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To Fix Antibiotic Resistance: A Cabinet Post And More Money

Turkeys in a North Carolina intensive farm.
Turkeys in a North Carolina intensive farm.
Photograph by Mercy for Animals via Wikimedia Commons.

A White House panel of experts has made a striking recommendation: the United States needs a champion—perhaps even a new Cabinet member—backed with plenty of funding to fight antibiotic resistance.

This champion, who could also be an assistant secretary, would guarantee the issue does not slip away beneath short-term priorities and agency infighting. And most of all, as the group mentions numerous times, the effort needs money: “The (government) must commit sufficient resources to solving the problem with funding continued over a long period of time… Key elements necessary to achieve the goals of the national action plan are underfunded.”

Eighteen months ago, the Obama White House made a historic commitment—the first by any administration—to combating antibiotic resistance. The administration announced a national strategy against resistance, President Obama signed an executive order launching the effort, and the White House subsequently held a first of its kind Forum on Antibiotic Stewardship.

To figure out what the country should do, the White House named a Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria. Today that panel of experts launches a two-day meeting to start dealing with the practicalities, and has issued a 126-page report out of their first 180 days of research.

Other priorities (which will be familiar from other examinations of resistance such as the reports from the British Review on Antimicrobial Resistance): improve surveillance to detect resistance faster, stimulate the development of new drugs, foster innovation in rapid diagnostic devices to cut down on useless  prescribing, explore international agreements on conserving antibiotics,  try to educate the public on appropriate antibiotic use.

From the launch of the national strategy and the council’s being named, many advocates have criticized its makeup for being long on medical research but short on the kind of public health insight that could push back against the agricultural status quo. So it’s encouraging that the group put at the top of their list a commitment to a “One Health” approach, which is to say, considering human and animal issues to be connected, and not separate realms. Each of the major issues examined by the report contains a “One Health” addendum.

At the same time, the report (which will be voted on Thursday at the meeting’s conclusion) has relatively little to say about the specifics of reducing antibiotic use in agriculture, beyond support for the ongoing Food and Drug Administration policies that are forcing relinquishment of growth promoter antibiotics by next year. Dr. David Wallinga, a senior health officer at the Natural Resources Defense Council, expands on this in a Medium post, saying the US is going down a path that failed in Europe, which found that growth-promoter bans led to sneaky label changes.

“The Advisory Council should take a step back,” he writes. “Evaluate what’s not working for the U.S. to reach its ultimate goal of reducing widespread overuse of antibiotics. And issue a Plan B, one that recommends meaningful targets for reducing of antibiotic use in livestock, or alternatively recommends an end to the use of antibiotics in livestock for both growth promotion and disease prevention.”

The lack of specificity is frustrating, given that recent news has made the connection between agricultural use and human health threats even more clear than scientists have demonstrated previously. The extremely resistant superbug MCR-1, a gene that confers resistance to the last resort drug colistin, has now moved around the world. As I reported last fall, MCR arose because human medicine had dismissed colistin as not-useful,  agriculture took up the drug, and then medicine decided it was needed after all. Since then, MCR has been identified in more than 20 countries, in humans, farm animals, food or the environment. Recently, researchers in Tunisia found MCR in chickens on several large farms there, and traced the birds back to hatcheries in France.

As Laurent Poirel and Patrice Nordmann, two prominent European researchers into antibiotic resistance, wrote Tuesday in the Journal of Antimicrobial Chemotherapy: “MCR-1 is one of the few and clear examples of the animal origin of a resistance trait that may later hit the entire human health system.”

The expansion of that last-ditch resistance is unlikely to slow down without explicit international regulations and targets. As Bloomberg reported Tuesday night in a blockbuster set of stories reported in India, farms there are freely using colistin and other crucial antibiotics (Cipro, Levaquin, doxycycline) including ones banned in Western agriculture (Baytril, gentamicin) in multi-drug cocktails that are likely to encourage multi-resistant organisms.

As the think tank CDDEP has demonstrated, the demand for meat is rising in the developing world—and with it, antibiotic use to support meat production is rising too. The use of antibiotics in agriculture is a crucial part of the fight against resistance. It’s important that the White House effort examine that issue with the detail it gives to other parts of the puzzle.

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To Slow Down Antibiotic Resistance, Focus on the Basics

Washing hands.
Washing hands.
Photograph by Arlington County, Flickr (CC).

A project chartered by the British government, which has been examining everything that can be done to stem the tide of antibiotic resistance, in its next-to-last report has focused on the basics: municipal sanitation and hospital hygiene.

It’s something of a change in tone for the Review on Antimicrobial Resistance, a two-year effort created by Prime Minister David Cameron, supported by the Wellcome Trust and chaired by Lord Jim O’Neill, the former chief economist of Goldman Sachs (who now also serves in an unpaid post in Cameron’s government). The Review’s previous reports have examined what could be changed or created to solve problems that contribute to the rise of resistance: funding drug development, supporting vaccine research, detecting counterfeit drugs, innovating rapid-diagnosis devices and improving vaccine use.

In its new analysis, the group backs away from technological optimism to address seemingly intractable problems: how hospitals continue to cause antibiotic-resistant infections in their most vulnerable patients, and how the lack of clean water and sanitation both create diseases that demand antibiotic use, and also spread antibiotic-resistant bacteria.

Obviously neither of those concerns are new: Ignaz Semelweis  linked unwashed hands to fatal childbed fever in 1847, and John Snow made the connection between contaminated water and a cholera outbreak in 1854. Yet today, just in the United States, more than 1.7 million people contract healthcare-associated infections each year, and worldwide, more than 2 million people die from waterborne diarrheal disease.

So the problems are not solved. “We felt it would be of value to point out that just doing the basics can make a huge amount of difference,” Lord O’Neill said by phone. “It is concerning that not enough has happened, and that’s a reason for a new, independent voice to highlight that.”


The Review commissioned an analysis from postgraduate students at the London School of Economics which found that, just in four countries with emerging economies (India, Indonesia, Nigeria and Brazil), 494 million cases of diarrhea each year are treated with antibiotics, a number that could rise to 622 million cases by 2030. If infrastructure were improved, 60 percent of those courses of antibiotics could be foregone. The report says that contaminated water also allows bacteria to cycle between humans and the environment, spinning up the dissemination of resistance genes. (In fact, in 2011, the team who discovered the resistance supergene NDM identified municipal water supplies and puddles as a major contributor to the spread of that almost untreatable bug.)

If sanitation seems a simple goal, so does hygiene—yet the Review finds that persistent neglect of simple tasks such as washing hands is fueling the spread of resistance. As few as 30 to 40 percent of hospital staff wash their hands as often as they should, it says, and doctors perform worse than nurses or staff who are lower in the hierarchy. Though it is crucial those rates be improved, there group finds there is nowhere near enough research into what actually motivates healthcare workers to change their behavior, and recommends funding studies that could pick apart what works. (Dismayingly, that does not now happen. A few years ago, infection-prevention specialist Dr. Eli Perencevich and several colleagues analyzed funding awarded by the National Institutes of Health to study AIDS, versus funding for research into hospital infections. For every US death from AIDS, they found, the NIH awarded the equivalent of $69,000; for every US death from MRSA, drug-resistant staph, $570.)

In its final comments, the Review calls for something that, for years, researchers deep in the trenches of antibiotic resistance research have been begging for: the creation of a comprehensive, global, rapid surveillance system that could alert the world when something new emerges. Two examples of where that would have made a difference: NDM was first identified in Sweden in 2008, but was subsequently found to have been diagnosed in India, its place of origin, as early as 2006. And MCR-1, the most recent dismaying superbug—which is resistant to the utterly last-resort drug colistin—was found last fall to have spread to more than a dozen countries, but was first identified in China in 2013.

“Even in some of the world’s most developed health systems, AMR surveillance data is often patchy and retrospective—virtually none is ‘real time’,” the Review says. “Without effective monitoring, we will lack early warning of emerging patterns of drug resistance, and lack the insights needed to guide and evaluate our response.”

The Review will conclude its two years of research with a final presentation of big-picture recommendations for health agencies and governments this summer, with presentations to the World Health Assembly and the United Nations.

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As Antibiotics Fail, We Need More Vaccines

The global problem of antibiotic misuse that allows bacteria to become resistant can be solved in part by more use—not of antibiotics, but of vaccines and other compounds, which could reduce the occurrence of diseases that antibiotics are otherwise used to treat.

A patient receives a vaccination injection at Gorkha district hospital in Nepal. Photograph by Alex Treadway, National Geographic Creative
A patient receives a vaccination injection at Gorkha district hospital in Nepal. Photograph by Alex Treadway, National Geographic Creative

That is the latest piece of analysis of the worldwide resistance problem from the Review on AMR, the British project that is conducting a two-year examination of antibiotic resistance at the request of UK Prime Minister David Cameron. The group, which is supported by the Wellcome Trust, is closing in on its deadline of May 2016 for presenting comprehensive recommendations to ameliorate resistance. On the way, it has examined reducing agricultural use of antibiotics, funding drug development, promoting increased use of diagnostic devices, combatting over-the-counter sales and counterfeits, and achieving better data on the occurrence and cost of resistance.

“This year, 2016, is a critical year for action on the wider issue of drug-resistant infections, and both vaccines and alternative therapies have a crucial role to play as part of the strategy to tackle this threat. Internationally there will be focus on this issue at the World Health Assembly, the G7, G20 and UN General Assembly,” the report says. “This is a crucial time for the world to make significant progress – a moment that needs to be seized.”

The project is chaired by Lord Jim O’Neill, the former chief economist for Goldman Sachs, who is also Commercial Secretary to the Treasury in Cameron’s government. “Drug resistant infections could be compared to a slow-motion car crash,” he said. “Antibiotics are important to tackle this threat, but if we can encourage the development and use of vaccines and other alternatives we give the world a better chance of beating drug resistance.”

In the newest report, the Review proposes that better use of vaccines, along with development of new vaccines and other non-antibiotic compounds, could reduce the need for antibiotic use. But what stands in the way, it says, is a lack of funding both for getting existing vaccines to vulnerable populations, and also for developing crucially needed new vaccines.

Vaccines, it says, can reduce the occurrence of bacterial infections for which antibiotics are used; viral infections, for which the drugs are often given in error, increasing resistance; infections that occur in hospitals, a setting in which bacteria often become multi-drug resistant; and infections in farm animals, forestalling the huge use of antibiotics on farms.

Crucially needed vaccines are not being developed.
Crucially needed vaccines are not being developed.
Graphic courtesy the Review on Antimicrobial Resistance.

The report finds that existing vaccines are not being used as much as they might be: globally, pneumococcal and rotavirus vaccines reach only 31 percent, and 18 percent, of children eligible for them. If pneumococcal vaccine were fully deployed, it says, the lives of 800,000 children younger than 5 could be saved every year—and in addition, 11.4 million days of antibiotic consumption, almost half the global usage for that disease, could be prevented.

But there is also a need for new vaccines to address specific diseases which antibiotic resistance makes worse. In 2013, the US Centers for Disease Control and Prevention compiled a long list of the resistant bacteria that it considers the most serious threats to health. There are no vaccines for the problems that it ranked as most urgent: resistant gonorrhea, Clostridium difficile, and bacteria such as E. coli and Klebsiella that have become resistant to the last-resort antibiotic class carbapenems and collectively are known as CRE.

Unlike antibiotics, vaccines can be attractive moneymakers for pharma companies, but the size of the clinical trials needed to get them to market means that many candidates stall in development, the report notes. To improve vaccine’s prospects in the market, it proposes additional funding to buy existing vaccines for low-income countries and to support early-stage research, and the creation of reward commitments (also known as advance market commitments or market entry rewards) for vaccines that make it through the development pipeline and reach the market.

Elizabeth Jungman, director of public health at The Pew Charitable Trusts, said about the proposals:  “This report highlights the need to take a multifaceted approach to addressing antibiotic resistance. Vaccines and some alternatives can play a critical role in the fight against antibiotic resistance by preventing infections, and other alternatives can make antibiotics more effective or even replace them for treatment.”

Vaccine syringes.
Vaccine syringes.
Photograph by Debora Cartagena, CDC.gov.

The new report is being released just after midnight in Britain, and a number of experts gave the Review their comments to release at the time of publication.

Dr. Jeremy Farrar, Director of the Wellcome Trust, said: “Our own analysis on how we might use vaccines and other alternatives to tackle this crisis supports the O’Neill team’s report, and suggests they will be an important way we can reduce – but not replace – our need for antibiotics. Vaccines are also critical for controlling epidemics, like Ebola, and endemic diseases such as TB and dengue fever, and how we incentivise developing news ones must take the whole picture into account.”

Dr. Seth Berkley, CEO of Gavi, the Vaccine Alliance—which is praised in the report for innovative funding strategies that allow vaccines to flow to poor countries—said: “It is exciting to see such a powerful argument on the important roles vaccines play, not just in preventing diseases and therefore reducing antibiotic usage, but also in directly reducing antimicrobial resistance. New incentives are needed to further accelerate their development.”

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Last-Ditch Antibiotic Resistance: What Is The Role Of Food?

A cattle feedlot in California's Imperial Valley. Photograph by Gerd Ludwig, Nat Geo Creative
A cattle feedlot in California’s Imperial Valley. Photograph by Gerd Ludwig, Nat Geo Creative

As concern for Zika virus ramped up in January, the recent and sudden recognition that last-ditch antibiotic resistance is moving across the globe has all but vanished from the news.

But it’s about to become important again. Two letters published in Lancet Infectious Diseases, the journal that has published all the revelations of the newly identified MCR-1 gene that protects bacteria from the last-resort antibiotic colistin, reveal a worrisome new development. In both humans and animals in China, bacteria have been found that harbor both MCR, and also NDM, the last perilous superbug gene, which confers resistance to a crucial class of drugs called carbapenems.

In the last set of publications about MCR several weeks ago, researchers revealed that bacteria with MCR resistance were doing the equivalent of assembling a winning hand at cards, shuffling the DNA for different resistance factors into shared mobile genetic elements that are capable of transferring among bacteria. With the acquisition of NDM, the hand gets stronger—and the bacteria, closer to lethally untreatable.

Hong Du and colleagues report that, once MCR was identified last November, they went back into the sample banks of a hospital in Suzhou, China. They found four bacteria possessing mcr-1, two E. coli and two Klebsiella, that were collected between January 2013 and November last year. The bacteria came from three patients, two inpatients and one outpatient, and two of the samples, the Klebsiellas, also carried ndm-5, which confers resistance to the carbapenems. The researchers say this is is “of great global public health concern.”

Xu Yao and colleagues, from the team that initially identified MCR, separately report a further discovery of a different MCR-NDM combination, from the initial analysis of human, food and animal samples that first yielded MCR. They found:

…one E. coli strain, THSJ02, recovered from a chicken wing sample purchased at a large supermarket in Guangzhou in July, 2014, was resistant to all antimicrobial drugs tested except doxycycline and tigecycline… This strain carried blaNDM-9, fosA3, rmtB, blaCTX-M-65, and floR, accounting for carbapenem, fosfomycin, aminoglycoside, cephalosporin, and florfenicol resistance, respectively, in addition to mcr-1 accounting for colistin resistance.

Here, they say, is why this is mysterious, and critical:

Recovery of an E. coli strain co-producing MCR-1, NDM-9, and FosA3 from chicken … is concerning since carbapenems and fosfomycin are not approved for use in food animals in China. Given that colistin and carbapenem-resistant E. coli can be found in retail meat, and that the resistance genes for crucial antimicrobials are located on conjugative plasmids, such strains might colonise the human intestinal tract and transfer the resistance plasmids to other Gram-negative pathogens, which might result in untreatable infections.

It’s been clear from the first identification of MCR that the use of last-ditch antibiotics in agriculture is driving its emergence—completely legal use in the case of colistin, as I explained in this analysis of European colistin-use statistics. It’s hard to know, at this point, where the resistance in these newest results comes from, since as the authors say those drugs are not used legally in Chinese livestock. Were they used without authorization? Did the resistance migrate from animals or livestock originating in countries with less oversight than China now applies? Or, since the finding came from an animal part that had been handled several times—at slaughter, while being butchered, while being packaged or displayed—does it represent human contamination, and from whom?

If there is any good news to be found in these reports, it is that MCR and NDM are not moving together. Both sets of researchers say that mcr-1 and the two varieties of the ndm gene are housed on separate plasmids, the mobile genetic elements that can move between organisms. So MCR and NDM resistance have not combined in a single mobile element. Nevertheless, as these dire resistance factors combine and move, it’s going to be crucial to try to identify their sources—possibly healthcare, possibly people in the community, very likely food—and to attempt to slow their march toward an invincible combination.

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Last-Ditch Resistance: More Countries, More Dire Results

An E. coli bacterium.
An E. coli bacterium.
Photograph by the Public Health Image Library, CDC.gov.

The frantic international hunt triggered by the discovery of genetically mobile resistance to colistin, a last-resort antibiotic, is producing many more findings this evening. The resistance factor is showing up in more countries, but, much more important, it has combined in some bacterial samples with genes conferring resistance to other potent drugs, creating bacteria that look effectively untreatable.

These disclosures are made in letters from research groups in a number of countries that are being published by the journal Lancet Infectious Diseases at 11:30pm London time, which is 6:30pm East Coast time here in the US. They represent evidence that this drug resistance, which was driven by agricultural use of colistin during the years that human medicine did not make use of it, is an imminently serious issue for human health.

“We’re watching our demise in real time,” Lance Price, PhD, a prominent resistance microbiologist and founder of the Antibiotic Resistance Action Center at George Washington University, who not involved in any of the research, told me. “I guess this is one of the advantages of next-generation DNA sequencing, is we can watch ourselves fall apart.”

Here’s a quick way to think about what follows. It’s natural to imagine that antibiotic resistance proceeds step-wise; that in the leapfrog between bug and drug, bacteria gain resistance to one drug, and then the next toughest drug presented to them, and then a last-resort drug after that. But in the wild, the way bacteria accumulate resistance DNA is more like being dealt cards in a hand of poker: one might have a 3, a 5, and a Jack, while another has a King, a Queen and a 10.

In these papers published tonight, researchers are finding bacteria that already possess colistin resistance— call it the Ace—and are accumulating the rest of a winning hand. Only, what looks like winning would be losing, for us. Here are the details:

Laurent Poirel and colleagues in Switzerland have identified an E. coli strain, recovered from an 83-year-old Swiss man who was hospitalized last month, that possesses both colistin resistance and also VIM resistance to the carbapenems, the family of antibiotics that was considered the last and toughest before colistin. The colistin-resistance gene shared a plasmid with genes conferring resistance to chloramphenicol, flofenicol and co-trimoxazole. The authors warn, “Such accumulation of multidrug resistance traits may correspond to an ultimate step toward pandrug resistance.”

Our data suggest that the advent of untreatable infections has already arrived.

Marisa Haenni and collaborators in France and Switzerland queried the Resapath network in France, which conducts surveillance for antibiotic resistance in animals, found that 21 percent of bacterial samples collected from veal calves on French farms between 2005 and 2014 carried the signal of mobile colistin resistance, the gene mcr-1. There were 106 positive samples (out of 517) and they came from 94 different farm properties. On seven of those isolates, the mcr gene lived alongside ones for ESBL resistance—that’s to penicillins and to the first three generations of cephalosporin drugs—and also genes for resistance to sulfa drugs and tetracycline.

Linda Falgenhauer and collaborators in the Reset consortium in Germany examined the sequences of 577 isolates taken from human patients and livestock and from the environment since 2009. They identified four carrying the mcr-1 gene, three from humans and one from a hog. The three from swine also possessed ESBL resistance; the one from the human was also carbapenem-resistant (KPC-2). One of the swine samples dated back to 2010. They say, somberly: “Our data suggest that the advent of untreatable infections has already arrived, as every colistin-resistant isolate described in this study is also resistant to either third-generation cephalosporins or to carbapenems.”

Surbi Malhotra-Kumar and colleagues at the University of Antwerp examined 105 E. coli strains collected from piglets and calves in 2011 in Belgium that had previously been identified as colistin-resistant. They found mcr-1 in 13 of them, and also found that it is being carried on a different plasmid than those identified in China and in Denmark. They descrcibe this as “a marked presence of mcr-1 in animal pathogenic bacteria in Europe, an indication that this is already a truly global phenomenon”— and also note that the 92 resistant strains that did not contain mcr might indicate other transferable colistin resistance that has not yet been identified.

In a separate letter, the same research group and several Vietnamese collaborators report mcr-1 in nine out of 24 E. coli collected from chickens and pigs in two provinces in Vietnam. One isolate contained resistance to eight additional drug families. They also screened 112 ESBL E. coli from three hospitals in Hanoi, but, they report, did not find any mcr.

Nicole Stoesser and colleagues from England and collaborators in Virginia and Bangkok examined sequences from a database of E. coli and Klebsiella collected in North America, Europe and Southeast Asia between 1967 and 2012, and found only a single isolate carrying mcr. It was taken frmo a child hospitalized in Cambodia in 2012, and also possessed ESBL resistance.

In Japan, Satowa Suzuki and collaborators from several institutions say they scoured the sequences of  1,747 plasmid genomes from Gram-negative bacteria, originally taken from human patients and livestock and from the environment, and found five animal isolates carrying mcr, but no human ones. None carried other resistance genes. They also examined a separate database of E. coli from livestock and, out of 9.308, found only two carrying mcr—but 88 others that were colistin-resistant.

And in the eighth letter, Mauro Petrillo and colleagues of the European Union’s Molecular Biology and Genomics Unit present a hypothesis for how the mcr-1 gene is being acquired.

There are some important leads in these reports: that mcr is in more countries,  is appearing on different plasmid backbones, and, apparently, seems more common in animals than in humans in the locations where it has been found. That may suggest, as the CDC said last month, that molecular analysis allowed this to be identified relatively earlier than other dire resistance factors have been in the past.

But the discovery that colistin resistance is combining in the same plasmids with other resistance genes should especially raise alarm bells. That indicates that using any of those drugs—some of which are very common—could amplify this resistance and and increase its spread. It signals that, as serious as mobile colistin resistance appeared at first, it is even more complex and more urgent.

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Last-Ditch Drug Resistance: China and Europe Respond

A cattle feedlot from the air.
A cattle feedlot from the air.
Photograph by Wongaboo (CC), Flickr.

I have a couple of pieces of news regarding the discovery of resistance to colistin, the last-resort antibiotic that is the only thing that works for some multi-drug resistant infections. Two are positive news, and the third is a corrective to some earlier reporting, and a revelation of how complex the antibiotic traffic between human and animal medicine can be.

The positive news first: Both Europe and China are moving to examine the use of colistin in agriculture. The European Medicines Agency has asked the European Commission to be allowed to examine whether colistin use should be restricted. And in China, the central government is studying whether it should ban the drug from agricultural use altogether.

Timothy Walsh, DSc, a British microbiologist who has been studying antimicrobial resistance in China’s agriculture and who collaborated with Chinese researchers on the blockbuster paper announcing the colistin discovery, told me: “The Chinese government have been very receptive” to concerns being expressed about colistin use. He added, “They are conducting a review now, to look at the impact of removing colistin from animal feed, and it is hoped in the next couple of weeks that they will indeed remove colisitin from animal feed.”

Quick update, if you’re coming to this fresh: Colistin is an old drug, first isolated in 1949, that languished on the shelf for decades but was recently revived. It it the only antibiotic that works against a growing category of serious infections; if widespread resistance to it developed, those infections, known as CREs, would become untreatable. In November, Walsh and his collaborators made the bombshell announcement in Lancet Infectious Diseases that they had found resistance to colistin in China, contained in a mobile genetic element that can reproduce and move freely among bacteria, and that its existence—in pigs, pork meat, and human patients—was due to colistin use in agriculture.

That news set off an international furor and also a hunt. The mcr-1 gene conferring this resistance was swiftly identified in stored bacterial samples in Denmark, and then England; the count is now up to 10 countries. (With more no doubt to come.)

That brings us up to date, and also to the corrective piece of news.

The early days of reporting about mobile colistin resistance gave the impression that it arose through China callously wasting a crucial drug. (This slots into China’s well-documented reputation for dubious food safety.) The message was that, unlike Europe and the United States, which have taken steps to control farm antibiotic use, China is allowing a free-for-all.

Turns out, it’s not that simple. The situation is not that agriculture, in China or elsewhere, is using up a drug that medicine has always needed. It’s more that medicine handed the drug to agriculture in the 1950s, and now wants it back.

Colistin use in agriculture in Europe in 2011 (expressed in a per-animal measure).
Colistin use in agriculture in Europe in 2011 (expressed in a per-animal measure).
Grpahic by the European Medicines Agency, original here.

You can see this most clearly in Europe. The EU has had the word’s strictest control on livestock antibiotics  since 2006, when it banned the routine micro-doses called growth promoters that make animals put on weight more quickly. Yet it is an abundant user of colistin. An eye-opening paper published last September lists colistin (and a related drug; both belong to the polymyxin class) as being used in “rabbits, pigs, broilers, veal and beef cattle, and meat-producing sheep and goats; furthermore, the antibiotic is used also in laying hens and dairy cattle, sheep and goats producing milk.” Of all the classes of antibiotics used in animals in Europe, the polymyxins were the 5th most-sold. That is all prophylaxis, to prevent the occurrence of diseases, which remained legal under the 2006 ban.

“Colistin is a survivor of the ban on antimicrobial growth promoters in Europe,” Boudewijn Catry, DVM, PhD, told me. Catry is the first author on that paper and the head of healthcare-associated infections and antimicrobial resistance at Belgium’s Scientific Institute of Public Health. He said that colistin gets so much use for two reasons: first, because it was so toxic in humans that it seemed medicine would never want it; and second, because other drugs were taken away from agriculture over the years precisely because medicine needed them preserved. Those other drugs include penicillin, the tetracyclines, and vancomycin, the last-resort drug for MRSA (agriculture used a close analog, avoparcin). Catry added: “When many compounds were banned, others were still possible to give in large quantities by the oral route, for prevention of major diseases, and colistin is one.”

Multi-drug resistant CREs began moving across the globe in the mid-2000s. There were different categories—the KPCs in the US, NDM in South Asia, OXA in the Mediterranean—but what they all had in common was resistance to carbapenems, essentially the last reliable, nontoxic drugs for highly resistant organisms. With nothing else left, human medicine was forced to turn back to colistin.

At that point, the European Union began re-evaluating the way that it had allowed agriculture to use the drug. In 2013, the European Medicines Agency recommended disallowing preventive use, and that recommendation has been chugging through the system since, without great urgency because resistance migrating from agriculture did not seem to be a problem. With the discovery of mobile colistin resistance, that has changed.

The MCR story is going to go on for a while, but right now, there are two important things to note. The first is that antibiotic control is porous. Colistin resistance is occurring in Europe because it entered agriculture through allowed preventive use; when the United States finalizes its long-awaited actions against growth promoters in 2016, it will allow preventive use too.

The second is that the progress of resistance is unpredictable. Medicine allowed agriculture to use avoparcin because it never thought vancomycin would be important; it allowed polymyxin use in agriculture because it never though it would need colistin either. It turns out both drugs are crucial. That seems to me a lesson that all antibiotics should be used conservatively. We never know what will arise next.

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MRSA In Sports: Long-Standing, Simple to Prevent, Still Happening

Big news in sports the past few days: Daniel Fells, tight end for the New York Giants, is battling a MRSA infection so severe that he has been hospitalized in isolation and had multiple surgeries. Some news stories have speculated doctors may amputate his foot in an attempt to corral the infection.

It’s a tragic situation for the player, and no doubt frightening for the team, which is reported to have sought medical advice and scrubbed down their locker rooms to prevent any additional cases.

What it’s not, unfortunately, is new. MRSA—the acronym for methicillin-resistant Staphylococcus aureus, staph bacteria that are resistant to multiple classes of antibiotics—has been dogging sports teams for more than 20 years. And for at least 10 of those years, we’ve known what to do to prevent it. But it’s not at all clear that teams treat that prevention as a routine thing they should be doing—and because of that, every athlete’s infection seems like a random tragedy, instead of an avoidable mistake.

Among the long litany of MRSA cases in athletes, some have been high-profile: Lawrence Tynes, who is suing the Tampa Bay Buccaneers over a career-ending infection (two of his teammates were infected as well); Brandon Noble of the Washington Redskins, who lost his pro career over a knee infection (six of his teammates developed infections too); Kenny George of  the University of North Carolina-Asheville, who had part of his foot amputated.

But the list of those known to have been affected (and this is certainly not complete) is much longer. Some other names: Kellen Winslow (and five teammates) of the Cleveland Browns, Peyton Manning, Drew Gooden, Mike Gansey, Sammy Sosa, Alex Rios, Paul Pierce, Kenyon Martin, Braylon Edwards, and Grant Hill. And, in addition, the St. Louis Rams, the USC Trojans, and dozens of college and high school teams going back to 1993.

MRSA infections seem like they sweep in out of nowhere, especially the apocalyptically bad ones (such as MRSA pneumonia, which can kill a child in days). But in fact, some MRSA cases are very predictable. They are more likely to occur in what the Centers for Disease Control and Prevention call the “5 C’s“: places where there is crowding, skin-to-skin contact, compromised skin from cuts or abrasions, contaminated items and surfaces, and lack of cleanliness.

Add all those together, and you have a pretty good description of a football field, and a locker room after a game.

MRSA is simple to catch: The bacterium lives on the surface of our skin, and in our nostrils and other warm, damp body crevices, and causes an infection when the skin is breached and the bacteria slip into tissue or the bloodstream. In hospitals, where MRSA first became a problem in the 1960s, that breach could come from surgery, or an incision made to allow for a catheter or an IV. But in the everyday world, where MRSA has been a problem since the mid-1990s, the source is more likely to be a cut or a scrape—in the kitchen, in the outdoors, or, in sports, from a razor, training equipment, artificial turf, a wrestling mat, or pads or straps cutting into a shoulder or a shin. (And sometimes, nothing at all. Toxins manufactured by the bacterium can break down the skin, causing the hot pinpoint infections that people often mistake for spider bites.)

Fells is supposed to have been infected at some point in the past few weeks, after a toe and ankle injury and a cortisone shot to the ankle. I don’t have inside intel on his treatment, or on what the Giants do in their locker rooms. But I know what teams that had MRSA problems in the past did to shut their outbreaks down. It wasn’t complicated—but it required commitment and attention, and it took a while.

Between 2002 and 2006, the Trojans, the Rams, and the Redskins were all so spooked by epidemics among their players that they asked the CDC and local health departments for help. (The stories of the outbreaks are told in my last book, Superbug.) They learned that stopping the infections and protecting their players took many steps: requiring everyone to shower post-game. Scouring the hydrotherapy tubs. Disinfecting the training equipment and massage tables. Discouraging body shaving, even though it makes taping up—and untaping—a lot less uncomfortable. Raising the water temperature in the laundry machines. Making sure no one shared bars of soap in the shower or towels on the field.

After Noble’s injury, the Redskins ripped out their entire training facility and installed a new one, spraying germ-killing coatings on the lockers and discarding the shared benches for individual stools. The teams practiced these steps over and over, chastising and sometimes fining players who didn’t bother, and shut their outbreaks down.

MRSA is also a serious problem for school teams; in fact, it was school outbreaks—in a Vermont high school in 1993, a Pennsylvania college in 2000, a Connecticut university in 2003, and throughout Texas high schools for several years in a row—that first alerted researchers that athletes might be at special risk. When I was writing Superbug, I spent a lot of time with trainers and coaches, and it was striking how open they were about the problem. Whether because of affection for their students, responsibility to parents, or fear of lawsuits, athletic programs all over the US were educating kids and staffs about the danger, and teaching them how to protect themselves.

Pro teams, which clamp down on information about players’ injuries as competitive intelligence, mostly don’t talk about their MRSA plans. But it’s not clear they are training and protecting as comprehensively as schools do. A year ago, the Washington Post took a look back at Brandon Noble’s career-ending infection, and reported that MRSA prevention is not uniform across NFL teams. This season, Duke University’s Infection Control Outreach Network Program for Infection Prevention in the NFL, known for short as DICON, began working with the NFL Players Association to distribute a manual on infection prevention to all 32 teams and to train their personnel. That the teams agreed to participate is a big step—but that the program was needed suggests how vulnerable some players still are. Until MRSA prevention becomes routine in locker rooms, other players may end up as ill as Fells now is.

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Introducing Germination: Diseases, Drugs, Farms, and Food

When I was a kid, my favorite part of school wasn’t class — even though I loved studying, and liked showing off what I knew. It wasn’t the uniforms, though my boarding school’s dresses and blazers, and shoes for indoor and outdoor games, were a puzzle that came together differently every time. And it certainly wasn’t the food: School dinner in England was a mystery of boiled sprouts and stewed rhubarb, even if the Texas high school lunches that came after taught me how to make Frito pie.

What I loved most about school, with a fierceness that bordered on devotion, were school supplies. The incense of a just-sharpened pencil. The order in a fresh box of pen cartridges. And more than anything, the promise in a new notebook, and the anticipation of filling its empty, perfect pages with everything I would discover and learn.

I’m feeling a similar thrill now, viewing this new space at Phenomena. Welcome to Germination, a blog that will explore public health, global health, and food production and policy—and ancient diseases, emerging infections, antibiotic resistance, agricultural planning, foodborne illness, and how we’ll feed and care for an increasingly crowded world.

If you followed me here from my previous blog Superbug at Wired, thanks, and get comfortable. If I’m a new discovery for you, here’s a capsule bio. I’m a freelance journalist working mostly for magazines (Wired,  Scientific American, Nature, Slate, the Atlantic, the Guardian and Modern Farmer, along with an array of women’s magazines). I’ve written two books so far—Superbug, about the global rise of antibiotic resistance, and Beating Back the Devil, about the Epidemic Intelligence Service, the disease-detective corps of the US Centers for Disease Control and Prevention—and am working on a third, about how we came to use antibiotics in agriculture, and what a mistake that turned out to be.

Before I was a magazine writer, I was a newspaper reporter, doing mostly investigative work: on the causes of cancer clusters, the social effects of drug trafficking, and a mysterious illness in reservists that turned out to be the first cases of Gulf War Syndrome. In my last newspaper job, I covered the CDC, under orders from the editor who hired me to “get in there and tell us these people’s stories.” I spent a lot of time talking my way into investigations and onto planes in the middle of the night. It was enormous fun.

Me, at TED, on March 18, 2015. Original here/a>.
Me, at TED, on March 18, 2015. Original here.
Maryn McKenna speaks at TED2015 - Truth and Dare, Session 6, March 16-20, 2015, Vancouver Convention Center, Vancouver, Canada. Photo: Bret Hartman/TED

I’m also a Senior Fellow of the Schuster Institute for Investigative Journalism at Brandeis University, and just finished a fellowship at MIT. I do some video. And I just gave a TED talk, on imagining what the world will be like after we’ve used up antibiotics. (The video has not gone up yet, but I’ll let you know when it does.)

As a journalist, my interest is complexity, inadvertence, and unintended consequences. (My Phenomena colleague Ed Yong jokes that he covers the “Wow” beat; I think of what I do as the “Oops” beat.) We got to widespread resistance because we wanted to cure infections quickly; we got to factory farming because we wanted to ensure affordable food. There isn’t (much) malfeasance in either of those endeavors,  but there is a ton of good intentions—and good intentions gone bad are a rich, rewarding subject. We might be here a while.

Here’s what you can expect at Germination: reports on new scientific findings; inquiries into policy initiatives; profiles and interviews with researchers doing cool things; history; and, occasionally, whimsy. I have been writing for a year for National Geographic‘s food platform The Plate, and some posts that deal more purely with food will be loaned or cross-posted there. (About which: You make Frito pie by opening a serving-size bag of Fritos along the back seam and plopping in a ladle of chili and some shredded yellow cheese. It tastes best when served by a lunch lady in a hairnet and a Texas Longhorns jersey.) If you’d like to hear more about my plans, head over to The Loom, where my new colleague Carl Zimmer has kindly conducted a Q&A with me.

When I think back to being a kid at the start of a school year, the initial thrill might have been those pristine new notebooks—but the bigger thrill was filling them. Phenomena is the most exclusive science-writing club on the internet, and I’m excited to join it. Please come along.

(Much gratitude to Jonathan Eisen, PhD, for suggesting Germination as a blog name.)


UCLA Superbugs Reveal Stubborn Resistance Problem

Guest Post by Maryn McKenna

The UCLA Health System announced earlier this week that seven patients—two of whom died—became infected by highly drug-resistant bacteria that remained on pieces of medical equipment after disinfection, and 179 more were exposed to the bacteria and are at risk of developing infections.

The outbreak is one of several that have occurred in the United States in connection with duodenoscopes, complex flexible tubes that are used to treat problems in narrow ducts in the liver and pancreas. In each outbreak, despite the devices being cleaned, patients have been infected with superbugs known as CRE, short for carbapenem-resistant Enterobacteriaceae: a group of bacteria that reside benignly in the gut but have acquired an array of genetic defenses against antibiotics, including to the last-resort drugs carbapenems. CREs remain vulnerable to only one or two antibiotics, and CRE infections can kill two in five patients.

On Thursday, the Food and Drug Administration issued a warning about the difficulty of cleaning the devices, which it said are used at least 500,000 times per year in the US. The agency said it has been notified of 135 patient infected with CRE by duodenoscopes since January 2013 and added, “It is possible not all cases have been reported.”

The UCLA episode follows a large outbreak at a Seattle hospital and a separate one in Illinois along with smaller ones in other states. It is causing alarm because the superbugs transmitted by the scopes are a growing problem in the US, and because there can be such a long lag time—weeks or months—between when patients are exposed and when they develop symptoms of infection.

For a better understanding of the problem, I talked to Dr. Alexander J. Kallen, a medical epidemiologist in the division of the Centers for Disease Control and Prevention that handles infections transmitted in healthcare.

Maryn McKenna: Are all these outbreaks similar?

Alexander Kallen: They’re related in that they all involve a small number of scopes—duodenoscopes, which are specialized endoscopes—with persistent contamination, which ended up in each case with 100 to 200 people exposed. Most people did not develop infections; they ended up colonized with the bacteria, but that is still a problem from a community standpoint (because they may be able to pass the bacteria along).

MM: Is there any other relationship among them?

AK: All three large outbreaks that we’re aware of, while they were CRE, were all different types of CRE—and all types that are unusual in the United States. In Illinois, which we at the CDC investigated, it was a type called NDM, in Los Angeles it is a type known as OXA, and in Seattle it was a type known as Amp-C. These are very unusual organisms, so to have a cluster of them definitely prompts an investigation. And they may turn out to be a canary in the coal mine for the difficulty of cleaning these scopes. If what had been passed between these patients because of the scopes was regular old E. coli, we would never have noticed, because it is not an unusual bug.

MM: Do you have any sense of where the infections originated?

AK: They were likely imported originally by people who got healthcare outside the United States. But we looked hard in Illinois for instance to try to identify the original person and were not able to.

MM: Surely this isn’t the first time there have been outbreaks of illness, even of resistant bacteria, from endoscopes?

AK: No. But the outbreak we investigated in Illinois in 2013, which we reported in the Journal of the American Medical Association, is the first time that we know of where there was transmission of a highly resistant pathogen, from a scope, unrelated to an infection-control breach. You almost always see that someone forgot this step or that step. But in these last three outbreaks, there was persistent contamination despite not identifying a breach, and that is fundamentally different. It starts to raise the suspicion this is more a fundamental issue with these types of scopes, rather than just failures to adhere to recommendations for cleaning.

MM: These scopes are obviously complicated. It is possible that they just can’t be sterilized?

AK: Technically they’re not sterilized, because they aren’t intended for use in sterile spaces in the body the way surgical instruments are. They undergo high-level disinfection, a step below sterilization. All these devices are required to have instructions for cleaning that are validated by the FDA, but it is possible that what is validated via tests in a lab under certain circumstances is one thing, and performing the steps in practice is something different. That may also be true for a scope that is brand new versus one that has been used for a year or two, that it acquires persistent contamination that once established can be very difficult to eradicate. In our investigation in Illinois, the scope that was sent to us had been out of use for weeks or months and we were still able to recover bacteria from it.

MM: At the CDC, you’ve been watching the CRE problem build for 15 years. What do these outbreaks mean for that larger epidemic?

AK: It’s important to say that the spread from duodenoscopes is a tiny portion of the CRE problem. But it highlights that the central issue with CRE is person to person spread between people in medical facilities. The people who are at risk, and who get CRE, tend to be people who have complex medical problems and spend a lot of time in hospitals, nursing homes, long-term acute care facilities. In the Illinois investigation, people were infected in the hospital and then were sent out to long-term care and transmitted CRE to their roommates.

MM: Do you see any hope for controlling further spread?

AK: CRE is still rare in most places in the US, but we have not previously been able to identify outbreaks early enough to intervene. There is a movement in the CDC and in some parts of healthcare to change the approach to preventing the transmission of multi-drug resistant organisms by collecting very granular data and sharing it regionally among institutions. I personally think that has a great chance of success.

Maryn McKenna blogs for National Geographic’s the Plate and is writing a book about antibiotic use in agriculture for National Geographic Books.

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A New Antibiotic That Resists Resistance

The British chemist Lesley Orgel had a rule: Evolution is cleverer than you. Antibiotic-resistant bacteria have repeatedly proven him right.

Since humans started making antibiotics for ourselves in the 1940s, bacteria have evolved to counteract our efforts. They are now winning. There are strains of old foes that withstand everything we can throw at them. Meanwhile, our arsenal has dried up. Before 1962, scientists developed more than 20 new classes of antibiotics. Since then, they have made two.

More, hopefully, are coming. A team of scientists led by Kim Lewis from Northeastern University have identified a new antibiotic called teixobactin, which kills some kinds of bacteria by preventing them from building their outer coats. They used it to successfully treat antibiotic-resistant infections in mice. And more importantly, when they tried to deliberately evolve strains of bacteria that resist the drug, they failed. Teixobactin appears resistant to resistance.

Bacteria will eventually develop ways of beating teixobactin—remember Orgel—but the team are optimistic that it will take decades rather than years for this to happen. That buys us time.

Teixobactin isn’t even the most promising part of its own story. That honour falls on the iChip—the tool that the team used to discover the compound. Teixobactin is a fish; the iChip is the rod. Having the rod guarantees that we’ll get more fish—and we desperately need more.

Bacteria have been fighting each other for billions of years before we arrived, so environmental microbes are a rich source of potential new antibiotics. The problem is that 99 percent of them won’t grow in lab conditions. So, why not bring the environment into the lab?

That’s what the iChip does. It’s just a board with several holes in it. The team fill the holes by collecting soil, shaking it in water to release any microbes, heavily diluting the sample, mixing it with liquid agar, and pouring the agar into the iChip. The dilution ensures that each hole, now plugged by a disc of solid agar, contains just one bacterial cell. They then covered the discs in permeable membranes and dunked the whole board into a beaker of the original soil. The microbes are constrained to the agar, but they can still soak up nutrients, growth factors, and everything else they need from their natural environment. And thus, the ungrowable grows. “We have access to things that haven’t been seen before,” says Lewis.

“The method has the potential to be truly transformative, giving us access to a much greater diversity of environmental bacteria than previously imagined,” says Gautam Dantas from Washington University in St Louis.

Among these new microbes, the team found one species that kills staph bacteria efficiently. It belongs to an entirely new genus and is part of a group that’s not known for making antibiotics. They called it Eleftheria terrae. It yielded a compound—teixobactin—that could kill important rogues like the bacteria behind anthrax and tuberculosis, and Clostridium difficile (which causes severe diarrhoea). The team exposed some of these microbes to low levels of teixobactin for several weeks, to see if resistant strains would evolve. None did.

“I thought: Aw, damn it,” says Lewis. “We discovered a detergent.”

Counter-intuitively, if you see a total lack of resistance, it usually means that you’ve discovered a compound so toxic that it’s never going to work in an actual human. Hence: Lewis’s dismay. But when his team applied the drug to mammalian cells, it wasn’t toxic at all. It seemed safe, stable in blood, and capable of protecting mice from lethal doses of MRSA (drug-resistant staph). Things were looking up.

Losee Ling from NovoBiotic Pharmaceuticals and Tanja Schneider at the University of Bonn showed that teixobactin works by withholding two molecules—Lipid II, which bacteria need to make the thick walls around their cells, and Lipid III, which stops their existing walls from breaking down. When teixobactin is around, bacterial walls come crumbling down, and don’t get rebuilt.

The drug also sticks to parts of both Lipid II and Lipid III that are constant across different species of bacteria. It’s likely that these parts can’t be altered without disastrous consequences, making it harder for bacteria to avoid teixobactin’s double-punch. This might explain why it’s so hard to evolve resistance to the drug.

This won’t work on every bacterium. Many of them, like E.coli, Salmonella, and Helicobacter, have another membrane around their cell walls that can deflect teixobactin. So does E.terrae—the microbe that makes the drug in the first place. That’s actually a good thing. Lewis says that many of the resistance mutations that defuse antibiotics originate the microbes that produce those drugs—after all, they must protect themselves. But since E.terrae is impervious to teixobactin, it doesn’t need any such mutations. It has no countermeasure for other bacteria to borrow. “It started looking to us like a fool-proof case of no resistance,” he says.

The existing antibiotic vancomycin also works by sticking to Lipid II, albeit to a different part of the molecule that changes more from one microbe to the next. It took 30 years for bacteria to start resisting vancomycin, and Lewis hopes that teixobactin resistance will take even longer to appear.

We are constantly in need of new antibiotics with novel mechanisms of action, especially ones that can evade known resistance mechanisms,” says Karen Bush from Indiana University. Teixobactin certainly fits that bill, but Bush is sceptical that it is as resistance-proof as it first appears. “Other agents have been studied in similar kinds of resistance selection studies as described in the paper.  Although those drugs had no demonstrable resistance under that set of conditions, more stringent selection procedures resulted in detection of resistant strains,” she says.

Laura Piddock, a microbiologist at the University of Birmingham and leader of Antibiotic Action, adds that other environmental bacteria might harbour countermeasures to teixobactin. “To be sure that resistance to this new antibiotic is unlikely to occur in the clinical setting, bacteria isolated from the same environmental niche should be screened for teixobactin-resistance conferring genes,” she says in an email.

Meanwhile, Lewis’ team are doing more tests with teixobactin in other animals, with a view to eventually getting FDA approval. They’re also trying to tweak the compound and make it more soluble, which would allow them to give people higher doses. And, of course, he will continue to use the iChip to identify even more potential drugs.

Will we ever return to the glory days of antibiotic discovery?

“There’s no doubt in my mind that we’ll do exactly that,” he says.

Reference: Ling, Schneider, Peoples, Spoering, Engels, Conlon, Mueller, Schaberle, Hughes, Epstein, Jones, Lazarides, Steadman, Cohen, Felix, Fetterman, Millett, Nitti, Zullo, Chen & Lewis. 2015. A new antibiotic kills pathogens without detectable resistance. Nature. http://dx.doi.org/10.1038/nature14098

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Bug becomes instantly resistant to insecticide by swallowing the right bacteria

Many insects eventually evolve to resist insecticides. This process typically takes many generations and involves tweaks to the insect’s genes. But there is a quicker route. Japanese scientists have found that a bean bug can become instantly resistant to a common insecticide by swallowing the right bacteria.

The bug forms an alliance with Burkholderia bacteria, and can harbour up to 100 million of these microbes in a special organ in its gut (see arrow above). Some strains of Burkholderia can break down the insecticide fenitrothion, detoxifying it into forms that are harmless to insects. In fields where the chemical is sprayed, these pesticide-breaking bacteria rise in number. And if bugs swallow them, they become immune to the otherwise deadly chemical.

I’ve written about this story for The Scientist, so head over there to read the details of the study.


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Isolated for millions of years, cave bacteria resist modern antibiotics

The caverns of Lechuguilla Cave are some of the strangest on the planet. Its acid-carved passages extend for over 120 miles. They’re filled with a wonderland of straws, balloons, plates, stalactites of rust, and chandeliers of crystal.

Parts of Lechuguilla have been cut off from the surface for four to seven million years, and the life-forms there – mainly bacteria and other microbes – have charted their own evolutionary courses. But Gerry Wright from McMaster University in Canada has found that many of these cave bacteria can resist our antibiotics. They have been living underground for as long as modern humans have existed, but they can fend off our most potent weapons. Drug resistance may be causing problems for us now, but for bacteria, it’s just an ancient solution to an ancient problem.


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Bacteria: resisting antibiotics since at least 30,000 BC

The rise of drug-resistant bacteria is one of the most important threats facing modern medicine. One by one, our arsenal of antibiotics is coming up short against microbes that can pump them out, slip under their notice, deactivate them, or even eat them. But these tricks aren’t new. Bacteria have been defeating antibiotics for millennia, long before Alexander Fleming noticed a piece of mould killing off bacteria in a Petri dish. And the best proof of that longstanding struggle has just emerged from the ice-fields of Alaska.

In 30,000-year-old samples of frozen soil, Vanessa D’Costa and Christine King from McMaster University have found a wide variety of antibiotic-resistant genes. They would have allowed ancient bacteria to shrug off many modern drugs such as tetracyclines, beta-lactams and vancomycin.

Vancomycin resistance is especially interesting. This drug has traditionally been used as weapon of last resort, a drug to use when all others have failed. When vancomycin-resistant bacteria first emerged in 1987, it was a surprising blow. Since then, resistant versions of more common bacteria, such as staph (VRSA) have reared their heads.

These superbugs neutralise vancomycin using a trio of genes known collectively as vanHAX. Together, they alter the protein that’s attacked by the drug, rendering it useless. D’Costa and King found that their ancient sequences include the entire vanHAX cluster. They even resurrected these ancient genes, created proteins from them, and showed that they have the same shape, and do the same thing, as their modern counterparts.

D’Costa and King write that their results disprove the idea that antibiotic resistance is a modern phenomenon. Instead, it’s been part of bacterial life long before the modern use of antibiotics. But I’m really not sure how many people would still hold to that view. First, many antibiotics come from natural sources. Penicillin, the first to be synthesised, famously comes from Fleming’s surreptitious mould. These natural antibiotics evolved to keep bacteria at bay between 40 million and 2 billion years ago, so it’s extremely likely that bacteria have been resisting them for just as long.

Second, we know that the environment is teeming with resistance genes. In her own earlier study, D’Costa found that soil bacteria are a massive reservoir for resistance genes – a “resistome “ – which infectious bacteria could draw upon. Meanwhile, Gautam Dantas found that our soils are so full of resistant bacteria that random sampling produced strains that not only resist antibiotics, but actually eat them. He also found that the bacteria in our guts are another reservoir of resistance.

Regardless, D’Costa and King’s point stands: they have certainly found the oldest known examples of resistance genes. There have been similar claims in the past, but all of them controversial. Bacteria are so omnipresent that any team claiming to have found ancient samples must bend over backwards to prove that these aren’t modern contaminants. And none of the previous groups did this well enough, which means that their claims have not been replicated.

To show that their samples are authentically ancient, D’Costa and King pulled out all the stops. They did all of their lab work in special clean rooms. They showed that their samples included DNA from other animals that lived at the right time, such as mammoths, but nothing from species that are common today, like elk, moose or spruce. They even sprayed their drilling equipment, and the surface of their unearthed ice cores, with glow-in-the-dark bacteria. This way, they could immediately tell if anything from the outside world had leached into the interior parts of the cores – the parts where they drew their samples from. Nothing had.

So what does this mean for the problem of antibiotic resistance today? Is this an old problem that is being blown out of proportion? Can we let the wanton use of antibiotics in modern healthcare and agriculture off the hook? Hardly. These conditions still create intense evolutionary pressures that favour the rise of resistant bacteria. The fact that resistant genes are widespread and ancient does not change that. It simply means that in times of need, beleaguered bacteria have a vast and longstanding range of defences to draw from. For every new sword that we fashion, there is a millennia-old shield lying around, just waiting to be brandished again.

Reference: D’Costa, King, Kalan, Morar, Sung, Schwarz, Froese, Zazul, Calmel, Debruyne, Golding, Poinar & Wright. 2011. Antibiotic resistance is ancient http://dx.doi.org/10.1038/nature10388

More on drug-resistant bacteria

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House mice picked up poison resistance gene by having sex with related species

Since 1948, people have been poisoning unwanted rats and mice with warfarin, a chemical that causes lethal internal bleeding. It’s still used, but to a lesser extent, for rodents have become increasingly resistant to warfarin ever since the 1960s. This is a common theme – humans create a fatal chemical – a pesticide or an antibiotic – and our targets evolve resistance. But this story has a twist. Ying Song from Rice University, Houston, has found that some house mice picked up the gene for warfarin resistance from a different species.

Warfarin works by acting against vitamin K. This vitamin activates a number of genes that create clots in blood, but it itself has to be activated by a protein called VKORC1. Warfarin stops VKORC1 from doing its job, thereby suppressing vitamin K. The clotting process fails, and bleeds continue to bleed.

Rodents can evolve to shrug off warfarin by tweaking their vkorc1 gene, which encodes the protein of the same name. In European house mice, scientists have found at least 10 different genetic changes (mutations) in vkorc1 that change how susceptible they are to warfarin. But only six of these changes were the house mouse’s own innovations. The other four came from a close relative – the Algerian mouse, which is found throughout northern Africa, Spain, Portugal, and southern France.

The two species separated from each other between 1.5 and 3 million years ago. They rarely meet, but when they do, they can breed with one another. The two species have identifiably different versions of vkorc1. But Song found that virtually all Spanish house mice carry a copy of vkorc1 that partially or totally matches the Algerian mouse version. Even in Germany, where the two species don’t mingle, a third of house mice carried copies of vkorc1 that descended from Algerian peers.


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Fighting evolution with evolution – using viruses to target drug-resistant bacteria

We are losing the war against infectious bacteria. They are becoming increasingly resistant to our antibiotics, and we have few new drugs in the pipeline. Worse still, bacteria can transfer genes between each other with great ease, so if one of them evolves to resist an antibiotic, its neighbours can pick up the same ability. But Matti Jalasvuori from the University of Jyvaskyla doesn’t see this microscopic arms-dealing as a problem.  He sees it as a target.

Usually, antibiotic-resistance genes are found on rings of DNA called plasmids, which sit outside a bacterium’s main genome. Bacteria can donate these plasmids to one another, via their version of sex. The plasmids are portable adaptations – by trading them, bacteria can rapidly respond to new threats. But they aren’t without their downsides. Plasmids can sometimes attract viruses.

Bacteriophages (or “phages” for short) are viruses that infect and kill bacteria, and some of them specialise on those that carry plasmids. These bacteria may be able to resist antibiotics, but against the phages, their resistance is futile.