Antimicrobial resistance is a global public health threat. Antimicrobial-resistant infections are on the rise and are associated with increased morbidity, mortality, and health care costs. Infants and children are affected by transmission of antimicrobial-resistant zoonotic pathogens through the food supply, direct contact with animals, environmental pathways, and contact with infected or colonized humans. Although the judicious use of antimicrobial agents is necessary for maintaining the health and welfare of humans and animals, it must be recognized that all use of antimicrobial agents exerts selective pressure that increases the risk of development of resistance. This report describes historical and recent use of antibiotics in animal agriculture, reviews the mechanisms of how such use contributes to development of resistance and can adversely affect child health, and discusses US initiatives to curb unnecessary use of antimicrobial agents in agriculture.
Introduction
Antimicrobial resistance is a public health crisis. Antimicrobial-resistant infections are often costly to treat, increase health care utilization, and increase morbidity and mortality.1–3 The Centers for Disease Control and Prevention (CDC) report that more than 2.8 million Americans become ill with antimicrobial-resistant infections each year, with more than 35 000 resulting deaths.4 Antimicrobial-resistant infections are estimated to cost between $21 billion and $34 billion annually, resulting in 8 million additional hospital days.3,5–7 The misuse and overuse of antibiotics in human and animal medicine is a significant contributor to the emergence and spread of resistant pathogens.
Antimicrobial Sales in Food Animals
Scope of Use
Food animals are animals that are raised and used for food production or consumption by humans.8 At the present time, there are limited data on veterinary use of antimicrobial agents in the United States. In contrast, the European Union has implemented legislation to increase transparency, such as mandatory monitoring of antimicrobial use on farms.9 In the United States, the most readily available data are antimicrobial sales and distribution data collected by the US Food and Drug Administration (FDA). However, the FDA cautions that these data do not reflect actual usage data. In 2020, antimicrobial sales for food animals accounted for more than 23 million pounds of antimicrobial drug active ingredients (including drug classes not used in humans, such as ionophores) in the United States.10 In 2020, approximately 60% of the antimicrobial agents sold for use in food animals were also important in human medicine (Table 1).10 Historically, according to the FDA, at least 97% of medically important antimicrobial agents that were sold in 2012 for use in food-producing animals had an over-the-counter dispensing status.11 In response, the FDA implemented Guidance for Industry (GFI) #209 in 2012 to discourage use of antibiotics for production purposes by requiring veterinary oversight for antibiotics used in food-producing animals and limiting medically important antimicrobial drugs to uses that are considered necessary for ensuring animal health.12 In 2020, after implementation of the FDA GFI #213 (the Veterinary Feed Directive),13 only 4% of antibiotics used in agriculture were dispensed over-the-counter without a prescription, and the remainder were dispensed under the direction of a licensed veterinarian or with a prescription.10 Additionally, in 2021, the FDA issued GFI #263, and as of June 11, 2023, all sales of antimicrobial agents are now under veterinary oversight, eliminating over-the-counter sales of medically important antimicrobial agents for animal production in the United States.
Antimicrobial Drugs Approved for Use in Food-Producing Animals: 2020 Sales and Distribution Data Reported by Drug Class, United States
. | Drug Class . | Annual Totals (kg)f . | Subtotal, % . | Grand Total, % . |
---|---|---|---|---|
Medically importanta | Aminoglycosides | 322 734 | 5 | 3 |
Amphenicols | 51 788 | 1 | <1 | |
Cephalosporinsc | 26 262 | <1 | <1 | |
Fluoroquinolones | 24 176 | <1 | <1 | |
Lincosamidesc | 147 026 | 2 | 1 | |
Macrolides | 433 394 | 7 | 4 | |
Penicillinsc | 762 888 | 13 | 7 | |
Sulfonamides | 282 572 | 5 | 3 | |
Tetracyclinesc | 3 948 745 | 66 | 38 | |
NIRc,d | 2470 | <1 | <1 | |
Subtotal | 6 002 056 | 100 | 57 | |
Not medically importantb | Ionophores | 3 619 265 | 81 | 35 |
Pleuromutilins | 161 723 | 4 | 2 | |
NIRe | 666 432 | 15 | 6 | |
Subtotal | 4 447 420 | 100 | 43 | |
Grand total | 10 499 476 | — | 100 |
. | Drug Class . | Annual Totals (kg)f . | Subtotal, % . | Grand Total, % . |
---|---|---|---|---|
Medically importanta | Aminoglycosides | 322 734 | 5 | 3 |
Amphenicols | 51 788 | 1 | <1 | |
Cephalosporinsc | 26 262 | <1 | <1 | |
Fluoroquinolones | 24 176 | <1 | <1 | |
Lincosamidesc | 147 026 | 2 | 1 | |
Macrolides | 433 394 | 7 | 4 | |
Penicillinsc | 762 888 | 13 | 7 | |
Sulfonamides | 282 572 | 5 | 3 | |
Tetracyclinesc | 3 948 745 | 66 | 38 | |
NIRc,d | 2470 | <1 | <1 | |
Subtotal | 6 002 056 | 100 | 57 | |
Not medically importantb | Ionophores | 3 619 265 | 81 | 35 |
Pleuromutilins | 161 723 | 4 | 2 | |
NIRe | 666 432 | 15 | 6 | |
Subtotal | 4 447 420 | 100 | 43 | |
Grand total | 10 499 476 | — | 100 |
From FDA, Center for Veterinary Medicine. 2020 summary report on antimicrobials sold and distributed for use in food-producing animals. 2021. Available at: https://www.fda.gov/media/154820/download. NIR, not independently reported.
FDA GFI #213 states that all antimicrobial drugs and their associated classes listed in Appendix A of FDA’s GFI #152 are considered medically important in human medical therapy.
Not medically important refers to any antimicrobial class not listed in Appendix A of FDA GFI #152.
Includes antimicrobial drug applications that are approved and labeled for use in both food-producing animals (eg, cattle and swine) and nonfood-producing animals (eg, dogs and horses).
Antimicrobial classes for which there were <3 distinct sponsors actively marketing products domestically are not independently reported. These classes include the following: Diaminopyrimidines, polymyxins, and streptogramins.
Antimicrobial classes for which there were <3 distinct sponsors are not independently reported. These classes include the following: Aminocoumarins, glycolipids, orthosomycins, polypeptides, and quinoxalines.
Antimicrobial class includes drugs of different molecular weights, with some drugs labeled in different salt forms. Antimicrobials that are labeled in IUs (eg, penicillins) were converted to kg.
Indications for Use
In food animals, antimicrobial agents are approved for a variety of indications (Table 2).14 Approved indications for antimicrobial use in food animals include treatment, prevention, and control of infectious diseases.14 Treatment involves episodic use of therapeutic doses of antimicrobial agents for treatment of infectious diseases in clinically ill animals. On a population basis, treatment involves administration of an antimicrobial to animals within the group with evidence of an infectious disease. Prevention is when antimicrobial agents are administered to individual animals to reduce the risk of acquiring infection in certain scenarios, like after undergoing major surgery. On a population basis, prevention is the administration of an antimicrobial to a group of animals, none of which have evidence of disease or infection, when transmission of existing undiagnosed infections, or the introduction of pathogens, is anticipated. In the United States and many other countries, medically important antimicrobial agents are no longer approved for use in production or for nontherapeutic indications in animals, including “feed efficiency” and “growth promotion,” which are unrelated to disease management. These uses typically involve administration of subtherapeutic doses of antimicrobial agents in the feed or water of an entire herd or flock to promote faster growth. However, antibiotics used for disease prevention and given at nontherapeutic doses for extended durations may select for antibiotic-resistant organisms, as is observed in human health. Notably, antibiotics not considered medically important in human medicine, such as ionophores used in feed, are still available without veterinary oversight and could still drive antibiotic resistance in humans.15
Indications for Antimicrobial Use in Food Animals14
Indication . | Description . | Notes . |
---|---|---|
Treatment | Individual level: Provide episodic, therapeutic doses of antimicrobial agents for treatment of infection in clinically ill animals Population level: Administration of an antimicrobial to those animals within the group with evidence of an infectious disease | Approved indication, with veterinary oversight |
Prevention | Individual level: Provide to animals who are well but in a situation where disease is likely to occur if the drug is not administered Population level: Administration to a group of animals, none of which have evidence of disease or infection, when transmission of existing undiagnosed infections, or the introduction of pathogens, is anticipated on the basis of history, clinical judgement, or epidemiologic knowledge | Restricted, may be appropriate in certain situations with veterinary oversight Often referred to as prophylaxis |
Control | Individual level: Provide to an animal with a subclinical infection to reduce the risk of the infection becoming clinically apparent, spreading to other tissues or organs, or being transmitted to other individuals Population level: Provide antimicrobial agents to a group of animals to reduce the incidence of bacterial disease within the group | Sometimes referred to as metaphylaxis Often refers to reducing the frequency or severity of disease in a population |
Indication . | Description . | Notes . |
---|---|---|
Treatment | Individual level: Provide episodic, therapeutic doses of antimicrobial agents for treatment of infection in clinically ill animals Population level: Administration of an antimicrobial to those animals within the group with evidence of an infectious disease | Approved indication, with veterinary oversight |
Prevention | Individual level: Provide to animals who are well but in a situation where disease is likely to occur if the drug is not administered Population level: Administration to a group of animals, none of which have evidence of disease or infection, when transmission of existing undiagnosed infections, or the introduction of pathogens, is anticipated on the basis of history, clinical judgement, or epidemiologic knowledge | Restricted, may be appropriate in certain situations with veterinary oversight Often referred to as prophylaxis |
Control | Individual level: Provide to an animal with a subclinical infection to reduce the risk of the infection becoming clinically apparent, spreading to other tissues or organs, or being transmitted to other individuals Population level: Provide antimicrobial agents to a group of animals to reduce the incidence of bacterial disease within the group | Sometimes referred to as metaphylaxis Often refers to reducing the frequency or severity of disease in a population |
Antimicrobial Use in Food Animals and Antimicrobial Resistance
Antimicrobial Resistance
Antimicrobial resistance is an organism’s ability to survive exposure to an antimicrobial agent that was previously an effective treatment. Resistance traits can be acquired either through new mutations16 or through transfer of genetic material between organisms (by bacteriophages or mobile genetic elements, such as plasmids, cell-free DNA, or transposons).17,18 Any use of antimicrobial agents, including appropriate use of antimicrobial agents, leads to elimination of susceptible organisms, allowing resistant organisms to survive. Use of antimicrobial agents places antimicrobial pressure on bacteria,19 selecting for resistant organisms and facilitating overgrowth of resistant organisms as susceptible flora are eradicated. Long-term use of a single antimicrobial agent can lead to resistance not only to that agent, but to multiple agents.16
Antimicrobial Use in Food Animals and Antimicrobial Resistance
Use of antimicrobial agents in animals has been shown to lead to emergence and spread of antimicrobial resistance.20–29 In a classic experiment, Levy et al30 demonstrated that, among chickens receiving a prolonged course of low-dose tetracycline administered in feed, single-drug resistance developed and led rapidly to multidrug resistance; resistance then spread beyond individual animals to chickens in the same environment, and resistant organisms were also identified in specimens from people living on the farm. Once tetracycline feed supplementation was stopped, there was a decrease in resistant organisms detected in the people living on farms where tetracycline feed supplementation had been used.
Increasing evidence has linked resistant pathogens to antibiotic use in food animals. Staphylococcus aureus has been found to acquire tetracycline and methicillin resistance in livestock.31 In a 2011 study, meat and poultry samples from 5 US cities32 demonstrated Staphylococcus aureus contamination in 77% of turkey samples, 42% of pork samples, 41% of chicken samples, and 37% of beef samples. Ninety-six percent of Staphylococcus aureus isolates in the meat and poultry samples were resistant to at least 1 antimicrobial agent, and many were additionally resistant to other antimicrobial classes. More than half of the meat and poultry samples were multidrug resistant, defined as intermediate susceptibility or complete resistance to 3 or more antimicrobial classes. Patient exposure to swine or livestock industrial agriculture has also been associated with increased risk of community-acquired and health care-associated methicillin-resistant Staphylococcus aureus (MRSA) infection.33,34 In recent years, ST 398, a MRSA lineage that originated in the community and is associated with exposure to livestock, has emerged in different countries worldwide, including the United States.35 One study in the Netherlands demonstrated low prevalence of MRSA overall, but increased risk of MRSA carriage among persons living in close proximity to livestock farms but not living or working on the farm.36
Antimicrobial-resistant extraintestinal Escherichia coli strains that can cause human urinary tract infections, sepsis, and other infections have also been linked to antibiotic use in food animals.37–39
Transmission of Pathogens Between Animals and Humans
A “One Health” approach recognizes that the health of people is closely connected to the health of animals and our shared environment.40 Antimicrobial-susceptible and -resistant animal pathogens can reach humans through the food supply, by direct contact with animals, or through environmental contamination, including human wastewater treatment runoff, hospital effluent, and birds and other freely moving wildlife. Children may also be exposed to pathogens through direct interaction with colonized or infected adults or animals, including companion animals (ie, family pets). Pathogen transmission is not unidirectional; humans can also spread antimicrobial-susceptible and -resistant pathogens to animals, termed reverse or bidirectional zoonoses.41–43
Resistant bacteria from animals or humans can be spread through fecal material, wastewater, or environmental contact, leading to environmental reservoirs of pathogens and resistance genes.44,45 Feces can contaminate foods when manure that has not been properly composted contains resistant organisms and is applied to agricultural soils and the organisms and resistance genes are then present in farm runoff.46,47 Cross-contamination of fruits and vegetables can occur when wastewater is used to irrigate crops, and fish raised in contaminated water can also be exposed.48 Active antimicrobial agents have been detected in surface waters and river sediments,49 and resistance genes identical to those found in swine waste lagoons have been found in groundwater and soil microbes hundreds of meters downstream.50 These findings raise concerns that environmental contamination with antimicrobial agents from agricultural and human use could present microbial populations with selective pressure, stimulate horizontal gene transfer, and amplify the number and variety of organisms that are resistant to antimicrobial agents. It is important to note that other human sources, including hospital wastewater and industrial production of antimicrobial agents, can lead to significant spread of antimicrobial-resistant organisms.51–54 Another important source of potential pathogen exposure is companion animals.55 Dogs and cats are increasingly recognized as carriers of carbapenemase- and extended-spectrum beta-lactamase–producing organisms, and transmission between companion animals and humans has been documented.56–61 Raw pet food diets have become more popular and can also be a source of pathogen transmission among households because of improper food handling, as can pet treats.62–65
For prevention of any foodborne illness, it is important to remember common mechanisms to prevent transmission to children, including proper hand hygiene when cooking or handling raw meat, after visiting petting zoos or farms, after handling any pet food or treats, and after contact with companion animals. As advocated by the American Veterinary Medical Association, it is especially important to wash hands before preparing, serving, or consuming food and drinks or preparing baby bottles. People should not consume raw eggs or food containing raw eggs, raw or undercooked meat, or unpasteurized milk or raw milk products.66
Child Health Effects
Humans can acquire zoonotic pathogens through the food supply, direct contact with animals, and environmental pathways.66 In 2020, a total of 18 462 infections, 4788 hospitalizations, and 118 deaths among children and adults were reported to the Foodborne Diseases Active Surveillance Network, a CDC surveillance system covering 15% of the US population.67 For most infections, incidence was highest among children younger than 5 years.68 Data on transmission of 2 organisms causing common childhood infections that can be related to foodborne or direct transmission, Salmonella species and Campylobacter species, are summarized here.
Salmonella Species
Nontyphoidal Salmonella species are a leading cause of foodborne illness in children. In 2015, the incidence of laboratory-confirmed Salmonella infections per 100 000 US children was 58 in children younger than 5 years, 18 in children 5 through 9 years of age, and 11 in children 10 to 19 years of age.69 Scallan et al70 estimated that Salmonella infection results in 123 452 illnesses, 44 369 physician visits, 4670 hospitalizations, and 38 deaths annually among children younger than 5 years in the United States. Neonatal infections caused by Salmonella species have been attributed to indirect exposure to foodborne sources.71,72 With the rise in ownership of backyard poultry and reptile pets, a higher proportion of Salmonella illness in children younger than 5 years are linked to animal contact outbreaks than to foodborne outbreaks.73 Children have also acquired Salmonella infections from direct contact with livestock74 and live poultry and other animals or their environments.75,76 Pediatric Salmonella infections caused by exposure to contaminated pet food have also been documented.77 The CDC estimated in 20194 that there were 1.35 million nontyphoidal Salmonella infections in the United States per year, of which 20 800 were resistant to 3 or more classes of antibiotics. Of particular note, 3% are resistant to ceftriaxone, a first-line empirical therapy for salmonellosis in pediatrics.4 As highlighted previously, antimicrobial use in agriculture likely contributes to these high rates of resistance but is not the sole driver of resistance.
Campylobacter Species
Campylobacter species are also a leading cause of foodborne illness in children. In 2015,69 the incidence of laboratory-confirmed Campylobacter infections per 100 000 children was 21 in children younger than 5 years, 8 in children 5 through 9 years of age, and 8 in children 10 to 19 years of age in the United States. Campylobacter infections have been estimated to cause 81 796 illnesses, 28 040 physician visits, 1042 hospitalizations, and 6 deaths annually in US children younger than 5 years.69 Campylobacter infection has been associated with eating undercooked meat products and unpasteurized dairy products, as well as exposure to untreated water and contact with farm animals, backyard poultry, petting zoos, and companion animals.78
Antimicrobial resistance among Campylobacter species is increasing.79 Resistance to ciprofloxacin increased from 13% in 1997 to 28% in 2017.4 The CDC estimated in 20194 that there are 1.5 million Campylobacter infections per year, of which 448 400 have reduced susceptibility to fluoroquinolones or macrolides. When treatment is indicated for children, azithromycin and erythromycin are the preferred treatment of Campylobacter gastrointestinal tract infection. Fluoroquinolones may be effective against Campylobacter species, but resistance is common. One outbreak of extremely drug-resistant Campylobacter included 168 patients with 117 (70%) reporting contact with a dog before symptoms and 69 (41%) reporting contact with a pet store puppy.80
Interventions to Improve Judicious Use of Antimicrobials in Animal Agriculture in the United States
FDA Guidance
As outlined in Table 3, the FDA finalized GFI #209 in 2012, recommending 2 principles regarding the judicious use of medically important antimicrobial drugs:
Antimicrobial Stewardship Policies, Initiatives, and Guidance for Antibiotic Use in Humans and Animals
Policy/Initiative/Guidance . | Description . | Web Site . |
---|---|---|
National Action Plan for Combatting Antibiotic Resistant Bacteria 2020–2025 | Goals to: 1. slow emergence of resistant bacteria and prevent the spread of resistant infections; 2. strengthen national One Health surveillance efforts to combat antimicrobial resistance; 3. advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria; 4. accelerate basic and applied research and development for new antibiotics, other therapeutics, and vaccines; and 5. improve international collaboration and capacities for antibiotic resistance, prevention, surveillance, and control, and antibiotic research and development | https://www.hhs.gov/sites/default/files/carb-national-action-plan-2020-2025.pdf |
WHO Global Action Plan on Antimicrobial Resistance | Goals to improve awareness and understanding of antimicrobial resistance, strengthen knowledge through surveillance and research, reduce the incidence of infection, optimize the use of antimicrobial agents, and ensure sustainable investment in countering antimicrobial resistance | https://www.emro.who.int/health-topics/drug-resistance/global-action-plan.html |
Joint Commission Antimicrobial Stewardship Requirements | Developed standards for inpatient and outpatient antimicrobial stewardship to achieve accreditation | https://www.jointcommission.org/-/media/tjc/documents/standards/r3-reports/r3_antibioticstewardship_july2022_final.pdf |
IDSA 10 × ‘20 Initiative | Goal of developing 10 new antimicrobial agents to treat antimicrobial-resistant infections by 2020 | https://www.idsociety.org/policy--advocacy/antimicrobial-resistance/antibiotic-development-the-10-x-20-initiative/#:∼:text=IDSA%20is%20working%20to%20counter,thousands%20of%20lives%20each%20year |
FDA GFI #209 | Limits medically important antimicrobial drugs administered in feed or water to uses that are necessary for ensuring animal health and requiring veterinary oversight for antibiotics used in food-producing animals | https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-209-judicious-use-medically-important-antimicrobial-drugs-food-producing-animals |
FDA GFI #213 (Veterinary Feed Directive) | Provides recommendations for how to voluntarily modify use of medically important antimicrobial agents to align with the 2 principles outlined in GFI #209 | https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-213-new-animal-drugs-and-new-animal-drug-combination-products-administered-or-medicated-feed |
FDA GFI #263 | Requires veterinary prescription for all dosage forms of medically important drugs administered to nonfood (companion) or food-producing animals through any route of administration | https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-263-recommendations-sponsors-medically-important-antimicrobial-drugs-approved-use-animals |
USDA Antimicrobial Resistance Action Plan | Outlines current surveillance efforts | https://www.usda.gov/sites/default/files/documents/usda-antimicrobial-resistance-action-plan.pdf |
Policy/Initiative/Guidance . | Description . | Web Site . |
---|---|---|
National Action Plan for Combatting Antibiotic Resistant Bacteria 2020–2025 | Goals to: 1. slow emergence of resistant bacteria and prevent the spread of resistant infections; 2. strengthen national One Health surveillance efforts to combat antimicrobial resistance; 3. advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria; 4. accelerate basic and applied research and development for new antibiotics, other therapeutics, and vaccines; and 5. improve international collaboration and capacities for antibiotic resistance, prevention, surveillance, and control, and antibiotic research and development | https://www.hhs.gov/sites/default/files/carb-national-action-plan-2020-2025.pdf |
WHO Global Action Plan on Antimicrobial Resistance | Goals to improve awareness and understanding of antimicrobial resistance, strengthen knowledge through surveillance and research, reduce the incidence of infection, optimize the use of antimicrobial agents, and ensure sustainable investment in countering antimicrobial resistance | https://www.emro.who.int/health-topics/drug-resistance/global-action-plan.html |
Joint Commission Antimicrobial Stewardship Requirements | Developed standards for inpatient and outpatient antimicrobial stewardship to achieve accreditation | https://www.jointcommission.org/-/media/tjc/documents/standards/r3-reports/r3_antibioticstewardship_july2022_final.pdf |
IDSA 10 × ‘20 Initiative | Goal of developing 10 new antimicrobial agents to treat antimicrobial-resistant infections by 2020 | https://www.idsociety.org/policy--advocacy/antimicrobial-resistance/antibiotic-development-the-10-x-20-initiative/#:∼:text=IDSA%20is%20working%20to%20counter,thousands%20of%20lives%20each%20year |
FDA GFI #209 | Limits medically important antimicrobial drugs administered in feed or water to uses that are necessary for ensuring animal health and requiring veterinary oversight for antibiotics used in food-producing animals | https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-209-judicious-use-medically-important-antimicrobial-drugs-food-producing-animals |
FDA GFI #213 (Veterinary Feed Directive) | Provides recommendations for how to voluntarily modify use of medically important antimicrobial agents to align with the 2 principles outlined in GFI #209 | https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-213-new-animal-drugs-and-new-animal-drug-combination-products-administered-or-medicated-feed |
FDA GFI #263 | Requires veterinary prescription for all dosage forms of medically important drugs administered to nonfood (companion) or food-producing animals through any route of administration | https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-263-recommendations-sponsors-medically-important-antimicrobial-drugs-approved-use-animals |
USDA Antimicrobial Resistance Action Plan | Outlines current surveillance efforts | https://www.usda.gov/sites/default/files/documents/usda-antimicrobial-resistance-action-plan.pdf |
IDSA, Infectious Diseases Society of America; WHO, World Health Organization.
1. limit medically important antimicrobial drugs to uses that are considered necessary for ensuring animal health; and
2. limit medically important antimicrobial drugs to uses in animals that include veterinary oversight or consultation.12
In 2013, the FDA announced GFI #213,13 which provided recommendations for how to voluntarily modify use of medically important antimicrobial agents to align with the 2 principles outlined in the GFI #209. Pharmaceutical companies were asked to voluntarily remove production purposes from the labels of all medically important antibiotics administered in feed for food producing animals through changes in the Veterinary Feed Directive. Additionally, veterinary oversight was strengthened for antibiotics administered in water for disease treatment, control, and prevention, through voluntary efforts by pharmaceutical companies to remove over-the-counter sales and change product labels to veterinary prescription only status. Most importantly, the FDA announced full implementation of GFI #213 in January 2017. All pharmaceutical companies with affected products either adopted the FDA’s judicious use approach for requiring veterinary oversight or withdrew affected drugs from the market. In 2019, the FDA reported a 38% decrease from 2015 to 2018 in medically important antibiotics sold for use in food-producing animals,81 although sales of cephalosporins and fluoroquinolones increased 21% and 63%, respectively, for agricultural use from 2009 to 2020.9
In September 2018, the FDA unveiled a 5-year plan82 to foster antimicrobial stewardship in animal agriculture and veterinary settings. Notable elements of the plan include provisions to ensure appropriate veterinary oversight for all medically important antibiotics, define appropriate duration for their use, improve collection of data, and update the list of medically important antibiotics. On June 10, 2021, the FDA issued GFI #263, which took effect June 11, 2023, and requires a veterinary prescription for all medically important animal antimicrobial agents through any route, an important step in ensuring appropriate use of antimicrobial agents.83 The FDA has additionally prohibited extra-label (or “off-label”) use of certain antimicrobial agents in food-producing animals.84
Strengthening Surveillance of Animal and Zoonotic Pathogens
The US Department of Agriculture (USDA) published an Antimicrobial Resistance Action Plan85 in 2014 that outlines current surveillance efforts, including (1) the National Animal Health Monitoring System, (2) the Agricultural Resource Management Survey, (3) the Food Safety and Inspection Service sampling in slaughter plants, and (4) the US National Residue Program. Many of these surveillance systems are questionnaire- or survey-based (the National Animal Health Monitoring System, Agricultural Resource Management Survey, and National Residue Program). The Food Safety and Inspection Service uses product sampling through random sampling of animals in the National Antimicrobial Resistance Monitoring System and product sampling through the Salmonella Pathogen Reduction: Hazard Analysis and Critical Control Points verification sampling. The National Antimicrobial Resistance Monitoring System is a public health surveillance system that takes a One Health approach in monitoring slaughter, retail meats, humans, and surface water, and tracks changes in the susceptibility profiles of foodborne and other enteric bacteria.
The USDA has strengthened collection of data about antimicrobial resistant pathogens and is working to continue to bolster information collected about antibiotic use in agriculture. Two important monitoring systems currently in place are the Veterinary Laboratory Investigation and Response Network,86 managed by the FDA, and the National Animal Health Laboratory Network Antimicrobial Resistance Pilot Project,87 managed by the USDA Animal and Plant Health Inspection Service. According to a Pew Charitable Trusts report in 2016,88 the FDA, USDA, and CDC outlined a draft plan for collecting additional data on farm-level antibiotic use that draws on existing data collection systems. The FDA collects aggregate data on total antibiotic sales from veterinary drug companies and in 2016 moved to enhance these data by requiring companies that make antibiotics used in farm animals to estimate the amount of antibiotics sold for use in food animals. Although it is possible to track volume of antibiotics, surveillance systems are unable to identify what drives trends in antibiotic use.89
The National Action Plan for Combating Antibiotic-Resistant Bacteria 2020–2025 was published in 2020 by the US Department of Health and Human Services.90 One of the goals of the plan is to strengthen national One Health surveillance efforts to combat antimicrobial resistance. Anticipated challenges include encouraging stakeholders to collect and share data across the human, animal, plant, and environmental sectors. Additionally, challenges will likely arise in sharing electronic data about antibiotic use and resistance, developing and implementing minimum data-quality standards of measurement, and ensuring sufficient resources to support isolate and data repositories.
Food Procurement Initiatives
Collective efforts to purchase animal products raised without the use of nontherapeutic antibiotics may impact the food supply chain through market pressure toward more judicious agricultural practices. Institutional purchasing initiatives have included, for example, large school districts and health systems committing collectively to purchasing animal products for meals that are produced without antibiotic exposure.91,92 However, the effectiveness of such efforts at mitigating risk of infection and antimicrobial resistance has not been evaluated.
Remaining Gaps in Surveillance, Reporting, Oversight, and Regulations and Opportunities for Future Action
As outlined in the National Action Plan for Combating Antibiotic-Resistant Bacteria 2020–2025,90 anticipated challenges to strengthening surveillance for antibiotic use and resistance include encouraging local, state, and private partners and stakeholders to collect and share data across the human, animal, plant, and environmental sectors. There should be an effort to limit antibiotic durations, increase tracking and reporting, and create public-facing dashboards about antimicrobial use in all animals, including those in agriculture and companion pets to reflect nationally representative data on antimicrobial use in animals, as the European Union does.9 Systematic reporting and transparency of veterinary antibiotic prescriptions and their indications may ensure accountability of appropriate antibiotic use. Additionally, there is a new ban on antimicrobial use for disease prevention in the European Union.9 Because of legislation in the European Union, antimicrobial sales for food animal production dropped by 43.2% on a biomass-adjusted (mg per population correction unit) basis from 2011 to 2020.9
Federal departments and agencies will need to write new policies and processes for the secure and confidential storage and sharing of data. Additionally, public health laboratories will need more support for training and testing capacity to detect resistant organisms. Another weakness in current surveillance systems is that surveys do not track the same farms over time, making it difficult to identify causal factors associated with patterns of antimicrobial use or resistance.85 Sales data are currently reported at the national level and only annually, limiting ability to track geographic and temporal trends. Future reporting systems should track data at a state and local level. Tracking antibiotic use in animals using a biomass-adjusted index can help to infer use data instead of simply following sales data, as the European Union has done and as proposed by the FDA.93 One of the many advances in improving antimicrobial use in agriculture has been the development of certification programs that promote best practices by providing training and education on antibiotic stewardship in agriculture and ensure a minimum set of standards to achieve certification.94
Resources for Further Information and Advocacy Opportunities
A variety of resources exist for further information about antimicrobial use in agriculture and advocacy opportunities to improve appropriate use, including:
One Health Commission: https://www.onehealthcommission.org/
Infectious Diseases Society of America: https://www.idsociety.org/policy–advocacy/antimicrobial-resistance/Antibiotics_in_Agriculture/
United Nations: https://www.fao.org/3/cb5545en/cb5545en.pdf
Coalition to Preserve Antibiotics: https://www.preserveantibiotics.org/
Conclusions
Antimicrobial resistance threatens global public health. The majority of antibiotic sales in the United States occurs for use in farm animals, potentially selecting for emergence and spread of drug-resistant pathogens than can harm the health of all individuals, including children. Evidence supports a link between antibiotic use in food-producing animals and the occurrence of antibiotic-resistant infections in humans. Recent regulatory policies enacted to reduce nontherapeutic antibiotic use in farm animals have resulted in positive changes. To further curtail antibiotic overuse, additional regulatory efforts and oversight are required. More advocacy, political will, and resources are needed to strengthen the One Health approach to judicious antibiotic use in all sectors, including in agriculture.
Lead Authors
Sophie E. Katz, MD, FAAP
Ritu Banerjee, MD, PhD, FAAP
Committee on Infectious Diseases, 2022–2023
Sean T. O’Leary, MD, MPH, FAAP, Chairperson
James D. Campbell, MD, MS, FAAP
Monica I. Ardura, DO, MSCS, FAAP
Ritu Banerjee, MD, PhD, FAAP
Kristina A. Bryant, MD, FAAP
Mary T. Caserta, MD, FAAP
Robert W. Frenck, Jr, MD, FAAP
Jeffrey S. Gerber, MD, PhD, FAAP
Chandy C. John, MD, MS, FAAP
Athena P. Kourtis, MD, PhD, MPH
Angela Myers, MD, MPH, FAAP
Pia Pannaraj, MD, MPH, FAAP
Adam J. Ratner, MD, MPH, FAAP
José R. Romero, MD, FAAP
Samir S. Shah, MD, MSCE, FAAP
Kenneth M. Zangwill, MD, FAAP
Ex Officio
David W. Kimberlin, MD, FAAP – Red Book Editor
Elizabeth D. Barnett MD, FAAP – Red Book Associate Editor
Ruth Lynfield, MD, FAAP – Red Book Associate Editor
Mark H. Sawyer, MD, FAAP – Red Book Associate Editor
Henry H. Bernstein, DO, MHCM, FAAP – Red BookOnline Associate Editor
Liaisons
Cristina Cardemil, MD MPH, FAAP – National Institutes of Health
Karen M. Farizo, MD – US Food and Drug Administration
Lisa M. Kafer, MD, FAAP – Committee on Practice Ambulatory Medicine
David Kim, MD – HHS Office of Infectious Disease and HIV/AIDS Policy
Eduardo López Medina, MD, MSc – Sociedad Latinoamericana de Infectologia Pediatrica
Denee Moore, MD, FAAFP – American Academy of Family Physicians
Lakshmi Panagiotakopoulos, MD, MPH – Centers for Disease Control and Prevention
Laura Sauvé, MD, MPH, FAAP, FRCPS – Canadian Pediatric Society
Jeffrey R. Starke, MD, FAAP – American Thoracic Society
Jennifer Thompson, MD – American College of Obstetricians and Gynecologists
Melinda Wharton, MD, MPH – Centers for Disease Control and Prevention
Charles R. Woods, Jr, MD, MS, FAAP – Pediatric Infectious Diseases Society
Staff
Jennifer M. Frantz, MPH
Gillian Gibbs, MPH
Council on Environmental Health and Climate Change, 2022–2023
Aaron S. Bernstein, MD, FAAP, Chairperson
Sophie J. Balk, MD, FAAP
Lori G. Byron, MD, FAAP
Gredia Maria Huerta-Montañez, MD, FAAP
Steven M. Marcus, MD, FAAP
Abby L. Nerlinger, MD, FAAP
Nicholas C. Newman, DO, FAAP
Lisa H. Patel, MD, FAAP
Rebecca Philipsborn, MD, FAAP
Alan D. Woolf, MD, MPH, FAAP
Lauren Zajac, MD, MHP, FAAP
Former Members
Aparna Bole, MD, FAAP, Chairperson
Philip J. Landrigan, MD, FAAP
Liaisons
Kimberly A. Gray PhD – National Institute of Environmental Health Sciences
Jeanne Briskin – US Environmental Protection Agency
Nathaniel G. DeNicola, MD, MSc – American College of Obstetricians and Gynecologists
CDR Matt Karwowski, MD, MPH, FAAP – CDC National Center for Environmental Health and Agency for Toxic Substances and Disease Registry
Mary H. Ward, PhD – National Cancer Institute
Staff
Paul Spire
Drs Katz and Banerjee both made substantial contributions to drafting, critical review, and final approval of the manuscript, and agree to be accountable for all aspects of the work
Technical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, technical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent.
The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.
All technical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.
This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.
FUNDING: No external funding.
FINANCIAL/CONFLICT OF INTEREST DISCLOSURE: The authors have indicated they have no potential conflicts of interest to disclose.
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