Is there such a thing as an “evolution-proof” drug? (part the third)

A claim that scientists need to quit making:

I’ve written about these types of claims before. The first one–a claim that antimicrobial peptides were essentially “resistance proof,” was proven to be embarrassingly wrong in a laboratory test. Resistance not only evolved, but it evolved independently in almost every instance they tested (using E. coli and Pseudomonas species), taking only 600-700 generations–a relative blip in microbial time. Oops.

A very similar claim made the rounds in 2014, and the newest one is out today–a report of a “super vancomycin” that, as noted above, could be used “without fear of resistance emerging.” (The title of the article literally claims “‘Magical’ antibiotic brings fresh hope to battle against drug resistance”, another claim made in addition to the “no resistance” one in the Scripps press release by senior author Dale Boger). This one claims that, because the modified vancomycin uses 3 different ways to kill the bacteria, “Organisms just can’t simultaneously work to find a way around three independent mechanisms of action. Even if they found a solution to one of those, the organisms would still be killed by the other two.”

A grand claim, but history suggests otherwise. It was argued that bacteria could not evolve resistance to bacteriophage, as the ancient interaction between viruses and their bacterial hosts certainly must have already exploited and overcome any available defense. Now a plethora of resistance mechanisms are known.

Within the paper itself, the limitations are much more clearly laid out. Discussing usage of the antibiotic, the authors note of these conventional semisynthetic vancomycin analogs:

“However, their use against vancomycin-resistant bacteria (e.g., VRE and VRSA), where they are less potent and where only a single and less durable mechanism of action remains operative, likely would more rapidly raise resistance, not only compromising its future use but also, potentially transferring that resistance to other organisms (e.g., MRSA).”

So as they acknowledge, not really so resistance-proof at all–only if they’re used under perfect conditions and without any vancomycin resistance genes already present. What are the odds of that once this drug is released? (Spoiler alert: very low).

Alexander Fleming, who won the 1945 Nobel Prize in Physiology or Medicine, tried to sound the warning that the usefulness of antibiotics would be short-lived as bacteria adapted, but his warnings were (and still are?) largely ignored. There is no “magic bullet;” there are only temporary solutions, and we should have learned by now not to underestimate our bacterial companions.

Part of this post previously published here and here.

Antibiotic resistance: myths and misunderstandings

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.


(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.


Is there such a thing as an “evolution-proof” drug?

Eleven years ago, two scientists made a bet. One scientist wagered that a new type of antimicrobial agent, called antimicrobial peptides, would not elicit resistance from bacterial populations which were treated with the drugs. Antimicrobial peptides are short proteins (typically 15-50 amino acids in length) that are often positively charged. They are also a part of our body’s own innate immune system, and present in other species from bacteria to plants. It is thought that these peptides work primarily by disrupting the integrity of the bacterial cell, often by poking holes in them. Sometimes they work with the host to ramp up the immune response and overwhelm the invading microbe. Because the peptides are frequently targeted at the bacterial cell wall structure, it was thought that resistance to these drugs would require a fundamental change in membrane structure, making it an exceedingly rare event. Therefore, these antimicrobial peptides might make an excellent weapon in the fight against multiply drug-resistant bacteria.

Additionally, the remarkable diversity of these peptides, combined with the presence of multiple types of peptides with different mechanisms of action present at the infection site, rendered unlikely the evolution of resistance to these molecules (or so some reasoning went). However, evolutionary biologists have pointed out that therapeutic use of these peptides would differ from natural exposure: concentration would be significantly higher, and a larger number of microbes would be exposed. Additionally, resistance to these peptides has been detailed in a few instances. For example, resistance to antimicrobial peptides has been shown to be essential for virulence in Staphylococcus aureus and Salmonella species, but we didn’t *witness* that resistance develop–therefore, it might simply be that those species have physiological properties that render them naturally resistant to many of these peptides, and were never susceptible in the first place.

The doubter of resistance, and the bet instigator, was Michael Zasloff of Georgetown University, who wrote in a 2002 review of antimicrobial peptides:

Studies both in the laboratory and in the clinic confirm that emergence of resistance against antimicrobial peptides is less probable than observed for conventional antibiotics, and provides the impetus to develop antimicrobial peptides, both natural and laboratory conceived, into therapeutically useful agents.

Certainly in the short term, resistance may be unlikely to evolve for reasons described above. However, if these peptides are used over an extended period of time, could the mutations necessary to confer resistance accumulate? This was the question asked in a new study by Dr. Zasloff along with colleagues Gabriel Perron and Graham Bell. Following publication of his 2002 paper where he called evolution of resistance to these peptides “improbable,” Bell challenged Zasloff to test this theory. Zasloff took him up on the offer, and they published their results in Proceedings of the Royal Society

The result?

Zasloff had egg on his face. Resistance not only evolved, but it evolved independently in almost every instance they tested (using E. coli and Pseudomonas species), taking only 600-700 generations–a relative blip in microbial time. Oops.

Well, everything old is new again. A very similar claim has been making the rounds recently, originating from the press release for a new paper claiming to have found bacteria’s “Achilles’ heel,” advancing the claim that “Because new drugs will not need to enter the bacteria itself, we hope that the bacteria will not be able to develop drug resistance in future.”  A grand claim, but history suggests otherwise. It was argued that bacteria could not evolve resistance to bacteriophage, as the ancient interaction between viruses and their bacterial hosts certainly must have already exploited and overcome any available defense. Now a plethora of resistance mechanisms are known.

Alexander Fleming, who won the 1945 Nobel Prize in Physiology or Medicine, tried to sound the warning that the usefulness of antibiotics would be short-lived as bacteria adapted, but his warnings were (and still are?) largely ignored. There is no “magic bullet;” there are only temporary solutions, and we should have learned by now not to underestimate our bacterial companions.

Part of this post previously published 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

Great Plains Emerging Infectious Diseases Conference–Registration Open

I mentioned last month that we are planning an Emerging Diseases conference here in April. Things are moving quickly and registration is now open (here). Abstract submission is also up and running here.

The details:

Oral and poster presentation research abstracts are due by 5:00pm on March 23, 2012. Individuals may submit up to two research abstracts. Abstracts must not exceed 250 words in length. There are a limited number of spots available for those interested in providing a 15-minute oral presentation. Abstracts submitted for oral presentations that are not selected for a talk will automatically be considered for the poster session. Please do not submit an abstract if your attendance is questionable. Confirmation of participation must be received no later than April 1, 2012.

Monetary awards will be conferred upon the top three student presentations (oral or poster).

Authors will be notified of the review committee’s decision by April 2, 2012.

If you have any questions regarding the conference, registration, or abstract submission, drop me a line or visit the conference website. We’re also still accepting ideas for breakout sessions in an unconference format, so feel free to contact me about thoughts for those as well. Hope to see some of you there!

The human origins of “pig” Staph ST398

I recently gave a talk to a group here in Iowa City, emphasizing just how frequently we share microbes. It was a noontime talk over a nice lunch, and of course I discussed how basically we humans are hosts to all kinds of organisms, and analysis of our “extended microbiome” shows that we share not only with each other, but also with a large number of other species. We certainly do this with my particular organism of interest, Staphylococcus aureus. There are many reports in the literature showing where humans have apparently spread their strains of S. aureus to their pets (dogs, cats, hamsters)–and sometimes the pets have been nice enough to share it right back. My own research looks at S. aureus in pigs and the humans who care for them, and many studies have shown that a “pig” type of MRSA, dubbed sequence type 398 (ST398), can be transmitted from pig carriers to their human caretakers. The assumption has been that this is truly a “pig” strain, originating in swine, and has spread to humans (and other animals, including cattle, poultry, dogs and horses) from pig hosts, either directly or indirectly via contaminated meat products.

According to a new study (open access in mBio), it seems that there has been more sharing of ST398 than we’d realized. Led by Lance Price at TGEN (full disclosure–I’m a coauthor on the paper), his group analyzed 89 ST398 isolates from China, Europe, and North America, including isolates from humans and animals as well as both methicillin-susceptible and -resistant strains. Using whole genomic sequence typing, the evolutionary history of these isolates was reconstructed.

The findings throw the ST398 story a bit on its head. Instead of being a true pig strain, ST398 appears to have originated as a methicillin-susceptible human strain which was transferred into the pig population, picked up antibiotic resistance genes (including resistance to methicillin and tetracyclines), and then has been passed back to farmers as more resistant organisms. Some prophages were also gained or lost along the way, probably due to selection by host factors.

This also suggests that there is still likely a low level of “native human” ST398 circulating in people. There have been a few case reports of ST398 colonization and/or infection in people without any known livestock contact. Some of these have been resistant to methicillin and/or tetracycline, which are more frequently associated with livestock-adapted strains. Are these truly “human” strains which aren’t involved in livestock at all, or are these ST398 findings in people lacking livestock contact still due to some livestock exposure along the chain of transmission (farmer neighbors? Transmission via food?) We still don’t know, but carrying out more of this WGST will give us better targets in order to be able to differentiate true “human” ST398 strains from those that have been hanging out in animals, and then transmitted back to people.

Now, for long-time science blog readers, this story may sound a bit familiar. Indeed, it looks like ST398 has taken a very similar path to that of another animal-associated S. aureus strain, ST5. As Ed Yong described back in 2009, humans are also the ultimate origin of a “chicken” type of S. aureus ST5, which spread around the world in broiler chicken flocks. In Ed’s article, the first author of the chicken ST5 paper, Bethan Lowder, notes that the change in chicken farming from small farms to multinational corporations likely aided the spread of this organism–and the exact same thing has happened with pig farming.

One difference between the two is that ST5 causes disease in chickens, whereas ST398 seems to be a very rare cause of illness in pigs. This is likely one reason that ST398 in pigs went undetected until relatively recently–it’s simply not much of an economic issue for pig producers, whereas in chickens, S. aureus can cause several nasty diseases (such as bumblefoot and BCO) leading to animal loss (and thus, less money for the farmer).

So, where do we go from here? Clearly studies like this show the utility of using WGST to examine the evolution and spread of these strains. If you look at how spa types are distributed throughout the tree, you can see that those alone don’t tell you much about where the strain came from, or if it’s fully “human” or a pig-adapted lineage. Ideally, a set of simple markers could be found to distinguish ancestral human strains from livestock strains (as methicillin-sensitive ST398 can also be found in pigs, so methicillin resistance alone isn’t enough of an indicator that it’s a “pig” strain). We’ll be working on this in ST398 and other strains we see being shared between animals and humans, in order to better understand this generous sharing we’re doing amongst species.


Lance B. Price, Marc Stegger, Henrik Hasman, Maliha Aziz, Jesper Larsen, Paal Skytt Andersen, Talima Pearson, Andrew E. Waters, Jeffrey T. Foster, James Schupp, John Gillece, Elizabeth Driebe, Cindy M. Liua, Burkhard Springer, Irena Zdovc, Antonio Battisti, Alessia Franco, Jacek Żmudzki, Stefan Schwarz, Patrick Butayej, Eric Jouy, Constanca Pomba, M. Concepción Porrero, Raymond Ruimy, Tara C. Smith, D. Ashley Robinson, J. Scott Weese, Carmen Sofia Arriola, Fangyou Yu, Frederic Laurent, Paul Keima,, Robert Skov, & Frank M. Aarestrup (2012). Staphylococcus aureus CC398: Host Adaptation and Emergence of Methicillin Resistance in Livestock mBio, 3 (1), 305-311 : 10.1128/mBio.00305-11

MRSA in pork products: does the “antibiotic-free” label make a difference?

Back in November, I blogged about one of our studies, examining methicillin-resistant Staphylococcus aureus (MRSA) in Iowa meat products. In that post, I mentioned that it was one of two studies we’d finished on the subject. Well, today the second study is out in PLoS ONE (freely available to all). In this study, we focused only on pork products, and included 395 samples from Iowa, Minnesota, and New Jersey. We also looked at not only conventional meats, but also “alternative” meat products. Most of the latter were products labeled “raised without antibiotics” or “raised without antibiotic growth promotants”–in the markets we tested, very few USDA-certified organic products were available unfrozen, and we were looking for fresh meat products.

In our previous paper, we found MRSA on 1.2% of 165 meat samples. In the current study, we found a higher prevalence–6.6% of 395 samples were contaminated with MRSA. (More about the differences in methods between our two studies later). Interestingly, we didn’t find a statistically significant difference in MRSA prevalence on conventional versus alternative pork products–a finding that surprised me, as it contradicts what we’ve found to date looking at the sources of this meat–conventional versus “alternative” pig farms. Other groups have also found differences on-farm versus on-meat: a 2011 study looking at feedlot cattle didn’t find any MRSA in animal samples, though the same group found MRSA in beef products. So, our disparate findings between farms and meat samples are not unheard-of. However, even though our sample size was larger than other U.S. studies to date, it was still fairly small overall–300 conventional and 95 alternative pork samples over a 4-week sampling period from 3 states, so larger multi-state studies are needed to further examine this angle.

It also suggests that we need processing plants and packing companies to work with us to determine where products are being contaminated–because while there may be arguments about the public health importance of MRSA on meats (or lack thereof), it’s very likely that if S. aureus are ending up on meat products, other pathogens are as well.

What does the molecular typing tell us, speaking of contamination source? We carried out analyses on all the MRSA and found that the most common type of MRSA was ST398, the “livestock” strain that we previously found on pig farms in the U.S. We also found two “human” types were common: USA300 (a “community-associated” strain) and USA100 (typically considered a “hospital-associated” strain). In the simplest analysis of these findings, these molecular types (a combination of “human” and “pig” strains) suggests that MRSA on raw pork products may be coming both from farms and from food handlers. However, in real life, it’s not quite so straightforward. USA100 types have also been found in live pigs. So has USA300. As such, the source of contamination and relative contributions of live pigs versus human meat handlers currently isn’t certain.

Within the MRSA strains, we found high levels of antibiotic resistance, similar to what was reported in the recent Waters et al. study. In ours, 76.9% were resistant to two or more antibiotics and 38.5% were resistant to three or more antibiotics tested. (I’ll note that we only had funding to test the MRSA–we weren’t able to do these tests on all the methiciin-susceptible strains).

Did MRSA prevalence increase in the period between our first study (spring 2009) and this one (late summer/fall 2010)? I doubt it. For this paper, we used a different sampling method, adding the samples to a sterile stomacher bag so that the entire sample was immersed in the culture medium; for the first paper we used external swabbing and so likely didn’t capture as many bacteria. This current study more likely represents the “true” MRSA prevalence. But–all isolates were only called as positive/negative, and we didn’t measure the number of bacteria on each piece of meat. So, there theoretically could have been just a few colonies of MRSA on the entire piece of meat, and that would have been called a positive sample, while another meat product covered with hundreds of MRSA would have been put in the same category. Therefore, more subtle differences may exist that we didn’t pick up in this study, but we will examine in other ongoing studies.

So–what’s the take-home here? Don’t assume that any meat product is contamination-free, and always use good food handling/cooking practices when dealing with raw meats. As far as the titular question, well, we’re still hashing that one out.


Hanson et al. Prevalence of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) on retail meat in Iowa.

Waters et al. Multidrug-Resistant Staphylococcus aureus in US Meat and Poultry.

O’Brien et al. MRSA in conventional and alternative retail pork products.

Lin et al. Evidence of multiple virulence subtypes in nosocomial and community-associated MRSA genotypes in companion animals from the upper midwestern and northeastern United States.

Weese et al. The Prevalence of Methicillin-Resistant Staphylococcus aureus Colonization in Feedlot Cattle.

Weese et al. Detection and quantification of methicillin-resistant Staphylococcus aureus (MRSA) clones in retail meat products.

MRSA found in Iowa meat

I’ve blogged previously on a few U.S. studies which investigated methicillin-resistant Staphylococcus aureus in raw meat products (including chicken, beef, turkey, and pork). This isn’t just a casual observation as one who eats food–I follow this area closely as we also have done our own pair of food sampling investigations here in Iowa, and will be doing a much larger, USDA-funded investigation of the issue over the next 5 years.

Let me sum up where the field currently stands. There have been a number of studies looking at S. aureus on raw meat products, carried out both here in North American and in Europe. In a study from the Netherlands, a large percentage of samples were found to harbor MRSA (11.9% overall, but it varied by meat type–35.3% of turkey samples were positive, for example). Most of there were a type called ST398, the “livestock” strain. This was also found in one Canadian study (5.5% MRSA prevalence, and 32% of those were ST398), but no ST398 were found in a second study by the same group.

Here in the US, prevalence has found to be lower than in that Dutch study (from no MRSA found, up to 5% of samples positive). Furthermore, in the previously-published studies, no MRSA ST398 was found in samples of US meat, though this paper did find plenty of methicillin-sensitive S. aureus (MSSA) ST398 strains. Instead, most of the MRSA isolates have been seemingly “human” MRSA types, like USA100 (a common hospital-associated strain) and USA300 (a leading community-acquired strain).

Why am I rehashing all of this? We have a new paper out examining S. aureus in Iowa meats–and did find for the first time MRSA ST398, as well as MRSA USA300 and MSSA strains including both presumptive “human” and “animal” types. This was just a pilot study and numbers are still fairly small, but enough to say that yes, this is here in the heart of flyover country as well as in the other areas already examined.

As I mentioned, this is one of two studies we’ve completed examining MRSA on meat; the other is still under review and much more controversial, but I will share that as soon as I’m able. And with the USDA grant, we’ll be working on better understanding the role that contaminated meats play in the epidemiology and transmission of S. aureus for the next several years, so expect to see more posts on this topic…


Hanson et al. Prevalence of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) on retail meat in Iowa. J Infect Public Health. 2011 Sep;4(4):169-74. Link.

Waters et al. Multidrug-Resistant Staphylococcus aureus in US Meat and Poultry . Clin Infect Dis. 2011 May;52(10):1227-30. Link.

Weese et al. Methicillin-resistant Staphylococcus aureus (MRSA) contamination of retail pork. Can Vet J. 2010 July; 51(7): 749-752. Link.

De Boer et al. Prevalence of methicillin-resistant Staphylococcus aureus in meat. Int J Food Microbiol. 2009 Aug 31;134(1-2):52-6. Link.

Pu et al. Isolation and characterization of methicillin-resistant Staphylococcus aureus strains from Louisiana retail meats. Appl Environ Microbiol. 2009 Jan;75(1):265-7. Link.

Bhargava et al. Methicillin-resistant Staphylococcus aureus in retail meat, Detroit, Michigan, USA. Emerg Infect Dis. 2011 Jun;17(6):1135-7. Link.

MRSA and bedbugs?

An ahead-of-print paper in Emerging Infectious Diseases is generating some buzz in the mainstream media. While the findings are interesting, I’m honestly not sure how they got published, being so preliminary.

Like many areas, Vancouver, British Columbia has seen a jump in the prevalence of bedbugs. After finding impoverished patients infested with the bugs, researchers decided to collect some and test them for pathogens–specifically, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). So, they tested 5 bugs from 3 patients. That’s it–it doesn’t even appear to be 5 bugs apiece, but just 5 total. And the bugs were simply homogenized and streaked–not an uncommon way to test bugs for microbes, but one that has pretty severe limitations if you’re really looking at transmission via biting.

They did find MRSA (and VRE)–obviously, or it wouldn’t have made news. VRE was isolated from 1 bug each from 2 patients; MRSA was isolated from 3 bedbugs from the remaining patient. At first read, I thought they’d confirmed the MRSA strains were USA300, but they didn’t even do that–all they did was note the antibiotic susceptibility profiles of the isolates were consistent with USA300 (though headlines are already screaming “flesh eating bacteria isolated from bedbugs!” as you can see from the link up top). However, what we don’t know if whether the bedbugs were simply externally contaminated (perhaps from close contact with their human hosts), or if they were actually carrying the organisms in their salivary glands (as has been previously reported for S. aureus). If it’s the latter, an infection risk seems more plausible, although I suppose a bite from an externally-contaminated bedbug could also introduce organisms into an open wound.

Still, the paper is really, really, really sparse on data. I’ll sum up with words expressed in the newspaper story above:

Medical health officer Dr. Reka Gustafson said the St. Paul’s study is so small that no public health warning is necessary. She noted the superbug MRSA can be found on “doctors’ ties” and chairs in public places and that it’s more important to counsel people “to wash their hands thoroughly and use antibiotics wisely.”

Lowe CF, Romney MG (2011). Bedbugs as Vectors for Drug-Resistant Bacteria Emerging Infectious Diseases