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International Journal of Antimicrobial Agents 30 (2007) 101–107

Review

Withdrawal of growth-promoting antibiotics in Europeand its effects in relation to human health

Ian Phillips ∗

Calle Cabello 7, Malaga 29012, Spain

bstract

The glycopeptide avoparcin, bacitracin, the macrolides spiramycin and tylosin, and the streptogramin virginiamycin were withdrawn asrowth promoters in the European Union between 1995 and 1999 on the basis of the Precautionary Principle. Relevant resistance thereuponiminished among enterococci (the indicator organisms) isolated from animal and human faeces. However, animal enterococci were showno differ from those that caused human infections, although their resistance genes were sometimes indistinguishable and thus probably havecommon origin. Before the ban, human clinical isolates of enterococci resistant to vancomycin or teicoplanin were uncommon in many,

ut not all, parts of Europe and resistance to quinupristin/dalfopristin in the case of Enterococcus faecium was very rare. After the ban, theseesistances increased in prevalence almost universally, to the detriment of human health. Campylobacters, normally susceptible to macrolides,ncreased in prevalence before and after the ban. Analyses suggest that the added risk to human health from resistance among enterococci and

ampylobacters selected by growth promoter use is small, whilst the benefit to human health from their use, hitherto largely ignored, mightore than counterbalance this.2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

eywords: Food animals; Growth promotion; Antibiotics; Resistance; Epidemiology; Human clinical isolates; Human health

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. Introduction

‘Whenever the evidence in a dispute is inconclusive thecientific vacuum is filled by the assertion of contradictoryertitudes’, John Adams [1].

It is now more than a decade since the Union-wide with-rawal of selected growth-promoting antibiotics started inurope. Sweden had discontinued their use in 1986, and

he Danes withdrew the glycopeptide avoparcin, rapidly fol-owed by the rest of the European Union (EU), in 1995.y the middle of 1999, the growth-promoting use of bac-

tracin, spiramycin, tylosin and virginiamycin had ceasedn the whole EU on the basis of the Precautionary Prin-iple, since it was agreed by those who had the task of

anaging the perceived hazard that evidence of actual risk

o human health was not forthcoming [2]. This puts theuestion of harm to human health in the field of virtual

∗ Tel.: +34 952 226 792; fax: +34 952 226 792.E-mail address: i3phillips@telefonica.net.

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924-8579/$ – see front matter © 2007 Elsevier B.V. and the International Societyoi:10.1016/j.ijantimicag.2007.02.018

isk, with all that goes with that categorisation [1]. Thepplication of the Principle, which discounts the contradic-ory interpretations of scientific findings, still carried witht an obligation that further evidence be obtained [3]. Iteems reasonable now to assess both whether such evi-ence has indeed been sought and what has been the effectf the withdrawal of these antibiotics in relation to humanealth.

There are those who believe that the case against antibioticrowth promoters is settled. For example, Collignon, com-enting on a review of which I was a co-author [4], expressed

ismay that we ‘were defending what nearly all microbi-logists know are grave abuses of antibiotics’ [5]. Mølbak6] and Angulo et al. [7] have expressed a similar opinion.owever, others are not so sure. Those of us who wrote a

eview of the evidence in 2004 and the reply to criticisms [4,8]

learly do not agree. Going beyond our statements, Wasse-aar has it that ‘veterinary usage of antimicrobial agents’oes not cause ‘a major health risk’ [9]. Accepting that therere still two points of view, Lord Soulsby, the chairman of

of Chemotherapy. All rights reserved.

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he House of Lords committee that strongly supported theiriscontinuation, has recently admitted that controversy con-inues and that expectations of limitation of antibiotic use

ay be naıve [10]. Turnidge, also commenting on our review,ecognised the continued controversy [11]. Conflicting viewsontinue to be held, probably because attempts to produce fur-her evidence for or against discontinuation in the context ofntibiotic growth promoter use have been few. It seems thatany of those in a position to obtain the evidence have not

een persuaded of the need for it, presumably feeling that theegulatory battle has been won without such scientific efforts.ndeed, the Court of First Instance of the European Commu-ities in Luxembourg concluded in 2002 that there was stillisagreement among scientific experts and ruled that the banhould stand, still on the basis of the Precautionary Princi-le [12]. Forrester and Hanekamp have recently discussedegal implications of the judgment [13]. One has to haveome sympathy for the lawyers called upon to make suchecisions, although one might have hoped that they wouldnderstand that natural scientists are not able to offer proof,ut merely hypotheses that might be more or less persua-ive. When asked for guarantees of future events—for goodr ill—the scientist should make it clear that the question isot one that should be asked, if the court will permit him too so!

It is unfortunate that there has been no opportunity forisinterested discussion of the discontinuation of antibi-tic growth promoters in a purely scientific forum, whosebjective might have been to produce a balanced view onhat is agreed and what is disputed in relation to sci-

nce, and more importantly, how the lack of evidenceight be tackled. Furthermore, the true breadth of con-ict of interest, apparent to some of us in meetings thatave taken place, for example that held in Copenhagen14], is not apparently widely recognised. The editors ofhe Journal of Antimicrobial Chemotherapy have recentlyrawn attention to religious, personal, political, academicr financial conflicts of interest, and while insisting onransparency in relation to the last of these, have inviteduthors to draw attention to any of the others [15]. Theame transparency might be asked of participants in con-resses.

Leaving virtual risks to human health aside, there haveeen a number of attempts to assess other outcomes of theuropean antibiotic withdrawals, which, it should be remem-ered, was based on a totally uncontrolled experiment. I haveeveral times suggested that if their laboratory microbiolog-cal experiments were conducted to similar standards, thenvestigators would be rightly castigated, and I continue toee no reason why lower standards should be acceptable ineld experiments. Nonetheless, a World Health OrganizationWHO)-sponsored group concluded that the Danish experi-

ent had been a success, but it is notable that they did not

ssess its cost, including the provision of alternative mea-ures, and they did not assess its effect on human health16].

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crobial Agents 30 (2007) 101–107

. Effects of the ban

.1. Observance of the ban

It seems clear that the ban was obeyed, with objective evi-ence in those countries that collect statistics on the detailsf antibiotic use. For example, in Denmark, the growth-romoting use of the banned antibiotics declined from ca.00 tonnes in 1997 to nil by the end of 1999, and remainedo [17]. The Norwegians [18] followed a similar path. How-ver, macrolides, previously used both for growth promotionnd for the prevention and treatment of infection, continuedo be used legitimately for disease control, and their use forherapy increased markedly after the ban [17].

.2. Advances in scientific methodology

Improvement in the techniques relevant to the surveil-ance of the microbiological effects of growth-promotingntibiotics is worthy of comment. Methods for speciationf relevant bacteria have improved and have been moreidely used, especially in the distinction between Entero-

occus faecalis and Enterococcus faecium, in which contexttreptogramin resistance was important [4]. There has alsoeen progress on the standardisation of antibiotic resistancereakpoints [19], important for valid comparison of resis-ance rates from time to time and from place to place. Alearer general appreciation of the difference between micro-iological (or epidemiological) and clinical breakpoints istill needed. Genetic methods are now well developed for theetection of resistance genes. One has only to look back at theriginal methods of typing enterococci, introduced largelyo study the relationship of animal and human isolates, toppreciate the progress that has been made in this field asell [4]. A prime example is the work that has been done

o improve our knowledge of staphylococcal relationshipsnd evolution, particularly fruitful for methicillin-resistanttrains [20]. According to the multilocus sequence typingebsite (http://www.mlst.net), systems now exist for typingoth E. faecalis and E. faecium, and these are suitable fornvestigation of the evolution of strains [21]. There have alsoeen advances in knowledge of pathogenicity, for examplemong enterococci from infected humans [21]. Campylobac-ers from animal and human hosts are also a good target foruch studies. Methods of surveillance have also improved andeen more widely applied [22]. Finally, one might note anncreased interest in analysis of risk and benefit, exemplifiedn the debates on oily fish and micronutrients [23,24].

.3. Food–animal faecal flora

The ban was followed by, and very probably resulted in,

reduction in the prevalence of resistance among so-called

ndicator bacteria in the faecal contents of food animals, ofhich enterococci are important in relation to the anti-Gram-ositive growth-promoting antibiotics. In a multinational

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tudy involving six European countries, which by chance wasonducted in two periods immediately before and after thean came into effect [25], there was a statistically signifi-ant decrease in prevalence of E. faecium strains resistanto spiramycin and tylosin or to virginiamycin. There waso change in the already low prevalence of glycopeptideesistance (not surprising since avoparcin use had been dis-ontinued earlier) or in susceptibility to bacitracin (to whichhe enterococci are usually resistant regardless of the use ofhe antibiotic, as shown by results from Sweden where it hadot been used for many years). These findings corroboratend extend those from Denmark, Sweden and The Nether-ands [4]. In 2005, streptogramin resistance rates had fallenrom 40–60% in the late 1990s to 16% in pigs and 13% inhickens in Denmark [17]. It has been concluded that theesistance gene pool has been reduced, and this view was sup-orted by the WHO review panel [16]. A more conservativeiew would be that one of the streams had been cleared whilstther sources of pollution may have been created. The sizef the pool cannot even be guessed at. However, even thisonclusion requires caution, since more sensitive methodsf detection of resistant enterococci reveal that the resistantrganisms may lurk in smaller numbers. A recent study inortugal illustrates this point. In chicken collected in retailutlets, no vancomycin resistance was detected in 19 iso-ates of E. faecalis and in only 2 of 14 E. faecium isolates inon-selective cultures, but was detected in 8/8 and 61/61 iso-ates, respectively, in cultures on plates containing 6 mg/Lancomycin. A similar result was obtained for high-levelentamicin resistance with plates containing no antibioticr 125 mg/L gentamicin. On the other hand, resistance toetracycline, ciprofloxacin and quinupristin/dalfopristin wasommonly detected on non-selective plates [26]. Such resultsight be expected if samples contained few enterococci resis-

ant to vancomycin or gentamicin but larger numbers resistanto the other antibiotics. The significance of reduced numbersf resistant enterococci rather than total absence remains toe studied.

Other organisms that might be expected to have becomeore susceptible as a consequence of the ban are campy-

obacters in relation to macrolides, although the increased usef therapeutic macrolides in food animals [17] may have miti-ated the effect. It is a problem that Campylobacter jejuni andampylobacter coli are intrinsically of only modest suscepti-ility to macrolides, with erythromycin minimum inhibitoryoncentrations (MICs) typically ranging from 0.5 mg/L tomg/L for strains without acquired resistance [17,27]. Theanes consider this to indicate susceptibility, whilst theireighbours, the Norwegians, have considered them suscepti-le for animal isolates but of intermediate susceptibility forsolates from humans [18]: the latter conclusion is in keep-ng with the pharmacology of erythromycin in humans whilst

he former is a purely microbiological (or epidemiological)reakpoint [19]. The European Committee on Antimicrobialusceptibility Testing (EUCAST) clearly has more work too! Considering only the microbiological (MIC > 16 mg/L)

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esistance of C. jejuni, the prevalence has always been lown the faecal flora of food animals in Denmark between 1996nd 2004 — usually 0–1% in broilers (with the exceptionf a 5% result in 2000) and 0–4% in cattle (with the excep-ion of 8% in 2001) [17]. A European study showed a similarow prevalence of macrolide resistance in isolates of C. jejunirom chickens and cattle [27]. The case of fluoroquinolones isot directly relevant here since they were not used as growthromoters. However, it may be noted that resistance levels insolates from broilers never exceeded 8% and levels from cat-le were always below 10% except in 2000 and 2002 (15% and1%, respectively) until it shot up to almost 30% in 2005 [17].n other parts of Europe, the prevalence of fluoroquinoloneesistance in animal isolates varies widely [22,27].

.4. Carcass and animal-derived food contamination

One might expect that the prevalence of resistant entero-occi from food animals at slaughter might be similar to therevalence in organisms contaminating animal-derived food.he evidence is confusing. For example, in 2005, whilst therevalence of macrolide resistance in E. faecium was 50% inhe faecal content of pigs, it was only 13% in Danish pork,hilst 59% of isolates from pigs were resistant to tetracy-

line but only 21% of isolates from pork [17]. On the otherand, in 2004, the last year for which results are currentlyvailable, resistance rates for streptogramins were very simi-ar for E. faecium from domestic broilers and broiler meat24% and 17%) and from domestic pigs and pork (13%nd 13%) [28]. It may be that enterococcal contaminationften arises from other sources (such as food handlers or byross-contamination) or that some antibiotic-resistant strainsurvive better on meat, but virtually nothing is known of theynamics within the normal enterococcal pool.

For campylobacters, macrolide resistance had a compat-ble prevalence of 0–3% in C. jejuni from Danish chickensnd broiler meat in 2004 and 2005 [17,28].

.5. Human faecal flora

It was established before the withdrawal of avoparcin thatancomycin-resistant enterococci (VRE) could be found inhe faeces of healthy humans, with a prevalence varyingepending on the methodology used. A decline in prevalenceas noted after the ban. Likewise, streptogramin-resistant E.

aecium was found in human faeces [4]. In the UK in 2001,nly four streptogramin-resistant E. faecium strains, inhibitedy 8–32 mg/L virginiamycin, were isolated from 2000 humanaecal samples collected in a rural community [29]. However,n Denmark, resistance to streptogramins of human faecal iso-ates of E. faecium had reached 54% in 2005, although MICsere only marginally elevated [17], in some contrast to the

ates of resistance for either domestic or imported chickenr pigs (see Sections 2.3 and 2.4). On the other hand, therevalence of macrolide resistance also increased in 2004nd 2005, having previously fallen in parallel with results for

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igs and pork [17]. Both of these changes occurred 5 yearsfter the ban of streptogramins and macrolides as growthromoters.

.6. Human clinical isolates

The prevalence of vancomycin resistance among clin-cal enterococcal isolates varied widely in Europe beforehe growth promoter ban [4] and has continued to do so30]. It remains possible that the increases in prevalence oflycopeptide-resistant enterococcal infection seen in someountries during the period when avoparcin was being usedn animals (before 1995 in the EU) might have been relatedo the high prevalence of similar resistance in food–animaltrains—but events in the USA clearly showed that such aource was not necessary. We have rehearsed our own reser-ations at some length [4]. Appropriate molecular methodsave recently been applied to human outbreaks of infection.t seems possible now to conclude that the animal bacteriahemselves are not an important cause of serious infection inumans [21] but that resistance genes in animals and humansre on occasion the same [31]. Transferred genes may thusave had a role, but if so it required the extra factor of humanntibiotic use to bring about increases in the frequency of clin-cal isolates. The increasing use of vancomycin for treatmentf necrotising enterocolitis or methicillin-resistant Staphylo-occus aureus (MRSA) infection may have been a factor—asas probably the case in the USA [4]. Since the ban, manyarts of Europe are increasingly experiencing epidemics ofirulent resistant enterococci, clearly well adapted to humans,hatever the source of their resistance genes [21]. Accord-

ng to the European Antimicrobial Resistance Surveillanceystem (EARSS) 2004 annual report [30], the incidence ofRE among invasive isolates of E. faecium reached more

han 25% in Greece, Ireland, Israel, Portugal and the UK in005. Overall, 9% of the E. faecium isolates submitted toARSS were vancomycin resistant in 2004, rising to 14% in005 [30], a phenomenon that the ban was surely expected byome to prevent. However, Scandinavia and much of Easternurope reported very few or no isolates of VRE. It is alsolear that streptogramin resistance in E. faecium was raremong human clinical isolates during the period of exten-ive virginiamycin use in animals but increased rapidly whenuinupristin/dalfopristin started to be used [4]. Ironically, iniew of their concern, Denmark is among the few countriesot reporting on enterococci to EARSS.

As a contribution to the discussion of potential sources ofampylobacter, it is interesting to study reports of quinolonend tetracycline resistance in chicken and human isolates of. jejuni in Denmark. The discrepancies have been a stim-lus for endless apologetics. Considering only quinoloneesistance, over the past few years resistance rates have not

een above 8% for broilers or broiler meat but reached 29%or domestically acquired human campylobacter infection in004. This has been attributed to the ingestion of importedhicken, isolates from 49% of which were fluoroquinolone

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crobial Agents 30 (2007) 101–107

esistant in 2004 [28]. It is not clear that the 30% importationate quoted for chicken meat is capable of explaining the dis-repancy between food and human isolates in any simple way.his discussion is relevant to growth promoters only in thease of macrolides, since erythromycin resistance rates areimilar in chicken and human C. jejuni, a finding that is com-atible with the hypothesis that chickens are a major sourcef human campylobacteriosis, at least in Denmark, and thatacrolide use in chickens might be the driver of macrolide

esistance in humans. However, since there are sources ofampylobacter other than food animals, efforts spent in con-rolling antibiotic use—or even campylobacters—in animalsre likely to have a limited effect on humans. Perhaps a thor-ugh investigation of the types involved would contributend a start has been made. In a recent study in Austria, inhich modern molecular typing methods were used, differ-

nces between animal and human strains were striking; of02 types, only three (in ten isolates) were found both in ani-als and humans [32]. The castigation meted out in response

o our suggestion that chickens may not be the most impor-ant source of campylobacter infection [4,8,33–36] may yetrove not totally deserved.

.7. Human health

The crucial question is what effect the growth promoteran has had on human enterococcal and campylobacter infec-ion. The question should nowadays be separated into theuestions of benefit and harm.

.7.1. BenefitIn Denmark, the ban could have had little benefit in relation

o enterococci since human infection caused by organismsith relevant resistance, such as VRE or streptogramin-

esistant E. faecium, was always vanishingly rare there [4]. Inhe rest of Europe, increases in the prevalence of infectionsith such organisms has already been noted [30]. The clinical

mpact of VRE in immunocompromised patients is not ques-ioned, and efforts to reverse trends are clearly desirable, buto benefit from the ban is apparent, unless it is argued thathe increases in incidence, escalating almost 10 years afterhe ban, might have been still greater.

For C. jejuni, the Danes have found no obvious benefitrom the ban of macrolides as growth promoters since humansolates in Denmark are consistently, albeit marginally, moreften macrolide resistant than are isolates from chickens,hether home-produced or imported, and the increased ther-

peutic use of macrolides in food animals appears not to haveelected resistant campylobacters [17].

.7.2. Harm to human health arising from the banThe use of growth-promoting antibiotics in food animals

ight benefit human health, a possibility apparently notonsidered important by enthusiasts for a ban. A potentialechanism is the deterioration in animal health observed

fter the ban and arguably the result of the ban—an

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rgument not universally accepted. Whatever the reason forhe undoubted deterioration of animal health, there was austained increase in the use of therapeutic antibiotics inood animals in the years after the ban, introducing newressures on antibiotics of direct relevance to human diseaseunlike most of the growth promoters). The effects of thisave been varied, with resistance to some of them increasingnd some not affected. Thus, pig enterococcal isolates haveecome more often resistant to tetracyclines but not torythromycin despite increased therapeutic use of both [17].

But another problem of potentially greater importancerises. Unhealthy animals, including those that are subclini-ally infected and would not be rejected as food for humanonsumption, are more likely to produce faecally contami-ated carcasses than are healthy animals, probably becausehey are less standardised in size. This results from damageo the intestines during mechanical evisceration. The visibleaecal contamination is accompanied by increased bacterialontamination [37] and it has been shown in one investiga-ion that campylobacter contamination levels may increasey ten-fold [38]. Such contamination might have an effecthroughout the food chain up to ingestion by humans—andlthough adequate hygiene and thorough cooking would bexpected to counter this, it is well recognised that deficienciesn both are not uncommon. There is an urgent need for thisossibility to be investigated further—and the experimentsre not difficult to devise or perform! The relentless increasen the prevalence of human campylobacteriosis in the EU [22]s so far unexplained, but we are not aware of any effort tonvestigate its potential relationship to the cessation of use ofrowth-promoting antibiotics.

The authoritarian denial of such harm potentially arisingrom growth promoter withdrawal [34] is not a sufficientesponse, especially from those who have seen significancen equally unproved relationships between growth promoterse and harm.

.8. Risk and risk–benefit assessment

In the absence of direct evidence of harm to humanealth, it has been suggested that risk analysis and math-matical modelling might usefully inform the debate. Theethodology of risk analysis has significantly improved,

specially with the emphasis on quantitation. Several purelyisk analyses, both qualitative and quantitative, have noween published, as discussed by Snary et al. [39]. All of themuggest a small additional risk either of death or prolongationf illness arising from growth-promoter use. The importancef this extra morbidity and mortality is not doubted. However,s Lothario said to Anselmo, who invited him to test his wife’sdelity on his behalf, ‘for men to execute designs which arelearly of more hurt than benefit, is the province of madness

nd temerity’ [40]. When we made the suggestion that harmo human health might arise from the ban (and we admitted toaving no direct evidence) we too were accused of ‘madnessnd temerity’ [33–36], although more for disagreeing with

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crobial Agents 30 (2007) 101–107 105

nterpretations and the views of ‘experts’ rather than with theasic science [8]. The methodology of cost–benefit analy-is is just evolving, and I am aware of only two publishedost–benefit studies, relating to the use of virginiamycin41] or macrolides [42], which conclude that the benefito human health arising from the use of growth-promotingntibiotics outweighs the risk. More such analyses are calledor.

. Conclusions

In the face of continuing enthusiasm for the growth pro-oter ban in Europe several years after its introduction, we

ttempted to assess the evidence, emphasising the evidencegainst it since others had often failed to admit dissent. Over-ll, little seems to have changed.

It is agreed that the ban on growth-promoting antibioticsas resulted in their actual withdrawal in those countrieshat have relevant surveillance. It is also agreed among sci-ntists that the human pathogens likely to be affected byhe ban on antibiotic growth promoters in the EU are ente-ococci and campylobacters (since other common zoonoticathogens are not susceptible to them) and these have beenhe target of surveillance. It is further agreed that the banesulted in an immediate diminution in the number of ani-als and humans carrying resistant faecal enterococci, at

east in easily detectable numbers. The story is rather dif-erent when more sensitive methods of detection are used.his may have resulted in a diminution of the resistance geneool, a reasonable hypothesis but not a validated scientificonclusion since the pool has never been measured. How-ver, the prevalence of some resistance among animal faecalsolates has subsequently decreased only partially or has evenncreased, probably as a result of the increased use of ther-peutic antibiotics in animals in response to an increase inhe prevalence of certain infections. Not all are agreed aso whether these infections in food animals have resultedrom the ban or have had an independent origin. Whateverhe explanation, the increased use of therapeutic antibioticsas persisted. Whilst resistant faecal bacteria from animalsay contaminate animal-derived food, this is not the only

ource of the relevant species. Food contaminants may reachumans via the imperfectly protected food chain. In the casef enterococci, this might result in transient human faecalarriage of strains of animal origin, and this might in turnrovide an opportunity for resistance gene transfer to resi-ent human enterococci, although controversy continues aso whether this specific genetic transfer occurs in real life.ut this has not been shown to occur naturally in man [43].ontroversy regarding the effect on human health contin-es, complicated by the confounding effect of recognised as

ell as potential virulence mechanisms. Meanwhile, analy-

es suggest that a small risk to human health arises from these of a variety of growth-promoting antibiotics, whilst therst risk–benefit analyses suggest that this risk might be more

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han compensated by benefits to human health arising fromheir use.

We are thus little further advanced in the scientific debatehan we were 10 years ago when the Scientific Committee fornimal Nutrition (SCAN) advised that evidence of harm touman health from growth-promoting antibiotics was lack-ng. It has been suggested that since the ban on antibioticrowth promoters in Europe is a fait accompli, it is time toove on. If this means that novel scientific effort, as opposed

o more of the same, will be devoted to the major problem ofntibiotic resistance in human pathogens, I applaud it. How-ver, if it is shown that there is harm as well as good arisingrom the EU ban, I would hope that disinterested scientistsill rediscover an interest in antibiotic growth promoters.

eferences

[1] Adams J. Risky business. London, UK: Adam Smith Institute; 1999. p.31.

[2] The Council of the European Union. Council regulation (EC) No.2821/98 of 17 December 1998 amending, as regards withdrawal of theauthorization of certain antibiotics, Directive 70/524/EEC concerningadditives in feedingstuffs. Official Journal of the European Communi-ties (1998); L 351/4–8.

[3] Commission of the European Communities. Communication from theCommission on the Precautionary Principle. Commission of the Euro-pean Communities; 2000. COM (2000) 1.

[4] Phillips I, Casewell M, Cox T, et al. Does the use of antibiotics in foodanimals pose a risk to human health? A critical review of publisheddata. J Antimicrob Chemother 2004;53:28–52.

[5] Collignon P. Antibiotic growth promoters. J Antimicrob Chemother2004;54:272.

[6] Mølbak K. Spread of resistant bacteria and resistance genes from ani-mals to humans—the public health consequences. J Vet Med B InfectDis Vet Public Health 2004;51:364–9.

[7] Angulo FJ, Nargund VN, Chiller TC. Evidence of an associationbetween use of anti-microbial agents in food animals and anti-microbialresistance among bacteria isolated from humans and the health conse-quences of such resistance. J Vet Med B Infect Dis Vet Public Health2004;51:374–9.

[8] Phillips I, Casewell M, Cox T, et al. Does the use of antibiotics in foodanimals pose a risk to human health? A reply to critics. J AntimicrobChemother 2004;54:276–8.

[9] Wassenaar TM. Use of antimicrobial agents in veterinary medicine andimplications for human health. Crit Rev Microbiol 2005;31:155–69.

10] Soulsby EJ. Resistance to antimicrobials in humans and animals. BMJ2005;331:1219–20.

11] Turnidge J. Antibiotic use in animals—prejudices, perceptions andrealities. J Antimicrob Chemother 2004;53:26–7.

12] The Court of First Instance of the European Communities. Luxem-bourg, September (2002). Case T-13/99.

13] Forrester I, Hanekamp JC. Precaution, science and jurisprudence: a testcase. J Risk Res 2006;9:297–311.

14] Copenhagen Recommendations. Report from the European Conferenceon ‘The Microbial Threat’, Copenhagen, Denmark, 9–10 September1998. Copenhagen, Denmark: Ministry of Health and Ministry of Food,Agriculture and Fisheries; (1998).

15] Jeeves CL, Drummond CWE, Reeves DS. Conflict of inter-est/transparency: new policy. J Antimicrob Chemother 2005;56:609–10.

16] World Health Organization. Impacts of antimicrobial growth pro-moter termination in Denmark. Foulum, Denmark: WHO; 2003.

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crobial Agents 30 (2007) 101–107

http://www.who.int/salmsurv/links/gssamrgrowthreportstory/en/[accessed 7 March 2007].

17] Danish Integrated Antimicrobial Resistance Monitoring and ResearchProgramme. DANMAP 2005. Use of antimicrobial agents and occur-rence of antimicrobial resistance in bacteria from food animals, foodand humans in Denmark. Statens Serum Institut, Danish Veterinaryand Food Administration, Danish Medicines Agency,;1; Danish Insti-tute for Food and Veterinary Research; 2006. http://www.danmap.org[accessed 12 March 2007].

18] NORM/NORM-VET 2004. Usage of antimicrobial agents and occur-rence of antimicrobial resistance in Norway. Tromsø/Oslo. 2005.

19] European Committee on Antimicrobial Susceptibility Testing.EUCAST procedure for harmonising and defining breakpoints.http://www.srga.org/Eucastwt/bpsetting.htm [accessed 7 March2007].

20] Robinson DA, Enright MC. Multilocus sequence typing and the evo-lution of methicillin-resistant Staphylococcus aureus. Clin MicrobiolInfect 2004;10:92–7.

21] Leavis HL, Bonten MJM, Willems RJL. Identification of high-risk ente-rococcal clonal complexes: global dispersion and antibiotic resistance.Curr Opin Microbiol 2006;9:454–60.

22] European Food Safety Authority. The community summary reporton trends and sources of zoonoses, zoonotic agents and antimicro-bial resistance in the European Union in 2004. EFSA J (2005); 94.http://www.efsa.europa.eu [accessed 7 March 2007].

23] Tuomisto JT, Tuomisto J, Tainio M, Nittynen M. Risk–benefit analysisof eating farmed salmon. Science 2004;305:476.

24] Renwick AG, Flynn A, Fletcher RJ, et al. Risk–benefit analysis ofmicronutrients. Food Chem Toxicol 2004;42:1903–22.

25] Bywater R, McConville M, Phillips I, Shryock T. The susceptibilityto growth-promoting antibiotics of Enterococcus faecium isolates frompigs and chickens in Europe. J Antimicrob Chemother 2005;56:538–43.

26] Novais C, Coque TM, Costa MJ, Sousa JC, Baquero F, Peixe LV. Highoccurrence and persistence of antibiotic-resistant enterococci in poul-try food samples in Portugal. J Antimicrob Chemother 2005;56:1139–43.

27] Bywater R, Deluyker H, Deroover E, et al. A European survey ofantimicrobial susceptibility among zoonotic and commensal bacte-ria isolated from food-producing animals. J Antimicrob Chemother2004;54:744–54.

28] Danish Integrated Antimicrobial Resistance Monitoring and ResearchProgramme. DANMAP 2004. Use of antimicrobial agents and occur-rence of antimicrobial resistance in bacteria from food animals, foodand humans in Denmark. Statens Serum Institut, Danish Veterinaryand Food Administration, Danish Medicines Agency, Danish Insti-tute for Food and Veterinary Research; (2005). http://www.danmap.org[accessed 12 March 2007].

29] Solway S, Vincent L, Tian N, Woodford N, Bendall R. Isolationof streptogramin-resistant Enterococcus faecium from human andnon-human sources in a rural community. J Antimicrob Chemother2003;52:707–10.

30] European Antimicrobial Resistance Surveillance System (EARSS).Annual Reports 2004, (2005). http://www.rivm.nl/earss/result/Monitoring reports [accessed 7 March 2007].

31] Willems RJL, Top J, van den Braak N, et al. Molecular diversity andevolutionary relationships of Tn1546-like elements in enterococci fromhumans and animals. Antimicrob Agents Chemother 1999;43:483–91.

32] Hein I, Schneck C, Knogler M, et al. Campylobacter jejuni iso-lated from poultry and humans in Styria, Austria: epidemiology andciprofloxacin resistance. Epidemiol Infect 2003;130:377–86.

33] Tollefson L. Factual errors in review article. J Antimicrob Chemother2004;54:271.

34] Jensen VF, Neimann J, Hammerum AM, Mølbak K, Wegener HC. Doesthe use of antibiotics in food animals pose a risk to human health? Anunbiased review? J Antimicrob Chemother 2004;54:274–5.

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35] Chiller TM, Barrett T, Angulo FJ. CDC studies incorrectly summarizedin ‘critical review’. J Antimicrob Chemother 2004;54:275–6.

36] Karp BE. Comment on: Does the use of antibiotics in food animalspose a risk to human health? A critical review of published data? JAntimicrob Chemother 2004;54:273–4.

37] Berrang ME, Smith DP, Windham WR, Feldner PW. Effect of intestinalcontent contamination on broiler carcass Campylobacter counts. J FoodProt 2004;67:235–8.

38] Russell SM. The effect of airsacculitis on bird weights, uniformity, fecal

contamination, processing errors, and populations of Campylobacterspp. and Escherichia coli. Poult Sci 2003;82:1326–31.

39] Snary EL, Kelly LA, Davison HC, Teale CJ, Wooldridge M. Antimicro-bial resistance: a microbial risk assessment perspective. J AntimicrobChemother 2004;53:906–17.

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crobial Agents 30 (2007) 101–107 107

40] de Cervantes Saavedra, M (1605), trs Smollett, T (1755, corrected1770). The history and adventures of the renowned Don Quixote. Lon-don, UK: Folio Society; (1995), p. 231.

41] Cox Jr LA. Potential human health benefits of antibiotics used infood animals: a case study of virginiamycin. Environ Int 2005;31:549–63.

42] Singer RS, Cox Jr LA, Dickson JS, Hurd SH, Phillips I, Miller GY. Mod-eling the relationship between food animal health and human foodborneillness. Prev Vet Med 2007;79:186–203.

43] Lester CH, Frimodt-Møller N, Sørensen TL, Monnet DL, HammerumAM. In vivo transfer of the vanA resistance gene from an Enterococcusfaecium isolate of animal origin to an E. faecium isolate of human originin the intestines of human volunteers. Antimicrob Agents Chemother2006;50:596–9.