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A 396 VOLUME 110 | NUMBER 7 | July 2002 • Environmental Health Perspectives

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Antibiotic Resistance in Livestock:

More at Stake

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Environmental Health Perspectives • VOLUME 110 | NUMBER 7 | July 2002 A 397

Focus • More at Stake than Steak

Imagine, for a moment, this scenario: you, like millions of other peoplearound the world, are lying in a hospital bed suffering from a bacteri-al infection. Your doctors have told you that your disease, which oncewould have been easily treated, no longer responds to available drugs.

In addition to feeling shock and disbelief, you’d probably wonder how thiscould have happened.

You would not be alone. The specter of antibiotic resistance is consideredby many to be one of the most pressing scientific questions today. Witheach passing year, former wonder drugs like penicillin, erythromycin, andtetracycline are less effective against strains of treatment-resistant “super-bugs.” By decreasing the number of effective drugs in the medical arsenal,antibiotic resistance is making bacterial infections and related conditionsmore difficult to treat. Scientists also worry that the spread of resistancegenes among even unrelated strains of bacteria could turn what are nowtreatable illnesses into killers.

Where are these resistance traits coming from? Certainly overuse inhuman medicine is an important source. But agricultural uses, particularly

in livestock, also contribute significantlytoward the problem of antibiotic resistance,scientists say.

As much as 70% of the antibiotics pro-duced in the United States today (includingthose approved but never or not currentlymarketed) are for use in food animals,according to the Union of ConcernedScientists, a Cambridge, Massachusetts–based organization of experts that advocatesfor precautionary principles in environ-mental debates. In addition to treatingdisease, substantial amounts of these drugsare given to healthy animals to prevent ill-ness and to promote growth. Exactly whyantibiotics enhance weight gain is unclear.Many experts believe they allow animals toconserve energy that would otherwise bedevoted to fighting pathogens. But thisexplanation isn’t universally accepted, andthe question is still debated.

An Industry under PressureThe pressure on agriculture to alter its useof antibiotics has never been greater.Earlier this year, in response to pressurefrom environmental groups, theMcDonald’s, Wendy’s, and Popeyes fast-food chains announced that they would nolonger buy chicken treated with an antibi-otic called enrofloxacin because it’s relatedto ciprofloxacin, a fluoroquinolone drugused to treat Campylobacter—andanthrax—in humans. The U.S. Food andDrug Administration (FDA) is now with-drawing approval for enrofloxacin (market-ed as Baytril) from its producer, Bayer, due

to fluoroquinolone resistancein strains of Campylobacterthat infect humans. (Thecompany refused to voluntar-ily remove the drug from thepoultry market.) Three com-panies—Tyson Foods, PerdueFarms, and Foster Farms—which combined produce athird of the chickens raised inthe United States today,announced last February thatthey will no longer giveantibiotics to healthy birds.And two bills in theCongress, one authored byRepresentative SherrodBrown (D–Ohio) and theother by Senator Edward Kennedy(D–Massachusetts), have proposed phasingout uses of antibiotic formulations used inboth human and veterinary medicine inhealthy farm animals altogether.

The Alliance for the Prudent Use ofAntibiotics (APUA), an advocacy groupbased in Boston, Massachusetts, publisheda report in the 1 June 2002 supplement toClinical Infectious Diseases culminating anexpert review of approximately 500 pub-lished studies. The report calls for majorchanges in antibiotic use. Echoing thegroup’s conclusions, Sherwood Gorbach, aprofessor of community medicine at TuftsUniversity Medical School in Boston and amember of the APUA’s scientific advisoryboard, says, “Nontherapeutic use of antibi-otics in healthy animals for growth promo-

tion and feed efficiency should be discon-tinued. Furthermore, certain antibioticsthat are critically important in humanmedicine, such as fluoroquinolones andthird-generation cephalosporins, shouldbe restricted to use only in critically illanimals and refractory cases under a vet-erinarian’s prescription.”

Some stakeholders insist these drasticmeasures are unwarranted because antibiot-ic use among people—not animals—is themain cause of resistance to human antibi-otics. They also question the degree towhich resistance genes in animal bacteriaare transferred to human bacteria. Dataaddressing this question are just now beingcollected, says Abigail Salyers, a professor ofmicrobiology at the University of Illinois atUrbana-Champaign and president of theAmerican Society for Microbiology. What’sneeded, she explains, are more studies thattrace resistance genes back to agriculturalsources—something scientists are begin-ning to explore.

In the meantime, industrial agricul-ture has plenty of incentive to turn theuncertainty to its advantage. Hanging inthe balance are billions in drug sales andthe future of industrial meat production,which some argue can’t be sustained with-out antibiotics at current use levels. Allacross the United States, small farms aregiving way to huge consolidated feedlotsthat facilitate the rapid spread of bacteriaand disease. Feedlots housing up to100,000 cows within a few hundred acresare not uncommon, according toGeneNet, a Hays, Kansas–based livestockmarketing organization. In 1945, the typ-ical henhouse contained 500 birds. Today,the average ranges from 80,000 to175,000. In 1980, there were 650,000hog farms in the United States. In 2001,there were 81,000, including Circle FourFarms in Milford, Utah, a mega-facility



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No day at the spa. Some experts blame the increase in non-therapeutic uses of antibiotics in animals, at least in part, for theincreasing resistance of microbes to antibiotics.

A shot in the dark? Researchers don’t really know how—and how much—the use of antibioticsin animals may contribute to resistance in antibiotics that are also used in humans. Many say live-stock breeders should err on the side of caution in antibiotic use until more is known.



Healthy Animals, Unhealthy People? Popular Antibiotics on Farms and in Pharmacies

Sources:

Cornaglia G. The spread of macrolide-resistant streptococci in Italy. APUA Newsletter 16(1):1,4 (available: http://www.healthsci.tufts.edu/apua/Newsletter/16_1b.html).

CDC. Aminoglycoside resistance in Enterobacteriaceae and Pseudomonas aeruginosa. Atlanta, GA:U.S. Centers for Disease Control and Prevention, 1999(available: http://www.cdc.gov/ncidod/hip/Lab/FactSheet/amino.htm).

CDC. Quinolones and the clinical laboratory. Atlanta, GA:U.S. Centers for Disease Control and Prevention, 1999 (available: http://www.cdc.gov/ncidod/hip/Lab/FactSheet/amino.htm).

Corwin RM, Nahm J. Antiprotozoal drugs. Columbia, MO:University of Missouri College of Veterinary Medicine, 1997 (available: http://www.parasitology.org/Drugs/Antiprot.htm).

Dromigny J-A et al. Emergence and rapid spread of tetracycline-resistant Vibrio cholerae strains, Madagascar. Emerg Infect Dis 8(3):336-338 (2002) (available:http://www.cdc.gov/ncidod/EID/vol8no3/01-0258.htm).

Hart S, Korey E, Stamatis G. Nearly one-third of Streptococcus pneumoniae are resistant to newer antibiotics: study in doctor’s office patients points to resistance rates in children. 1998 (available: http://www.kidsource.com/kidsource/content4/resistent.antibiotics.html).

Rossiter S et al. High prevalence of bacitracin resistance among enterococci isolated from humans stools and grocery store chicken in the United States. American Society for MicrobiologyGeneral Meeting. Orlando, FL, May 2001 (available: http://www.cdc.gov/narms/pub/presentations/asm/2001/rossiter_s.htm).

Sköld O. Resistance to trimethoprim and sulfonamides. Vet Res 32: 261-273 (2001) (available: http://www.edpsciences.com/articles/inra-vet/abs/2001/03/v1304/v1304.html).

Stamey K et al. Multi-drug resistant Salmonella Senftenberg isolated from patients in a Florida hospital. American Society for Microbiology General Meeting. Orlando, FL, May 2001(available: http://www.cdc.gov/narms/pub/presentations/asm/2001/stamey_k.htm).

Swedish Medical Products Agency. Cefadroxil: summary of product characteristics. Uppsala, Sweden:Swedish Medical Products Agency, 1999 (available: http://www3.mpa.se/spc/SPC.A-E/Cefadroxil_NM_Pharma_caps.ENG.pdf).

U.S. GAO. Food safety: the agricultural use of antibiotics and its implications for human health. RCED-99-74. Washington, D.C.:U.S. General Accounting Office, 1999 (available:http://www.gao.gov/).

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Macrolides(erythromycin,tilmicosin, tylosin)

Polypeptides(bacitracin)

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housing 500,000 hogs in a 35-square-milearea, according to the U.S. Department ofAgriculture (USDA).

“If you take away the tools we have tomanage and control disease, we’ll have tolook for other alternatives,” says RonPhillips, a spokesperson for the AnimalHealth Institute, a Washington,D.C.–based trade group representing drugcompanies that make antibiotics for thefood animal industry. “And to date, no onehas found an alternative that can matchantibiotics for disease control on the scale atwhich we produce food today—at least notone which allows consumers to buy meat atsuch low prices.”

While no one disputes industry’s rightto treat sick animals with antibiotics, thereal issue, Salyers says, concerns industry’sright to give antibiotics to healthy animalsfor so-called nontherapeutic uses. Andwhat exactly are nontherapeutic uses? “Theanswer to that question is the core of thiswhole problem,” she says. “For example,consider antibiotics used for prophylaxis,meaning disease prevention. A farmermight treat an entire flock or herd becausehe believes there is a threat of disease, evenin the absence of sick animals. Is this ther-apeutic? The industry would say it is. Mostactivists would say it is not. Same forgrowth promotion, which some industryexperts might consider to be prophylactic.You could say antibiotics promote growthbecause they limit infections. In this con-text, growth promotion with antibiotics

can be said to be prophylactic. If you want-ed to, you could even argue that all uses aretherapeutic.”

This kind of semantics is where the pro-posed changes in antibiotics-use policies gethung up. In addition to restricting the use ofagricultural antibiotics that are also used inhumans, groups like the APUA want toeliminate agricultural nontherapeutic uses,particularly growth promotion. In response,industry is striving to minimize the numberof defined nontherapeutic use categories.

The Resistance PhenomenonAntibiotic resistance has been a recognizedmedical problem ever since the drugsbecame widely available in the 1940s. Witheach passing decade, emergent strains ofbacteria that defy not only single but alsomultiple antibiotics have become increas-ingly common. Some strains of humanpathogens, including Enterococcus faecalis,Mycobacterium tuberculosis, and Pseudo-monas aeruginosa, are now resistant to morethan 100 drugs. Meanwhile, diseases oncethought to be nearly eradicated—tuberculo-sis, for instance—are making a troublingreturn due to antibiotic resistance.

Bacteria acquire resistance genes byany of three routes: inheritance, sponta-neous mutationsthat produce newresistance traits,or acquisition ofgenes from otherbacteria in their

vicinity in a process known as “horizontaltransfer,” or “bacterial sex.” Jokes Salyers,“Evidence is mounting that your intestinaltract is a swinging singles’ bar for bacteria.”She adds, “And it’s all-inclusive. We’re talk-ing about gene transfer across genus andspecies lines. That’s like a human impreg-nating a slug.”

Evidence for horizontal transfer ofresistance genes from bacteria that infectanimals to those that infect humans isbeginning to emerge. In her own laboratorystudies, Salyers has found that the sameresistance gene exists in both enterococci ofanimal origin and Bacteroides—the mostcommon bacteria in the human colon. Thesmoking gun, she says, is in the gene’s DNAsequence: the resistance genes have an iden-tical genetic sequence even though thegenomes of the organisms themselves aresubstantially different.

The single greatest factor driving resist-ance to a given antibiotic is simply use ofthe drug. The more an antibiotic is used,the more the bacteria become resistant to it.For this reason, experts say, antibioticsshould be used sparingly, and at dose levelsintended to kill all or as many of the bacte-ria causing an infection as possible. If toolittle antibiotic is used (undertreatment),

the most susceptiblebacteria are killed off,leaving a hardy groupof survivors that growand multiply intoresistant strains.

Human abuse ofantibiotics in particu-lar is a major publichealth problem. Manypatients demand anti-biotics routinely, andjust as many doctors

dispense antibiotics indiscrimi-nately—often for viral infectionsagainst which the drugs are useless.And it’s not uncommon forpatients to stop taking antibioticsas soon as they feel better, killingonly a fraction of the bacteria thatare making them sick. Antibioticuse around the world is character-ized by widespread chronic under-treatment.

Chronic undertreatment inagriculture, particularly for non-therapeutic uses no matter howthey are defined, is also endemic.Regarding the extent of undertreat-ment in the poultry industry,Richard Lobb, a spokesperson forthe National Chicken Council, aWashington, D.C.–based trade



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Murder most fowl? Bacteria such as Salmonella (inset) and Campylobacter, often associated with con-sumption of undercooked meat, are linked to millions of illnesses and many deaths each year.



group, says, “Antibiotics for growth pro-motion are given at very low levels: gramsper ton of feed. The compounds are usedto manage the gut flora of the bird, whichallows it to process feed more efficiently.”According to Lobb, the dosage rate fortherapeutic use is “considerably higher,”although the exact amount depends on thespecific drug.

Salyers says her own lab studies showthat long-term low-dose use patterns are byfar the most effective at selecting for resist-ant bacteria. “These dosing regimens alsogive the bacteria time to acquire geneticchanges that make them more fit,” sheadds. “Keep in mind that bacteria predateplants and animals by billions of years, andthey are extremely adaptable. If they haveextra time to adapt, they will do so withmaximal efficiency. That’s why the low-doseuses are such a concern.”

The Human Health Risk fromAntibiotics in AnimalsPeople are typically exposed to resistantfoodborne bacteria when they come intocontact with farm animals or when they eatmeat and meat products. Although manytypes of foodborne bacteria cause humanillness, two are a key concern because theyinfect so many people. Salmonella andCampylobacter are each linked to millions ofcases of food poisoning annually, accordingto the Centers for Disease Control andPrevention (CDC). “These switch sides asthe number-one and number-two causes ofbacterial foodborne disease in the UnitedStates,” says Lyle Vogel, who heads theScientific Activities Division at theAmerican Veterinary Medical Association.The effects caused by either organism rangefrom barely noticeable, to uncomfortable,to fatal in rare cases involving infants, theelderly, or people with compromisedimmune systems.

Resistant strains of these bacteria havebeen emerging with some frequency. Forexample, in 1999, scientists at the CDCbegan tracking a new variety of Salmonellacalled Newport 9+, which is named for itsunprecedented resistance to nine antibioticsincluding ceftriaxone, one of the few drugsthat kills most bacteria and the drug ofchoice for children whose Salmonella infec-tions enter the bloodstream (a condition thatkills about 1,000 Americans every year).

The National Antimicrobial ResistanceMonitoring System (NARMS) surveillancemechanism, which is coordinated by theFDA, the CDC, and the USDA, providesdata that allow researchers to correlatetrends in animal antibiotic use to resistancein human pathogens. Currently, NARMS

collects data on Salmonella, Escherichia coliO157, Campylobacter, and Shigella and theirsusceptibility to 17 antimicrobial drugs.Results can be compared with data fromprevious years to look for changes in theresistance of the organisms to these drugs.According to data collected by NARMS,12% of all Salmonella isolates obtained fromhuman clinical samples in 2000 were resist-ant to at least five antibiotics, includingampicillin, chloramphenicol, streptomycin,sulfamethoxazole, and tetracycline. All ofthese drugs or the classes of drugs theybelong to are used in agriculture. In 1996,the year NARMS began gathering data,only 6% of human Salmonella isolatesshowed this resistance pattern.Furthermore, a series of studies published inthe 18 October 2001 issue of the NewEngland Journal of Medicine showed highlevels of resistant foodborne pathogens insupermarket chicken.

While untreatable food poisoning canmake someone very sick, an even more

serious problem can result if resistantstrains of enteric bugs escape the digestivetract and infect other parts of the body.The most likely scenario for this to happenis during surgery. Says Salyers, “If yourbowels are accidentally perforated suchthat intestinal bacteria get into the blood-stream, the chance of developing a hard-to-treat postsurgical infection is greatlyincreased.”

Stuart Levy, a professor of molecularbiology, microbiology, and medicine atTufts University Medical School and presi-

dent of the APUA, adds that the flow ofresistance genes is hardly limited to food-borne pathogenic bacteria. As members ofa microbial ecosystem, any bacterium—even a benign strain—could acquire aresistance gene and pass it on to its neigh-bors, including the dangerous bugs thatcause pneumonia, urinary tract infections,and sexually transmitted diseases. Thus, aresistance gene that starts out in an animalstrain of Salmonella typhimurium couldend up in Klebsiella pneumoniae (a cause ofhuman pneumonia); similarly, a resistancegene in an animal strain of Enterococcusfaecium could end up in Staphylococcusaureus, which causes intractable hospital-based infection resistant to nearly 100drugs. “It would be hard to trace anuntreatable urinary tract infection toantibiotic use on a farm,” Levy says. “Butit’s nevertheless possible that farm usecould be the source of the resistance.”

A Dwindling ArsenalA troubling parallel to the problem ofresistance is the lack of new effective antibi-otics—the pipeline for fresh drugs has beenrunning low for years. The goal for publichealth is therefore to retain the usefulness ofas many existing antibiotics as possible.Those used purely in animals—such asionophores, which improve feed efficiencyin sheep and cattle but are too toxic for usein people—are of little concern. The antibi-otics experts worry about most are thosethat are used in both animals and people:mainly tetracycline, fluoroquinolones,third-generation cephalosporins, andmacrolides, according to Vogel.

Lately, to industry’s dismay, activistshave targeted a drug called virginiamycinthat has been used in animals, mainly poul-try, for 25 years. Virginiamycin is related toa new human drug called Synercid, whichis an emerging replacement for one of themost valuable antibiotics in the clinician’sarsenal, vancomycin. Practitioners wereshocked when vancomycin-resistant strainsof E. faecium began to emerge in the late1990s. The source of at least some van-comycin resistance in E. faecium was tracedback to a related antibiotic calledavoparcin—never approved for use in theUnited States—which was used for growthpromotion in the European poultry indus-try. These uses have since been discontin-ued. Activists worry that a similar scenariomay play out for virginiamycin.

To date, regulatory action to remove ananimal antibiotic because of a human resist-ance threat is limited to the FDA’s offensiveagainst fluoroquinolones in the poultryindustry, but the FDA is conducting a riskPh

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Draining the supply. In addition to use inanimals, the overuse of antibiotics in humansis considered a major factor in the reduction ofthe number of effective antibiotics.

assessment of virginiamycin use. Industrywatchers say Baytril withdrawal isn’t likelyto happen anytime soon—stakeholders saythe FDA’s campaign against Bayer couldtake anywhere from 10 to 20 years. In fact,some critics complain that the FDA’s handsare inadvertently tied by a multilayered setof hearings and appeals. “The agency does-n’t have an effective way to deal with thiskind of problem,” says Tamar Barlam,director of the Antibiotic Resistance Projectat the Center for Science in the PublicInterest, a Washington, D.C.–based advo-

cacy group. “The only practical solutionsare voluntary industry withdrawals or legis-lation that bans sale of the drug.”

Both the Kennedy and Brown bills pro-pose to ban the use of ciprofloxacin-likeantibiotics to treat sick poultry. In addition,both bills would ban the use of eighthuman antibiotics in feed animals withintwo years of enactment unless the FDAdetermines that these uses don’t contributeto antibiotic resistance problems.

In recent years, the FDA has revampedits new drug approval process for animalantibiotics, specifically targeting potentialhuman resistance problems as a safety endpoint. As part of this new approach, saysStephen Sundlof, director of the FDA’sCenter for Veterinary Medicine, the agencyis asking drug companies for better infor-mation about resistance implications. “Butthis is difficult to evaluate,” Sundlof says.“We can’t really predict when and if resist-ance will happen and at what rate. If youassume the worst you’ll never approveanother drug, and if you’re too lenient

you’re not doing your job either. So we’reusing a risk-based process that takes intoaccount the importance of the drug inhuman medicine.”

The Future for Food Safety andProductionSo what happens if antibiotic use in animalsis reduced or eliminated? The Europeanexperience provides one perspective on theimplications of reducing food animalantibiotics. Since 1999, the EuropeanCommission has tightly regulated animal

antibiotics related to those used in humanmedicine. The leader in these efforts isDenmark, which reduced its animal use ofantibiotics by roughly 60% from 1994 to2000.

According to a 27 March 2002 article inThe Washington Post, the use of growth-pro-moting antibiotics in Denmark has fallen tozero from a 1994 peak of 128 tons. In thearticle, Henrik C. Wegener, a researcherwith the Danish Veterinary Institute inCopenhagen, is quoted as saying theDanish ban has markedly decreased theprevalence of drug-resistant bacteria but hasnot affected the health of the animals or theprice of meat. Wegener does acknowledgethat more feed is required to maintain ani-mal weight, but these costs are balanced bythe savings in drug costs.

However, Vogel, who represents the vet-erinary profession on matters related toantibiotics, is skeptical of the Danish claims.Denmark also reports a 30% increase in theuse of antimicrobials to treat diseases in2000, he says. “Until the illnesses are

resolved, the health and welfare of the ani-mals are clearly impacted.”

Ultimately, the issue of agriculturalantibiotic use and resistance boils down tofamiliar questions in public health: shouldprecautionary measures be taken to mini-mize a threat that isn’t well characterized, orshould we wait until more data are availablebefore taking conclusive actions? Just as careproviders and patients alike have a role toplay in conserving antibiotics, so do farmersand drug companies. But controlling thespread of resistance won’t come without a

certain degree of economic pain and, poten-tially, a detrimental effect on animal healthand welfare. “If you want cheap meat fromcows that are confined to a small number oflocations rather than wandering in the sub-urbs and parks, then you have to face theconsequences of that desire,” says Salyers.“One of those consequences is massive useof antibiotics.”

Reducing antibiotic inputs will requirechanges in animal husbandry that promotehygiene and minimize the spread of bacte-ria. Just how the U.S. food animal industrywill accommodate these changes is unclear.“Farmers are going to need help,” Salyerssays. “We can’t get them addicted to antibi-otics and then just tell them to quit coldturkey. We need to have some respect fortheir problems. If we’re going to move toreduce antibiotics in agriculture, we’regoing to have to work with agriculture onmaking that transition.”

Charles W. Schmidt



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The economic equation. Livestock breeders say that reducing the use of antibiotics in ani-mals will significantly impact the cost of meat, though environmentalists and others say thecost of antibiotic resistance would be far greater.

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