Antibiotic resistance: myths and misunderstandings

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A pig flying at the Minnesota state fair. Picture by TCS.

I’ve been involved in a few discussions of late on science-based sites around yon web on antibiotic resistance and agriculture–specifically, the campaign to get fast food giant Subway to stop using meat raised on antibiotics, and a graphic by CommonGround using Animal Health Institute data, suggesting that agricultural animals aren’t an important source of resistant bacteria. Discussing these topics has shown me there’s a lot of misunderstanding of issues in antibiotic resistance, even among those who consider themselves pretty science-savvy.

I think this is partly an issue of, perhaps, hating to agree with one’s “enemy.” Vani Hari, the “Food Babe,” recently also plugged the Subway campaign, perhaps making skeptics now skeptical of the issue of antibiotics and agriculture? Believe me, I am the farthest thing from a “Food Babe” fan and have criticized her many times on my Facebook page, but unlike her ill-advised and unscientific campaigns against things like fake pumpkin flavoring in coffee or “yoga mat” chemicals in Subway bread, this is one issue that actually has scientific support–stopped clocks and all that. Nevertheless, I think some people get bogged down in a lot of exaggeration or misinformation on the topic.

So, some thoughts. Please note that in many cases, my comments will be an over-simplification of a more complex problem, but I’ll try to include nuance when I can (without completely clouding the issue).

First–why is antibiotic resistance an issue?

Since the development of penicillin, we have been in an ongoing “war” with the bacteria that make us ill. Almost as quickly as antibiotics are used, bacteria are capable of developing or acquiring resistance to them. These resistance genes are often present on transmissible pieces of DNA–plasmids, transposons, phage–which allow them to move between bacterial cells, even those of completely different species, and spread that resistance. So, once it emerges, resistance is very difficult to keep under control. As such, much better to work to prevent this emergence, and to provide conditions where resistant bacteria don’t encounter selection pressures to maintain resistance genes (1).

In our 75-ish years of using antibiotics to treat infections, we’ve increasingly found ourselves losing this war. As bacterial species have evolved resistance to our drugs, we keep coming back with either brand-new drugs in different classes of antibiotics, or we’ve made slight tweaks to existing drugs so that they can escape the mechanisms bacteria use to get around them. And they’re killing us. In the US alone, antibiotic-resistant infections cause about 2 million infections per year, and about 23,000 deaths due to these infections–plus tens of thousands of additional deaths from diseases that are complicated by antibiotic-resistant infections. They cost at least $20 billion per year.

But we’re running out of these drugs. And where do the vast majority come from in any case? Other microbes–fungi, other bacterial species–so in some cases, that means there are also pre-existing resistance mechanisms to even new drugs, just waiting to spread. It’s so bad right now that even the WHO has sounded the alarm, warning of the potential for a “post-antibiotic era.”

This is some serious shit.

Where does resistance come from?

Resistant bacteria can be bred anytime an antibiotic is used. As such, researchers in the field tend to focus on two large areas: use of antibiotics in human medicine, and in animal husbandry. Human medicine is probably pretty obvious: humans get drugs to treat infections in hospital and outpatient settings, and in some cases, to protect against infection if a person is exposed to an organism–think of all the prophylactic doses of ciprofloxacin given out after the 2001 anthrax attacks, for example.

In human medicine, there is still much debate about 1) the proper dosing of many types of antibiotics–what is the optimal length of time to take them to ensure a cure, but also reduce the chance of incubating resistant organisms? This is an active area of research; and 2) when it is proper to prescribe antibiotics, period. For instance, ear infections. These cause many sleepless nights for parents, a lot of time off work and school, and many trips to clinics to get checked out. But do all kids who have an ear infection need antibiotics? Probably not. A recent study found that “watchful waiting” as an alternative to immediate prescription of antibiotics worked about as well as drug treatment for nonsevere ear infections in children–one data point among many that antibiotics are probably over-used in human medicine, and particularly for children. So this is one big area of interest and research (among many in human health) when it comes to trying to curb antibiotic use and employ the best practices of “judicious use” of antibiotics.

Another big area of use is agriculture (2). Just as in humans, antibiotics in ag can be used for treatment of sick animals, which is completely justifiable and accepted–but there are many divergences as well. For one, animals are often treated as a herd–if a certain threshold of animals in a population become ill, all will be treated in order to prevent an even worse outbreak of disease in a herd. Two, antibiotics can be, and frequently are, used prophylactically, before any disease is present–for example, at times when the producer historically has seen disease outbreaks in the herd, such as when animals are moved from one place to another (moving baby pigs from a nursery facility to a grower farm, as one example). Third, they can be used for growth promotion purposes–to make animals fatten up to market weight more quickly.  The latter is, by far, the most contentious use, and the “low hanging fruit” that is often targeted for elimination.

From practically the beginning of this practice, there were people who spoke out against it, suggesting it was a bad idea, and that the use of these antibiotics in agriculture could lead to resistance which could affect human health. A pair of publications by Stuart Levy et al. in 1976 demonstrated this was more than a theoretical concern, and that antibiotic-resistant E. coli were indeed generated on farms using antibiotics, and transferred to farmers working there. Since this time, literally thousands of publications on this topic have demonstrated the same thing, examining different exposures, antibiotics, and bacterial species. There’s no doubt, scientifically, that use of antibiotics in agriculture causes the evolution and spread of resistance into human populations.

Why care about antibiotic use in agriculture?

A quick clarification that’s a common point of confusion–I’m not discussing antibiotic *residues* in meat products as a result of antibiotic use in ag (see, for example, the infographic linked above). In theory, antibiotic residues should not be an issue, because all drugs have a withdrawal period that farmers are supposed to adhere to prior to sending animals off to slaughter. These guidelines were developed so that antibiotics will not show up in an animal’s meat or milk. The real issue of concern for public health are the resistant bacteria, which *can* be transmitted via these routes.

Agriculture comes up many times for a few reasons. First, because people have the potential to be exposed to antibiotic-resistant bacteria that originate on farms via food products that they eat or handle. Everybody eats, and even vegetarians aren’t completely protected from antibiotic use on farms (I’ll get into this below). So even if you’re far removed from farmland, you may be exposed to bacteria incubating there via your turkey dinner or hamburger.

Second, because the vast majority of antibiotic use, by weight, occurs on farms–and many of these are the very same antibiotics used in human medicine (penicillins, tetracyclines, macrolides). It’s historically been very difficult to get good numbers on this use, so you may have seen numbers as high as 80% of all antibiotic use in the U.S. occurs on farms. A better number is probably 70% (described here by Politifact), which excludes a type of antibiotic called ionophores–these aren’t used in human medicine (3). So a great deal of selection for resistance is taking place on farms, but has the potential to spread into households across the country–and almost certainly has. Recent studies have demonstrated also that resistant infections transmitted through food don’t always stay in your gut–they can also cause serious urinary tract infections and even sepsis. Studies from my lab and others (4) examining S. aureus have identified livestock as a reservoir for various types of this bacterium–including methicillin-resistant subtypes.

How does antibiotic resistance spread?

In sum–in a lot of different ways. Resistant bacteria, and/or their resistance genes, can enter our environment–our water, our air, our homes via meat products, our schools via asymptomatic colonization of students and teachers–just about anywhere bacteria can go, resistance genes will tag along. Kalliopi Monoyios created this schematic for the above-mentioned paper I wrote earlier this year on livestock-associated Staphyloccocus aureus and its spread, but it really holds for just about any antibiotic-resistant bacterium out there:

And as I noted above, once it’s out there, it’s hard to put the genie back in the bottle. And it can spread in such a multitude of different ways that it complicates tracking of these organisms, and makes it practically impossible to trace farm-origin bacteria back to their host animals. Instead, we have to rely on studies of meat, farmers, water, soil, air, and people living near farms in order to make connections back to these animals.

And this is where even vegetarians aren’t “safe” from these organisms. What happens to much of the manure generated on industrial farms? It’s used as fertilizer on crops, bringing resistant bacteria and resistance genes along with it, as well as into our air when manure is aerosolized (as it is in some, but not all, crop applications) and into our soil and water–and as noted below, antibiotics themselves can also be used in horticulture as well.

So isn’t something being done about this? Why are we bothering with this anymore?

Kind of, but it’s not enough. Scientists and advocates have been trying to do something about this topic since at least 1969, when the UK’s Swann report on the use of Antibiotics in Animal Husbandry and Veterinary Medicine was released. As noted here:

One of its recommendations was that the only antimicrobials that should be permitted as growth promotants in animals were those that were not depended on for therapy in humans or whose use was not likely to lead to resistance to antimicrobials that were important for treating humans.

And some baby steps have been made previously, restricting use of some important types of antibiotics. More recently in the U.S., Federal Guidelines 209 and 213 were adopted in order to reduce the use of what have been deemed “medically-important” antibiotics in the livestock industry. These are a good step forward, but truthfully are only baby steps. They apply only to the use of growth-promotant antibiotics (those for “production use” as noted in the documents), and not other uses including prophylaxis. There also is no mechanism for monitoring or policing individuals who may continue to use these in violation of the guidelines–they have “no teeth.” As such, there’s concern that use for growth promotion will merely be re-labeled as use for prophylaxis.

Further, even now, we still have no data on the breakdown of antibiotic use in different species. We know over 32 million pounds were used in livestock in 2013, but with no clue how much of that was in pigs versus cattle, etc.

We do know that animals can be raised using lower levels of antibiotics. The European Union has not allowed growth promotant antibiotics since 2006. You’ll read different reports of how successful that has been (or not); this NPR article has a balanced review. What’s pretty well agreed-upon is that, to make such a ban successful, you need good regulation and a change in farming practices. Neither of these will be in place in the U.S. when the new guidance mechanisms go into place next year–so will this really benefit public health? Uncertain. We need more.

So this brings me back to Subway (and McDonald’s, and Chipotle, and other giants that have pledged to reduce use of antibiotics in the animals they buy). Whatever large companies do, consumers are demonstrating that they hold cards to push this issue forward–much faster than the FDA has been able to do (remember, it took them 40 freaking years just to get these voluntary guidelines in place). Buying USDA-certified organic or meat labeled “raised without antibiotics” is no 100% guarantee that you’ll have antibiotic-resistant-bacteria-free meat products, unfortunately, because contamination can be introduced during slaughter, packing, or handling–but in on-farm studies of animals, farmers, and farm environment, studies have typically found reduced levels of antibiotic-resistant bacteria on organic/antibiotic-free farms than their “conventional” counterparts (one example here, looking at farms that were transitioning to organic poultry farming).

Nothing is perfect, and biology is messy. Sometimes reducing antibiotic use takes a long time to have an impact, because resistance genes aren’t always quickly lost from a population even when the antibiotics have been removed. Sometimes a change may be seen in the bacteria animals are carrying, but it takes longer for human bacterial populations to change. No one is expecting miracles, or a move to more animals raised antibiotic-free to be a cure-all. And it’s not possible to raise every animal as antibiotic-free in any case; sick animals need to be treated, and even on antibiotic-free farms, there is often some low level of antibiotic use for therapeutic purposes. (These treated animals are then supposed to be marked and cannot be sold as “antibiotic-free”). But reducing the levels of unnecessary antibiotics in animal husbandry, in conjunction with programs promoting judicious use of antibiotics in human health, is a necessary step. We’ve waited too long already to take it.

Footnotes:

(1) Though we know that, in some cases, resistance genes can remain in a population even in the absence of direct selection pressures–or they may be on a cassette with other resistance genes, so by using any one of those selective agents, you’re selecting for maintenance of the entire cassette.

(2) I’ve chosen to focus on use in humans & animal husbandry, but antibiotics are also used in companion animal veterinary medicine and even for aquaculture and horticulture (such as for prevention of disease in fruit trees). The use in these fields is considerably smaller than in human medicine and livestock, but these are also active areas of research and investigation.

(3) This doesn’t necessarily mean they don’t lead to resistance, though. In theory, ionophores can act just like other antibiotics and co-select for resistance genes to other, human-use antibiotics, so their use may still contribute to the antibiotic resistance problem. Studies from my lab and others have shown that the use of zinc, for instance–an antimicrobial metal used as a dietary supplement on some pig farms, can co-select for antibiotic resistance. In our case, for methicillin-resistant S. aureus.

(4) See many more of my publications here, or a Nature profile about some of my work here.

 

Waste not, want not? Poultry “feather meal” as another source of antibiotics in feed

The ecology of antibiotic resistance on farms is complicated. Animals receive antibiotic doses in their food and water, for reasons of growth promotion, disease prophylaxis, and treatment. Other chemicals in the environment, such as cleaning products or antimicrobial metals in the feed, may also act as drivers of antibiotic resistance. Antibiotic-resistant organisms may also be present in the environment already, from the air, soil, or manure pits within or near the barns. Ecologically, it’s a mess and makes it more difficult to attribute the evolution and spread of resistance to one particular variable.

A new paper emphasizes just what a mess it really is, and what animals are exposed to in addition to “just” antibiotics. Led by Keeve Nachman at the Johns Hopkins University Center for a Livable Future, his team took a different approach to examining farm exposures, by looking at “feather meal.” What is feather meal, you may ask? I did when I met with Keeve last month at Hopkins as we discussed his research. Well, feathers are one obvious byproduct of chicken slaughtering, and waste not, want not, right? So feathers are processed into meal, which can then be used in a number of ways–among them fertilizer, and as an additive to feed for chickens, pigs, fish, and cattle.

We already knew that chickens receive antibiotics in their food and water supplies, just as other farm animals do. It was also known that some antibiotic residues persisted on chicken feathers–another potential driver of resistance in farm animals. However, Nachman and colleagues wanted to assess what other chemicals may be present in this feed meal besides antibiotics, and also whether those antibiotic residues persisted in the feather meal after processing/treatment of the feathers. As lead author David Love notes:

Why study feather meal? We know that antibiotics are fed to poultry to stimulate growth and to make up for crowded living conditions in poultry houses, but the public does not know what types of drugs are used and in what amounts. It turns out that many of these drugs accumulate in poultry feathers, so by testing feathers we have a non-invasive way of learning about what drugs are actually fed to poultry.

To do this, they examined 12 feather meal samples from the U.S. (n=10) and China (n=2). All 12 samples contained at least one antibiotic residue, and some contained residues of 10 different drugs (both of those were from China). While many of the antibiotics were ones used in poultry farming (or their metabolites), they also found drugs they did not expect. Most significantly, this included residues of fluoroquinolones, which they found in 6 of 10 U.S. feather meal samples. Why is this important? Fluoroquinolone use was banned in U.S. poultry production as of 2005 because of the risk to human health–so where are these residues coming from? The authors make a few suggestions for this:

These findings may suggest that the ban is not being adequately enforced or that other pathways, for example, through use of commodity feed products from livestock industries not covered by the ban, may inadvertently contaminate poultry feed with fluoroquinolones. Furthermore, if feather meal with fluoroquinolone residues is fed back to poultry, this practice could create a cycle of re-exposure to the banned drugs. Unintended antimicrobial contamination of poultry feed may help explain why rates of fluoroquinolone-resistant Campylobacter isolates continue to persist in poultry and commercial poultry meat products half a decade after the ban.

Interestingly, the authors tested whether antibiotic residues at the level they found could influence bacterial growth, and found that they did inhibit growth of wild-type E. coli, but allowed a resistant strain to flourish.

Besides antibiotic residues, a number of other chemicals were also detected, including many I’d never thought to associate with farming. In the U.S. samples, they found caffeine–apparently chickens may be fed coffee pulp and green tea powder, which may account for this finding; acetaminophen (Tylenol), which can be used to treat fevers in poultry just as it can for humans; diphenhydramine (the active ingredient in Benadryl), which apparently is used for anxiety issues in poultry; and norgestimate, a sex hormone. Any kind of health significance to these (either to people or to the animals who are ingesting these via feather meal) is uncertain. In an interview with Nick Kristof in the New York Times, Nachman noted:

“We haven’t found anything that is an immediate health concern,” Nachman added. “But it makes me question how comfortable we are feeding a number of these things to animals that we’re eating. It bewilders me.”

So what we’re seeing here are the presence of antibiotics and other drugs in feather meal, which is spread around as a fertilizer or fed to many species of domestic animals as an additive. It’s difficult to keep up with these additional feed additives–in addition to feather meal, many animals could also receive distiller’s grains in their diet, ethanol by-products which are another potential source of antibiotic residues.

This, my friends, is a clusterfuck.

Though I’ve focused on the U.S. data here, the paper notes that the Chinese samples are relevant as well–while most feather meal used here is domestically produced, we do import some, and about a quarter of what we import is from China, where antibiotics that are restricted or banned in the U.S. may still be in use. Furthermore, farmers may not even know this is in the feed they’re using, as many mixes are proprietary. (And if farmers don’t know, you can imagine how difficult it is for a researcher to determine if this is playing a role in antibiotic resistance or other public health issues on these farms).

Works cited

Love, D., Halden, R., Davis, M., & Nachman, K. (2012). Feather Meal: A Previously Unrecognized Route for Reentry into the Food Supply of Multiple Pharmaceuticals and Personal Care Products (PPCPs) Environmental Science & Technology, 46 (7), 3795-3802 DOI: 10.1021/es203970e

New paper: Staphylococcus aureus ST398 in a childcare worker

One of the reasons I’ve not been blogging as much over the past 2 years or so is that it’s been just insane in the lab. As I was still living off start-up funds and pilot grants, I didn’t have anyone full-time to take care of everything, so all the work has been done by myself and a handful of excellent graduate & undergrad students. Happily, some of the initial projects are wrapping up, and publications are starting to come out (I’ll be blogging about others in the coming days/weeks). One of them was published yesterday in Emerging Infectious Diseases: Livestock-associated Staphylococcus aureus in Childcare Worker. More after the jump.
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Danger, Will Robinson? Safety in scientific field work

Interesting discussion over at The Spandrel Shop and Cackle of Rad on doing field work in the sciences–and the potential dangers that might be encountered. Now, Prof-like Substance and Cackle of Rad are discussing field work along the lines of biological sample collection, sometimes in the middle of nowhere, which isn’t something I’ve ever done. However, we have our own issues when carrying out our epidemiological field sampling; more after the jump.
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