On Jan 3, the US Food and Drug Administration (FDA) announced the full implementation of Guidance for Industry (GFI) #213, a moment that the agency calls a "significant milestone" in national efforts to reduce the use of medically important antibiotics in food-producing animals. But questions remain about how much of an impact the policy will have.
While the policy has its critics, the changes are the most significant moves made by the agency regarding the use of antibiotic in food production in decades. Prior to GFI #213, farmers could use low doses of antibiotics such as penicillin and tetracycline—both commonly used in human medicine—in the feed and water of livestock and poultry to promote growth. And they didn't need a prescription. They could just buy the products over the counter.
But under GFI #213, which was first announced in 2013 and has taken 3 years to fully implement, pharmaceutical companies have been asked to voluntarily remove production purposes (such as growth promotion) from the labels of all medically important antibiotics used in food production. All affected companies have done so as of Jan 3, the FDA says.
In addition, the guidelines require veterinary oversight for the continued use of these drugs for disease prevention and control in herds and flocks. From now on, all antibiotics used in water will require a prescription from a licensed veterinarian, and those used in feed will need a veterinary feed directive (VFD).
"Use of these drugs in any other manner is not allowed," the FDA told CIDRAP News via e-mail.
Will "judicious use" cut use significantly?
The FDA believes that with this new policy, the use of medically important antibiotics in livestock will now meet "judicious use" principles, maximizing the therapeutic efficacy of the drugs while minimizing the potential to promote antibiotic resistance. It's a move that antibiotic resistance experts say is long overdue given their belief that the routine use of antibiotics in food animals is substantially driving resistance, though the exact mechanisms are unclear.
But experts also say the policy may not by itself have a huge impact on medically important antibiotic use in food-producing animals, which accounts for a significant portion of overall antibiotic sales nationally. Approximately 70% of all medically important antibiotics in the United States are sold for use in animals.
"The effectiveness of this guidance depends on how the guidance is followed and monitored through the control of antibiotics in food-producing animals," says Stuart Levy, MD, a professor of medicine and director of the Center for Adaptation Genetics and Drug Resistance at Tufts University School of Medicine.
Levy, who's also the founder and board chairman of the Alliance for the Prudent Use of Antibiotics, has been a longtime critic of the FDA for its policies on antibiotics. He says that while he's pleased with the new policy, the FDA should follow through with monitoring to ensure that the guidance is being observed. The FDA says it "intends to look for ways to reinforce the importance of the principles of judicious and appropriate use" and is in the early stages of implementing its overall strategy.
Timothy Johnson, DVM, a professor of veterinary medicine at the University of Minnesota, also agrees that the new policy should have an impact on medically important antibiotic use in food production, but he says there are other factors at work.
"The guidance will have an impact on the use of medically relevant antibiotics," Johnson says. "But I think it's the guidance in combination with already existing consumer pressures that is going to have the biggest impact."
What Johnson's referring to is the increasing desire of consumers for meat and poultry that's completely free of medically important antibiotics. As a result of this consumer pressure, several fast-food chains have said they will stop selling chicken raised on antibiotics. McDonalds stopped doing so last year, and the parent company that owns Burger King recently said it will make the change this year.
Questions about disease prevention
Others are questioning whether the FDA has gone far enough. A significant concern, raised in a 2016 petition to the FDA from the Natural Resources Defense Council and several other environmental groups, is that ending the use of medically important antibiotics for growth promotion doesn't really solve the problem. These groups argue that growth promotion accounts for only 10% to 15% of medically important antibiotic use in food animals, a figure based on estimates from the Animal Health Institute, a group that represents veterinary pharmaceutical companies.
The bigger issue that's not being addressed by the FDA, these groups and other critics say, is the continued use of medically important antibiotics for disease prevention, which involves administering low or "subtherapeutic" doses of antibiotics through feed and water to herds and flocks for long periods. These low doses can help promote resistance by creating selection pressure and enabling antibiotic-resistant strains of bacteria that would have been killed by higher doses to survive.
The FDA, in an e-mailed response to this criticism, says it considers uses associated with the treatment, prevention, or control of specific disease to be "uses that are necessary for assuring the health of food-producing animals."
"I, and many others, have had concerns that what the FDA approach will result in is essentially a rebranding of antimicrobial use in food animals," says Keeve Nachman, PhD, MHS, a scientist with the Johns Hopkins Center for a Livable Future who researches the human health effects of drugs used in food animals.
In Nachman's view, disease prevention isn't a therapeutic use because it's not targeting a specific microbial disease. Furthermore, since the approved doses for disease prevention in some drugs are identical to what they were for growth promotion, it will be difficult to determine how farmers are using them.
"My big worry is that we're going to stop calling it growth promotion and we're going to start calling it disease prevention," says Nachman. As a result, he adds, "use, in practice, might not change all that much."
To illustrate, Nachman points to comments made to the Wall Street Journal by a pharmaceutical executive in 2013 about the potential impact of the guidance. In the interview, Zoetis CEO Juan Ramon Alaix told the paper he didn't think the FDA's decision to end the use of antibiotics for growth promotion would have an impact on the company's revenues.
"If it's not going to impact their sales, then why would you expect it would have an impact on use?" Nachman asks.
Levy also has concerns about the continued use of medically important antibiotics for disease prevention, noting that while GFI #213 should have some impact on antibiotic use, "it will not be as effective as would be comprehensive control of antibiotic usage, especially in subtherapeutic doses."
The role of veterinary oversight
Johnson says he thinks the added layer of veterinary involvement will ensure more appropriate use of medically important antibiotics going forward. And the FDA makes it clear that veterinarians will play an essential role in enforcement of the policy. "The FDA believes veterinary medical practitioners play a critically important role in assuring these drugs are used appropriately and judiciously," the agency said via e-mail.
The question for some, though, is what veterinary involvement actually looks like. In the FDA's VFD final rule, a component of the agency's broader strategy to curb medically important antibiotic use on the farm, one of the key elements that defines the veterinary client-patient relationship is having "sufficient knowledge of the patient by virtue of patient examination and/or visits to the facility where the patient is managed," the agency says on its Web site.
But that doesn't mean a veterinarian has to examine or see animals every time they issue a prescription for antibiotics. That simply won't be possible in some cases, explains Gail Hansen, DVM, especially in remote areas.
"If you have animals that are sick, and a vet can't get out there for 2 to 3 days, animals are going to die," says Hansen, a public health and animal medicine consultant. "That's not good for the producers, it's not good for the vets, and it's not good for animal health."
The VFD final rule also requires veterinarians to adhere to state-defined veterinarian client-patient relationship standards, which may be different from the FDA standards but must include the key elements required by the FDA. The FDA says this will ensure that veterinarians are conducting oversight in accordance with nationally consistent principles, while allowing for the "flexibility needed to accommodate the diversity of circumstances that veterinarians encounter."
For Nachman, the flexibility is a concern.
"I get that there has to be some flexibility in implementation, but my worry is that there's so much flexibility in the way the rule is specified that it could be abused," he says.
But Johnson bristles at the idea that veterinarians would potentially abuse their oversight role.
"The veterinarians I know in the poultry field have a high moral and ethical obligation to their profession," Johnson says. "They take this very seriously, and they understand the problem of antibiotic resistance just as much, if not more, than the public does."
Hansen says the veterinarians she's spoken with have told her, "If they're a client of mine, they'll need a visit."
At the same time, Johnson suggests veterinarians will now face the same type of pressure that physicians face when confronted with a patient who wants antibiotics but may not necessarily need them. In the same way that it may be hard for a physician to refuse antibiotics for a child with an earache or a sore throat, a veterinarian overseeing a poultry flock with high mortality might find it difficult to tell a producer that antibiotics aren't warranted.
"It's the same type of problem," Johnson says.
More data needed
FDA data on sales and distribution of antibiotics in food-producing animals will provide some clue as to whether GFI #213 is making a difference. In December, the agency released a report showing that sales and distribution of medically important antibiotics in food animals increased by 2% from 2014 through 2015 and by 26% since 2009, the first year such data were provided. Groups like NRDC say this is proof that the FDA's efforts to reign in medically important antibiotic use on the farm need to be stronger.
But that data came before full implementation of the new policy, and some observers expect that GFI #213 will produce some results now that it is fully implemented. As Karin Hoelzer, DVM, senior officer with the Pew Charitable Trusts, explains, more than 90% of the medically important antibiotics sold to farmers in 2015 were purchased over the counter. "That should change dramatically" with full implementation of GFI #213, Hoelzer says.
Still, it might take a few years before we see a decline in the sales and distribution of medically important antibiotics for use in food-producing animals. And even then, Hoelzer, Nachman, and others say we need more than just sales data to understand how often antibiotics are being used on farms, why they are being used, and how that use influences antibiotic resistance.
"At the end of the day, what we're worried about is the application of selection pressure," Nachman says. "So, it doesn't matter what we call use. If we are applying selection pressure unnecessarily, then we are unnecessarily increasing the risk that we are going to generate one of these bugs and that these bugs are going to find their way to people and cause resistant infections."
FDA fact sheet on VFD Final Rule
Jan 3 FDA news release on GFI #213
Dec 22 CIDRAP News story "FDA: Antibiotic use in food animals continues to rise"
Sep 15 CIDRAP News story "Petition calls on FDA to limit antibiotic use in food animals"