Worries Rise Over Effect of Antibiotics in Animal Feed
Humans Seen Vulnerable To Drug-Resistant Germs

By Marc Kaufman
Washington Post Staff Writer
Friday, March 17, 2000; Page A01

A 66-year-old woman was recovering from a heart bypass in a hospital near Detroit when she suddenly developed respiratory failure and a serious infection. Doctors quickly gave her an antibiotic that usually works. This time, however, it didn't. The bacteria causing the woman's infection were resistant to the drug.

The woman's doctors immediately turned to a newly approved antibiotic, a powerful one designed specifically to attack the kind of dangerous antibiotic-resistant microbes that had infected her. But her physicians were dismayed to find that drug didn't work either--the bacteria in her body were resistant to it as well. The woman died soon after.

Cases like this around the country have caused rising alarm among infectious disease doctors and public health experts. They are also at the center of an increasingly acrimonious dispute now before the Food and Drug Administration over how antibiotics are used in this country--specifically, how farmers use them to promote the growth of livestock.

Experts have long known that the overuse of antibiotics by doctors and their patients has reduced the ability of those drugs to cure infections. Now there is mounting evidence that the antibiotics widely used on farm animals are also diminishing the power of important antibiotics to help people.

Giving animals antibiotics in their feed can cause microbes in the livestock to become resistant to the drugs. People can then become infected with the resistant bacteria by eating or handling meat contaminated with the pathogens.

"Many of us believe there is a tremendous overuse of antibiotics for animals," said Marcus Zervos, an infectious disease specialist at William Beaumont Hospital in Royal Oak, Mich., who was involved in the Michigan case. "There is some very strong opposition to our view that animal antibiotics are undermining antibiotics for people, but this whole area has to be reconsidered."

Most of the antibiotics used on the farm are not administered to treat sick animals. Instead, farmers feed livestock a low-level diet of antibiotics to attack bacteria that might require the animal's body to expend energy to kill off. This allows animals to grow more quickly and, from a producer's point of view, more efficiently.

But this practice has increasingly become the focus of concern. Researchers have already found evidence that the use of antibiotics on farms has led to an increase in antibiotic-resistant cases of food poisoning caused by campylobacter and salmonella bacteria in people.

Now, doctors and researchers point to the antibiotic the Michigan woman received--Synercid, an important drug-of-last-resort in fighting life-threatening infections--as a case study illustrating why they are so concerned.

While Synercid was approved for human use only last fall, a closely related drug called Virginiamycin has been used on livestock since 1974. Researchers have found Virginiamycin-resistant bacteria in as much as 50 percent of supermarket chicken, turkey and pork. That alone causes concern that the effectiveness of Synercid is already significantly reduced in humans.

"It's clear that the use of Virginiamycin to promote the growth of food animals is a hazard to human health," said Frederick J. Angulo of the federal Centers for Disease Control and Prevention (CDC). "It's difficult to track the chain of evidence we need to say for certain that the Virginiamycin in animals results in resistance to Synercid in humans. But we do believe the seeds for Synercid-resistant [bacteria] were planted on the farm, and are likely to blossom in hospitals."

Defenders of animal antibiotics say the scientific evidence linking Virginiamycin resistance in animals to Synercid resistance in humans remains inconclusive, and that animal antibiotics in general pose no immediate danger to people. Studies have found Synercid resistance in 1 percent to 4 percent of humans tested, they point out, and that is far below the rate of Virginiamycin resistance found in animals.

"We're not at all convinced, based on the data, that Virginiamycin is the cause of the Synercid resistance, however minimal, in the human population," said Carl Johnson of Pfizer Inc., which developed Virginiamycin and later sold the rights to Synercid to Aventis Pharmaceuticals. "We believe it is coming from hospital use."

Others see a need for immediate action. In Europe, officials have already banned the farm use of Virginiamycin and three other growth-promoting antibiotics, following recommendations from the World Health Organization. Legislation to impose a similar ban in the United States was introduced in Congress last year by Rep. Sherrod Brown (D-Ohio). And consumer and public health groups petitioned the FDA last year to stop the use of any drugs used as animal growth promoters that are also used to treat diseases in people.

In response, the FDA is trying to fully understand and quantify the risk to humans posed by antibiotic use in animals, and will undertake a formal risk assessment of Synercid and Virginiamycin this spring.

"Experts are saying they're seeing resistance to Synercid, and that it must be coming from the animal use of Virginiamycin," said Sharon Thompson of the FDA's Center of Veterinary Medicine. "That is exactly the concern we are looking at. We're collecting information now and there will be a thorough review."

More than a year ago, the FDA proposed new guidelines to limit the spread of antibiotic resistance, and late last year claimed authority to require drug companies to prove any new animal antibiotics won't dangerously increase antibiotic resistance in humans. In the future, FDA officials said, the agency will also review some animal antibiotics already on the market, and will require new testing and new standards for those closely related to vital human antibiotics.

The FDA's actions have left drugmakers and livestock producers worried and angry. They say that animal antibiotics have been safe and very useful for decades, and that farmers need them to keep their animals healthy and growing as fast as they can. Without them, American meat and poultry would not be as safe from disease-causing organisms, and prices would rise as well, they say. And they complain that the FDA has already imposed a "de facto moratorium" on new animal antibiotics while the proposed guidelines are debated.

The FDA "is adding new requirements for resistance information never asked for in the past, and almost impossible to actually gather now," said Richard Carnevale of the Animal Health Institute, which represents pharmaceutical companies that supply farm drugs.

"In essence, we can't get products approved because we can't learn what we have to prove," he said. "One company has been working for more than a year on a protocol [to test antibiotic resistance], and the FDA is never satisfied and just tells them to keep tweaking."

Carnevale asserted that the FDA slowdown in animal antibiotic approvals has discouraged drug companies from investing in the costly development of new antibiotics for humans, too.

Livestock growers also are fighting efforts to limit antibiotic use. They consider the medications essential to their business, and are rushing as well to protect the FDA from what they consider to be nonscientific influences.

"Unlike Europe, we want to make sure decisions are based on science alone here," said Gary M. Weber of the National Cattlemen's Beef Association. "At this point, we don't see any evidence of an identifiable problem regarding antibiotic resistance from animal feed. And in the absence of good science showing that, we think it would be a real blunder to ban or limit its use."

The European Union asserts that governments can take action when they believe a health danger is present, even if it cannot be scientifically proven at the time. But the U.S. Trade Representative has opposed the ban--supporting the U.S. industry position that the risks of animal antibiotics have not been scientifically assessed--and has threatened to take its case to the World Trade Organization.

Researchers agree that many aspects of antibiotic resistance remain unresolved. But they say that more precise methods of studying bacteria on the molecular level have recently allowed them to demonstrate that resistant forms of at least two common bacteria--campylobacter and salmonella--are being passed from animals to humans. These organisms have become increasingly resistant to antibiotics known as fluoroquinolones--which include the most widely used antibiotic to treat food-borne infections, Ciprofloxacin.

Researchers found that chicken treated with fluoroquinolones were being colonized by campylobacter bacteria resistant to the drug, and that those bacteria were being passed to humans. An FDA-commissioned risk assessment concluded in December that at least 5,000 Americans will suffer longer bouts of campylobacter food poisoning annually because of fluoroquinolone resistance passing from chicken to people.

The threat from Synercid-resistant bacteria is potentially greater, because the drug generally is used to control infections when a patient's immune system is already severely compromised--during organ transplants and chemotherapy, for instance. But the pathway from Virginiamycin resistance in animals to Synercid resistance in humans is more complex than with campylobacter or salmonella.

Virginiamycin in feed produces resistance in bacteria called enterococci, which inhabit the intestines of humans and animals. They generally do not cause disease, and so there is no inherent risk involved with their development of antibiotic resistance. They can, however, become very dangerous if their resistance transfers to other enterococci that inhabit human wounds, catheter infections and other hospital-acquired contagions. Synercid was approved to attack a dangerous form of enterococci resistant to the antibiotic that used to be doctors' last resort, Vancomycin.

Researchers believe that animal resistance to Virginiamycin is appearing as Synercid resistance in those now very dangerous enterococci. But the scientific debate over this is fierce, and the newest scientific methods have not conclusively traced Synercid resistance in humans from Virginiamycin resistance in animals.

"The Synercid story is just starting to play out," said J. Glenn Morris of the University of Maryland in Baltimore, a specialist in the field. "We know we have a major problem on our hands in terms of antibiotic resistance in our hospitals. The question about Synercid is whether we'll act to protect it now, or just accept the risk that it and other important antibiotics may become ineffective sooner because of this animal use."

Drugs in the Food Chain

Farm animals treated with low levels of antibiotics are developing drug-resistant forms of bacteria, posing potential health risks in humans.

Resistant infections

Researchers are concerned that animals fed the antibiotic Virginiamycin are passing along antibiotic-resistant forms of enterococci (shown) to humans.

Possible health risks

Food poisoning

Bacteria from farm animals, such as salmonella and campylobacter, have been causing antibiotic-resistant cases of food poisoning in people.

SOURCE: Centers for Disease Control and Prevention

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