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Apocalypse Pig: The Last Antibiotic Begins to Fail

A pig being home-raised for a festival in China.
A pig being home-raised for a festival in China.
Photograph by Clemson, flickr (CC).

I mentioned on Monday that this past week was intended by the CDC, WHO and other health authorities to be a global awareness week for antibiotic resistance. Alarming news that came out of China at the end of the week certainly created new awareness of resistance, but possibly not what the organizers had in mind.

On Thursday, researchers from several Chinese, British and US universities announced in the journal Lancet Infectious Diseases that they have identified a new form of resistance, to the very last-ditch drug colistin—and that it is present in both meat animals and people, probably comes from agricultural use of that drug, can move easily among bacteria, and may already be spreading across borders.

This is very bad news.

To understand why, it’s necessary to know a little bit about colistin. It is an old drug: It was first introduced in 1959. It has been on the shelf, without seeing much use, for most of the years since, because it can be toxic to the kidneys. And precisely because it hasn’t been used much, bacteria have not developed much resistance to it. It remains effective.

That neglect turned out to be very fortunate a few years ago when several different resistance factors—NDM, OXA, KPC—started hopscotching around the globe. All of them made bacteria invulnerable to a group of drugs called carbapenems that had been considered a last line of defense: They were the last drugs that were in common use and were able to take care of complex infections that happen in hospitals, caused by E. coliKlebsiellaAcinetobacter and similar gut-dwelling organisms. Once those bacteria became resistant to carbapenems (earning them the general name of “carbapenem-resistant Enterobacteriaceae,” or CREs), colistin was all that was left—and colistin use began rising.

(From around that time: Here’s a great story that Jason Gale of Bloomberg wrote about colistin, and one I wrote for Nature about CREs. A long series of posts I wrote for WIRED about the discovery of NDM and the bitter political fights over its apparent origin in India can be found  here. Of note, one of the discoverers of NDM is one of the authors of this new research.)

A thing about colistin, which no one seems to have connected the dots on: Because it is an old drug, it is cheap. And because it is cheap, it is an affordable addition to animal feed for all the uses I’ve talked about before: to make animals put on muscle mass faster, and protect them from the conditions of intensive farming.

Which, apparently, is how it is being used in China—but not only in China. From the paper:

China is… one of the world’s highest users of colistin in agriculture. Driven largely by China, the global demand for colistin in agriculture is expected to reach 11,942 tonnes per annum by the end of 2015 (with associated revenues of $229·5 million), rising to 16,500 tonnes by the year 2021, at an average annual growth rate of 4·75%. Of the top ten largest producers of colistin for veterinary use, one is Indian, one is Danish, and eight are Chinese. Asia (including China) makes up 73·1% of colistin production with 28·7% for export including to Europe.

Where sampling for the MCR resistance study took place.
Where sampling for the MCR resistance study took place.
Graphic from Liu et al, Lancet Infectious Diseases; original here.

The findings reported this week originate in an ongoing project in which the Chinese authors were looking for resistance in the E. coli that reside in the guts of food animals. (It’s encouraging that such a project exists.) They say they first perceived a colistin-resistant E. coli in 2013, in a pig from an intensive farm near Shanghai, and then noted increasing colistin resistance over several years. They expanded their research to include, not just samples from animals as they were slaughtered, but sampling of retail meat from supermarkets and street markets, and testing of samples previously taken from patients in two hospitals. The samples were collected between 2011 and 2014.

Here’s what they found. The gene they discovered, which directs colistin resistance and which they dubbed MCR-1, was present:

  • in  78 (15 percent) of 523 samples of raw pork and chicken meat
  • in 166 (21 percent) of 804 pigs in slaughterhouses
  • and in 16 (1 percent) of 1,322 samples from hospital patients with infections.

That last is important: The bacteria possessing this resistance were not, as sometimes happens, merely gut bacteria that had acquired the necessary DNA but were hanging out quietly in the intestines and not causing trouble. They are already causing human infections.

And, of most concern: The MCR-1 gene that creates this resistance is contained on a plasmid, a small piece of DNA that is not part of a bacteria’s chromosome. Plasmids move freely around the bacterial world, hopping from one bacterium to another; in the past, they have transported resistance DNA between bacterial species, facilitating resistance’s rapid movement around the globe. This gene, the authors predict, will be able to do that as well.

The rapid dissemination of previous resistance mechanisms (eg, NDM-1) indicates that, with the advent of transmissible colistin resistance, progression of Enterobacteriaceae from extensive drug resistance to pan-drug resistance is inevitable and will ultimately become global.

“Pan-drug resistance,” to be clear, means that nothing at all will work—that infections are untreatable by any known compound.

How plasmids (the blue loops) move among bacteria.
How plasmids (the blue loops) move among bacteria.
Graphic via Wikimedia Commons.

It’s worth noting that not every dire superbug prediction comes true. In the early 2000s, physicians were very alarmed when resistance to vancomycin—like colistin, another last-resort antibiotic preserved from the 1950s—moved via a plasmid from Enterococcus into Staphylococcus aureus, or staph. At the time, people were already worried about the better-known form of drug-resistant staph, MRSA; the emergence of VRSA, as it became known, ratcheted worries way up. In the end, though, VRSA turned out not to be much of a threat: In 15 years, there have been only 14 such infections in the United States.

But what makes MCR, this new colistin resistance, different from VRSA is the role that agriculture seems to be playing in its evolution and dispersal. There are two problems here. First, that thousands to millions of animals are getting the drug, which exponentially expands the opportunities that favor resistance. And second, that projects such as the Chinese one that allowed the new gene to be discovered are rare—so colistin resistance could begin moving, from animals and into people, without being noticed.

And, in fact, it may be on the move now. The authors note that, while they were writing up their findings, the European Molecular Biology Laboratory received five submissions of bacterial data that appeared to contain the MCR gene—but not from China; from Malaysia.

What will happen next? Unfortunately, we have to wait and see—and hope that systems are  built that will perceive this new resistance if it arrives. Meanwhile, I especially appreciate the reaction of Mike the Mad Biologist, who knows a great deal about resistance in his real life and can be counted on to be exasperated and blunt. He said, about this discovery:

If this doesn’t convince people to get serious about the agricultural side of the problem, I don’t know what will.

49 thoughts on “Apocalypse Pig: The Last Antibiotic Begins to Fail

  1. I saw a twitter feed in the last few days on this from another source and was blindly going to flip it to you…glad I waited and actually read your article first…

    An eloquent narrative on such an important part of our infectious disease posture…not much of an arsenal appears to remain…


    MM: thank you!

    1. Thank you Maryn for such an informative article. Despite what some of your detractors say here, sustained Colistin resistance in agriculture is reason enough to raise the antenna in the Public Health arena.

  2. I take it you didn’t get the memo?


    MM: I did read this story. But what this describes is a recognition in a lab — not a functioning antibiotic in a human being. Developing a compound to the market stage can take 10-15 years and billions of US dollars, and there are many potential missteps along the way. To declare that antibiotic resistance is solved at this early point is overly optimistic.

    1. Also worth noting that this new drug (teixobactin) has no activity against Gram negative bacteria like E coli or Klebsiella – which carry the new mcr-1 gene mediating colistin resistance.

      MM: Thank you!

    2. I guess you didn’t read it well enough:

      Teixobactin has been found to treat many common bacterial infections such as tuberculosis, septicaemia and C. diff, and *could be available within five years*

      1. I would guess the author did read that; what you’ve quoted doesn’t contradict what he said. It’s been found to be effective in lab testing, not in real-world trials, and “could be available in 5 years” is very different from “will definitely be available in 5 years without fail”.

      2. Teixobactin doesn’t work against gram-negative bacteria so it won’t help. Colistin was our last ditch effort against gram-negative bacteria. So teixobactin isn’t going to help us out in this situation against gram-negative. It’s awesome at killing gram-positive bacteria so it’ll help out quite a bit against those in the future but not against the other gram-negative bacteria. You’re comparing two different classes of antibiotics.

        MM: Thank you!

      3. And it might be useless again in 30 years.
        “Crucially, the scientists believe that bacteria will not become resistant to Teixobactin for at least 30 years because of its multiple methods of attack.”

  3. This is another doom and gloom article. Even if what you stipulate in this argument as possible becomes reality, there are still viable options available. Bacteriophages, vaccinations, and natural compounds have all been effective in treatment.

    1. This isn’t the first I’ve heard of this, we’ve been hearing this on the news and in other articles for years. Vaccinations are for viruses, not bacterial infections for one. And as for natural compounds, I’ve tried many of those at the behest of my wife for many different things, all to no effect. And bacteriophages, or macrophages, can only take so much of a fight to the bacteria. I currently have a tooth infection and my face got really swollen, my macrophages weren’t taking care of it by themselves until I got an antibiotic. I’ve had to take the antibiotic for a couple weeks so far, twice as long as the doctor originally meant to have me on them. If you don’t want to wake up and see that antibiotic resistant bacteria are growing, then that’s your problem, but don’t talk others into being bling along with you.

      1. Although the comment to which you responded doesn’t consider routine medical treatments, I wanted to correct your misperception about ‘bacteriophages’.

        They are completely unrelated to macrophages, which are a core element of your immune system.

        Bacteriophages, on the other hand, are viruses that infect bacteria including a subset which kill and lyse bacterial cells.

      2. I have had some pretty good luck with plant extracts for my prostate infection. Actually, the natural compound cleared it up better than the anti-biotics…..granted, I might have built up some resistance to the anti-biotics.

        1. Salvador, it’s the bacteria that develop resistance, not the person taking the anti-biotics. People thinking that _they_ get resistant might want to diminish that risk by not finishing the course of ABs thereby contributing to bacterial resistance.

  4. MM – thank you for this incredibly important article. This pan-drug futility is man made, and fed by our gluttony for animal flesh. This circumstance was not inevitable.

    1. Technically, the mechanics and speed of bacterial evolution means the development of a strain resistant to this drug was indeed inevitable, it just could have taken much much longer had it not been for its heavy use in agriculture. Of course, it’s possible that had it taken longer, the extra time could have allowed us to develop a stronger antibacterial or two that could take its place by the time it became ineffective, so in that sense, it may not have been inevitable, but in my personal opinion, it would almost certainly only be a matter of time before a strain of bacteria developed resistance faster than we could develop new antibacterials.

      Although, I’d hazard a guess that this entire situation is largely a case of hindsight being 20/20. I highly doubt that there were a lot of people who had real reason to suspect this would happen any time soon. That isn’t to say no one, of course – I’m sure the people who conducted this study would certainly fall into this category – but the people running the farms probably had little knowledge about bacterial immunology, and most of the scientists who study that field probably had little knowledge of how much of this drug was being used in farms.

      1. The use of low-level antibiotics in feed has been controversial for decades, and the fact that it is still permitted is another case of “innocent until proven guilty” applied to a chemical, when the precautionary principle should be used. Thank you, lobbyists for agribusiness. Let us hope the public wakes up and demands action.

        But taking antibiotics out of feed wouldn’t necessarily mean the end of meat grown at scale. Denmark adopted much stricter regulations on antibiotic use on farms 20 years ago, and have shown that it is possible to raise livestock with far, far less:


        MM: I agree! And not only Denmark. The Netherlands went even further in restrictions, and has maintained both its level of productivity and also its profits. http://modernfarmer.com/2014/06/abstinence-method/

  5. MM is right. Despite the great threats, significant incentives (grants, tax credits) and acceleration of the regulatory pathways have to be initiated immediately to support the launch of new antibiotics and technologies to control and treat infectious diseases. Aequor is a small business that developed a portfolio of new molecules validated to kill medical bacteria in the lab. We have also discovered molecules that remove bacterial biofilm and inhibit biofilm formation. (Biofilm is the first line of defense of most bacteria and every pathogen on the CDC lists of potential pandemic threats, urgent infectious diseases, bioterrorist threats, etc.) I hope I will still be alive to see at lease one of our molecules get through the clinical trials, assuming that Aequor can raise the money to fund them!

  6. The bacterial march along the road to resistance and immunity to antibiotics is irrepressible.
    We have only one hope – genetics.

  7. On Thursday, researchers from several Chinese, British and US universities announced in the journal Lancet Infectious Diseases that they have identified a new form of resistance, to the very last-ditch drug colistin—and that it is present in both meat animals and people.
    What is a meat animal?

  8. I was a vegetarian for over 20 years would I have this resistance as well? How would I get tested?

    MM: Susan, you don’t need to be tested! People don’t become “resistant”; bacteria do.

  9. I’m a pharmacist student and this very alarming for me. Hope they find a drug that will combat this bacteria. and also

  10. The American Academy of Pediatrics just warned that the mass use of antibiotics in agriculture is a serious and growing threat. The AMA warned of this a dozen years ago (I drafted their policy statement). California just adopted stricter regulations on ag. use which need to be implemented and spread nationwide. “Apocalypse” is not too alarming a word in this case.

    AAP: Animal Antibiotics Threaten Kids’ Health
    Drug-resistant organisms spreading, and children are most vulnerable

    MM: Thank you very much for the link, and for mentioning your past history with this. I’d like to be in touch about that privately.

  11. Hey Maryn,

    Nice detailed post on what has been ailing the health industry for while now. No matter how much awareness we have created so far is very little when it comes to excessive antibiotic use and there is clearly a need to do much much more.

    While this seems like the beginning of the end, believe there is still time, if we act fast and promote trials of alternate antibiotics that are going through the usual grind of becoming a market circulated offering. University of Queensland has been doing some work on this and I have written about it in my blog post http://www.coffeetablescience.com/2015/09/your-next-dose-of-antibotic-sugar.html, where simpler substances like cell wall sugars are being redesigned to work as antibiotics.

    I think this holds great promise. Don’t you?

  12. We need to stop treating animals inhumanely so that we have to give them antibiotics! Raising animals in a humane way is more expensive, but the benefits are many. From a health perspective, we get to eat healthier meat from stress-free animals. From a spiritual perspective, we get to feel good about treating animals with respect instead of cruelty. From an environmental POV, it is better and from a world health POV – not giving 85% of our antibiotics to livestock is better. We could stop the evolution of drug-resistant superbugs if we got rid of the factory farms. Of course, one result is that we’d have to eat smaller amounts of more expensive meat, but that’s also healthier for us. I currently get my meat from a local organic farm where the animals graze in pastures instead of being crowded in dank cells ankle deep in feces, and while I do pay more for my meat, I am healthier for eating antibiotic-free, pesticide free, cruelty-free meat. I eat smaller portions of meat so I can still fit it into my budget, and eat more veggies.

    1. Raising animals in a humane way would be relatively less expensive if the farm bill was ended. The farm bill is one of the farm subsidies that support monocultures and concentrated animal feeding operations.

  13. Shefali:
    Animals take antibiotics when they fall ill, not for fattening, please. Into the farms, the conditions are excellent and we can produce healthy meat (and cheap, yes). At least it is so in my country.

    Is very easy a “bucolic” discuss when population rises continuately, resources disminish and people are diying of hunger.

  14. Bacterial infections and the need for antibotics would decrease if we stopped factory farming which forces animals into environments that will weaken their immune system making it necessary to treat with systemic broad spectrum antibotics…healthy animals means healthy food.l

  15. OMG can we just STOP animal agriculture. So, so much suffering for the animals and that’s just not going to change at scale with the financial incentive to cut corners, on top of which we have all the garbage with pollution, GHG emissions, water waste, childhood obesity, and bacteria that we have NO other way of containing than to just stop exploiting and killing other animals.

    No speciesist nonsense excuses, just stop listening to flesh-peddling propagandists, animal agriculture sucks and it’s time to get rid of it.

    1. Good idea… We need to kill and eat all of the endangered wild animals that are pooping on, and eating all of the vegetarian’s plants.

  16. Various forms of oxygen therapy are supposed to be effective against bacterial and viral infections, as well as against cancer.

  17. I have searched for this article in the Lancet but could not find it. What is the Title?

    MM: My link was bad, sorry (I accidentally copied it from within my university account, so no one else would have been able to access it). I’ll fix it. But the cite is:

    Liu et al. “Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.” Lancet Infectious Diseases, published online Nov. 18, 2015. DOI: http://dx.doi.org/10.1016/S1473-3099(15)00424-7. Stable link: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00424-7/abstract.

  18. This is very alarming – and somewhat distressing – news. Part of the blame rests on the heads of physicians who are wary of offending their patients/clients who demand something to alleviate their symptoms of discomfort will give into pressure prescribing antibiotics when they can’t possibly be effective e.g. viral infections.

    The agricultural industry is also partly responsible – they feed antibiotics to livestock as growth promoters.

    But ultimately the public takes most of the blame. People don’t realize that bacteria are living creatures and they can adapt to environmental change, if they’re continually exposed to antibiotics, they will eventually become resistant. Yet when people use antibacterial soaps, or clamor for bigger and juicier meat products, they’re putting their lives at risk.


    The natural microflora within our bodies, or on the surface of our skin will be exposed to these chemicals and over time, the bacteria will become immune to the drugs or replace bacteria that do succumb to the antibiotics.

    So this is a problem that the public has brought upon itself.

  19. I am a vegan/vegetarian, which means I strive to eat vegan, but will cross over into dairy, occasionally. I recently watched the movie documentary “Forks Over Knives” It is a fascinating story of two doctors, who grew up on farms, that come to realize the ill effects of a western diet. I was able to watch the movie on Netflix. This is also a great mystery on how a handful of patients fare on a vegan diet. To eat or not to eat meat is the question. Here is a link to a 2011 review by Roger Ebert of “Forks Over Knives”. If you don’t want to know what happens in the movie, I would recommend watching it and then reading the review. http://www.rogerebert.com/reviews/forks-over-knives-2011. I agree with other suggestions to do away with factory farming as we pursue a much healthier vegan diet that will benefit the world and it’s inhabitants.

    1. I am not vegan or vegetarian but I do see the truth in this. The human race is the master of its own demise and is a failed species. Sadly, we consistently fail to do the right thing unless it is convenient – we cannot control our population growth, hatred of those different to “us” or our waist lines here in the western world. As a veterinarian, I am aware of the horrors of factory farming. Farmers aren’t horrible – but the tough economics of the industry create a harsh environment. A colleague of mine insists that we should have to have a license to eat meat – eating chicken? You have to kill a chicken. Like lamb? You get to cut one’s throat… We are too detached from the origins of our food. Disagree? Visit the kill floor of a pig slaughterhouse and I defy you to not be changed by the experience.
      Harsh, Pessismistic, cynical or just accurate? 🙂
      A light read but illuminating ” Rich Roll’s, Finding Ultra” shows how a vegan can be an amazing endurance athlete, proving we don’t need meat.

  20. The simple solution seems like it would be to stop using these antibiotics in livestock. It may save money for the meat industry, but weighed against the human cost, in that it has been demonstrated to contribute to uncontrollable virulent diseases, the choice seems like a ‘no-brainer’ to me.

  21. The industrialization of food will no doubt lead to an eventual massive loss of human life. By many metrics, the significant rates of obesity and heart disease are already proof. It is striking that during a time of presidential election, not a single candidate raises the issue that is the largest killer of Americans. Imagine the hue and cry if the terrorist death toll approached that of 600,000 for heart disease.

    MCR-1 is simply next in a very long line of mutations. Bacteria modify, adapt, and mutate in order to survive, certainly not due to any intellectual capacity, but because this is a law of species development. The idea of continually developing new magic drugs ignore this fundamental natural law. It is akin to thinking you will develop an airplane by designing a better pogo stick. It may get you in the air longer than the last one, but you will not stay there very long.

    Antibiotics are a precious resource that have been massively squandered in animal feed, especially in countries without significant controls. The use of antibiotics in fish farms is another vector of mutation where caution is not being given due consideration. The use of antibiotics in feed for swine aptly resonates with the biblical passage of casting pearls before swine where at the end of the paragraph it cautions that they will “turn and tear you to pieces”.

  22. Irrespective of current incidence in the human population or elsewhere of colistin resistance, there are known, significant and very high risks to human health and losses in aquaculture / animal production from continued use of colistin in feeds.

    Its continued commercialization as a class of “antibiotic growth promoter” by pre-mix and compound feed companies which provide access to global feed markets for the manufacturers appears highly irresponsible. Similarly its use by vertically integrated meat producers who themselves both produce livestock and commercialize meat to the multinational retailers and restaurant chains.

    The shorter term risks to farm and slaughterhouse workers and those involved in the feed industries are most acute People in raw meat handling and processing have also frequently been exposed to resistant strains.
    However because of the mechanics of resistance diffusion through populations, there is a major risk elsewhere particularly in institutionalized subjects including those in the armed forces.

    The concept of due diligence in the marketing of such products does not yet seem to have surfaced. Are such meat producers and feed companies opening themselves to class action litigation in USA ?
    Several European countries with civil law, have made changes in recent years to allow consumer organizations to bring claims on behalf of consumers.

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