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Suggested Citation:"Summary." 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:"Summary." 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:"Summary." 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 3
Suggested Citation:"Summary." 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 4
Suggested Citation:"Summary." 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 5
Suggested Citation:"Summary." 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 6
Suggested Citation:"Summary." 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:"Summary." 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:"Summary." 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.
×
Page 9
Suggested Citation:"Summary." 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.
×
Page 10
Suggested Citation:"Summary." 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.
×
Page 11
Suggested Citation:"Summary." 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.

Summary1 The COVID-19 pandemic has forced society to confront human vulnerability to microbial pathogens (including viruses, bacteria, parasites, and fungi) in a way that has not been necessary in much of the world for a century. Before the mass production of penicillin in the 1940s, deaths from bacterial infections were common, elevating the risk not only of common illnesses such as pneumonia, but also that associated with surgery and other lifesaving procedures and even life events such as childbirth. The extent to which antimicrobial medicines changed these risks, though hard to overstate, is easily taken for granted. As these medicines have been used, sometimes overused, microbes’ resistance to them has grown, threatening to undermine almost a century of health gains. Microbes are constantly responding to selective pressures, including the pressures from antimicrobial medicines. One response is a classic, Darwinian evolution wherein beneficial traits are passed from one generation to another. Microbes can also pass genes to unrelated organisms through proximity or by way of mobile genetic elements. Such horizontal gene transfer allows traits to pass quickly within microbial communities. The genetic adaptability of microbes contributes to the emergence of resistance, compelling careful attention to human actions that aggravate the problem. Efforts to mitigate the emergence and spread of resistant pathogens are complicated by the fact that antimicrobial resistance is notoriously difficult to measure. Although most obvious in human health, resistance emerges in animal health and in the environment. Marshalling response to such a problem requires cooperation at many levels. In the United States, the 2014 National Strategy for Combating Antibiotic-Resistant Bacteria (hereafter, the national strategy) sets out a plan for government work to mitigate the emergence and spread of antimicrobial resistance. Direction on the implementation of this strategy is provided in 5-year national action plans, the first for the period from 2015 to 2020, the second covering 2020 to 2025. In 2019, Congress directed the National Institute of Allergy and Infectious Diseases (NIAID) to support a consensus committee study under the auspices of the National Academies of Sciences, Engineering, and Medicine to examine progress against the national strategy. NIAID staff, in collaboration with their counterparts at other government agencies implementing the national action plans, developed a charge for this committee. This charge includes questions on managing effective surveillance for infections related to antimicrobial resistance, measuring the health and economic consequences of antimicrobial resistance, interventions in animal health, and the incentives for developing new medical products to prevent and treat resistant infections. 1 References are not included in the Summary. For the full list of the works cited view the body of the report. S-1 PREPUBLICATION COPY: UNCORRECTED PROOFS

S-2 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE THE SCOPE OF THE PROBLEM Use of antimicrobial medicines in both human and animal health drives antimicrobial resistance. Clinicians may prescribe antimicrobial medicines empirically, based on their best judgement of a patient’s presentation, but without precise diagnostic information on the organism causing the infection. Empiric treatment often involves broad-spectrum drugs active against a range of pathogens. Such drug use creates selective pressure that encourages resistance and leaves patients vulnerable to other illnesses. Antimicrobial treatment in both humans and animals ideally uses the most narrow, focused agent for the shortest effective duration. Narrowing antimicrobial treatment can be challenging in animal agriculture, where the distinction between prophylactic and therapeutic treatment is not always clear. Infections can spread quickly through a flock or herd, so when one animal is diagnosed with an infection, prophylactic treatment of others in the group may control spread. Mass medication of mostly healthy animals accounts for 90 percent of veterinary antimicrobial use in some places. Adequate biosecurity measures, good husbandry, and other practices used in modern animal production systems can greatly reduce—sometimes eliminate—the need for antimicrobials in animal agriculture. Vaccines and other preventive tools are important alternatives to antimicrobials, but there is a shortage of efficacious and affordable vaccines for animals. Antimicrobial resistance is a global health problem, or, more accurately, a web of related problems. The relationships between different nodes on this web are always changing making it difficult to predict how actions in one setting will affect outcomes in others, a feature of the problem sometimes described as the adaptive challenge. Adaptive challenge makes it difficult to predict where and in what pathogen–drug combinations resistance will emerge. The mutual dependence of human and animal health and the health of the environment is central to the One Health approach. A One Health analysis is well suited to the problem of antimicrobial resistance as it requires an interdisciplinary, multisectoral collaboration. It includes attention to the often-neglected environmental dimension of resistance, especially important in light of climate change, which will almost certainly aggravate the problem THE HEALTH AND ECONOMIC BURDEN OF RESISTANCE In response to the charge to examine the long-term health and economic effects of antimicrobial resistance, the committee reviewed a cross-section of recent literature. First was the Centers for Disease Control and Prevention’s (CDC’s) Antibiotic Resistant Threats in the United States 2019, which drew on population surveillance and research from electronic medical records to estimate that every year 2.8 million resistant infections in the United States cause 35,900 deaths, with Clostridioides difficile infection killing another 12,800 people. The CDC report also attempted to put some economic parameters on the problem, estimating the direct costs of treating six, common, multidrug-resistant pathogens at $4.6 billion a year, with C. difficile adding another $1 billion and drug-resistant gonorrhea adding another $133.4 million. The Organisation for Economic Co-operation and Development (OECD) Health Committee, in collaboration with the European Centre for Disease Prevention and Control, has also given considerable attention to estimating the future health and economic burden of antimicrobial-resistant infections. Their reports estimate that the United States and Europe PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-3 together account for about 60,000 deaths a year from resistant infections, with 1.75 million years of healthy life lost every year across 33 of the OECD countries. The same infections could cost the health systems of these countries about $3.5 billion a year. There are challenges in measuring morbidity and mortality associated with resistant infections. Most outcomes research is limited to readily observable, short-term clinical outcomes (e.g., deaths, number of days hospitalized). The downstream consequences of resistant pathogens are harder to predict. Without effective alternatives and enhanced infection control, removal of antimicrobials from animal agriculture could increase animal disease burden and mortality, leading to compromised animal welfare and productivity losses, with potential downstream effects on food security and livelihoods. Better estimates of the burden of antimicrobial resistance in humans and animals depend on better microbiological data and more clarity on the appropriate design of epidemiological research. There are also challenges related to the complex adaptive nature of the problem. The same resistant infection can have drastically different consequences in humans and animals, depending on whether it is acquired in hospital or outside of it, in a high-income country or a low-income one. STRENGTHENING SURVEILLANCE Surveillance systems are critically important for understanding the burden of antimicrobial resistance, detecting the emergence and spread of resistant pathogens, targeting interventions, and measuring their effectiveness. In an effort to improve global surveillance for antimicrobial resistance, the World Health Organization developed the Global Antimicrobial Resistance and Use Surveillance System (GLASS), which provides information technology, standards, and tools for the surveillance of priority bacterial infections in humans. Private industry, academic researchers, and various disease-specific programs also collect information about resistance and are useful sources of complementary data to inform estimates of the burden of the antimicrobial resistance. One commonly used tool to monitor resistance patterns is the antibiogram, a profile of phenotypic susceptibility test results drawn from aggregate data. Antibiograms are useful for monitoring trends in resistance to different drugs and are invaluable in both clinical medicine and surveillance. At the same time, since antibiograms do not give information into the mechanisms of resistance, they cannot be used to predict resistance patterns. The National Center for Biotechnology Information (NCBI), a division of the National Library of Medicine (NLM) at the National Institutes of Health (NIH), has made public considerable information about resistance genes, genome sequences, antimicrobial susceptibility data, and bacterial genomes. The committee commends NCBI for this work. At the same time, valuable information about phenotypic antimicrobial susceptibility is generated in clinical laboratories all over the world. Collected and aggregated, this data could give valuable insight into trends in antimicrobial resistance. Recommendation 4-1: The National Library of Medicine (NLM) should establish an open-source, unified antimicrobial resistance database that integrates raw phenotypic data from national and international efforts. This database should support automatic importation from hospitals, laboratories, PREPUBLICATION COPY: UNCORRECTED PROOFS

S-4 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE and surveillance networks and linking to genotypic data when available. NLM should engage the Centers for Disease Control and Prevention, the U.S. Department of Agriculture, and other relevant stakeholders to determine the necessary data elements and confidentiality procedures. An automated data ingestion pipeline could take disparate formats of collected antimicrobial resistance data and, either by a simple set of translation rules or potentially using more advanced machine learning techniques, automatically format and deposit the data in a consistent fashion. Once an initial pipeline from the laboratory information system is established, data deposition from these devices could be almost fully automated. A standard data deposition form could also help new laboratories or regional laboratories that currently do not generate their own standardized antibiograms by providing a default template, contributing to standardized reporting across the United States and internationally. Increasing the environmental isolates collected by surveillance networks and stored in the proposed NLM database would contribute to a more holistic understanding of antimicrobial resistance. However, environmental monitoring of resistance is still limited. The challenge for environmental monitoring is to determine what factors amplify resistance genes in the environment and what factors encourage their transmission, possibly threatening public health. Some insight into the source of the resistance genes, resistant pathogens, or antimicrobial residues in the environment could come from analyzing the places contaminants enter water. Wastewater treatment plants are one such place, equipped to contain and remove water contaminants but not to eliminate resistance traits or drug residues. Treatment plants typically discharge directly to aquatic environments, making them an important bridge between human- made contamination and the natural environment. Recommendation 4-2: The Environmental Protection Agency should provide guidance and funding to states for testing point source discharge at wastewater treatment plants for antimicrobial resistance traits and integrating these data with other surveillance networks. STEWARDSHIP AND INFECTION PREVENTION Efforts to improve antimicrobial stewardship in human medicine often turn first to hospitals, as infections can spread quickly in hospitals and pose a serious threat to patients. Almost 90 percent of hospitals in the United States have programs that incorporate all seven of the CDC’s core elements of antimicrobial stewardship, up from only about 40 percent in 2014. Such rapid progress is heartening, but there are still many practice settings where the need for antimicrobial stewardship is pronounced. Nursing homes, dialysis centers, and long-term acute care hospitals all see considerable misuse and overuse of antimicrobials among patients who are, by definition, immunocompromised or infirm. Recommendation 5-1: The Centers for Medicare & Medicaid Services should require nursing homes, long-term acute care hospitals, and dialysis centers to have antimicrobial stewardship programs and include that information on PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-5 the Care Compare website. These programs should, at a minimum, designate key staff, a system for preauthorization of restricted antimicrobials, and a process for regular review of all antimicrobial prescriptions. Tailored antimicrobial stewardship programs may need to make use of telemedicine when infectious disease consultations are needed. Some modernization of record keeping may also be helpful in settings that do not routinely use electronic medical records, which could be used for preauthorization for restricted antimicrobials and to discourage treatment of asymptomatic infections. Including antimicrobial stewardship in the quality measures on the Care Compare website, a public clearinghouse for quality indicators, could help raise its prominence with facility administrators as well as with consumers and their families. Many of the basic principles of antimicrobial stewardship are the same in human and animal medicine, but the practice differs considerably. Veterinarians often work in relatively small practices; they also dispense medicines directly from their clinics, making the roles of both administrators and pharmacists, crucial in human stewardship programs, far less relevant. Partly for these reasons there is a greater emphasis on veterinarians’ individual responsibility to serve as stewards of antimicrobial medicines. The ability to track antimicrobial use is a key part of any stewardship program, but the United States does not have a strong system to track antimicrobial use in animals. The Food and Drug Administration (FDA) could promote better antimicrobial stewardship by investing in strategies to advance the use of electronic prescriptions and to encourage the sharing of prescription information currently held in proprietary hands. Recommendation 5-2: The Food and Drug Administration’s Center for Veterinary Medicine should establish a process and clear metrics to facilitate better tracking of antimicrobial consumption in animals. This information would support the design and implementation of stewardship programs. Challenges in using diagnostic tests can stand in the way of good stewardship. There are logistical barriers to testing animals, especially large animals, and a testing expense that the animal owner usually pays out of pocket. A lack of susceptibility test breakpoints specific to the species tested is another barrier. The ability to develop new susceptibility test breakpoints depends on collecting and creating pharmacokinetic and pharmacodynamic data for different drugs in different species and on convening experts to review and interpret these data. Despite agreement that more animal- specific breakpoints are needed, the time and expense of building the evidence needed to inform breakpoint analysis stand in the way. Therefore, development of needed breakpoints has not kept pace with the demand for them, especially in light of increasing emphasis on antimicrobial stewardship in veterinary medicine. Recommendation 5-3: The Food and Drug Administration’s Center for Veterinary Medicine should convene an advisory committee to coordinate development of antimicrobial susceptibility test breakpoints in animals and identify priority animal, drug, and pathogen combinations. When necessary, PREPUBLICATION COPY: UNCORRECTED PROOFS

S-6 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE the Center for Veterinary Medicine would fund the research needed to develop the priority breakpoints. Choosing priorities for breakpoint development from among the many combinations of pathogen, drug, and animal species of interest should be done in a more deliberate way, with more open communication among clinicians, diagnostics laboratories, standards organizations, and academic researchers. Attention from the FDA could help make veterinary susceptibility testing less ad hoc, but after setting out the priority bug, drug, and species combinations there will still be a need for pharmacokinetic and pharmacodynamic data to establish the needed breakpoints. By designating funding for this research, the agency could remove another major barrier to better antimicrobial stewardship in animals. Appropriate diagnostic testing could reduce inappropriate antimicrobial use in human medicine as well. But the value of diagnostics, especially in terms of changes in patient outcomes such as morbidity and length of hospital stay, or financial outcomes such as cost of treatment or repeated office visits, are not usually readily apparent. Evidence of this value could inform clinical guidelines that emphasize diagnostic testing and are a step toward reimbursing the full value of the tests. Recommendation 5-4: The Department of Health and Human Services agencies, including the Centers for Disease Control and Prevention, the Food and Drug Administration, and the Centers for Medicare & Medicaid Services, and the Patient-Centered Outcomes Research Institute should support outcomes research in diagnostic testing to drive an iterative process of guidelines development and to influence reimbursement for diagnostic testing. Evidence establishing the value of diagnostics will be challenging to generate. It will depend on enrollment of patients at multiple clinical sites, as the inferences made from aggregate, multisite data are more generalizable and better able to detect small but meaningful differences. Vaccines have the potential to reduce the need for antimicrobials and control the spread of antimicrobial resistance. Despite a plausible reason to suspect that vaccination could reduce antimicrobial use and control the emergence and spread of resistant bacteria, the relationship is not well studied. Incorporating questions about antimicrobial use or resistance into ongoing vaccine trials could yield valuable information on this question with relatively little additional effort or expense. Recommendation 5-5: The National Institutes of Health and the Centers for Disease Control and Prevention should provide supplemental research funding to track antimicrobial use and antimicrobial resistance in immunization trials and large cohort studies to measure the indirect benefits vaccines provide and to provide evidence to enhance vaccine deployment as a tool to mitigate antimicrobial resistance. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-7 Better quality evidence, ideally from randomized, controlled trials could clarify the relationship between vaccine use, antimicrobial consumption, and the emergence of resistance and the multiple, often complex relationships among them. Better clarity on the full public health value of immunization could help inform wider vaccine uptake, especially in low- and middle- income countries. BRINGING NEW PRODUCTS TO MARKET AND ENSURING THEIR REACH Treating resistant infections depends on new antimicrobials, and the challenges of bringing these drugs to market is at the center of much public discourse. At the same time, new antimicrobials are not the only innovative products needed. Society would benefit from an integrated investment across different product types, some preventive and some therapeutic, for human and animal medicine. The medicines needed to treat resistant infections are complicated to develop and have a relatively small market both in terms of duration of use, usually only a few days, and need. Although there are over 2.8 million resistant infections every year in the United States, infections with any one resistant pathogen are relatively rare. When new antimicrobials are brought to market, good stewardship requires that older drugs be used first, even if there were no difference in price. There is, therefore, a mismatch in society’s need for new antimicrobials and industry’s willingness to invest in them. The government invests in drug development to help fill this gap, offering different programs working at different places on the development pipeline. Push incentives work early in this pipeline, aiming to reduce the cost of research and development by spreading those costs among many interested parties. Early grant funding is a push incentive as are various government programs that make information about resistant organisms more available to researchers. Other push incentives fund preclinical and early clinical trials. The NIH and the Biomedical Advanced Research and Development Authority (BARDA) provide considerable support for preclinical and clinical trials, both directly and through the public–private partnership Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X). In general, these and other push incentives have direct benefits to the drug developers and broad, indirect benefits to society. Preclinical and early clinical research is also the riskiest stage of drug development and may therefore be the most appropriate place for public spending. Pull incentives, on the other hand, reward successful drug development. The 2012 Generating Antibiotic Incentives Now (GAIN) Act, for example, provides additional years of market exclusivity to new drugs designated as “qualified infectious disease products” and revisions to the amount CMS will reimburse hospitals for new antimicrobials. On the whole, the package of push and pull incentives in place appears to have improved the number of products in the antimicrobial drug pipeline by about 10 percent between 2014 and 2019. Over this time, the FDA approved 20 new antimicrobial drugs, 12 of them under priority regulatory review afforded as qualified infectious disease products. While this is a promising development, most of these products and the others in the pipeline do not appear to be meaningfully different from existing medicines. Only 6 of the 50 antibacterials currently in the pipeline meet even one criteria for being innovative. Most of the antimicrobials approved recently offer little to no added clinical value over existing treatments. Market entry rewards between $500 million and $2 billion are often suggested as an incentive to develop an innovative antimicrobial that, for logistical and public health reasons, PREPUBLICATION COPY: UNCORRECTED PROOFS

S-8 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE will not likely sell well. These estimates appear to be based on the assumption that large pharmaceutical companies will not enter the market for profitability below $50 to $500 million, expectations based on blockbuster drug sales. But average peak-year drug sales have decreased by 50 percent since 2010. Given such trends, it may be more prudent to benchmark reward payments to market averages, thereby reducing the likelihood of over incentivizing and inciting rent seeking. Market entry rewards require significant investment of taxpayer dollars. Before funding any market entry reward, the government needs to be clear that it is rewarding a truly novel and useful antimicrobial. Recommendation: 6-1: A Department of Health and Human Services (HHS) interagency committee should establish well-targeted, objective criteria to identify novel antimicrobials with high potential for filling a critical, unmet need. HHS should then support trials to establish the additional clinical benefit and optimal use of these drugs. The proposed committee would serve as an arbiter on what constitutes an unmet need. This strategy would also provide public funding for the trials that establish clinical value, a major incentive for drug developers as such trials are costly to run. Challenges Related to Diagnostic Testing When clinical microbiology laboratories cannot test the susceptibility of a pathogen to a new antimicrobial, clinicians may not feel comfortable prescribing it, seriously limiting the use of the new medicine. There are multiple barriers to susceptibility testing for new antimicrobials. Integrating a new antimicrobial on automated testing systems is one of these barriers, as most hospitals in the United States use only automated methods for susceptibility testing. Adding a new antimicrobial to an automated susceptibility test plate means removing another drug and forfeiting the associated diagnostic information. Balancing the need for a new test that will be used infrequently against older ones that may be used more is a difficult question for the device companies. The companies must also regularly re-evaluate the time needed to bring a new test through regulatory review against obligations to support changes for drugs already in wide use. As antimicrobial resistance continues to emerge, breakpoint changes will only be needed more frequently. Every investment in keeping automated testing devices up to date is an investment in keeping clinical practice more responsive to antimicrobial resistance and protecting public health. Recommendation 6-2: To reduce regulatory hurdles in bringing automated susceptibility tests to market, the Food and Drug Administration should coordinate the review of new antimicrobials with the review of their automated susceptibility tests and work with the Clinical Laboratories Standards Institute to issue and update breakpoints for microbe–drug combinations. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-9 Ideally, automated susceptibility testing devices would include new antimicrobials upon market entry and revised breakpoints for older drugs as they are approved. For logistical reasons the processes work sequentially, with the device application beginning after the new drug approval. Through cooperative work, the FDA and the manufacturers could likely find less restrictive, faster methods for validation studies. Congress could also defray the expense of bringing new automated tests to market with tax credits against clinical trial expenses. Recommendation 6-3: Congress should make automated susceptibility test manufacturers eligible for tax incentives to bring new automated susceptibility tests to market. There are also some antimicrobials that simply will not be suitable candidates for inclusion on automated test devices. For such drugs, manual testing will be necessary, and such testing is difficult for many laboratories. The CDC Antibiotic Resistance Laboratory Network (ARLN) can bridge this gap by providing testing through public health laboratories. There is room to improve on this valuable service by expanding the network’s capacity. Recommendation 6-4: The Centers for Disease Control and Prevention (CDC) should expand the capacity of the Antibiotic Resistance Laboratory Network by offering expedited, expanded susceptibility testing of all broad- spectrum antibiotics via certain CLIA–certified laboratories.2 The CDC should also promote this service to clinical laboratories. A One Health approach to product development takes a broad view of the need for new therapeutic and preventative products. Such a model is helpful in guiding countries’ support for products intended for animal agriculture, aquaculture, and the environment. The international product development partnerships put in place for COVID-19 have transferrable elements especially relevant to product development for other infectious threats. This is the ideal framework upon which to build a coordinated product development partnership for antimicrobial resistance, with coordinated action on the human, animal, and environmental fronts. Recommendation 6-5: The Department of Health and Human Services should establish a public–private partnership similar to ACTIV for antimicrobial resistance, bringing together the Biomedical Advanced Research and Development Authority, the National Institutes of Health, the U.S. Department of Agriculture, the Environmental Protection Agency, and the Department of Defense and interested academic, industry, and nonprofit organizations. The partnership would have working groups on diagnostics, alternatives to antibiotics, and prevention, with a goal of supporting a diversified and balanced portfolio of tools to reduce antimicrobial resistance using a One Health approach. 2 The Clinical Laboratory Improvement Amendments (CLIA) regulate testing and are required for laboratories handling human samples. PREPUBLICATION COPY: UNCORRECTED PROOFS

S-10 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE The program envisioned would streamline the U.S. government’s national investment on antimicrobial resistance. This model can help avoid duplication of effort both within the United States and internationally. There is also a need to balance investments in antimicrobial resistance across new medicines, diagnostics, and preventive products. Some products have considerable market potential that the private sector will recognize; not all product development needs the same level of government investment. Determining the right balance of investments across product types is challenging and would benefit from explicit public discussion of the sort a prominent public– private partnership could engender. THE NATIONAL ACTION PLAN FOR COMBATING ANTIBIOTIC-RESISTANT BACTERIA Action against antimicrobial resistance requires coordinated efforts across many branches of government. This collaboration is emphasized in the National Action Plan for Combating Antibiotic-Resistant Bacteria 2015–2020 (hereafter, the 2015 action plan) which provided agencies with a road map to meet the goals set out in the national strategy. In an effort to understand agencies progress against the goals, the committee commissioned an analysis from the Center for Infectious Disease Research and Policy (CIDRAP). This analysis, which relied on review of published progress reports and agency self- reports, found that 93 percent of the 230 assigned milestones were completed, the vast majority on time, and without serious duplication of effort. This is not entirely consistent with a 2019 evaluation from the Government Accountability Office (GAO) that indicated agencies faced understandable difficulties with overlapping responsibilities, and technical challenges in implementing the action plan. A reliance on process outcomes makes it easier to claim successes, but such process milestones will not necessarily translate into meaningful improvements in antimicrobial use or the spread of resistant pathogens. Both the 2015 national action plan and its more recent iteration for 2020 to 2025 have open-ended targets for which the responsible agency is not always clear. It is difficult to establish accountability in such cases. The committee supports the systematic tracking of activities and outcomes related to the milestones and goals presented in the 2020 action plan. Independent assessment of these goals and reporting of their related expenditures would facilitate a process of adaptive management and course correction when necessary. It would also help experts in the United States and abroad understand the best and most effective strategies to combat antimicrobial resistance. Recommendation 7-1: Congress should direct the Government Accountability Office (GAO) to conduct biennial evaluations of federal agencies’ progress toward meeting the goals of the 2020–2025 National Action Plan for Combating Antibiotic-Resistant Bacteria to ensure objective assessment of agencies’ activities. Congress and the GAO should consider ways to use their evaluations to direct course corrections when necessary. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-11 Congress can facilitate course corrections on complex government programs by designating the program as high risk. Adding federal action against antimicrobial resistance to the GAO High Risk List might bring welcome attention to the topic, especially in the face of uncertainty regarding how the COVID-19 pandemic will influence antimicrobial resistance. A ROLE FOR THE UNITED STATES IN COORDINATED GLOBAL ACTION The effectiveness of a national strategy to combat antimicrobial resistance will depend on global investment and sustained international engagement integrated across human, animal, and environmental health. Part of the challenge of responding to antimicrobial resistance is that, while the U.S. strategy and action plan, like most countries’ strategies and action plans, evoke a One Health grounding, putting it into practice is difficult. Ultimately, every implementing agency involved in the response to antimicrobial resistance has its own mandate and mission, and none of these is explicitly a One Health mission. The integration of surveillance data from human, animal, and environmental sources will be a critical component of a global strategy against antimicrobial resistance. The largest increases in antibiotic consumption over the past 2 decades, for both humans and livestock, have occurred in low- and middle-income countries. These countries also have a high burden of infectious disease and a growing demand for animal-source foods that could contribute to increased antimicrobial use. Serious international investment in combating antimicrobial resistance is both morally compelling and in the best interest of the United States. A national response proportionate to the size and scope of the threat would work across government agencies and in collaborative bilateral and multilateral relationships internationally. A program modelled on the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) may be best suited to this problem. Recommendation 8-1: Congress should expand the United States global engagement on antimicrobial resistance by (1) strengthening surveillance of resistant pathogens both by supporting existing, multilateral surveillance systems and by expanding U.S. agencies’ international surveillance programs; (2) reducing need for antimicrobials by broadening agencies’ work on infection prevention and antimicrobial stewardship in humans and animals; and (3) ensuring sustained leadership and critical evaluation by creating a Global Coordinator for Antimicrobial Resistance similar to the Global AIDS Coordinator. Any program or policy intended to combat antimicrobial resistance depends on a foundation of reliable information that surveillance networks supply, yet recent analysis has found surveillance and One Health integration to be common weak spots in countries’ antimicrobial resistance action plans. The United States could help build on the GLASS framework to give more attention to animal and environmental health surveillance. Good surveillance can, in turn, inform effective stewardship programs especially in resistance hotspots. By attacking root problems, such as crowding, contaminated water and food, lack of sanitation, and infection prevention, the U.S. government could do much to prevent the development of antimicrobial resistance abroad. PREPUBLICATION COPY: UNCORRECTED PROOFS

S-12 COMBATING AMR AND PROTECTING THE MIRACLE OF MODERN MEDICINE The ambitious global program envisioned in this recommendation will require coordination with an increasingly large group of stakeholders both in the United States and abroad. A designated national leader modelled on the Global AIDS Coordinator would be crucial to managing this coordination and efficient response. By supporting a truly systemic, One Health response, the recommended program may be able to drive progress on a range of health indicators, including, but not limited to, the burden of resistant infections. 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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