To win the battle against antibiotic-resistant bacteria, Ellen Silbergeld believes that we first must determine its source.

by Melissa Hendricks
photos by Thomas Arledge

This is a world that never sleeps.

In a long, low-slung building on a Maryland poultry farm, the lights are always on so the birds will eat around the clock. For as far as the eye can see, a field of white undulates over the ground like waves. Thousands of chickens are pecking, rambling, and squawking in a discordant clamor that is overridden every few minutes by the loud whirring of an industrial fan. A fine, powdery dust fills the air, and an acrid odor — of ammonia and manure — clings to the nostrils and coats the back of the throat.

With the endless eating beneath the fluorescent lights, the chickens reach their optimum five-pound broiler weight when they are about seven weeks old. When that happens, the poultry company will bus in a crew of seven or eight chicken catchers. The men will spend the day grabbing chickens by their feet, and stuffing them into plastic crates for the trip to the processing plant. Bare hands make catching easier, and many chicken catchers have the scars to bear testament. They do not wear masks to block out the dust and stench, and they do not wash up before taking a lunch break — there is no place to. It is a dirty job, and some of the farmers and poultry workers who spend their days in houses like this say they have frequent health problems — bouts of diarrhea, chronic respiratory problems. But no one has linked their work environment to their health problems.

That is where Ellen Silbergeld comes in. A professor of Environmental Health Sciences at the School, Silbergeld stands outside the chicken house, against a wall that partly buffers the wind. She is dressed in sweatshirt and slacks, and has closely cropped hair and a smile that rarely leaves her face. When she talks, she speaks with the emphasis and clarity of an experienced teacher, and at this moment she is chatting with a chicken grower named Carol Morison, enumerating the potential health hazards of working in a chicken house. Silbergeld believes the list is long, though one aspect of chicken growing currently troubles her most. She is holding some of it in a small plastic bag. The bag contains chicken feed.

Producers began mixing tetracycline, penicillin, and other antibiotics into feed for poultry more than 50 years ago after reports showed the drugs hastened growth in chickens. Over the years, they continued to blend in the drugs to stave off infections and promote growth in poultry, as well as swine and cattle. But public health and consumer groups fear that the antibiotics used in agriculture have contributed to the frightening emergence of antibiotic resistance among disease-causing bacteria — a problem that is growing and becoming more inimical, as more infections show resistance to two, three, or more antibiotics. Until recently, research and surveillance efforts to control this problem have focused on resistance carried to consumers through the food chain. But Silbergeld wants to understand what antibiotic-resistant bacteria might be doing in a different place: down on the farm. Few scientists have looked here before.

"This is a completely neglected issue," says Margaret Mellon, director of the Food and Environment Program at the Union of Concerned Scientists. "Very few people in the scientific community have addressed this issue. Ellen Silbergeld is stepping into the breach."

Silbergeld, who joined the School's Department of Environmental Health Sciences in January, plans a systematic study aimed at understanding how antibiotic resistance emerges and spreads through farms and beyond, and she is visiting Maryland's Eastern Shore to begin recruiting volunteers on the Delaware-Maryland-Virginia peninsula known as Delmarva.

"We hypothesized that there are two sources of antibiotic-resistant infection: chickens and clinical use," she explains. "What are the odds that a person is carrying a bug that came from chickens? What are the odds that a person is carrying a bug that came from a clinic?"

In a study now in the planning stages, Silbergeld will use novel molecular technology to discern which infections came from either source. She will also use the same technology to track the flow of resistance as it wends its way through land, water, people, and the overall ecosystem of the community.

Silbergeld has earned a reputation as an astute scientist and tenacious advocate who chooses her research projects carefully and is wholly dedicated to the work she decides to pursue. Trained at Hopkins in environmental engineering sciences (PhD '72), she has published hundreds of papers in environmental toxicology, including research on the biological effects of lead, dioxin, and mercury. That work undoubtedly contributed to her winning a MacArthur Foundation Fellowship (popularly known as the "genius award") in 1993. But in 1982, she left what she calls her "scientific cocoon" for a decade of advocacy work with the Environmental Defense Fund.

Silbergeld is still humbled by the power of bacteria. "They rule this planet," she says. "Bacteria can and will develop resistance."

As director of the toxic chemicals program at EDF, Silbergeld argued for policy and legislative changes to protect the public against toxins such as lead and dioxin. The job pitted her against some formidable opponents, such as the big guns of the petroleum industry who were fighting efforts to remove lead from gasoline. What has given her fortitude during such moments is the teaching of her parents, Joseph and Mary Kovner, who were activists in the labor and civil rights movements, and her Quaker upbringing. "I have a big belief," she declares. "If you can discern the truth, speak truth to power."

Silbergeld was drawn to the study of antibiotic resistance for the same reasons she chose the myriad other environmental problems that mark her career. "The science has so many elegant questions," she explains. "Yet the issue doesn't have the attention it deserves. This is the opportunity to do important science and to do something important." She has been told that she behaves like a magpie. "I see something bright and glittering, and I go after it."

A relative newcomer to the study of microbes, Silbergeld is still awed and humbled by their power. "There's the dogma of the bacteria: they rule this planet," says Silbergeld. "Bacteria can and will develop resistance. The antibiotics we use are all-natural molecules. Penicillin comes from a fungus. So [in a community of] bacteria, [some] already possess the resistance genes. They have ancestral knowledge of our little weapons we're selling in bottles."

A seminar a few years ago at the University of Maryland launched Silbergeld on this research trajectory. The topic was nosocomial infections — infections originating in the hospital — and the speaker alluded to the role of food-borne bacteria such as salmonella in transmitting antibiotic resistance. Silbergeld prodded a colleague sitting next to her for more information.

Her colleague explained that chickens are fed sub-therapeutic amounts of antibiotics, not enough to battle a full-blown infection but enough to make them grow faster and stave off infection, and consequently, an ideal amount to nurture resistant bacteria. Antibiotic-resistant bacteria in manure could then stick to a bird all the way to the dinner plate.

Silbergeld was intrigued but puzzled. Sure, a microscopic amount of manure might remain on a chicken, but what about the rest of the waste? As an environmental engineer, says Silbergeld, "I know waste." And she knew that the poultry industry in Delmarva alone produces hundreds of thousands of tons of it each year. Her environmental engineering sensibilities suggested that parts of the antibiotic resistance story had not yet been told.

In the meantime, Silbergeld also spoke to University of Maryland law professors Sherrilyn Ifill and Christopher Brown, whom she had met when Brown was filing lawsuits on behalf of lead-poisoned children. The lawyers were helping chicken workers who had formed a group called the Delmarva Poultry Justice Alliance to seek ways to improve their working conditions and procure better wages.

Brown introduced Silbergeld to the workers, and Silbergeld began talking to them about their health concerns. She knew immediately that the workers should be part of the study she envisioned. "An axiom of environmental health and something [Hopkins Professor] Reds Wolman taught me is if you're worried about environmental exposure, go look at occupational exposure."

Silbergeld also began visiting poultry farms, talking to chicken workers and growers, and simply "hanging out." A grower with whom she has worked closely is Carol Morison, who is also the executive director of the Delmarva Poultry Justice Alliance.

Morison jokes that she became a farmer the day she said "I do" to her husband, Frank, who has been in the business for all of his 43 years. "It's a good life but you can't make a living on it," she asserts. Both she and her husband have full-time jobs outside of the farm.

Speaking to Silbergeld behind the chicken house, Morison points to a feed bin. Decades ago, Delmarva had many independent chicken farmers, she says. "Now, farmers don't own the chickens or the feed. We contract with Perdue [or another company]. The company formulates the feed and dumps it in the feed bin." The feed ticket lists some of the ingredients, but the precise formula is a mystery. "Perdue doesn't tell us what the mixture is," says Morison. "It's supposedly a trade secret."

Silbergeld recently completed a study in which she examined whether chicken workers, with all their exposure to the birds and manure, were being colonized by bacteria (including resistant microbes) that frequently grow in chickens. She also wanted to know whether other members of the community were becoming infected, perhaps through contact with poultry workers or some other pathway. With funding from the U.S. Food and Drug Administration, she and her colleagues enrolled 34 chicken workers and community residents, and screened their stool samples for bacteria.

The researchers found that 41 percent (7/17) of chicken catchers were colonized with Campylobacter jejuni, a bacterium rarely found in healthy people but found in many chickens and other farm animals. They also identified campylobacter in 63 percent of poultry processing plant workers. Further, and perhaps most surprising, all nine of the community members who lived near but did not work in the poultry industry tested positive for the bacterium. Silbergeld calls these data "very worrisome."

The scientists are still analyzing the data, and do not yet know whether the campylobacter are antibiotic resistant. However, many of the volunteers did harbor antibiotic-resistant enterococci, a common source of nosocomial infections such as blood infections or urinary tract infections. Silbergeld says it's conceivable that a person infected with enterococci may not experience any symptoms and unwittingly act as a vector, passing infection to others. She reported these findings in March at the International Conference on Emerging Infectious Diseases in Atlanta, sponsored by the Centers for Disease Control and Prevention.

Is campylobacter making the workers ill? That is hard to tell since many of the poultry workers lack health insurance and do not go to a doctor or hospital when they are sick. But informally, Silbergeld has found that workers frequently have gastrointestinal symptoms that would be consistent with campylobacteriosis.

Silbergeld is now embarked upon a research project that builds and expands upon this survey. It is the most ambitious study that she, and perhaps any scientist, has undertaken to understand the ecological flow of antibiotic resistance.

With agricultural microbiologist Sam Joseph and agronomist Lewis Carr, both from the University of Maryland, Silbergeld will first define a region of several hundred square miles in the farm country around Salisbury and Pocomoke City, Maryland. She will then recruit volunteers in this geographic area, and determine whether antibiotic-resistant infections among the group originated at a local hospital or a farm. The researchers are focusing on enterococcus, which has shown increasing antibiotic resistance. The key to the study is a gene chip, similar to the technology scientists recently used to search for the source of the anthrax used in the fall terrorism attacks. Shyam Biswal, PhD, assistant professor, Environmental Health Sciences, is designing the microchip for this study. The tool enables researchers to trace the path of a bacterium through its evolutionary genetics — the constant genetic mutations that occur as bacteria divide, multiply, and move through the environment.

While encouraged by announcements from major poultry companies that they are reducing antibiotics in their feed, Silbergeld wants to see the data.

The gene chip will contain all of the genetic regions for antibiotic resistance in enterococcus that vary from one strain of the bacterium to the next. These variable regions include both the single nucleotide polymorphisms (SNPs) and the longer sequences called variable number tandem repeats (VNTRs).

Using the chip, Silbergeld and her colleagues will determine the genetic resistance signatures of enterococci from farms as well as those from local hospitals (possibly by screening sewage). They will then use it to analyze enterococci resistance genes isolated from volunteers' stool samples. By comparing genetic signatures, the researchers will deduce which cases of genetic resistance originated in the hospital and which on the farm.

Further, the scientists plan to use the technology to test bacterial genes obtained from dirt, dust, and groundwater around the farm to map the flow of resistance. Silbergeld entertains many scenarios for a potential pathway. In one, for example, an antibiotic-resistant bacterium would colonize a chicken, be excreted in the bird's feces, get spread on a farm field with the manure, then seep into the groundwater and maybe even into wells.

Hearing this, Morison nods knowingly and points to the fields surrounding the chicken house. Land could not get any flatter or lower than this. Many farmers have shallow wells, she notes.

"But there could be other scenarios," says Silbergeld. "The airborne route could be the sleeper." The study includes plans to test the air in chicken houses.

The web of resistance is likely to be intricate, says Silbergeld. She notes that resistance genes can cross species. "That's why bacteria are so evil and cool. That's the hot scientific aspect of this."

Part of the challenge in solving the antibiotic resistance quandary is that no one knows how much antibiotics are used in American agriculture. The Food and Drug Administration does not require companies that manufacture antibiotics for agriculture to report these amounts. Last year, however, the Union of Concerned Scientists published an estimate showing that U.S. livestock producers use 24.6 million pounds of antibiotics every year for non-therapeutic purposes, which UCS says is 70 percent of the total used in the country.

The American Medical Association, the World Health Organization, and many other health and scientific groups are seeking restrictions or bans on the use of medically important antibiotics in agriculture. Sweden and Denmark have banned the use of antibiotics for growth promotion in agriculture. The European Union now has a similar prohibition.

Industry sees things differently. The UCS estimate is "way off base," says Ron Phillips, a public information officer with the Animal Health Institute, a trade group representing animal pharmaceutical manufacturers. According to an AHI survey, only 20.5 million pounds of antibiotics go to animal use, and most of it for treating and preventing disease. Further, AHI asserts that agricultural use of antibiotics accounts for less than 5 percent of antibiotic resistance in humans.

Nevertheless, Perdue and two other poultry companies, Tyson and Foster Farms, say they have been reducing the amount of antibiotics in their feed, according to a story in the Feb. 10 New York Times. Perdue and Tyson say they are using only antibiotics that are not similar to those used in human medicine. Foster Farms has withdrawn all antibiotics except those used for treating sick birds.

Richard Lobb, a spokesman for the National Chicken Council, explains: Companies have been able to decrease antibiotic use without sacrificing animal survival, he says, due to improved growing conditions. "It's related to improved breeding of animals, better husbandry, bio-security," he says.

Some companies, he says, now ask farmers to wear protective suits and booties or to use a footbath before entering a chicken house to protect the flock.

Out by the chicken house, Morison says she is dubious. Pointing toward the building, she says that without antibiotics in the feed "those birds would be dying." They are simply too densely packed to avoid the spread of infection.

Silbergeld maintains her scientific reserve. Rather than rely on company statements, she wants data. She plans to analyze the feed samples she's gathered for their antibiotic content. Tucking the bag safely in a pocket, she declares, "Just prove it."

But she is buoyed by the news story. It suggests that poultry companies are starting to pay attention to public health and citizens' groups, says Silbergeld. "We certainly welcome a very productive and progressive attitude."

Many questions remain, however. "We don't really know to what extent the agricultural use is part of the big picture of drug-resistant infections," adds Silbergeld. "Ten percent? Is it only through food? Are there other ways of transferring resistance? Are there reservoirs of resistance?"

Despite these questions, the data are there to justify taking measures to protect public health, says Silbergeld. She believes the FDA, for example, should not license any further dual-use antibiotics - those prescribed for both people and animals. In a New York Times op-ed this past November, Silbergeld called on Bayer to withdraw its agricultural drug Baytril, a fluoroquinolone that is chemically similar to Ciprofloxacin, the antibiotic widely used last fall in treating those exposed to anthrax.

It would be naïve to expect the United States to immediately halt agricultural antibiotic use, she adds. Only relatively small countries have taken such a step, and they've had to climb a steep learning curve. In the vastly larger U.S. agricultural system, reducing the industry's dependence on antibiotics would take a lot more thinking and planning. "It would be as big as taking lead out of gasoline," remarks Silbergeld. But tough questions should not stymie efforts to try, says this seasoned advocate.

What drives her to find the answers, says Silbergeld, are her visits with the poultry workers. She has promised to return to Delmarva this spring to explain the results of her study at an open meeting. She will do the same when she completes her current study. This promise, she says, keeps her focused. "We've got something to live up to."

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