Antimicrobial drugs are a broad class of drugs that combat many pathogens, including bacteria, viruses, fungi, or parasites. Antibiotics are a subset of these drugs that work against bacteria. Antibiotics work by killing the bacteria directly or halting their growth. According to WHO, the evolution of strains of bacteria that are resistant to antibiotics is a natural phenomenon that occurs when microorganisms exchange resistant traits; however, WHO also states that the use and misuse of antimicrobial drugs, including antibiotics, accelerates the emergence of resistant strains. Antibiotic resistance began to be recognized soon after penicillin, one of the first antibiotics, came into use over 70 years ago. Antibiotic- resistant bacteria can spread from animals and cause disease in humans through a number of pathways (see fig. 1). The use of antibiotics in animals is an integral part of food animal production. To improve efficiencies, modern industrial farms raise animals in high concentrations, but this practice has the potential to spread disease because animals live in close confinement. Long-term, low-dose treatments with antibiotics may help prevent diseases, particularly where animals are housed in large groups in close confinement facilities, such as concentrated animal feed operations. The concentrated nature of such agricultural operations means that a disease, if it occurs, can spread rapidly and become quickly devastating—increasing the need to rely on antibiotics as a preventive measure. The purposes for which FDA approves the use of antibiotics can be divided into four categories: to treat animals that exhibit clinical signs of disease; to control a disease in a group of animals when a proportion of them exhibit clinical signs of disease; to prevent disease in a group of animals when none are exhibiting clinical signs of disease, but disease is likely to occur in the absence of an antibiotic; or to promote faster weight gain (growth promotion) or weight gain with less feed (feed efficiency). Antibiotics for food animals are administered either by mixing them into feed or water, or by injection and other routes. For example, according to representatives from the poultry industry, the majority of antibiotics used in poultry production are administered through feed and water. In lactating dairy cattle, mastitis—an inflammation of the udder—is the most common reason for antibiotic use and antibiotics are given by injection either to treat or prevent disease, according to representatives from the National Milk Producers Federation. Antibiotics for food animals may be sold or dispensed in several ways, with varying levels of restriction. Some antibiotics may be purchased over-the-counter and used by producers without veterinarian consultation or oversight. Certain antibiotics added to feed must be accompanied by a veterinary feed directive, a type of order for this use. The directive authorizes the producer to obtain and use animal feed containing a certain drug or drug combination to treat the producer’s animals in accordance with the conditions for use approved by FDA. Some antibiotics may require a prescription from a licensed veterinarian. Although veterinarians may prescribe most approved drugs “extra label” (for a species or indication other than those on the drug label), restrictions on the extra-label use of antibiotics in food animals exist. For example, no extra-label use of approved drugs, including antibiotics, is legally permissible in or on animal feed, according to FDA officials. Certain types of drugs, including some types of antibiotics, are prohibited from extra- label use in food animals under any circumstances because the use of these drugs may lead to antibiotic resistance in humans (e.g., fluoroquinolones—broad-spectrum antibiotics that play an important role in treatment of serious bacterial infections, such as hospital-acquired infections). Antibiotics used for food animals can be the same, or belong to the same drug classes, as those used in human medicine. FDA and WHO have sought to identify antibiotics that are used in both animals and humans and that are important to treat human infections—such antibiotics are known as medically important antibiotics. In 2003, FDA issued guidance to industry on the use of antibiotics in food animals, which included a list of antibiotics that it considers important to human medicine. In this guidance, FDA ranked each antibiotic according to its importance in human medicine, as “critically important” (the highest ranking), “highly important,” or “important” based on criteria that focused on antimicrobials, including antibiotics, used to treat foodborne illness in humans. Similarly, WHO developed criteria for ranking antimicrobials, including antibiotics, according to their importance in human medicine and first ranked them in 2005. Two federal departments are primarily responsible for ensuring the safety of the U.S. food supply, including the safe use of antibiotics in food animals—HHS and USDA. Each department contains multiple agencies that contribute to the national effort to control, monitor, and educate others on antibiotic use and resistance. For example, HHS’s CDC and FDA as well as USDA’s APHIS and FSIS have responsibilities related to the White House’s 2015 National Action Plan for Combating Antibiotic- Resistant Bacteria. The plan identifies several goals, including a goal to slow the development of resistant bacteria and prevent the spread of resistant infections as well as a goal to strengthen national “one-health” surveillance efforts to combat resistance, which include collecting data on antibiotic use and resistance. The “one-health” concept recognizes that the health of humans, animals, and the environment are interconnected. Table 1 provides information on selected agencies’ efforts related to antibiotic resistance. To help ensure public health and the safety of the food supply, HHS’s CDC leads investigations of multi-state foodborne illness outbreaks, including those involving antibiotic-resistant pathogens, and collaborates with USDA, FDA, and state public health partners in this effort. To identify an outbreak, CDC monitors data voluntarily reported from state health departments on cases of laboratory-confirmed illness and analyzes these data to identify elevated rates of disease that may indicate an outbreak, according to CDC officials. According to CDC’s website, determining the food source of human illness is an important part of improving food safety. In general, foods often associated with foodborne illnesses include raw foods of animal origin—meat, poultry, eggs, and shellfish, and also unpasteurized (raw) milk—that can cause infections if undercooked or through cross-contamination. Since 2011, HHS has increased veterinary oversight of antibiotics in food animals and, along with USDA, collected additional data on antibiotic use and resistance, but gaps exist in oversight and data collection, and the impact of the agencies’ efforts is unknown. For medically important antibiotics administered in animal feed and water, HHS’s FDA increased veterinary oversight and prohibited certain uses through a combination of guidance and regulation. In addition, agencies in HHS and USDA made several improvements in collecting and reporting data on antibiotic sales, resistance, and use. However, the agencies’ actions do not address oversight gaps such as long-term and open-ended use of medically important antibiotics for disease prevention or collection of farm-specific data, and FDA and APHIS do not have measures to assess the impact of their actions. To promote the judicious use of antibiotics in food animals, FDA increased veterinary oversight of medically important antibiotics in feed and water through voluntary guidance to industry and revising the veterinary feed directive regulation. As a result, as of January 2017, medically important antimicrobials, including antibiotics, in the feed and water of food animals may only be used under the supervision of licensed veterinarians, according to FDA officials (see app. II for a list of these drugs). Voluntary Guidance to Industry. In 2012, FDA finalized guidance that lays out a strategy for phasing out the use of medically important antibiotics for growth promotion or feed efficiency, and for bringing other uses under veterinary oversight. Specifically, in Guidance for Industry #209, FDA outlined and recommended adoption of two principles for judicious use of antibiotics in food animals: (1) limit medically important antibiotics to uses that are considered necessary for assuring animal health, such as to prevent, control, and treat diseases, and (2) limit antibiotic uses to those that include veterinary oversight. In 2013, to help ensure implementation of its strategy, FDA issued Guidance for Industry #213, which asked animal drug companies to voluntarily stop labeling antibiotics for growth promotion or feed efficiency within 3 years. The guidance also recommended more veterinary oversight. Specifically, FDA (1) asked drug companies to voluntarily revise labels of medically important antibiotics to remove the use for growth promotion and feed efficiency; (2) outlined procedures for adding, where appropriate, scientifically supported uses for disease treatment, control, or prevention; and (3) recommended that companies change the means of sale or dispensation from over-the-counter to require veterinary oversight—either through a veterinary feed directive for antimicrobials administered through feed or through a prescription for antimicrobials administered through water—by December 31, 2016. According to FDA, as of January 3, 2017, all applications for medically important antimicrobials, including antibiotics, for use in the feed or water for food animals have been aligned with the judicious use principles as recommended in Guidance for Industry #213, or their approvals have been voluntarily withdrawn. As a result of these actions, these products cannot be used for production purposes (e.g., growth promotion) and may only be used under the authorization of a licensed veterinarian, according to FDA. Agencies Respond to Colistin Resistance In May 2016, the U.S. Department of Defense identified the first person in the United States to be carrying E.coli bacteria with a gene that makes bacteria resistant to colistin. The U.S. Department of Agriculture (USDA) also found colistin-resistant E. coli in samples collected from the intestines of two pigs. According to the U.S. Department of Health and Human Services (HHS), these discoveries are of concern because colistin is used as a last- resort drug to treat patients with multidrug- resistant infections.