Maryn McKenna

Journalist and Author

Antibiotics and farming — how superbugs happen

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Constant readers: There’s an important new paper that’s been out for a week that I haven’t gotten to you. I apologize; it’s been busy. (Let’s not even talk about the important paper that’s been out for two weeks. Maybe over the weekend…)

We’ve talked for ages now about the potential dangers of unrestricted antibiotic use in agriculture, and how it’s analogous to the inappropriate antibiotic use that human health authorities disapprove of in humans. The main culprits, in farming, are subtherapeutic dosing, also known as growth promotion — that’s giving routine smaller-than-treatment doses to animals to increase their weight — and prophylactic dosing, which is giving a treatment dose to an entire herd or flock either routinely, if there is thought to be a disease threat, or when there is known to be disease in some members of the herd/flock. In either case, animals are getting antibiotics when they do not need them — when they are not sick. And just as in humans who take antibiotics when they are not sick, or take too-low doses when they are sick (such as not finishing a prescription), these practices in animals encourage the development of resistant bacteria.

(Necessary comment here: No one, to my knowledge, objects to giving the appropriate doses of antibiotics to animals that are sick. Why would you?)

The interesting research question is how, exactly, resistance develops. (My real scientist readers may want to take a break, or cut me a break, for the next few sentences. Please.) The classical assumption has been that, through a variety of stimuli and the random copying errors of reproduction, bacteria are constantly acquiring small mutations. Some of those may give the bugs an advantage when they are exposed to a drug, some slight difference that allows the bacteria to disarm or turn aside that drug’s particular method of assault — so that the weak die, the strong survive, and the strong then reproduce more abundantly into that extra living space freed up by the death of the weak. The survivors and their descendants retain that mutation, because it gave them an advantage against the drug. And because bacteria can share resistance factors not only vertically mother-to-daughter, but horizontally in the same generation, once the resistance has emerged, it is likely to spread.

But no matter how quickly it spreads, that process I’ve just described involves acquiring resistance to just one drug or drug family at a time. Provocative new research from Boston University’s medical school and deoartment of biomedical engineering now suggests, though, that multi-drug resistance can be acquired in one pass, through a different mutational process triggered by sublethal doses of antibiotics — the same sort of doses that are given to animals on farms.

In earlier work, the authors found that antibiotics attack bacteria not only in the ways they are designed to (the beta-lactams such as methicillin, for instance, interfere with staph’s ability to make new cell walls as the bug reproduces, causing the daughter cells to burst and die), but also in an unexpected way. They stimulate the production of free radicals, oxygen molecules with an extra electron, that bind to and damage the bacteria’s DNA.

That research used lethal doses of antibiotics, and ascertained that the free-radical production killed the bacteria. In the new research, the team uses sublethal doses, and here’s what they find: The same free-radical production doesn’t kill the bacteria, but it acts as a dramatic stimulus to mutation, triggering production of a wide variety of mutations — what the researchers, in a press release, called “a zoo of mutants.” The plentiful, scattershot mutations included ones that created resistance to a number of different drugs — in some cases, even though no mutation was present that created resistance to the drug being administered.

You can easily see how this is applicable to factory farming: The sublethal dosing applied experimentally is analogous to the subtherapeutic dosing used in agriculture. Is it applicable to MRSA? Yes, absolutely. The two organisms the researchers used to test their hypothesis were S. aureus and E. coli.

making the implication clear, senior author James J. Collins said on the paper’s release:

“These findings drive home the need for tighter regulations on the use of antibiotics, especially in agriculture; for doctors to be more disciplined in their prescription of antibiotics; and for patients to be more disciplined in following their prescriptions.”

The cite is: Kohanski MA, DePristo MA and Collins, JJ. Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis. Molecular Cell, Volume 37, Issue 3, 311-320, 12 February 2010.

UPDATE: There’s a great discussion of the paper at the blog Mental Indigestion.

Postscript: I suppose I’ve been working too long without a break, because while I was reading about this process of creating multiple resistance factors at once, what I heard in my head was Mickey Mouse chirping: “Seven at one blow!”

CBS antibiotics and farming, day 2 – and more on the Danish experience

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Constant readers, I hope you watched the second day of CBS News’ series on antibiotic use in farming, and how it promotes the emergence of antibiotic-resistant infections in animal and humans. I found it surprisingly hard-hitting. Here’s the video and the text version.

Most of the report explored the farm experience in Denmark, which in 1998 banned its farmers from using small doses of antibiotics to make animals gain weight faster — the practice that’s various called subtherapeutic dosing or growth promotion. Important distinction: The country still permits sick animals to be treated with antibiotics; the ban extends only to giving drugs to animals who are not sick.

That ban has often been represented as a failure for Danish farming [NB: See the update below], but research on the results shows that it was actually a success. Here’s an article by Laura Rogers of the Pew Charitable Trusts explaining what happened in Denmark from her own on-the-ground reporting:

Antibiotic use on industrial farms has dropped by half while productivity has increased by 47 percent since 1992. Danish swine production has increased from 18.4 million in 1992 to 27.1 million in 2008. A decrease in antibiotic-resistant bacteria in food animals and meat has followed the reduced use of these vital drugs. …

The average number of pigs produced per sow per year has increased from 21 to 25 (this is an important indicator of swine health and welfare, according to veterinarians). Most important, total antibiotic use has declined by 51 percent since an all-time high in 1992. Plus, the Danish industry group told us that the ban did not increase the cost of meat for the consumer.

 There are multiple scientific papers done by Danish authors backing up her observations. Here are just a few from just last year:

  • Antibiotic-resistant organisms in chickens raised in Denmark declined since the ban — but they remain high in chicken meat imported from other countries that do not have such bans, and passed to Danish consumers who ate that imported meat. (Skjot-Rasmussen et al., May 2009)
  • Antibiotic resistance in E. coli in pigs increases when pigs are given antibiotics, and those antibiotic-resistant organisms pass to humans (Hammerum et al., April 2009)
  • Antibiotic-resistant organisms found in pigs when they are slaughtered increase when pigs receive more antibiotics (Abatih et al., March 2009)

The industry that supports industrial-sized farms has strongly objected to the CBS series. You can see one detailed response here, from Pork Magazine. The Minneapolis-based Institute for Agriculture and Trade Policy predicts that this is likely just the first wave, and that opposition to any change in agricultural practices will grow stronger as a bill to curb unnecessary antibiotic use gains traction in Congress.

And — you knew I had to do this — here comes the obligatory self-promotion: There is a primer on antibiotic use in farming, and an account of the emergence of MRSA ST398 as a result of antibiotic use in pigs, in SUPERBUG. Which is now 41 days away from publication. And is available for pre-order at a discount! But you knew that.)

UPDATE: FairFoodFight has a great post and a long comments conversation about the CBS series, ag antibiotic use, and particularly the World Health Organizaton research that originally made people doubt the “Danish experiment,” The WHO report is here and a Pew analysis of it is here.

CBS antibiotics and farming package, day one

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Constant readers, I hope you saw the CBS News package on antibiotics in farming Tuesday night. (It continues Wednesday.) MRSA played a prominent role, in an account of infections among workers at a chicken plant (the same outbreak, I think, as was described by Prevention magazine last August) and in questions about MRSA in pig farms in the Midwest (with a prominent mention of Tara Smith’s research into “pig MRSA” ST398).

Here’s the 7-minute video and the text version.

Earlier Tuesday, CBS’s Early Show ran an additional package on the death of a Chicago toddler from MRSA. That toddler’s name is Simon Sparrow, and you’ll be able to read his sad story — told by his mother, Everly Macario — in SUPERBUG.

Warning on ST398: Monitor this now

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Drawing your attention: I have a story up tonight at CIDRAP on a new paper by Dr. Jan Kluytmans, a Dutch physician and microbiologist and one of the lead researchers tracking “pig MRSA,” ST398. (All past stories on ST398 here.) It’s a review paper, which is to say that it summarizes key existing findings rather than presenting original research.

Still, it’s important reading because Kluytmans is one of the few scientists who have some history with this bug and understand how quickly and unpredictably it has spread across borders and oceans, from pigs to other livestock, to pig farmers and veterinarians, into health care workers and hospital patients who have no known livestock contact, and now into retail meat in Europe, Canada and the United States.

Take-away: A plea and warning for better surveillance, so that we can track not only the bug’s vast range, but also its evolution as it moves into new ecological niches — including humans who are buying that retail meat and possibly becoming colonized with it as they prep it for cooking in their home kitchens.

To honor fair use (and in hopes you’ll kindly click over to CIDRAP), I won’t quote much, but here’s the walk-off:

Because the novel strain has spread so widely and has already been identified as a cause of hospital outbreaks, it should not be allowed to spread further without surveillance, Kluytmans argues.”It is unlikely that this reservoir will be eradicated easily,” he writes. “Considering the potential implications of the reservoir in food production animals and the widespread presence in meat, the epidemiology of [MRSA] ST398 in humans needs to be monitored carefully.”

The cite is: Kluytmans JAJW. Methicillin-resistant Staphylococcus aureus in food products: cause for concern or case for complacency? Clin Microbiol Infect 2010 Jan;16(1):11-5. The abstract is here.

H1N1 flu and swine surveillance – more relevance for MRSA

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Constant readers, you probably know that yesterday the World Health Organization declared the first flu pandemic in 41 years. I want to point out for you a side issue in the H1N1 story that has great relevance for MRSA, especially ST398.

As described in this article I wrote last night for CIDRAP, three medical journal articles have now pointed out that the virus, or its major components, could have been recognized in swine months to years ago. We missed it, though, because there is so little regular surveillance in pigs for diseases of potential importance to humans. As the authors of the most recent article, in Nature, said yesterday: “Despite widespread influenza surveillance in humans, the lack of systematic swine surveillance allowed for the undetected persistence and evolution of this potentially pandemic strain for many years.”

This is important for our purposes because we know that we are in the same situation with MRSA ST398: The strain was first spotted in France, and has been a particular research project in the Netherlands, but has been found pretty much wherever researchers have looked for it, throughout the European Union, in Canada, and most recently in the United States. All told, though, the scientists concerned with it are still a small community; there is no broad surveillance looking for this bug.

And that’s a problem, for MRSA, for influenza, and for any number of other potentially zonotic diseases: We cannot anticipate the movement of pathogens from animals to humans if we don’t know what’s in the animals to start with. That’s the argument behind the “One Health” movement, which has been arguing for several years now for including veterinary concerns in human health planning. (The human health side would probably say that the animal health side just wants more money. This is also true, which does not make it unimportant.)

To understand the need to look at animal health in order to forecast threats to human health, you can’t do better than the map I’ve inserted above (because Blogger, annoyingly, won’t let me put it below). It has appeared in various forms in various publications for about 10 years but originates I think from the IOM’s Emerging and Reemerging Diseases report in the early 90s. (This iteration comes from the One Health Initiative website.) It depicts the movement of new diseases from animals to humans over about 30 years. It’s up-to-date through SARS and through the 2003-05 movement of H5N1 avian flu around the world. I’m sure H1N1 will be added soon. How many of those outbreaks could we have shortcircuited if we had been warned of their threat in good time?

Does ethanol production produce resistant bacteria too?

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One of the challenges of disappearing down the rabbit hole of a gnarly chapter — gee, it’s dark down here — is that I get behind on my RSS feeds, and suddenly every entry in my Google Reader is at 1000+ and it’s all just too daunting.

So, trying to catch up a bit, I found two related, interesting and troubling stories from the Associated Press (4 April) and the online magazine Grist (7 April — yes, I said I was behind…).

Synopsis/synthesis: Corn-based ethanol, former darling of the energy and large-scale agriculture industries, suddenly doesn’t look like such a good idea – and not just because the market for it is crashing. Turns out that ethanol is made by adding yeast and sugar to corn mash; the yeast convert the carbohydrates to the alcohol that is the basis of the fuel. (Yes, just like making beer.) However, the mash is particularly attractive to Lactobacillus and other bacteria that produce lactic acid as a waste product rather than alcohol, and a tank full of lactic acid doesn’t make very good fuel. So, to keep the bacteria under control, ethanol producers add antibiotics. Specifically, penicillin and erythromycin — you’ll recognize those — and tylosin and virginiamycin, two macrolides, related to erythromycin, that are approved in the US for veterinary use.

Now, the problem with this practice, as you might predict, is that if the mash is not appropriately dosed, the presence of antibiotics within it can prompt some of the bacteria to develop resistance. (Here’s an article from the trade magazine Ethanol Producer discussing just that possibility.)

And the further complication of this is that the leftover mash, now called “distillers’ grains,” is sold as animal feed. Ask yourself: Where in animal production are animals most likely to eat grains? Answer: At finishing, in feedlots. In other words, fermented grains that may contain antibiotic residue, and may contain resistant bacteria, are being sold as feed to animals that are already being raised in conditions that have been shown to foster the development of resistant bacteria through subtherapeutic and prophylactic antibiotic use. In fact, some research has drawn an explicit link: Kansas State University scientists have found higher levels of E. coli O157 in the guts of cattle that were fed distillers’ grains.

All of this was new to me, but there’s an additional facet to the story that the AP and Grist pieces don’t highlight, and that just makes my head hurt: the use of virginiamycin. For those new to the story, virginiamycin is an allowed, widely used veterinary antibiotic in the US. However, it is not used in the European Union: It was banned there in 1998 because the EU’s ag authorities believed that it promoted resistance to the drug Synercid (quinupristin+dalfopristin), which is a drug of last resort against vancomycin-resistant bacteria such as VRE. (Here’s a Lancet paper that talks about that resistance mechanism.) Synercid was approved by the FDA in 1999 — two years after Synercid resistance had already been found in the US. (For a long but cogent explanation of the complex story of virginiamycin, see the book The Killers Within.)

So, just to recap: We have an industry whose long-term earnings are shaky, whose economic survival is partially secured by the sale of its waste product, and which via that waste product is putting antibiotic residues and antibiotic-resistant bacteria into the environment, and is conveying them into food animals, and is making particular use of an antibiotic that other countries have banned because they believe that, via its use in animals, it exerts an adverse impact on human health.

Something to remember the next time ethanol subsidies come up.

Antibiotic resistance in food animals all across Europe

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Via a journal that’s new to me — the Acta Veterinaria Scandinavica, the open-access journal of the Veterinary Associations of the Nordic Countries — comes an amazing review of the prevalence of antibiotic resistance in cattle in 13 European countries. Based on 25,241 isolates collected over three years, Denmark, Britain, the Netherlands, Norway, Sweden and Switzerland do well, but “many isolates from Belgium, France, Italy, Latvia and Spain were resistant to most antimicrobials tested.“

Most resistant pathogen: E. coli. MRSA is present as well:

Of major concern is the level of resistance to oxacillin and 3rd generation cephalosporins (i.e. ceftiofur) in S. aureus. The prevalence of oxacillin resistance in Spain (3.7%) and France (8.3%) and the resistance towards cephalosporins in Spain (0.9% in 2004) and France (4.2% in 2002; 1% in 2003) indicate the presence of methicillin resistant S. aureus (MRSA) in these two countries.

The authors ascribe the differences among countries to different patterns of antimicrobial use by veterinarians and stress that it is time for veterinarians to begin using measurements of local resistance patterns (in human medicine, an “antibiogram”) before prescribing. Cite coming when the Acta site is updated. UPDATE: The paper is here; cite is: Hendriksen, RS et al. Prevalence of antimicrobial resistance among bacterial pathogens isolated from cattle in different European countries: 2002-2004. Acta Veterinaria Scandinavica 2008, 50:28doi:10.1186/1751-0147-50-28.

I wasn’t aware that this same set of authors (Hendriksen, RS et al.) just a few weeks ago published a similar review of antimicrobial resistance in pigs in Europe. It looks at several bacterial species in pigs, but unfortunately for our purposes, no S. aureus.

Great post elsewhere on antibiotic use in animals

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There will be a bit of a blog break, as I’m traveling for a week. But here as a walk-off is an excellent post from the marvelous public-health blog Effect Measure about the complexities (to be kind) of food companies declaring antibiotic use in food animals.

Very short version of the story: Massive chicken producer Tyson advertised its chickens as being “raised without antibiotics”; the chicken eggs were actually being treated with gentamicin before hatch (therefore technically not being “raised”; the US Department of Agriculture objected, then backed down, then objected again after Tyson’s competitors acted on their own.

Tyson announced it is “voluntarily” withdrawing the label. Which is more than the USDA did, apparently, its hand having been forced by Tyson’s competitors organized into the Orwellian-named Truthful Labeling Coalition (including Perdue Farms Inc., Sanderson Farms Inc. and Livingston, California-based Foster Farms). Perdue and Sanderson had sued over a label they considered “clearly false and misleading,” and a federal judge agreed, ordering Tyson to stop them from running any advertisements with the claim last month. Now, belatedly, the USDA is acting.

The entire post is worth reading, as is Effect Measure (which is running on a “summer schedule” and therefore posting only once a day, thus making us all look bad. Hmm, perhaps a Public Health Blog Truthful Labeling Coalition is in order…)

Closing the loop: meat, meat-eaters, health-care workers

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A posting on the international disease-alert mailing list ProMED led me to a scientific abstract presented at a European meeting this spring on the ST 398 MRSA strain. It adds another, quite unnerving piece to the emerging interplay of MRSA in pigs, humans who have close contact with pigs, humans who have contact only with pig meat, and health-care workers who treat those humans.

Brief precis: About a year ago, Dutch health authorities discovered that a patient who had come in for surgical debridement of a diabetic foot ulcer had an unrecognized MRSA strain in that ulcer. Subsequently, they discovered that four other patients and five health-care workers in the same institution were carrying the same strain. None of the patients reported any contacts with pigs (or calves, which have also been found to carry the strain). One of the health-care workers lived on a farm that raised pigs, but said that she had no contact with the animals in her daily life; nor did her partner.

The authors conclude:

While the source is not fully established it could be the HCW living on a pig farm. This outbreak makes clear that transmission on a larger scale can occur, even with NT-MRSA.

(Hat-tip to Helen Branswell of the Canadian Press for telling me about the ProMED report. And a note to loyal readers: The “MRSA in meat” story is being picked up by some US newspapers. Doesn’t it feel good to know you’ve been reading about the issue here for months? And if you’re a reader of Helen’s work, months more? Of course it does.)