Nontherapeutic Use of Antimicrobial Agents in Animal Agriculture: Implications for Pediatrics

Antimicrobial resistance is a growing public health crisis. Antimicrobial-resistant infections are often more costly to treat, prolong health care use, and can increase morbidity and mortality.^1,–3 The Centers for Disease Control and Prevention (CDC) reported that more than 2 million Americans become ill with antimicrobial-resistant infections each year, with more than 23 000 resulting deaths.⁴ National costs to the US health care system attributable to antimicrobial-resistant infections have been estimated to be $21 billion to $34 billion annually, resulting in 8 million additional hospital days.^3,5,–7 Although overuse and misuse of antibiotic drugs in human medicine play a significant role in the problem, the focus of this analysis is on a less commonly recognized contributor: the use of antimicrobial agents in food animals.

Antimicrobial agents are widely used in food animals in the United States. In 2012, animal antimicrobial sales represented a substantial proportion of overall antimicrobial sales in the United States: more than 32.2 million pounds of antimicrobial drug active ingredients (including drug classes not used in humans, such as ionophores),⁸ compared with an estimated 7.25 million pounds⁹ of antimicrobial products for human use. Approximately 60% of the antimicrobial agents sold for use in food animals are considered to be important in human medicine. Many antimicrobial agents used in food animals are the same as or similar to those used in human medicine (Table 1).¹⁰ Unlike in human medicine, antibiotic agents in food animals may often be used without a prescription or any veterinary oversight. The Food and Drug Administration (FDA) reported that 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 food animals, antimicrobial agents are approved for a variety of indications, commonly categorized into treatment, disease control, prevention, and production uses.¹² The FDA and the World Health Organization define antimicrobial use for treatment, prevention, and control of specific diseases as “therapeutic use.” Treatment uses involve episodic use of therapeutic doses of antimicrobial agents for management of specified infectious diseases in clinically ill animals. When used to control spread of infection, antimicrobial agents are administered not only to ill animals but also to those that are likely to come into contact with ill animals.

Antimicrobial agents are also approved for use in animals without an identifiable infectious illness. Preventive uses of antimicrobial agents involve giving antimicrobial drugs to healthy animals at high risk of infection in situations in which there is a history of a specific disease, such as during transportation or when confined to crowded areas such as those common to animals raised under industrial conditions. Duration of preventive use can vary. Production uses (nontherapeutic use) include “feed efficiency” and “growth promotion” uses, which are unrelated to disease management. These uses typically involve administration of subtherapeutic antimicrobial agents in the feed or water of an entire herd or flock to promote faster growth with less feed. The mechanism of action is not fully understood; hypotheses include that production uses may have an overlapping effect of preventing disease, which facilitates more rapid growth or alterations in the microbiome. Animal studies link antibiotic-induced alterations in the microbiome to changes in metabolism, adiposity, and higher fat mass.¹³ 

Many antimicrobial agents used for growth promotion are also used for disease prevention, including antibiotic classes ranked by the FDA as critically or highly important to human medicine, such as macrolides, streptogramins, and tetracyclines.¹¹ National data describing antimicrobial use in food animals by indication are sparse. In 2012, most antimicrobial agents sold for food animal use in the United States (94%) were intended to be delivered through animal feed or water; only 4% of antibiotic drugs sold that year were intended to be administered by injection.¹¹ 

Antimicrobial resistance is an organism’s ability to evade inhibition by an antimicrobial agent. Resistance traits can be acquired either through new mutations¹⁴ or through transfer of genetic material between organisms (by bacteriophages or mobile genetic elements, such as plasmids, naked DNA, or transposons).¹⁵ Any use of antimicrobial agents leads to elimination of susceptible organisms, allowing resistant organisms to survive. Overuse or misuse of antimicrobial agents places antimicrobial pressure on bacteria,¹⁶ 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.^13,14 

Therapeutic and subtherapeutic use of antimicrobial agents in animals has been shown to lead to antimicrobial resistance.^17,–26 In a classic experiment, Levy et al²⁷ demonstrated that in 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 exposed to the antimicrobial agent to other members of their species in the same environment, and resistant organisms were also identified in specimens from humans living on the farm. Once tetracycline feed supplementation was stopped, there was a decrease in resistant organisms detected in the farm-dwelling humans.

In recent years, evidence has emerged linking additional resistant pathogens to antibiotic use in food animals. Methicillin-resistant Staphylococcus aureus (MRSA) has been found to acquire tetracycline and methicillin resistance in livestock.²⁸ MRSA has also been found to be prevalent in meat and poultry in the United States; samples from 5 US cities²⁹ demonstrated S. aureus contamination in 77% of turkey samples, 42% of pork samples, 41% of chicken samples, and 37% of beef samples. Ninety-six percent of S. aureus isolates were resistant to at least 1 antimicrobial agent, and many were additionally resistant to other antimicrobial classes, including tetracycline, ampicillin, penicillin, erythromycin, quinupristin/dalfopristin, fluoroquinolones, oxacillin, daptomycin, and vancomycin. More than half of samples were multidrug resistant, defined as intermediate or complete resistance to 3 or more antimicrobial classes. Patient exposure to swine or livestock industrial agriculture exposure has also been associated with increased risk of community-acquired and health care–associated MRSA infection.^30,31 

Extraintestinal Escherichia coli infections have also been linked to antibiotic use in food animals.³² Extraintestinal pathogenic E. coli is a term used to describe E. coli lineages that cause disease at nonintestinal sites. Extraintestinal pathogenic E. coli organisms, including antimicrobial strains, have been associated with human urinary tract infections, sepsis, and other infections.^33,34 

Since 2008, the FDA has been collecting limited data about antimicrobial drug sales for use in food animals in the United States and publicly reports sales data by drug class (Table 1).

Susceptible and resistant animal pathogens can reach humans through the food supply, by direct contact with animals, or through environmental contamination.

Increasingly, food animals are raised in large numbers under close confinement, transported in large groups to slaughter, and processed very rapidly. These conditions can cause increased bacterial shedding and contamination of hide, carcass, and meat with fecal bacteria. Dissemination of pathogens through the food chain is amplified by centralized food processing and packaging processes and broad distribution through food wholesalers and retail chains. By these mechanisms, organisms found in contaminated meats and other food products have been shown to be transmitted to humans through the food supply.^32,37,38 

Resistant bacteria can spread to humans through direct exposure^39,–41 from infected or contaminated animals, such as on farms or in processing facilities. Farmers, farm workers, and farm families¹⁶ as well as casual visitors⁴² are at greater risk of infection compared with the general population.²⁷ 

Resistant bacteria from animals can be spread through fecal material, wastewater, or environmental contact, leading to environmental reservoirs of pathogens and resistance genes.^43,44 Animal feces can contaminate foods when manure containing resistant organisms is applied to agricultural soils and the organisms are then present in farm runoff.⁴⁵ 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. Active antimicrobial agents have been detected in surface waters and river sediments,⁴⁶ and resistance genes identical to those found in swine waste lagoons have been found in groundwater and soil microbes hundreds of meters downstream.⁴⁷ 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.

Infants and children are affected by transmission of susceptible and resistant food zoonotic pathogens through the food supply, direct contact with animals, and environmental pathways. In 2013, a total of 19 056 infections, 4200 hospitalizations, and 80 deaths were reported to the Foodborne Diseases Active Surveillance Network, a CDC surveillance system covering 15% of the US population.⁴⁸ For most infections, incidence was highest among children younger than 5 years.⁴⁹ Data on food-related transmission of Campylobacter species, Salmonella species, and E. coli are summarized here.

Nontyphoidal Salmonella species are a leading cause of foodborne illness in children. In 2013,⁵⁰ the incidence of laboratory-confirmed Salmonella infections per 100 000 children was 63.49 in children younger than 5 years, 19.33 in children 5 through 9 years of age, and 11.26 in children 10 to 19 years of age.⁵¹ Scallan et al⁵² estimated that Salmonella results in 123 452 illnesses, 44 369 physician visits, 4670 hospitalizations, and 38 deaths annually among children younger than 5 years. Neonatal infections caused by Salmonella species have been attributed to indirect exposure to foodborne sources.^39,53 Pediatric Salmonella infections caused by exposure to contaminated pet food have also been documented.⁵⁴ Food contaminated with Salmonella is not the only route of transmission; children have also acquired Salmonella infections from direct contact with livestock⁵⁵ and live poultry and other animals or their environments.^56,57 

The CDC estimated in 2013⁴ that there are 1.2 million Salmonella infections in the United States per year, of which 100 000 are drug-resistant. Five percent of nontyphoidal Salmonella are resistant to 5 or more classes of antibiotic drugs. Of particular note, 3% are resistant to ceftriaxone, the first-line therapy for salmonellosis in pediatrics.

Campylobacter species are also a leading cause of foodborne illness in children. In 2013,⁵⁰ the incidence of laboratory-confirmed Campylobacter infections per 100 000 children was 24.08 in children younger than 5 years, 10.54 in children 5 through 9 years of age, and 9.42 in children 10 to 19 years of age.⁴⁵ Campylobacter species have been estimated to cause 81 796 illnesses, 28 040 physician visits, 1042 hospitalizations, and 6 deaths annually in children younger than 5 years.⁴⁶ Campylobacter infection has been associated with eating poultry and nonpoultry meat products and unpasteurized dairy products as well as exposure to untreated water and contact with farm animals.⁵⁸ 

Antimicrobial resistance, specifically resistance to ciprofloxacin, in Campylobacter species is increasing⁵⁹; resistance increased from 13% in 1997 to almost 25% in 2011.⁴ The CDC estimated in 2013⁴ that there are 1.3 million Campylobacter infections per year, of which 310 000 are drug resistant. Of all Campylobacter samples tested, 23% were resistant to ciprofloxacin, and 2% were resistant to erythromycin. In children, azithromycin and erythromycin are the preferred treatment of Campylobacter gastrointestinal tract infection. Fluoroquinolones may be effective against Campylobacter species, but resistance is common, and fluoroquinolones are not approved for this indication by the FDA for use in children.

MRSA infections cause a variety of human illnesses, including skin and wound infections, pneumonia, and sepsis. MRSA has been demonstrated to be transmitted from animals to humans through close contact with livestock.⁶⁰ In recent years, a MRSA clone, which originated in the community and is associated with exposure to livestock, has emerged in different countries worldwide, including the United States. Even more concerning, countries with a historically low prevalence of MRSA, including the Netherlands and Denmark, have seen an increase in livestock-associated MRSA.^61,62 

The CDC estimates that there are 80 461 severe MRSA infections in the United States per year and 11 285 deaths.

Despite the evidence that nontherapeutic use of antibiotic agents selects for resistance, that bacterial resistance in humans is determined by the same mechanism as in animals, and that resistance genes can disseminate via the food chain, initiatives to reduce antibiotic have met with opposition from the agriculture and farming industry.

The first ban on farm use of antibiotic agents as growth promoters was enacted in 1986 in Sweden, followed by Denmark, the United Kingdom, and other countries of the European Union. In 1995, Denmark established DANMAP, a system for monitoring antibiotic resistance in farm animals to follow the effect of banning antibiotic drugs as growth promoters. Danish swine and poultry production continues to thrive without a loss in meat production, and Denmark has experienced major reductions in antimicrobial consumption and resistance. Likewise, using a similar monitoring program, Sweden has noted no loss of production after the ban and dramatic reductions in the sales of antibiotic agents for animals, from 45 tons to approximately 15 tons by 2009.⁶³ 

In 2013, the FDA implemented a plan to phase out the use of medically important antimicrobial agents in food animals for food production purposes, such as to increase growth or improve feed efficiency. The plan is not a ban but a roadmap for animal pharmaceutical companies to voluntarily revise their approved labels for antibiotic use in animals. The CDC encourages and supports efforts to minimize inappropriate use of antibiotic agents in animals, including the FDA’s strategy to promote the judicious use of antibiotic drugs that are important in humans. The CDC has also contributed to curriculum for veterinarians on the prudent use of antibiotics in animals.⁴ Despite the FDA’s policy, a recent report by the Pew Charitable Trusts identified many antibiotic agents approved for disease prevention purposes that were also approved for growth promotion. A quarter (66) of the 287 antibiotic agents reviewed can be used for disease prevention at levels that are fully within the range of growth promotion dosages and with no limit on the duration of treatment. Because the lines between disease prevention and growth promotion are not always clear, the current FDA policy may allow drug manufacturers to continue using ambiguous language on labels of antibiotic drugs. The Pew Charitable Trusts urged the FDA to take additional steps to ensure that food animals receive antibiotic agents only when medically necessary.⁶⁴ 

Congress is also pursuing a path to curb antibiotic use in animals. The Preservation of Antibiotics for Medical Treatment Act (H.R. 1150) would protect 8 classes of antibiotic agents important for treating infections in humans. The act proposes withdrawal of antibiotic use from food animal production unless animals or herds are sick with disease or unless pharmaceutical companies can prove that their use does not harm human health. A bipartisan companion bill, the Preventing Antibiotic Resistance Act (S. 1256), was introduced in the 113th Congress. Bills have also been introduced to improve data collection and reporting on antibiotic use in food animals: the Antimicrobial Data Collection Act (S. 895) and the Delivering Antimicrobial Transparency in Animals Act (H.R. 820). In September 2014, the President’s Council of Advisors on Science and Technology released its report, “Combating Antibiotic Resistance,” and President Obama signed an executive order directing key federal departments and agencies to take action to combat the increase of antibiotic-resistant bacteria. Among these, the FDA was directed to continue taking steps to eliminate agricultural use of medically important antibiotics for growth promotion purposes.⁶⁵ 

Finally, the World Health Organization, in its recent report on antimicrobial resistance, outlined a global plan that includes integrated surveillance of food-producing animals and the food chain.⁶⁶ 

Antimicrobial resistance is considered one of the major threats to the world’s health. The use of antimicrobial agents in agriculture can harm public health, including child health, through the promotion of resistance. Because of the link between antibiotic use in food-producing animals and the occurrence of antibiotic-resistant infections in humans, antibiotic agents should be used in food-producing animals only to treat and control infectious diseases and not to promote growth or to prevent disease routinely.

Jerome A. Paulson, MD, FAAP

Theoklis E. Zaoutis, MD, MSCE, FAAP

Jerome A. Paulson, MD, FAAP, Chairperson

Samantha Ahdoot, MD, FAAP

Carl R. Baum, MD, FAAP

Aparna Bole, MD, FAAP

Heather L. Brumberg, MD, MPH, FAAP

Carla C. Campbell, MD, MS, FAAP

Bruce P. Lanphear, MD, MPH, FAAP

Jennifer A. Lowry, MD, FAAP

Susan E. Pacheco, MD, FAAP

Adam J. Spanier, MD, PhD, MPH, FAAP

Leonardo Trasande, MD, MPP, FAAP

John Balbus, MD, MPH – National Institute of Environmental Health Sciences

Todd Brubaker, DO – AAP Section on Medical Students, Residents, and Fellowship Trainees

Nathaniel G. DeNicola, MD, MSC – American Congress of Obstetricians and Gynecologists

Ruth A. Etzel, MD, PhD, FAAP – US Environmental Protection Agency

Mary Mortensen, MD – Centers for Disease Control and Prevention/National Center for Environmental Health

Sharon Savage, MD – National Cancer Institute

Paul Spire

Carrie L. Byington, MD, FAAP, Chairperson

Yvonne A. Maldonado, MD, FAAP, Vice Chairperson

Elizabeth D. Barnett, MD, FAAP

H. Dele Davies, MD, FAAP

Kathryn M. Edwards, MD, FAAP

Mary Anne Jackson, MD, FAAP, Red Book Associate Editor

Dennis L. Murray, MD, FAAP

Ann-Christine Nyquist, MD, FAAP

Mobeen H. Rathore, MD, FAAP

Mark H. Sawyer, MD, FAAP

Gordon E. Schutze, MD, FAAP

Rodney E. Willoughby, MD, FAAP

Theoklis E. Zaoutis, MD, FAAP

Henry H. Bernstein, DO, FAAP – Red Book Online Associate Editor

Michael T. Brady, MD, FAAP – Red Book Associate Editor

David W. Kimberlin, MD, FAAP – Red Book Editor

Sarah S. Long, MD, FAAP – Red Book Associate Editor

H. Cody Meissner, MD, FAAP – Visual Red Book Associate Editor

Doug Campos-Outcalt, MD, MPA – American Academy of Family Physicians

Karen M. Farizo, MD – US Food and Drug Administration

Marc A. Fischer, MD, FAAP – Centers for Disease Control and Prevention

Bruce G. Gellin, MD – National Vaccine Program Office

Richard L. Gorman, MD, FAAP – National Institutes of Health

Lucia H. Lee, MD, FAAP – US Food and Drug Administration

R. Douglas Pratt, MD – US Food and Drug Administration

Joan L. Robinson, MD – Canadian Paediatric Society

Marco Aurelio Palazzi Safadi, MD – Sociedad Latinoamericana de Infectologia Pediatrica (SLIPE)

Jane F. Seward, MBBS, MPH, FAAP – Centers for Disease Control and Prevention

Geoffrey R. Simon, MD, FAAP – Committee on Practice Ambulatory Medicine

Jeffrey R. Starke, MD, FAAP – American Thoracic Society

Tina Q. Tan, MD, FAAP – Pediatric Infectious Diseases Society

Jennifer M. Frantz, MPH

CDC

Centers for Disease Control and Prevention

FDA

US Food and Drug Administration

MRSA

methicillin-resistant Staphylococcus aureus