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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Page 59
Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Page 60
Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Page 61
Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Suggested Citation:"2 The Scope of the Problem." National Academies of Sciences, Engineering, and Medicine. 2021. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine. Washington, DC: The National Academies Press. doi: 10.17226/26350.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

2 The Scope of the Problem Responding to a complex problem like antimicrobial resistance requires some attention first to its root causes. As the previous chapter explained, microbes have many ways of surviving the agents used to fight them. Selection pressure from exposure to antimicrobials leads to the proliferation of mutations that render microbes immune to these agents. At the same time, the ability of microbes, especially bacteria, to pass genes horizontally even among different species in the same ecosystem speeds the spread of resistance traits. Mobile genetic elements, a plasmid, for example, may carry multiple different resistance genes. The selection of one resistance trait can therefore lead to the co-selection of other traits conveying resistance to other medicines (Lowy, 2009). The concept of resistance is hard to separate from its application in medicine. Even the central concept of microbial virulence is often defined, without clear consensus, in terms of the microbes’ capacity to harm its host; the innocuous or beneficial relationship between most microbes and their hosts are not as widely investigated (Casadevall and Pirofski, 2019). Even among pathogenic microbes, commensalism and colonization are more common outcomes of the relationship between microbe and host than disease (Casadevall and Pirofski, 2019). In these states, antimicrobial resistance may come at the cost of disease pathogenic potential (called pathogenicity) or may be the result of a complex relationship between antimicrobial resistance and microbial pathogenesis that allow microbes to survive in harsh conditions and niches (Dewan et al., 2018). Mobile genetic elements that can be transferred among bacterial strains belonging to the same or different species can co-select for both resistance and pathogenicity (Cepas and Soto, 2020). Other microbial characteristics such as biofilm formation, efflux pumps, and cell wall changes can contribute to both resistance and pathogenicity (Schroeder et al., 2017). In an immune-suppressed host, these features can increase the disease potential of otherwise less virulent microbes. However, the genetic connection between antimicrobial resistance and pathogenicity, especially in the context of multispecies communities, is not well understood (Beceiro et al., 2013; Schroeder et al., 2017). It is possible that anti-virulence molecules have a role as anti-infective agents that could supply less selection pressure. There is considerable uncertainty regarding how microbes and their hosts interact in states of health and disease. While the depth of this relationship is beyond the scope of this report, this chapter gives background on the ways human antimicrobial use encourages resistance. First, the chapter explores the ways in which human action contributes to resistance, 2-1 PREPUBLICATION COPY: UNCORRECTED PROOFS

2-2 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE then it gives more context on the global nature and distribution of resistant infections. The last section discusses the dynamic and adaptive nature of the problem, explaining why it is difficult to both measure and counteract. HUMAN ACTION EXACERBATES RESISTANCE Antimicrobials are used frequently in human medicine, the field for which they were developed and the one with the highest, most direct stake in their preservation. Antimicrobials are also widely used in veterinary medicine. Animal agriculture accounts for the largest total use of antimicrobials today, while aquaculture accounts for a smaller, but faster growing share of total use (Ritchie, 2017; Schar et al., 2020). Finally, antimicrobials are also used in crop agriculture on field and tree crops (Williams-Nguyen et al., 2016). Common problems across settings contribute to misuse and overuse. As the previous chapter explained, microbes can spread through water, air, and soil; through travel, including the travel of wildlife; and through environmental contamination. It can be difficult to disentangle the relative contribution of any one type of use to the global burden of resistance, though Figure 2-1 indicates the substantial evidence that the overuse and misuse of antimicrobials in both human and animal medicine drives much of the problem (Holmes et al., 2016). FIGURE 2-1 A conceptual framework for the role of modifiable drivers of antimicrobial resistance. NOTES: An infographic to show the considered potential contribution of each factor as a driver for antimicrobial resistance. Associated relative contribution, supporting evidence, and potential population affected (diameter of bubble) was created from a two-round Delphi method of Holmes and colleagues, who identified factors from review of the national and international antimicrobial resistance literature. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to identify the quality of the evidence (the study with the highest GRADE estimate was cited) supporting each driver as being contributory to the rise in antimicrobial resistance. PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-3 SOURCE: Adapted from Holmes et al., 2016. The Misuse and Overuse of Antimicrobials in Human Medicine Antimicrobials are fast-acting, powerful medicines that can avert considerable suffering. For this reason, prescribers may be quick to use them, even before the precise cause of their patients’ illness can be determined. An empirical diagnosis is one based on the best judgement of the clinician considering the patient’s history and the clinical presentation (Leekha et al., 2011). In the absence of information suggesting otherwise, a clinician suspecting bacterial infection will usually start with a broad-spectrum drug that has action against a wide range of pathogens. Broad-spectrum treatment carries risks. It wages a somewhat indiscriminate attack on a wide swath of potential pathogens, as well as commensal bacteria, thereby disrupting the gut microbiome (see Box 2-1). By disrupting the commensal bacteria, broad-spectrum treatment can leave patients vulnerable to Clostridioides difficile infection (Crowther and Wilcox, 2015; Johanesen et al., 2015). Broad-spectrum treatment also supplies the selective pressure that breeds resistance. For these reasons, microbiological information about the pathogen should inform a switch to a narrow-spectrum antimicrobial whenever possible (a process called de-escalation) (Leekha et al., 2011). Clinicians may be reluctant to switch medicines when a patient seems to be responding, however. In outpatient medicine, only about 10 percent of patients are correctly de- escalated (Leekha et al., 2011). Even in hospitals, where microbiological diagnosis is easier, there can be reluctance to de-escalate (Goldstein et al., 2016). The antimicrobial stewardship programs now common in the United States have improved antibiotic de-escalation in hospitals, a topic discussed more in Chapter 5, though local norms can vary widely (Liu et al., 2016). BOX 2-1 Antimicrobials and the Microbiome Antimicrobials, either through direct medical use or environmental exposures, can alter the human microbiome, the trillions of microorganisms that live in the human body, mostly in the gut. The diversity of organisms and composition of the microbiome influences the functioning of the immune system and may be related to obesity and a range of gastrointestinal diseases. Age and other factors such as gastric acidity can influence the composition of the microbiome and may underlie the increased risk of Clostridioides difficile infection over age 65. A healthy and diverse microbiome can help control the spread of resistant pathogens by increasing the competition for nutrients and other resources. Because antimicrobial treatment alters microbial ecology, there is growing interest in therapeutic steps to restore the microbiome after an infectious disease, as well as therapies that work to combat resistance by moderating host immunity through the microbiome. Already research in the microbiome has identified some promising phages, viruses that attack bacteria that may be useful in treating drug-resistant infections. Microbiome treatments may be most useful for people whose conditions make frequent exposure to broad-spectrum antimicrobials necessary, such as cancer and organ transplant patients. Tools to restore the microbiome in such cases are still in early development. The transplanting of microbes from healthy donors, as through fecal transplantation, and the use of probiotics and other nutritional tools may be able to beneficially alter the microbiome. Other research draws on animal studies, mathematical modelling, and genomic analysis to better understand what constitutes a healthy microbiome and how microbiome deficiencies might be corrected. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-4 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE SOURCES: Benler et al., 2021; Buffie et al., 2015; CDC, 2018a; Shreiner et al., 2015; The Nutrition Source, 2021. Rapid diagnostic testing could do much to change broad-spectrum empiric treatment, a topic discussed more in Chapter 6. In the absence of such tests, empiric antimicrobial therapy is part of the practice of medicine. Microbiological analysis of patient specimens is time consuming at best. Even in U.S. hospitals, there is at least a 2-day turnaround time for microbiological identification of most pathogens; susceptibility test results even longer (Tabak et al., 2018). Laboratory diagnostics are less available in low- and middle-income countries and testing kits more expensive, making empiric treatment the only practical option in many cases (Engel et al., 2016; Ombelet et al., 2019). An acknowledgement that empiric diagnosis is part of the practice of medicine is reflected in the World Health Organization (WHO) AWaRe System, which gives guidance on the empiric treatment of common infections (WHO, 2019d) (see Box 2-2). BOX 2-2 The WHO AWaRe System The WHO Model List of Essential Medicines is a tool used in the selection and supply of medicines for primary health care in low- and middle-income countries, updated every other year since 1977. The 2017 revision to the list introduced a system of categorizing antibiotics based on their potential for resistance to guide optimal use in cases when laboratory diagnosis is not possible. By categorizing antibiotics into access, watch, and reserve groups (AwaRe) the WHO aimed to preserve the effectiveness of powerful, new medicines. Access Group: The first-choice treatments for the 25 most common infections; these 29 medicines are described as “the core set of antibiotics that should be available everywhere.” Watch Group: Antibiotics with greater potential for resistance or toxicity; medicines on this list are highly valuable in human medicine and should not be used in agriculture; their use is routinely monitored to ensure consistency with WHO guidelines. Reserve Group: These medicines of last resort are only used for serious or life- threatening infections when other drugs have failed or cannot be used. This category includes the newer antibiotics being held in reserve as part of international stewardship efforts. The AWaRe system also gives useful guidance on the best treatment of 25 common infections. The information is now available in an interactive database that can be used to guide clinical decisions and public health surveillance. This database also identifies medicines to avoid at all costs, namely irrational fixed-dose combinations of broad-spectrum antibiotics for which there is no treatment guideline to support their use. The AWaRe classification has its limits. As with any broad categorical grouping, there is an element of arbitrariness; it is not always clear which category a drug should fall into. Furthermore, the decision to use a medicine or hold it in reserve is largely influenced by the local burden of disease and local cost and availability of medicines. There are doubtless examples of watch group medicines that should be first-line treatments in certain settings. PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-5 The system is, nevertheless, an invaluable tool for antibiotic stewardship and for tracking access and use in low- and middle-income countries. SOURCES: Sharland et al., 2018; WHO, 2019d. Not all misuse of antimicrobials is made under such constrained circumstances, however. Claims data suggest that roughly 17 percent of antibiotic prescriptions in the United States are made in the absence of any diagnosis of infection, while another 20 to 30 percent are not associated with any clinical visit at all (Fischer et al., 2020). The Centers for Disease Control and Prevention (CDC) estimates that, despite improvement in antibiotic prescribing practices, more than 30 percent of antibiotics prescribed in outpatient medicine are inappropriate (CDC, 2011). More recent prospective research has found that more than 20 percent of antibacterials prescribed in outpatient medicine are not associated with a bacterial infection (Fischer et al., 2021). The common use of antibacterials to treat viral respiratory tract infections accounts for considerable overuse of antimicrobials (CDC, 2011). Furthermore, the broad-spectrum agents that encourage resistance are the most commonly prescribed antibacterials in primary care (Shapiro et al., 2014). The same trends are seen in the treatment of children. National data indicate that about a third of antimicrobial prescriptions made to children in emergency department visits are not indicated (Poole et al., 2019). The overuse of broad-spectrum treatment may be especially common in children under 2 years of age (Alzahrani et al., 2018). The clinicians responsible for this misuse are often pressured by their patients or, for pediatricians, their patients’ parents (Sirota et al., 2017). They may also be acting on a sense of obligation. Faced with a seriously sick, feverish patient and uncertainty about the source of the infection, a doctor may prescribe an antibiotic even knowing that the infection is likely viral, out of a misplaced caution, or from the cumulative effect of various social pressures, or an insufficient time to explain the ambiguity in their diagnosis (Imanpour et al., 2017; Pichichero, 2002). The risk of secondary bacterial infections may drive clinicians to prescribe prophylactic antimicrobials in some patients (Manohar et al., 2020). Prophylactic antimicrobial treatment in dentistry, for example, often uses broad-spectrum antibiotics to control the risk of wound infections after an extraction or oral surgery (Singh Gill et al., 2018). However, trial data does not support the routine use of prophylactic antimicrobials in routine dental implants or extractions in healthy patients (Singh Gill et al., 2018). Nevertheless, there is still wide variation in national practice guidelines on antimicrobial prophylaxis in dentistry and other clinical practices (Bakhsh et al., 2020). Confusion over treatment guidelines can drive antimicrobial use in medicine as well. Long treatment regimens with antimicrobials were common historically, driven partly by a limited understanding of mechanisms of action or biomarkers of cure (Wald-Dickler and Spellberg, 2019; Wilson et al., 2019). For example, the optimal duration of antibiotic therapy even for the common infections, such as community acquired pneumonia, was not established for decades. Now, despite multiple national and international guidelines recommending a maximum of 5 to 8 days of antibacterial treatment for most patients, community-acquired pneumonia patients are treated on average for 10 days or longer (Fally et al., 2021; Lim et al., 2009; Mandell et al., 2007; Tansarli and Mylonakis; Woodhead et al., 2011). Up to 40 percent of uncomplicated cases receive antimicrobials for more than 10 days (Walsh et al., 2018; Welte et al., 2012). Such prolonged treatment puts patients at risk for a range of health problems (e.g. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-6 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE allergic reactions, diarrhea, organ toxicity and extremely low white blood cell count) and even death (Keighley et al., 2019; Murphy et al., 2016; Tamma et al., 2017). Evidence also supports shorter course therapy for otitis media, skin and soft tissue infections, acute bacterial sinusitis, and uncomplicated urinary tract infection (Wilson et al., 2019). Shorter therapies for these and other infections have been shown to have similar clinical outcomes and far lower risk of adverse events, but many prescribers, especially primary care doctors, default to treatment regimens of 10 days or longer (CDC, 2019b; Lee et al., 2021). The Misuse and Overuse of Antimicrobials in Veterinary Medicine Many of the same psychological factors and adherence to outdated treatment guidelines that influence doctors, dentists, and nurses to overuse antimicrobial medicines apply to veterinarians as well. One important difference however, lies in the size of their practice. The steps in treating companion animals are largely similar to those for humans: an individual, clinical evaluation followed by diagnosis then administering medicine. The process for treating food-producing animals however, can involve dosing groups of animals (Aarestrup, 2015). In swine and poultry, this treatment would be administered through feed or water, and in young calves through injection (Agriculture.com Staff, 2018; National Chicken Council, 2014; Word et al., 2020; Zangaro, 2018). Therefore a single veterinarian may routinely treat animals in herds or flocks of hundreds or thousands at a time (Cima, 2017; USDA, 2019; Widmar, 2017). Partly for this reason, the volume of antibiotics used in animal agriculture often exceeds the use in human medicine (Woolhouse et al., 2015). In some parts of the world, agricultural use exceeds human use by four times in volume (Laxminarayan et al., 2013). Some antimicrobials are reserved for human use only, such as the isoniazid group of antibiotics used to treat tuberculosis (McEwen and Collignon, 2018). Others, ionophores for example, are toxic to humans and used only in animals (McEwen and Collignon, 2018). Most classes of antimicrobial medicines, however, are used in both human and animal medicine, including the treatment of fish, livestock, birds, honeybees, and pets (McEwen and Collignon, 2018). The limited pool of medicines can be a source of tension, some people are uncomfortable with animal use (more specifically, livestock use) of antimicrobials that are important for human health (Aarestrup, 2015; Mellon, 2013). As in human medicine, the antimicrobial treatments in animals should be judicious, with an emphasis on the shortest effective duration of treatment and lowest effective dose through the most effective route of administration (MSU, 2011). At the same time, care should be taken not to exaggerate the risk animal antimicrobial use poses to humans, and understand the need for treatments to control animal diseases that could affect food security and human health. Determining the minimal effective dose of antimicrobials can be less straightforward in animal agriculture, however, as the line between prophylactic and therapeutic treatment is not always clear. After one animal in a flock or herd has been diagnosed, all or part of that group may be treated to control the risk of an outbreak or to treat animals already infected but not yet showing signs of illness (Farm Antibiotics, 2017). This control treatment is sometimes administered before animals are transported or brought into close or otherwise stressful conditions (MSU, 2011). European surveillance data suggest that the mass medication of mostly healthy animals, especially pigs and poultry, accounts for 90 percent of veterinary antimicrobial consumption (Baptiste and Pokludová, 2020). There is relatively little hard evidence on the effects reducing such use would have on animal health, welfare, or productivity (Aarestrup, 2015). PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-7 Such estimates do not account for the mass treatment of livestock and fish with antimicrobials to enhance growth. The mechanisms through which these medicines promote growth is unclear, but the use of subtherapeutic doses of antibiotics in feed and water was common practice by the 1950s, and highly favorable to selecting for and retaining resistant bacteria (Kirchhelle, 2018; Van et al., 2020; Wall et al., 2016; Woolhouse et al., 2015). The extent to which antimicrobial growth promoters improve yields is unclear. Studies from the 1950s and 1960s suggest increases of 8 to 12 percent of body weight in poultry, but predate modern good agricultural practices, high-efficiency feeds, or selective breeding (Graham et al., 2007). More recent research in the United States suggests much lower gains (Graham et al., 2007). Antimicrobial growth promoters appear to confer a minimal advantage when the biosafety and preventive measures are strong, and on a background of optimal genetic potential (Laxminarayan et al., 2015; Wall et al., 2016). But in places where baseline water sanitation and husbandry measures are lacking, even a marginal offset from growth-promoting antibiotics can be a meaningful difference in yields (Laxminarayan et al., 2015). Nevertheless, because of the implications for public health, antimicrobial growth promoters have been banned in Europe since 2006 and more recently in the United States (Casewell et al., 2003; Cogliani et al., 2011; FDA, 2017; Sneeringer, 2015). Agricultural use of antimicrobials in low- and middle-income countries is difficult to measure, but demand for animal-source foods and for antimicrobials used in their production is increasing (Nadimpalli et al., 2018; Schar et al., 2018). It is not clear that regulatory interventions to curb this use would be effective, given relatively unrestricted retail access to antimicrobials and limited capacity to enforce regulations (Schar et al., 2018; Wellcome, 2020). India, for example, has bans on using antimicrobials important for human medicine in livestock, but the majority of antimicrobials that WHO designates as “critically important for human health” can be found in poultry feeds in India (Thakur and Panda, 2017; Wellcome, 2020). At the same time, there is good evidence the situation is improving. The World Organization for Animal Health, known by the historical acronym OIE, monitors antimicrobial use in animals; its most recent survey found that only 26 percent of 160 countries still allow the use of antimicrobial growth promoters in livestock—the lowest proportion since the organization began monitoring (OIE, 2021). Recent reports highlight decreasing antimicrobial use, especially in China (Schoenmakers, 2020; Tiseo et al., 2020b). By 2030 global antimicrobial sales are expected to rise only about 11 percent relative to a 2017 baseline (Tiseo et al., 2020b). Aquaculture also accounts for considerable antimicrobial use, especially in the fish- farming countries in Asia (Van Boeckel et al., 2015). A recent study of small fish farms in the Mekong Delta found that 84 percent of tilapia and 69 percent of catfish farms used antibacterials, usually for three days or longer, often with different drugs tried sequentially after treatment failure—a serious risk factor for emergence of resistance (Ström et al., 2019). The amount of drugs used and the way they are deployed in some countries poses high risk, not just to human health from exposure to drug residues, but to aquatic biodiversity (Lulijwa et al., 2019). At the same time, these products are important for livelihoods and food security, especially in poor rural areas (Olaganathan, 2017). The key challenge is to support farmers in efficient animal husbandry that makes minimal use of antimicrobials. The demand for food from animal sources is increasing in low- and middle-income countries, driven by population growth and a higher standard of living (Baltenweck et al., 2020; FAO, 2018). Even if economic growth were to stagnate, demand for meat is projected to increase 77 percent in Asia and 280 percent in Africa by 2050 (Baltenweck et al., 2020; FAO, 2018). To PREPUBLICATION COPY: UNCORRECTED PROOFS

2-8 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE respond to this demand, animal agriculture in low- and middle-income countries is shifting from small-scale farming to a more intensive, specialized farming of larger flocks or herds (Hedman et al., 2020; Lam et al., 2016). By some projections, antimicrobial use in livestock may double total antimicrobial consumption in Brazil, China, India, Russia, and South Africa by 2030 (Manyi- Loh et al., 2018; Van Boeckel et al., 2015). At the same time, a sharp decrease in antimicrobial sales in some countries, notably China, mean that global antimicrobial use is projected to rise only about 11 percent by 2030 (relative to 2017 levels) (Tiseo et al., 2020a). There are numerous examples that good animal husbandry can significantly reduce or eliminate the need for antibiotics. In Norway for example, salmon production in the 1980s was consuming the same amounts of antibiotics by weight as human medicine (Simonsen, 2020). As Figure 2-2 shows, antimicrobial use in Norwegian salmon farming dropped off in the mid-1990s with the development of vaccines against furunculosis and vibriosis, common infectious disease of salmonids (WHO, 2015b). The vaccine, combined with a labor-saving automated delivery system, brought about a sharp reduction in the industry’s reliance on antibiotics (NORM/NORM-VET, 2019). Coupled with improvements in husbandry practices and biosecurity, including the rotating and scheduled disinfecting of holding areas, vaccination has brought the Norwegian salmon industry’s use of antimicrobials to negligible levels since 2013 (NORM/NORM-VET, 2019; WHO, 2015b). A similar emphasis on prevention, combined with increasingly specialized systems and knowledgeable farmers allowed the Danish pig producers to reduce antibiotic use by 50 percent between 1992 and 2008, even as production increased by 8.7 million weaned pigs a year (Jul et al., 2019; Levy, 2014). Perdue Farms, a major U.S. poultry producer, has used similar tools (sanitation, vaccination, and re-engineering barns) to stop using antibiotics in their branded products between 2002 and 2017, with other U.S. chicken producers following suit (Bunge, 2016; Leventini, 2018). FIGURE 2-2 Historic use of antibiotics in Norwegian aquaculture. SOURCE: Simonsen, 2020. PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-9 Replicating these successes depends on wider access to vaccines and other preventative products and tools. But despite the demonstrated benefits of vaccination, there is still significant shortage of efficacious and economically affordable vaccines for animal agriculture, a topic discussed more in Chapters 6 and 8 (Hoelzer et al., 2018). Compared to human vaccines, the market for animal vaccines is smaller both in market size and in unit prices, translating to a lower return on investment for companies (Meeusen et al., 2007). At the same time, the range of hosts and pathogens is greater, and the ways they interact are more complicated than for human vaccine production (Hoelzer et al., 2018; Meeusen et al., 2007). While some tools, such as genetically modified live vaccines are promising, widely divergent regulatory barriers across markets present another barrier to use (Hoelzer et al., 2018). Furthermore, raising farm animals without antimicrobials comes at a cost. Especially in parts of the world where basic water and sanitation infrastructure is lacking, antibiotics are often used as a stopgap. Labor costs are also a concern. Vaccines that can be administered without individually handling each animal in the herd or flock are desirable as the labor costs of vaccinating the group are lower. Similarly, treating groups of animals via feed or water is less labor intensive than identifying a sick animal and treating it individually (Lekagul et al., 2019). Farmers pay out of pocket for animal medicines and diagnostics. The cost of culture and susceptibility tests is difficult to justify especially when empiric treatment is relatively cheap (Norris et al., 2019). As in human medicine, there is considerable unmet need for rapid veterinary diagnostics (Buller et al., 2020). As long as animal samples have to be sent to a central lab and the test results reported back to a veterinarian, the opportunity cost alone will get in the way of more judicious use (Buller et al., 2020). Resistant Pathogens Overlap Human and Animal Hosts The extent to which antimicrobial use in farm animals threatens human health is not clear, nor is the direction of this relationship one-way (Muloi et al., 2018). Animals may acquire resistant infections from humans and vice versa; shared water sources may be an important conduit transmitting microbes between and among species (Iramiot et al., 2020). In some cases, the direction of transmission may be inferred from context. Carbapenems, for example, have never been widely used in veterinary medicine, so carbapenem resistance in animals is likely of human origin (Davies and Wales, 2019). Most examples of transmission of resistance between species are less clear, however. The majority of studies in a 2018 systematic review on the transmission of resistant Escherichia coli from animals to humans found overlap in resistant bacteria between humans and food animals, but only about 18 percent claimed to identify animal-to-human transfer of pathogens, and these studies often based their claims on evidence only of co-occurrence of pathogens between species (Muloi et al., 2018). In short, the complexity of potential transmission routes through which resistant bacteria may pass among and between species and the lack of detailed environmental monitoring make it difficult to establish the source of resistant bacteria or resistance genes in a population (Argudin et al., 2017). At the same time, the cross-transmission of resistant pathogens is likely whenever humans and animals have close contact. Farmers, veterinarians, and other people who handle livestock may be at higher risk for contracting resistant pathogens from animals, especially when personal protective measures (i.e. wearing of masks, gloves, eye protection) are limited (Franceschini et al., 2019). There are also points in animal production, livestock auctions for example, which involve the comingling of different animal populations, a higher risk for PREPUBLICATION COPY: UNCORRECTED PROOFS

2-10 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE transmission of resistant pathogens within and between herds or flocks (Argudin et al., 2017; Lhermie et al., 2019a). Food is another vehicle through which resistant bacteria may spread from animals to humans (Wall et al., 2016; Wright, 2010). Whole genome sequencing, discussed at length in Chapter 4, and other trace-back tools can help determine the source of antibiotic-resistant infections spread through food (CDC, 2019a; Wall et al., 2016; Wee et al., 2020; Wright, 2010). Such tools were used in a 2019 CDC investigation of Salmonella enterica that was traced from patients in 32 states to infected cattle in Mexico and a Texas slaughterhouse (Plumb et al., 2019). Cases like these can raise concern about the risks of antimicrobial resistance in livestock. At the same time, the risk of transmission of resistant pathogens through food is not necessarily higher than from human-to-human transmission. Livestock-associated methicillin-resistant Staphylococcus aureus (MRSA), for example, is associated with lower risk of severe disease than human MRSA subtypes (Davies and Wales, 2019). Biosecurity measures in farms can help control the spread of resistant bacteria between humans and livestock (Davies and Wales, 2019). Efforts to eliminate rodents and other wildlife that act as vectors of pathogens may also be helpful (Davies and Wales, 2019). The potential contribution of antimicrobial use in animals to the development of resistance is of concern largely because of the volume of antimicrobials involved, which is in turn a reflection of the number and size of livestock animals relative to humans. For this reason, antimicrobial use in livestock is usually expressed relative to the target animal biomass, which accounts for the number of animals and a standard weight at time of exposure (Brault et al., 2019). But most people, especially in the United States, do not have anything close to the level of contact with animals as veterinarians or agricultural workers do. In contrast, many people share their homes with pets, for which there are no restrictions on the use of medically important antimicrobials (Morley et al., 2005; Odoi et al., 2021). A recent CDC investigation of an extensively drug-resistant Campylobacter jejuni outbreak, for example, found molecular or epidemiological links to pet store puppies in 97 percent of cases (Francois Watkins et al., 2021). The potential emergence of resistant pathogens in companion animals and the transmission of these pathogens to humans is not an area that is well studied, however (Joosten et al., 2020). Efforts to better monitor antimicrobial use in veterinary medicine, discussed in Chapter 5, will be essential to better understanding this relationship. Ultimately a shared environment between humans and animals is central to any understanding of antimicrobial resistance. The Use of Antimicrobials in Crop Agriculture A full analysis of antimicrobial use, especially the environmental risk it poses to humans and animals, also considers the use of antimicrobials to combat some bacterial and fungal diseases of plants. There is some uncertainty regarding such use. Recent research from the WHO and the Food and Agriculture Organization of the United Nations (FAO) found that only 14 of 154 countries surveyed have a system to monitor antimicrobial use in crops (FAO and WHO, 2019). Antibacterials are a relatively expensive way to control plant diseases, so application is limited to high-value fruit and vegetable crops and ornamental plants (McManus et al., 2002; Stockwell and Duffy, 2012). In the United States, crop agriculture accounts for only about 0.12 percent of agricultural use of antibacterials (Stockwell and Duffy, 2012). Experts estimate that PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-11 globally crops account for between 0.26 and 0.50 percent of antibacterial use in agriculture (Taylor and Reeder, 2020). The most widespread use of antibacterials on U.S. crops is to control fire blight, a disease caused by the gram-negative bacterium Erwinia amylovora, in apples and pears (Taylor and Reeder, 2020). Antibacterials can also be used on vegetable crops, especially in Latin America, and to control rice diseases in Asia (Taylor and Reeder, 2020). More recently, EPA authorized oxytetracycline and streptomycin for use against huanglongbing, a bacterial disease of citrus trees more commonly referred to as citrus greening (EPA, 2016, 2018, 2021b). Unlike antibacterials, antifungals are relatively widely used in crop agriculture. Fungi are common causes of infections in plants, and fungicides have been used in agriculture for more than 150 years (Fisher et al., 2018). Antifungals can be important tools for food security. FAO data suggest that crop losses from fungal infections alone would be enough food for 500 million people (Almeida et al., 2019). The azoles are a class of antifungal medicines used on crops and in humans and animals (Fisher et al., 2018). Although fungicide use data are not widely available for most countries, azoles account for almost a quarter of global fungicide sales (ECDC, 2013). Use of a specific group of azoles, the triazoles, has become widespread in the last 30 years, with a noticeable increase in the last 15 years (Toda et al., 2021). In the United States, triazole application increased by over 400 percent between 2006 and 2016, driven largely by its use in wheat (Toda et al., 2021). Increasing use of triazole contributes to selective pressure on the Aspergillus spp. which can cause aspergillosis, a severe and often fatal fungal infection in humans (Toda et al., 2021). Triazoles are one of only two or three classes of antifungal medicines able to treat aspergillosis (Toda et al., 2021). Work by the International Society for Human and Animal Mycology and the European Confederation of Medical Mycology indicates that triazole-resistant aspergillosis has been increasing since 2007 and that most clinical isolates showing resistance contain mutations associated with environmental exposures (Resendiz Sharpe et al., 2018). Azole use has been linked to the emergence of drug resistant Candida auris; climate change is also thought be a contributing factor (Arora et al., 2021; Casadevall et al., 2019). Climate change may be selecting fungal pathogens with ability to survive at higher temperatures and in varied hosts (Casadevall et al., 2019). C. auris, for example, can survive in harsh conditions, in wet or dry environments, and at varied temperature and salinity (Arora et al., 2021). Drug-susceptible strains of C. auris have been recovered in ecosystems relatively untouched by humans, but its drug-resistant strains may have emerged in response to contact with soil and plants (Arora et al., 2021). Fungi are also easily spread by high winds and flood waters (Nnadi and Carter, 2021). Given the influence of the environment on the emergence of both resistance and infectious disease, some consideration for how resistance moves through the environment is important. Antimicrobial Resistance in the Environment All antimicrobial use, be it in human or veterinary medicine, in terrestrial animals, aquaculture, or crop agriculture selects for resistance genes. Human and animal waste both contain antimicrobial residues and resistance genes, as does the runoff from pharmaceutical factories. Research from various manufacturing sites has found high concentrations of antimicrobials downstream of factory wastewater (Bielen et al., 2017; Hogerzeil et al., 2020; Kristiansson et al., 2011; Li et al., 2008). Nevertheless, the evidence indicating the extent to PREPUBLICATION COPY: UNCORRECTED PROOFS

2-12 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE which resistant organisms and resistance genes from environmental sources pass to humans is lean (Chatterjee et al., 2018). The movement of resistant bacteria from water or soil to humans or other animals, while plausible, is something few studies have investigated with sufficient rigor to allow causal inferences to be drawn (Chatterjee et al., 2018). To complicate the matter, antimicrobials are not the only chemicals in the environment that select for resistance. Metals such as copper are used in agriculture as biocides, and can co- select for resistance,1 as can disinfectants, surfactants, and chemical solvents (Holmes et al., 2016; Singer et al., 2016a). The concentration of resistance genes in the environment is dynamic and influenced by the concentration of the antimicrobial they protect against, as well as such factors as temperature and microbial ecology. The many pathways through which resistance genes and antimicrobial residues enter the environment raises concerns about the safety of the wider ecosystem (Singer et al., 2016a). As Figure 2-3 shows, water is a particularly important potential vehicle for spreading antimicrobial residues and resistance genes. The substances enter the water from human and animal waste, as well as industrial and agricultural runoff (Holmes et al., 2016; Singer et al., 2016a). Antimicrobial-polluted water can be used to irrigate crops or water animals; it can also be consumed directly by humans (Wall et al., 2016). Research on blaNDM-1, the gene that encodes metallo-beta-lactamase 1 (NDM-1), an enzyme that conveys resistance to carbapenems and other antimicrobials, has been found in surface and tap water samples in New Delhi (Lubick, 2011; Walsh et al., 2011). Water can bring microbes, residues, and resistance genes into contact with varied microbial ecosystems. Research in Chinese estuaries has found the concentrations of antimicrobial residues and resistance genes in water to be driven by human activity in the area, including veterinary and human medical uses and pharmaceutical manufacturing (Zhu et al., 2017). Other research in the United States has found a correlation between human activity, especially animal agriculture, and the concentration of resistance genes in rivers (Pruden et al., 2012). Hospital wastewater is an even more concentrated source of medicine residue and resistant bacteria (Aga et al., 2018). Research from Sweden, where antimicrobial consumption per capita is low, has shown hospital wastewater to have sufficient antibacterial activity to kill all susceptible bacteria in a sample, leaving only the drug-resistant organisms (Kraupner et al., 2021). In South Africa, Pseudomonas aeruginosa isolates recovered from hospital wastewater showed virulence and resistance traits that could translate into serious infection in a host (Mapipa et al., 2021). As the hospital effluent enters the wastewater treatment, however, antimicrobial byproducts appear to be diluted and less activity can be measured (Kraupner et al., 2021). 1 Co-selection can occur when one resistance gene encourages the selection of others, regardless of any competitive advantage conferred; it can also be the result of one resistance trait offering protection against multiple toxic chemicals (Singer et al., 2016a). PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-13 FIGURE 2-3 Drivers of antimicrobial resistance in the environment. SOURCE: Adapted from Singer et al., 2016a. Treated wastewater is typically discharged to surface waters, but it can also be reused in agriculture, industry, or for drinking, or to replenish groundwater supplies (EPA, 2021a). Resistance genes can remain in wastewater after treatment, raising concerns about its use in irrigation and the potential to introduce resistance traits into the environment (Fahrenfeld et al., 2013). Wastewater treatment is also an important point of contact for treating raw sewage. After treatment, the remaining nutrient-rich material, called biosolids, can be used as fertilizer. This practice is at least a theoretical risk for the introduction of human antimicrobial residues to soil and crops (Williams-Nguyen et al., 2016). Some research suggests that mobile genetic elements associated with resistance persist in the biosolids and in the environment after their use (Law et al., 2021). Other studies have found that the application of biosolids do not have an effect on the concentration of resistance genes in soil or increase phenotypic resistance (Rahube et al., 2014; Rutgersson et al., 2020). The even more common practice of using animal manures for fertilizer may be higher risk, however. While methods such as composting can decrease the concentration of resistance genes by an order of magnitude, methods for processing manure vary widely (Checcucci et al., 2020; Szogi et al., 2015). Less can be said about trace antimicrobials, which can remain unmetabolized in an animals’ gut (Elmund et al., 1971; Halling-Sorensen et al., 1998). These compounds are then excreted, some of them retaining their antimicrobial activity. Concentrations of antibiotic resistance genes in manures are considerably higher than in sewage biosolids (Munir and Xagoraraki, 2011). But on the whole, the relationship between resistance genes and drug metabolites in manure and risk for antimicrobial resistance in humans or animals PREPUBLICATION COPY: UNCORRECTED PROOFS

2-14 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE is not clear, and information about antibiotic half-lives in manure is not usually available (Williams-Nguyen et al., 2016). Furthermore, even the limited research on environmental reservoirs of antimicrobial resistance is mostly from high-income countries. In developing countries, the risk factors for all kinds of water and environmental contamination are higher. Wastewater is generally discharged partially or wholly untreated into rivers and other water sources (WHO, 2019b). Less than a third of the world’s population uses sanitation connected to formal wastewater treatment (WHO, 2019b). About a billion people use a basic pit latrine; open defecation is common practice for another 673 million (WHO, 2019b). Poor sanitation is itself a cause of infectious disease; it also brings resistant bacteria and antimicrobial by-products into contact with the environment, including untreated surface and groundwater. The WHO estimates that 2 billion people worldwide drink water contaminated with feces, 144 million drink directly from surface water (WHO, 2019a). Only about 40 percent of people in low- and middle-income countries have trash collection, and even that is not necessarily removed to engineered landfills or industrial incinerators (Vikesland et al., 2019). This brings people into closer contact with trash, including trash from hospitals and clinics containing antimicrobials (Vikesland et al., 2019). For all these reasons, soil and water concentrations of antimicrobials appear to be higher in low- and middle-income countries (Vikesland et al., 2019; Williams-Nguyen et al., 2016). At the same time, a higher burden of antimicrobial resistance and greater antimicrobial use are common in these parts of the world, making it difficult to estimate the relative contribution of the environmental reservoir to the overall burden of resistance or even to separate cause from effect in this circular problem. ANTIMICROBIAL RESISTANCE IS A GLOBAL PROBLEM At the root of the problem of antimicrobial resistance are disparities among countries, disparities in wealth, living conditions, health systems, and access to medicines. As the previous chapter discussed, the parts of the world that have the highest burden of drug-resistant infections have, not coincidentally, the most serious problems with crowding and infection control that allow infectious diseases to spread quickly among humans and livestock. In 2018, a modest majority (55 percent) of the world’s people lived in cities; by 2030 this share is projected to grow to close to 70 percent (UN, 2018). Increasing urbanization puts a strain on health systems, partly because of the increasing demand for good quality, free primary health care and also through the increasing crowding and slum conditions that drive infectious disease (Elsey et al., 2019; Shawar and Crane, 2017). Partly for these reasons, the WHO included antimicrobial resistance on its 2020 list of urgent health challenges for the decade, carrying over from its previous year’s list of top global health threats (WHO, 2019c, 2020d). In introducing the urgent challenges, the WHO Director General emphasized how most of them are interlinked (WHO, 2020d). This is especially true of antimicrobial resistance, a problem that contributes to and is aggravated by other health challenges. The proliferation of substandard medicines,2 for example, means that patients can be exposed to subtherapeutic doses of antimicrobials, providing the selective pressure that encourages resistance (Ayukekbong et al., 2017). Problems with the drug supply and 2 Defined by the WHO as, “authorized medicines that fail to meet either their quality standards or specifications, or both” (WHO, 2018c). PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-15 procurement of essential medicines can mean that many patients use the wrong antimicrobial, the wrong dose, or the wrong length of treatment (Loosli et al., 2021). Poor availability of human and animal health services create a void where patients turn to less regulated providers, introducing considerable confusion into diagnosis and treatment, including the diagnosis and treatment of infections (Loosli et al., 2021). Drug-resistant infections are hard to treat and carry an elevated risk of serious illness or death (WHO, 2020a). They are more often resistant to the inexpensive, off-patent drugs in the WHO Access Group. The medicines needed to fight them are newer and more expensive, putting a strain on health budgets among payers in high-income countries and putting them out of reach of many patients in low- and middle-income ones (Alvarez-Uria et al., 2016; WHO, 2020a). To complicate the problem, microbes are famously difficult to confine. Recent research indicates that international travel, including the travel of livestock, wildlife, birds, and fish, is an important spreader of antimicrobial resistance (D’Souza et al., 2021; Frost et al., 2019). Increasingly, policy attention to antimicrobial resistance recognizes the global nature of the problem (Podolsky, 2018). In 2011, Britain’s Chief Medical Officer, Sally Davies, released an influential report comparing antimicrobial resistance to climate change both in the size of the threat, described as a “ticking time bomb … for the world,” and in its costs, which will be considerably higher in the future if mitigating steps are delayed (Davies, 2013). The International Monetary Fund (IMF) echoed the parallels with climate change in 2014, naming antimicrobial resistance one of the four global health threats of the twenty-first century (Jonas et al., 2014). The IMF analysis presented it as a problem of the commons, growing to our shared, global detriment because, “no single patient, physician, hospital, insurer, or pharmaceutical company has an incentive to reduce antibiotic use” (Jonas et al., 2014). On the contrary, antimicrobial consumption is often in best interest of the individual user (Laxminarayan, 2016). Unlike most commons problems however, the shared resource that overuse destroys is not the supply, but the effectiveness of these medicines (Laxminarayan, 2016). Antimicrobial Resistance and the Changing Global Burden of Disease With the effectiveness of antimicrobial medicines at risk, some experts caution that mortality from infectious disease could return to levels not seen since the nineteenth century (Podolsky, 2018; Shallcross et al., 2015). The specifics of this claim are debatable; as the 2014 IMF report observed, “antibiotics are not a substitute for good public health policy, vaccinations, clean water, and proper sanitation. The infectious disease mortality rates in low- and lower- middle-income countries today vastly exceed those in high-income countries before antibiotics were introduced in 1941” (Jonas et al., 2014). Still, the underlying premise that untreatable infections would have ramifications across the health system, changing the risk calculations underlying routine procedures, is undeniable. The irony of the problem is that the same factors that drive the high burden of infectious disease, including poor sanitation, lack of primary care, and limited access to medicines, in turn encourage the emergence of resistant pathogens. The prevalence of multidrug resistant organisms, especially E. coli and Klebsiella spp., in gut bacteria that can spread partly through contaminated food and water, decreases with rising gross national income (Alvarez-Uria et al., 2016) (see Figure 2-4). The medicines that treat these pathogens are expensive and often unavailable in low- and middle-income countries, while treating the resistant infection with an ineffective antimicrobial provides selective pressure that encourages the spread of resistant pathogens (Alvarez-Uria et al., 2016). PREPUBLICATION COPY: UNCORRECTED PROOFS

2-16 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE FIGURE 2-4 Prevalence of third-generation cephalosporin-resistant (3GCR) E. coli3 (A) and Klebsiella spp. (B) against gross national income per capita, predicted values with 95% confidence intervals. SOURCE: Alvarez-Uria et al., 2016. PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-17 An epidemiological transition in low- and middle-income countries has increased their relative burden of noncommunicable diseases, especially cardiovascular disease, cancer, respiratory diseases, and diabetes (Ritchie and Roser, 2018; WHO, 2018b). The increasing global burden of chronic diseases could, ironically, lead to greater demand for effective anti-infective medicines. Conditions such as cancer and diabetes weaken the immune system, increasing susceptibility to infection. Some surgery and cancer treatments require prophylactic antibacterials, which carry their own risks and trade-offs relating to development of resistance (Liss and Cornely, 2016; WHO, 2018a). The consequences of resistance for cancer and surgical treatments are also serious. By recent estimates 39 to 51 percent of surgical site infections in the United States are resistant to standard prophylactic antibiotics, as are about a quarter of infections after cancer chemotherapy (Teillant et al., 2015). Further reductions in the efficacy of prophylactic antibiotics, even a relatively modest decrease of 10 percent, could cause an additional 2,100 deaths a year in the United States alone (Teillant et al., 2015). Such figures are especially troubling in light of recent attention to the unmet global need for surgery. Around 60 percent of the world’s surgeries happen in high-income countries, home to less than 20 percent of population, while the third of the world living in the poorest countries account for only 6 percent of surgeries (Weiser et al., 2016). This disparity has tangible consequences. By 2015 estimates, almost a third of the global burden of disease has a surgical component, including the almost two-thirds of cancer patients who will need surgery and the roughly 15 percent of pregnant women who will need surgery to deliver safely (Meara et al., 2015; Shrime et al., 2015). The Lancet Commission on Global Surgery concluded that an additional 143 million surgeries a year are needed in low- and middle-income countries (Meara et al., 2015). A worldwide increase in surgery will carry an increasing risk of surgical site infections, a common form of hospital-acquired infection. Already infections at the surgical incision contribute to 4 million postoperative deaths a year (Allegranzi et al., 2011; Nepogodiev et al., 2019). In the United States, 2 to 4 percent of surgical patients may develop these infections (PSNet, 2019). Less can be said about the roughly 122 million surgeries that happen annually in low- and middle-income countries, though evidence indicates rates of surgical site infections to be much higher, affecting roughly 17 percent of surgical patients (Bhangu et al., 2018; Rickard et al., 2020; Stanley, 2020). The limited culture data available indicate that postoperative infections in low- and middle-income countries are also more likely to be drug resistant. Analysis of data from 66 countries found over 35 percent of surgical site infections in the least developed countries to be drug resistant (Allegranzi et al., 2011). Studies from teaching hospitals in Ghana and Egypt have found the majority of surgical site infections to be resistant to multiple drugs (Bediako-Bowan et al., 2020; Elsayed Sabal et al., 2017). Chronic disease patients also have more contact with the health system and more hospital stays. Resistant pathogens are common in hospitals and can spread easily, surviving in sink drains and on surfaces, occasionally spreading through the hospital staff or contact with medical equipment (CDC, 2019c). In the United States, non-susceptible pathogens, meaning those pathogens either resistant or not entirely susceptible to treatment, are most commonly acquired from contact with catheters, central lines, and ventilators (Weiner-Lastinger et al., 2020). CDC data on infections acquired in hospitals from devices indicate that almost half of Staphylococcus aureus are not susceptible to methicillin and over 80 percent of Enterococcus faecium are not susceptible to vancomycin (Weiner-Lastinger et al., 2020). Resistant pathogens are at least three times higher in hospitals in low- and middle-income countries than in United States, and PREPUBLICATION COPY: UNCORRECTED PROOFS

2-18 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE infections associated with hospital devices are up to 13 times higher (Allegranzi et al., 2011; WHO, 2015a). The Risk Resistant Pathogens Pose to Children Increasing resistance has consequences for everyone, described in more detail in Chapter 3. Resistant pathogens pose some of their most serious threats to children. The combination of immature immune systems and frequent, repeated exposure to viruses and bacteria makes children more vulnerable to infections (WHO, 2020c). Despite marked declines over the past 30 years, infectious diseases are still among the leading causes of death for children under 5 worldwide, including over 800,000 deaths from pneumonia and over 500,000 from diarrhea (Dadonaite, 2019; WHO, 2020b). Sepsis, a life-threatening and dysregulated response to infection, is especially dangerous to children as their symptoms may be hard to recognize and their deterioration rapid (Plunkett and Tong, 2015; Singer et al., 2016b). Children under age 5 account for almost half of the world’s roughly 49 million sepsis cases a year and about a quarter of all sepsis deaths (Rudd et al., 2020). Neonatal infections are often caused by drug-resistant pathogens (Folgori et al., 2017; Laxminarayan et al., 2016). Roughly 214,000 neonates die from resistant, septic infections every year (Laxminarayan et al., 2016) (see Figure 2-5). Of particular concern for newborns are the gram-negative infections that are difficult to treat for reasons described in Box 2-3 (Folgori et al., 2017). Enterobacterales, the order of gram-negative bacteria that includes pathogens such as Escherichia coli and Klebsiella spp., are adept at sharing genes and developing resistance, and are a major threat to neonates (CDC, 2019d; Folgori et al., 2017; Partridge, 2015). Enterobacterales-producing extended-spectrum beta-lactamase (ESBL), an enzyme that conveys resistance to the beta-lactam family of antibiotics, are increasingly common in neonates, both in hospitals and in the community (Folgori et al., 2017; Stapleton et al., 2016). Studies in Asia, South America, and the Middle East have found ESBL-producing bacteria in a majority of neonatal sepsis patients (Folgori et al., 2017). More recent research in seven low- and middle income countries indicates ampicillin-gentamicin is no longer an effective treatment for neonatal sepsis because of high rates of resistance (Thomson et al., 2021).3 3 Bangladesh, India, Pakistan, Ethiopia, Nigeria, Rwanda, and South Africa. PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-19 FIGURE 2-5 Estimated neonatal sepsis deaths caused by bacteria resistant to first-line antibiotics in five high-burden countries, estimates with maximum and minimum values from Latin Hypercube Sampling. SOURCE: Laxminarayan et al., 2016. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-20 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE BOX 2-3 The Challenge of Treating Gram-Negative Bacteria The description of bacteria as gram negative or gram positive refers to the results of a laboratory staining test called the Gram stain. Differences in the structure of the bacterial cell wall cause bacteria either to retain a crystal violet dye (gram positive) or be decolorized and retain a pink color upon treatment with a counterstain (gram negative). Although not all bacteria fall clearly into one of these two groups, Gram stain is traditionally the first step in identifying a bacterial pathogen. Four of the six most problematic, multidrug resistant pathogens found in hospitals (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are gram-negative bacteria. As the figure below shows, gram-negative bacteria have less permeable cell walls than gram-positive ones. Gram-negative bacteria have an envelope made up of three layers: a phospholipid outer membrane, a rigid, peptidoglycan cell wall, and an inner phospholipid membrane. The outer membrane of gram-negative bacteria provides crucial protection and acts as a selective barrier that can restrict access of certain antibiotics into the cell, providing intrinsic resistance to antibiotics that target processes within the cell. Gram-negative bacteria can also produce enzymes that can degrade the antibiotic or modify its shape to inactivate it (e.g., beta- lactamases inactivate the beta-lactam antibiotics). The cell envelopes of gram-negative bacteria also contain efflux pumps, structures that remove toxins, including antibiotics, from the bacteria. By removing antibacterial agents from the cell, drug efflux raises the concentrations of these agents in their vicinity, thereby reducing the growth of commensal bacteria, and triggering a shift in the composition of the bacterial community, with more resistant bacteria dominating in only a few generations. SOURCE: Mahadevia, 2017. SOURCES: Breijyeh et al., 2020; Bush and Bradford, 2020; Delcour, 2009; Ramirez et al., 2014; Soto, 2013; Wen et al., 2018. PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-21 Prompt treatment with effective antimicrobials could avert hundreds of thousands of child deaths every year. Pneumonia deaths alone could be reduced 75 percent, meaning over 400,000 deaths averted among children under 5 every year (Laxminarayan et al., 2016). Yet access to these medicines is uneven. Survey data from health posts, hospitals, and dispensaries in 20 low- and middle-income countries indicate even Access Group antibiotics are available less than half the time, most of that driven by fairly reliable stocks of only three drugs: co- trimoxazole, amoxicillin, and metronidazole (Knowles et al., 2020) (see Figure 2-6). FIGURE 2-6 Antibiotic availability at health facilities, survey data from 20 low- and middle-income countries, 2014–2017. SOURCE: Knowles et al., 2020. ANTIMICROBIAL RESISTANCE IS A COMPLEX ADAPTIVE PROBLEM Antimicrobial resistance is complex. It is a health and, less obviously, an environmental problem. It affects everyone, both today and in the future in a, “shared, interdependent PREPUBLICATION COPY: UNCORRECTED PROOFS

2-22 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE vulnerability … that will have a substantial impact on all aspects of our lives” (Littman et al., 2020). A global health response will be central to any mitigation strategy, but it is difficult to find transferable strategies from other global health problems, as antimicrobial resistance is not the result of any one pathogen or casual process, but a complex web of related problems, sometimes related only loosely (Hoffman et al., 2020). The dynamic relationships among different nodes on this web mean that action in one setting can reverberate in another in ways that are not direct or linear. This feature of the problem is sometimes described as an adaptive challenge (Hinchliffe et al., 2018; Pham, 2017). Because of the adaptive challenge, it is difficult to predict how resistance will emerge, despite wide agreement that global changes will influence both antimicrobial use and resistance (Lambraki et al., 2021). The inappropriate or irrational use of antimicrobials in human medicine is often the first feature of this complex adaptive problem to attract policy attention. Antimicrobial use in farming, especially animal agriculture and aquaculture, is another common point of discussion, though the ramifications for the price of food and livelihoods of farmers are less well studied (FAO, 2017; Hinchliffe et al., 2018). But there is relatively little known about the economic and ecological impact of antimicrobials that leach into the environment through water and soil contamination. Box 2-4 gives an example of how disruptions to the microbiome in a species of ecological importance may have serious downstream ramifications, even among species not generally referenced in discussions of antimicrobial resistance. PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-23 BOX 2-4 The Ecosystem Value of the Oyster Microbiome Ecosystem services is a way of describing the benefits, both direct and indirect, humans draw from their interactions with the ecosystem. These services can be tangible (e.g., wood, food) or intangible (e.g., recreation, spiritual experiences). They can be basic, underlying processes that sustain systems such as nutrient cycling and photosynthesis, or the benefits humans accrue from the processes that make the environment clean, sustainable, and resilient. The ability of oysters to remove nitrogen from coastal waters is an example of the last type of ecosystem service. Shellfish, especially oysters, are a keystone or foundational species in coastal ecosystems, meaning that they influence the environment in ways that allow other species in the ecosystem to survive. With the exception of their harvest for food, most of the services oysters provide do not have an obvious dollar value. Attempts to quantify the value of the ecosystem services oysters provide have to consider a range of factors including their filtering sediment and plankton, allowing light to penetrate further into the water, aiding the growth of aquatic plants, and the influence of oysters and their reefs in protecting other fish species. Such analyses have put the value of ecosystems services oysters provides between $55,000 and $99,000 per hectare per year. One of the valuable ecosystem services oysters provide is denitrification, the process of converting dangerous waste into a harmless gas. Denitrification by oysters is bacterially mediated, meaning that the microbiome in oysters’ gut and shell drive the process. Antimicrobial residuals and other pollutants in wastewater and agricultural runoff disrupt these microbiomes. A decrease in colonization with beneficial bacteria and a rise in the concentrations of pathogenic bacteria poses a threat not just to oysters, but to the entire ecosystem they support and the humans who consume them. No economic analysis to date has looked at these distal, but potentially devastating, consequences. SOURCES: Arfken et al., 2017; Britt et al., 2020; Grabowski et al., 2012; NWF, 2021; Schug et al., 2009. As the concentration of antimicrobials in water and soil increases, so does the likelihood of encountering resistant microbes. Horizontal gene transmission, working against a background of increasing selection pressure and microbial diversity, increases the chances of a microbe acquiring resistance (Knapp et al., 2010). In this regard, susceptibility of pathogens to antimicrobial medicines, most of them descendants of soil bacteria, is a natural resource. The erosion of this resource is to some degree inevitable, but its rate is not. The challenge remains to preserve susceptible microbial communities that benefit the ecosystem (Jørgensen et al., 2018). The introduction of new medical products, both to avoid unnecessary use and replace ineffective medicines, will be central to any response strategy. So will a better understanding of the interrelatedness of resistance in human, animal, and environmental reservoirs (Jørgensen et al., 2018). An emphasis on new medicines and a multisectoral response to antimicrobial resistance was a feature of the O’Neill report, a 2-year expert review of rising antimicrobial drug resistance and policy recommendations to mitigate it (Review on Review on AMR). The final report, published in 2016, set out seven steps to reduce demand for antimicrobials, thereby prolonging PREPUBLICATION COPY: UNCORRECTED PROOFS

2-24 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE the useful life of the medicines available today, and two further steps to increase the supply of new antimicrobials (Review on Review on AMR). The O’Neill report encouraged global interest in the problem of antimicrobial resistance (Collier and O’Neill, 2018; SfAM, 2018). Its call for the attention of the United Nations (UN) and the G7 and G20 forums resulted in antimicrobial product development partnerships such as the Global Antibiotic Research and Development Partnerships and CARB-X (officially, the Combating Antibiotic Resistance Biopharmaceutical Accelerator) discussed in Chapter 6, and the UN High-Level Meeting on Antimicrobial Resistance (Evans, 2017; UN, 2016a). At this meeting the UN General Assembly called for wide support for national action plans for antimicrobial resistance and for coordinated action at the global, regional, and national levels (UN, 2016b). At the same time, progress against most of the O’Neill commission’s recommendations has been partial at best (Collier and O’Neill, 2018). As with other complex adaptive problems, change can be slow and progress difficult to measure. ONE HEALTH IS A COMPLEX ADAPTIVE RESPONSE Response to the global health problem of antimicrobial resistance needs to consider the relationships among human, animal, and plant health, and the role of the environment as a source and conduit of resistance. This mutual dependence is central to the One Health approach, a way of working on health problems at the interface of human, animal, and environmental health (CDC, 2018b). The One Health movement has its roots in recognition of the intermeshed vulnerabilities of animals and humans (McEwen and Collignon, 2018). One Health adds attention to the environment, acknowledging the equal importance of the environmental health and natural resources to human and animal health problems (McEwen and Collignon, 2018). The environmental component of antimicrobial resistance includes not only the watershed and soil management of drug residues and resistance genes, but the likelihood that climate change will aggravate the problem. Historical data strongly suggest a relationship between an increasing burden of antibiotic resistance and an increasing average temperature (MacFadden et al., 2018). The mechanism driving this relationship is not clear, but may be related to increasing horizontal gene transfer (including transfer of resistance genes) at higher temperatures (Burnham, 2021). Higher temperatures are also a key predictor of bacterial growth rates and are therefore thought to drive an increased bacterial carriage in both humans and animals (Burnham, 2021). Research on resistant isolates collected in Europe over 16 years found ambient temperature to be the most important contributor to the emergence of resistance (McGough et al., 2020). Average minimum temperature and population density are associated with an increasing percentage of resistance among common pathogens (MacFadden et al., 2018). While rising temperature and water levels have a role in encouraging resistance, it is also likely that more complicated social factors related to climate change are driving antimicrobial pollution in the environment. As the climate warms, for example, the atmosphere retains more water, causing more severe storms and flooding. Floods in turn, displace people, increasing crowding and infections, and bring more humans and livestock into contact with contaminated sewage (Burnham, 2021). Ripple effects of climate change will aggravate the crowding and sanitation problems that cause diseases such as tuberculosis, cholera, and dengue (McMichael et al., 2003; Murray et al., 2020). Increasing temperatures and rainfall will influence the survival, breeding, and biting rates of mosquitoes and other arthropod vectors of disease (Franklinos et al., 2019; McMichael et al., 2003). All of these changes will cause a great demand for effective PREPUBLICATION COPY: UNCORRECTED PROOFS

THE SCOPE OF THE PROBLEM 2-25 antimicrobial medicines, medicines that are themselves in jeopardy, partly for the same root reasons. Antimicrobial resistance is a textbook One Health problem (Mackenzie and Jeggo, 2019; Robinson et al., 2016). Because of the rapid spread of microbes internationally it has also been described as a “One World” problem (Mackenzie and Jeggo, 2019; Robinson et al., 2016). It is a priority item in the World Bank’s One Health Operational Framework (Berthe et al., 2018). Most national and international strategy documents for action against antimicrobial resistance, including the U.S. government’s national strategy and action plans for combating antibiotic- resistant bacteria, emphasize the importance of an integrated, cross-sector, One Health response (CARB, 2020; PCAST, 2015; White and Hughes, 2019). Nevertheless, the capacity to put One Health principles into practice tends to lag the realization of their importance (Mackenzie and Jeggo, 2019; Queenan et al., 2017; Sinclair, 2019). It can be difficult to bring experts from different agencies or disciplines together, especially when there are competing needs and trade-offs to be made among the different sectors (Lhermie et al., 2019b; Robinson et al., 2016). At the same time, without joint ownership and shared intellectual effort that One Health affords, some perspectives will be pushed to the margin (Waltner-Toews, 2017). A One Health response may be complicated, but is an unavoidable reflection of the complexity of the problem. One Health gives a style of analysis well suited to complex and adaptive systems. The nature of the collaboration recognizes the interrelationships between humans, animals, and the environment (Complex adaptive systems, 2010). Though sometimes cumbersome, such collaboration can help ensure communication among all stakeholders (Waltner-Toews, 2017). REFERENCES Aarestrup, F. M. 2015. The livestock reservoir for antimicrobial resistance: A personal view on changing patterns of risks, effects of interventions and the way forward. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 370(1670):20140085. Aga, D., J. Davies, S. Gandra, B. Kasprzyk-Hordern, J. Larsson, J. McLain, A. Singer, J. Snape, H. Slijkhuis, and A. Sweetman. 2018. Initiatives for addressing antimicrobial resistance in the environment: Current situation and challenges: Wellcome; The U.S. Centers for Disease Control and Prevention; The UK Science and Innovation Network. Agriculture.com Staff. 2018. Feeding medicated chicken feeds. https://www.agriculture.com/livestock/poultry/feed/medicated-chicken-feeds_292-ar13577 (accessed September 10, 2021). Allegranzi, B., S. Bagheri Nejad, C. Combescure, W. Graafmans, H. Attar, L. Donaldson, and D. Pittet. 2011. Burden of endemic health-care-associated infection in developing countries: Systematic review and meta-analysis. Lancet 377(9761):228-241. Almeida, F., M. L. Rodrigues, and C. Coelho. 2019. The still underestimated problem of fungal diseases worldwide. Frontiers in Microbiology 10:214. Alvarez-Uria, G., S. Gandra, and R. Laxminarayan. 2016. Poverty and prevalence of antimicrobial resistance in invasive isolates. International Journal of Infectious Diseases 52:59-61. Alzahrani, M. S., M. K. Maneno, M. N. Daftary, L. Wingate, and E. B. Ettienne. 2018. Factors associated with prescribing broad-spectrum antibiotics for children with upper respiratory tract infections in ambulatory care settings. Clinical Medicine Insights: Pediatrics 12:1179556518784300. Arfken, A., B. Song, J. S. Bowman, and M. Piehler. 2017. Denitrification potential of the eastern oyster microbiome using a 16s rrna gene based metabolic inference approach. PloS One 12(9):e0185071. PREPUBLICATION COPY: UNCORRECTED PROOFS

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THE SCOPE OF THE PROBLEM 2-39 Zhu, Y. G., Y. Zhao, B. Li, C. L. Huang, S. Y. Zhang, S. Yu, Y. S. Chen, T. Zhang, M. R. Gillings, and J. Q. Su. 2017. Continental-scale pollution of estuaries with antibiotic resistance genes. Nature Microbiology 2(4):16270. PREPUBLICATION COPY: UNCORRECTED PROOFS

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Antimicrobial resistance is a health problem that threatens to undermine almost a century of medical progress. Moreover, it is a global problem that requires action both in the United States and internationally.

Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine discusses ways to improve detection of resistant infections in the United States and abroad, including monitoring environmental reservoirs of resistance. This report sets out a strategy for improving stewardship and preventing infections in humans and animals. The report also discusses the strength of the pipeline for new antimicrobial medicines and steps that could be taken to bring a range of preventive and therapeutic products for humans and animals to the market.

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