What is the harm in agricultural-use antibiotics?

After this post on antibiotic resistance, many of you may have seen an exchange on Twitter calling me out for being "knee-jerk" about my call to action to do something about the overuse of antibiotics. In that post, I focused on antibiotic use in agriculture, giving only brief mention to human clinical use. There are a number of reasons for this, and while I didn't discuss them extensively on Twitter, I did want to provide an overview here in order to better explain my position and concern about antibiotic use in agriculture.

How are antibiotics used in animal production?

To start, some background on the issues. Antibiotics are used in agriculture in a number of different ways. Like humans, they're used to treat disease when animals get sick. This type of use isn't disputed for the most part--no one wants animals to die from treatable disease, nor do they want sick animals to enter the food chain. Antibiotics can also be used to prevent disease, such as when animals are stressed (as when they're moved from farm to farm) and disease has a tendency to break out, or if a few animals in the herd are sick and owners want to prevent the rest of the herd from falling ill. This type of use is somewhat controversial, and many have argued that this type of use is only necessary because hygienic conditions on farms aren't up to snuff--and that if better husbandry was practiced, this prophylactic use could also be significantly decreased or eliminated. Others argue that it's necessary even with good husbandry.

The practice which is most widely disputed is the use of antibiotics for growth promotion. We've known for roughly 60 years that animals, when fed antibiotics at low doses (below the level required for disease treatment),  grow to their slaughter weight faster (and therefore, with less food input). This is the "low-hanging fruit;" the practice that even some in industry agree could end with pretty much no (or minimal) side effects to industry; and the practice that the European Union has already ended. It's also the target of FDA guidance 213, which asks the phamaceutical industry to voluntarily phase out the use of growth promotant antibiotics in feed and water given to livestock. Twenty-five of 26 companies have agreed to this already, so again, there's really not much dispute that this is a process that will be ending, after over 60 years of use and 45 years after a government report suggested that rising rates of antibiotic resistance in humans was tied to agricultural antibiotic use in the Swann report. (Maryn McKenna has a great timeline of other developments here).

Why am I (and many others) concerned about the use of antibiotics in agriculture?

First, and most compelling to me, is the fact that between 70-80% of all antibiotics used in the United States are used in agriculture. I'm linking to a PolitiFact report because they drill down into the caveats with that number in more detail than I want to go into for this post, but I will note that it's tough to get good numbers because the industry won't release them, and that the numbers we do have include drugs that are not used in human medicine--but that doesn't mean they may not be important. More on that later.

Second, this is my area of expertise. I study antibiotic-resistant pathogens in the agricultural environment, so naturally this is my interest and where I know the literature the best. Third, antibiotic use in agriculture just isn't as intensively studied when it comes to methods to reduce antibiotic-resistant microbes that may emerge from this setting. In the hospital and clinics, patients need a prescription to get antibiotics. The amount of antibiotics that are prescribed are tracked and those data are available. Hospitals often have stringent infection-control policies put in place to reduce the generation and spread of antibiotic-resistant "superbugs." Hell, there's enough research on these policies that my colleagues have a blog devoted just to that topic. In human medicine, no one is ignoring the generation and spread of resistant pathogens.

None of these control and monitoring policies are present on livestock farms as a matter of routine. Rather, as my colleague Lance Price has noted more than once, if he was going to try to create a superbug, farm use of antibiotics--subclinical dosing of thousands of animals at a time--would be an ideal way to create one.

What if we remove "growth promotant" antibiotics?

What remains an issue is what will happen after growth-promotant antibiotic use is stopped. There is already a "natural  experiment" going on in the EU, where such antibiotics were banned back in 2006. As I noted here, the results have been mixed when antibiotics have been removed from agricultural practices. Sometimes resistance persists, sometimes it goes down. A modeling paper examined the use of antibiotics for agricultural use, and suggested that their biggest impact happens before we even realize it via surveillance, and by the time we notice it, it may be too late to make much of a difference, which is depressing.  So even if antibiotics are banned for growth promotion purposes, there is a chance that we won't see much of a dent in antibiotic resistance overall--or if we do, it may take years to see it decrease. This is an argument against removal of these sub-therapeutic uses--if we can't 100% guarantee it will help, why change the status quo?--but at this point, even the current status quo is better than an ever-increasing arc of resistant bacteria.

Another concern that persists and muddies the waters is that no meaningful reduction in antibiotic use in animals will occur, but that rather antibiotics used for growth promotion will just be repackaged as "prophylactic" use, which will still be allowed under the new guidance. The industry says this won't happen, but without meaningful and transparent surveillance, how can we know if it is or not?

Additionally, other sources of low-level antibiotics may still be present on farms and in feed, such as the use of distiller's grains in animal feed which may still contain some antibiotics. And even if antibiotics that are important for human medicine are removed altogether, resistance still may linger or even climb if we allow for other classes of antimicrobials (such as ionophores, which are part of that group I mentioned above that are used in agriculture but not in human medicine) to still be used on the farms. Why could this be an issue? Right now, we really don't know if any of these drugs co-select for resistance to important human medicines. For example, in some cases, antibiotic resistance genes are together as cassettes that can move around between bugs, such as on a plasmid or other mobile genetic element. That's why using tetracycline on a pig farm can select for methicillin resistance--not because the drugs are the same (they're totally different classes), but because the resistance genes come as a package deal. Is this happening with ionophores? Don't know. It's a messy area and makes any clear-cut cause-and-effect research very difficult to carry out.

To make matters even messier, because there's so much transport of animals across state, national, and international lines, even if antibiotics are reduced in one place, new resistant bugs could be imported from elsewhere where no reduction in antibiotic use has taken place, mucking up the data and making it appear that antibiotic withdrawal has had no effect.

Furthermore, there is no directive for companies to actually track and report antibiotic usage differences after growth-promotant antibiotics are removed. We can't even get good data on the industry as a whole, much less finer-level data describing how much goes to pigs, how much to cattle, how much on Iowa pig farms versus North Carolina, or for Smithfield versus Hormel farms, etc. It's a surveillance nightmare. Even if we did have this data, surveillance of resistant pathogens is quite limited, especially on the farms themselves. Most of the data we have comes from NARMS--the national antimicrobial resistance monitoring system, which examines gram negative pathogens in people, meat samples, and live animals (taken at slaughterhouses). It's a start, but what if we don't see an effects in these organisms--but might in other commensal pathogens, or in the microbiome as a whole? Or in gram positives like my pet bug, Staphylococcus aureus? NARMS right now would miss those, and so might lead to false impressions of how reduction in antibiotics is really affecting resistance in the bacteria originating on farms.

Soooo....as you can see, this is a messy area. However, as I noted on Twitter, one should look at the totality of the research rather than searching for any particular "smoking gun" publication (a fallacy, I might add, that is employed by many types of science "skeptics"). There have been many, many papers that have shown, usually in ecological studies, that use of antibiotics on the farm is linked to generation of resistant bacteria, and that these bacteria (and associated resistance genes) can spread to humans via food, water, environmental runoff/contamination, air, and other mechanisms. Pew Health has an extensive bibliography of many of these studies here, and it's barely even scratching the surface when it comes to publications in this field. In the end, though it's messy, it breaks down to a simple truth: antibiotic use leads to antibiotic resistance, and reduced use is a goal to strive for--be it use in humans or in animals.

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> antibiotics ... repackaged as “prophylactic” use

So for "growth promotion" they would presumably have given all the animals antibiotics, I'd guess?

And "prophylactic" use would also be to protect _all_ of them, right?

So what's the difference? Is there a criterion in actual practice -- purchase and delivery of the antibiotics -- that would be different, to distinguish the two uses?

Is there a definition of "prophylactic" that distinguishes that sort of use? Perhaps it could mean starting to feed the animals only some specific antibiotic, only in response to an identified disease outbreak detected locally, or in the adjacent counties, or in the state, or adjacent states, or ... what?
Thanks for writing about this.

By Hank Roberts (not verified) on 28 May 2014 #permalink

Dosage is a bit different--it's typically higher for prophylactic use than growth promotion purposes, but still not as high as for therapeutic purposes. Prophylactic use can be when there is disease diagnosed in some percentage of the herd and they want to prevent it breaking into the rest, but more commonly is used at various phases during growth when, historically, disease has broken out (such as when piglets are weaned, or moved to a new farm, etc.) The definition, though, is somewhat "squishy", hence the concern that some uses could be substituted if growth promotion antibiotics are removed.

We can't move on climate change, and the agricultural industries are propagandizing like mad with specious antibiotic claims to confuse the public, much like the tobacco industry did in the past. Yes, there are many areas of ambiguity here, but the antibiotic resistance is so crucial and pressing that there's no question we should ban antibiotics as growth promoters and enforce that ban with painful penalties. Europeans did it and the sky has not yet fallen.

By Kenneth Rubenstein (not verified) on 29 May 2014 #permalink

What do you think is the most likely mechanism for the growth-promoting effects of antibiotics? Prevention of subclinical disease? Alteration of gut microbiomes with resulting effects on animal physiology (as has been suggested for human obesity)? Something else? Thanks!

By Ben Murray (not verified) on 10 Jun 2014 #permalink

Excellent post Tara.
Hank: trying to answer your question quickly without oversimplifying, growth promotion in order to work has to be administered to all animals during the whole productive cycle at low dosages with a substance with as wide spectrum of action as possible because the objective is to reduce the microbial burden therefore reducing energy consumption with the immune system in the animal and improving food conversion ratios (FCR). Additionally low dosages also help with wothdraw periods and preventing antimicrobial residues being passed to consumers.
Prophylactic use requires a clear therapeutical objective, therefore a higher dosage because it has to be therapeutical and would tend to be more limited in time and possibly targeted to certain classes of animals on farm although it does not always work like that because certain agents (digestive parasites are particularly notorious at doing this) induce no immunity in susceptible animals and require a whole herd approach to stamp them out.

ref. ionophores - restrictions in their use would cause modern poultry rearing impossible because of coccidiosis. Europe has not banned their use because of coccidiosis. Additionally, research that I have had access to indicates that there is no significant resistance in coccidia spp. Not sure why, one of the working theories is that ionophores do not wipe out target populations but reduce their rate of reproduction and in the case of coccidia clinical disease is very much dictated by the rate of reproduction occurring in the bird's gut.
You have access to articles indicating otherwise? Or indicating resistance rise in other microrganisms?

By Lowlander (not verified) on 16 Jun 2014 #permalink

Mechanisms of sub therapuetic antibiotic use differs between species. Ionophores in ruminants selectively inhibit the growth of methane producing bacteria. This allows more of the cabohydrates consumed to be captured by the animal as VFA's. This increases the feed efficiency of the animal. The big economic driver of antibiotic use is improved feed efficiency. Increased growth has only minimal economic value.

In swine and poultry, subtherapuetic levels of antibiotics have been hypothesized to increase uptake of nutrients from the digesta. The mechanism is less well understood than how ionophores improve rumen feed efficiency.