Alarming new data from the Pub-lic Health Agency of Canadasuggests that widespread off-

label use of cephalosporin antibiotics inpoultry hatcheries is triggering humanresistance to the class of antibiotics.

Experts say the data warrants restric-tions on off-label (use of drugs for unap-proved clinical indications, also known asextra-label) farm use of cephalosporins inthe interest of public health.

Health Canada’s response to datehas been the introduction of nonbindinglabels warning against off-labelcephalosporin use in agriculture — ameasure that critics say has had littleeffect on usage levels.

Although the department promisedthe European Commission almost adecade ago that it would tighten controlson off-label use of drugs in agriculture,and acknowledges that it could ban thesale of cephalosporins for use in all orsome food animals, it contends that ju-risdiction over farm use of the antibi-otics falls within the purview of theprovinces. Health Canada, a spokesmansays, “does not have authority over ex-tra-label drug use.”

Critics counter that the governmentis simply dodging action on a growingpublic health problem and should obli-gate meat and poultry producers to curbantibiotic use and modify practices thatstress animal health.

Much of the debate surrounds sur-veillance data from the Canadian Inte-grated Program for Antimicrobial Re-sistance (CIPARS), which stronglyindicates that cephalosporin resistancein humans is moving in lockstep withuse of the drug in poultry production.

Financed by a $3-million annual con-tribution from the Public Health Agencyof Canada, CIPARS has been trackingantimicrobial-resistant bacteria in foodand on farms since 2002. In 2005, it re-ported startling levels of cephalosporin-resistant bacteria in chicken samplespurchased in grocery stores in Quebec

and Ontario and in samples taken fromhumans (www.phac -aspc .gc .ca /cipars -picra/2005-eng.php). At the same time,a study revealed near-universal use ofceftiofur, a cephalosporin- type antibi-otic, in Quebec chicken hatcheries.

The resistance levels in Quebecwere so high that hatcheries voluntarilyagreed to temporarily suspend ceftiofuruse. CIPARS director Rebecca Irwinsays the temporary ban led to a rapidreduction in cephalosporin resistance insalmonella samples taken from humansas well as from retail chicken products.

But more than 2 years after the vol-untary ban was lifted, the latest data onpoultry products purchased in theprovince indicate that resistance in sal-monella bacteria is again rising, Irwintold researchers at a May conference atthe University of Guelph, in Guelph,Ontario. “We are seeing an animal con-nection that we never saw before.”

In fact, CIPARS has issued 4 an-nual reports since 2005 that reinforcethe suspicion that ceftiofur use inchicken hatcheries is helping drive re-sistance to cephalosporins. Such re-sistance is “becoming a community-wide problem in Canadian cities,”

says Johann Pitout, a medical micro-biologist with Calgary LaboratoryServices in Calgary, Alberta.

A CIPARS update released in Marchindicated that ceftiofur resistance inbacteria in chicken and in humans rosedramatically in Ontario in 2008, (www.phac-aspc.gc.ca/cipars-picra /heidelberg/heidelberg_090326-eng.php).

Specialists on antimicrobial resist-ance say that the cumulative evidenceis overwhelming and that the time hascome to protect one of the most valu-able classes of antibiotics used to treattough-to-beat human infections.

“The CIPARS data are the mostconvincing I have ever seen,” saysFrank Aarestrup, a specialist on antibi-otic resistance with the Danish Techni-cal University in Copenhagen whohelped introduce a system of compre-hensive surveillance of all veterinarydrug use in Denmark since 2000.

Researchers have been intensivelyprobing links between antibiotics inagriculture and antibiotic resistance inhumans for well over a decade, Aare-strup says.

CIPARS has settled the issue, headds. “Taken in context with all the

The perils of poultry

CMAJ News

CMAJ • JULY 7, 2009 • 181(1-2)© 2009 Canadian Medical Association or its licensors

21

Cephalosporin antibiotics are routinely injected in chicks as a prophylactic.

Reu

ters

/Zo

hra

Ben

sem

ra

Published at www.cmaj.ca on Jun. 17.

other knowledge we have, anyone stillopposing a link between antibiotic usein food animal production and directhuman health impact does so for otherreasons than science.”

James Johnson, an infectious diseasespecialist with the Veterans Adminis-tration Medical Center in Minneapolis,Minnesota, concurs. “In the world ofobservational studies, the CIPARS ef-fort is as good as it gets.”

The CIPARS studies focused in parton ceftiofur, a third-generationcephalosporin antibiotic marketed byPfizer Canada Inc. for use in turkey,cattle, swine, lambs, dogs and horses. Ithas not been approved for use inchicken or eggs but is often roboticallyinjected — on an off-label basis — intoeggs as a prophylactic. It prevents po-tentially costly infection outbreaks inchickens, explains Daniel Venne, a vet-erinarian with Quebec hatchery opera-tor Couvoir Scott Ltee.

Venne and other veterinarians cau-tion that the CIPARS data do not con-clusively prove a link between theiruse of ceftiofur and the parallel emer-gence of cephalosporin-resistantpathogens in humans.

Other experts, though, argue that thedata warrant the introduction of stricterfederal regulations. “The CIPARS dataappears to be answering the questionabout a linkage between usage of an-tibiotics in animals and human resist-ance,” says Jim Hutchinson, chair ofthe Canadian Committee of Antimicro-bial Resistance.

In the United States, a review of theCIPARS data helped lead the Food andDrug Administration (FDA) to proposea ban in July 2008 on the off-label useof cephalosporins (http://edocket .access.gpo.gov/2008/E8-15052.html).

But after meat and poultry industryassociations fought back, the FDA re-tracted the proposal in favour of furtherconsultations. “The FDA has revokedthe order prohibiting the extra-label useof cephalosporins to allow our scien-tists the time necessary to consider sub-stantive public comments,” explainsagency spokeswoman Laura Alvey.

The CIPARS data helped fuel an in-tense political fight in Washington,D.C., says Morgan Scott, an epidemiol-ogist at Kansas State University in

tibiotic use and resistance. “It comesdown to finalizing the protocol and se-curing the financing.”

What national data that now exist onceftiofur usage is based on informationcollected by hatcheries, confirms RachelOuckama, a veterinarian with MapleLodge Farms in Port Hope, Ontario.

A glimpse into usage was providedto CIPARS in May at a closed meetingorganized by the Public Health Agencyof Canada and Health Canada, atwhich, Ouckama says, indications weregiven that ceftiofur is routinely injectedinto eggs in hatcheries in Ontario, Que-bec and the rest of country. The PublicHealth Agency of Canada wants the“poultry industry to better define an-timicrobial use to facilitate interpreta-tion of our CIPARS data.”

Meanwhile, resistance continues torise. In late March, CIPARS released

Manhattan, Kansas. “A lot of us wereblown away by what we saw in theCIPARS data,” says Scott, adding thatthe FDA recently signalled its intentionto reintroduce regulations limitingcephalosporin usage in agriculture.

Aaerstrup says Canadian manage-ment of veterinary use of antibiotics isless stringent than in many Europeancountries. He notes that as early as2003, a Danish supermarket chain re-jected quail meat contaminated withsalmonella resistant to cephalosporins,“as a food safety precaution.”

By contrast, in Canada, it appearsthat industry concerns trump precau-tionary principles.

Jérôme Castillo, a University ofMontréal veterinarian who serves onCIPARS’ scientific advisory board, saysthat chicken hatcheries began using cef-tiofur due to difficulties obtaining drugscapable of containing disease outbreaks.

A single injection of ceftiofur intoeggs “proved quite effective,” he ex-plains. But the subsequent appearanceof cephalosporin resistance in chickenswas also pronounced, he adds.

Nevertheless, Castillo warns that the“causal relationship between what thepoultry veterinarians did and what ap-peared in the human laboratories issomething that has to be taken withcaution. It’s not something that is nec-essarily cause and effect.”

Some of the uncertainty about thelink appears to stem from an inabilityto collect data that might confirm thecase. Irwin has frequently complainedof trouble accessing drug-usage data inmany provinces because of commercialbarriers. “People can hide behind what-ever,” she told researchers at theGuelph gathering in May. “We’re stillgetting the ‘hear no evil, see no evil,speak no evil’ from numerous sources.”

Steve Leech, national program man-ager of the Chicken Farmers of Canada,explains that although antibiotic-usagedata from chicken flocks is submittedto inspectors with the Canadian FoodInspection Agency, CIPARS does nothave access to the data because both in-dustry and the inspection agency con-sider it confidential business informa-tion. But Leech says the chickenindustry is working now with CIPARSto improve on-farm surveillance of an-

News

CMAJ • JULY 7, 2009 • 181(1-2)© 2009 Canadian Medical Association or its licensors

22

The most recent CIPARS update indi-cates that antibiotic resistance in retailchicken bacteria increased in Quebec,Ontario, British Columbia andSaskatchewan from 2007 to 2008.

Pho

tos.

com

an update indicating that from 2007 to2008, resistance in retail chicken bacte-ria increased in Quebec, Ontario,British Columbia and Saskatchewan —with BC posting the highest gain from29% to 46%.

“The rates of resistance are certainlyalarming,” says University of BritishColumbia Faculty of Medicine infec-tious disease specialist Bill Bowie.“Since ceftiofur resistance likely corre-lates with resistance to drugs like ceftri-axone, and similar cephalosporins inuse in human medicine, this resistancein poultry predicts that proportions ofthe human population are being ex-posed to the resistance factors.”

Further concern was expressed inDecember 2008 by Ontario’s AuditorGeneral, who reported that “no correc-tive action” was taken in response to aprovincial antibiotic residue-testingproject that indicated “a high number ofadverse results” for a number of animalclasses (www.auditor.on.ca/en/reports_en/en08/309en08.pdf).

Some members of industry havealso expressed concern. At a 2005 con-ference, Bill Ballantyne, technical di-rector for procurement with Maple LeafFoods, which operates 2 Ontario hatch-eries and markets Canada’s leadingbrand of chicken, indicated that the“uncertainties” of antimicrobial resist-ance “represent a significant risk for themeat industry.” Ballantyne added thatthe industry was “confused by the ap-parent inability to separate political,economic and scientific agendas onfarm safety programs.”

Maple Leaf, though, declined re-quests to interview Ballantyne or acompany veterinarian about ceftiofurusage. “Our veterinarians administerantibiotics in the hatcheries when theyare needed,” spokesperson RachelDouglas stated in an email. “We sourcefrom a list of federally approved antibi-otics for limited use in our hatcheries.”

Although Health Canada says itdoes not have up-to-date informationabout such off-label usage, a 1990 sur-vey commissioned by the departmentfound that 260 of 310 veterinarians em-ployed off-label use of veterinarydrugs, either to species not indicated onthe label, or at higher dosages than rec-ommended (www.hc-sc.gc.ca/dhp-mps

/pubs /vet /eldu -umdde_issue-enjeux_final_10-12-2004-eng.php).

The extent of off-label use has al-ready had trade implications. In 2000, ateam of European Commission trade in-spectors concluded that Canadian meatproducts did not meet European safetystandards largely because of “inade-quate restrictions” on off-label usage.

European Union inspectors foundnumerous safety violations and notedthat approximately 50 veterinary drugs— including a carcinogen banned inEurope and antibiotics banned for theirrole in the development of resistantbacteria — “are freely available forfarmers and feedlot operators as med-icating ingredients authorized for incor-poration in livestock feedingstuffs.”The investigators also noted that manydrugs were administered directly byfarm workers without veterinary supervi-sion (ec.europa.eu /food /fs/inspections /vi/reports /canada /vi_rep _cana_1188-2000_en.pdf).

In response, Ottawa promised theEuropean Commission that it wouldenhance control of off-label drug use“through the combined force and im-pact of federal and provincial legal andregulatory frameworks.” The govern-ment launched a national study, whichwas eventually abandoned.

Similarly, in 2002, Health Canadawas advised by its Advisory Commit-tee on Animal Uses of Antimicrobialsand Impact on Resistance and HumanHealth to develop a more restrictiveoff-label farm-use policy.

The government responded by ap-pointing a committee to study the issuein 2004. It warned that farmers wereimporting “unapproved products” foroff-label use. Unregulated off-label usewas even allowing farmers to “com-pound” or make their drug mixes, apractice that “may involve humandrugs, approved or unapproved drugproducts” (www.hc-sc.gc.ca/dhp-mps/pubs/vet/eldu-umdde_issue-enjeux_final_10-12-2004-eng.php).

In 2008, the Canadian VeterinaryMedical Association issued guidelinesstating that ceftiofur should only beused in chickens and eggs in emer-gency situations.

Eventually, Health Canada took ac-tion, adopting a nonbinding and unen-

News

CMAJ • JULY 7, 2009 • 181(1-2)© 2009 Canadian Medical Association or its licensors

23

Abbott Laboratories Ltd,Humira,

1/3 page vertical4 clr,

May 26

CMA Secretary-General

The search may have been na-tionwide but the solution wasin-house as the Canadian Med-

ical Association concluded its hunt fora new secretary-general and chief ex-ecutive officer by appointing Paul-Émile Cloutier to the position.

Cloutier will set aside his currentduties as assistant secretary-general foradvocacy, communications and publicaffairs on Jul. 20 to assume the helm ofthe association’s operational arm.

“I think there’s 2 challenges,”Cloutier says. “One is to keep the doc-tors together under one voice, espe-cially in light of some of the major de-bates that we have within CMA, anddebates outside CMA. The next one isto find ways to bring CMA to membersand find a value or define what valuewe bring to PTMAs, the provincial-territorial associations. It’s our time tostart thinking of how we best respondto their needs.”

It’s important that CMA alwaysspeaks on behalf of its 70 000 mem-bers, particularly with respect to trans-formation of the health care system, hesays. “You don’t want to be perceivedout there as being an organization towhich there are different camps. Youwant to speak to everyone, at least from

needs; and implementing CMA’s newgovernance structure (CMAJ 2008; 179[6]:520).

If there are extant concerns aboutgovernance, “we must find solutions toensure that none of our divisions, andnone of our members, feel disconnectfrom CMA.”

Asked what possessed him to throwhis hat in the secretary-general’s ring,Cloutier replied that he has a “passionfor what we do and I believe in whatwe do, for both the profession and forpatients, for Canadians. … CMA needsto lead that debate in health care trans-formation or health care reform and mywhole career has been outreach and ad-vocacy and I felt there was something Icould bring to the table.”

Cloutier joined CMA in 2002 afterstints in the Ontario ministry of inter-governmental affairs; the federal de-partments of Indian affairs, immigra-tion and foreign affairs; and Via RailCanada.

Cloutier replaces interim secretary-general Barbara Drew, who assumedthe position when William Tholl re-signed after more than 7 years in thejob (CMAJ 2008;179[10]:994).

Cloutier is married to Dr. JocelyneLalonde, a family physician inGatineau, Quebec. The couple have a9-year-old son, Pierre-Alexandre.

a public point of view, that we are oneforce.”

At their core, all doctors desire “tolook at what are some of the betterways of doing the business that they arein, which is patient care.”

Among immediate priorities are ex-panding the membership base; meetingprovincial and territorial medical asso-ciations to discuss how the national as-sociation might better serve their

For the record

News

CMAJ • JULY 7, 2009 • 181(1-2)© 2009 Canadian Medical Association or its licensors

24

forceable policy in 2008 that required asafety warning advising against off-label usage to be added to ceftiofurpackages.

“Based on the available scientificdata, including results from CIPARS,”department spokesman Stéphane Shankexplains, Health Canada “concluded thatcertain uses of ceftiofur in certain foodproducing animals have increased thepotential for antimicrobial resistance.”

Hutchinson calls the new labelwarning a tepid response. “In the scaleof possible regulatory actions, a labelchange is a very soft step. I don’t thinka label change is enough.”

Hatchery veterinarians in Quebec,Ontario, Alberta and BC confirm that

these drugs for food. These regulationsare enforceable.”

With no indication from HealthCanada that such restrictions are evenbeing contemplated, Hutchinson lamentsthe inaction. “We’ve been crying fromthe rafters that we need a whole lot moreoversight of antimicrobials,” he says.“Antimicrobial resistance is one of thebiggest health problems confronting theplanet. There is need for federal over-sight on this. But the overriding interestseems not to be in human health. Andthat is a problem for Canadians.” —Paul Webster, Toronto, Ont, with filesfrom Aruna Handa, Toronto, Ont.

DOI:10.1503/cmaj.091009

routine off-label usage of ceftiofur nowcontinues in nonemergency situations.

Even so, Shank defends his depart-ment’s response. “The practice of medi-cine including veterinary medicine, andhence the use of drugs, is under the au-thority of the provinces,” he says.“Therefore, Health Canada does not haveauthority over extra-label drug use.”

But in the event a drug is found toraise safety issues — which HealthCanada acknowledges is why warningsagainst off-label usage were added toceftiofur packages — Shank confirmsthat “Health Canada could introduceregulations to ban the sale of certaindrugs for use in food animals and pro-hibit the sale of animals treated with

Paul-Émile Cloutier

Mar

k H

olle

ron