact on prescribing decisions. prescribing norms, unclear roles and responsibilities, implicit expectations about knowledge levels, uncertainty A negative cultural hierarchy appears to be ingrained in about application of knowledge in practice Recently the medical profession and studies have reported that this trained junior doctors, who may be more knowledgeable culture has a strong influence on prescribing (Papoutsi et about AMR, have difficulty challenging clinical decisions al. 2017).such interventions are often adopted without an of more senior doctors and consultants. Broom et al. adequate understanding of the challenges facing doc- (2016) studied the social context of the practice of anti- tors-in-training as key prescribers.\nMethods: The review biotic prescribing in Australian hospitals, finding that followed a realist, theory-driven approach to synthesizing suboptimal antibiotic use is a real and pragmatic choice qualitative, quantitative and mixed-methods literature. within a complex social context. Drivers of prescribing Consistent with realist review quality standards, articles behavior were more about protecting patients, managing retrieved from electronic databases were systematically time pressures, gaining and achieving social capital, and screened and analysed to elicit explanations of antimi- expressing a benevolent identity, rather than focusing on crobial prescribing behaviours. These explanations were the threat of antimicrobial resistance. consolidated into a programme theory drawing on social Understanding Our Approaches To Date  41 Prescribing cultures within the veterinary sector also have governments to engage in AMS; lack of coordination of been linked to AMR. For example, multidrug use and AMS across different sectors and specialties (Tiong et subtherapeutic drug use are particularly strong drivers of al. 2016); and economic viability (Ibrahim et al. 2018). A AMR. Both of these practices are prevalent in agriculture recent systematic review (Van Dijck et al. 2018) of AMS in (Silbergeld et al. 2017), where the high cost of diagnostic LMIC settings concluded that most of the AMS interven- testing leads to empirical prescribing with few veterina- tions had a positive effect. However, general conclusions rians following official guidelines (Hardefeldt et al. 2018). about their effectiveness could not be made, probably Veterinarians often feel pressure from farmers to overpres- due to context-specific variables in certain settings. cribe for several reasons (Coyne et al. 2014). Implementation of AMS among the veterinary and ani- Therefore, in both animal and human health, cultural mal health sector also is challenging, with uptake of AMS factors and their influence on prescribing behaviors need programs being particularly low in the veterinary sector to be taken into consideration when implementing AMR (Hardefeldt et al. 2018). interventions. The general public—users of antimicrobials Prescribing guidelines exist in many LMICs, albeit in many instances they are not surveillance-based; yet even when Globally, the public has low levels of knowledge of AMR. they do exist, they are not always followed due to lack of Furthermore, they find the language and concepts resources, time pressure, and insufficient staff (Edelstein behind AMR complex and difficult to grasp. Public health et al. 2017). Antimicrobial stewardship (AMS) programs messages need to be carefully worded to appropriately aim to improve prescribing and advocate for following emphasize the severity of the AMR situation. Reviews guidelines, but the success of AMS interventions remains of public awareness campaigns mainly show whether a debated issue. people improve their knowledge—fear of AMR—rather than any other impact, such as unintended consequences Official guidelines for antimicrobial stewardship of raising awareness or inadvertently getting people to move automatically to next-line antibiotics in fear that Many healthcare settings produce prescribing guide- current drugs are not working. lines for advising clinicians about antibiotics that are appropriate for specific bacterial or viral infections. For Many studies and surveys have reported a lack of example, the Royal College of general practitioners (GPs) knowledge of both antibiotic use and AMR among the has produced the TARGET (Treat Antibiotics Responsibly, public. The European Commission (2016) carries out regu- Guidance, Education, Tools) toolkit, which includes links to lar surveys to assess public awareness and knowledge of tables with antibiotic guidelines. antimicrobials and AMR. The results from 2016 revealed that only 24 percent of participants answered all ques- The concept of antimicrobial stewardship (AMS) is defined tions correctly, with only 43 percent and 56 percent being as “a coherent set of actions that promote using antimi- aware that antibiotics are ineffective against viruses and crobials in ways that ensure sustainable access to effective against colds and flu respectively. therapy for all who need them” (Dyar et al. 2017). Actions might include prescribers making accurate diagnoses, fol- A WHO (2015a) survey of 12 member states found that lowing guidelines, reviewing their prescriptions in a timely 57 percent of participants thought there was nothing an manner, formulary restrictions, and preauthorization of individual can do to help stop AMR, and 76 percent did certain antimicrobials. not know why AMR occurs. Results were similar for both LMICs and HICs. People also exhibit concerning behaviors Some studies have shown that AMS guidelines have in their use of antibiotics, such as sharing of medicines provided a significant contribution to combating AMR among family members or storing leftover antibiotics for (Huttner et al. 2014), while other research findings future use without medical advice (Barker et al. 2017). challenge their effectiveness. Key barriers to effective AMS include a lack of effective strategies to implement In the United Kingdom (Wellcome Trust 2015), the public AMS, particularly in the LMIC setting; poor response from finds terms such as “superbugs” unhelpful and the concept 42  Pulling Together to Beat Superbugs © ARNE HOEL / WORLD BANK of AMR does not have much meaning to them. In Sweden, into the best way to go about implementing these cam- where the use of antibiotics has been reduced, research paigns. Different populations may require different inter- teams attributed success to well-designed public awareness ventions; nontraditional tools such as social media could and education campaigns. Finding language with impact be beneficial. and meaning in a particular setting is vital in getting the mes- A major barrier to tackling AMR is public disconnect, lack sage understood, with a first challenge being to ensure the of understanding, and indifference. Public health cam- target audience understands the meaning of words. paigns have been suggested as a key way to implement Framing AMR in terms of crisis language as a threat to change by multiple high-profile agencies, including the national security has been proposed (Kamradt-Scott et al. IACG, WHO, and the O’Neill Report. However, there is a 2017). However, others suggest acting with caution, as a lack of evidence for these campaigns, and multiple studies sense of crisis could lead to a fatalistic attitude (Lindland report a lack of effectiveness (Kardaś-Słoma et al. 2013; and Volmert 2017) since this could strengthen a sense of McNulty et al. 2010). There is also little information and fatalism and disincentivize action. Careful consideration guidance from the seminal works on how to establish and must be taken as to the best communication strategy manage public awareness campaigns. For an LMIC to start and messaging for specific socioeconomic and cultural from scratch to organize an AMR public health campaign contexts. is extremely challenging, especially given the poor base- line starting point. The seminal works on AMR call for campaigns, yet there is a distinct lack of evidence for the effectiveness of AMR WHO published a paper in 2016 exploring public awar- public health campaigns and there remains little research eness campaigns designed to tackle AMR and included Understanding Our Approaches To Date  43 © SARAH FARHAT / WORLD BANK both LMICs and HICs. The authors contacted 93 countries authorities and governments fail to deliver the correct and received no response from 40 percent of them (Saam AMR message, then user-generated social media could et al. 2016). Of those that did respond, only 25 percent amplify and perpetuate misconceptions. Nevertheless, a had campaigns that ran all year, with the rest either study published in July 2018 described how social media temporary or seasonal (Saam et al. 2016). Those who res- for health-related purposes are expanding in LMIC set- ponded to the survey reported that financial issues were tings and have potential as a tool to address AMR (Hagg a significant barrier to implementation, as well as lack of et al. 2018). political support (Saam et al. 2016). Furthermore, there Looking at the demographics of antimicrobial usage may was a lack of program appraisals, with 60 percent of cam- help to frame communication interventions. Studies have paigns having no formal evaluation. shown that teenagers and adolescents are the highest Today social media have an important and influential role users of antibiotics in Europe (Hawking et al. 2017). These and could be a potential platform for AMR interventions, studies also revealed a widespread lack of knowledge and but getting the framing right is essential. Research bodies understanding about antibiotics. An online educational conclude that Twitter is underused for AMR public health tool has been developed in the UK (e-Bug) with favorable messages and could be a useful tool given the volume of feedback from teachers and educators (Eley et al. 2018). users and enormity of the platform (Dyar et al. 2017). In This type of intervention is less applicable to LMICs, where contrast, however, a 2018 study linked the use of social internet access might be limited and alternative methods media and print media with an increase in misuse of anti- are needed. However, studies have shown that wireless microbials and misunderstandings about AMR (Groshek access and electronic health (e-health) technologies and et al. 2018). It is vital to get an accurate message out using resources are increasing in LMICs, so this could potentially social media platforms. If public and veterinary health be expanded and implemented in the future (Clifford 44  Pulling Together to Beat Superbugs 2016). Although internet access is not essential, and are incapable of foregoing individual benefits in favor of the hygiene, sanitation, infections, antimicrobials and resis- greater public good? How do we persuade the individual to tance are concepts to be included early in curricula in all take responsibility and change his or her behavior? This is also schools. valid for health professionals: the ‘just in case’ antimicrobial prescription and the ‘just once will not have any consequence’ Changing the individual’s behavior around antimicrobial thoughts justify many instances of inappropriate consump- use remains a key challenge. tion of antimicrobials. Human behavior In Sweden and other Scandinavian countries, where use Interventions discussed in this section are inextricably linked of antibiotics has been successfully reduced, the impor- through the realization that AMR control ultimately depends tance of educating the public about the consequences entirely on changes in human behavior. There is currently for both society and the individual specifically were little literature that addresses behavior change in relation highlighted as important interacting factors (Wellcome to AMR that uses sound psychological theory (reviewed Trust 2015). by Donald 2016). One recent study (Pinder et al. 2015) Translation and application of findings such as these into addresses the application of behavior change research with other regions and societies is not easy and must be condi- respect to reducing the use of antibiotics in the UK. tioned by prevailing social beliefs and norms, given that Some research groups describe human behavior as a signi- failure to change behavior will derail the best-laid technical ficant obstacle and state that a “cultural change” is needed plans. Understanding the drivers of human behavior in rather than education alone (Harbarth et al. 2015). AMR has the context of AMR is a neglected area of research, yet is been described as a tragedy of the commons (Baquero and an essential prerequisite for designing and implementing Campos 2003; World Bank 2017), where the behavior to bene- impactful awareness-raising interventions. The “one health” fit an individual is taken at the expense of communal interests approach is necessary, but insufficient without the inclusion (Hollis and Maybarduk 2015). A key question to address is: of greater interdisciplinary contributions from the social Does the individual user view AMR differently than the public sciences —such as ethnography, anthropology, sociology, as a whole? Is it the case that, even with full knowledge and and psychology (Harbarth et al. 2015)—if real culture change understanding of the societal implications, as individuals we is to be achieved. Understanding Our Approaches To Date  45 KEY KNOWLEDGE AND IMPLEMENTATION GAPS © ARNE HOEL/WORLD BANK 46  Pulling Together to Beat Superbugs Cha pter 3 Key knowledge and implementation gaps The aim of this chapter is to organize key knowledge and implementation gaps (#KKIGs) that were identified in the previous chapters. The cross-disciplinary narrative that emerges from our analysis carries two intertwined findings: (1) that AMR needs to be reframed as a development issue; and (2) that AMR-sensitive interventions are needed in LMICs to address the underlying weaknesses driving emergence and spread of AMR. The focus is the critical knowledge needed—and how to harness this knowledge—to support countries, particularly LMICs, in addressing AMR. Much of the action on AMR to date has focused on misuse of antimicrobials, but a country’s AMR risk profile is also determined by context. Building on this understanding, we propose a typology for countries to better understand risk and susceptibility to AMR, as well as research needs. MAPPING KNOWLEDGE GAPS IN A been completed. The IACG recognized the need to better understand the current efforts and enhance collaboration, RESEARCH LANDSCAPE and called for a coordinated global mapping of research As mentioned in the introduction to this report, there is and development and funding activities to address AMR a rapidly growing body of evidence on AMR, supported (IACG 2019 b). by a similarly growing number of research projects. In One approach is to analyze the breadth of research fun- this study, however, we have identified a number of gaps ded by public, private, and philanthropic donors. This was in terms of knowledge and implementation. Those gaps undertaken by the Joint Programming Initiative for AMR (KKIGs) have been identified in chapters one and two. (JPIAMR), which mapped the scale and scope of 1,939 They are presented in a synopsis table (Table 1) with their research investments across its membership, collecting area of relevance. Nine gaps relate to the contemporary information from 22 countries, in addition to information narrative on AMR and to the current state of thinking; supplied by the EU commission and the Wellcome Trust four relate to our capacity to establish an enabling envi- (JPIAMR 2017), recording a total investment of $2 billion ronment for AMR control, which entails agenda setting, equivalent in AMR research [excluding the animal health regulation and legislation, and surveillance; seven pertain sector]. This inventory can reasonably be considered as to reducing the need for antimicrobial use (which can be a reflection of the current engagement to address the referred to as adaptation), including hygiene, infection threat of AMR through research and development. The prevention and control, water and sanitation, vaccination, mapping, however, has some limitations. The number of animal husbandry, and consumer preference; and three participating countries and the geographical area covered deal with limiting use of antimicrobials (i.e., mitigation), is one of them. Similar to AMR-sensitive and AMR-spe- which includes economic incentives and disincentives, cific interventions, a number of research initiatives also precision use of antimicrobials, as well as education, awar- may not have been tagged as AMR research, although eness, and behavior of professionals. the outcomes of some of these projects may contribute Describing comprehensively the entire landscape of AMR to the AMR agenda. Finally, only research projects were research is a daunting challenge given the high number captured by JPIAMR, in order to ensure comparable and of initiatives planned, undertaken, or having recently consistent information being collated. So surveillance sys- Key Knowledge and Implementation Gaps  47 TABLE 1 Twenty-three key knowledge and implementation gaps (#KKIGs) and their area of relevance The contemporary narrative, enabling environment for AMR control, adaptation, and mitigation CONTEMPORARY NARRATIVE ENABLING ENVIRONMENT 1 What is the significance of a specific resistance 10 How to accelerate and increase the level of implementation determinant? How to translate this in terms of risk of of NAPs? (p. 24) absence of treatment options or drug obsolescence? 11 What are the specific contributions of SDGs and other How can this help to focus on priority resistance relevant agendas to AMR? How can these be quantified determinants? (p. 3) (cobenefits) in different contexts? (p. 26) 2 What areas of the AMR problem would behavioral and 12 What are the essential characteristics of an enabling social sciences be most effective and impactful? How environment for AMR control? How countries should should AMR research and implementation activities prioritize efforts towards establishing an enabling best incorporate the social sciences to add value and environment within their contexts? (p. 28) improve progress? What proportion of overall AMR 13 What are the critical data and data models for meaningful control effort should be devoted to social science surveillance and monitoring of priority AMR determinants? research? (p. 4) How can they be incorporated into facility and population surveillance, monitoring and reporting systems? (p. 29) 3 What is the current level of consumption (use) of antimicrobials in humans and animals? How can this be ADAPTATION reliably quantified in practice? How this can be used to 14 What are the major obstacles in implementing effective set targets and monitor progress on reducing the use of hygiene, infection prevention and control in specific antimicrobials? (p. 5) contexts? How to overcome them? (p. 32) 4 How to adequately capture the issue of access, especially 15 What are the major obstacles in implementing good in the context of acute and chronic poverty? What agriculture practices, biosecurity and food safety in specific strategies can be developed to simultaneously address contexts? How to overcome them? (p. 33) the double burden of access and excess? (p. 6) 16 What are the major obstacles in accessing clean water and sanitation? How to overcome them? (p. 33) 5 What would be the most cost-efficient relative distribution of AMR related investments across countries 17 What are the priority vaccines that could be developed for and regions and between intervention types (research, reduction of antimicrobials? What are their projected effects implementation, AMR-specific, AMR sensitive etc.)? How on reducing consumption of antimicrobials? (p. 34) could this help prioritize where and how funding should 18 What measures can be taken to improve uptake and use of be used for greatest global benefit? (p. 6) vaccines in specific contexts? (p. 35) 19 What strategies can be developed to transition the livestock 6 What are the multiple applications of antimicrobials sector to become not only independent of antimicrobials as –including disposal practices- and their contextual growth promoters but also less dependent on antimicrobials drivers in anthropogenic activities? How to assess their for prophylactic and metaphylactic use? (p. 35) relevance to the AMR threat? (p. 10) 20 How to accelerate adoption of high farm and food industry 7 What factors contribute to the spread of AMR? How can antimicrobial stewardship through market forces and their importance be assessed, in locally and regionally consumer preferences, awareness, and transparency? (p. 36) specific contexts (e.g. urban vs rural; rich vs poor, community vs hospital)? (p. 11) MITIGATION 21 What financial incentive schemes can be devised to reduce 8 How changes in drivers of spread, such as the lack farmer risk in adopting good AM practices? (p. 39) of adequate sanitation infrastructure, inappropriate waste management, low expenditure on health per 22 What are the priority diagnostic tools that could be capita, low public share of total health expenditure, developed to reduce use of antimicrobials? What is their weak governance, and corruption, might impact AMR? projected effect of reducing antimicrobial consumption in (p. 12) different country contexts? (p. 39) 23 What is the long-term impact of interventions to change 9 How can ‘prudent and responsible’ be better defined? behaviors and social norms regarding antimicrobials? What What factors determine individuals’ adoption of the interventions will engender sustainable change in behaviors “prudent and responsible” principle? (p. 18) and social norms regarding antimicrobials? (p. 40) 48  Pulling Together to Beat Superbugs tems—increasingly core programs receiving institutional our ability to treat critically ill patients at larger hospitals. funding—were not captured (Kelly et al. 2015). It should be considered whether an improved unders- tanding of drivers for resistance to front-line drugs and Another angle taken to draw this AMR research landscape efficient first-time treatment would not be much more is bibliometric. As noted earlier, this has become a dense financially efficient and have a bigger impact overall. area of publication, with a significant increase in peer-re- viewed articles over the past five years (11,158 articles The paucity and low reliability of information about the published in 2017). We have used PubMed as a most pro- geographical distribution of AMR over time and trends minent publicly accessible database to search the scienti- in prevalence and incidence in human and animal popu- fic literature and allocated 51,138 records—from 2014 to lations makes reliable assessments of the health burden date—to the six JPIAMR priority areas (Kelly et al. 2015). attributable to AMR difficult (Hay et al. 2018). This is a This also has limitations. First and foremost, the records critical knowledge gap (captured by #KKIGs 1 and 13) are peer-reviewed scientific papers published in English, that continues to weaken the evidence on which to steer hence ignoring grey literature and the significant number research and policy agendas to combat AMR on the basis of articles published in other languages. of sound evidence. It points at surveillance of resistance as We believe that combining bibliometric and funding data an area that requires attention. We have also identified the may help to elaborate AMR research activity to a reasonable lack of data and information on the use of antimicrobials extent. The six proposed research areas are presented in (#KKIG 3) to be a significant problem. It is not only about Table 2, along with the share of funding, percentage of antimicrobial consumption (use) by humans and infor- publications, and relevant key knowledge and implemen- mation on animal species use, but our analysis also shows tation gaps. It shows that the big share of the funding has that antimicrobials have become infrastructures of moder- been allocated to the area of therapeutics, followed by dia- nity. Their widespread use in almost every anthropogenic gnostics and interventions (Table 2). In contrast, in terms of activity calls for a systematic inventory of antimicrobial publications, diagnostics take the lion’s share, followed by use (#KKIGs 3, 6), including inconspicuous uses of antimi- intervention and surveillance. Most of the key knowledge crobials, to assess them in terms of risk. and implementation gaps that were identified in the course Considering multiple applications of antimicrobials and of our analysis relate to interventions. their disposal practices (#KKIG 6), the current focus on According to the JPIAMR records, 76.2 percent of invest- antibiotics, and their misuse in humans and livestock ment-supported research projects focused on antibiotic could be far too narrow. It has often been compared to resistance, followed by 20.6 percent on anti-parasitic and “searching at night around lampposts.” This does not allow 3.2 percent on anti-fungal resistance research. In this for the AMR community to comprehend the full realm report, we have also focused on AMR primarily as resis- of the issue and address it along its multiple dimensions tance to antibiotics. There are, however, rising concerns (#KKIGs 2, 3, 6, 7, and 8). about resistance to antiviral, antifungal, and anti-parasitic AMR is a catchall term that encompasses a broad range of drugs—far beyond resistance to antibiotics and the rise resistance determinants, emergence, and spread mecha- of resistant bacterial infections. The overwhelming atten- nisms. Discussions about AMR often oversimplify this bio- tion to antibiotic resistance may not reflect the reality of logical complexity. As a matter of fact, if AMR is a global resistance of microorganisms to the broader spectrum of threat, not all resistance determinants equally threaten antimicrobials. In the absence of any systematic and stan- public health and development. It is prudent to set priori- dardized collection of data and information on resistance, ties of highly relevant pathogen/resistance combinations attention remains focused on what is already known, can for which the community needs to pay particular atten- easily be known, and leaving some potentially important tion, globally or locally. areas unknown. This is true for resistance to different types of antimicrobials, and also true for different types of Disparate data sources from public and private sectors resistance to antibiotics. For example, a central focus has are often not collated at the national and international been on newly emerging resistance, last resort drugs, and levels and contain little information on individual patients Key Knowledge and Implementation Gaps  49 TABLE 2 Six priority areas for AMR research defined by JPIAMR Along with the percentage of funding (2017, n= 1939), percentage of publications (2014–2019, n= 51138) and relevant key knowledge and implementation gaps (#KKIGs) Sources: Kelly et al. 2015; JPIAMR 2017; PubMed (accessed on April 28, 2019). Priority areas Definition Funding Publications #KKIG Therapeutics Improvement of current antibiotics and 57.6 16.4 1 treatment regimens, development of new antibiotics and therapeutic alternatives to antibiotics. Diagnostic Improvement of diagnostics and the 13.1 52.5 1; 17; 18; 22 development of novel rapid diagnostics to stimulate better use of current antibiotics and support the development and use of new antibiotics and alternatives to antibiotics. Interventions Study of preventive and control interventions 11.3 38.7 2; 4; 5; 7; 9; that focus on improved antibiotic stewardship, 10; 11; 12; compliance and prevention of transmission 14; 15; 16; of AMR and to determine and improve their 19; 20; 21; 23 efficacy. Transmission Comprehensive, multi-disciplinary 7.5 5.4 7; 8 understanding of the transmission mechanisms by which AMR can spread between bacterial populations and between different animal and human reservoirs and to translate this knowledge into the development of evidence- based strategies to minimize the spread of resistance. Surveillance Establishment of an international, standardized 6.7 25.8 3; 6; 13 surveillance program for AMR and antibiotic use in human, and agricultural settings. Environment Assessment of the contribution of pollution 3.8 10.5 6; 7; 8; 19 of the environment with antibiotics, antibiotic residues and resistant bacteria on the spread of AMR and the development of strategies to minimize environmental contamination by antibiotics and resistant bacteria. 50  Pulling Together to Beat Superbugs and their outcomes. Furthermore, there are fundamental of Achaogen and its flagship plazomicin (Zemdri), a novel issues of selection bias in terms of who is tested for AMR intravenous aminoglycoside antibiotic with activity against and whether or not that information is entered into faci- carbapenem-resistant Enterbacteriaceae. This calls for new lity-based laboratory data systems (#KKIGs 1 and 13). Addi- models to stabilize the market for antimicrobials and sti- tionally, systematic efforts are yet to be made to quantify mulate private sector innovation without exposing public antimicrobial drug utilization patterns by animal species, funders to all the risk. which would yield important data to address AMR (#KKIG 3). No new antibiotic class has been discovered since the 1970s. Protocols for diagnostic methods and data collection need Currently, candidate antibiotics for further development to follow international standards where available to allow an display limited innovation. New antimicrobial drugs without accurate depiction of the true health burden of AMR. preexisting cross-resistance are in very short supply, despite These problems are exacerbated in low- and middle-in- being still urgently needed, especially for certain infections come countries, where there is often inadequate surveil- and geographical areas. Although new antibiotics are lance, minimal laboratory capacity, and limited access to urgently needed, they will neither stop nor curb AMR. essential antimicrobials (#KKIG 13). Surveillance and moni- Resistance itself does not necessarily mean drug obsoles- toring for antimicrobial use and resistance is one of the cence; in many instances, drugs continue to be used five strategic priorities of the Global Action Plan developed despite resistance being known to occur. Hence, the signi- by WHO in collaboration with OIE and FAO and adopted ficance of a specific resistance determinant or resistance/ by the OIE and FAO member countries. It has also been pathogen combination needs to be better understood, as identified by the IACG as a priority (IACG 2018b; 2019a well as how that translates in terms of risk under specific and b). Surveillance is an area that apparently receives low contexts (#KKIG 1). Not all resistance determinants have attention, in terms of research funding (6.7 percent, accor- the same significance. This knowledge gap connects with ding to JPIAMR 2017), although the area appears more the need to be more systematic on the epidemiology of prominent (25.8 percent) in terms of publications. There resistance determinants, and the broadly recognized need are areas where knowledge in relation to surveillance for better surveillance and monitoring (#KKIG 13) in line needs to be adapted and implemented, the methodology with the principles of evidence for action (and improve- standardized, and the results utilized for the management ment of prescription guidelines, for example, or better of infections in the context of AMR and AMS. targeting of drug discovery). The majority of research funding remains directed toward The area of therapeutics covers the improvement of current the area of therapeutics (JPIAMR 2017). This can be partially antibiotics and treatment regimens, the development of explained by the volume of research initiatives, but also by new antibiotics, and also therapeutic alternatives to anti- its overall cost compared to other types of research area. biotics. This knowledge area does not explicitly show up in During the course of this study, we described the traditional our analysis, not because it is unimportant, but because of approach to combatting AMR by producing new antimicro- our focus on the underlying causes of the AMR crisis and bials. Despite large investments observed in therapeutics, the drivers of resistance emergence and spread (#KKIGs 2, 6, the discovery pipeline is almost empty and the void in new 7, and 8). Therapeutic alternatives to antibiotics are needed antimicrobials still persists. According to The Pew Charitable in relation to the low rate of drug discovery and absence Trusts (2019), as of September 2017, approximately 48 of new classes of drugs. Additional research areas, such new antibiotics with the potential to treat serious bacterial as that of bacteriophages and the detailed study of resis- infections were in clinical development. The success rate for tance mechanisms to find out new ways to fight resistance clinical drug development remains low and historical data deserve our attention and financing efforts. show that, generally, only one in five products that enter human testing (phase 1 clinical trials) will be eventually Similarly, our analysis emphasizes the need to better approved for patients. There seems to be a problem to a understand how vaccines contribute to reducing the use of viable path for new drugs, no matter how valuable they antimicrobials (#KKIG 17), and certainly how to increase vac- are to society. An illustration of this is the 2019 bankruptcy cine acceptance and uptake (#KKIG 18). These are impor- Key Knowledge and Implementation Gaps  51 tant areas of research to address the existing knowledge addressed. Gaining a better understanding of these risk fac- and implementation gaps, but they should not oversha- tors is essential because in many situations, they represent dow the continuous need for new and improved vaccines. the most significant contribution to rising AMR and the pre- valence and incidence of drug-resistant infections. Drug discovery has a crucial role to play in maintaining our ability to successfully treat infections. However, the drug This is closely associated with another knowledge gap discovery approach to AMR has essentially resulted in an related to the environment (3.8 percent of the funding, arms race between new products and constantly evolving according to JPIAMR). This requires more attention, with a resistant microbes—a race we are losing and will be unable focus on pollution of the environment with antimicrobials, to win in the absence of a clear understanding of the their residues, and resistant microorganisms (#KKIG 6). This fundamental drivers of resistance emergence and spread is an area of research critical to gain better knowledge (#KKIGs 2, 7, and 8). Addressing these underlying causes of about the spread of AMR and the development of the AMR crisis is therefore of central importance. Under- strategies to minimize its evolution, contamination, and pinning this, we highlight the need to better understand transmission in the environment, particularly through antimicrobials as socio-technical objects, and propose a AMR-sensitive interventions (#KKIG 8). conceptual model around the way we think and use anti- The area of diagnostics—with projects aiming at the microbials. This critically connects to our knowledge regar- improvement or the development of diagnostics for bet- ding consumption and use (#KKIG 3) and the high value of ter use of current antibiotics—is relatively well funded. a comprehensive disaggregated inventory of antimicrobial It also overlaps with therapeutics (see area definitions in use in the different sectors to better describe and unders- Table 1), as some of these projects also support the deve- tand the existing tensions around antimicrobials—that is, lopment and use of new antibiotics and alternatives to the way we think and use them and external drivers. antibiotics. We have identified the need for improved and Surprisingly, transmission receives relatively little attention novel diagnostic tools to prevent empirical prescribing, in terms of research funding, which is in contrast with particularly in LMICs (#KKIG 22). our analysis and several key knowledge gaps identified Overall, there is a major “know–do” gap. While a substantial in relation to transmission, spread and contamination and growing body of evidence exists on AMR and drug-re- (#KKIGs 7, 8). Transmission of AMR is not a unique issue, sistant infections, the challenge of using this knowledge in of course, because in essence it is about transmission of policy and practice remains formidable. Efforts to address infectious diseases, some of which may potentially be AMR are compromised by the low level of implementa- drug resistant. Also, indirect mechanisms such as the tion, the fragmentation of interventions, their sequencing transmission of MGE-mediated resistance (thus, interspe- in time and geography, and their deployment in diffi- cies resistance) play an important role and enmesh AMR cult environments for AMR control measures (#KKIG 10). concepts. Research projects allocated by JPIAMR to this Knowledge exists, yet people do not seem to know what category typically aim at understanding the transmission to do, how to do it, or how to bring it to scale. Typical mechanisms by which resistance determinants can spread examples of implementation gaps exist in the areas of between bacterial populations and between different hygiene, food safety, water, and sanitation. (#KKIGs 14, 15, (animal, human, plant and environmental) reservoirs. Both and 16). This calls for a major research effort in addressing levels of the transmission question are important, and the gap between knowledge and actions in real-world the knowledge generated from this research should be settings and the practicalities of achieving national and translated into evidence-based strategies to minimize the global AMR goals. Implementation research involves the spread of resistance. Our analysis shows that the focus has creation and application of knowledge to improve the mainly been on use of antimicrobials as a major driver for practical implementation of interventions through policies, emergence. We have shown that this may be true under programs, and practices. This type of research builds on certain circumstances and specific contexts. However, there partnerships among community members, implementers, is more than use as a driver for AMR; the question of spread researchers, and policy makers, with a strong focus on and related risk factors needs to be more systematically practical approaches to action on the ground to enhance 52  Pulling Together to Beat Superbugs Isatu gets a vaccination for her 5 week old son Isatu Bah gets a vaccination for her 5 week old son, Mohamed Ka- mara at the Ola During Children’s Hospital in Freetown, Sierra Le- one on February 29, 2016. Photo © Dominic Chavez/World Bank © DOMINIC CHAVEZ/WORLD BANK equity, efficiency, scale-up, and sustainability. Research crucial. We need to understand much more fully what projects focusing on interventions represent—so far— constitutes an enabling environment in which interven- only 11.3 percent of the funding (JPIAMR 2017). They focus tions are able to deliver on AMR (#KKIG 12) and better on preventive and control interventions for improved identify enablers and barriers in context. antibiotic stewardship (AMS), compliance and prevention Public and philanthropic funding for research on AMR is of transmission of AMR, and to determine and improve increasing, making substantial research funds available, their efficacy. We have identified a number of related gaps, including to social scientists (Roope et al. 2019). Still this such as the availability of data on long-term follow-up and has not yet become visible in terms of publications or sustainability of successful interventions focusing on beha- portfolio analysis. Social sciences, however, have much vioral change and social norms (#KKIGs 2, 9, and 23), or key to contribute to the question of drug-resistant infections components of AMS and what makes an AMS program and can open avenues to bridge the knowledge-to-action successful, which can be seen as a combination of both gap. There are several areas where we have identified gaps knowledge and implementation gaps. related to human behavior (#KKIG 2, 9, 23), which should One major implementation gap is in transitioning the be further investigated to better understand the interac- livestock sector to become less dependent on antimicro- tions between norms and behaviors in the conceptual bials—not only as growth promoters, but also in their pro- model proposed in chapter 1 (#KKIG 2). One question, in phylactic and metaphylactic use. This is an important part particular, is to understand consumer awareness and pre- of the resilience agenda we have identified (#KKIG 19, 20). ferences, and how can this influence the food industry in positive ways for better antibiotic stewardship (#KKIG 20). Intervention research was clearly being overlooked by research funders and the research community, yet it is Key Knowledge and Implementation Gaps  53 Modeling the potential impact of AMR-specific interven- mendations to countries by way of cost-benefit analyses tions has been performed, but this has been done for a (Roope et al. 2019). Among the many questions eco- limited number of mainstream interventions and mostly nomists could help answer is how to improve livestock in the context of high-income countries. There should be owners’ access to programs and insurance schemes that efforts to model the impact of interventions in low-re- promote appropriate antibiotic use while protecting far- source settings of LMICs (#KKIG 11). One of the most mers against market risks (#KKIG 21). pressing challenges, also faced by global AMR surveillance Similar to AMR-sensitive interventions, a number of and monitoring, is in the generation, sharing, systematic research initiatives may not be recognized as AMR-related analysis, and dissemination of data (#KKIG 13). research, although the outcomes of these projects may The discipline economics could make valuable contri- contribute to the AMR agenda. It will be important to put butions. Economic analyses successfully inform recom- an “AMR lens” for research funding. CASE STUDY 6: WHEN AMR IS AN INCONSPICUOUS ISSUE Ghana, like many other LMICs, is rapidly urbanizing, with guidelines on antibiotic use. In one study, bacterial isolates a 3.6 percent annual rate of urban increase from 2015 to from hospitals across Ghana were surveyed and found to 2018 and over 56 percent of its population of almost 30 have a high prevalence of resistance (up to 78.7 percent million now living in urban areas (UN Statistics Division in Streptococcus species other than S. pneumoniae) across 2019). With this intensification of people, the demand for the country (Newman et al. 2011). This unregulated use of fresh fruits and vegetables is also increasing, and urban antibiotics by both humans and animals can contribute to and peri-urban smallholder agriculture is developing to the emergence of resistant bacteria that may be found in meet this demand. Urban and peri-urban farms are highly fecal matter and wastewater. Without decontamination of dependent on the informal use of wastewater to irrigate wastewater, such antimicrobial-resistant bacteria can enter fields, presenting the risk that food products will be soils and agricultural products grown in them. contaminated with bacteria—some of which are resistant Wastewater management is a pervasive challenge to antibiotics. related to urbanization. Ghana faces significant need on Although Accra, the capital of Ghana, is equipped this front, with household-level access to basic sanitation with water treatment facilities, many of these are facilities at approximately 14 percent across the country nonfunctional (KNUST 2016). A 2016 report showed in 2015 (WHO/UNICEF Joint Monitoring Program 2019). In that fecal bacterial contaminants were present in water addition to such technical challenges, urbanization also sources in Accra as well as sampled vegetables (Amoah brings societal change: although fresh salads are not part et al. 2006), suggesting the application of contaminated of the traditional Ghanaian diet, they are now common water to fields. Bacteria harboring resistance in fast food establishments. In Accra alone, an estimated determinants can also be transferred through wastewater 200,000 people consume salads daily (Amoah et al. 2007). to irrigated soils (FAO 2018). Examining external drivers of AMR, such as urbanization Ghana is a pioneer country in the fight against AMR. and changing food habits, is essential to addressing risks Several ministry-based units, agencies, and development in both the human and animal health sectors. partners are working to address AMR, but participation Expanded testing, including AMR monitoring by the animal health and environmental sectors to date and surveillance of water and waste effluent by the has been limited. A situational analysis conducted in 2017 Environmental Protection Agency (EPA), has been (Yevutsey et al. 2017) showed that, in the human health identified as a critical need for AMR risk reduction and sector, antibiotics are commonly prescribed and often food safety in Ghana. To address such needs, the Ghana dispensed by unauthorized personnel. Furthermore, in the National Action Plan on Antimicrobial Resistance Use and animal health sector, there are no national standards or Resistance was approved in December 2017. This plan 54  Pulling Together to Beat Superbugs identified points of entry for AMR risk reduction in various next five years, EPA plans to expand testing to include ministries and other agencies, with key stakeholders antimicrobial-resistant microorganisms and antimicrobial forming the AMR Policy Platform. Although contributions residues. To protect food safety, implementation of to the plan came from the Ministries of Health, Food this routine monitoring will need to be followed with and Agriculture, Environment, Science, Technology, and enforcement of regulations that limit the release of Innovation, and Fisheries and Aquaculture Development, contaminated water into agricultural fields. and the plan was designed with an explicit “one health” This case study illustrates the need to think about approach, most of the responsibility for implementation AMR even outside the antimicrobial system. It shows that still falls to human health-focused agencies. Significant besides emergence, spread is a component of AMR to expansion of this plan to the animal health and consider. Seen from the point of view of our conceptual environmental sectors will likely require external funding, model (the way we think and use antimicrobials, and as well as commitment by urban farmers and the diverse externalities), the case study emphasizes the existence agencies and actors responsible for human, animal, and of drivers outside the human health sector. For example, environmental health. rapid urbanization and changes in food systems that are For example, the Ghana EPA is an entity under needed to meet growing demand must be examined; the Ministry of Environment, Science, Technology, and and governance, underscoring the importance of a Innovation that sets environmental standards and holistic approach, must advocate for a comprehensive conducts environmental surveillance. This surveillance framework. Finally, this case study is an example of how includes monitoring of effluent from health facilities, AMR-sensitive interventions, such as water treatment and aquaculture enterprises, and farms, but is currently sanitation programs, can become game changers in the limited to detection of Escherichia coli bacteria. In the fight against AMR. TAILORING A RESEARCH AGENDA countries and donors in tailoring a research agenda to address critical AMR knowledge and implementation TO COUNTRY NEEDS gaps. In the first chapter of this report, we reframed AMR as a Our analysis emphasizes the importance of context. By sustainable development challenge, acknowledging that, considering exposure to risk factors, i.e., antimicrobial use in many cases, antimicrobials have become substitutes for (low vs high) and expected influence of drivers for spread imperfect infrastructures and failing systems, which not (low vs high), four types of countries can be identified, only drives the emergence but also the spread of AMR. It with different levels of risks, essentially driven by diffe- is also an issue that cannot be solved with technical solu- rences in likelihood. Table 3 summarizes the four situa- tions only. In the second chapter, we reviewed our most tions for countries, which have different expected levels of common interventions, showing that much of the action risk related to AMR in terms of emergence and spread. on AMR to date has focused on use of antimicrobials and Defining risk related to AMR would be more accurate on AMR-specific interventions. than using AMR levels (usually expressed in percen- In this chapter we have seen that key knowledge and tage of samples) that do not equally translate into risk, implementation gaps do not necessarily match the defined as a combination of probability of occurrence current focus of the research community, be it in terms for a specific hazard (likelihood) and consequences of funding or publications. Too little is allocated to sur- (impact). Risk should therefore be assessed for different veillance and interventions, and far too little is allocated types of resistance determinants (i.e., hazards). Both to environment and transmission. Little consideration is likelihood and impact may vary between countries and usually given to local contexts, and most of the time a local conditions. By defining an acceptable level of risk “best practice” approach continues to prevail. Building (ALOR), countries would be able to set targets—moving on this understanding, we propose a framework to guide from an input-based approach (reduce quantities of anti- Key Knowledge and Implementation Gaps  55 TABLE 3 Four types of countries based on levels of antimicrobial use and exposure to contextual risk factors for AMR Type A Type B Type C Type D Level of antimicrobial use Low High High Low Exposure to other contextual risk factors High High Low Low Expected level of AMR risk Medium High Medium Low microbial use) to an outcome-based approach (reduce have improved with expected effect in reducing the the risk posed by specific types of resistance in specific contribution of spread to the high level of risk related communities). to AMR. Stronger systems and better infrastructures—in terms of water management, improved sanitation, and Type A countries correspond to countries where use of access to quality health services, among others—make antimicrobials could be low, but exposure to contextual these countries less susceptible to increased levels of risk factors for spread is high, resulting in a medium level AMR. Beyond the point of inflection of the curve (Figure of risk. Low public investment in health and high out-of- 5), this type of country is starting to win the battle against pocket costs, particularly relative to income per capita, AMR. There may be inertia, however, between efforts and may considerably limit access to and availability of anti- effect on the ground; as resilience increases, risk will be microbials in the general population. Antimicrobial use only slowly reducing. in animals may be limited as livestock industries remain relatively traditional, with limited adoption of intensive Type D countries have managed to bring both risk fac- or industrial practices. However, substandard medicinal tors and antimicrobial use under control. Large public products are thriving in informal markets. Issues of poor investments in health and education, optimal financial sanitation, unsafe waste management, weak governance, protection against out-of-pocket healthcare costs, strong and corruption are more likely to be present and may exa- governance, and improved sanitation and waste mana- cerbate the severity of spread of resistance determinants, gement have facilitated the development of systems that even though antimicrobial use would be still limited in are less reliant on antimicrobials and also provide little volume. opportunity for spread. In addition, normative change to address behavioral drivers of the non-therapeutic use of In type B countries, use of antimicrobials (both in abso- antimicrobials—either through information campaigns lute and per capita terms) is increasing sharply driven by or more stringent regulatory actions such as bans on the better access, increasing revenues, or [counterintuitively] use of antimicrobials in livestock production—are likely improved education. Meanwhile, risk factors contributing to have been implemented successfully. Overall, these to high levels of spread remain significant, hence contri- countries are still to face health and economic risks from buting to the AMR risk. For example, growing populations AMR, but efforts to minimize the volume of antimicro- and improved incomes are increasing demand for animal bial demand and the risk of contagion bring the risk to a products, and with intensification of the livestock sector, lower level compared to the other types of countries (A, B the quantities of antimicrobials used in livestock produc- and C). However, only some of the type D countries have tion are expected to rise steadily (Van Boekel et al. 2015; effectively brought their risk below an acceptable level World Bank 2017a). Global consumption of antibiotics in and in a sustainable manner. agriculture is expected to increase by 67 percent from 2010 to 2030, mainly in transitioning economies. The four types of countries described in Table 2 are also displayed in Figure 5. The theoretical risk curve proposed Type C countries correspond to countries where the here is based on levels of “AMR risk” (as driven by use and demand for and use of antimicrobials remain high; howe- additional contextual risk factors) as a function of “resi- ver, factors affecting the spread of resistance (contagion) lience and preparedness” (driven by commitment to an 56  Pulling Together to Beat Superbugs AMR agenda, economic development, resilience to AMR to avoid the recurrent failures of the “good/best practice” shocks). It shifts our way of thinking about AMR and sheds approach. For countries to make progress on AMR to beat light on relationships that are not yet well understood. superbugs, it is important that AMR knowledge be trans- There are substantial data gaps, as expressed earlier in this lated into national context to bridge implementation gaps. report; nevertheless, this theoretical curve is intended to In the context of limited resources for development activi- describe the risk profile of countries and articulate how to ties, AMR-sensitive interventions can be designed through integrate contextual factors in the design of research to tailoring and refining existing and planned interventions. address specific knowledge and implementation gaps. Low-, lower-middle-, and upper-middle-income countries While necessary, and despite some countries demons- are already making significant investments in a range of trating progress, current efforts to curb antimicrobial use development activities. There is a critical need to better are not sufficient to fight AMR on a global scale. Radically understand the cobenefits of AMR-sensitive interventions reducing the misuse of antimicrobials is a crucial and (#KKIG 11). necessary step toward controlling AMR. However, this will AMR cobenefits can be defined as the benefits of policies not be sufficient in isolation, given the vast interactions and programs that are implemented for various reasons at between risk factors and antimicrobial use in ultimately the same time—including AMR. The concept of cobenefit determining the emergence and spread of AMR. acknowledges that most interventions also can have AMR Figure 5 emphasizes type B and C countries as those impacts. The total flow of development assistance includes requiring the most pressing attention. It should be noted funds for the building of roads, ports, and other urban that context is treated as country specific but in reality, developments, as well as interventions to build health sys- within the same country, areas exist belonging to different tems and improve water and sanitation efforts. Harnessing types (e.g., cities, peri-urban slums and rural areas may AMR-sensitive interventions does not mean business as differ significantly). usual. It is not enough to reinforce health systems, improve water and sanitation, urban planning etc. These activities Where countries can understand their risk profile with should be considered for the impact they stand to have on regard to AMR (Type A to D), it may be easier to build AMR, hence generating scope to translate a host of deve- AMR research and intervention (implementation research) lopment research into AMR-sensitive research. agendas at lower cost and potentially high reward. A situation analysis of countries would help determine this A focus on an AMR-sensitive agenda does not mean that risk profile based on antimicrobial use and other factors AMR-specific research and interventions are not relevant. related to spread. Depending on the outcome of the ana- AMR-specific actions are always needed—including lysis, different sets of interventions—either AMR-specific in Type A countries for their capacity to materialize and/or AMR-sensitive—could be identified for prioritization. the AMR national agenda and energize actors on the ground. Focusing exclusively on AMR-sensitive interven- An outcome of national action plans and situation analy- tions would not provide the catalytic effect of AMR-spe- sis is the identification of key bottlenecks, at the national cific interventions. or subnational levels. Interventions as well as research should be prioritized based on their likely impact on bott- Rigorous planning and tailoring of interventions are lenecks and capacity to reach targets. A major contribu- vital to ensure that investments in research address tion of situation analysis is to provide realistic assumptions the drivers of resistance. Reviewing the situation in enabling better appraisal of the “likely” impacts, by better relation to sanitation, public health, governance, edu- identifying enablers and barriers. cation, and other relevant areas to ensure the research agenda is designed to provide a sound evidence base The success of interventions will depend on the existence to minimize the risk of emergence and spread needs of an enabling environment and include consideration of to become a top priority if countries intend to win the norms and behaviors, as well as governance or externa- fight against AMR (Table 4). Not every research project lities. Assessing the feasibility of interventions and their will be able to have an impact on AMR, but careful likely impact in light of this framework will be important Key Knowledge and Implementation Gaps  57 FIGURE 5 Theoretical risk curve representing four types of countries (A to D) AMR-sensitive FIGURE 5 interventions are critical to countries in type A and B, and to a lesser extend to C and D. AMR-specific interventions are always needed for their catalytic role in NAPs. Research agenda addressing knowledge and implementation gaps should pay AMR and Level of Development in Countries Worldwide attention to dimensions related to norms and behaviors, governance of antimicrobials and external factors. While relevance of AMR to SDGs remains across the board, the relevance of SDGs for AMR tends to decrease from A to D. Areas of priority for intervention AMR risk Acceptable level of risk [ALOR] Type A Type B Type C Type D AMR resilience & preparedness index Relative significance across AMR country types AMR-SENSITIVE AMR-SPECIFIC NORMS AND BEHAVIORS USE AND GOVERNANCE OF ANTIMICROBIALS EXTERNAL FACTORS RELEVANCE OF SDGS RELEVANCE TO SDGS 58  Pulling Together to Beat Superbugs analysis and tailoring of the national portfolio can play can be made AMR-sensitive needs to be highlighted. In a significant role. In some instances, it will be more per- all environments, however, it is a blend of AMR-specific tinent to continue focusing on AMR-specific interven- and AMR-sensitive interventions that will be feasible, tions, such as infection control programs. In other envi- affordable, and highly impactful, ensuring that we all ronments, a focus on ensuring that other investments can share in a healthy future. TABLE 4 Country risk profiles (A to D) and attributes for research and intervention agendas Type A Type B Type C Type D Status of AMR AMR agenda focused AMR agenda focused Building strong Mature public and policies and on access to quality on responsible political and societal animal health systems, programs health services and prudent use of consensus on regular light-touch (enabling and quality of antimicrobials, further addressing AMR, AMR interventions and environment) medicinal products, basic health system scaling up of pilot programs, continuous strengthening of strengthening and programs, monitoring adjustments needed basic public and capacity building, and surveillance, to respond to new animal health piloting new complete policy and risks, maintained systems, education on programs, establishing regulation reforms, awareness, continued hygiene and infection baselines through mass awareness surveillance prevention surveillance and campaigns monitoring, continued efforts in education on hygiene and infection prevention Status of AMU Low use of Increasing use of Systems still Achievements in and AMR (risk antimicrobials, lack antimicrobials with struggling to reducing use of and resilience) of access to quality increasing revenues manage the rise of antimicrobials, AMR medicinal products, and consumption, antimicrobial demand remains a concern, basic systems and underperforming and use, AMR on but citizen trust services failed systems and services, the rise and high restored in the system, AMR slowly emerging on the civil society established capacity as an issue in civil agenda, outcomes to detect emergence society of surveillance and of new resistance monitoring raise determinant public concern over AMR Importance of High High Medium Low AMR-sensitive interventions Relevance of the High High Medium Low SDGs Key Knowledge and Implementation Gaps  59 CASE STUDY 7: THE PIVOT OF COBENEFITS Madagascar is one of the 193 countries that signed a on Financing Preparedness 2017). In the aftermath UN Resolution calling for a coherent global action to of the epidemic response, Madagascar faces many address the AMR issue and recognizing that failure to ongoing challenges to public health, including endemic address AMR will undermine sustainable food production tuberculosis and a rise in AMR (Gay 2017). As noted by and jeopardize global sustainable development. Since Bonds et al. (2018), there may not be the needed pivot then, the country has prepared and adopted a national to stabilize the economy, maintain essential healthcare action plan on AMR (Repoblikan’i Madagasikara capacity and risk awareness campaigns that were 2018). It is strongly aligned to the Global Action Plan, established during the epidemic, and develop long-term articulating activities around five strategic objectives, investments in the health, agriculture, and environment which include improving awareness and understanding sectors. In July 2018—after the epidemic—Madagascar’s of antimicrobial resistance, strengthening knowledge Ministry of Health organized an After Action Review (AAR) through surveillance and research, reducing the incidence using WHO methodology, identifying 23 priority actions of infection, optimizing the use of antimicrobial agents, to improve preparedness and response. From 19 August and promoting support to research and alternative 19, 2018, to April 21, 2019, a new plague season occurred, solutions. This plan has been developed through a strong with a lower number of 257 isolated cases reported. This multisectoral partnership and endorsed by four line progress shows national ability to shift from epidemic ministries of the presidency (health, agriculture, fisheries, response to long-term management, and the capacity to and environment). The cost of the plan is slightly below confront the challenges of multisectoral coordination on $14 million for a five-year period. complex problems. As for many countries, the challenge comes with Within the 2018 World Bank (IBRD) portfolio, implementation of such a plan. Madagascar’s progress $385 million was committed to investments in health, toward the goal of ending extreme poverty in a agriculture, environment, and other sectors. Although sustainable manner is challenged on many fronts (World no project is currently explicitly dedicated to limiting Bank 2015). The World Bank systematic country diagnostic AMR, there are opportunities to make components of concludes that poor governance, which partially finds existing and planned projects AMR-sensitive. A similar its origin in poor dynamics among the economic elite approach was recently taken by the country to address and political instability, affects the ability of the state to climate change effects on public health (Bouley et al. collect revenues and prevents the state from undertaking 2018). Access to basic education, health, water, sanitation, investments to support a structural transformation of the and nutrition services is critical. A few examples of such economy and from providing sufficient basic services to projects within the Bank’s portfolio illustrate where AMR develop the country’s human capital. cobenefits could be identified and exploited. Regarding plague—a public health issue with Nutrition and health programs have high potential high relevance for AMR—Madagascar shows results. for AMR cobenefits. The objective of the Multiphasic On average, 400 cases of bubonic plague are reported Programmatic Approach on Improving Nutrition yearly, and the disease is most prevalent in the rural Outcomes (2017–23) is to reduce stunting by providing areas, especially the central highlands. Plague season reproductive and maternal and child healthcare services runs from August to April. The response to the 2017 and implementing nutrition interventions in specific plague outbreak in Madagascar was large and effective. regions of the country. More specifically, objectives In total, 2,348 cases and 202 deaths were attributed to include (a) scaling up a standardized platform of primary the epidemic (WHO 2017 f). The epidemic was curtailed care facilities and community-based services to which largely by contact tracing and free antibiotic treatment selected services can be added/scaled to address the supported, in part, by $1.5 million in WHO emergency needs of specific populations, regions, or priorities; (b) funds. However, international responses quickly fade, a modernizing the training of primary care and community cycle of panic and neglect (International Working Group workers, using technology; (c) providing information 60  Pulling Together to Beat Superbugs technology (IT) solutions to improve data-based potential contributions of their sector to the emergence program management and quality service delivery; and spread of antimicrobial resistance and to build the and (d) strengthening capacity in regions and districts necessary skills to promote ongoing AMR monitoring and to effectively manage delivery of the reproductive, surveillance in their sectors. maternal, and child health and nutrition (RMCHN) In this case study, we illustrate how development interventions minimum package. Each of these objectives projects can be made “AMR aware” and increase their could provide a platform to increase awareness on AMR-sensitive potential (cobenefits) by adjusting appropriate use of antibiotics, change in prescribing interventions, with only marginal costs. This potential practices, and contribute to mitigation and reduction of does not come entirely for free; incorporating AMR- AMR emergence. sensitive interventions is not business as usual. It requires Multisector programs are fertile ground for AMR some marginal costs to give an AMR-sensitive design cobenefits: The Sustainable Landscape Management to project components and make this transformation project (2017–22) seeks to increase access to irrigation possible. This also requires a thorough portfolio analysis services, strengthen natural resources management by with an “AMR lens.” In this case study, we have imagined, landholders, and facilitate emergency response. Designed based on evidence presented throughout this report, how with a proof-of-concept approach, this project brings AMR might be tackled by “piggy-backing” AMR sensitive together the Ministries of the Presidency for Agriculture actions on other development investments to create AMR and Livestock; Water, Sanitation, and Hygiene; and cobenefits at little additional cost. Most development Environment, Ecology and Forests, offering a potential partners share this ability to leverage ongoing platform to introduce AMR surveillance and monitoring investments, laying a strong base for AMR-specific across relevant sectors other than public health. In interventions. By reviewing development activities and particular, AMR-sensitive packages might be added under identifying underlying cobenefits, countries would be the data collection and decision support tools component in a much better position to tailor their AMR research and the capacity building component, allowing line questions and design appropriate research agendas. ministries to better understand and appreciate the Key Knowledge and Implementation Gaps  61 Conclusion We have known since the very beginning of the antimi- From a practical point of view, three broad categories of crobial era that using these drugs would fuel a natural intervention can be employed to tackle AMR. They aim selection process, an accelerated Darwinian evolution no at establishing an enabling environment for AMR control, less, that inevitably produces drug-resistant microorga- reducing the need for antimicrobial use (adaptation), nisms. Yet, we have collectively ignored the risks and have and limiting use of antimicrobials (mitigation). A review been “playing with fire” for the past half century. of the most common interventions shows that we are Our capacity to effectively treat infectious diseases is a not sure how they can best deliver in specific contexts at global public good, which is now seriously at risk. AMR is the country or community level. More work is needed on already a big problem—plaguing and claiming the lives of translating knowledge into effective action. In addition, hundreds of thousands—and could potentially become a a broad array of interventions, which are not specifically much bigger problem if we fail in our collective action to aimed at AMR, could nevertheless have an impact and preserve this public good. reap cobenefits. The focus of research attention should also be broadened to encompass this field: we do not Failure, however, would unlikely come from lack of fully know how to identify AMR-sensitive interventions, knowledge. Much is known about AMR, and even if signi- how to assess the potential cobenefits they bring, or mea- ficant gaps remain, in many cases they are about imple- sure the associated marginal costs to make those inter- mentation. We know what needs to be done, but we are ventions most impactful on AMR. not doing it—or we do not know how to do it. This report puts emphasis on implementation research; an integrated In terms of knowledge and implementation, twenty-three concept that links research and practice to accelerate the gaps have been identified in the course of this work. Nine development and delivery of successful interventions. It relate to the contemporary narrative on AMR and the cur- involves the generation and application of knowledge to rent state of thinking; something we referred to as taking improve the implementation of policies, programs, and a new look at an old challenge. The AMR conversation practices. has largely been carried out within a circle of technical professionals and experts focused on the science of AMR, Such policies, programs, and practices do not relate only and there is a need to re-frame the discourse on AMR. to the areas of health and agriculture. Looking at the The remaining gaps relate to our approach so far. They many uses of antimicrobials across sectors and looking at are about what has been tried and what has been done AMR in terms of emergence and spread, we propose to to establish an enabling environment, reduce the need re-frame AMR as a development issue. for (adaptation), and limiting the use of antimicrobials Antimicrobials have become infrastructures of modernity, (mitigation). These key knowledge and implementation and it is indeed the gradual failure of these infrastructures gaps are not so much a research agenda but more likely that now make antimicrobials—and AMR—visible to pointers for the community. They highlight the relevance societal attention. It is now clear that technical solutions of implementation research. on their own will not be enough to curtail AMR; it will also The seven case studies included in this study have be necessary to unravel the many complex social tensions brought us successively to Vietnam, Senegal, India, Thai- around antimicrobials. We propose to conceptually orga- land, Denmark, Ghana, and Madagascar. The choice of nize these tensions as (a) norms and behaviors (the way countries is unavoidably arbitrary; many more cases could we think antimicrobials), as socio-technical objects; (b) use have been built for the purpose of this study. These case and governance (the way we use antimicrobials); and (c) studies illustrate how contextualization will be paramount external trends influencing the system. This conceptual to success in the collective effort to curtail AMR. Using model provides a powerful framework to identify enablers best practices at the wrong time in the wrong place will and blockers.   63 not help in moving the needle. Each case study highlights available financing more astutely. By applying a more how context is critical to identify enablers and blockers. rigorous and imaginative AMR lens to all investments, and by designing these interventions to maximize their poten- Although each and every country, or community, is tial impact on AMR, humanity and our children all stand to unique, a typology of countries and communities can be gain from a healthier future. defined based on the risk posed by AMR in terms of emer- gence and spread. Such a typology allows the identifica- Better understanding the gaps in our collective tion of the critical action areas for different country types, knowledge of antimicrobial resistance, and the limitations with different blends of AMR-specific and AMR-sensitive of our capacity to implement this knowledge is critical to interventions, different relevance of SDGs and targets, success in action. However, it is by no means an excuse and a different relative importance to focus on use. It can for inaction. Action is needed now, and there is more than also help us in becoming more conscious of how our enough knowledge for evidence-based policies, pro- investments for development can affect AMR and in using grams, and practices aiming at curbing AMR. 64  Pulling Together to Beat Superbugs A primer on AMR Key facts about antimicrobial resistance not work to kill or control them. As a result of AMR, treat- (AMR) ments become ineffective and infections may become  AMR threatens the effective treatment of infectious lethal or persist, increasing the risk of further spread. diseases caused by bacteria, viruses, parasites, and Pathogens can also be resistant to several antimicrobials. fungi. Multidrug resistance (MDR) is a property of a pathogen that is resistant to two or more antimicrobial agents in  Although exact numbers are difficult to ascertain, three or more antimicrobial classes. The term extensive it is estimated that currently 700,000 deaths are drug resistance (XDR) is also used, defined as resistance annually attributable to drug-resistant infections. If to at least one agent in all but two or fewer antimicrobial unabated, this number could increase to 10 million categories (i.e., bacterial isolates remain susceptible to deaths annually by 2050, more than deaths currently only one or two categories). Pan drug resistance (PDR) attributed to cancer. is defined as resistance to all agents in all antimicrobial  AMR has been alarmingly rising for certain diseases, categories. Those microbes developing resistance to mul- including gonorrhea, malaria, and tuberculosis. It is a tiple drugs are sometimes referred to as “superbugs.” An threat not only to global public health but also to the infection caused by a superbug is harder to treat because global economy and socioeconomic development. fewer effective drugs are available. In some extreme cases, treatment may not even exist. It is important to remember  Unchecked, AMR could cause large economic losses, that when a species (e.g., Escherichia coli) is resistant to in excess of $1 trillion annually after 2030, comparable an antibiotic (e.g., amoxicillin), this does not mean that all to the 2008–09 global financial crisis. Low-income E. coli individuals are resistant. Resistance appears in few countries would experience larger drops in economic individuals and can gradually expand; this is the bases growth and the impacts of AMR on gross domestic that support the responsible and prudent use of antimi- product (GDP) would be felt for a long period. crobials as a way to curb AMR.  AMR requires immediate action across all government sectors and society. There may be gaps existing in Emergence and spread of antimicrobial knowledge, but there is sufficient existing knowledge resistance for action. Evolution of microbes able to survive and reproduce in  Investing in AMR containment efforts, and more different environments has been occurring as part of specifically in AMR-sensitive interventions, has a Darwinian natural selection ever since their first appea- potentially high return, particularly in low- and middle- rance on earth millions of years ago. AMR is a naturally income countries. occurring phenomenon, resulting from various mecha- nisms such as mutations and transfer of genetic material between different microbes. Any use of antimicrobials Antimicrobial resistance can result in the development of AMR. The more anti- Antimicrobial resistance (AMR) happens when microbes microbials are used, the more likely microorganisms will (bacteria, fungi, viruses, and parasites) change in response develop resistance. Misuse of antimicrobials—including to exposure to antimicrobials, by mutating or by “horizon- using an incorrect dose or administering an antimicrobial tal” acquisition of resistance genes from already resistant at the wrong frequency or for an insufficient or excessive microbes or from mobile genetic elements (MGE) freed duration—speeds up the emergence of AMR. What is new in the environment. AMR is the resistance of microbes to is that, with the advent of modern antimicrobials in the antimicrobials. When microbes are resistant, the drugs do 1940s, greater selection pressure has increasingly been   65 applied and microbes have responded accordingly due to cific targets also will contribute to tackling AMR. AMR is their massive and rapid reproductive capability. Even the framed as a development problem, but it clearly affects most appropriate, prudent use of antibiotics and other both LMICs and HICs. antimicrobials to treat infections will inevitably promote emergence of resistant microbes, although an appropriate A quintessential “one health” issue use have more chances to effectively kill all involved Antimicrobial resistance is a complex problem that affects microbes and, thus, no individual will have the ability to all of society and is driven by many interconnected factors share its resistance to another. Alexander Fleming issued a related to people, animals, plants, and ecosystems. Single, warning about this in his Nobel Prize acceptance speech, isolated interventions will have limited impact, if any. “One which has gone unheeded for the past half century. Health” is defined as a collaborative approach for stren- Examples of misuse include when people take antibio- gthening systems to prevent, prepare, detect, respond to, tics without medical oversight during viral infections like and recover from primarily infectious diseases and related colds and flu, and when antibiotics are given as growth issues such as antimicrobial resistance that threatens promoters in animals or used routinely prophylactically in human, animal, and environmental health collectively. healthy animals because of suboptimal husbandry prac- Coordinated One Health action is required to minimize tices. the emergence and spread of antimicrobial resistance. Spread of microbes resistant to antimicrobials can hap- pen between people but also between people, animals, A problem in communities and a global issue plants, and the environment (in water, soil and air). Poor AMR is primarily a problem in communities where it hygiene and infection control, inadequate sanitary condi- emerges and spreads. While resistance determinants tions, and inappropriate food handling all contribute to emerge locally, they can spread globally. No single the spread of AMR. country is isolated from what happens in other countries regarding the emergence and spread of AMR. Increased In this report, the use of antimicrobials together with connectivity driven by globalization—such as trade, imperfect infrastructures and failing systems are conside- transport, and tourism—makes the spread of AMR from red as main drivers of the emergence and spread of AMR. one part of the world to another even more likely by the sheer scale of movements of people, animals, plants, and A major public health concern and a commodities. The international community, well aware of development problem this potential, has initiated actions to raise awareness and AMR increasingly threatens the ability to treat common propose steps for dealing with AMR. In 2016, 193 coun- infectious diseases in humans, resulting in prolonged tries signed a UN Resolution calling for coherent global illness, increased cost of treatment, and disability and action to address the issue and recognizing that failure to death. Without effective antimicrobials for prevention and address AMR will undermine sustainable food production treatment of infections, the risks associated with medical and jeopardize global sustainable development. procedures such as major surgery and complications of chronic disease conditions increase significantly. But in A worrying present and a gloomy future this AMR scenario, even a usually uncomplicated infection Patients infected with drug-resistant bacteria are at such as an otitis in a young child could be fatal. AMR also increased risk of poor clinical outcomes and even death. increases the cost of health care with more and longer They incur higher health-care costs compared to patients treatments, lengthier stays in hospitals, and more inten- infected with the susceptible strains of the same bacteria. sive care required. For example, resistance to carbapenem treatment in Kleb- In this report, we re-frame AMR as a development pro- siella pneumoniae, a common intestinal bacteria that can blem. Addressing AMR is necessary to attain many of the cause life-threatening infections, has spread globally. This sustainable development goals (SDGs), and it is likewise pathogen is a major cause of hospital-acquired infections true that making progress on several SDGs and their spe- 66  Pulling Together to Beat Superbugs such as pneumonia, bloodstream infections, and infec- share ideas and experiences, compare progress, and acce- tions in newborns and intensive-care unit patients, which lerate national efforts. in some countries renders treatment ineffective in more Global coordinating bodies are responsible for advancing than half of affected patients. compliance to the WHO International Health Regulations Similarly, resistance of Escherichia coli to fluoroquinolone (IHR), the OIE International Standards, the WHO List of Cri- (one of the most widely used medicines for the treatment tically Important Antimicrobials in human medicine, and of urinary tract infections) is very widespread and there the OIE List of Antimicrobial Agents of Veterinary Impor- are many countries where this treatment is now ineffec- tance. Under the IHR, 196 countries have committed to tive in more than half of patients. work together to prevent, detect, report, and manage public health emergencies, such as infectious diseases Treatment failure to the last resort medicine for gonorrhea outbreaks. It is important that countries designate institu- (third generation cephalosporin antibiotics) is increasing tions to be responsible and accountable for following up in an alarming number of countries, and is rapidly sprea- on the evaluation results so that IHR can accelerate AMR ding in urban settings, leading WHO to update the treat- action and focus global support together with the Global ment guidelines for gonorrhea due to widespread high Action Plan and country-specific NAPs. Global coordina- levels of resistance. ting bodies also are responsible for building collaborative Treatment guidelines for chlamydial infections and syphi- research networks so that funding allocations can be opti- lis have also been updated due to growing resistance. mized to meet globally relevant AMR priorities. Another example is resistance to colistin—a last resort A challenge is to incorporate and weigh the unique treatment that has recently been detected in several contexts of each country, which is where national plan- countries and regions—making infections caused by ning mechanisms can play an important role. Such plans resistant Enterobacteriaceae untreatable. are effective mechanisms for countries to translate the Resistance of bacteria causing tuberculosis is also an global policy agenda to fit their respective context. increasing concern, with high incidence of multidrug-re- sistant tuberculosis (MDR-TB), a form of tuberculosis that The ad hoc Interagency Coordination Group is resistant to the two most powerful anti-tuberculosis In 2016, the United Nations Secretary-General established drugs (isoniazid and rifampin), as is the rise of extensively an ad hoc Interagency Coordination Group on Antimicro- drug-resistant tuberculosis (XDR-TB), a form of tuberculo- bial Resistance (IACG) to improve coordination between sis that is resistant to isoniazid and rifampin, plus any fluo- international organizations and to ensure effective global roquinolone and at least one of three injectable second- action against this threat to global health security. The line drugs (i.e., amikacin, kanamycin, or capreomycin). IACG was co-chaired by the UN Deputy Secretary-General Resistance is also increasingly emerging and spreading and the Director General of WHO. Its members included in malaria, HIV, influenza, and candidiosis, as well as many representatives of the Tripartite (World Health Organi- other common infectious diseases. zation, Food and Agriculture Organization of the United Nations, and World Organisation for Animal Health) plus A global agenda representatives of relevant UN agencies, and other inter- national organizations, including the World Bank. Along- WHO’s Global Action Plan on AMR (2015) created a broad side members from UN agencies, there were 15 inde- and comprehensive high-level policy agenda for the glo- pendent experts, including three co-conveners. The diver- bal AMR prevention and containment effort. Countries sity of expertise and countries represented in this group participate in global and regional coordination of AMR reflected the One Health and global nature of AMR and efforts and commit to national implementation. Regional the multidisciplinary approach that is required to tackle and global coordination mechanisms are important to it. The group seek to increase collaboration and mobili- enable sharing of knowledge across a variety of national zation of all forces to address the AMR issue. It has been situations and can help countries learn from each other, mandated to (a) review progress globally since September   67 2016, providing oversight and using its convening power global knowledge generation and dissemination, and to advocate for concrete action to address AMR; (b) pro- advocacy. The Bank has a track record in implementing vide practical guidance for approaches needed to ensure “one health” principles and it supports country efforts sustained effective global action to address AMR, groun- to tackle AMR by systematically including it in relevant ded in an understanding of varied country situations; and investments. The Bank conceptualizes the AMR issue in (c) recommend governance model(s) for future improved terms of activities that are AMR-specific (those with the coordination and accountability to ensure continued primary purpose—in objective and design—to reduce political momentum and sufficient action is taken. The AMR) and AMR-sensitive (those whose primary purpose IACG delivered its report to the UN Secretary General (SG), is not AMR control, but which can be designed and who incorporated the 14 IACG recommendations into his delivered in such a way that they contribute cobenefits report to the member states. in addressing AMR). The Bank can play a significant role by putting an AMR lens on existing and planned invest- The link to investment ments and blending of AMR-specific and a broad range of AMR-sensitive interventions across multiple sectors, The World Bank recognizes AMR as an important deve- together with partners. Not only do AMR-sensitive invest- lopment issue, with the potential to disproportionately ments have the potential to reap high returns, but they and significantly affect low- and middle- income coun- are particularly effective in the context of scarce resources tries. AMR poses a major risk in our ability to help reduce for development activities. The total flow of development extreme poverty and promote shared prosperity. The assistance includes funds for the building of roads, ports, Bank’s 2017 report—Drug Resistant Infections: A Threat and other urban developments, as well as interventions to our Economic Future—assessed the global economic to build health systems and improve water and sanitation impact of AMR, identifying the urgent need to harness efforts. Using available financing more astutely and being development finance for this important challenge. more conscious of how existing and future investments A range of activities is underway to engage the Bank and affect AMR is a powerful way to design AMR-sensitive advance this issue with a focus on concessional funding, interventions and curb resistance. 68  Pulling Together to Beat Superbugs Abbreviations and acronyms AMR antimicrobial resistance MGE mobile genetic element AMU antimicrobial use MRSA methicillin-resistant Staphylococcus aureus AMS antimicrobial stewardship NAP national action plan ARG antimicrobial resistant gene NGO nongovernmental organization ASU antibiotic smart use NGS next generation sequencing DALY disability-adjusted life year OECD Organisation for Economic Co-operation and Development DDD defined daily doses OIE World Organisation for Animal Health EEA European Economic Area OTC over the counter FAO Food and Agriculture Organization of the United Nations SDGs sustainable development goals (of the UN 2030 Global Agenda) GDP gross domestic product SF substandard and falsified (medicinal products) GLASS Global Antimicrobial Resistance Surveillance System UEMOA Union Economique et Monétaire Ouest Africaine GP general practitioner UN United Nations HIC high-income countries UNGA United Nations General Assembly HIV-AIDS Human Immunodeficiency Virus – Acquired immunodeficiency syndrome VMP veterinary medicinal product IACG Inter Agency Coordination Group WASH Water, Sanitation and Hygiene IHR international health regulations WHO World Health Organization IPC infection prevention and control WTO World Trade Organization LMIC low- and middle-income country XDR extensive drug resistance MDR multidrug resistance Note: All dollar amounts are U.S. dollars unless otherwise indicated. All tons are metric tons.   69 Glossary of selected terms We recognize that several of the following terms may Drivers  Drivers are issues, which may act as facilitators or have different meanings. This glossary provides contextual modifiers of the emergence and spread of AMR. definitions for the purpose of this report. These definitions First-line antimicrobials  First line antimicrobials have been adapted from a variety of sources. are usually narrow spectrum antimicrobials that are Antimicrobial  Antimicrobial is a general term for the empirically recommended for common infections in drugs, chemicals, or other substances that either kill, community and healthcare settings. inactivate, or slow the growth of microbes, including Implementation research  Implementation research is bacteria, viruses, fungi, and protozoa. An antibiotic is an integrated concept that links research and practice to a type of antimicrobial developed to treat bacterial accelerate the development and delivery of interventions. infections. It involves the generation and application of knowledge Antimicrobial resistance  Antimicrobial resistance to improve the implementation of policies, programs, and (AMR) is the ability of microbes to grow in the presence practices. of substances specifically designed to kill, inactivate, or Metaphylaxis  Metaphylaxis is the treatment of a group slow their growth. It is the result of microbes changing of animals after the diagnosis of an infection has been in ways that reduce or eliminate the effectiveness of established in some individuals from the group, with the drugs, chemicals, or other agents used to cure or prevent aim of preventing the spread of the infectious agent to infections they cause. animals considered at risk. AMR sensitive  AMR-sensitive interventions contribute Monitoring  Monitoring is the intermittent performance indirectly to combating AMR. Their primary purpose is and analysis of routine measurements and observations, not AMR control; they can be designed and delivered aimed at detecting changes in the environment or health to maximize their impact on AMR (see also cobenefit). status of a population. See also surveillance. Improving access to clean water and sanitation, thereby reducing the spread of infections, is an example of an Multidrug resistance  Multidrug resistance (MDR) AMR-sensitive intervention. is a property of a pathogen that is resistant to three or more antimicrobial agents in three or more antimicrobial AMR specific  AMR-specific interventions have as classes. Researchers have also proposed the term their main purpose the reduction of AMR; for example, extensive drug resistance (XDR), defined as resistance to promulgating and enforcing regulations to ensure people all but two or fewer antimicrobial categories (i.e., bacterial can only obtain antimicrobial medicines with a valid isolates remain susceptible to only one or two categories). prescription. Pan drug resistance (PDR) is defined as resistance to all Cobenefit  The benefits of policies and interventions agents in all antimicrobial classes. that are designed and implemented to address important One Health  One Health is a collaborative approach rationales (e.g., related to objectives of development, for strengthening systems to prevent, prepare, detect, sustainability, and equity) can also have AMR impacts. respond to, and recover from primarily infectious diseases Defined daily dose  The defined daily dose is the and related issues such as antimicrobial resistance that assumed average maintenance dose per day for a threaten human, animal, and environmental health drug used for its main indication in adults. It does not collectively. necessarily reflect the therapeutic doses for individual Pathogens  Pathogens are microbes that induce patients, which take individual characteristics into account infectious disease patterns in their human, animal, or (e.g., age, weight, population differences, type and plant hosts, usually as a way to spread and advance their severity of infection). Drug utilization data presented in own reproduction. DDDs only give a rough estimate of consumption and not an exact picture of actual use. 70  Pulling Together to Beat Superbugs Prophylaxis  Prophylaxis is the treatment of an animal Subtherapeutic use  Subtherapeutic use refers to or a group of animals before clinical signs of infectious levels of antimicrobials below the ones required to disease are observed in order to prevent the occurrence cure infections. In countries where it is still permitted, of disease or infection. antibiotics may be given to animals on an ongoing basis at subtherapeutic doses for growth promotion. Resistance determinant  Resistance determinant is a catch-all term that includes the mechanisms that give Superbug  Microbes developing resistance to multiple a microbe the ability to resist the effects of one or more drugs are sometimes referred to as “superbugs.” An drugs, usually an antimicrobial resistant gene (ARG) or a infection caused by a superbug is harder to treat because mobile genetic element (MGE) carrying the gene/s. fewer effective drugs are available; in some extreme cases, treatment may not exist. Resistome  The resistome is the complete set of antibiotic resistance genes and their precursors in Surveillance  Surveillance is the ongoing systematic both pathogenic and non-pathogenic bacteria. This is collection, collation, and analysis of information related to composed of four different types of genes: resistance public health (animal, human and the environment), and genes found on pathogenic bacteria; resistance genes the timely dissemination of information so that action can found on antibiotic producers; cryptic resistance genes; be taken. The information is used, for example, in actions and precursor genes. that prevent and control an infectious disease. See also monitoring. Risk  Risk means the likelihood of the occurrence of a resistance determinant and the likely magnitude of its Therapeutic use  Therapeutic use is the curative biological and economic consequences or effect on treatment of a person, a sick animal or plant, or a group of sustainable development. animals or crops, following the diagnosis of infection and/ or clinical disease in those individuals Stewardship  Stewardship is a coherent set of actions that promote using antimicrobials in ways that ensure their efficacy and sustainability for all who need them. Actions might include, for example, prescribers making accurate diagnoses, following guidelines, reviewing their prescriptions in a timely manner, formulary restrictions, and preauthorization of certain antimicrobials.   71 References Aarestrup, F.M., Y. Agerso, P. Gerner–Smidt, M. Madsen, and L.B. Baker, S., N. Thomson, F.X. 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Dis. 19: 298–307. Woods, A. 2019. “Decentring antibiotics: UK responses to the diseases https://doi.org/10.1016/S1473-3099(18)30673-X of intensive pig production (ca. 1925-65).” Palgrave Commun. 5: 41. https://doi.org/10.1057/s41599-019-0246-5 World Bank. 2017a. «Drug resistant infections: a threat to our economic future». World Bank, Washington, DC. https://www.worldbank.org/en/ topic/health/publication/drug-resistant-infections-a-threat-to-our- economic-future   81 Antimicrobials have saved hundreds of millions of lives and substantially contributed to development and economic growth. However, they are now losing their power because of the microorganisms’ acquired capacity to withstand the drugs designed to kill them, to inactivate or slow their growth: antimicrobial resistance (AMR). Unchecked, AMR could severely reduce global economic output and hobble human and sustainable development progress in the decades ahead. AMR is a development issue. The report shows that we are facing a major gap between “knowing” and “doing.” Abundant knowledge exists about many aspects of AMR, yet people do not seem to know what to do, or how to do it. This calls for major efforts to be made in the field of implementation research to bridge knowledge and actions in real-world settings. AMR-sensitive interventions can be designed and delivered in such a way that they contribute cobenefits in addressing AMR. In building roads, ports and other urban developments, as well as through interventions to build health systems, improve animal husbandry, or improve water and sanitation, there are opportunities to maximize impact on AMR.