USDA PHOTO/GENE A L E X A N D E R
GOVERNMENT & POLICY epidemiology and preventive medicine at the University ofMaryland School of Medicine, Baltimore. So FDAs recent steps— proposing a ban on fluoroquinolones in poultry and publishing a threshold document—indicate a strong policy shift.
HOGGING IT Antibiotics used in animals may contaminate bodies of water.
FUROR OVER ANIMAL ANTIBIOTIC USE Rising resistance to microbes in humans leads FDA to propose antibiotic livestock restrictions BETTE HILEMAN, C&EN WASHINGTON
O
VER THE PAST SIX MONTHS, THE
Food & Drug Administration has given a great deal of attention to the issue of antibiotic resistance. Last October, it proposed banning the use of fluoroquinolones in poultry, saying their use increases the risk that humans will become infected with drug-resistant bacteria. And last month, it published a draft proposal that lays out general criteria for restricting or banning particular antibiotics in livestock. OnJan. 22-24, the agency held a public meeting to discuss the proposal. For more than a decade, the Centers for Disease Control & Prevention (CDC) has been warning that the use of antibiotics in livestock, especially when added to food or water for growth promotion, contributes to the rising problem of antibiotic resistance in humans. Nearly 80% of farm animals—mainly hogs, poultry, and catde—receive subtherapeutic levels of antibiotics in their feed at least part of the time. Over the same period, the Department of Agriculture was claiming there was little evidence that antibiotic use in agriculture posed a risk to human health and that HTTP://PUBS.ACS.ORG/CEN
more research was needed before restrictions were placed on such use. Its view was validated by a 1998 National Research Council (NRC) study that concludes: "The use of drugs in the food animal production industry is not without some problems and concerns but does not appear to constitute an immediate public health concern. There is a link between the use of antibiotics in food animals, the development of bacterial resistance to these drugs, and human disease—although the incidence of such disease is very low" From 1977 until last year, FDA's policy on antibiotic use in livestock more or less mirrored USDA's. In 1977, FDA tried to ban the use of penicillin and tetracycline in animal feed, but Congress intervened and required the agency to do more research before instituting a ban. As a result, FDA made almost no attempt to control antibiotic use in animals for more than a decade, regulating only antibiotic toxicity "Resistance development was not seen as something that should concern the FDA in terms of a regulatory role," saysJ. Glenn Morris Jr., chairman of the department of
ANTIBIOTIC RESISTANCE in microorganisms that cause disease in humans and animals has risen sharply over the past several decades. Food-borne illness has become an increasing problem in the U.S. Each year, CDC says, an estimated 1 million infections, 8,000 to 18,000 hospitalizations, 2,400 bloodstream infections, and 500 deaths are associated with foodborne Salmonella infections. A strain of Escherichia coli—E. coli 0157:H7—has emerged that kills 50 to 100 people each year. Most patients who become gravely ill, or die, from food-borne bacteria are infected with strains—usually Salmonella, Campylobacter, orE. coli— that resist all or nearly all antibiotics. One in 1,000 foodborne Campylobacter infections results in the paralyzing disease Guillain-Barre syndrome. CDC has tested microorganisms from human isolates for antibiotic resistance every five years since 1970. "When you look at decades of trends, you see remarkable increases in antibiotic resistance," says Frederick J. Angulo, who heads the National Antimicrobial Resistance Monitoring System (NARMS) unit at CDC. In the past five years, since fluoroquinolones were first used in poultry, fluoroquinolone resistance has increased in human isolates of Campylobacter and is emerging in Salmonella bacteria, Angulo says (C&EN, Nov 6,2000, page 11). Fluoroquinolones are important human drugs. Resistance to another major human drug class—third-generation cephalosporins— which was not present five years ago, has now emerged, he says. At the same time that the incidence of food-borne illness has risen, FDA has found that the meat supply has become highly contaminated with bacteria. Campylobacter, for example, infects 4% of beef, 31.5% of swine, and 88% ofbroiler chicken carcasses. NARMS data indicate that the levels of certain resistant bacteria in meat and poultry carcasses have increased over the past few years. OF THE 19 CLASSES of antibiotics approved for use as growth promoters in animals, six are important antibiotics in human medicine. Antibiotics given to animals exert a selective pressure on the bacteria in the animals' guts, killing those that C&EN
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GOVERNMENT & POLICY are susceptible and sparing the resistant ones, Angulo explains. Some of the resistant microbes then end up in food in the grocery store. "It is clear that increasing resistance in some foodborne pathogens is the direct consequence of antibiotic use in food animals," he says. Antibiotic resistance in certain strains of bacteria also results from misuse and overuse of antibiotics in humans. But this probably does not play a major role in Campylobacter and ANGULO (left) and HANSEN Salmonella resistance, Morris explains. Those bacteria are in most instances transtypes of regulatory approaches based on ferred directly from food animals to thresholds aimed at arresting the further humans, and there is not that much secemergence of resistant food-borne ondary transmission, he adds. pathogens. The thresholds —a human health threshold and a resistance thresh"What we are seeing in human mediold in animals—are meant to provide a reacine is a rapidly increasing problem in the sonable certainty that the use of an antibidevelopment of antibiotic resistance," otic in food-producing animals will cause Morris says. "There are major concerns no harm to human safety that we are losing the ability to utilize these very powerful tools—antibiotics—in medT h e human health threshold, as icine," he warns. As a consequence, the described in the document, is reached medical community has become increaswhen there is an "unacceptable prevalence" ingly convinced that antibiotic use in farm of human infections caused by bacteria animals must be restricted. that are resistant to a drug and the resistance is attributable to the use of an antibiFDA's threshold document is intended otic in animals. Unacceptable prevalence to reverse these trends. It proposes two
Shared drugs Most antibiotics used in livestock are also used in humans DISEASE TREATMENT
ANTIBIOTIC CLASS (EXAMPLES)
Aminoglycosides (streptomycin, neomycin) Penicillins (amoxicillin, ampicillin) Cephalosporins (cefadroxil, ceftiofur) Chloramphenicol Cycloserines Glycopeptides lonophores (monensin, salinomycin) Lincosamides Macrolides (erythromycin) Monobactams Polypeptides (bacitracin) Quinolones (sarafloxacin) Streptogramins (virginiamycin) Sulfonamides Tetracyclines Bambermycin Carbadox Novobiocin Spectinomycin
• • B3 •
• • • • • • •
LIVESTOCK USES DISEASE PREVENTION
GROWTH PROMOTION
• • •*
• • • • • • • • • • •
a Third-generation cephalosporins only. SOURCE: Government Accounting Office
HUMAN USE
• • • • • • • • •
• • • •
• • • • • • • • • •
is defined as the level at which "there is no longer certainty that there is no harm to human health." T h e resistance threshold for animals is defined as the maximum allowable prevalence of resistant bacteria isolated from meat or poultry. The threshold document proposes triggers for both voluntary and mandatory regulatory steps. For example, if the efficacy of an antibiotic used in animals and humans declines, or if the prevalence of resistant bacteria in meat or poultry increases, FDA may call for voluntary steps to curtail the use of the antibiotic in livestock. But if a threshold is exceeded, FDA would move to ban the drug in a particular animal species. MOST EXPERTS in antibiotic resistance say FDA's document is an important step forward. "I think the threshold document is an excellent start," Morris comments. "It begins to deal with the issue of recognizing that antibiotic resistance is a problem and that it is a side effect of antibiotic use in agriculture. "FDA has shifted the discussion away from 'We will do something when we see a problem in humans' to saying W e will potentially do something when we see development of resistance in animals.'To my mind, that is a major positive step," Morris says. "I am pleased that FDAseems to be moving in a rational direction." Stuart B. Levy, professor of molecular biology and microbiology at Tufts University School of Medicine, says FDA must keep in mind when developing its approach that bacterial resistance selected by a single drug often expands to other drugs. Another consideration, he maintains, is that a large fraction of antibiotics consumed by animals and humans passes unchanged through the digestive system. As a result, antibiotics end up in streams and groundwater, exerting selective pressure on bacteria there. So FDA should set thresholds as conservatively as possible, Levy tells C&EN. Although environmental and consumer groups find some deficiencies in FDA's document, they basically applaud it. 'Addressing resistance as a concern is a positive step," states Michael K. Hansen,
At the same time that the incidence of food-borne illness has risen, FDA has found that the meat supply has become highly contaminated with bacteria. 48
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GOVERNMENT & POLICY INFORMATION
LACKING
Estimates Of Antibiotic Usage In Livestock Differ Vastly
R
eliable information about the amounts and types of antibiotics used in animals is essential for determining correlations between antibiotic resistance and patterns of usage. But so far, definitive information is lacking because no usage figures are available from industry or government. For years, the Animal Health Institute (AHI), which represents the manufacturers of animal medicines, has maintained that about 2 lb of antibiotics are used in human medicine for every 1 lb that is used in livestock in the U.S. But a recent analysis by the Union of Concerned Scientists (UCS) calculates that 10 million lb of antibiotics are fed each year to hogs, 11 million lb are given to poultry, and 4 million lb are given to cattle for growth promotion, while only 3 million lb are used in human medicine. To compute total usage in livestock,
the UCS study's authors compiled data on the amounts of antibiotics in various feeds and the average consumption of drug-containing feed by hogs, poultry, and cattle. To compute human medical usage, the authors multiplied the total number of prescription units given each year by the average size of each dose. According to the report, "Hogging It: Estimates of Antimicrobial Abuse in Livestock," the total use of antibiotics in healthy livestock climbed from 16 million lb in the mid-1980s to 25 million lb today in the U.S. "The public has been flying blind," says Margaret Mellon, coauthor of the report and director of the Food & Environment Program at UCS. "The government should act now to collect the needed data." In contrast, AHI claims that 17.8 million lb of antibiotics are used in all ani-
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mals and of this only 3.1 million lb are used for growth promotion. AHI calculated these numbers from data obtained in a survey of 80% of its members. It says its usage totals are more precise than UCS's because they are calculated from data obtained directly from industry. However, AHI doesn't reveal its raw data or the methods it used to compute total usage, or the percent of antibiotic production that is represented by 80% of AHI members. "The study by UCS overestimates use in several drug categories and implies that all antibiotics used in animals are also used to the same degree in humans," says Carole Throssell duBois, AHI vice president for public affairs. Although some aspects of the UCS report are consistent with data produced by AHI, many of UCS findings are based on erroneous assumptions, she says.
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The conflict between UCS and AHI
research associate at Consumer Policy
ance genes on plasmids—between unre-
data may be resolved eventually. The
Institute, the research arm of Consumers
lated bacteria, he says.
Centers for Disease Control &
Union. FDA's choice of the standard of
Still other organizations, such as the
Prevention (CDC) has indicated that it
"reasonable c e r t a i n t y of no harm" to
Food Animal Concerns Trust (FACT),
will set up an ad hoc group to review
human health, rather than balancing the
claim that subtherapeutic antibiotics are
the UCS report. And FDA has said it
risks and benefits of the use of an antibi-
not needed and that the food supply would
will propose a regulation that will
otic in a food animal, is an especially pos-
be safer and animal health and welfare
allow it to collect data on the
itive development, he says. It means, he
improved if their use were banned.
amounts of antibiotics used in
explains, that the FDA process does not
livestock. "If we had usage information, addressing the misuse and overuse of
allow the weighing of economic risks and
SWEDEN BANNED the use of antibiotic
benefits in decisions about whether to ban
growth promoters in 1986. For ayear after
an animal drug.
antibiotics could be much more pre-
the ban, there was increased mortality in
"FDAhas laid out an approach. And that
young pigs, says Steven A. Roach, FACT's
cise," and therefore less burdensome
may be the most important thing—that
farm program manager. But Swedish farm-
for industry, says Frederick J. Angulo,
the government is moving on finding away
ers made minor changes in the production
head of CDC's National Antimicrobial
to reduce this huge, overwhelming volume
system. They used a deep-bedded straw
Resistance Monitoring System. Without
of antibiotic use in the agricultural sector,"
system rather than allowing manure to run
accurate usage information, "we have
says David B. Wallinga, director of the
over a bare concrete floor. They improved
to have broader safeguards," he
Antibiotic Resistance Project at the Insti-
the hygiene, increased space and air for the
explains.
tute for Agriculture & Trade Policy, Min-
animals, decreased the protein and in-
neapolis. However, the threshold docu-
creased the fiber content of the feed, and
relative amounts of antibiotics used in
m e n t does have some drawbacks, he
used zinc oxide to control diarrhea, he says.
humans and farm animals, and if bans
explains. For example, "even though we
With these changes, pigs survived nearly as
and restrictions on antibiotic use in
know people differ in their vulnerability
well and were raised nearly as economi-
livestock result from FDA's new pro-
to resistant microbes, that was kind of
cally as they had been before the ban.
posals, they could have a huge impact
buried in an appendix," he says. And the
U.S. farmers rarely use fluoroquinolones
on the market for pharmaceuticals.
document doesn't really account for resist-
to treat chickens in the summer, Roach
ance transfer—through transfer of resist-
says. But in winter, they crowd chickens in
If the UCS study is correct about the
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C&EN / FEBRUARY 1 9, 2001 51
GOVERNMENT & POLICY < LU
m
OVERCROWDING Need for antibiotics may stem from bad management. poultry houses with too little ventilation. Then the chickens become infected with viruses andE. colt, and farmers add fluoro quinolones in drinking water for the entire flock to kill the bacteria. So the need for fluoroquinolones stems from bad man agement practices, he says. "The shame is that we've been so quick to use one way of looking at this issue," Wallinga says. "We haven't stepped back
and said, if our goal is to protect public health and keep antibiotics as effective as possible for as long as possible, then maybe we should start off with the questions: Do we really need these antibiotics? How might we raise animals without them?" he explains. On the other hand, the Animal Health Institute (AHI), which represents the man ufacturers of antibiotics for livestock, says
there is little scientific evidence that antibi otic use in agriculture presents a human health risk. "The use of antibiotics ensures an abundant food supply and makes it more healthful and safer for human con sumption," says Carole Throssell duBois, AHI vice president of public affairs. Given the strong feelings the medical community has about the rise in antibiotic resistance and the robust scientific evi dence linking a large part of the resistance to antibiotic use in food animals, FDA is unlikely to reverse course and abandon the idea of restricting antibiotic use. However, any moves the agency makes to reduce or ban livestock antibiotics are sure to face intense opposition from industry Lawyers representing pharmaceutical makers at the FDA public meeting last month were already threatening to sue if the agency uses a standard of reasonable certainty of no harm to public health. And FDAs proposal to ban fluoroquinolones in poultry is facing intense opposition from one of the two manufacturers, Bayer Corp. Abbott Laboratories, however, immedi ately withdrew its fluoroquinolone prod uct when FDA announced its proposal. •
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