Establishing a direct cause-and-effect relationship between antibiotic use in livestock and antibiotic resistance in humans may be only slightly more difficult than mapping a path between trends in coffee consumption and the color of a penguin’s beak.
At least it is if you demand scientific proof rather than extrapolation and inferential leaping.
The idea bears repeating: Establishing a direct link between antibiotic use in livestock and antibiotic resistance in humans. Not the fact that antibiotic use in each creates antibiotic resistance within that same population. Not that humans and animals can swap antibiotic-resistant organisms back and forth.
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“Current literature is inadequately detailed to establish a causal relationship between antibiotic use in agricultural animals and antibiotic-resistant campylobacteriosis in humans,” says Mary A. McCrackin, DVM, veterinary medical officer and associate professor of comparative medicine at the Medical University of South Carolina.
McCrackin is the primary author of a recent study looking for a link between antibiotic use in food animals and drug-resistant foodborne campylobacteriosis. In a companion study, with similar results, she and fellow researchers looked for a link between antibiotic use in food animals and salmonellosis in humans.
How bad is it?
According to Antibiotic Resistant Threats in the United States, a report from the Centers for Disease Control and Prevention (CDC), campylobacteriosis and salmonellosis are among the most serious threats in terms of antibiotic-resistant infections in humans.
In 2013, minimum estimates of drug-resistant Campylobacter infections were 310,000, with deaths estimated at 28. For drug-resistant non-typhoidal Salmonella, it was 100,000 infections and 40 deaths. In total, CDC listed 18 antibiotic-resistant microorganisms, resulting in 2.05 million infections and 23,488 deaths.
“At least sometimes, Campylo-bacter and Salmonella can get through the food chain to people. So, that’s one question,” explained Mike Apley, a BEEF Vet’s Opinion columnist, veterinarian and professor of production medicine and clinical pharmacology at Kansas State University’s College of Veterinary Medicine, during an Animal Care Resources webinar earlier this year. He was talking about the application of antibiotic stewardship in veterinary medicine.
“The other question is about the reservoir of resistance,” Apley says. What about us selecting for resistant organisms in animal agriculture, and then those pass to people through the food chain, through direct contact or through the environment? Then those resistance genes lay awaiting opportunity in our intestinal flora. Then when we take antibiotics, they flare up and cause a problem? Apley asks.
So far, Apley says there is insufficient information to say whether or not antibiotic use in livestock could be even a small part of contributing to a resistance reservoir in humans.
“If you look at these 2 million cases and 23,000 deaths (CDC data above) and add in Clostridium difficile, [which may be] some part of 400,000 infections between Salmonella and Campylobacter, we wouldn’t be all of those,” Apley says. “And those two account for 60 deaths total.”
This isn’t to trivialize that in any way, but to put it in perspective, Apley says. “Yes, I think food animals do have a direct relationship through the food chain with direct cause, [but are] a really small piece of the overall pie. The question of whether it’s part of establishing a resistance reservoir that contributes [to antibiotic-resistant pathogens in humans], I don’t know.”
There are plenty of theories about how antibiotic-resistant bacteria can be spread from animals to humans, but Apley explains scientists on both sides of the argument struggle to prove probability. In lieu of such information, regulators increasingly rely on something referred to as the precautionary principle. It’s a widely recognized approach in Europe.
“The precautionary principle says that if there’s enough information to cause me as a regulator to think that there’s a potential harm to human health, and that threat is big enough that if it snowballs and we can’t stop it [and] there can be great harm, then I’m going to remove that threat until someone can prove to me that it’s not a threat,” Apley says.
In other words, guilty until proven innocent.
“The FDA will adamantly deny using the precautionary principle, but when you look at the data showing that growth promotion use [of antibiotics] can be separated from prevention, control or therapeutic uses as far as selection for resistance — well, there is none.”
What scientific literature says
At last fall’s Antibiotic Symposia hosted by the National Institute for Animal Agriculture, McCrackin explained the aforementioned studies she was involved with explored one basic question:
“What published literature evidence actually exists to determine if there is a direct link between the use of antibiotics in agricultural animals that are being produced for food for people? And is there a clear connection between that antibiotic use and an increase or apparent increase in the prevalence of antibiotic resistant infections in humans, specifically related to food-borne illness?”
The studies revolved around systematic literature reviews that included scoring studies based on the level of subjectivity to scientific rigor.
“We were very interested in the connections between the farm and the fork, between cows on the farm, the products that came from them and ultimately whether there was there a link to people,” McCrackin explains. They did the same with other species, including pork and poultry.
McCrackin emphasizes the Campylobacter study review doesn’t consider the environment, direct contact with domestic pets or wildlife. She also mentions that what she shared represented her own opinion based on the information.
Among highlights of various literature, one study looked at 30,000 growing turkeys. They were split between a control group and the treatment group receiving Tylosin in the water, according to label directions.
Macrolide (a class of antibiotics) resistance increased immediately after treatment and then declined after the antibiotic was removed. Detection of organisms in the resulting carcasses post-chill was very low.
Another study compared the prevalence of campylobacteriosis in conventionally raised hogs with those grown on antibiotic-free farms.
The prevalence of campylobacteriosis in animals on the farm was about the same, although the percentage of those organisms resistant to antibiotics was higher on conventional farms in the presence of antibiotics use.
But, McCrackin explains, “What is the long-term consequence of that in terms of what makes it to the consumer? Well, for beef and pork there may not be as a big of a problem as sometimes people would like to think … Campylobacteriosis is found at such low rates in commercial pork and beef that NARMS [National Antimicrobial Monitoring System] doesn’t even monitor for campylobacteriosis in those food products anymore.”
McCrackin and her group did find one paper showing direct transmission of antibiotic-resistant campylobacteriosis from an animal product to humans. It was from raw milk traced back to a Pennsylvania farm.
“A frustration in that particular paper is that there was no information about antibiotic use on that farm,” McCrackin explains. “We don’t know if the farm even used antibiotics, and we have no information about the people who were sick … had they had antibiotic treatment before they were exposed to the raw milk? We just don’t know because the information wasn’t there.”
McCrackin says such information gaps are common.
“In the context of food-borne illness, remember that there are lots of things besides bacteria that cause food-borne illness. In fact, norovirus causes much more gastrointestinal illness than campylobacteriosis.”
Keep in mind that McCrackin and her fellow researchers aren’t saying that campylobacteriosis and salmonellosis — the focus of their study — are the primary problems; but that in the context of antibiotic resistance, they are the problems their study addresses.
None of this is to say that looking for such relationships should be ignored. It is to say that antibiotic resistance in any species, let alone the links in between, are too complex for the kind of easy explanations that some proponents on both sides of the debate are fond of applying.
“It’s not about blaming other people. It shouldn’t be about the human health care industry blaming the agricultural or veterinary industries, or vice versa; this just happens. Biology happens regardless of which setting it’s in, and we all have to think about how we’re going to play our part,” McCrackin says.
This is the fifth part in a six-part series. Next month: Judicious use versus antibiotic stewardship.