In January, the U.S. Food and Drug Administration released a preliminary proposal as a follow-up to its 2018 action plan that aimed to bring animal antibiotic use into alignment with principles of antimicrobial stewardship. Central to this goal is ending unnecessary long-term antibiotic treatment of food-producing animals by implementing duration limits for all medically important antibiotics, some of which currently are given to animals for weeks or months. These limits would be an important step toward reducing the risk of antibiotic resistance.
Unfortunately, FDA’s proposal, outlined in a concept paper, will take years to implement—and fails to offer a viable solution to end long-term antibiotic use on farms and feedlots.
This interview—with answers prepared by David Hyun, M.D., who directs The Pew Charitable Trusts’ work on antibiotic resistance, and Mark Eichelberg, Ph.D., who works on the Trusts’ antibiotic resistance project—has been edited for length and clarity.
Q: How commonly are animals given antibiotics for long durations?
A: Most types of antibiotics administered to animals have a treatment duration of a few days, but for certain conditions, such as liver abscesses in cattle, animals regularly undergo treatment periods that can last months. A 2011 survey from the U.S. Department of Agriculture found that more than 70% of feedlot cattle received a macrolide antibiotic, the type of antibiotic commonly prescribed to prevent liver abscesses. A study published in November 2020 showed that beef cattle on 22 feedyards in the U.S. were treated with macrolide antibiotics for an average of 135 consecutive days. Because any antibiotic use contributes to the emergence of resistance, such extended use is likely to fuel the spread of antibiotic-resistant superbugs.
Q: Why do some cattle growers use antibiotics for such long durations?
A: Antibiotics are regularly given to cattle on feedyards to prevent liver abscesses, a condition associated with the highly enriched grain-based diets that cattle growers use to rapidly increase animal weight before slaughter. Cattle with liver abscesses rarely exhibit clinical signs, but the abscesses can result in liver condemnation, which results in an economic loss for cattle producers. So, producers rely on extended antibiotic use as the most cost-effective way to reduce the incidence of abscesses.
Q: Do liver abscesses actually require long-duration antibiotic treatment?
A: There are alternative ways to manage or reduce the severity of the disease without relying on injudicious antibiotic use. Improving the diet of cattle by adding roughage such as cottonseed hulls or chopped alfalfa can significantly reduce the incidence of abscesses. Some research has suggested that essential oil supplements can reduce the amount of the bacteria that cause abscesses. And evidence suggests that a vaccine may protect cattle under some conditions, and research is ongoing to optimize vaccination strategy.
Q: What are macrolide antibiotics?
A: Macrolides are a class of antibiotics that treat a wide range of infections in both humans and animals. Macrolides such as erythromycin and azithromycin are commonly prescribed to treat pneumonia and other respiratory tract infections, skin infections, urinary tract infections, and sexually transmitted diseases. Both FDA and the World Health Organization (WHO) classify macrolides as critically important for human health because they’re used to treat large numbers of infections and because, for some bacteria, such as Campylobacter, few alternative therapies are available.
Q: What’s an example of the impact of long-term macrolide use?
A: Ongoing use of these antibiotics fuels resistance. For example, rates of erythromycin resistance in invasive Group A streptococcal infections nearly tripled from 8% in 2010 to 23% in 2017. The Centers for Disease Control and Prevention (CDC) considers this pathogen a concerning threat, noting that increasing resistance to macrolides complicates treatment of both strep throat and severe invasive infections.
Q: But what’s the connection between human health and the overuse of macrolides on farms?
A: Although erythromycin and azithromycin aren’t used in animals, a bacterial gene that provides resistance to one macrolide can give resistance to all clinical macrolides; these genes are often carried on plasmids, meaning that they can easily spread from one type of bacteria to another. Multiple scientific studies have shown that macrolide use in farm animals increases the prevalence of bacteria that are resistant to human medicines. Humans can then become exposed to these bacteria via contaminated food or through close contact with animals.
Q: Have these macrolide-resistant bacteria been found on farms in the U.S.?
A: Yes. The National Antimicrobial Resistance Monitoring System reported an alarming increase in erythromycin-resistant Enterococcus in beef cattle, from 2.1% in 2013 to 11.4% in 2018. Enterococci are notorious for their ability to transfer a wide range of antibiotic resistance genes to other bacteria, making them a reservoir for antibiotic resistance that can be acquired by more serious pathogens. However, data has shown that this proliferation of antibiotic-resistant pathogens can be reversed—if FDA places meaningful limits on duration to end the overuse of these antibiotics.
Q: How does the FDA propose to establish duration limits for medically important antibiotics?
A: Under FDA’s plan, drugmakers would write proposed updates to their drug label instructions that would indicate a duration of use and provide FDA with any data necessary to support that duration.
Q: How is the proposal flawed?
A: Unfortunately, the proposal gives drug companies unwarranted flexibility in how they can define a duration of use. Under the proposal, durations can be defined as a time range, with no limitations or guidance on establishing the maximum end of a range. Furthermore, durations could be defined without specifying an appropriate length of time or number of doses—instead, using guidelines such as animal age or body weight—or without any specific limit on duration at all, and instead potentially permitting a veterinarian to subjectively determine when a treatment should end.
Q: How could these loosely defined criteria for duration limits affect complex diseases such as liver abscesses?
A: Allowing drugmakers to defer to veterinarian discretion effectively allows producers to continue to use antibiotics without limit as long as the drugs are administered under the nominal oversight of a veterinarian. For a condition such as liver abscesses, the animals seldom exhibit clinical signs of disease, so a lack of a specific duration of use deprives veterinarians of the well-informed guidance necessary to make judicious clinical decisions.
Q: How should FDA update its plan to address long-term use of medically important antibiotics such as macrolides?
A: FDA should prioritize public health and the risk of antibiotic resistance in its approach to establishing duration limits for animal antibiotics. That means that duration limits should be specific and based on sound scientific information validated through clinical trials or field studies. FDA has already funded studies to investigate durations of use for macrolide treatment of liver abscesses, but the agency’s recent concept paper provides no guidance for drugmakers as to how—or even if—they should utilize the data from these studies. FDA should give drugmakers clear direction as to the standard of evidence needed to establish duration limits and hold them accountable for rapidly updating their animal drug labels without allowing them recourse to loopholes such as referencing animal age or body weight, subjective observation of symptoms, or unrestricted veterinary discretion.
Q: Beyond establishing duration limits, what else can FDA do to help producers manage diseases such as liver abscesses—while still reducing the overuse of antibiotics?
A: FDA should work with producers to support improved management practices that will keep animals healthy and reduce reliance on medically important antibiotics. This effort should include helping producers optimize management strategies, such as improving feed quality and raising cattle to build more robust immunity before they’re moved to a feedlot. FDA should also work with USDA to develop a well-coordinated research agenda that can support continued research into alternatives to antibiotics, such as vaccines, and identify optimal management strategies, such as improving feed quality and placing weaned calves into well-managed backgrounding operations, where young cattle can adjust to high-energy diets before being placed on a feedlot.
Q: Last word?
A: FDA has a responsibility to protect public health from threats such as antibiotic resistance. Establishing science-based duration limits is a critical step toward this goal, and it’s important that FDA develops a robust strategy to ensure that these life-saving drugs are used judiciously.