One evening in June 2011, at their home in a suburb of Portland, Ore., Melissa Lee and her husband sat down to a dinner of spaghetti and meatballs with their 10-month-old daughter. It was one of the first times Ruby Lee ever tasted meat. What followed, over the next few days, was a new parent’s nightmare of fever, diarrhea, listlessness, and doctors—culminating in an urgent phone call about blood test results: “Get Ruby to the hospital now.”
Ruby’s bloodstream was infected with a virulent bacterial strain, Salmonella Heidelberg, from the ground turkey she had eaten. She was one of 136 victims in that outbreak and among the 47.8 million cases, including 3,037 deaths, of food-borne illnesses in the United States that year. Medical detective work and DNA fingerprinting soon traced the outbreak back to Cargill, the privately owned agribusiness giant based in the Midwest, which had to recall more than 35 million pounds of ground turkey.
Ruby spent seven days in the hospital on an intravenous drip line. (The needle had to be moved from hand to foot to arm because her tiny body kept rejecting it.) Then she spent four days at home with an antibiotic line threaded into her heart. “The bacteria strain that she got, we didn’t find out till later, was antibiotic resistant,” Melissa Lee recalled not long ago. “So the fact that the antibiotic they gave her actually worked was a minor miracle.” Four other commonly prescribed antibiotics would have failed. “It was sheer luck that they gave her the right one.”
The problem for Ruby Lee and 2 million others in the U.S. who contract antibiotic-resistant infections every year is this: When antibiotics knock out unwanted bacteria, they make room for other bacteria, which are by some quirk in their genetics protected from the effect of the antibiotic. These survivors proliferate and eventually become so dominant that the drug simply has no effect on the patient. It’s natural selection, and the more antibiotics are in use, the faster it happens. The result is that important antibiotics no longer work against staph infections, urinary tract infections, gonorrhea, tuberculosis, and a growing list of other diseases. We thought we had conquered these ancient killers at the beginning of the antibiotic era (which started on D-Day, 70 years ago today), but our old enemies are back.
So after a lifetime in which a doctor could usually wipe away almost any infection simply by applying pen to prescription pad, we now stand at the brink of “a post-antibiotic era.” That’s according to an April 2014 report from the World Health Organization, and it could mean “an end to modern medicine as we know it,” Dr. Margaret Chan, director-general of WHO, recently warned. “Things as common as strep throat or a child’s scratched knee could once again kill.” In Britain, the top health official has said that antibiotic resistance threatens to become an “apocalyptic scenario,” with effects comparable to those of a catastrophic terrorist attack.
We know some of the culprits. The astonishing power of antibiotics to conquer disease made people so giddy at first that they proposed adding the drugs to canned foods, or even spraying them into the atmosphere at hospitals. Patients demanded antibiotics even when they weren’t necessarily appropriate, for a baby with an ear infection or a viral sickness. But doctors and hospitals began to see the results of misusing antibiotics almost immediately, in the form of resistant illnesses. With many old antibiotics no longer effective and no new ones coming onto the market to replace them, the medical community is now curtailing misuse of antibiotics to keep the last few lifesaving drugs effective for at least a few more years.
One large area of antibiotic misuse has hardly changed at all, however, partly because until recently no one knew just how astonishingly large it is: The single largest consumer of antibiotics worldwide since shortly after World War II isn’t the medical community at all; it’s the meat industry. The antibiotic era had just begun when researchers accidentally discovered that the addition to feed of low, or subtherapeutic, doses of antibiotics made livestock grow faster, possibly by suppressing bacteria in the gut.
From the start, researchers knew that chronic exposure to antibiotics would inevitably cause bacteria to become resistant. But the meat industry has argued that this resistance remains confined to animals and does not spill over to affect human health; the most it seems it will concede is Cargill’s statement on its website that “it is an ongoing debate about whether animal antibiotic use can adversely affect human health.” Proponents of continued livestock use also point out that antibiotics have made it possible to keep animals healthy in large-scale production facilities—enabling industry to provide cheap meat in abundance for American dinner tables. Routine use of antibiotics, and the resulting lower cost of meat, has been a significant factor in the doubling of meat consumption in this country, from just over 90 pounds per person in 1940 to 184 in the peak year of 2004. (Incidence of heart disease, stroke, type 2 diabetes, obesity, and certain cancers has spiked over the same period; medical science links all of these conditions to excessive meat consumption, which has put enormous pressure on the health care system entirely apart from the effects of antibiotic resistance itself.)
But scientific evidence about the public health risks of antibiotic use in meat production is becoming increasingly precise. That now pits much of the health care community and a broad coalition of political, social, and retail organizations against the giants that dominate the meat business—among them Cargill, Tyson Foods, ConAgra, Perdue Farms, Smithfield Foods (acquired by the Chinese firm Shuanghui International in fall 2013), and JBS S.A. (the Brazilian firm that acquired Swift + Company in 2007). Those companies account for the lion’s share of the 90-billion-plus pounds of red meat and poultry produced in the U.S. each year. Executives at these companies sometimes acknowledge the need to move away from some antibiotic uses, if only because of changing consumer attitudes on the issue. But antibiotics have made it possible to grow more animals faster and in more crowded conditions—the central premise of the highly concentrated modern livestock industry—so the prospect of reducing their use has little appeal. Moreover, demands for changes that could eat into the meat industry’s bottom line come as it faces sharply increased feed costs and annual meat consumption that’s down 18 pounds per capita since 2004. (Accounting varies, but meat producers still manage to rake in well over $100 billion a year.)
The companies that supply the antibiotics—Zoetis (which spun off from Pfizer), Eli Lilly’s Elanco, and Phibro Animal Health are some of the biggest suppliers—also have little incentive to change. Selling drugs for use in livestock and companion animals has been one of the industry’s few bright spots, according to pharmaceutical analyst Steve Scala at Cowen and Company. It’s been a stable source of growth at a time when the human side of the business looks flat, with drugs becoming more expensive and difficult to develop.
But the antibiotics controversy could become a drag on that market, because cases like Ruby Lee’s are becoming disturbingly more common. Infections that resist antibiotic treatment now kill at least 23,000 Americans every year and cost the economy as much as $35 billion annually in added health care and lost productivity. Though doctors, hospitals, and patients who over- and misuse antibiotics bear some of the blame, new studies are for the first time implicating livestock antibiotics, too, and that has increased the demand for limits.
Britain's top health official has warned that antibiotic resistance threatens to become an “apocalyptic scenario,” with effects comparable to those of a catastrophic terrorist attack.
Until recently, antibiotic use in food animals has been largely hidden from public view. It started in 1949, when the drug company Lederle Laboratories (which would become part of Pfizer) introduced antibiotics for routine use in food animals. A company scientist later admitted that Lederle described the new product at first merely as a source of vitamin B12, rather than as an antibiotic, “to avoid any registration problems.” It was another year before the Food and Drug Administration found out that American food animals were being fed antibiotics on a routine basis, and the FDA did not learn for another 60 years exactly what a whopping dose of antibiotics our food animals were consuming. But a law passed in 2008 required drug companies to report their agricultural sales more fully, and in 2010, the FDA shocked the world when it announced that 28.7 million pounds of antibiotics—80 percent of all use in this country—were being devoted to livestock production rather than to human health care.
Even now, drug industry executives almost never talk directly about this hefty business of selling antibiotics to livestock producers. Several of the biggest makers of antibiotics for livestock declined multiple requests for interviews with executives involved in that part of company business. Zoetis emailed its policy statement on the issue. An Elanco spokesperson acknowledged that antibiotic resistance is a problem in both human and animal medicine, but not that livestock antibiotics have been a factor in the developing crisis. He said the company would comply with measures being developed by FDA “to narrow the use” of antibiotics in food animals.
Hence, when journalists phone to talk about livestock antibiotics, pharmaceutical companies generally send them on to Ron Phillips, who works two blocks from the White House in Washington, D.C. He’s a vice president for legislative and public affairs—that is, a lobbyist—for the Animal Health Institute, an association of animal drug manufacturers. In an interview, Phillips argued that the industry is innocent of the charge of causing the resistance epidemic for what can seem like logical reasons: Only about half the antibiotics used on farms are medically important to humans, and the connection to human health care is a lot less clear than when doctors put antibiotics directly into human patients. Antibiotics also get added to feed in relatively small doses—a fraction of a standard therapeutic dose. “Animal antibiotics make our food supply safer and people healthier,” the Animal Health Institute declares on its website. Phillips cited 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 more than a decade old, based on a questionnaire answered by 20 people, and written by a consultant to Pfizer. That’s how it often goes with the science in support of antibiotic use in food animals. When proponents cite “more than 12,000 studies” backing its safety and effectiveness, they are generally referring to studies sponsored by the same drug companies that are selling the antibiotics. These studies mostly took place in the 1950s and seldom lasted more than a few weeks.
More recent studies indicate that it is routine for resistance to spill over from food animals to people, in ways we are only beginning to recognize. When the poultry industry in Quebec voluntarily (and temporarily) stopped using a cephalosporin-type antibiotic marketed by Pfizer Canada a few years ago, government researchers noticed that levels of resistant Salmonella and E. coli on supermarket chicken soon dropped. So did resistant Salmonella infections in humans. When the industry reintroduced the antibiotic, resistant bacteria reappeared in both meat products and human consumers. A Pfizer spokesperson commented that injecting the drug into chicken eggs before they have hatched, as the poultry companies had been doing, is an off-label use, and Pfizer does not sell for off-label uses. (This is a measured response considering that Pfizer in the first decade of the 2000s settled four separate cases involving criminal and civil charges, including once paying a fine of $2.3 billion for marketing human drugs for off-label use. And it’s estimated that 20 to 30 percent of drugs are prescribed off-label.) An author of the study countered that Pfizer sold the companies the vaccination machines used to administer the drug.
In another recent study, researchers shopping at supermarkets over a two-year period found resistant E. coli on almost every chicken product and to a lesser extent on beef and pork. Genetic analysis showed “extensive similarities” between the resistance genes in the E. coli on food and those in human patients suffering resistant E. coli infections, said James R. Johnson, M.D., a professor of medicine at the University of Minnesota and an infectious disease specialist at the Veterans Administration Health Care System in Minneapolis. Moreover, the drugs to which the E. coli were resistant were the same antibiotics that were being fed to livestock.
Proper cooking would of course kill these bacteria, but consumers still face a risk as they handle the raw meat in the kitchen. Children can pick up Salmonella and Campylobacter bacteria, Johnson said, just from riding in a supermarket cart with meat products nearby. In most cases, that kind of contamination is temporary: Different bugs prefer different hosts, and they pass through with no apparent ill effects.
E. coli is different. The same strains inhabit the intestines of humans and animals alike, and the species routinely swap them back and forth. It usually doesn’t matter much, so long as they stay in the gut. But they don’t, said Johnson, and there has been a frightening increase in the resistant infections that occur when E. coli gets in the urinary tract, the blood, and even the brain. Patients may go days or even weeks before doctors can find an antibiotic that still works. One result is that a seemingly routine urinary tract infection can now sometimes kill. Worldwide, an estimated 800,000 people die each year from extra-intestinal infections of all kinds caused by strains of E. coli. Even vegetarians are at risk: Over the past few years E. coli outbreaks have occurred in sprouts, packaged salads, spinach, and cookie dough.
For those who defend agricultural use of antibiotics, such studies add up to correlation, not causation. If the same resistance genes turn up in humans and food animals, said Charles Hofacre, a professor at the University of Georgia, that may just mean that overmedicated humans are infecting the food animals, rather than the other way around.
Johnson acknowledged 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 causation is elusive, much as it was when public health officials were trying to demonstrate the link between tobacco and cancer.
“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,” said Hofacre.
But while we argue about proof, said Tyler Smith, a researcher at The Johns Hopkins Center for a Livable Future, “we are squandering a medical miracle on the basis of very limited evidence that it is necessary to produce animals.” Denmark and Sweden have already sharply restricted the use of antibiotics in food animals, he noted, without “long-term negative effects on industry.”
The lack of Hofacre’s “slam-dunk” proof, combined with pressure on Congress from agricultural interests, has led the FDA to take an uncharacteristically light-handed approach to livestock antibiotics over the years, an approach that has earned it some scathing criticism. “For over thirty years,” a federal judge declared in a 2012 ruling, the FDA “has been confronted with evidence of the human health risks associated with the widespread subtherapeutic use of antibiotics in food-producing animals and…has done shockingly little to address these risks.” A court also ordered the FDA to act on its own 1977 finding that use of tetracycline and penicillin in livestock feed contributes to drug-resistant bacteria strains and should only be used for therapeutic purposes, and demanded that the FDA belatedly determine whether five other antibiotic classes are safe to use in food animals.
In contradictory fashion, the FDA is appealing that order while, it says, it is pressuring drug manufacturers and meat producers to use antibiotics more judiciously. Under current rules, for instance, a farmer can walk into an agricultural supply store, buy a bottle of veterinary penicillin off the shelf, and treat his own animals with the drugs. Instead, the FDA proposes for the first time to require a prescription from a veterinarian for use of antibiotics in food animals. Over the next three years, livestock producers would also phase out the use of antibiotics merely to promote growth, one of the four uses (or “labels”) allowed under current FDA rules.
Things as common as strep throat or a child’s scratched knee could once again kill.
Dr. Margaret Chan, director-general of the World Health Organization
But that would be voluntary, and getting rid of the growth-promotion label might not reduce antibiotic use. Drug companies understand “that there are other ways to get antibiotics into animals without calling it growth promoting,” said Gail Hansen, a veterinarian and senior officer, human health & industrial farming, at The Pew Charitable Trusts. One veterinarian who defended current practice even argued that routine feeding of subtherapeutic antibiotics could increase under the new rules, merely re-labeled as “prevention.” To further complicate the issue, the same federal judge who reprimanded the FDA in 2012 has described its voluntary approach as “contrary to the statutory language,” adding that the agency has “forsaken” its obligation to ensure the safety and effectiveness of drugs.
Opacity about agricultural use of antibiotics also continues to handicap the agency, according to Tyler Smith at Johns Hopkins. The FDA can readily track human antibiotic use and draw detailed maps correlating it with local patterns of antibiotic resistance. But under current rules, it has no idea where agricultural antibiotics go after leaving the drug companies for the feed mills. The feed mills are required to record, but not report, how they mix the antibiotics into their products. That loophole, said Smith, means that an FDA epidemiologist trying to figure out why resistant infections are hospitalizing more people in a particular area has to visit the mills to inspect the physical records. But there are hundreds of them.
European governments, meanwhile, have responded to the resistance crisis with aggressive disclosure requirements. Germany now collects data on both human and animal use of antibiotics down to the postal code level, making it easier for 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.
William T. Flynn, a deputy director for science policy at the FDA’s Center for Veterinary Medicine, thinks it’s doubtful anything that rigorous “would even be workable” here, he said, given the scale and complexity of U.S. agriculture. Instead, the FDA has sought public comment on options for improved disclosure. Some of those comments will be included in the agency’s next summary report on the issue, said Flynn, and may help the agency evaluate whether its voluntary strategy for reducing use of antibiotics on livestock is working. Industry has rejected reporting requirements as too cumbersome and costly. But secrecy may lose its appeal as farmers and the livestock industry begin to confront their own potential vulnerability on the front lines of the resistance crisis.
Changing the debate in startling ways is rapidly expanding research on the microbiome. Advances in DNA technology now allow researchers to study the microbes living within our bodies and in our domesticated animals in unprecedented detail—and that promises news both good and bad for the meat industry.
The harbinger of this change was a bacterial strain that first came to the attention of public health officials in 2003, after Eric and Ine van den Heuvel, a farm couple in the Netherlands, scheduled their six-month-old daughter for surgery to correct a congenital heart defect. Before Eveline could be admitted to the hospital, a test showed that she was carrying an unknown strain of Staphylococcus aureus bacteria resistant to the potent antibiotic methicillin. Researchers dubbed it MRSA ST398 (for “methicillin-resistant Staphylococcus aureus strain 398”). Investigators soon turned up other cases in Eveline’s family and in the surrounding community. This was a big deal: Methicillin was developed to treat bacteria resistant to most penicillins, and was one of the best drugs available for treating staph infections, which anyone can get from activities as routine as changing a diaper.
There has been a frightening increase in the resistant infections that occur when E. coli escapes the gut; it can take doctors weeks to find an antibiotic that still works.
All of the cases were closely tied to pig farms like that of the van den Heuvels, where antibiotics were routinely administered to healthy animals. Researchers went to work gathering samples of ST398 from humans and livestock in 19 countries. To investigate the strain in detail, they turned to whole genome sequencing, a powerful tool that now costs as little as $300 to analyze an organism’s complete DNA (down from $500,000 just a few years ago). This technology makes it possible to trace the recent evolutionary history, or phylogeny, of a bacterial strain and determine when and where a particular trait entered the genome.
“We went in thinking it was a pig strain,” said the principal investigator, Lance Price, professor at George Washington University and a leader in the field of genomic epidemiology. Instead, ST398 turned out to be a case of the humans contaminating the animals—but with a troubling wrinkle: The antibiotic methicillin worked just fine to control the original human strain of ST398. But after it jumped species, living in pigs forced it to adapt. By the time it jumped back to humans, exposure to the antibiotics used in pig farming encouraged the growth of a mutant strain with a resistance gene, rendering methicillin powerless. (It took months—and abandoning the use of agricultural antibiotics—but the van den Heuvels were able to purge Eveline of the strain and get her the heart surgery needed to save her life.)
A few years ago a small pilot study in this country found ST398 in 20.5 percent of pig farm workers. Michael Male, coauthor and veterinarian to Iowa pig farms, cautioned that this may just be a case of temporary contamination, not colonization or infection. ST398 is also a relatively innocuous strain of MRSA, at least so far. But he added, “It raises everybody’s eyebrows.”
It may also raise eyebrows among liability lawyers. Up to now, the cost of antibiotic resistance has fallen on society at large, not on hospitals or companies that misuse antibiotics. But over the next few years, whole genome sequencing could turn that around so the costs are borne by the individual company whose practices created the antibiotic resistant strain or promoted its spread.
Because of the ability of the new technology to do detailed detective work, said Rob Knight, a microbiome researcher at the University of Colorado, it won’t be like the fight over tobacco, in which it took decades to make the statistical connection to cancer convincing. “If you have the complete genome and the phylogeny that points you right back to one geographically isolated source that’s on one particular company’s feedlot, that’s going to be really hard to argue against,” Knight said. “And it’s easy to explain in the courtroom: Here’s the genome, and here’s how it matches up with this genome that we found on this company’s feedlot, and here’s 100,000 genomes from all over the country that don’t match.” In short: “slam-dunk” proof (provided that database of 100,000 genomes gets built).
Antibiotic resistance has figured in liability lawsuits only if it has complicated a client’s treatment, said Seattle attorney William Marler, who specializes in food poisoning cases. (He represented Ruby Lee, for instance, after conventional DNA fingerprinting tied her Salmonella strain directly to ground turkey from Cargill.) But resistance could play a bigger part in future lawsuits. “The one thing that genetic fingerprinting has done, and whole genome sequencing will do,” said Marler, “is, it narrows and solidifies what’s a case and what’s not a case.”
The other factor that may end or limit the practice of routine feeding of antibiotics to livestock is the market. Consumer Reports found in a survey last year that 61 percent of shoppers said “antibiotic-free” meat was worth an extra nickel a pound to them—and 37 percent said they’d pay up to a $1 a pound more. Restaurants from Panera Bread to Chipotle Mexican Grill have already anticipated this demand by enacting policies to reduce, phase out, or eliminate sourcing from suppliers that use antibiotics, as have supermarket chains such as Wegmans (stung in 2012 by an E. coli outbreak from a salad mix) and Whole Foods Market.
And some livestock producers are waking up to the idea that just getting rid of the “growth promotion” label may not be enough. “In the past, the big companies were less willing to have an honest, serious conversation about cutting back on antibiotics, and I am seeing that change,” said Helene York of Bon Appétit Management Co., which runs 500 cafés and restaurants for college campuses and corporations, including Google and Starbucks.
Bon Appétit decided back in 2003 that its poultry suppliers should not be routinely administering antibiotics, and in 2007 that its ground beef should be from animals that have never been given antibiotics, period. At first it struggled to find suppliers, said York. But the big meat-producing companies that once gave the company the polite brush-off now “know that how they are going to grow has to be more responsible than how they got to where they are.”
So far the rising concern about antibiotic resistance has been good news mainly for companies like Niman Ranch and Coleman Natural Foods (owned by Perdue) and independent farmers like Russ Kremer in Missouri. They’re making a market for premium-priced meat in those people in the Consumer Reports poll.
Kremer started out in the 1970s attending farming social events sponsored by drug companies, and he believed what they said about the magic of subtherapeutic antibiotics. But his own bout with a resistant infection, and a fear that he was helping to create “monster bugs” on his farm (which is, no kidding, in the unincorporated community of Frankenstein), caused a change of heart. The first year after “kicking the drug habit,” he recalls today, he saved $16,000 on drugs and veterinary fees, and his pigs were healthier to boot. Kremer now helps other farmers switch to the “sustainable value-added market.” They use probiotics—microorganisms thought to be beneficial—to keep their animals healthy and boost growth rates. Oregano oil is a standard ingredient. So are derivatives from colostrum—a form of milk produced just after childbirth—to help stimulate immune function.
It may sound like something out of the food co-op fringe, but this is where research into the microbiome promises to deliver good news even for the largest meat companies and perhaps also for their customers. Until recently, producers have been largely in the dark about the microbes that live in and around their livestock. They’ve never really known, for instance, exactly what it is that antibiotics do that makes animals grow faster. But microbiome research makes it possible to understand the microbes involved at every stage in an animal’s life—and also tweak them. That’s putting the big livestock companies, and the drug companies that supply them, on a new path.
I think we’re on the path to abandon antibiotics, and we’re going to get there sooner rather than later.
Mike Robach, vice president of food safety, Cargill
In response to the shifting marketplace, Eli Lilly’s animal health division, Elanco, is currently expanding its line of growth-promoting natural enzymes as an alternative to antibiotics in livestock feed. Likewise, probiotics are now a hot topic at Perdue Foods: “I would’ve said, 10 years ago when we were looking at it, that probiotics didn’t prove out any of the claims. Today they are much more refined,” said Bruce Stewart-Brown, senior vice president of food safety and quality for Perdue. “We’re still learning about these products and how they work in different kinds of chicken. But, oh, yeah, we use ’em.”
At Cargill, source of the meat that poisoned Ruby Lee with antibiotic-resistant Salmonella, researchers have been experimenting with competitive exclusion, a technique for getting chicks started by inoculating them with “good” intestinal bacteria so there’s no room for “bad” bacteria to take hold. “The turkey recall of 2011 got us thinking again,” said Mike Robach, vice president of food safety. “This popped out at us.” Early in 2012, company researchers treated half the turkey chicks in a test population with competitive exclusion. The other half served as a control, receiving no special treatment. Next day, researchers fed both groups a meal deliberately loaded with Salmonella. A week later, the treated birds had only a 10th as much Salmonella as the controls. If the technique wins FDA approval, said Robach, “it would allow us to continue to reduce the use of antibiotics in these animals.”
Would his company ever abandon subtherapeutic antibiotics completely? Robach would not put a timeline on it. But he didn’t flat-out dismiss the idea either. “I think we’re on that path,” he said, “and we’re going to get there sooner rather than later.”
The question is whether the industry will shake its antibiotics addiction before Chan’s nightmare scenario of “an end to modern medicine as we know it” comes true.
Either way, consumers may continue the trend toward giving up on mass-produced meat altogether. Ruby Lee is now a normal, healthy three-year-old—and a meat lover. Melissa Lee and her husband haven’t become Portlandia-style foodies. They aren’t health nuts. But the experience of seeing their child so deathly ill and a victim of antibiotic resistance has led them to avoid meat raised on a steady diet of antibiotics. “We’re just very careful what we give her, how we cook it, what it comes in contact with, everything,” she said.
They have plenty of company. In a survey by a marketing firm for the meat industry, 41 percent of consumers expressed concern about antibiotic use—and 23 percent said they were switching to naturally raised products, or not buying red meat at all. A spokesperson for the survey company said it was all a misunderstanding, and that consumers simply need to be educated.