Richard Conniff
Richard Conniff

Fellowship Title:

Pharming Bad Bacteria

Richard Conniff
December 10, 2012

Fellowship Year

In December 2003, a farm couple in the Netherlands scheduled their six-month-old daughter for surgery to correct a congenital heart defect. But before Eveline van den Heuvel could be admitted to the hospital, a test showed that she was carrying a strain of Staphylococcus aureus bacteria resistant to the potent antibiotic methicillin.

Because of an unusually vigilant prevention program, MRSA—methicillin- resistant Staphylococcus aureus—was almost unknown in the Netherlands until then. It came into the country mainly via people who had spent time in foreign hospitals. But Eveline had never left the country. By itself, her colonization by MRSA might have been harmless. (In other countries, an estimated 5-10 percent of people are colonized, but not infected, by MRSA.) The danger, with surgery, was that it might cause a lethal infection of her heart. But leaving her damaged heart valve untreated would also inevitably kill the child.

Her parents, Eric and Ine van den Heuvel began trying to de-colonize their child with a special nasal cream, a mouth wash, and antibacterial soap. Twice, the hospital rejected the child on re-testing. It turned out that both parents and Eveline’s two siblings also carried MRSA. They had inadvertently been re-colonizing her. Meanwhile, within a matter of weeks, the same hospital found two new cases of MRSA, again with no history of foreign hospitalization or other normal risk factors, and all three cases were from a MRSA bacterial strain the hospital could not identify. MRSA also turned up in 20 percent of the members of a farming club to which Eric belonged. Medical detective work soon revealed the single unifying factor: All of the cases were closely tied to pig farms—and more precisely, to pig farms where antibiotics were routinely administered to healthy animals.

Antibiotics, the miracle drugs of modern medicine, have always come with a built-in Catch-22: Using them means that sooner or later you will not be able to use them anymore. They become the victims, over time, of their own effectiveness. When an antibiotic works as intended and knocks down dangerous bacteria, it incidentally makes room for the handful of bacteria that happen to be protected by some quirk in their genetics. These survivors throw a party, proliferate, and eventually become so dominant that the antibiotic simply has no effect. It’s natural selection.

The challenge has always been to delay that point as long as possible, by carefully limiting antibiotic use. But it’s a challenge at which humans have almost universally failed. And, again, effectiveness is part of the problem: Right from the start, antibiotics seemed to have such magical power over so many intractable human diseases, like syphilis and tuberculosis, that doctors and hospitals quickly came to rely on them for almost everything. In 1946, soon after the introduction of penicillin, one surgeon even speculated in print that antibiotics might cure cancer, or make dictators and madmen mellow. Others seriously proposed adding them to canned food, or broadcasting them into the atmosphere to kill all Staphylococcus bacteria.

The idea of feeding antibiotics to farm animals as a way to make them grow faster fit this pattern of giddy excess, and, incredibly, it became the dominant way we have used antibiotics over the past 60 years. In 2009, according to the U.S. Food and Drug Administration, the livestock industry consumed almost 29 million pounds of antibiotics, about 80 percent of all antibiotic use in this country. The strikingly high proportion of antibiotics devoted to livestock production, rather than to human health care, is also typical of much of the rest of the world.

So why don’t we see more cases like Eveline van den Heuvel’s, where resistance seems to come from antibiotic use in livestock? Or why aren’t such cases better known? Everyone has heard about the epidemic of resistant infections in hospitals, and about the community-associated resistance that turns up on sports teams and among nursery school classmates. But researchers have only recently identified what they call livestock-associated resistance, with cases now showing up not just in Europe, but in Canada, Iowa, Minnesota, North Carolina, and Ohio.

The awkward truth is that no one knows how deeply, or how far back, the livestock industry is implicated in the larger epidemic of antibiotic resistance. But it is an increasingly urgent question. Resistant infections—whatever their source–kill an estimated 63,000 Americans and cost the health care system more than $20 billion each year. Moreover, some of the same pharmaceutical companies that sell the antibiotics for use in livestock feed–among them divisions of Pfizer, Merck, Roche, and Eli Lilly– also carefully cultivate a reputation for saving human lives.

Ron Philips of the Animal Health Institute, an industry group, cites a study suggesting that animal use of antibiotics accounts for no more than 3.5 percent of the resistance problem. But that study turns out to be 12 years old, written by a Pfizer consultant, and based on a questionnaire answered by 20 people. On the other side, Australian microbiologist Peter Collignon estimates that use of antibiotics in food animals is to blame for all resistance in Salmonella and Campylobacter infections, and about half in E. coli infections, mainly because these are food-borne pathogens. At the same time, Collignon blames medical misuse of antibiotics for resistance in a long list of other bacterial problems, including the vast majority of MRSA cases.

Regardless of who gets the blame, the numbers pile up alarmingly: Food-borne pathogens sicken 47.8 million people and kill more than 3000 in the United States each year, according to the Centers for Disease Control and Prevention. And just one strain of hospital- and community-associated MRSA, USA300, killed 18,600 Americans in 2005—more than HIV/AIDS.

The lack of adequate information about antibiotic use in livestock means that everyone engages in guesswork about the extent to which it affects how we live and die. Until 2009, the federal government did not require pharmaceutical suppliers to report how much antibiotics they sold for use in food animals, and it still doesn’t know where those antibiotics are being used, or for what purpose.

The food industry argues that it bears little blame for the resistance problem, for what can seem, at first glance, like logical reasons: Only about half the antibiotics used on farms are medically important to humans. And farms–unlike hospitals–are several steps removed from the general human population. Using antibiotics as a way to make livestock grow faster, or to prevent disease in healthy animals, also requires relatively small doses—typically 1/10 to 1/100 of a standard therapeutic dose. The Animal Health Institute argues that consumers actually benefit, and not just at the cash register: “Animal antibiotics make our food supply safer and people healthier.”

Even so, the science increasingly suggests that livestock-associated resistance has routinely spilled over into the human population, in ways we are only beginning to recognize. A 2011 paper by Tufts University microbiologists Bonnie M. Marshall and Stuart B. Levy cited more than a dozen studies over the past 30 years where resistant bacterial strains in farm animals and in humans shared striking genetic similarities. But the evidence that the animal resistance was actually causing the human resistance was always “circumstantial and largely implied,” according to Marshall and Levy. Industry could argue that the humans were contaminating the animals, and until recently, no one had the molecular tools to identify the culprit beyond a reasonable doubt.

Then a study published early this year in the online journal mBio delivered what may be the smoking gun. It used whole genome sequencing to trace the recent history of an unusual variety of MRSA called ST398—the same bacterial strain that had turned up in the Dutch pig-farming family of young Eveline van den Heuvel.

For the study, microbiologist Lance Price and his co-authors took nasal swabs of the bacteria in 89 humans and animals in 19 countries. Sequencing the whole genome for each sample required spelling out millions of molecules of DNA in detail. It’s an automated process that would have cost $500,000 per genome a few years ago, but the cost is now down below $300. The researchers then compared gene sequences from multiple samples to spot where differences first entered the genome. They used these differences to plot a kind of evolutionary tree for ST398.

“The big surprise, completely contrary to our hypothesis,” says Price, was that ST398 had started out in humans. “We went in thinking it was a pig strain. But the data painted a very clear picture.” At some point recently, perhaps within the past 20 years, ST398 had been jumping from people to pigs and adapted to live in its new host species. Later, the modified pig version jumped back to humans via farm families like the van den Heuvels.

But a significant change had taken place along the way. The original human strain of ST398 had been susceptible to the antibiotic methicillin, says Price. By the time it spread back to humans, though, exposure to the antibiotics used in pig-farming caused it to become methicillin-resistant. (Methicillin matters so much because it’s a critical second line of defense, specifically designed to foil the weapon that resistant bacteria use to resist traditional penicillin.) The researchers were able to pinpoint the genetic sequence that conveyed resistance, and they confirmed this finding by testing samples in the lab to see if they were susceptible or resistant to methicillin.

The ease with which pathogens can pass back and forth between humans and animals was startling. “We really thought the species boundaries, especially for Staphylococcus aureus, were stronger than they are,” says Price, a researcher at the Translational Genomics Research Institute in Flagstaff, Arizona. “We didn’t know that there could be a bi-directional zoonosis, passed back and forth between humans and animals.” Analyzing this two-way traffic, and identifying where resistance problems begin, will become far easier, says Price, as the cost of whole genome analysis drops below $50 in the next two years. “We’re extending our investigations and we’re seeing other strains that have taken the same trip and, again, who knows how often this has happened in the past?”

The distance from the farm to the dinner table turns out to be much shorter than we like to imagine. In 2011, Price and other researchers purchased 136 packages of beef, pork, chicken, and turkey from retail shops around the country, and found that almost half were contaminated with Staphyloccus aureusbacteria—a potential source of diseases, including skin infections, pneumonia, and endocarditis. The majority of them were resistant to at least three, and as many as nine, antibiotics. A 2010 study in Quebec was even more alarming. It found that, when the poultry industry there voluntarily withdrew a cephalosporin-type antibiotic made by Pfizer, levels of resistant Salmonella and E. coli on supermarket chicken fell. So did incidence of resistant Salmonella infections in humans. Then the industry re-introduced the antibiotic, and resistant bacteria reappeared in both meat products and human consumers.

Proper cooking would of course kill these bacteria, says James R. Johnson, M.D., an infectious disease specialist at the Veterans Administration Medical Center in Minneapolis. But consumers still face a risk from cross-contamination as they handle the raw meat in the kitchen and even at the supermarket. In one recent study, children had an increased risk of picking up Salmonella and Campylobacter bacteria just from riding in a supermarket cart with meat products nearby.

That kind of exposure is likely to lead to temporary contamination, rather than to the sort of colonization Eveline van den Heuvel experienced, says Johnson. Different bugs generally prefer different hosts. So even though “there’s a blizzard of them coming in, most don’t make it in humans. They pass right through.” But even in transit, they may pose a long-term threat because bacteria are highly promiscuous about swapping genes.

Spreading a trait through a population the traditional way, one generation to the next—scientists call it “vertical gene transfer”–takes time, even for bacteria. But bacteria are also adept at “horizontal gene transfer,” meaning that they can transfer antibiotic resistance right now to the bacteria all around them, even to entirely separate species and genera, including other human pathogens. This kind of gene transfer is now considered the primary reason antibiotic resistance has been able to spread so quickly. It also means pathogens can become resistant even to bacteria to which they have never been exposed.

The problem is more complicated with E. coli bacteria, says Johnson, because they don’t just pass through. The same strains inhabit the intestines of humans, companion animals, and livestock alike, and the species routinely swap them back and forth. It usually doesn’t matter much, so long as they stay in the gut, he says. But they don’t, and there has been a frightening increase in the resistant infections that occur when E. coli gets into the urinary tract, the blood, and even the brain. Such patients now often go days or even weeks before doctors can find an antibiotic that still works. According to a 2003 study, these E. coli infections are responsible for the deaths of 40,000 people each year in this country, and more than 800,000 people worldwide.

And yet when a team led by Johnson undertook its own two-year supermarket shopping study, they found resistant E. coli on almost every chicken product, and to a lesser extent on beef and pork. Genetic analysis showed “extensive similarities,” says Johnson, between the resistance genes in the E. coli on food and those in human patients suffering resistant E. coli infections. Moreover, the drugs to which the E. coli were resistant fit the pattern of antibiotics fed to livestock.

All of this, the livestock industry argues, is just correlation, not causation. And even Johnson acknowledged in an email that patients who die “tend to be older, sicker, more debilitated, more health care-dependent, and more antibiotic-exposed, all of which predispose to having a resistant strain.” Life is complicated like that, and it means that proof of causation is elusive. “It’s going to be quite difficult to slam-dunk prove that any of these resistance genes emerged because there was antibiotic usage in a food animal,” says Charles Hofacre, a researcher and poultry industry consultant at the University of Georgia.

But at a certain point, slam-dunk proof may be irrelevant, especially to consumers who do not like to think the food on their plate can kill them. That idea no longer seems so far-fetched. In a recent Consumer Reports survey, 61 percent of shoppers said they would pay a nickel a pound more for antibiotic-free meat. Retail food suppliers, from Hyatt Hotels to Chipotle Mexican Grill, already have responded to this demand with policies to phase out or eliminate antibiotics in their products.

Slam-dunk proof may also be irrelevant to companies like Pfizer, Merck, Roche, and Eli Lilly, where reputation and good will are not just nice words, but accounting concepts with billion-dollar implications. Shifting public attitudes may be one reason Pfizer is currently spinning off its animal health unit and giving it a new name, Zoetis. Likewise, Eli Lilly’s animal health division now offers an alternative to antibiotics in livestock feed, through its 2012 acquisition of a company that uses natural enzymes to improve growth.

Drug companies also face greater regulation of agricultural markets by the U.S. Food and Drug Administration, which has endured bitter criticism for its lax handling of the issue. It recently proposed requiring a prescription from a veterinarian for use of antibiotics in feed, and it would force drug companies to take feed additives through a more demanding labeling process. Part of the plan is to eliminate the “production” or “growth promotion” category of antibiotic use. (Gain Hansen, a veterinarian who now works on the issue at the Pew Charitable Trusts, warns that this will not necessarily mean any real reduction. Drug companies understand “that there are other ways to get antibiotics into animals without calling it growth promoting.”)

Disclosure requirements will probably also increase. Under the Animal Drug User Fee Act (ADUFA), which comes up for renewal in 2013, drug companies now report the antibiotics they sell to agricultural customers, but only broken down by national totals in four broad categories. From the drug companies, the antibiotics typically go to feed mills, which do not report how they mix the antibiotics into their products.

That loophole, says Tyler Smith, a researcher at the Johns Hopkins Center for a Livable Future, means an FDA epidemiologist trying to figure out why resistance is killing more people in a particular area has to visit the feed mills in person to inspect the physical records. But there are hundreds of feed mills, and the records do not reveal where the feed—and the antibiotics–actually end up. While the FDA’s proposals would make it easier to track antibiotic use, says Smith, they do not come close to disclosure requirements in Europe. Germany, for instance, now collects data on animal use of antibiotics down to the zip code level, enabling researchers to correlate usage patterns with changes in antibiotic resistance. Denmark has instituted a “yellow card” system to flag excessive antibiotic use by individual farms and veterinarians, requiring them to prepare a plan to decrease use.

One other reason that slam-dunk proof may not ultimately matter is that the farmers and livestock industry workers who actually raise and slaughter the animals are beginning to realize that they may be front-line victims of the resistance crisis. A new study led by epidemiologist Tara Smith at the University of Iowa (and funded by the National Pork Board) looked at pig farms in five states and found MRSA in 20.9 percent of workers. Michael Male, a co-author and veterinarian to Iowa pig farms, cautions that this may be another case of temporary contamination, not colonization. But he adds, “It raises everybody’s eyebrows.”

The MRSA strain found in those farm workers was ST398. It’s not a particularly virulent strain, so far. But in the Netherlands, where it was first recognized as a human medical issue, it has moved off the farm and now accounts for 40 percent of all MRSA cases.

On the pig farm where ST398 started, Eric van den Heuvel has responded by abandoning antibiotics. So have many of his neighbors. It means taking greater care of the animals and practicing what he calls “internal biosecurity“: He keeps different age classes separate, and completely cleans a compartment when all the animals move out, so germs don’t pass from one age group to the next. Rather than simply administering medicines to a whole group, the standard practice, he treats sick animals individually. He also sprays probiotics throughout the farm three times a week, on the theory that beneficial bacteria will crowd out their dangerous counterparts. So far, he says, it is working. Mortality is down, and so are his costs. Antibiotics used to make up about three percent of his budget, and without them, he has also found he no longer needs to spend as much on antiseptics and vaccines.

Abandoning antibiotics on the farm has also worked at home, he says. Back in 2003, Eveline was finally able to get her heart surgery after a powerful dose of antibiotics helped knock down the MRSA. She is now a healthy and entirely normal 11-year-old, and the entire van den Heuvel family now is free of MRSA.

Richard Conniff
Richard Conniff