Antibiotic Resistance: Additional Federal Actions Needed to Better Determine Magnitude and Reduce Impact

Bacterial infections have become more difficult, and sometimes impossible, to treat due to antibiotic resistance, which occurs when bacteria develop the ability to defeat the available drugs designed to kill them. Concerns about rising rates of resistance to available treatment options prompted the federal government to create the 5-year National Action Plan in 2015. The plan called for federal agencies to strengthen surveillance, advance the development of diagnostic tests and new antibiotics, and slow the emergence of resistant bacteria, among other things.

GAO was asked to review federal efforts to address antibiotic resistance. This report examines federal efforts and challenges related to (1) surveillance of antibiotic resistance, (2) the development and use of diagnostic testing to identify antibiotic resistance, (3) the development of treatments for resistant infections, and (4) appropriate antibiotic use. GAO reviewed literature and agency documents; interviewed agency officials and health care industry, drug industry, and other stakeholders; and held a meeting of international and U.S. experts to obtain their views.

The precise magnitude of the problem of antibiotic resistance is unknown. The Centers for Disease Control and Prevention (CDC) has made progress in expanding surveillance of infections from certain antibiotic-resistant bacteria in the United States and abroad but faces several challenges.

Note: This figure tracks a type of carbapenem-resistant Enterobacteriaceae (CRE), which, according to CDC, is a “nightmare bacteria” resistant to nearly all available antibiotics. Shading indicates CDC confirmed the presence of these bacteria within that state in that year or a previous one.

CDC faces challenges in conducting surveillance for antibiotic resistance due to the limited data it is able to collect through various surveillance systems. For example, CDC's primary surveillance system for gonorrhea—which CDC classified as an urgent antibiotic resistance threat affecting over half a million patients annually—currently tracks only an estimated 1 to 2 percent of all U.S. cases and only in males. CDC has not fully evaluated the representativeness of the gonorrhea surveillance system's results. However, it could do so, for example, by comparing the trends in their limited sample population with trends it can establish in the overall U.S. population via additional studies. Such an evaluation could give CDC more confidence that the system's data accurately reflect national trends.

Federal agencies have taken steps to advance the development and use of diagnostic tests to identify antibiotic-resistant bacterial infections, but these efforts have limitations. For example, agencies have conducted some studies to establish whether testing can lead to positive health care outcomes, such as reduced rates of antibiotic-resistant infections. However, more such studies are needed, according to experts and agency officials. Without information to guide test usage, clinicians may not be able to select appropriate treatments for their patients. One reason for the insufficient number of studies is that Department of Health and Human Services (HHS) agencies that are in a position to conduct or fund such studies—such as CDC and the Biomedical Advanced Research and Development Authority—disagree about what each agency should do. By clarifying roles and responsibilities, HHS agencies could more effectively address the need for more studies. The resulting studies could help demonstrate the value of diagnostic tests for antibiotic resistance, potentially increasing their use and improving patient care.

Experts warn that the current pipeline of antibiotics in development is insufficient to meet the threat of resistance. Several challenges impede the development of new treatments for resistant infections, notably inadequate return on investment for drug companies largely due to low prices and a limited patient population for whom these treatments would be appropriate. While HHS and Department of Defense agencies have provided financial premarket incentives to support antibiotic research and development, experts, federal officials and antibiotic developers agree that more postmarket incentives are needed to overcome the economic challenges. Advisory groups, including a presidential advisory council, and others have called for new postmarket incentives and identified multiple options for their design, including market entry rewards and reimbursement reform (see figure). However, HHS has not developed a strategy to further incentivize development of new treatments for antibiotic-resistant infections, and it may need to request authority and appropriations to create and implement certain types of incentives. Until such incentives are developed, more drug companies may exit the antibiotic development sector, and the pipeline of new treatments may continue to decrease.

Federal agencies have made several efforts to promote the appropriate use of antibiotics across health care settings through antibiotic stewardship—giving patients the right antibiotic at the right time, in the right dose, and for the right duration. However, key challenges remain. For example, federal agencies require only certain types of health care facilities to implement stewardship programs. In addition, CDC is limited in its ability to monitor and improve appropriate antibiotic use, in part because providers are not generally required to report antibiotic use data to a centralized database. The 5-year National Action Plan for Combating Antibiotic-Resistant Bacteria (National Action Plan) calls for strengthening antibiotic stewardship and for the timely reporting of antibiotic use data across health care settings. An executive order directs an interagency task force—the Combating Antibiotic-Resistant Bacteria (CARB) Task Force, coordinated by HHS—to provide annual updates to the President on, among other things, plans for addressing any barriers to full implementation of the National Action Plan. However, in its progress reports covering the first 4 years of the National Action Plan's implementation, the task force did not identify plans to address barriers to expanding antibiotic stewardship programs or the collection of antibiotic use data. Until it does so, the government will not have reasonable assurance that it is fully implementing the National Action Plan and addressing antibiotic resistance.

GAO is making eight recommendations to strengthen the federal response to combating antibiotic resistance. HHS concurred with seven recommendations and did not concur with one. More details are provided on the next page.

In response to the findings presented in this Highlights, GAO recommends that:

CDC ensure that its evaluation of its surveillance system for antibiotic-resistant gonorrhea includes measures of the system's representativeness of the U.S. population;

HHS identify leadership and clarify roles and responsibilities to assess the clinical outcomes of diagnostic testing;

HHS develop a strategy to further incentivize the development of new treatments for antibiotic-resistant infections, including through the use of postmarket financial incentives;

HHS direct the CARB Task Force to include in its annual updates to the President plans for addressing any barriers preventing full implementation of the National Action Plan.

In addition, GAO is making four recommendations to address other CDC efforts in surveillance and reporting and to address FDA efforts in monitoring diagnostic tests.

HHS did not concur with the recommendation that it develop a strategy that includes the use of postmarket financial incentives to encourage the development of new treatments for antibiotic-resistant infections, citing its ongoing analysis to understand whether postmarket incentives should be included in such a strategy. GAO recognizes the complexity of this issue and maintains that this recommendation is warranted given that experts and others have called for additional postmarket incentives and the insufficiency of the current pipeline of new treatments for antibiotic-resistant infections.

or Mary Denigan-Macauley at (202) 512-7114 or deniganmacauleym@gao.gov .

Since the discovery of penicillin in 1928, many life-saving antibiotics have  been developed that have allowed previously incurable infections to be  easily treated. However, many types of infections have become more  difficult or impossible to treat as bacteria have developed resistance to  most—or, in some cases, all—currently available antibiotics. The Centers  for Disease Control and Prevention (CDC) considers antibiotic resistance  to be one of the greatest global public health threats of our time. In 2019,  CDC estimated that at least 2.8 million people get sick and at least  35,900 die each year from antibiotic-resistant infections in the United  States.

While bacteria naturally develop resistance to antibiotics over time, this  problem has been accelerated by the overuse and misuse of antibiotics in  human health, food animals, and the environment. The World Health  Organization (WHO) has warned that the world urgently needs to change  the way antibiotics are prescribed and used, and CDC has highlighted the  need for antibiotics to be used more appropriately—a concept called  antibiotic stewardship—to preserve their effectiveness and help slow the  development of antibiotic resistance. CDC officials noted that poor  infection control and limited communication between health care facilities  also contribute to the spread of antibiotic resistance. Furthermore, WHO  and others warned that the pipeline of antibiotics in development is  insufficient to tackle the growing threat of antibiotic resistance.  Additionally, diagnostic testing used to identify antibiotic-resistant bacteria  is not available for all bacteria of concern. These gaps may hinder the  correct diagnosis of antibiotic-resistant infections, which could delay  treatment with appropriate antibiotics, contribute to antibiotic overuse, and  impede overall surveillance efforts.

Recognizing the growing threat of antibiotic resistance, by Executive  Order No. 13676, September 2014, the President established the Task  Force for Combating Antibiotic-Resistant Bacteria (CARB Task Force),  co-chaired by the Secretaries of the Departments of Health and Human  Services (HHS), Defense (DOD), and Agriculture. In 2015, the CARB  Task Force issued the National Action Plan for Combating Antibiotic- Resistant Bacteria (hereafter referred to as the National Action Plan),  setting forth goals over 5 years to slow the development of resistant  bacteria, strengthen national surveillance efforts, advance the  development and use of diagnostic tests, and accelerate the development  of new treatments, among other things. Because of the severity of the  problem that antibiotic resistance presents for humans and the federal  government’s commitment to fight it, you asked us to provide information  on federal efforts to combat antibiotic resistance. This report examines  1.  CDC’s efforts to conduct surveillance of antibiotic resistance and any  challenges to these efforts;  2.  federal efforts to advance the development and use of tests for  3.  challenges to developing new treatments for antibiotic-resistant  infections and federal efforts to address the challenges; and  4.  federal efforts to promote the appropriate use of antibiotics and any  challenges that remain.

To address all four objectives, we reviewed relevant agency reports and  documents; interviewed officials from federal agencies, experts on topics  related to antibiotic resistance, and representatives from stakeholder  organizations; reviewed relevant laws, regulations, policies, literature, and  GAO reports; and attended two national conferences. We focused our  review primarily on agency actions since 2015, when the National Action  Plan was published. We also focused our review on human health, as we  have reported on federal efforts to address the use of antibiotics in food  animals and recommended actions to improve these efforts for more than  20 years. Additionally, we focused our review on antibiotic-resistant  bacteria. Finally, we generally excluded federal efforts related to infection  prevention and control in human health care, on which we have  previously reported.

We interviewed officials from federal agencies responsible for  implementing the aspects of the National Action Plan related to our  objectives: HHS’s Office of the Assistant Secretary for Planning and  Evaluation, the Biomedical Advanced Research and Development  Authority (BARDA), CDC, the Centers for Medicare & Medicaid Services  (CMS), the Food and Drug Administration (FDA), the National Institutes of  Health (NIH), and the Office of Global Affairs; as well as DOD and the  Department of Veterans Affairs (VA). We also interviewed experts and  representatives from organizations involved in public health and  epidemiology, infectious diseases and microbiology, antibiotic research  and development (R&D), antibiotic stewardship, and other issues relating  to antibiotic resistance. Because antibiotic resistance is a global problem,  we also interviewed officials from WHO and other international entities.  We identified experts and organizations through literature and other  documents we reviewed and through referrals from agency officials and  other experts we interviewed. In addition, in September 2018, with the  assistance of the National Academy of Sciences, we convened a meeting  of experts in antibiotic resistance epidemiology, diagnostic testing,  antibiotic development, and antibiotic stewardship. (In this report, we refer  to such experts as “experts at our meeting.”) For each of our objectives,  we identified and reported on actions taken by federal agencies to  address antibiotic resistance, and we evaluated these actions against  relevant criteria, as applicable, such as Standards for Internal Control in  the Federal Government and GAO’s leading practices on interagency  collaboration.

To examine CDC’s efforts to conduct surveillance for antibiotic resistance  and any challenges to these efforts, we reviewed documentation and  conducted interviews with agency officials and other key stakeholders on  each of the surveillance systems across CDC that collects antibiotic  resistance data and reviewed CDC’s Antibiotic Resistance Threats in the  United States, 2013 (2013 Threats Report) and Antibiotic Resistance  Threats in the United States, 2019 (2019 Threats Report) reports. This  included a review of health care facility participation data by state and  territory in a CDC antibiotic resistance reporting system. We assessed the  reliability of these data by reviewing them for any outliers or anomalies  and inquiring with agency officials about their source and any known  reliability issues. We determined that these data were sufficiently reliable  for assessing facility participation rates by U.S. state and territory. We  also reviewed documents from WHO’s Global Antimicrobial Resistance  Surveillance System and interviewed WHO and CDC officials to identify  challenges that limit CDC’s ability to assess threats from abroad.

To examine federal efforts to advance the development and use of  diagnostic tests, we also interviewed a nongeneralizable sample of six  diagnostic test manufacturers to encompass different types of tests,  based a list of manufacturers compiled from our previous work, interviews  with select experts, and internet research. We limited our scope to FDA- authorized tests—which we are defining as tests that have been reviewed  and cleared or granted authorization by FDA for marketing in the United  States—that can identify resistance in at least one type of bacteria  categorized as a priority in CDC’s 2013 Threats Report. Some of these  tests are called antibiotic susceptibility tests, but we use “tests” to refer to  the entire class of such tests. We included in our scope tests that can  differentiate between viral and bacterial infections, because these types  of tests are included in the National Action Plan.

To identify challenges to developing new treatments for antibiotic- resistant infections and examine federal efforts to address these  challenges, we also reviewed literature and reports written by health  policy advisory groups on topics related to antibiotic development  challenges and incentives for development. Our examination of  challenges and related federal actions focused on treatments and,  therefore, did not include products designed to prevent infections, such as  vaccines. We also interviewed 11 randomly selected companies that  conduct R&D on new treatments for bacterial infections.

To examine federal agency efforts to promote the appropriate use of  antibiotics and any challenges that remain, we also analyzed CMS data  and related documentation on quality measures and improvement  activities related to antibiotics. We reviewed the data for any obvious  outliers or anomalies and determined that these data were sufficiently  reliable for reporting on the number of clinicians who reported  implementing these quality measures and improvement activities. In  addition, we reviewed aggregated data from CDC on the total number of  eligible U.S. hospitals reporting their antibiotic use data to a CDC system.  We assessed the reliability of the aggregated data by reviewing them for  any obvious errors or missing data totals and inquiring with agency  officials about their source and any known reliability issues. We  determined that these data were sufficiently reliable for reporting hospital  participation rates in CDC’s antibiotic use reporting system. We focused  our review on antibiotic use in the United States, rather than global  antibiotic use.

Appendix I contains more detailed information on the scope and  methodology of our review. Appendixes I and II contain more detailed  information about our expert meeting.

We conducted this performance audit from February 2018 to March 2020  in accordance with generally accepted government auditing standards.  Those standards require that we plan and perform the audit to obtain  sufficient, appropriate evidence to provide a reasonable basis for our  findings and conclusions based on our audit objectives. We believe that  the evidence obtained provides a reasonable basis for our findings and  conclusions based on our audit objectives.

Antibiotics are drugs that work by killing bacteria or slowing their growth.  However, some bacteria have developed ways to resist the effects of  antibiotics, for example, by preventing antibiotics from entering the cell or  pumping them out after the antibiotic enters. Bacteria that are able to  survive in the presence of antibiotics will multiply and pass on their new  genetic material that confers resistance to future generations of bacteria  and, in some cases, to other types of bacteria. Resistance can arise in  bacteria in humans, animals, and the environment, including in health  care settings, and can spread through contact with infected people or  animals, contact with contaminated water, soil or surfaces, or  consumption of contaminated food.

The spread of antibiotic resistance threatens not only the ability to fight  bacterial infections but also threatens to reverse some significant medical  gains. For example, in addition to treating infections, antibiotics have  allowed for numerous medical procedures, such as joint replacements,  caesarian sections, organ transplants, chemotherapy, and dialysis—all of  which would be significantly riskier without effective antibiotics. Antibiotic  resistance also poses a significant economic burden resulting from the  direct costs of treating those with resistant infections and the loss of  economic productivity from those who get sick or die.

In the 2013 Threats Report, CDC identified 17 bacterial pathogens that  the agency considers to be “urgent,” “serious,” or “concerning” because  they have developed enough resistance to antibiotics to be considered a  threat to human health. (See fig. 1.) According to CDC, certain types of bacteria, called gram-negative bacteria, are particularly worrisome  because they are becoming resistant to nearly all drugs that would be  considered for treatment.

The most serious gram-negative infections can be acquired in hospitals or  other health care settings and can cause pneumonia, bloodstream  infections, wound or surgical site infections, and meningitis. Nine of the  17 bacterial threats on CDC’s threat list are gram-negative. One of the  bacteria CDC considers to be an urgent threat—Clostridioides difficile (C.  difficile)—is classified as a threat not because it is resistant to antibiotics,  but because it is caused by the same factors that drive antibiotic  resistance, such as antibiotic use. CDC estimates that C. difficile alone  accounted for 12,800 deaths in U.S. hospitals in 2017. CDC’s 2013  Threats Report also identified one type of fungus—Candida auris—that it  considered to be a serious threat (see text box).

Candida auris Is a Resistant Fungal Threat Candida auris (C. auris) is an emerging infectious fungus that, according to the Centers  for Disease Control and Prevention (CDC), presents a global health threat in part  because it is highly resistant to anti-fungal drugs and is challenging to address. C. auris  was first identified in Japan in 2009. CDC reported 806 confirmed cases in the United  States, as of August 31, 2019. According to CDC, C. auris is highly transmissible and  some commonly used hospital surface disinfectants appear to be less effective against  C. auris. A CDC official told us C. auris is a good example of an emerging threat that  requires more research and associated efforts to properly address.

Addressing C. auris is challenging for reasons including the rise of resistance and  limitations in diagnostic tests. According to CDC, there are three classes of antifungals  available to treat C. auris. However, CDC has identified strains that are resistant to all  three classes. A CDC official noted that getting new antifungals to market is challenging  because, among other things, the demand for antifungals, relative to antibiotics, is low.  Additionally, according to FDA, although reliable tests for identifying C. auris exist,  commonly used laboratory tests may misidentify this fungus, posing a barrier to correct  diagnosis. In 2018, the Food and Drug Administration (FDA) cleared a test based on  mass spectrometry to identify C. auris, but this test cannot characterize resistance. FDA  officials told us there are three FDA-cleared tests available for testing for other Candida  species’ resistance to fluconazole. However, none of these tests can provide rapid  results, such as within an hour. Finally, interpretation of culture-based diagnostic tests,  which examine how well bacteria grow in the presence of an antibiotic, is challenging  due to the lack of established interpretive criteria for C. auris, by both the Clinical and  Laboratory Standards Institute, which promotes the development and use of voluntary  laboratory consensus standards and guidelines within the health care community, and  by FDA.

U.S. spending on antibiotics in health care from 2010 through 2015 was  estimated in one study to be nearly $56 billion, ranging from $8.4 billion to  $10.6 billion annually. While CDC states that antibiotic prescribing  improved nationally with a 5 percent decrease from 2011 to 2016, the  agency estimated in 2017 that at least 30 percent of antibiotics used  across both outpatient and inpatient settings are still prescribed  unnecessarily or incorrectly and, therefore, are considered  inappropriate. According to CDC, approximately 85 to 95 percent of the nation’s antibiotic use, by volume, occurred in outpatient settings from  2010 through 2015; and roughly 270 million antibiotic prescriptions— equivalent to 836 per 1,000 persons in the United States—were written in  these settings in 2016. (For more information on antibiotic use in the  United States, see text box.)

Antibiotic Use in the United States A 2017 Centers for Disease Control and Prevention (CDC) report estimates that about  30 percent of antibiotics used in U.S. hospitals are inappropriate (unnecessary or  prescribed incorrectly), and as much as 50 percent of antibiotics prescribed in  outpatient settings—such as physicians’ offices, emergency departments, urgent care  centers, and retail clinics—may be inappropriate. For example, CDC reports that each  year, an estimated 47 million unnecessary antibiotic prescriptions are written in  physicians’ offices and emergency departments. Most of these unnecessary  prescriptions are for respiratory conditions most commonly caused by viruses— including common colds, viral sore throats, and bronchitis—that do not respond to  antibiotics, or for bacterial infections that do not always need antibiotics, like many  sinus and ear infections. Furthermore, CDC reports that even when antibiotics are  needed, prescribers often favor drugs that may be less effective and may carry more  risk over more targeted, “first-line” drugs recommended by nationally recognized  antibiotic prescribing guidelines. (First-line drugs are the drugs generally recommended  for initial treatment for a given diagnosis, often combining the best efficacy with the best  safety profile or the lowest cost.) According to CDC, antibiotics are among the most  frequently prescribed medications in nursing homes, with up to 70 percent of residents  receiving one or more courses of systemic (non-topical) antibiotics in a year; CDC also  cites studies showing that 40 to 75 percent of antibiotics prescribed in nursing homes  may be inappropriate. CDC further reports that harms from antibiotic overuse include  the risk of serious diarrheal infections from C. difficile, increased adverse drug events  and drug interactions, and increased risk of infection with antibiotic-resistant organisms.

According to CDC officials, “unnecessary” antibiotic use means the antibiotic was  prescribed when no antibiotic was needed, based on clinical practice guidelines.  “Inappropriate” antibiotic use includes both unnecessary antibiotic use, as well as  inappropriate antibiotic selection, dosing, or duration when antibiotics are indicated. CDC  officials also told us they consider “misuse” and “inappropriate use” to be synonymous  terms.

The National Action Plan and Federal Agency Responsibilities

Vaccines Can Also Help Prevent Antibiotic  Resistance  While we did not include vaccines in the  scope of this report, vaccines play a role in  helping combat antibiotic resistance because  they are designed to prevent infections,  including resistant infections. In addition, by  preventing infections from occurring, they can  reduce the need to use antibiotics, which in  turn, can slow the development of antibiotic  resistance. For example, according to the  Centers for Disease Control and Prevention  (CDC), since introduction of the  pneumococcal conjugate vaccine among  children in 2000, rates of antibiotic-resistant  infections caused by certain Streptococcus  pneumoniae strains decreased by 97 percent  among children under 5 and by more than 60  percent among adults. However, few vaccines  are available that target antibiotic-resistant  bacteria on CDC’s threat list.

In September 2014, the President signed Executive Order No. 13676  (Executive Order), which directed that several federal actions be initiated  related to antibiotic resistance. For example, the Executive Order directed  the creation of the National Action Plan, which the White House released  in 2015, to provide a roadmap for federal agencies to respond to the  threat of antibiotic resistance. The National Action Plan set five major  goals over 5 years related to (1) slowing the emergence of resistant  bacteria and preventing the spread of resistant infections; (2)  strengthening national One-Health surveillance efforts to combat  resistance; (3) advancing the development and use of rapid and  innovative diagnostic tests for the identification and characterization of  resistant bacteria; (4) accelerating basic and applied R&D for new  antibiotics, other therapeutics, and vaccines; and (5) improving  international collaboration and capacities related to the first four goals.  In addition, the National Action Plan discusses the importance of  preventing and controlling infections, such as through rapid detection, to  combat antibiotic resistance domestically and globally (see text box).  Within each of these five goals, the National Action Plan contains  numerous objectives, sub-objectives, agency-specific milestones, and  other performance targets called significant outcomes. For example, the  National Action Plan set a significant outcome of reducing inappropriate  antibiotic use by 50 percent in outpatient settings and by 20 percent in  inpatient settings by 2020.

According to the World Health Organization (WHO), effective infection prevention and  control measures are a practical and scientific approach to reduce health care- associated infections in patients and health care workers, and help combat antibiotic  resistance. Infection prevention and control measures serve as the cornerstone of  actions needed to address epidemics, pandemics, and antibiotic resistance. Such  measures include implementing hand hygiene practices, providing vaccinations,  cleaning and disinfecting hospital rooms, isolating patients with infectious diseases,  decontaminating and sterilizing medical equipment, and tracking data about emerging  infectious diseases. WHO states that health care-associated infections are a global  challenge from which no country or health care facility is immune. The Centers for  Disease Control and Prevention (CDC) has taken actions to address and track health  care-associated infections, including antibiotic-resistant infections. For example, in  2009, CDC issued guidance for infection control targeting Enterobacteriaceae that may  be resistant to carbapenem, a class of antibiotics. In 2018, CDC published a study  suggesting that a tracked decline in the proportion of resistant bacteria, including  carbapenem-resistant Enterobacteriaceae, observed in some health care settings,  could be attributable—at least in part—to actions such as those outlined in its 2009  guidance. In addition, CDC has reported that U.S. hospitals have made major progress  since 2005 in declining rates of methicillin-resistant Staphylococcus aureus (MRSA)  bacteremia because of infection prevention measures.

The interagency CARB Task Force, which was created by the Executive  Order to issue and monitor the implementation of the National Action  Plan, is co-chaired by the Secretaries of Defense, Agriculture, and HHS,  and is additionally comprised of representatives from VA and several  other agencies. Representatives from HHS agencies—including BARDA,  CDC, CMS, FDA, and NIH—make up nearly two-thirds of the task force’s  participants (see table 1). According to the HHS Assistant Secretary for  Planning and Evaluation officials who coordinate it, the task force is  developing a new National Action Plan that will span the years 2020  through 2025. To provide additional advice to the CARB Task Force and  the Secretary of HHS, the Executive Order also created the Presidential  Advisory Council on Combating Antibiotic-Resistant Bacteria  (PACCARB), which is composed of 15 non-governmental members.

The Executive Order also charged the CARB Task Force with providing  annual updates to the President regarding progress made in  implementing the National Action Plan, plans to address any barriers  preventing its full implementation, and recommendations for any new or  modified actions, taking federal government resources into consideration.  Since 2015, the CARB Task Force has produced four progress reports,  which summarize agency actions toward meeting the goals and  milestones laid out in the National Action Plan; these reports were  provided to the President and are publicly available.

CDC Has Expanded Surveillance of Antibiotic Resistance, but Faces Challenges Determining the Magnitude of the Problem CDC Has Expanded Surveillance of Priority Bacteria

Since the National Action Plan was released in 2015, CDC has made  progress in expanding surveillance for antibiotic resistance in the United  States and abroad. However, the magnitude of the problem and its trends  over time remain unknown, in part because of challenges in three areas:  (1) tracking antibiotic resistance across all health care settings, (2)  reporting complete and timely information on magnitude and trends of  antibiotic resistance, and (3) tracking and assessing the global antibiotic  resistance threat.

To better assess the full extent of antibiotic resistance, CDC has  expanded its surveillance of priority bacteria in the United States in order  to better assess the full extent of antibiotic resistance since the 2015  National Action Plan was released.

CDC tracks antibiotic resistance through several infectious disease  surveillance systems in collaboration with state and local health officials,  health care providers and facilities, and laboratories. Rather than  establishing a single surveillance system for antibiotic resistance, CDC  generally incorporates tracking of antibiotic resistance into broader  surveillance systems, according to agency officials. The surveillance  systems are spread across various divisions within CDC that specialize in  specific types of infection or certain settings. (See table 2 for a description  of each system and the resistant bacteria it tracks.)

According to CDC and other officials and documents we reviewed,  including the National Action Plan Year 3 Progress Report, CDC has  taken the following actions, among others, to expand surveillance in order  to better assess the scope of antibiotic resistance:

Established the Antibiotic Resistance Laboratory Network in 2016 to  improve testing capacity to better identify antibiotic resistance in the  United States. The network consists of 55 state and local (including  Puerto Rico), and seven regional, public health laboratories and the  National Tuberculosis Molecular Surveillance Center. The network is  improving and expanding laboratory capacity response at public  health laboratories around the country, as well as at regional centers,  according to representatives from two national professional  organizations of state and local health officials and epidemiologists.

Expanded antibiotic resistance-related efforts in its Emerging  Infections Program (EIP), a network that seeks to monitor, prevent,  and control emerging infectious diseases. For example, since 2015,  more of the existing 10 EIP sites are conducting surveillance for  invasive Staphylococcus aureus infections, carbapenem-resistant  Enterobacteriaceae, and C. difficile, among others. Separately, the  National Action Plan had included a goal for CDC to expand EIP by  adding up to 10 sites within 3 years. However, CDC officials told us  that in light of resource limitations, they chose to instead increase the  number of pathogens reported at existing EIP sites. They told us they  determined this was a better use of the limited funds, and that existing  EIP sites are sufficient for current EIP efforts related to antibiotic  resistance.

Updated the domestic tuberculosis surveillance system by  incorporating advanced drug susceptibility testing and reporting and  by developing capacity for state surveillance systems to report their  tuberculosis test data electronically to CDC laboratories.

Supported state and local health departments to better track,  investigate, and prevent resistant foodborne disease, among other  things, through the National Antimicrobial Resistance Monitoring  System for Enteric Bacteria (NARMS). For example, the system can  now carry out whole genome sequencing for all the pathogens it  tracks, which enhances its detection and response capabilities, such  as by expanding CDC’s ability to detect new and emerging resistance,  according to CDC officials.

Launched the Enhanced Gonococcal Isolate Surveillance Program  (eGISP), which augments the main Gonococcal Isolate Surveillance  Program (GISP). Whereas GISP only collects samples from the  urethras of men with symptoms of gonorrhea, in select sexually  transmitted disease clinics, eGISP also collects samples from women  and from other sites on the body, such as the throat. The specimens  are sent to regional laboratories for resistance testing.

CDC has also worked with international partners to expand surveillance  of antibiotic resistance abroad. These efforts involved CDC collaborations  with WHO, the European Center for Disease Prevention and Control, the  government of the United Kingdom, other governments, and other multi- country efforts, such as the Surveillance and Epidemiology of Drug- Resistant Infections Consortium and the Transatlantic Taskforce on  Antimicrobial Resistance (TATFAR). The collaborations aimed to  develop technical guidance to help improve surveillance in other nations  and to organize an international forum. CDC also launched its Antibiotic  Resistance (AR) Solutions Initiative, which invests in national and  international infrastructure to address resistant infections across health  care settings and communities and from food.

The Precise Magnitude and Trends of Antibiotic Resistance Are Unknown, in Part Because of Challenges CDC Faces in Three Areas

CDC faces three general challenges in tracking and reporting trends in  antibiotic resistance. First, it faces limitations in data reporting and  resistance testing from hospitals, as well as challenges ensuring that its  resistant gonorrhea surveillance system is representative of the U.S.  population. Second, CDC faces challenges in reporting complete and  timely information on the magnitude of and trends in antibiotic resistance.  Finally, CDC faces challenges to detecting resistance threats abroad.

The first challenge CDC faces in tracking trends in resistance is  addressing low hospital participation in a new option of CDC’s National  Healthcare Safety Network (NHSN) system intended to address some  limitations in NHSN. NHSN is, among other things, an online system for  tracking health care-associated infections. It provides facilities, states,  regions, and the nation with data needed to identify problem areas,  measure the progress of prevention efforts, and ultimately eliminate  health care-associated infections, according to CDC.

Patients in settings such as hospitals and  long-term care facilities (e.g., nursing homes)  in many cases already have a weakened  immune system or an underlying illness,  making an antibiotic-resistant infection  especially dangerous, according to the  Centers for Disease Control and Prevention  (CDC). A high proportion of the morbidity and  mortality associated with antibiotic resistance  is seen in health care-associated infections.  Tracking resistance in health care settings is  therefore critical to national surveillance  efforts.

CDC established three modules within NHSN that allow hospitals to  report select antibiotic-resistant infections, among other things, which  include reporting required by states or by CMS, according to agency  officials. Two modules track patients who have an infection associated  with a medical device or resulting from a surgical procedure. Hospitals  only report on resistance in these modules for specific combinations of  antibiotics and bacteria, such as carbapenem-resistant  Enterobacteriaceae. The third module tracks certain hospital patients who  test positive for certain multidrug-resistant infections, including methicillin- resistant Staphylococcus aureus (MRSA)—a type of bacteria found on  people’s skin that is usually harmless but can cause serious infections,  according to CDC. However, according to CDC, many antibiotic- resistant infections detected during hospital care do not fall into one of  these three modules and therefore would not be captured in NHSN,  limiting CDC’s ability to identify important new resistances or trends.

In 2014, to help address this limitation, CDC officials told us they  introduced a new option for hospitals to report data on antibiotic  resistance—the Antimicrobial Resistance Option (AR Option). This option  allows for reporting of data on antibiotic resistance for certain bacteria,  regardless of whether the patient has a health care-associated  infection. In contrast to the other three modules, reporting to the AR  Option is voluntary.

As a result, while about 86 percent of the 17,529 eligible U.S. health care  facilities participate in at least one of the older three antibiotic-resistance  reporting modules, only about 10 percent of the 6,836 eligible hospitals  participate in the newer, voluntary AR Option, according to our analysis of  NHSN hospital participation data as of January 2020. The hospital  participation rate among U.S. states and territories ranged from no  participation (in nine states and territories) to about 27 percent.  Representatives from a national association of state public health officials  we interviewed said that this low rate limits the value of the data, a view  that echoed the findings of a 2018 report by the Joint Public Health  Informatics Task Force.

CDC officials acknowledged that participation in the AR Option is low and  cited reasons for this, including hospital resource limitations, and—in  many cases because participation is voluntary—because hospitals do not  prioritize submitting data to the AR Option. According to CDC officials, it  is particularly challenging for many smaller hospitals and Indian Health  Service facilities with resource constraints to participate, as it requires  significant information technology investment. The Joint Public Health  Informatics Task Force report noted two other common challenges: low  capacity for information technologies needed to support data submission  to the AR Option, and a lack of motivated leadership, such as a facility  “champion,” to oversee the development and maintenance of needed  reporting infrastructure. For example, the maintenance of reporting  infrastructure could address changes to electronic medical records that  are not immediately compatible with the AR Option reporting format.

CDC officials told us the agency is taking some steps to increase  participation in the AR Option. For example, it is encouraging the over  1,500 hospitals (as of December 31, 2019) that are participating in a  related reporting effort—known as the Antimicrobial Use Option (AU  Option)—but not in the AR Option to participate in both. In addition, the  agency is working with vendors of equipment and electronic health record  software to make it easier for hospitals to participate in the AR Option.

One of CDC’s goals for the AR Option is to use reported data to conduct  regional and national assessments of resistance. To help meet this goal,  officials said they would like participation by all eligible hospitals in the AR  Option, but they have not determined the needed participation rates or  appropriate distribution of participating hospitals. Our past work has  shown that leading practices for federal strategic planning include  articulating specific goals, establishing a method to assess progress  toward these goals, and aligning the plans and goals with the agency’s  mission. By taking steps to determine the participation rates and  distribution of participation hospitals needed for CDC to meet its goal of  conducting regional and national assessments of antibiotic resistance of  public health importance, CDC would have more reasonable assurance  that it can achieve its goal.

The second challenge CDC faces is ensuring representativeness of its  resistant gonorrhea surveillance system. CDC has classified resistant  gonorrhea as one of the most urgent antibiotic-resistance threats in the  nation, affecting over half a million patients annually. According to the  agency, resistant gonorrhea warrants this designation because of the  limited remaining treatment options, the high number of gonorrhea  infections, potential adverse outcomes (such as increased transmission of  HIV), and the prospect that gonorrhea may become incurable if new  resistance arises and spreads.

The Urgent Threat of Resistant Gonorrhea According to the Centers for Disease Control  and Prevention (CDC), gonorrhea is the  second most commonly reported notifiable  disease in the United States, with over  500,000 infections reported in 2017. However,  CDC estimates that the true number could be  as many as 820,000 each year. In addition to  being a very common infection, gonorrhea is  developing resistance to treatment options. As  recently as 2006, CDC had five recommended  options, but it estimates that nearly half of  U.S. infections are now resistant to available  antibiotics, including combinations.  Consequently, it now recommends only one  regimen. In 2014, a case of dual-therapy  failure was reported in the United Kingdom,  and in February 2018, a similar case in the  United Kingdom was reported that also failed  to respond to the last-resort therapy,  spectinomycin, resulting in treatment failure.  As of June 2019, CDC reported that it had not  received any reports of verified clinical  treatment failures to any cephalosporin in the  United States.

It is not clear, however, that GISP data are representative of the general  U.S. population because GISP draws on a limited sample of that  population. Specifically, GISP collects culture specimens—-called  isolates—and accompanying epidemiologic data from only the first 25  men with inflammation of the urethra consistent with gonorrhea visiting  each participating sexually transmitted disease clinic each month. It does  not collect culture specimens from women. In addition, the number of  participating clinics each year has varied from 21 to 30 (see fig. 2 for the  current sites). CDC estimates that the cases of gonorrhea identified  through GISP surveillance represent only about 1 to 2 percent of all  reported cases of gonorrhea in the United States each year. Further, the  GISP sample design also over-represents cases in the western United  States, where antibiotic-resistant gonorrhea has tended to initially  emerge, according to CDC. According to CDC, this design allows for  more rapid detection of emerging resistance by ensuring a sufficient  sample size from the western United States because resistance tends to  emerge from that area. CDC has two projects—Strengthening the United  States Response to Resistant Gonorrhea (SURRG) and eGISP— intended to, among other things, enhance domestic gonorrhea  surveillance and learn more about the representativeness of GISP  through limited testing of women and of body sites other than urethras,  respectively.

However, CDC’s current methodology may limit its ability to establish a  representative trend. According to CDC officials, GISP could improve its  representativeness by adding clinics or covering more of the population at  its current sites. However, efforts to expand GISP would be difficult due to  limited local capacity (see text box).

Barriers to Expanding the Gonococcal Isolate Surveillance Program (GISP)

GISP currently tracks a limited sample of the U.S. population. According to Centers for  Disease Control and Prevention (CDC) officials, a more thorough expansion of GISP  would be more difficult because of limited local capacity to conduct culture-based  testing for resistance in gonorrhea. Specifically, laboratories increasingly use newer  gonorrhea testing technology that gives more rapid results but cannot currently be used  to test for resistance. This trend has contributed to the reduced capability of many  laboratories to perform the gonorrhea culture-based testing for antibiotic susceptibility  testing, to the point that many clinics cannot collect specimens for testing, according to  CDC officials. Furthermore, officials said that adding new clinics to GISP would require  financial and other resources for, among other things, establishing culture testing for  resistance and information technology needed to report data to the system.

Most gonorrhea cases are diagnosed outside sexually transmitted disease clinics.  However, expanding GISP to non-sexually transmitted disease clinic sites could be  particularly costly and inefficient, officials said, because these sites tend to see many  fewer gonorrhea cases per year compared to sexually transmitted disease clinics;  therefore they may not be able to contribute significant data to GISP. Through the  Strengthening the United States Response to Resistant Gonorrhea (SURRG) project,  CDC is currently exploring options to work with states to enhance gonorrhea testing  capacity. This program was established in 2016 but has not received the funding  needed to expand capacity to the extent CDC had planned. In addition, physicians and  other providers have limited time to devote to data collection and reporting needed to  participate in GISP. CDC officials also told us the reimbursement rates for providers for  these services are inadequate.

CDC has taken some steps to assess the representativeness of the  current GISP design, but it has not conducted a comprehensive study to  assess the representativeness of the trends identified in GISP. A 2015  CDC evaluation concluded that the representativeness of GISP was  “good” on a scale of fair, good, or great. However, the evaluation  covered only part of fiscal year 2014 and consisted of a limited  comparison of selected demographic characteristics captured in  gonorrhea cases identified in GISP to those captured through the  National Notifiable Diseases Surveillance System, according to CDC  officials, and which has its own limitations. Further, the results of this  evaluation have not resulted in any changes to the GISP design. CDC  officials told us they hope to learn more about the representativeness of  GISP urethral isolates from testing women, patients in non-sexually  transmitted disease clinic sites in the SURRG project and eGISP, and testing at other body sites, and then comparing some of these results to  those of GISP. However, these efforts overall were not specifically  designed to fully assess the representativeness of GISP and may not  provide a sufficient assessment for impacting changes to the GISP  design.

CDC’s guidelines of efficient and effective public health surveillance  systems state that, in order to be representative, the data from a public  health surveillance system should accurately reflect the characteristics of  the health-related outcome—such as resistant gonorrhea—under  surveillance. A more precise evaluation of the representativeness of the  surveillance system can be done via carefully designed studies to obtain  complete and accurate data for the health event in question—namely, the  urgent threat of antibiotic-resistant gonorrhea. By evaluating the  surveillance system for resistant gonorrhea to ensure that it includes  measures of its representativeness, such as by comparing the trends in  the sample population with those in the overall U.S. population, using  specially designed studies if needed, CDC would have better assurance  that the trends detected in GISP accurately reflect the characteristics of  the health-related outcome the system is designed to monitor.

In addition to the limited design of GISP, CDC faces the challenge of  competing priorities under reduced funding that precluded it from  completing its plans to expand the SURRG project. The SURRG  expansion was designed to address a National Action Plan goal of  controlling resistant gonorrhea, among other things, but also affects  surveillance, as CDC officials told us SURRG was established to address  some limitations in GISP surveillance. Specifically, one of the plan’s  milestones assigned to CDC is to maintain advanced capacity for rapid  response to antibiotic-resistant gonorrhea for at least 20 state health  departments. Such capacity includes detection, diagnosis, and  investigation of suspected resistant cases within their state or region and  assistance for health care providers in appropriately treating infected  patients. CDC officials told us that because they received about half of  the appropriations they had requested, CDC had to make cuts in some of  their projects, and SURRG was one of those that CDC chose to reduce.  Eight SURRG sites, rather than the 20 recommended by the National  Action Plan, collect and analyze data. However, in its progress reports  covering the first 4 years of the National Action Plan’s implementation, the  CARB Task Force did not identify plans to address barriers related to  expanding the SURRG project. The CARB Task Force coordinators told  us that the progress reports have not identified plans to address barriers  largely because the task force focused on reporting the agencies’  accomplishments in implementing the National Action Plan. The  coordinators also said that, in response to our inquiries during this review,  the task force intends to identify agencies’ plans for addressing barriers in  the progress report to be published in fall 2020.

The Executive Order directs the CARB Task Force to provide annual  updates to the President on federal government actions to combat  antibiotic resistance, including progress made in implementing the  National Action Plan, plans for addressing any barriers preventing its full  implementation, and recommendations for any new or modified actions,  taking federal government resources into consideration. Without reporting  its plans to address such barriers, the CARB Task Force has not provided  all the information required by the Executive Order and has not fully  carried out its role to facilitate and monitor implementation of the National  Action Plan, which may reduce the effectiveness of federal efforts to  combat antibiotic resistance.

The third challenge CDC faces tracking antibiotic resistance is addressing  limitations to the use of test results in surveillance in health care settings.  For example, some health care facilities are not using the most up-to-date  testing methods for determining whether the bacteria causing an infection  are resistant to certain antibiotics, according to CDC officials and a report  from the Antibiotic Resistance Surveillance Task Force. In addition,  laboratories may only report an interpretation of the test result to CDC  (e.g., whether the bacteria is resistant or susceptible to an antibiotic) and  not the quantitative results (e.g., measures of the growth of bacteria in the  presence of the antibiotic). This presents a challenge for comparing data  from different laboratories, since they may not be using consistent testing  thresholds for determining antibiotic resistance. Another limitation is that  some test equipment may be designed to give limited results for the  purposes of guiding treatment recommendations and stewardship efforts,  which may also limit the information available to CDC. For example, the  test may inform the user that the infection is susceptible to one antibiotic  but “suppress” information on susceptibility to other antibiotics, in order to  guide the user toward treatment with the preferred first-line treatment.  The Antibiotic Resistance Surveillance Task Force report noted that some  suppression is done by the testing equipment itself and some by software  systems that record, manage, and store data for clinical laboratories.  CDC officials told us they are working with some diagnostic test  manufacturers to explore these issues and develop solutions to address  them. The Antibiotic Resistance Surveillance Task Force is also working  to address the diagnostic test challenges related to antibiotic resistance  surveillance.

Challenges in Reporting Complete and Timely Information on Magnitude and Trends

CDC also faces challenges in reporting timely and complete information  on the magnitude of and trends in antibiotic resistance in the agency’s  Threats Reports. One challenge is in providing information in these  reports on the uncertainties in reported numbers of deaths from antibiotic- resistant infections. Another challenge is in issuing such reports in  regular, timely intervals. As a result of these challenges, among others,  the true magnitude of, and trends in, antibiotic resistance over time are  unknown, including trends in various places and among people with  various characteristics.

Surveillance for antibiotic resistance is complex and costly, according to  experts at our meeting, CDC officials, and literature we reviewed. Experts  told us such surveillance encompasses diverse pathogens, diseases, and  health care settings and requires a variety of data sources and collection  efforts. Furthermore, experts from our meeting told us the fundamental  data required—such as data on the number of illnesses and deaths  attributable to resistance and data on related health care costs—are  currently insufficient. One expert added that there is a lack of real-time  monitoring data, such as data that are available within hours or days of  being generated. The data gaps are especially large for infections  acquired in the community, as opposed to in a health care setting,  because there is very limited tracking of such infections and whether they  are resistant. As a result, CDC officials said, it is challenging to provide  ranges of uncertainty, a critical component of any effort to measure and  report on magnitude and trends.

Neither the 2013 Threats Report nor the 2019 Threats Report provided  quantitative measures of uncertainty, such as confidence intervals, for  CDC’s estimates of morbidity and mortality resulting from antibiotic- resistant infections. For example, the report stated that there are at least  23,000 deaths a year as a direct result of antibiotic-resistant infections,  but it did not include an upper limit or a single point estimate for this  number. Similarly, the 2019 Threats Report stated that there are at least  35,900 deaths a year, without an upper limit or a single point estimate. A  recent re-estimate by a group of scientists has put the likely minimum  number of deaths annually in the United States at approximately 153,000,  or about four times the 2019 CDC minimum estimate.

CDC officials told us that because of several limitations, its estimates  were the best that could be derived from the data available. For example,  for the 2013 Threats Report, CDC only had data from a national hospital  survey intended to produce estimates of all health care-associated  infections and indirect estimates of the proportion of infections that were  resistant. These data did allow CDC to calculate confidence intervals for  infections by specific pathogens, but this information was not disclosed in  the Threats Reports. Because the data sources were not intended for this  purpose, the 2013 intervals were wide, from approximately 26 percent to  380 percent of the point estimates for each pathogen. CDC officials told  us they elected not to include these ranges of uncertainties to avoid  confusion in the 2013 Threats Report, because the report was intended  for a variety of audiences, including the general public. Officials told us  they planned to provide confidence intervals in an appendix of the 2019  Threats Report, but they did not. CDC officials explained that they  elected not to include confidence intervals in the 2019 Threats Report  because several publications are pending that provide more granular data  for many of the estimates included in the report. It is thus unclear  whether CDC plans to include any measures of uncertainties in future  Threats Reports.

Federal standards for agency dissemination of information it produces  stipulate that when information products are disseminated, error  estimates are calculated and disseminated to support assessment of the  appropriateness of the uses of the estimates or projections. Providing  measures of uncertainties in antibiotic resistance estimates, such as  standard errors or confidence intervals, as appropriate, in its Threats  Reports would help CDC and others compare information within and  across reporting efforts, without having to consult multiple documents  over time. CDC and others could use this information to draw appropriate  conclusions about the characteristics of antibiotic resistance in the United  States, including limitations associated with reported findings and  conclusions.

Additionally, CDC does not have a plan for timely, regular issuance of  their Threats Reports. It took CDC over 6 years to update the 2013  Threats report. CDC officials told us this length of time between reports  was in part because, following issuance of the 2013 Threats Report, the  agency was focused on implementing priority actions to improve antibiotic  resistance surveillance data, including those efforts prescribed by the  National Action Plan. In some cases, implementing these actions involved  new data collection efforts that took time to establish, including that it can  take up to 2 years to get new surveillance variables cleared by the Office  of Management and Budget (OMB), CDC officials told us. In addition,  CDC officials said it is time consuming to coordinate across the  decentralized structure of antibiotic-resistance tracking at CDC to compile  a consolidated report.

However, lack of timely, regular updates may affect the information  available to the public as well as policy-makers. For example, the 2013  Threats Report stated that there are at least 23,000 deaths a year as a  direct result of antibiotic-resistant infections. The 2019 report stated the  number of deaths each year to be at least 35,900 deaths a year. This  report also revised the 2013 estimate from 23,000 to 44,000 deaths a  year, suggesting a nearly two-fold revision to the initial 2013 estimate.

CDC officials told us they would like to publish the report more frequently  than every 6 years, and that it is reasonable they would develop such a  plan for frequency of publication following the 2019 report. However, they  said the agency does not currently have a plan for how often it will  release future consolidated reports. CDC’s attributes of efficient and  effective public health surveillance systems include timely data  dissemination for planning, implementing, and evaluating public health  policies and programs. By developing a plan for more frequent  dissemination of consolidated reporting on priority pathogens at regular  intervals, CDC would have more timely trend data and other information  necessary for users of the data, including policymakers, to prioritize, plan,  implement, and evaluate public health actions to address antibiotic  resistance.

Challenges in Tracking and Assessing the Global Threat

In October 2015, the World Health  Organization (WHO) launched the Global  Antimicrobial Resistance Surveillance System  (GLASS). The objectives of GLASS are to  foster national surveillance systems and  harmonized global standards and estimate  the extent and burden of antimicrobial  resistance globally by selected indicators,  among other things. As of November 2019, 86  countries were enrolled in GLASS, a 25  percent increase over 2018. Participants were  in various stages of economic development  (13 lower-income countries, 23 lower-middle- income countries, 17 upper-middle-income  countries, and 33 high-income countries) and  in all WHO regions. Seventy-five countries  provided descriptive information on their  surveillance systems for tracking antimicrobial  resistance, and 57 countries provided  resistance data for 2018. antibiotic resistance from the national surveillance systems of some  countries are incomplete because of a lack of capability and  resources for implementing standardized protocols, according to  WHO officials. Moreover, most information on antibiotic-resistant  infections is limited to laboratory test data and does not include  epidemiological data, such as data on the patient and location, which  could provide additional insight about the circumstances around the  resistant infection. Also, a lack of a sampling strategy for the detection  of cases that are antibiotic-resistant may bias the representativeness  of the data and interpretation of results. Specifically, when case  identification is done only on the population of patients that seeks  medical care and is tested, or when testing of the population varies  such as across health care settings, the incidence and trends  determined from this population may not represent the total population  of concern.

Aggregated data reporting. Some countries report aggregated,  rather than isolate, or infection-level, data to the WHO’s Global  Antimicrobial Resistance Surveillance System (GLASS), a practice  that WHO officials stated creates a challenge for data analysis and  results interpretation. According to officials, such aggregation limits  statistical analysis that can be performed and limits analysis of factors  such as the specific antibiotic-resistant bacteria, or the age or gender  of the patient, among other things.

Surveillance is a complex function. Many different health care and  public health professionals are involved in the multistep process for  generating data, according to a WHO report on GLASS. According to  WHO officials, obtaining the staff commitment and training needed to  ensure high-quality data can pose a challenge to public health  agencies and health care organizations.

As we noted above, CDC has worked with, and continues to work with,  international partners to expand surveillance of antibiotic resistance  abroad, including through U.S. participation in GLASS. For example, CDC  has helped develop technical guidance for surveillance programs in other  countries and has organized international forums for surveillance. CDC  officials also told us portions of domestic surveillance systems data  collection include collection of patient travel history.

Federal Agencies Have Helped Advance Diagnostic Tests and Promoted Their Use, but These Efforts Have Limitations

Federal agencies have helped advance the development of new FDA- authorized tests and the use of existing tests for diagnosing antibiotic- resistant infections, but these efforts have limitations. Specifically, HHS  and DOD have funded studies and taken other steps to advance testing,  but they have not defined leadership, roles, and responsibilities to  address a key barrier to the use of tests: a lack of clinical outcome  studies. FDA has taken additional steps to advance testing; however, it  has not regularly monitored test updates.

Agency Efforts toward the Development and Use of Diagnostic Tests

HHS and DOD Have Funded the Development of New Tests

HHS and DOD have awarded grants and contracts for the development of  new FDA-authorized tests for diagnosing antibiotic-resistant infections.  Some of these awards address specific needs in the current availability of  FDA-authorized tests, while others support more general research and  development efforts. In addition, these agencies have taken steps to help  reduce the chances of duplicative funding. According to experts, tests for  antibiotic resistance not only help clinicians decide what antibiotics to use,  they also provide important information for surveillance, including the  number of cases of resistant infections in a population and the  mechanisms of resistance. to the 2013 Threats Report.

Differentiate between viral and bacterial infections. Such a test would  be useful primarily in preventing use of antibiotics for viral infections,  which can contribute to the development of resistance in bacteria,  among other things.

HHS and DOD have awarded funding to address these needs. For  example:

CARB-X—a program supported by NIH and BARDA within HHS—has  awarded funding to a company to develop a rapid test to both  diagnose gonorrhea and test for antibiotic resistance.

CARB-X is funding other companies to, among other things, develop  rapid testing for identification of and resistance in bloodstream  infections, including for some priority bacteria.

In September 2016, NIH and BARDA announced the Antimicrobial  Resistance Rapid, Point-of-Need Diagnostic Test Challenge. As of  December 2019, there were five finalists, working on such projects as  developing a rapid test to differentiate viral from bacterial infections  and developing a test that can identify or detect antibiotic-resistant  bacteria, including antibiotic-resistant gonorrhea.

Within DOD, the Defense Advanced Research Projects Agency  officials told us that the agency used fiscal year 2015 funding on  contracts for the development of rapid molecular tests for resistant  gonorrhea and to distinguish between viral and bacterial infections.

Federal agencies have also funded more general research and  development efforts related to resistance testing. For example:

NIH officials told us their agency has supported extramural projects  related to the development of tests for antibiotic resistance by issuing  grants and entering into contracts since fiscal year 2015.

Separately from the Antimicrobial Resistance Diagnostic Challenge,  BARDA entered into contracts with three organizations to develop  tests focusing on the advanced stages of test development, including  clinical trials, according to BARDA officials.

Within DOD, the Defense Threat Reduction Agency is funding three  projects using Other Transaction Authority or direct funding to a DOD  Service laboratory, for developing tests.

Federal agencies have also taken steps to help reduce the chances of  duplicative funding, including working with some international efforts to  develop tests, according to agency officials. For example, NIH reviews  current and pending support of key project personnel prior to issuing of  any research award, to help ensure NIH support complements support  from other agencies and organizations. Similarly, officials from HHS’s  Office of Global Affairs worked during the creation and launch of the NIH- BARDA challenge and an analogous United Kingdom innovation  foundation competition called the Longitude Prize to help ensure these  programs were designed to support different aspects of needed  diagnostics.

HHS Has Funded Some Studies of Clinical Outcomes, but Has Not Clearly Identified Leadership, Roles, and Responsibilities

HHS has funded some studies to assess the extent to which testing  patients to identify whether they have antibiotic-resistant infections leads  to improved clinical outcomes, such as more effective treatment for  patients or more judicious use of antibiotics. However, HHS has not  identified relevant leadership, roles, and responsibilities among the HHS  agencies that could fund such studies.

Clinical outcome studies are important for encouraging the use of  diagnostic tests for antibiotic resistance, among other things, because  such studies can demonstrate the benefits of those tests. According to  PACCARB, there is very limited information on why clinicians sometimes  forgo diagnostic testing, but one possible explanation is that there may be  limited data demonstrating the value of such testing. In the absence of  such data, a clinician may choose to treat the patient immediately rather  than using a test for antibiotic resistance that has unknown value.  Research into the clinical outcomes associated with such testing could  therefore be used to help promote the use of those resistance tests that  are found to be beneficial. As a result, patient care could be improved and  clinicians could be guided towards appropriate antibiotics to prescribe.

Two HHS agencies have awarded grants for studies on the clinical  outcomes of resistance testing, according to agency officials. For  example, NIH provided grant support for a study that found, among other  things, that using a rapid blood test for a range of potential bacteria and  antibiotic resistance led to more judicious use of antibiotics. Similarly,  officials from the Agency for Healthcare Research and Quality (AHRQ)  stated that the agency is funding investigator-initiated grant studies to  assess the impact of tests on antibiotic stewardship. However, agency  officials only mentioned these and a few other examples of studies they  have funded on clinical outcomes.

International Needs for Diagnostic Tests  for Antibiotic Resistance  To better understand international needs for  antibiotic resistance tests, we interviewed  officials from international organizations and  the Office of Global Affairs within the  Department of Health and Human Services  (HHS). A Public Health England official told us  that United Kingdom users are not confident  that these tests will have a clinical impact or  be cost effective. Similarly, an official from a  trade organization of British medical test  manufacturers told us that the value of tests  for antibiotic resistance needs to be captured  and disclosed, especially because people are  more willing to pay for treatment than for  tests.  However, other factors could also be  important in determining which tests will be  useful internationally. World Health  Organization officials told us that they are  working to determine what characteristics  health care providers worldwide identify as  key to making tests useful, so industry can  develop such tests. They noted that tests  designed for use in the United States may not  be suitable for use in other countries. They  also noted that laboratories in developing  countries may not have the capacity to culture  bacteria, so many need to use culture- independent tests.  Office of Global Affairs officials told us that a  big challenge is developing accessible tests  for use internationally. Their ideal test would  be inexpensive, rapid, and capable of point- of-care use. They noted that cost and usability  are the barriers to test use, not technology,  and that use of existing tests remains limited,  including within the United States.

Agency officials and experts agree that more needs to be done to  evaluate clinical outcomes associated with use of diagnostic tests for  antibiotic resistance. For example, in 2017, PACCARB reported that  “there is a lack of clinical and economic outcome studies showing that  any diagnostic test could prevent the emergence of antibiotic-resistant  bacteria and would be cost effective.” Officials we interviewed from  AHRQ, BARDA, CDC, FDA, and NIH all agreed with that PACCARB  statement. Additionally, experts told us that such studies are lacking but  important for advancing the use of tests. For example, one health care  organization official told us the decision to adopt a test is based at least in  part on whether there will be a clinical benefit. An infectious disease  expert noted that to provide incentives for test use there needs to be  some evidence that tests affect and improve care, but that most tests do  not come with any evaluation of how they perform in practice.  International organizations expressed similar opinions.

One reason for the relatively low number of studies is that those agencies  that could conduct or fund diagnostic outcome studies have not clearly  identified leadership, roles, and responsibilities for doing so. Although  they agree that more such studies are needed, they have not identified  which agency or agencies should take the lead, and what the roles of the  other agencies should be. Instead, agencies have offered differing views  on what each agency could do. For example, BARDA officials told us their  agency has not funded such studies because it generally does not play a  role in test adoption. BARDA officials, as well as officials from DOD and  NIH, said that CDC should play a role in funding or conducting the  studies. However, CDC officials told us that a lack of resources has  prevented their agency from doing so, and that the responsibility should  fall at least partly on BARDA.

Our previous work shows that key practices for interagency collaboration  include identifying a lead agency (or, if leadership is shared, clearly  identifying roles and responsibilities among the lead agencies), as well as  clarifying the roles and responsibilities of all participating agencies. By  taking these actions, agencies—including AHRQ, BARDA, CDC, FDA,  and NIH—could more effectively address the need for clinical outcome  studies. Those studies, in turn, could help demonstrate the value of  diagnostic tests for antibiotic resistance, potentially increasing their use,  improving patient care, and enhancing stewardship efforts.

CMS and FDA Have Taken Steps to Advance the Use of Tests, but Experts Have Identified Challenges with Payments

CMS and FDA have taken some steps to advance the use of tests,  including those to identify antibiotic-resistant bacteria. For example, FDA  established a Payor Communication Task Force, which helps facilitate  communication between test manufacturers and payors. Such  communication is important because payors decide whether tests will be  covered by insurance, among other things. According to an FDA web  page, by communicating with payors, test manufacturers could, for  example, learn what data payors need to approve a test for coverage and  then use this information to design clinical trials to provide that  information. This process could reduce the time between when a test is  cleared or approved by FDA and when it is covered.

A similar step FDA and CMS took to advance the use of tests was to  extend the Parallel Review program indefinitely, a move they announced  in 2016. This program established a mechanism for FDA and CMS to  simultaneously review clinical data, with the aim of reducing the time  between FDA’s approval and CMS’s decision on whether to pay for the  test.

Experts told us challenges remain with test payments that may result in  lower test use. For example, a PACCARB report states that “currently,   for many diagnostic tests is not aligned with the value of the  test,” and noted that supplementing payments for tests could drive test  development and use. BARDA officials also told us that a major factor  affecting adoption of new tests is the cost of the test relative to  reimbursement. Additionally, experts, including those at our meeting, told  us that test payments remain insufficient to encourage broad test use.  For example, two experts from our meeting said that there is not always a  clear link between the medical value of a test and the payment level for  that test. One of these experts added that their laboratory decided not to  adopt a test because low payment levels relative to costs made doing so  a money-losing proposition. Three other experts we interviewed agreed  that disparities between cost and payment can discourage test adoption.

Regarding federal payments for tests involving CMS and their payments  through Medicaid and Medicare, there are limits to CMS’s ability to  address any disparities. For example, CMS officials told us the payments  for some tests are based on a weighted, median, private-payor rates  pursuant to the Protecting Access to Medicare Act of 2014, so CMS  cannot specify the methodology used to set those rates. Further, for  inpatient tests, Medicare pays hospitals a single, bundled payment per  patient stay, which is based on multiple factors, including the patient’s  diagnosis and treatment strategy, rather than on a specific service. As  such, a separate payment for individual tests is not made under  Medicare.

FDA Efforts to Advance the Development of New Tests

FDA Has Taken Steps to Speed the Development of Tests for Newly Approved Antibiotics

FDA has taken steps toward the development of FDA-authorized tests for  resistance for newly approved antibiotics—a process that currently can  take months to years, according to experts and agency officials. The  delay stems in part from the need for a critical testing threshold known as  a breakpoint—the threshold that is used to help a clinician decide whether  or not a pathogen is resistant to the antibiotic (see text box). The  breakpoint of a new antibiotic is generally finalized only when FDA has  approved the antibiotic. This means that breakpoints may often not be  available for test manufacturers until after a new antibiotic is FDA- approved. As a result, test manufacturers generally may not be able to  complete developing FDA-authorized culture-based tests for resistance to  a specific antibiotic until after the antibiotic is commercially available. The  result is that the development of such culture-based tests may be  generally delayed even after the new antibiotic is approved by FDA. This  delay could affect the ability of clinicians to treat patients. For example,  according to an expert, such a delay could lead to underuse of a newly  available antibiotic, among other things, because a clinician may not be  willing to prescribe the antibiotic without test results to guide treatment.

How Breakpoints Are Used to Interpret Tests According to officials from the Food and Drug Administration (FDA), breakpoints, also  referred to as “susceptibility test interpretive criteria,” are used to define susceptibility  and resistance to antibiotics to help guide patient care. Culture-based tests rely on  breakpoints to provide a determination of resistance to clinicians. In the United States,  breakpoints (based on clinical or microbiological data) are established by standards- development organizations such as the Clinical and Laboratory Standards Institute  (CLSI) and FDA.  One example of how breakpoints are used involves the Kirby-Bauer disk diffusion test.  This test is conducted by spreading bacteria on a laboratory agar plate containing  bacterial nutrients, and then placing paper disks containing a known amount of  antibiotics on the “lawn” of bacteria. Plates are observed after overnight incubation to  determine the extent of bacterial growth. Closer to the disk, there is a higher  concentration of antibiotic, and the concentration declines with distance. Around most  disks, there is a “zone of inhibition,” where the concentration of antibiotic is too high for  bacteria to grow. After allowing the bacteria to grow for a defined period of time, the  diameter of the zone of inhibition is measured in millimeters.  Procedure for Assessing Antibiotic Resistance Using Breakpoints  If the diameter is larger than or equal to the breakpoint, then the strain of bacteria is  considered susceptible to the antibiotic, suggesting that the antibiotic can be used to  treat infections caused by that strain. If the diameter is smaller than the breakpoint,  then the strain is considered resistant, suggesting that the antibiotic should not be  used. According to FDA, in most cases, there is a range of “intermediate” or  “susceptible dose-dependent” diameters for which treatment might be effective.  Other types of culture-based diagnostic tests for resistance have analogous  breakpoints for interpreting the test. For example, the minimum inhibitory  concentration—the lowest concentration of an antibiotic that prevents growth of  bacteria—can be compared to a breakpoint to establish whether the bacteria are  considered resistant.

In addition to antibiotic developers waiting until FDA approves an  antibiotic before a breakpoint is finalized, there are technical hurdles in  developing a test for some new antibiotics, according to FDA officials. For  example, it may be challenging for certain automated test manufacturers  to address unique growth properties of certain bacteria in the presence of  specific antibiotics or combinations of antibiotics. According to a test  manufacturer, these hurdles include the need for additional studies, and  such studies may not be straightforward because of the need to  determine what clinical data FDA requires. In addition, in the case of  automated tests, a representative from a test manufacturer association  told us the software used to run and interpret a new test needs to be  revised, which can be time consuming.

The delay between approval of an antibiotic and the availability of a test  for resistance could result in suboptimal treatment and increase burdens  on the health care system. For example, one expert stated that during this  delay, laboratories need to create or modify tests and then validate those  tests instead of using a FDA-authorized test, which increases the time  required and places demands on facility personnel and budgets. This  expert added that to conduct validation studies, the laboratories need a  variety of samples for testing, called “isolates,” which may not be  available. A second expert said that the delay leads to both overuse and  underuse of the new antibiotic: in the absence of a test, some clinicians  will prescribe the antibiotic when it may be inappropriate, leading to  overuse; some other clinicians refrain from prescribing the antibiotic, even  if appropriate, leading to underuse.

To help address this delay, FDA has created a process known as  coordinated development, whereby test manufacturers can submit a  coordinated development plan to FDA describing the test manufacturer’s  intent to coordinate with the antibiotic manufacturer. The plan is submitted  prior to, or shortly after, submission of an application to market a new  drug.

Under the coordinated development program, FDA shares breakpoint  information from the antibiotic manufacturer with a prospective test  manufacturer. It then reviews the test application at the same time as  the antibiotic application and takes other steps to facilitate more timely  clearance of the test. FDA officials told us this process has significantly  reduced the delay between approval of the antibiotic and clearance of the  test.

Another FDA step to help test manufacturers speed development of tests  is the establishment, in collaboration with CDC, of a centralized repository  of bacterial strains with well-characterized antibiotic resistance profiles.  These strains are available to test manufacturers and others to help them  design, validate, and evaluate tests by checking that they give the correct  results for bacteria whose profile of antibiotic resistance is known.  Finally, FDA officials also said that they offer pre-submission advice,  whereby a test manufacturer can ask for initial guidance on the design of  clinical studies for their tests.

FDA Has Taken Steps to Improve Breakpoint Recognition

In the United States, breakpoints are established and updated by  organizations such as the Clinical and Laboratory Standards Institute  (CLSI). After CLSI establishes a breakpoint, FDA may review and  recognize the breakpoint, according to FDA officials. Test manufacturers  rely on breakpoints recognized by FDA to support marketing authorization  of their tests.

An expert who works for CLSI identified more than 50 breakpoints that  have not been recognized by FDA, and for which CLSI considers FDA  recognition important in order to help make FDA-authorized tests  available. Experts, including one from our meeting, cited the following  examples of breakpoints needing recognition:

CDC recommends a dual therapy of antibiotics—azithromycin and  ceftriaxone—to be taken together to treat gonorrhea. However, FDA  does not recognize any azithromycin breakpoints for N. gonorrhoeae,  which an expert from our meeting told us could be a barrier to  developing FDA-authorized culture-based tests for N. gonorrhoeae  resistance to the recommended dual therapy.

Colistin is an antibiotic used in hospitals because of its efficacy  against carbapenem-resistant bacteria, according to one  manufacturer of a test for colistin resistance. This manufacturer  markets its test in many countries but not in the United States,  because FDA does not recognize colistin breakpoints.

FDA has taken some steps to address unrecognized breakpoints, which  are a potential barrier to developing some tests for antibiotic resistance.  For example, FDA officials told us that the agency conducts regular  internal reviews of breakpoints. According to FDA officials, the agency  reviewed the 2019 CLSI breakpoint standards and updated FDA’s  website with changes to recognized breakpoints as of June 2019. FDA  has been posting such updates since December 13, 2017.

FDA also accepts public comments requesting the recognition of new  breakpoints, according to agency officials. However, we found there  was some confusion between CLSI officials and experts and the FDA  involving the number of comments FDA could review each year, which  FDA later clarified on its website. One expert at our meeting later told us  that CLSI adjusts its process for submitting comments based in part on  their understanding of FDA’s communication. This expert added that FDA  making a public commitment to a specific number of comments they  would review would help CLSI improve its planning.

FDA officials told us there is no legal requirement for FDA to  communicate the number of comments the agency can review, but that in  previously published notices of opportunities for public comments, there  was nothing that indicated there would be limits. However, after we  informed FDA officials of concerns by experts regarding the number of  comments FDA could review, FDA updated their webpage to clarify that  they will review all submitted comments.

FDA Has Taken Limited Steps to Monitor Use of Updated Breakpoints

FDA has taken limited steps to monitor whether FDA-authorized tests are  using new breakpoints after these breakpoints are updated and accepted  by FDA. Because bacteria can develop increasing resistance to  antibiotics, it is sometimes important to change the breakpoints used for determining whether or not bacteria are resistant to a given antibiotic.  Using tests with out-of-date breakpoints could result in misidentifying a  resistant infection as non-resistant, which can lead to treating a patient  with an ineffective antibiotic and the further spread of the infection. FDA  officials told us the agency has taken limited steps to monitor the status of  breakpoint updates, and that out-of-date breakpoints being used in tests  should be a rare occurrence.

In contrast, a CDC official told us that keeping tests updated is a  significant concern. This official cited the example of carbapenem- resistant Enterobacteriaceae infection, which triggers specific procedures  to limit the spread of these bacteria. If the test breakpoint is out of date,  the infection may not be detected in a timely manner, and the pathogen  could spread broadly as a result. A recent study looking at hypothetical  scenarios in one U.S. county estimated that a 32-month delay in updating  tests to match CLSI breakpoints for carbapenem-resistant  Enterobacteriaceae would have resulted in an average of almost 2,000  additional carriers of these bacteria county-wide. Additionally, an expert  told us that use of out-of-date breakpoints could lead to improper patient  care, improper surveillance reporting, and slower detection of emerging  resistance. However, the true impact of this issue is challenging to  discern (see text box).

The Extent of Any Negative Effects of Out-of-Date Breakpoints on Public Health  Is Unclear Experts and agency officials voiced a range of opinions on the public health effects of  tests with out-of-date breakpoints. For example, one Centers for Disease Control and  Prevention (CDC) official told us that despite the lack of breakpoint updates, cases of a  type of carbapenem-resistant Enterobacteriaceae were likely ultimately caught by  hospitals because a second test was used by all but a small number of hospitals. One  expert stated that how quickly test breakpoints are updated is less important when  deciding what test to adopt than other factors, such as ease of use. However, another  expert noted that laboratories addressing emerging threats may feel the need to use  non-Food and Drug Administration (FDA) cleared tests, because they are aware that  FDA-cleared tests may not be updated as quickly as needed. Test updates may be an  issue for smaller laboratories, which do not have dedicated personnel keeping track of  breakpoint revisions, Department of Veterans Affairs officials told us.

FDA officials told us that because manufacturers are strongly motivated  to keep their tests current, only a few tests have out-of-date  breakpoints. However, the only confirmation FDA officials offered for  this statement was to mention an unofficial internal survey of FDA’s  database of existing tests, conducted in March 2019, which concluded  that all FDA-authorized tests had implemented breakpoint updates made  since December 13, 2017. They said this survey is not conducted  regularly. They also stated that it is possible that some tests have not been updated to reflect breakpoint updates made prior to December 13,  2017, but that FDA is unaware of any such tests that also pose a public  health threat.

To assess the extent to which there are FDA-authorized tests using out- of-date breakpoints, we spoke with experts and stakeholders and  reviewed studies they identified. We identified several FDA-authorized  tests with breakpoints that were changed nearly a decade ago. Some of  these tests could be used for diagnosing infection with carbapenem- resistant Enterobacteriaceae, which CDC identified as an urgent threat.  One manufacturer told us that one of their tests has not been updated  with new breakpoints nearly 10 years after a breakpoint revision. FDA  officials acknowledged it is possible some FDA-authorized tests might  continue to rely on outdated breakpoints. Further, in 2019, a scientific  article listed four different test manufacturers offering tests that have not  been fully updated to reflect revised breakpoints, including some affecting  antibiotics for some types of carbapenem-resistant Enterobacteriaceae.  Finally, CDC officials told us they asked hospital laboratories in a survey  for 2017 and 2018 if they had updated their tests to reflect revisions in  breakpoints for carbapenem-resistant Enterobacteriaceae that were  implemented in 2010. According to CDC, nearly 1,000 of over 5,000  responding hospital laboratories had not implemented the revised  breakpoints, and, of these, over 85 percent were using FDA-authorized  tests.

One CDC official stated that there is significant concern for patient safety  associated with out-of-date breakpoints, and another said that there are  few justifications for failing to update the tests after 8 years. FDA officials  told us they have not received reports of suspected device-associated  deaths, serious injuries, or malfunctions that are specific to out-of-date  carbapenem-resistant Enterobacteriaceae breakpoints in FDA-authorized  tests using such breakpoints. The officials added that it is possible to  detect carbapenem-resistant Enterobacteriaceae under certain situations,  even if the test had an out-of-date breakpoint for a given antibiotic against  these bacteria.

However, FDA does not know the actual negative effect, if any, of out-of- date breakpoints because it does not know how many FDA-authorized  tests rely on such breakpoints. Since December 2017, FDA has  conducted one unofficial survey of tests to assess breakpoint updates  that was limited in scope and is not a regular event. Other than that, FDA  is relying on market incentives to drive manufacturers to make sure their  devices are updated.

According to FDA and others, the extent of the problem is not clear.  However, PACCARB identified updating test breakpoints as an important  issue in a 2017 report. Additionally, one of the sub-objectives in the  National Action Plan notes that rapid updating of breakpoints is essential  to provide accurate information to guide appropriate drug treatment.  Finally, the Standards for Internal Control in the Federal Government  directs management to establish and operate monitoring activities to  monitor its internal control systems and evaluate the results. In this  case, monitoring and evaluation of the status of breakpoint updates in  FDA-authorized tests could help FDA identify and address the National  Action Plan sub-objective, as well as a strategic priority in the mission  statement of its Center for Devices and Radiological Health: “FDA  assures that patients and providers have timely and continued access to  safe, effective and high-quality medical devices.”

FDA officials said they do not believe the issue is a significant problem,  but the agency has also not regularly evaluated any effects of using tests  for antibiotic resistance with out-of-date breakpoints. FDA officials  stated that there may be resource constraints to their ability to conduct  regular monitoring and evaluation. By regularly monitoring and evaluating  FDA-authorized tests, FDA would be better positioned to determine the  extent of tests relying on out-of-date breakpoints and may be better  positioned to provide assurance that patients and providers have timely  access to safe and effective tests. Furthermore, by regular monitoring,  FDA would be able to determine whether test manufacturers are updating  breakpoints as needed, and help ensure that patient care and infection  control efforts are effective.

Federal Efforts Have Not Fully Addressed Challenges to Developing New Treatments for Antibiotic-Resistant Infections

Experts, federal officials, and antibiotic developers have identified  economic and other challenges to developing new antibiotics. Federal  agencies, including HHS and DOD, have engaged in efforts to address  some of the challenges; however, experts said these efforts are not  sufficient and that additional federal incentives are needed to encourage  the development of new antibiotics.

Economic and Other Challenges to Developing New Treatments Exist

Experts are concerned about a void in the discovery of new antibiotic  classes and the current pipeline of antibiotics in development. According  to The Pew Charitable Trusts, a nonprofit public policy organization that  tracks the pipeline of antibiotics, no new classes of antibiotics approved  for human use have been discovered since 1984. In addition, experts  are concerned that the number of antibiotics in clinical development is  insufficient to meet the threat of antibiotic resistance. For example,  according to The Pew Charitable Trusts, only 42 antibiotics were in  clinical development globally—meaning clinical trials were being  conducted to test their safety and efficacy in humans—as of June 2019,  and only 24 of them targeted bacteria on CDC’s or WHO’s priority lists.  According to a recently published analysis, the authors found that the  pipeline of antibiotics that target gram-negative bacteria is dominated by  derivatives of existing classes of antibiotics and “does not sufficiently  address the problem of extensively drug-resistant gram-negative  bacteria”.

For example, one study estimated the average cost per new molecular compound that  received FDA approval between 2005 and 2013 to be $1.4 billion. See J. A. DiMasi, H. G.  Grabowski, and R. W. Hansen, “Innovation in the Pharmaceutical Industry: New Estimates  of R&D Costs,” Journal of Health Economics, vol. 47 (2016): pp. 20-33. Other studies  suggest lower development costs. For example, another study estimated a median cost to  develop cancer drugs of $0.6 billion. See V. Prasad and S. Mailankody, “Research and  Development Spending to Bring Single Cancer Drug to Market and Revenues After  Approval,” JAMA Internal Medicine, vol. 177, no. 11 (2017): pp. 1,569-1,575. for antibiotic-resistant infections have a narrow set of patients for  whom the treatment would be appropriate.

As a result of the perceived poor return on investment, many large  pharmaceutical companies have discontinued their antibiotic development  in recent years. In 2018, according to The Pew Charitable Trusts and  other published sources, four large pharmaceutical companies worldwide  had antibiotics in clinical development globally compared to 1990, when  18 were involved in antibiotic R&D. Two antibiotic companies declared  bankruptcy in 2019; in the case of one, the company filed for bankruptcy  only 10 months after its antibiotic, which targets resistant bacteria,  received FDA approval. The majority of antibiotics in the development  pipeline are being developed by smaller companies that do not have  other drugs on the market to help cover their R&D costs. However,  representatives from three small antibiotic developers we spoke with  noted that their field is struggling because it is difficult to raise funds from  private investors due to the low return on investment potential. with bacterial infections into certain clinical trials prior to initiating  treatment can be difficult due to a lack of available rapid diagnostic  tests to identify the type of infection and the urgent need to begin  treatment immediately for acute infections. According to FDA officials,  this is problematic for clinical trials because any prior treatment could  obscure the true efficacy of the drug under investigation. Recognizing  this often unavoidable issue, FDA has issued guidance giving  antibiotic developers additional, but limited, flexibility with their clinical  trial protocols in certain cases.

Superiority trials, which aim to show that  the drug being investigated is more  effective than an existing drug.  Non-inferiority trials, which aim to  demonstrate that the difference between  the effectiveness of the drug being  investigated and an existing drug is small  enough to show that the drug being  studied is also effective.

Typically, there are three phases of clinical  trials, with the sizes of the trials increasing  with each phase. FDA generally prefers that  when conducting clinical trials, developers  demonstrate the effectiveness of a new drug  by showing its impact on a clinical endpoint— a direct measure of how a patient feels,  functions, or survives. FDA also accepts  surrogate endpoints, which are laboratory  measures or physical signs used as a  substitute for a clinical endpoint that  reasonably predict a clinical benefit. developers told us that, for most antibiotics, it is difficult to conduct  superiority clinical trials and more feasible to conduct non-inferiority  trials, because the latter allows for smaller enrollment. (See side  bar for an explanation of clinical trial types.) They told us that the  inability to demonstrate their drug’s superiority limits their ability to  market the drug, because it can be difficult to convince purchasers  (e.g., hospitals) to choose the newly approved antibiotic over existing  antibiotics, especially when the new antibiotic is significantly more  expensive.

Gaining approval for multiple indications. FDA generally approves  drugs for a specific indication; therefore, antibiotic developers told us  they tend to design their clinical trials around common infection types,  largely because of the relative ease of enrolling patients. However,  some antibiotics can treat infections in multiple parts of the body,  which may not have been studied in a clinical trial. While providers  are able to prescribe drugs for “off-label” use—that is, for a condition  or patient population for which the drug has not been approved—they  may lack information on the safety and efficacy of the drug for such  use. In addition, such off-label use may not be reimbursed by the  patient’s insurance.

According to The Pew Charitable Trusts, there  were 29 nontraditional antibacterial products  in clinical development for the U.S. market in  June 2019. Among the 29 products in the  pipeline, nine were antibodies, seven were  vaccines, seven were live biotherapeutic  products, and six were other types of  products. No bacteriophages were in clinical  development. More than half of these  products are for the treatment of  Clostridioides difficile or Staphylococcus  aureus infections.

Experts, antibiotic developers, and federal officials also said it is  scientifically challenging to develop new antibiotics that can overcome  existing mechanisms of resistance. One expert at our meeting explained  that it is necessary to develop an antibiotic that works differently than  existing antibiotics so that bacteria are not resistant to it. In particular,  experts and federal officials have noted that it is challenging to develop  antibiotics that can kill certain types of bacteria, called gram-negative  bacteria, largely due to their double membrane that makes it difficult for  antibiotics to enter the bacterial cell, and to pumps that can remove the  drug once it enters. Three antibiotic developers we spoke to explained  that as bacteria continue to evolve new ways to resist antibiotics, it is  difficult for scientists to keep pace by developing new treatments that can  overcome those mechanisms. In addition, experts noted that scientists  have already discovered most of the antibiotics from known sources, such  as soil. As a result, scientists are now exploring new sources of chemicals  with antibiotic properties, such as insects.

As the rate of antibiotic discovery has slowed, scientists have also begun  to explore alternatives to traditional antibiotics—which we call  “nontraditional products” in this report. Many types of nontraditional  products are currently being researched and developed to treat antibiotic- resistant infections, including, among others, live biotherapeutic products,  antibodies, and bacteriophages. For example, one type of  nontraditional product in use for the treatment of recurrent C. difficile- associated disease—which causes diarrhea, abdominal cramps, and an  estimated 15,000 deaths in the United States each year, according to  CDC—is fecal microbiota for transplantation, more commonly known as  fecal transplants. (See text box.) However, scientists and companies  researching and developing certain types of nontraditional products face  development challenges. For example, according to a paper written by  BARDA officials and others, certain types of nontraditional products target  only one or a few types of bacteria, which makes enrollment of patients in  clinical trials difficult and potentially cost-prohibitive. The authors also  stated that additional research is needed to evaluate side effects and  measure the efficacy of some types of nontraditional products. According  to another published paper, more than half of the nontraditional products  in development are intended to be used concurrently with a traditional  antibiotic, and it can be difficult to demonstrate the additional clinical  benefit of adjunctive therapies in clinical trials. The authors also noted  that additional clinical trial endpoints still need to be developed and  validated for such nontraditional products.

Fecal Transplants  The goal of a fecal transplant—which involves collecting stool from healthy donors and  transferring it to patients via enema, oral capsule, or another modality—is to restore a  healthy gut microbiome for recipients. According to the National Institutes of Health  (NIH), multiple research studies have indicated that these transplants are effective, but  their long-term safety has not been established. Questions remain about the Food and  Drug Administration’s (FDA) policy regarding stool banks that collect, prepare, and  distribute fecal transplant products. FDA issued guidance in 2013 indicating its intention  to exercise enforcement discretion regarding Investigational New Drug requirements for  the use of fecal transplants to treat Clostridioides difficile infections, provided that the  treating physician obtained adequate consent from the patient or his or her legally  authorized representative. In other words, FDA’s guidance indicated it would not  require fecal transplant products to satisfy the Investigational New Drug requirements— which refer to the requirements for FDA’s approval before beginning clinical trials to test  a product on humans. [FDA, Enforcement Policy Regarding Investigational New Drug  Requirements for Use of Fecal Microbiota for Transplantation To Treat Clostridium  difficile Infection Not Responsive to Standard Therapies; Guidance for Industry;  Availability, 78 Fed. Reg. 42965 (Jul. 18, 2013).] However, FDA later issued draft  guidance in 2016 stating that FDA did not intend to extend enforcement discretion with  respect to the Investigational New Drug requirements applicable to stool banks  distributing fecal products. [FDA, Enforcement Policy Regarding Investigational New  Drug Requirements for Use of Fecal Microbiota for Transplantation To Treat  Clostridium difficile Infection Not Responsive to Standard Therapies; Draft Guidance for  Industry; Availability, 81 Fed. Reg. 10632 (Mar. 1, 2016).] FDA has not finalized the  2016 draft guidance, which leaves the final guidance from 2013 as the current policy.  According to FDA, the agency received many comments from patients and industry  groups in response to the 2016 draft guidance expressing concern about the effect that  the requirement for clinical trials would have on access to these products. In March  2019, FDA officials told us they were still reviewing comments to the 2016 draft  guidance and were unable to say whether or not it would be finalized. In November  2019, FDA held a public hearing to obtain further input on the use of fecal transplants to  treat C. difficile infection not responsive to standard therapies and to better understand  the effect of FDA’s enforcement policy on product development.

Federal Agencies Have Made Some Progress toward Addressing Treatment Development Challenges

Multiple federal agencies have supported the development of new  antibiotic treatments, including providing funding for antibiotic R&D,  issuing guidance related to antibiotic clinical trials, and implementing  Medicare payment mechanisms. Agencies have made available both  “push” incentives, which directly support antibiotic R&D, and “pull”  incentives, which offer financial benefit, either directly or indirectly, to  developers of successful antibiotics after they reach the market.

Federal funding for antibiotic R&D. Several federal agencies award  grants or contracts, create public-private partnerships, or use other  approaches to provide researchers the funding for R&D of new  treatments for antibiotic-resistant infections (see table 3). This type of pre- market R&D support is considered a “push incentive.”

See appendix III for additional examples of efforts to support antibiotic  R&D by NIH and DOD.

Among the products in the CARB-X portfolio,  12 would represent a new antibiotic class (if  approved) and 14 target a novel molecular  bacterial target.  Awardees were based in six  countries.

Issued guidance to support clinical trials. FDA has implemented  programs and issued guidance that help address some regulatory  challenges and encourage antibiotic development. In 2012, through the  Generating Antibiotic Incentives Now provisions of the Food and Drug  Administration Safety and Innovation Act, Congress created the Qualified  Infectious Disease Product (QIDP) designation. Drugs that FDA  designates as QIDPs, which include antibiotics and antifungals, may  qualify for 5 years of additional exclusivity and fast-track or priority review  designation during the FDA review process. The additional exclusivity  conferred to QIDP designees is a type of “pull incentive,” because it offers  the potential for enhanced financial gain after a drug receives FDA  approval and reaches the market. According to FDA officials, as of  September 2019, FDA had granted 192 QIDP designations, 24 of which it  has approved for marketing.

Also in response to the Generating Antibiotic Incentives Now Act, FDA  released final guidance in August 2017 to streamline clinical development  of antibiotics for patients with an unmet medical need—that is, those with  a serious bacterial disease that has few or no treatment options. FDA  explains in this guidance that it may consider drugs for these patients that  have higher risks than would be acceptable for a broad patient population  and provides information on types of antibiotics that could be eligible for  approval based on smaller, shorter, or fewer—as few as only one— clinical trials.

The 21st Century Cures Act required FDA to establish a Limited  Population Pathway for Antibacterial and Antifungal Drugs (LPAD). In  June 2018, FDA issued draft LPAD guidance, as required by the Act.  Under LPAD, eligible products—which are drugs and biologics intended  to treat a serious or life-threatening infection in a limited population of  patients with unmet needs—may follow a streamlined development  program, similar to the approaches described in its earlier unmet medical  need guidance. A biotechnology association noted in its public  comments to the draft LPAD guidance the need for FDA to issue  additional guidance to clarify its expectations for acceptable types of  efficacy data when clinical trials are small and to clarify its interpretation  of a “limited population of patients” for the purpose of the LPAD  pathway. An expert who attended our meeting later told us there is a  great need to address how to develop narrow-spectrum antibiotics—those  designed to treat a single or small number of bacterial pathogens—using  LPAD. FDA held a public meeting in July 2019 to solicit stakeholder  comments on the draft LPAD pathway guidance, and FDA officials told us  they expect to finalize the guidance by February 2020. However, as of  March 17, 2020, FDA had not yet issued final guidance.

In addition to issuing guidance, and to help inform future guidance, FDA  engages with industry stakeholders to discuss and identify possible  solutions to challenges related to the clinical development of antibiotics  and nontraditional products. For example, FDA has held multiple public  workshops, including one in November 2019 with experts from NIH’s  National Institute of Allergy and Infectious Diseases, the Infectious  Disease Society of America, and The Pew Charitable Trusts to better  understand the current state of antibiotic clinical trials in the United  States, and how to enhance enrollment and research in these trials.

FDA officials told us they believe it is too early to issue guidance that  would be broadly applicable and useful to nontraditional product  developers. They explained that for certain types of nontraditional  products, the approaches and specifics of product development are  varied and evolving quickly. Instead, FDA’s Center for Biologics  Evaluation and Research has a program in place that allows developers  to meet with FDA prior to beginning clinical trials to obtain advice on a  wide range of development-related topics.

Implemented Medicare payment mechanisms. CMS uses Medicare  payment mechanisms to help increase reimbursement to hospitals for  certain antibiotics. For qualifying antibiotics, these payments are a form of  indirect pull incentive because they have the potential to increase the  demand for the new antibiotics after they reach the market, which could in  turn improve their financial performance. Beginning in fiscal year 2020,  CMS updated how it will pay hospitals for treating Medicare patients who  have an antibiotic-resistant infection. Specifically, CMS changed the  eligibility criteria and payment amount for antibiotics that qualify for “new  technology add-on payments” and how it pays hospitals for treating  Medicare patients with antibiotic-resistant infections. These payment  changes are:

Revised eligibility criteria for and amount of add-on payments.  New technology add-on payments provide hospitals with additional  compensation for a period of 2 or 3 years when they use qualifying  new technologies or drugs that offer substantially improved clinical  treatment, and when regular Medicare payments for the hospital stay  are inadequate to cover the cost of the new technology or drug.  Generally, medical services and technologies must be new and must  demonstrate a substantial clinical improvement over existing services  or technologies to receive the additional payment. However, CMS  has acknowledged the difficulty antibiotic developers face in  demonstrating such substantial clinical improvement due to  manufacturers seeking FDA approval for most antibiotics on the basis  of noninferiority clinical trials, as described above. To make it easier  for antibiotics to qualify for the additional payments, under the  revisions to the CMS payment policy beginning in fiscal year 2021,  CMS will consider all antibiotics with a QIDP designation from FDA to  be “new” for purposes of the add-on payment, and these antibiotics  will not have to meet the substantial clinical improvement criteria.

In addition, CMS has increased the amount of the temporary add-on  payment for qualifying antibiotics. Prior to this change, the add-on  payments for qualifying antibiotics were limited to 50 percent of the  cost of the drug. Under the new policy, the payment percentage  increased to a maximum of 75 percent of the cost of the drug. CMS  has specified that two antibiotics are eligible for new technology add- on payments in fiscal year 2020.

Increased payment for hospital stays. CMS changed the severity  level designation for certain antibiotic resistance-related diagnosis  codes, in recognition of the added clinical complexity and cost of  treating patients with antibiotic resistance. This change in severity  level can result in higher payments to hospitals when treating patients  diagnosed with antibiotic resistance, which, according to the  Administrator of CMS in an August 2019 blog post, will create  “financial flexibility for physicians to prescribe the appropriate new  antibiotics.” The Administrator also noted that CMS made this  policy change because it recognized that new technology add-on  payments are temporary and “further action was needed to realign  financial incentives for antibiotics for the long-term.”

See appendix III for additional examples of efforts to support antibiotic  R&D by these and other federal agencies.

Federal Efforts Have Not Fully Incentivized Antibiotic Development, and HHS Lacks a Strategy to Develop New Incentives

Experts and antibiotic developers told us that the economic challenges  have remained despite the available federal push and pull incentives for  antibiotic R&D. Currently available premarket push incentives include  grants and awards from NIH and BARDA that fund antibiotic R&D;  currently available postmarket pull incentives include the additional  market exclusivity available through QIDP designation and Medicare add- on payments for antibiotics. (See fig. 3.) Both of the antibiotic companies  that declared bankruptcy in 2019 had received push incentives from  BARDA and pull incentives through Medicare New Technology Add-on  Payments and the QIDP 5-year extension of market exclusivity.

While experts at our meeting and antibiotic developers told us that push  incentives have been helpful, they also said push incentives alone are not  sufficient to sustain antibiotic development. For example, two antibiotic  developers we spoke with explained that push incentives have provided  needed funding for conducting R&D, but said that push incentives will not  help cover the costs they will incur after their drug reaches the market— for example, to manufacture and market their product.

Experts and antibiotic developers have indicated that the effects of the  existing pull incentives, QIDP market exclusivity, and Medicare add-on  payments on stimulating development of new antibiotics have been  limited for the following reasons:

QIDP and market exclusivity. As we previously reported, several  pharmaceutical companies told us that the market exclusivity  incentive may not stimulate the development of new antibiotics,  because the extension is unlikely to extend past the typical patent life  of a new drug. In addition, a representative from The Pew  Charitable Trusts said that, while the passage of the Generating  Antibiotic Incentives Now Act initially bolstered private investments in  antibiotics, it did not ultimately stabilize the pipeline of antibiotics in  development, noting that since then, several large pharmaceutical  companies have discontinued their antibiotics R&D programs.

Medicare updates to hospital payments. While CMS recently  increased new technology add-on payments for certain antibiotics  beginning in fiscal year 2020 to help improve access to antibiotics,  these payments are limited to antibiotics used to treat Medicare  patients. In addition, although Medicare increased the add-on  payment amount to up to 75 percent of the estimated costs of  qualifying antibiotics in excess of the regular Medicare payment,  hospitals could still face costs for providing these drugs that are not  covered by the Medicare payment. Furthermore, representatives from  an antibiotic company and a biotechnology trade association told us  the add-on payments do not directly incentivize hospital pharmacies  to purchase the drug, because the add-on payment may not flow back  to the pharmacy department’s budget. For these reasons, it remains  to be seen whether the Medicare new technology add-on payments to  hospitals for inpatient antibiotics will help improve the return on  investment for antibiotic developers and further stimulate the antibiotic  development pipeline. Similarly, it remains to be seen how CMS’s  policy change that provides increased payments for hospital stays  when Medicare patients have been diagnosed with certain types of  antibiotic-resistant infections will affect hospitals’ use of new  antibiotics.

In light of the limitation of existing incentives for antibiotic development,  experts, federal officials, and antibiotics developers have called for  additional postmarket pull incentives to reinvigorate the pipeline of  antibiotics under development. For example, PACCARB issued  recommendations to the Secretary of HHS in September 2017 and July  2019 for the adoption of pull incentives, calling for the development of  market entry rewards and options for plausible business models. In  addition TATFAR—of which officials from BARDA, CDC, FDA, and NIH  are members—reported that it is critical to develop a pull incentive  strategy now to ensure that enough antibiotics are available in the  future. Former FDA Commissioner Dr. Scott Gottlieb also stated in  2018 that he was “deeply concerned that without stronger pull incentives  that encourage more R&D, we’ll see a far less robust pipeline of products  than we need to address antimicrobial resistance.” Eight of the  antibiotic developers we interviewed told us they think additional financial  incentives are needed. For example, one developer said that sales  revenues from antibiotics will never be sufficient to justify R&D  investments, and another noted that financial incentives are needed  during the first few years after a new antibiotic reaches the market to  cover not only these costs, but also to conduct additional clinical trials to  help expand the drug’s possible market. Finally, several experts at our  expert meeting noted that, without pull incentives, most of the small  companies currently developing antibiotics are unlikely to survive, and  large pharmaceutical companies will likely continue to exit the antibiotic  market.

Advisory groups and others have identified multiple options for how  postmarket pull incentives could be designed, including market entry  rewards—either in the form of lump sum payments or transferable  vouchers that could be sold to confer additional market exclusivity to  other pharmaceutical drugs—or reimbursement reform, such as licensing  arrangements or add-on payments for hospital-administered antibiotics.  (See fig. 4.) The four advisory groups whose papers we reviewed each  recommended market entry rewards as effective pull incentive options.  While Commissioner of the FDA, Dr. Scott Gottlieb proposed an  antibiotics licensing arrangement, which he called a subscription model,  in a 2018 speech.

Views on the utility of reimbursement reform as a pull incentive strategy  are mixed. For example, representatives from The Pew Charitable Trusts  stated their view that, while CMS’s recent changes to Medicare payment  for antibiotics will likely be helpful to some degree, no reimbursement  policy on its own would be able to increase antibiotic sales revenues  sufficiently to transform the business model for antibiotics. An antibiotic  developer we spoke to also told us that reimbursement policies would not  be sufficient to support their business model because of low sales  volumes for new antibiotics. The developer explained that it can take 2 or  3 years of antibiotic sales to recoup their R&D costs and finance their  ongoing business operations, and that while larger pharmaceutical  companies can rely on other profitable drugs to offset those costs, they  could not because they did not have other drugs on the market. However,  a representative from a biotechnology trade association told us that  increasing reimbursement could help alleviate some of the economic  challenges faced by developers of antibiotics that are already on or about  to reach the market while policy makers explore longer-term pull incentive  strategies. TATFAR cautioned that simply increasing reimbursement for  antibiotics could potentially limit patient access, particularly for patients  without health insurance—including those in low-and middle-income  countries—and it could incentivize only antibiotics for common types of  infections with a large market potential, rather than for rare, yet  dangerous, types of pathogens.

Advisory groups and others have evaluated potential market entry reward  models, taking into consideration factors such as format, value, funding  sources, and eligibility criteria. Some have proposed that receipt of a  market entry reward should be delinked, fully or partially, from sales  revenues—that is, the developer would have to forgo some or all sales  revenue as a condition of receiving the reward. Proponents of delinkage  believe that separating revenues from antibiotics sales volumes would  discourage aggressive sales that could lead to overuse. An expert who  attended our meeting later told us that policies to incentivize use of new  antibiotics must be balanced with policies to monitor prescribing of new  drugs to prevent inappropriate use. Generally, advisory groups stipulate  that to maximize the public health benefit, only antibiotics that treat what  are deemed to be high priority bacteria should be eligible for a reward.  Specific recommendations and conclusions included the following:

TATFAR concluded in 2017 that a partially delinked market entry  reward of approximately $500 million would be the least disruptive  option but noted that additional assessment would be necessary to  select the most appropriate model and determine governance and  other design elements.

PACCARB expressed support for a delinked model, in which a  company accepting a market entry reward would be required to forgo  marketing activities and profits based on sales volume. In addition,  they suggested the establishment of an antibiotic incentive fund  supported by an antibiotic usage fee or the sale or auction of  transferable exclusivity vouchers as plausible options for financing pull  incentives.

The Duke University Margolis Center for Health Policy recommended  in 2017 a delinked, public-private market entry reward model. This  model was comprised of publicly funded market entry rewards for  qualifying antibiotics for the first 5 or 6 years, followed by privately  funded “value-based” contracts between antibiotic developers and  health care payors, in which the payor could agree, for example, to  pay a predetermined amount for full access to the antibiotics for a  given population. The Duke-Margolis Center proposal did not  specify a funding source, but it noted multiple options for  consideration, including general government funds, antibiotic use  taxes, or the sale of transferable exclusivity vouchers.

The European DRIVE-AB project recommended in 2018 an  internationally funded, partially delinked market entry reward valued at  approximately $1 billion per antibiotic, paid over the course of 5 or  more years. Recipients of a market entry reward would be allowed  to sell their drug on the private market, but they would agree to certain  marketing restrictions to discourage inappropriate use.

HHS may need to request authority and appropriations to create and  implement certain types of market entry rewards. For example, HHS does  not currently have authority to offer transferable exclusivity vouchers to  antibiotic developers, since that would require a change in statute.  Advisory groups also noted that the various pull incentive approaches  would require additional public or private expenditures and offered  possible sources of funding. For example, in addition to general fund  revenues, PACCARB suggested that pull incentives could be funded  through antibiotic usage fees, the auctioning of transferable exclusivity  vouchers, or by allowing developers of new antibiotics to earn a  transferable exclusivity voucher. The Duke-Margolis Center suggestions  included funding market entry rewards through a yearly per-member fee  for all health insurance plans. Transferable exclusivity vouchers may not  require an independent funding source, because the value of the reward  is based on the sale of the voucher to another drug developer. However,  vouchers would still increase public and private health care expenditures,  because expenditures would likely increase for drugs for which the extra  period of exclusivity was purchased due to the delayed entry of lower- priced generics. Finally, reimbursement reform could increase health care  expenditures for health care payors, including Medicare and private  health insurance carriers.

Although PACCARB, TATFAR, and other experts have called for  additional postmarket pull incentives to increase the antibiotic pipeline, as  of January 2020 HHS has not developed a strategy for creating these  incentives. HHS officials told us that the department created an  interagency workgroup within HHS in spring 2019 to identify possible pull  incentive options, among other things. The recently convened HHS  interagency workgroup is a step in the right direction toward exploring  options for new antibiotic development incentives. Through this  workgroup, HHS has an opportunity to determine which types of  postmarket incentives it believes would most effectively incentivize the  development of new treatments for antibiotic-resistant infections.  However, it is unclear whether the HHS interagency workgroup’s efforts  will include consideration of such incentives because, according to HHS  officials in January 2020, the interagency workgroup was still considering  possible recommendations for HHS leadership and had not produced any  specific documents to share with us.

The Government Performance and Results Act of 1993 (GPRA) and the  GPRA Modernization Act of 2010, which significantly enhanced agencies’  responsibilities under GPRA, include principles for federal agencies to  consider related to developing strategies for achieving results, among  other principles. We have previously reported that these principles can  serve as leading practices for planning at lower levels within agencies,  such as individual programs or initiatives. Our past work has shown  that strategic frameworks can serve as a basis for guiding policy makers,  including congressional decision makers and agency officials, when  making decisions about resources, programs and activities, particularly in  relation to issues that are national in scope, such as antibiotic  development. Developing a strategic framework that outlines new  postmarket pull incentives and their key design elements—such as  monetary value, eligibility criteria, and guidelines to prevent overuse— would be a first step toward identifying potential authorities and resources  that may be needed to create the incentives, and toward determining  agency roles for implementation and oversight of the incentives. Until  such incentives are developed, more drug companies may exit the  antibiotic development sector, and the pipeline of new treatments for  antibiotic-resistant infections may continue to decrease. Furthermore, the  current significant federal investment in push incentives to support  antibiotic R&D will remain a high-risk enterprise, if companies receiving  large R&D grants are unable to sustain their business once their  treatment reaches the market.

Federal Agencies Have Undertaken Several Efforts to Promote the Appropriate Use of Antibiotics, but Key Challenges Remain

Federal agencies have undertaken several efforts to promote the  appropriate use of antibiotics through stewardship programs and  activities. However, four key challenges remain that have limited this  progress.

Federal Agencies Have Undertaken Several Efforts to Promote the Appropriate Use of Antibiotics through Stewardship Programs

To promote the appropriate use of antibiotics across health care settings  through antibiotic stewardship programs and activities, federal agencies  have undertaken several efforts that aim to reduce inappropriate antibiotic  use, reduce health care costs, improve patient outcomes, and combat  antibiotic resistance. Selected examples of these efforts are discussed  below. (For more detailed information on agencies’ efforts to promote the  appropriate use of antibiotics, see app. IV.)

Published Requirements for Hospitals, Long-Term Care, and DOD and VA Facilities to Implement Antibiotic Stewardship Programs

Federal agencies require certain types of health care facilities to  implement antibiotic stewardship programs, as follows:

CMS. In September 2019, CMS finalized new health and safety  requirements for hospitals and critical access hospitals to implement  antibiotic stewardship programs by March 30, 2020, as a condition of  their participation in the Medicare and Medicaid programs. Under  these requirements, hospitals and critical access hospitals are  required, among other things, to implement these programs facility- wide (which includes emergency departments) and to adhere to  nationally recognized antibiotic prescribing guidelines. Nearly 3  years prior, CMS published similar requirements for nursing homes  and skilled nursing facilities—collectively known as long-term care  facilities—to establish antibiotic stewardship programs by December  4, 2017. Experts, including those at our meeting and the  PACCARB, credit these requirements with being a powerful lever for  promoting the appropriate use of antibiotics; Medicare comprises a  significant portion of the nation’s health care expenditures—$741  billion in 2018, covering 59.9 million beneficiaries.

DOD. DOD published a policy, effective October 2017, requiring the  establishment of antibiotic stewardship programs within its military  medical treatment facilities and, one year later, issued guidance for  implementation. Among other things, the policy specified that these  facilities’ antibiotic stewardship programs include components such as  (1) leadership commitment by each facility; (2) accountability; (3)  pharmacy expertise, including antibiotic prescribing and use  evaluation; (4) implementation of action for change that would  demonstrate commitment to the program; and (5) training for  clinicians regarding antibiotic resistance and prescribing practices.  DOD officials told us that all of these facilities (both inpatient and  outpatient) were in different stages of implementing the antibiotic  stewardship policy.

VA. In January 2019, VA updated its 2014 policy directive for the  implementation and maintenance of antibiotic stewardship programs  in its health care facilities, which provide both inpatient and outpatient  services to veterans. This policy directive includes requirements for  its facilities to develop a written policy, conduct an annual evaluation  of stewardship activities, ensure that adequate staff and resources are  in place, and identify medical and pharmacy personnel as stewardship  “champions.” According to department officials, VA has successfully  implemented antibiotic stewardship programs in all of its health care  facilities.

Developed Incentives for Clinicians to Implement Antibiotic Stewardship Activities

CMS has developed incentives for eligible clinicians in any type of health  care facility to improve antibiotic use and stewardship, as part of the  agency’s broader efforts to improve care for Medicare patients.  Through the Merit-based Incentive Payment System (MIPS) launched in  2017, CMS offers hundreds of quality measures and nearly 100  “improvement activities” on a wide range of topics—including the  appropriate use of antibiotics—on which eligible clinicians can choose to  report their performance to the agency. CMS then adjusts payments  higher for clinicians who report data and achieve a performance-based,  final score above a certain threshold—and penalizes clinicians who do  not achieve that threshold with lower payments.

Published Guidance on Implementing Antibiotic Stewardship Programs

Federal agencies have published guidance for health care facilities on  how to implement antibiotic stewardship, as follows:

AHRQ. Through a 5-year nationwide project, the AHRQ Safety  Program for Improving Antibiotic Use has provided technical  assistance and CDC’s guidance to hospitals, long-term care settings,  and physicians’ offices to promote implementation of antibiotic  stewardship activities and help clinicians select optimal antibiotic  treatment regimens. In December 2018, AHRQ completed  implementation of this guidance in more than 400 hospitals, which  included six DOD facilities and 79 critical access hospitals, according  to AHRQ officials.

CDC. Since 2014, CDC has published a series of guidance  documents—called the Core Elements of Antibiotic Stewardship (Core  Elements)—to promote the appropriate use of antibiotics in health  care. The Core Elements are tailored to hospitals, nursing homes,  outpatient settings, small and critical access hospitals, and low- and  middle-income countries with limited resources. Common elements in  these guidance documents include (1) leadership commitment, (2)  implementation of policies and interventions to improve antibiotic use,  (3) tracking and reporting antibiotic use, and (4) education to  providers on appropriate antibiotic use.

Expanded the Collection of Antibiotic Use Data

For more information on MIPS, see GAO, Health Care Quality: HHS Should Set Priorities  and Comprehensively Plan Its Efforts to Better Align Health Quality Measures, GAO-17-5  (Washington, D.C.: Oct. 13, 2016) and Medicare: Small and Rural Practices’ Experiences  in Previous Programs and Expected Performance in the Merit-based Incentive Payment  System, GAO-18-428 (Washington, D.C.: May 31, 2018). other sources. In particular, CDC has focused its efforts to expand  antibiotic use data collection from hospitals, where an estimated one in  two patients receives an antibiotic for at least one day during an average  hospital stay. CDC launched its AU Option in 2011 as a voluntary,  electronic reporting tool added on to the pre-existing NHSN. The AU  Option allows the nation’s 6,849 hospitals that are already reporting to the  NHSN to submit their antibiotic use data in a standardized format. CDC  then aggregates such data to calculate national benchmarks and allows  hospitals to compare their actual antibiotic use against those  benchmarks. In addition, CDC has periodically conducted prevalence  surveys through the EIP to gather data on health care-associated  infections and antibiotic use in about 200 hospitals and 161 nursing  homes in 10 states. With regard to outpatient settings, CDC has acquired,  through a proprietary source, 8 years of pharmacy data on antibiotic  prescriptions since 2011, which the agency is using to better characterize  patterns in outpatient prescribing and to develop targeted interventions for  high-prescribing areas.

Developed Antibiotic Stewardship Training for Various Health Care Settings

Federal agencies have developed training on antibiotic stewardship, as  follows:

CDC. In 2018, CDC launched a free, online training course for various  types of clinicians—including physicians, dentists, pharmacists,  physician assistants, and nurses—to inform them about proper  antibiotic prescribing and strategies for communicating with  patients. Clinicians can receive credit for partial completion (at least  50 percent) or full completion of this training as improvement activities  under MIPS in 2019.

CMS. CMS has provided training, technical assistance, and other  learning opportunities to more than 4,000 hospitals, 2,400 nursing  homes, and 7,600 outpatient settings on best practices for antibiotic  stewardship and guidance on C. difficile prevention. In addition, CMS  and CDC have developed and launched free, online training to help  nursing homes implement antibiotic stewardship and prevent and  manage C. difficile infections.

DOD and VA. These departments have also offered antibiotic  stewardship training to their health care facilities through webinars,  workshops, or briefings.

Federal agencies have funded research on antibiotic stewardship, as  follows:

AHRQ. Since 2015, AHRQ has increased its support for research to  develop improved methods to combat antibiotic resistance and  promote antibiotic stewardship, including through grants for research  that will total more than $57 million, according to AHRQ officials. This  research includes studies on the role of diagnostic tools in improving  antibiotic use and reducing antibiotic resistance. AHRQ has also  published numerous research studies on antibiotic or antimicrobial  stewardship that the agency funded or authored.

CDC. CDC supports research to identify, develop, and implement  practices to stop the spread of resistance and to promote appropriate  use of antibiotics in health care. CDC also supports research to fill  gaps in knowledge related to aspects of antibiotic use and resistance  that have public health impact. According to agency officials, CDC has  provided approximately $110 million since 2016 to support this  research through cooperative agreements and contracts.

Continued National Public Awareness Campaign

In 2017, CDC revised a national campaign to promote public awareness  about appropriate antibiotic use. The campaign, called “Be Antibiotics  Aware: Smart Use, Best Care,” is aimed at both health care providers and  the general public and refines the message from CDC’s earlier campaign  (“Get Smart: Know When Antibiotics Work”).

HHS’s Office of Global Affairs has collaborated with other countries,  including those participating in the TATFAR program, to promote the  appropriate use of antibiotics internationally. In addition, CDC and the  Office of Global Affairs launched the Antimicrobial Resistance Challenge  at the United Nations General Assembly in September 2018 to catalyze  global action against antibiotic resistance. A year later, CDC announced  this challenge had resulted in nearly 350 commitments from government  health officials, pharmaceutical and health insurance companies, and  others from 33 countries to make formal commitments that further the  progress against antimicrobial resistance, such as by improving  appropriate antibiotic use.

Four Key Challenges Have Limited Federal Efforts to Promote the Appropriate Use of Antibiotics

We identified four key challenges that have limited progress in federal  efforts to promote the appropriate use of antibiotics, based on our  analysis of documents, interviews with agency officials and experts, and  other information. First, federal requirements for antibiotic stewardship  programs apply only to certain types of health care facilities, and federal  incentives for clinicians to adopt antibiotic stewardship activities are  optional, limiting implementation of antibiotic stewardship across the  health care spectrum. Second, CDC faces challenges in collecting  complete antibiotic use data, limiting the agency’s ability to monitor and  improve antibiotic use. Third, the CARB Task Force has not identified and  reported on agencies’ plans to address the challenges related to  expanding antibiotic stewardship programs and antibiotic use data  collection across health care settings, so these plans are not publicly  known. Fourth, antibiotic stewardship training for health care providers  may have limited success in improving antibiotic prescribing behavior,  and federal agencies indicate that it is challenging to evaluate the  effectiveness of such training.

Federal Requirements and Incentives Are Limited

Federal requirements for antibiotic stewardship programs are limited to  certain types of health care facilities, and federal incentives for antibiotic  stewardship activities are optional and limited to eligible Medicare  clinicians, such as physicians.

Federal requirements for antibiotic stewardship programs are  limited to certain types of health care facilities. As previously  noted, federal requirements for antibiotic stewardship programs are  currently limited to hospitals and critical access hospitals, long-term  care facilities such as nursing homes, and DOD and VA health care  facilities. However, CMS has not yet developed requirements for  ambulatory surgery centers or dialysis centers to implement antibiotic  stewardship programs, which the National Action Plan called for being  implemented by March 2018. CMS officials told us that the agency  would develop those requirements once the rule for hospitals and  critical access hospitals—which was delayed—was finalized. In  addition, CMS’s health and safety requirements do not extend to other  types of outpatient settings—such as physicians’ offices, retail clinics,  and urgent care centers—where inappropriate antibiotic use has  been found to be high.

In the absence of regulatory levers, CDC and AHRQ encourage those  types of facilities to establish antibiotic stewardship programs on a  voluntary basis. Experts, including those at our meeting, indicate that  expansion of antibiotic stewardship across the health care spectrum is  likely to remain limited without additional federal requirements or other  meaningful incentives—thus hindering the nation from fully achieving  the benefits of appropriate antibiotic use. Such benefits include better  patient outcomes, lower health care costs, and slower growth of  antibiotic resistance.

CMS incentives for clinicians to improve antibiotic use are  optional, and implementation has been limited. The MIPS  program’s effect on incentivizing appropriate use of antibiotics is  limited, in part, because the incentives are available only to clinicians  who meet MIPS eligibility criteria and because eligible clinicians can  choose not to report data to CMS. In addition, participating clinicians  have a wide range and number of quality measures and improvement  activities, beyond those related to antibiotics, from which the clinicians  can choose to report data to CMS to meet program requirements;  thus, the likelihood that clinicians will choose to report on antibiotics- related measures or activities may remain low. For example, in 2017,  MIPS-eligible clinicians were generally required to select and submit  data to CMS on six out of 271 available quality measures; we  identified nine of those measures as being related to antibiotics.  MIPS-eligible clinicians were also generally required to select and  submit data that year for up to four out of 93 available improvement  activities; we identified one such activity as being related to  antibiotics.

Our analysis of CMS data on MIPS participation in 2017, the  program’s first performance year and the most recently available data,  indicates that implementation of the antibiotics-related quality  measures and improvement activities was limited. According to a  CMS report, a total of 1,057,824 clinicians were eligible for MIPS in  2017, of which 1,006,319 clinicians, or 95 percent, reported data.  Based on our analysis of data contained in the CMS report’s  appendix, the number of 2017 MIPS-participating clinicians who  reported to CMS on the nine antibiotics-related quality measures  ranged from 844 clinicians to 33,631 clinicians; the measure on  appropriate treatment for children with an upper respiratory infection  was the most reported antibiotics-related measure. By contrast, the  most frequently reported quality measures overall in 2017 were  controlling high blood pressure (510,723 clinicians), preventive care  and screening for tobacco use (492,357), and breast cancer  screening (473,819).

CMS’s data also show that for the 2017 MIPS improvement activities,  47,645 of the 1,006,319 participating clinicians reported on the one  improvement activity related to antibiotics that year: implementation of  an antibiotic stewardship program. Specifically, this activity referred  to implementation of an antibiotic stewardship program that measured  the appropriate use of antibiotics for several different conditions  (upper respiratory infections in children, pharyngitis, and bronchitis in  adults), according to clinical guidelines for diagnostics and  therapeutics.

CDC Faces Challenges in Collecting Complete Antibiotic Use Data, Limiting the Agency’s Ability to Monitor and Improve Appropriate Use

CDC’s ability to monitor and improve appropriate antibiotic use is limited  by challenges it faces in collecting complete antibiotic use data across  health care settings. According to CDC, experts we interviewed, and  documents we reviewed, more data are needed to identify the extent of  antibiotic use, including inappropriate use. In turn, CDC and experts say  that more antibiotic use data would enable health care providers, federal  agencies, and others to identify and target areas for improvement, track  results over time, and adjust antibiotic stewardship activities as  needed. We have also previously reported that monitoring antibiotic  use over time in both inpatient and outpatient settings is important for  understanding patterns in antibiotic resistance and for targeting  stewardship activities. In addition, WHO notes that data on global  antibiotic use is essential for obtaining a comprehensive picture of  antibiotic resistance and for identifying areas where actions are  needed.

Despite progress in collecting antibiotic use data (as previously  discussed), CDC faces several challenges in its efforts to collect complete  antibiotic use data. For example, health care providers across various  inpatient and outpatient settings do not record such data in one  centralized, electronic database. In addition, CDC officials told us that  there are no uniform requirements at the federal level (with the exception  of DOD and VA hospitals) for providers to report their antibiotic use data  to a centralized database such as the NHSN AU Option, and, according  to CDC officials and experts we interviewed, data collection can be costly  for CDC and health care providers. Because of these and other  challenges, CDC relies on data voluntarily reported by hospitals through  the AU Option, and the agency collects its own data or purchases  proprietary pharmacy data to estimate antibiotic use—and, to some  degree, to assess appropriateness of use—across health care settings.  However, these data are incomplete owing to several limitations, as  described by type of setting below.

Hospitals. Our analysis of CDC data shows that although the number  of hospitals participating in the AU Option has gradually risen since its  launch in 2011, participation remains limited, with 1,561, or 23  percent, of the 6,849 eligible hospitals reporting at least one month of  antibiotic use data as of January 1, 2020. (See fig. 5 for a map  showing the percentage of U.S. hospitals reporting antibiotic use data  to the AU Option, by state, plus the District of Columbia and Puerto  Rico, as of August 2019.) While CDC officials told us they considered  this level of participation to be an accomplishment given that  participation is voluntary, the National Action Plan set 95 percent  participation in the AU Option by 2020 as a significant outcome to  support the plan’s goal to strengthen national surveillance efforts to  combat resistance.

Experts, including those at our meeting, cite multiple challenges that CDC  faces in collecting hospitals’ antibiotic use data through the AU Option.  For example, The Pew Charitable Trusts has stated that current,  voluntary data are limited and that mandatory reporting would provide the  data needed to establish a more accurate baseline of antibiotic use,  identify stewardship interventions that would be most effective, and  measure progress toward reducing inappropriate prescribing. An expert who attended our meeting later suggested that CMS could implement a  pay-for-reporting program to incentivize hospitals to report data to the AU  Option, and that the program could transition to a pay-for-performance  program over time. In addition, experts we interviewed told us that a  participating hospital must be willing to spend as much as tens of  thousands of dollars for a vendor to customize software for their  electronic health record systems to use the AU Option, in addition to  investing time training staff on how to use it. CDC officials also told us  that the agency lacks the authority to require hospitals to report their  antibiotic use data, and that there is currently no federal funding available  to assist hospitals with the investment needed to participate in the AU  Option. Furthermore, hospitals’ voluntary participation in the AU Option  may remain limited until CDC’s benchmark measures are adequately risk- adjusted for different locations and patient populations. For example,  one expert we interviewed said that because the AU Option currently  aggregates data on the volume of antibiotics used without adequate risk  adjustment, a hospital with a patient population that might warrant higher  use of antibiotics may be reluctant to report its antibiotic use data to avoid  looking like an unnecessarily high prescriber. Regarding another data  source for antibiotic use in hospitals, CDC’s EIP provides more granular  data at the patient level that allows CDC to assess the appropriateness of  antibiotic use. However, CDC officials told us that the agency has been  unable to repeat its hospital prevalence survey since 2015 due to  insufficient resources (the next survey is expected in 2020) and that the  survey encompasses a limited number of hospitals, patients, and states.

Nursing homes. According to CDC, nursing homes may be the most  challenging health care setting from which the agency collects  antibiotic use data; CDC officials stated that this is because electronic  health record systems, from which data could be easily accessed, are  less common in nursing homes. In addition, CDC officials stated  that the agency’s collection of antibiotic use data through the EIP  nursing homes prevalence survey has been limited in scope and  frequency due to insufficient resources.

Outpatient settings. Collecting data for outpatient settings, such as  retail pharmacies, is also challenging. For example, CDC officials  stated that one proprietary source from which CDC purchases data  reflects the volume of pharmacy antibiotic prescriptions, but the data  do not contain diagnostic information, preventing the agency from  evaluating the appropriateness of those prescriptions. Other CDC or  proprietary data sources from which the agency collects or purchases  antibiotic use data are limited by the frequency with which those  sources release such data, the age range of patients included in the  data (i.e., whether they are over or under 65 years), or other  characteristics. As previously noted, approximately 85 to 95 percent of  the nation’s antibiotic use, by volume, occurred in outpatient settings  from 2010 through 2015.

The CARB Task Force Has Not Identified Plans to Address Challenges Related to Expanding Stewardship Programs and Antibiotic Use Data Collection

The National Action Plan calls for strengthening antibiotic stewardship  and for the timely reporting of antibiotic use data across health care  settings. Executive Order No. 13676, as previously noted, directs the  CARB Task Force to provide annual updates to the President on federal  government actions to combat antibiotic resistance, including progress  made in implementing the National Action Plan and plans for addressing  any barriers preventing its full implementation. These annual updates  are to include specific goals, milestones, and metrics for proposed actions  and recommendations, taking into consideration federal resources.  However, in its progress reports covering the first four years of the  National Action Plan’s implementation—which were provided to the  President and the public—the CARB Task Force has not identified plans  to address barriers that agencies face in expanding antibiotic stewardship  programs across health care settings. For example, the task force did  not include in the progress reports CMS’s plans to address barriers to  expanding its requirements for antibiotic stewardship programs in  hospitals, which were delayed, or in certain other types of health care  facilities.

In addition, in its progress reports to date, the CARB Task Force has not  identified plans to address the barriers to expanding the collection of antibiotic use data across health care settings. For example, the task  force did not include in the progress reports CDC’s plans to address  barriers to achieving the significant outcome of 95 percent of eligible  hospitals participating in the AU Option by 2020, although participation  was only 23 percent as of January 1, 2020. The CARB Task Force  coordinators said, in response to our inquiries during this review, that the  task force intends to identify agencies’ plans for addressing barriers in the  Year 5 progress report to be published in fall 2020. However, the  coordinators also stated that the progress reports to date have not  identified plans to address barriers largely because the task force focused  on reporting the agencies’ accomplishments in implementing the National  Action Plan. Until the CARB Task Force identifies and reports on  agencies’ plans to address barriers related to the expansion of antibiotic  stewardship programs and the collection of antibiotic use data across  health care settings to the extent feasible, the federal government will not  have reasonable assurance that it is fully implementing the National  Action Plan and addressing antibiotic resistance.

Antibiotic Stewardship Training May Have Limited Success in Improving Prescribing Behavior

While training is recognized as one component of an antibiotic  stewardship program, such training may have limited success in  improving antibiotic prescribing behavior, and federal agencies indicate  that it is challenging to evaluate the training’s effectiveness. CDC officials  and experts say that inappropriate antibiotic use could be improved  through stewardship training, but it is challenging because antibiotic  prescribing behavior is driven by multiple factors and can be difficult to  change. For example, a PACCARB report stated that prescribers often  feel pressure to prescribe antibiotics—even when antibiotics may not be  warranted—because of their perception that a patient is demanding such  a prescription, or a patient’s actual demand. In addition, CDC notes  that antibiotics are frequently prescribed for respiratory conditions most  commonly caused by viruses such as the common cold, against which  antibiotics are ineffective. Other factors that drive antibiotic prescribing behavior, as cited by experts, include habit, which may stem from what  physicians and other prescribers learn during their residencies or observe  in the workplace; the time it takes to explain to a patient why an antibiotic  is inappropriate; and “decision fatigue” caused by tiredness or hunger.  (See table 4 for examples of factors that drive or deter antibiotic  prescribing behavior.)

Nevertheless, federal agencies plan to evaluate the effectiveness of their  antibiotic stewardship training programs to some extent, although the  National Action Plan does not require the agencies to do so. For example,  CDC officials told us that their online training course for various types of  clinicians allows participants to fill out an evaluation that includes  questions about whether the participant will be able to apply knowledge  gained from the course, which the agency will use to refine and update  the course. In addition, for the antibiotic stewardship training for  nursing homes that CDC and CMS jointly developed, CDC officials told us  that participants will be asked 6 months after the training whether  participants implemented stewardship practices—and whether there have  been reductions in antibiotic use—as a result of the training. However,  CMS, DOD, and VA officials noted that it is difficult to isolate and  measure the effectiveness of antibiotic stewardship training specifically on  antibiotic prescribing behavior—compared to other, concurrent federal  efforts, such as requirements and guidance to promote appropriate  antibiotic use. For example, DOD officials told us that their department  has looked at antibiotic use data from DOD health care facilities as a  “surrogate” to evaluate whether antibiotic stewardship in general has  been effective—but noted that is an imperfect measure since there are  many factors that affect antibiotic prescribing behavior, and training is  only one of several interventions aimed at reducing inappropriate  antibiotic use.

Antibiotic resistance has been characterized as one of the greatest public  health threats the world faces. A concerted effort involving coordination of  multiple stakeholders and countries and across health fields is critical to  helping ensure that bacterial infections remain treatable. Steps by federal  agencies to expand surveillance, facilitate the development and use of  new diagnostic tests, fund R&D for the development of new treatments,  and issue requirements and guidance for antibiotic stewardship programs  are important efforts toward addressing the problem of antibiotic  resistance and implementing the National Action Plan.

Significant challenges to conducting surveillance remain. For example,  CDC has not determined the participation rates or appropriate distribution  of participating hospitals needed by the voluntary antibiotic-resistance  reporting option to achieve CDC’s goal of conducting regional and  national assessments of resistance. By taking steps to determine the  participation rates and distribution needed for this option, CDC would  have more reasonable assurance that it can achieve its goal. CDC  classified gonorrhea as one of the most urgent resistant threats in the  nation, but collects limited specimens—representing an estimated 1 to 2  percent of the reported cases in the United States—for GISP, its primary  surveillance system for resistant gonorrhea. However, CDC has not fully  evaluated the representativeness of the trends identified by this  surveillance system. By evaluating GISP to ensure that it includes  measures of its representativeness, such as comparing the trends in the  sample population with those in the overall U.S. population, using  specially designed studies if needed, CDC would have better assurance  that the trends detected in GISP accurately reflect the characteristics of  the health-related outcome the system is designed to monitor. Further,  neither the 2013 nor the 2019 Threats Reports provided quantitative  measures of uncertainty for CDC’s estimates of morbidity and mortality  resulting from antibiotic-resistant infections. Providing such measures,  such as standard errors or confidence intervals, as appropriate, in its  Threats Reports would help CDC and others compare information within  and across reporting efforts, and draw appropriate conclusions about the  characteristics of antibiotic resistance in the United States, including  limitations associated with reported findings and conclusions. Finally,  there has been a 6-year interval between CDC’s reports on antibiotic  resistance threats. By developing a plan for more frequent dissemination  of consolidated reporting on priority pathogens at regular intervals, CDC  would have more timely trend data and other information necessary for  users of the data, including policymakers, to prioritize, plan, implement,  and evaluate public health actions to address antibiotic resistance.

HHS has funded some studies to assess whether certain tests for  antibiotic resistance lead to improved clinical outcomes, including more  effective treatment for patients or more judicious use of antibiotics.  However, HHS agencies that are in a position to conduct or fund such  studies have not identified leadership, roles, and responsibilities to help  further such efforts. By taking steps to identify leadership, roles, and  responsibilities, agencies could more effectively address the need for  clinical outcomes studies, potentially increasing test use, improving  patient care, and enhancing stewardship efforts. In addition, for its part,  FDA has not regularly monitored tests for antibiotic resistance to assess  breakpoint updates or evaluated any effects of using tests for antibiotic  resistance with out-of-date breakpoints. By regularly monitoring and  evaluating FDA-authorized tests that rely on breakpoints, FDA would be  able to determine whether test manufacturers are updating breakpoints  as needed and help ensure that patient care and infection control efforts  are effective.

While government push incentives to support antibiotic R&D have been  helpful, experts and antibiotic developers have indicated that push  incentives alone are not sufficient to sustain antibiotic development.  PACCARB, TATFAR, and other experts have called for additional  postmarket pull incentives to increase the antibiotic pipeline, but HHS  does not have a strategy for doing so. Developing a strategic framework  that outlines key design elements of new incentives would be a first step  toward identifying potential authorities and resources that may be needed  and determining agency roles for implementation and oversight of the  incentives. Until such incentives are developed, more drug companies  may exit the antibiotic development sector, and the pipeline of new  treatments may continue to decrease.

Finally, in its progress reports covering the first four years of the National  Action Plan’s implementation, the CARB Task Force did not identify  plans, as required by the Executive Order, to address barriers that  agencies face in fully implementing the National Action Plan, such as  expanding (1) a CDC program designed to strengthen the U.S. response  to resistant gonorrhea; (2) antibiotic stewardship programs across health  care settings; and (3) antibiotic use data collection, to the extent feasible.  Without identifying plans to address these and other challenges, the  federal government cannot assure that the country is prepared to  overcome the urgent health consequences of antibiotic resistance. Until  the CARB Task Force, which is coordinated by HHS officials, identifies  and reports on agencies’ plans to address barriers preventing full  implementation of the National Action Plan, the federal government will  not have reasonable assurance that it is fully implementing the National  Action Plan and addressing antibiotic resistance.

We are making a total of eight recommendations, including four to CDC,  three to HHS, and one to FDA. Specifically:  The Director of CDC should take steps to determine participation rates  and distribution needed in the AR Option of the National Healthcare  Safety Network for conducting regional and national assessments of  antibiotic resistance of public health importance. (Recommendation 1)

The Director of CDC should ensure that CDC’s evaluation of its  surveillance system for antibiotic-resistant gonorrhea includes measures  of its representativeness, such as comparison of the trends in the sample  population with those in the overall U.S. population, using specially  designed studies if needed. (Recommendation 2)

The Director of CDC should provide information on uncertainties for  antibiotic resistance estimates in its consolidated Threats Reports,  including standard errors or confidence intervals, as appropriate.  (Recommendation 3)

The Director of CDC should develop a plan for timely, consolidated  reports of antibiotic resistance in priority pathogens at regular intervals.  (Recommendation 4)

The Secretary of HHS should identify leadership and clarify roles and  responsibilities among HHS agencies to assess the clinical outcomes of  diagnostic testing for identifying antibiotic-resistant bacteria.  (Recommendation 5)

The Commissioner of FDA should direct the Center for Devices and  Radiological Health to conduct additional monitoring and evaluation of the  status of FDA-authorized tests that rely on breakpoints, on a regular  basis, to determine whether test manufacturers are updating breakpoints,  seeking additional resources as needed. (Recommendation 6)

The Secretary of HHS should develop a strategic framework to further  incentivize the development of new treatments for antibiotic-resistant  infections, including through the use of postmarket financial incentives,  and, if appropriate, make recommendations to Congress for necessary  authority. (Recommendation 7)

The Secretary of HHS should direct the CARB Task Force to include in its  annual updates to the President plans for addressing any barriers  preventing full implementation of the National Action Plan and, as  appropriate, make recommendations for new or modified actions.  Specifically, the CARB Task Force should identify plans to address  barriers, such as those related to expanding (1) a CDC program designed  to strengthen the U.S. response to resistant gonorrhea; (2) antibiotic  stewardship programs across health care settings; and (3) antibiotic use  data collection across health care settings, to the extent feasible.  (Recommendation 8)

We provided a draft of this report to DOD, VA, and HHS for review and  comment. DOD and VA did not provide formal comments but generally  agreed with our report.

In its comments, reproduced in appendix V, HHS generally concurred  with our findings and seven of our recommendations, and did not concur  with one of our recommendations, as discussed below. HHS identified  several actions it intends to take to address our recommendations. DOD  and HHS also provided technical comments, which we incorporated as  appropriate.

In response to our first recommendation, HHS concurred and CDC stated  it is working with public health partners to promote the voluntary use of  the AR Option, providing technical support to states that may be  considering a state or local mandate to require AR and AU reporting, and  developing pilot programs to assess AR Option data and other data  sources for certain types of antibiotic resistance. While these actions are  helpful, we believe taking additional steps, such as determining goals for  participation rates and distribution for AR Option reporting, would give  CDC more reasonable assurance that hit can conduct regional and  national assessments of resistance.

In response to our second recommendation, HHS concurred and CDC  stated it is taking additional efforts to examine the representativeness of  data collected through its primary surveillance system for resistant  gonorrhea, including working to develop laboratory methods to reduce  dependence on cultured isolates. CDC stated that steps to refine and  improve collection of resistant gonorrhea data require additional  resources. We believe that CDC requesting such resources would help  ensure that such data are representative of the overall U.S. population.

HHS generally concurred with our third recommendation. CDC stated it  feels that it is critical to publish the data after peer review and then plans  to link the publications back to online resources of the 2019 Threats  Report. We believe that peer-reviewed publication is important, but it is  also important for CDC to take additional steps to establish and report  uncertainties for the national estimates or summary data that would help  CDC and others draw appropriate conclusions about the characteristics of  antibiotic resistance in the United States.

In response to our fourth recommendation, HHS concurred and CDC  stated it has plans to update its enterprise-wide AR Threats Report every  three years, and that it also issues regular reports on specific groups of  pathogens.

In response to our fifth recommendation, HHS concurred and stated that  the CARB Task Force leadership will work with relevant HHS agencies to  clarify roles and responsibilities and identify leadership, if appropriate, for  supporting research on clinical outcomes delated to diagnostic tests.

HHS concurred with our sixth recommendation, and FDA concurred with  conducting additional monitoring and evaluation of tests relying on  breakpoints when FDA identifies or recognizes new breakpoints. FDA  stated that it has taken major steps to help address challenges  associated with updating such tests to reflect the most current  breakpoints. We believe that in addition to these steps, monitoring and  evaluation of current FDA-authorized tests that may still be using out-of- date breakpoints will enhance FDA’s ability to provide assurance that  patient care and infection control efforts are effective.

HHS did not concur with our seventh recommendation that HHS should  develop a strategic framework to further incentivize the development of  new treatments for antibiotic-resistant infections, including through the  use of postmarket financial incentives. HHS noted that, while it agrees  that additional incentives are needed to address the limited pipeline for  novel and innovative treatments to combat antibiotic resistance, it is still  conducting analyses to understand whether postmarket incentives should  be included as a component of its forthcoming strategic framework to  further incentivize the development of new treatments. However, HHS did  not specify when its framework would be released. We support HHS’s  efforts to develop such a framework, as this is a complex issue with  multiple factors to consider. However, we believe our recommendation is  still warranted. Antibiotic resistance is one of the greatest global public  health threats, and experts, including the WHO, have warned that the  pipeline of new antibiotics in development is insufficient to combat the  threat. Without an adequate arsenal of treatments, we are likely to see  increasing mortality caused by these deadly infections. As we reported,  experts, advisory groups, federal officials, and antibiotic developers have  all called for additional postmarket incentives to reinvigorate the pipeline  of antibiotics under development. The current significant federal  investment in push incentives to support antibiotic R&D is helpful but will  ultimately be ineffective if companies receiving this investment are unable  to sustain their business once their treatment reaches the market.  Therefore, we maintain that it is important that HHS not delay the  development of a strategic framework that includes postmarket  incentives, which is just an initial step toward the creation of these  incentives. Until additional postmarket incentives are developed, more  drug companies may exit the antibiotic development sector, and the  pipeline of new treatments for antibiotic-resistant infections may continue  to decrease.

In response to our eighth recommendation, HHS concurred and stated  that beginning in 2020 and continuing annually thereafter, the CARB Task  Force’s progress reports will include discussion of any barriers preventing  full implementation of the National Action Plan, including, as appropriate,  barriers that GAO has identified. We emphasize that the CARB Task  Force should also identify plans to address such barriers—and, as  appropriate, make recommendations for new or modified actions—in  future progress reports, in accordance with Executive Order No. 13676.

As agreed with your offices, unless you publicly announce the contents of  this report earlier, we plan no further distribution until 30 days from the  report date. At that time, we will send copies to appropriate congressional  committees; the Secretaries of DOD, HHS, and VA; and other interested  parties. In addition, the report will be available at no charge on the GAO  website at http://www.gao.gov.

If you or your staff have any questions about this report, please contact  us at (202) 512-6888 or personst@gao.gov, or (202) 512-7114 or  deniganmacauleym@gao.gov. Contact points for our Offices of  Congressional Relations and Public Affairs may be found on the last page  of this report. GAO staff who made key contributions to this report are  listed in appendix VI.

Appendix I: Objectives, Scope, and Methodology

This report examines: (1) the Centers for Disease Control and  Prevention’s (CDC) efforts to address surveillance of antibiotic resistance  and any challenges to these efforts; (2) federal efforts to advance the  development and use of diagnostic tests for identification and  characterization of resistant bacteria and to address barriers to the  development of diagnostic tests; (3) challenges to developing new  treatments for antibiotic-resistant infections and federal efforts to address  the challenges; and (4) federal efforts to promote the appropriate use of  antibiotics and any challenges that remain.

We focused our review primarily on agency actions since 2015, when the  National Action Plan for Combating Antibiotic-Resistant Bacteria (National  Action Plan) was published. We also focused our review on human  health, as we have reported on federal efforts to address the use of  antibiotics in food animals and recommended actions to improve these  efforts for more than 20 years. Additionally, we focused our review on  antibiotic-resistant bacteria. We generally excluded federal efforts related  to infection prevention and control in human health care, on which we  have previously reported.

To address all four objectives, we reviewed relevant agency reports and  documents, such as CDC’s report, Antibiotic Resistance Threats in the  United States, 2013 (2013 Threats Report); conducted interviews with  officials from federal agencies, experts, and stakeholder organizations;  and we reviewed relevant literature, policy papers, and GAO reports. We  interviewed officials from federal agencies responsible for implementing  the aspects of the National Action Plan related to our research objectives:  the Department of Health and Human Services’ (HHS) Office of the  Assistant Secretary for Planning and Evaluation, the Biomedical  Advanced Research and Development Authority (BARDA), CDC, the  Centers for Medicare & Medicaid Services (CMS), the Food and Drug  Administration (FDA), the National Institutes of Health (NIH), and the  Office of Global Affairs; as well as the Department of Defense (DOD) and  the Department of Veterans Affairs. We also interviewed experts and  representatives from organizations involved in public health and  epidemiology, infectious diseases and microbiology, antibiotic research  and development (R&D), antibiotic stewardship, and other issues relating  to antibiotic resistance. Because antibiotic resistance is a global problem,  we also interviewed officials from the World Health Organization (WHO),  the European Centre for Disease Prevention and Control, the European  Medicines Agency, the Wellcome Trust, Public Health England, and the  Surveillance and Epidemiology of Drug-Resistant Infections Consortium  about various aspects of our review; and we reviewed relevant  documents from these entities. We identified experts and organizations  through literature and other documents we reviewed and through referrals  from agency officials and other experts we interviewed. In addition, we  attended several meetings and reviewed summaries of meetings held by  the Presidential Advisory Council on Combating Antibiotic-Resistant  Bacteria (PACCARB). Furthermore, we attended two conferences related  to antibiotic resistance: the World Anti-Microbial Resistance Congress  and the Gordon Research Conference on chemical and biological threat  defense, the latter of which had a session devoted to antibiotics and  antibiotic resistance. For each of our objectives, we identified and  reported on actions taken by federal agencies and key challenges that the  agencies face in addressing antibiotic resistance. We evaluated the  actions taken by federal agencies against relevant criteria, as applicable.

In addition, in September 2018, we convened a meeting of experts in  antibiotic resistance epidemiology, diagnostic testing, antibiotic  development, and antibiotic stewardship. This meeting of experts was  planned and convened with the assistance of the National Academy of  Sciences to better ensure that a breadth of expertise was brought to bear  in its preparation; however, all final decisions regarding meeting  substance and expert participation are the responsibility of GAO. Any  conclusions and recommendations in GAO reports are solely those of the  GAO. The Board on Population Health and Public Health Practice within  the National Academy of Sciences solicited expert nominations from  academia, public health laboratories, industry, and other organizations  working in topics relating to antibiotic resistance. From their list of 51  nominees, and additional nominees we independently identified, we  convened a meeting of 18 experts selected for their knowledge and  expertise related to antibiotic resistance epidemiology, diagnostic testing,  antibiotic development, and antibiotic stewardship. Eleven of the 18  experts who participated in our meeting also reviewed and provided  comments on a draft of our report. We refer to such experts in this report  as “experts at our meeting;” appendix II contains a list of the expert  participants.

To examine CDC’s efforts to address surveillance for antibiotic resistance  and any challenges to these efforts, we reviewed documentation and  conducted interviews with agency officials and other key stakeholders on  each of the surveillance systems across CDC that track antibiotic  resistance and reviewed CDC’s 2013 Threats Report and CDC’s  Antibiotic Resistance Threats in the United States, 2019 data. We further  focused our review on the 17 priority disease-causing bacteria listed in  CDC’s 2013 Threats Report. The CDC surveillance systems included:

Antibiotic Resistance Laboratory Network

Gonococcal Isolate Surveillance Program (GISP)

National Antimicrobial Resistance Monitoring System (NARMS)

National Healthcare Safety Network (NHSN)

National Notifiable Diseases Surveillance System

National Tuberculosis Surveillance System  For NHSN, we also assessed health care facility participation data by  state and territory. We assessed the reliability of these data by reviewing  them for any outliers or anomalies and by inquiring with agency officials  about their source and any known reliability issues. We determined that  these data were sufficiently reliable for assessing facility participation  rates by U.S. state and territory. Stakeholder organizations we  interviewed represented state and territorial epidemiologists and other  public health officials (the Council of State and Territorial Epidemiologists  and the Association of State and Territorial Health Officials) and an  international consortium to address challenges in surveillance of antibiotic  resistance (the Surveillance and Epidemiology of Drug-resistant  Infections Consortium). We also reviewed reports on antibiotic resistance  surveillance challenges from the Public Health Informatics Task Force  and the Antibiotic Resistance Surveillance Task Force. We also reviewed  documents from WHO’s global surveillance system and interviewed WHO  and CDC officials to identify challenges that limit CDC’s ability to assess  threats from abroad. We evaluated challenges and steps CDC has taken  against CDC’s “Updated Guidelines for Evaluating Public Health  Surveillance Systems;” Standards for Internal Control in the Federal  Government; prior GAO work; the Government Performance and Results  Act of 1993 (GPRA) and the GPRA Modernization Act of 2010; the Office  of Management and Budget Circular No. A-11 and Standards and  Guidelines for Statistical Surveys; relevant National Action Plan  objectives, aims, and milestones; and Executive Order No. 13676,  September 2014.

To examine federal efforts to advance the development and use of  diagnostic tests, we also interviewed representatives from a  nongeneralizable selection of six diagnostic test manufacturers to identify  challenges they face in developing tests for antibiotic resistance and  challenges in increasing user adoption of their tests. We further focused  our review on the 17 priority disease-causing bacteria listed in CDC’s  2013 Threats Report. The six manufacturers we interviewed were  Accelerate Diagnostics, Beckman Coulter, BioFire and its parent  company, BioMerieux, Bruker, Cepheid, and Roche Diagnostics. We  identified these manufacturers by compiling a list based on previous work  we conducted, interviews with select experts, and internet search. We  selected six manufacturers that were identified by more than one source  while encompassing different types of tests (culture and genotypic). We limited our scope to FDA-authorized tests—that is, tests that have been  reviewed and cleared by FDA for marketing in the United States—that  can identify resistance in at least one type of bacteria categorized as  priority bacteria in CDC’s 2013 Threats Report. Some of these tests are  called antibiotic susceptibility tests, but we refer to the entire class of such  tests as “tests.” We included in our scope tests that can differentiate  between viral and bacterial infection because these types of tests are  included in the National Action Plan. We evaluated the actions taken by  federal agencies against the Standards for Internal Control in the Federal  Government, relevant National Action Plan objectives, aims, and  milestones under Goal 3, and relevant sections in the PACCARB  Recommendations for Incentivizing the Development of Vaccines,  Diagnostics, and Therapeutics to Combat Antibiotic Resistance. We also  evaluated federal agency actions against the “leadership” and “clarity of  roles and responsibilities” leading practices from GAO’s Managing for  Results: Key Considerations for Implementing Interagency Collaborative  Mechanisms. We focused on these key practices when there was a lack  of specifically assigned roles in either the National Action Plan or the  PACCARB report for key activities.

To identify challenges to developing new treatments for antibiotic- resistant infections and examine federal efforts to address these  challenges, we also interviewed 11 randomly selected companies that  conduct research and development on new treatments for bacterial  infections. We included companies that are researching or developing  both traditional antibiotics and alternatives to antibiotics—which we call  “nontraditional products” in this report—and we included companies that  had and had not received funding from the Combating Antibiotic- Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) and  companies that do and do not have existing FDA-approved drugs on the market. We asked company representatives about challenges in  developing new antibiotics they have identified, support they may have  received from federal agencies, how effective the support has been to  them, and their views on additional incentives that would promote the  development of new antibiotics. We also interviewed experts on the topic  of antibiotic development and industry stakeholders, specifically The Pew  Charitable Trusts and the Biotechnology Innovation Organization. We  interviewed federal officials from BARDA, CMS, DOD, FDA, and NIH to  learn about their programs and actions to support the development of  treatments for antibiotic-resistant infections and requested information  about funding for antibiotic R&D from BARDA, DOD, and NIH. We  included relevant agency actions that began before the National Action  Plan was issued in 2015 if they continued after 2015. Finally, we reviewed  literature related to antibiotic development and reports about antibiotic  pull incentives written by health policy advisory groups, including the  PACCARB, the Transatlantic Taskforce on Antimicrobial Resistance  (TATFAR), the DRIVE-AB project, and the Duke Margolis Center for  Health Policy. We evaluated the actions taken by federal agencies to  help address the challenges to developing new treatments against  experts’ and advisory groups’ views on additional actions needed and  against the principles related to developing strategies outlined in GPRA  and the GPRA Modernization Act of 2010. We did not assess  challenges to developing products designed to prevent infections, such as  vaccines, nor federal actions related to these types of products.

To examine federal agency efforts to promote the appropriate use of  antibiotics and any challenges that remain, we also analyzed CMS data  and related documentation on the quality measures and improvement  activities related to antibiotics as part of CMS’s Merit-based Incentive  Payment System (MIPS) in 2017. Specifically, we identified CMS’s  antibiotics-related quality measures and improvement activities by  conducting a search for the words “antibiotic,” “antimicrobial,” “bacteria,”  “resistance,” and “resistant” on CMS’s MIPS website. We then reviewed  CMS’s data on the number of MIPS-eligible clinicians who selected and  reported on these measures and activities in 2017, the most recently  available data. In 2017, there were nine MIPS quality measures related to  antibiotics, as follows:  (1) acute otitis externa: systemic antimicrobial therapy - avoidance of  inappropriate use;  (2) adult sinusitis: antibiotic prescribed for acute sinusitis (overuse);  (3) adult sinusitis: appropriate choice of antibiotic: amoxicillin with or  without Clavulanate prescribed for patients with acute bacterial sinusitis  (appropriate use);  (4) appropriate testing for children with pharyngitis;  (5) appropriate treatment for children with upper respiratory infection;  (6) appropriate treatment of Methicillin-sensitive Staphylococcus aureus  bacteremia;  (7) avoidance of antibiotic treatment in adults with acute bronchitis;  (8) perioperative care: selection of prophylactic antibiotic – first- or  second-generation Cephalosporin; and  (9) total knee replacement: preoperative antibiotic infusion with proximal  tourniquet.

In addition, there was one MIPS improvement activity related to  antibiotics in 2017: implementation of antibiotic stewardship program. We  reviewed the MIPS data for any obvious outliers or anomalies, and we  determined that these data were sufficiently reliable for reporting the  number of clinicians who reported implementing these quality measures  and improvement activities. In addition, we reviewed aggregated data  from CDC on the total number of eligible U.S. hospitals voluntarily  reporting their antibiotic use data to a CDC system (the NHSN’s  Antimicrobial Use Option); we then calculated the percentage of eligible  hospitals reporting such data as of January 1, 2020. We assessed the  reliability of the aggregated data by reviewing them for any obvious errors  or missing data totals and inquiring with CDC officials about their source  and any known reliability issues. We determined that these data were  sufficiently reliable for reporting hospital participation rates in the system.  We also reviewed selected articles on antibiotic use and stewardship— compiled from a variety of sources, including CDC documents and  experts we interviewed—published in literature. In addition, we  interviewed experts on antibiotic use and stewardship, including  representatives from PACCARB, Emory University’s School of Medicine,  the University of Minnesota’s Center for Infectious Disease Research and  Policy, The Joint Commission, the Society of Infectious Diseases  Pharmacists, The Pew Charitable Trusts, and the Association for  Professionals in Infection Control and Epidemiology. We evaluated  federal efforts and challenges against relevant National Action Plan  objectives and milestones and Executive Order No. 13676. We focused  on antibiotic use in the United States, rather than global antibiotic use.

We conducted this performance audit from February 2018 to March 2020  in accordance with generally accepted government auditing standards.  Those standards require that we plan and perform the audit to obtain  sufficient, appropriate evidence to provide a reasonable basis for our  findings and conclusions based on our audit objectives. We believe that  the evidence obtained provides a reasonable basis for our findings and  conclusions based on our audit objectives.

Appendix II: Expert Meeting Participant List

We collaborated with the National Academy of Sciences to convene a  two-day meeting of experts to inform our work on federal efforts to  address antibiotic resistance; the meeting was held on September 17 and  18, 2018. The experts who participated in this meeting are listed below.  Many of these experts gave us additional assistance throughout our work,  including by providing additional technical expertise and answering  questions, and 10 of these experts reviewed and provided comments on  our draft report for technical accuracy.

Appendix III: Additional Examples of Federal Efforts to Support Antibiotic Research and Development

This appendix contains additional examples of efforts by agencies within  the Departments of Health and Human Services, Defense, and Energy to  provide support for antibiotic research and development beyond those  mentioned in the report. These examples do not comprise the full extent  of agencies’ efforts.

Appendix IV: Additional Information on Federal Efforts to Promote Appropriate Antibiotic Use

This appendix contains more detailed information on federal efforts to  promote the appropriate use of antibiotics in health care through antibiotic  stewardship programs and activities, organized by agency. These  examples do not comprise the full extent of agencies’ efforts.

Appendix V: Comments from the Department of Health and Human Services

Appendix VI: GAO Contacts and Staff Acknowledgments

In addition to the contacts named above, John Neumann (Managing  Director); Will Hadley, Anne K. Johnson, and Sushil K. Sharma, PhD,  DrPH (Assistant Directors); Josey Ballenger, Hayden Huang, PhD, and  Laura Tabellion (Analysts-in-Charge); and Amber Sinclair, PhD, made  key contributions to this report.

Nora Adkins, George Bogart, Jehan Chase, Anika McMillon, Laurie  Pachter, Eric Peterson, Sarah Sheehan, Ben Shouse, Sara Sullivan,  Walter Vance, Harris Weisz, and Emma Williams also made important  contributions.

Antibiotic-resistant infections can be difficult or impossible to treat.

We examined federal challenges to addressing antibiotic resistance:

Surveillance—Tracking resistant infections is tough because of reliance on sampling and voluntary reporting

Diagnostics—Lack of data on clinical outcomes impedes the development and use of antibiotic-resistance tests

New treatments—The pipeline of new antibiotics is inadequate and federal efforts haven’t fully incentivized development

Antibiotic use—Federal requirements to improve antibiotic use are mostly limited to hospitals and nursing homes

Our 8 recommendations are to strengthen federal efforts.