MEAT, ANIMAL, POULTRY AND FISH PRODUCTION ANDMANAGEMENT

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Contents

Antibiotic Growth PromotantsBeta-AgonistsBovine and Porcine SomatotropinDisease Control and Specific Pathogen Free Pig ProductionExotic and other SpeciesMeat Production in Organic FarmingPoultryRed Meat Animals

Antibiotic Growth PromotantsFR Dunshea, University of Melbourne, Parkville, VIC, AustraliaDN D'Souza, Australian Pork Limited, Barton, ACT, AustraliaBB Jensen, Aarhus University, Tjele, DenmarkRM Engberg, Danish Institute of Agricultural Sciences, Tjele, Denmark

r 2014 Elsevier Ltd. All rights reserved.

GlossaryAntibiotic growth promotants Sub-therapeutic levelsresulting in improved growth and reproductiveperformance.Antibiotic resistance Continual use of antibiotics caninvolve a resistance and this resistance can be transferred tohumans and other animals.Feed efficiency A measure of an animal's efficiency inconverting feed mass into increases of the desired output

Encyclop2

(meat in the case of meat animals and milk in the case ofdairy cows).Ionophore Ionophore antibiotics exert their antibioticaction by disrupting the transport of ions in the cellmembranes; ionophores are absorbed in small amountsand are deposited in various tissues including liver, muscle,fat, and skin.Sub-therapeutic Levels of antibiotic used that are belowthe dosage levels used to treat diseases.

Introduction

Antibiotics have now been used in livestock production formore than 60 years. Antibiotic growth promotants (AGPs)have provided a convenient dietary means of efficiently pro-ducing pork, beef and poultry meat and other animal prod-ucts. AGPs are orally active at sub-therapeutic levels, resultingin improved growth and reproductive performance. Anti-biotics are also used at moderate levels to prevent disease(prophylactics) and at therapeutic levels to treat a variety ofdiseases.

The swine and poultry industries have been the principalusers of AGP, but they are also used for beef cattle, dairy calves,sheep, and companion animals. The major impediment to theuse of AGP is the real and perceived risk of creating antibiotic-resistant microorganisms that can be transferred to humansand other animals. During the last 20 years, the growing

consumer demand for food products with credence valuessuch as safety, welfare friendly, healthy, and reduced en-vironmental impact has placed even further pressure on theuse of AGPs and the mandatory or voluntary removal of AGPsfrom a number of countries and market segments. The desireto reduce the use of AGPs in animal industries has resulted inmuch interest in the development of alternatives, many ofthese alternatives based on plant extracts, probiotics, bloodand yeast based extracts, although none of these can yet pro-vide the full efficacy of AGPs.

The Efficacy of Antibiotic Growth Promotants

The inclusion of growth-promoting antibiotics in pig feed canimprove live weight gain by 5–6% and feed conversion effi-ciency by 3–4% (Figure 1). The most pronounced effects are

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Figure 1 Effect of antimicrobial growth promotants on daily gain andfeed efficiency in different classes of pigs. Data are modified fromGaskins, H.R., Collier, C.T., Anderson, D.B., 2002. Antibiotics asgrowth promotants: Mode of action. Animal Biotechnology 13, 29–42.

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found in young pigs, with the response declining in finisherpigs. The efficacy of AGPs in broilers have also been welldocumented, particularly under adverse conditions such ashigh stocking rate, insufficient hygiene, and high pressure ofinfectious diseases.

The Mechanism of Action of Antibiotic GrowthPromotants

The exact mechanisms by which AGPs improve growth per-formance have not been fully elucidated, although severalhave been proposed. The proposed mechanisms include(1) an inhibition of subclinical infections, (2) a reduction ofgrowth-depressing microbial metabolites, (3) a reduction incompeting microbial use of nutrients, (4) an enhanced uptakeand use of nutrients through a thinner intestinal wall associ-ated with AGP-fed animals, and (5) reduced protein turnoverassociated with immune stimulation and intestinal tissuesynthesis. The common hypothesis is that intestinal bacteriadepress animal growth and this is supported through a lack ofeffect of AGPs in germfree animals.

Although statistically significant differences in growth ratehave never been well correlated with differences in bacterialcounts, either in specific intestinal segments or in the gastro-intestinal tract as a whole, several investigations have shownthat AGPs do produce significant changes in the compositionand activity of the gastrointestinal microbiota. The resultsstrongly indicate that AGPs accomplish their effect in the smallintestine, whereas they have little or no effect in the large in-testine. It is generally accepted that the small intestinalmicroorganisms compete with the host animal for easily di-gestible nutrients and at the same time produce toxic com-pounds. Experiments with slaughter pigs have shown that asmuch as 6% of the net energy in the pig diet could be lostowing to microbial fermentation in the small intestine.However, the microorganisms in the hindgut are believed tohave a beneficial effect on the host animal because they pro-duce energy by fermentation of feed material that has escapeddigestion in the small intestine. It has been calculated that on anormal Danish pig diet, 16.4% of the total energy supply for

slaughter pigs is achieved by microbial fermentation in thehindgut. Zinc bacitracin, virginiamycin, and salinomycin haveall been shown to reduce microbial activity in the small in-testine in pigs, whereas virginiamycin, spiramycin, and sali-nomycin have been shown to reduce microbial fermentationof carbohydrates in the small intestine. Quantification of theresults from these experiments indicates that the amount ofenergy saved for the animal by the reduced microbial fer-mentation in the small intestine almost equals the improvedfeed conversion. It is interesting to note that although differenttypes of bacteria may generate one or more of the growthdepression effects mentioned above, the Gram-positive bac-teria such as streptococci, lactobacilli, and clostridia that pre-dominate in the small intestine often contribute to theseeffects. As most of the AGPs target the Gram-positive bacteria,these observations are consistent with the involvement ofsmall-intestine Gram-positive bacteria in the growth de-pression. AGPs exert no benefits on the performance ofgermfree animals, which also clearly points to their effectbeing on the microflora rather than being a direct interactionwith the physiology of the animal.

Antibiotic Growth Promotants and Their Role inResistance Development

Since the introduction of antibiotics as growth promoters inanimal production in the 1950s, there has been great concernabout the development of resistant bacteria. Several studieshave shown that the occurrence of resistance is closely relatedto the use of a drug. This association has also been demon-strated for antibiotics used as growth promoters and it hasbeen shown that food animals may serve as reservoirs of re-sistant bacteria or resistance genes that may spread to thehuman population. For these reasons, international publichealth organizations have recommended termination or arapid phasing out of the use of AGPs that are also used forhuman therapy or that may give rise to multiple-resistantbacteria causing infections in humans. Examples includeavoparcin and virginiamycin.

Antibiotics Allowed as Antibiotic Growth Promotants

Until 1969 there was almost no restriction in the types ofantibiotics used as AGPs. In 1969, the Swann committee in theUK recommended tighter governmental control of the types ofantibiotics used as AGPs, and stated that antibiotics used totreat human diseases should not be used in animal feed. Thisled in 1971 to a ban of tetracyclines and other therapeuticantibiotics as AGPs in many countries. In 1986, Sweden wasthe first country to ban the use of all AGPs.

Since 1995 major changes in the use of antibiotics asgrowth promoters have occurred in Denmark. Avoparcin wasbanned in May 1995, and virginiamycin was banned inJanuary 1998. Furthermore, the food animal industries de-cided in 1998 to voluntarily stop all use of antibiotics asgrowth promoters by the end of 1999. The termination of theuse of antibiotics as growth promoters in 2003 has led to a

Table 1 Timeline of the European Union (EU) withdrawal of nontherapeutic antibiotics (NTAs) in food animal production timeline

1963–1965 Epidemic of resistant Salmonella typhimurium in the UK1969 Swann Committee in the UK recommends that antimicrobials for animals be divided into two groups: feed additives used without a

prescription and therapeutic agents used with a prescription; recommends restricting use of antimicrobial growth promoters1972–1974 The EU bans the use of tetracycline, penicillin, and streptomycin for growth promotion1986 Sweden bans the use of antibiotics for growth promotion in agriculture, as requested by Federation of Swedish Farmers

Sweden stops the use of all general prophylactic medications1988 Vancomycin-resistant enterococci (VRE) is reported in food animals in the UK1993 Denmark restricts direct sale of therapeutic antimicrobials from veterinarians and limits veterinary profits from antimicrobial sales.

Denmark bans routine prophylactic use of antimicrobials1994 Denmark bans the use of avoparcin for all purposes in agriculture. Danish Integrated Antimicrobial Resistance Monitoring and

Research Program (DANMAP) is initiated. Sweden and Finland join the EU and lobby for the EU-wide ban on agricultural growthpromoters

1995 Germany bans the use of avoparcin1996 The EU bans the use of avoparcin. Netherlands bans the use of olaquindox and carbadox1997 WHO Berlin meeting, ‘The medical impact of the use of antibiotics in food animals,’ concludes that use of medically important

antimicrobials as growth promoters should be stopped1998 The Copenhagen recommendations: recognition of antimicrobial resistance as a global threat; call for development of new

antimicrobials and establishment of a European Surveillance System. Denmark bans use of virginiamycin.1999 Scientific Steering Committee of the European Commission recommends phasing out antimicrobial growth promoters that are

medically important and implementing disease-preventive methods. The EU bans olaquindox and carbadox; suspendsauthorization of bacitracin, tylosin, spiramycin, and virginiamycin. European Antimicrobial Resistance Surveillance System(EARSS) is established. Sweden bans the use of remaining AGPs: flavophospholipol and avilamycin. The UK's AdvisoryCommittee on the Microbiological Safety of Food issues a report recommending improved veterinary training and surveillance ofresistance

2001 European Surveillance of Antimicrobial Consumption (ESAC) launched to collect data on antimicrobial use in ambulatory andhospital care

2006 The EU ban on all AGPs2008 European Surveillance of Veterinary Antimicrobial Consumption Project (ESVAC): European Commission asks the European

Medicines Agency to harmonize surveillance programs collecting data on antimicrobial sales and usage

Source: Reproduced from Cogliani, C., Goossens, H., Greko, C., 2011. Restricting antimicrobial use in food animals: Lessons from Europe. Microbe 6, 274−279.

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total reduction of the use of antibiotics in food animals inDenmark by 54%.

Before 1 July 1999, nine antibiotics were permitted as AGPsin the European Union (EU). In 2004, only four antibioticsremain authorized as AGPs in the EU: flavophospholipol,monensin sodium, salinomycin, and avilamycin. The dis-tinction between the AGPs banned, and those still allowed, isbased on whether the active component is used in humanmedicine or has similarities to a medical product used to treathuman disease. It is an ongoing discussion whether AGPsreally present a threat to human health. However, there is still– in spite of the fact that AGPs have been used for nearly 50years – no convincing evidence about unfavorable health ef-fects that can be directly linked to the use of sub-therapeuticlevels of antibiotics. AGPs are nevertheless now consideredpolitically unacceptable in the EU, and it is the plan that allAGPs were to be phased out in the EU by January 2006. InNorth America and many other parts of the world, the use ofAGPs is still permitted, and they are used frequently. Evenantibiotics used to treat infectious diseases in humans areallowed as AGPs in the United States.

Global Anitibiotic Growth Promotant Use Status

Growing concerns about antimicrobial resistance have causeda number of countries including the EU, New Zealand, andSouth Korea to implement restrictions or bans on the use ofAGPs. These bans apply to both domestic production as well

as imported products. The first ban on farm use of AGPs wasenacted in 1986 in Sweden. Since then Denmark, the UK, andfinally the EU banned the use of AGPs in food animal pro-duction. It is worth noting that initially, some of these banswere closely monitored from the outset, whereas others werenot fully enforced at first (Tables 1 and 2).

Ionophore Antibiotics (Coccidiostats)

Ionophore antibiotics are fermentation products of differentStreptomyces species and other fungi. They are polyether anti-biotics, which exert their antibiotic action by disrupting thetransport of ions in the cell membranes. In contrast to AGPs,ionophores are absorbed in small amounts following in-gestion and are deposited in various tissues including liver,muscle, fat, and skin. To prevent antibiotic residues in thecarcass, ionophore antibiotics are withdrawn from the dietsbefore slaughter.

Ionophore antibiotics are used as coccidiostats to preventcoccidiosis in poultry, a disease caused by protozoa of thegenus Eimera that may pass from one bird to another throughcontamination of the litter. The protozoa cause serious dam-age to the intestines of the animals, thus inhibiting the ab-sorption of nutrients and growth. Infections are often fatal andcan spread rapidly. Ionophore anticoccidials are mostly usedin broilers, but also to some extent in turkeys and laying hens.To prevent residues in eggs, laying hens may only be fed withionophore antibiotics during the rearing period.

Table 2 Country policies on AGP use in animal production. A summary of the country policies on AGP use in animal production

Country Overview of policies

Australia Allows use in feed of some drug classes that are important in human medicine, but is reviewing its policies for approveduses. Establishing a comprehensive surveillance system. Limited information is available on its data collection system

Brazil Limited information suggests that Brazil does not currently restrict the use of these drugs in feed. Information is notavailable to determine if Brazil has surveillance and data collection systems in place

Canada Allows use in feed of some drug classes that are important in human medicine, but is reviewing its policies for approveduses. Establishing a comprehensive surveillance and data collection system

China Limited information on current activities, as well as information on existing surveillance and data collection systemsEuropean Union (EU) Prohibits use of antibiotics in feed for growth promotion. Most of the EU members have established surveillance and

data collection systems. In 2011, the EU passed a resolution calling on its member states to ‘ensure a better controlover the implementation of the ban (2006) on antimicrobials being used as growth promoters,’ and to ‘work toward aninternational ban on antimicrobials as growth promoters in animal feed,’ and to bring this matter up in its bilateralnegotiations with other countries such as the United States

Hong Kong Limited information on current activities, as well as information on existing surveillance and data collection systemsJapan Some unconfirmed media reports indicate that Japan has increased or is considering increasing restrictions on

antimicrobial use in food animal production, whereas other reports indicate it is continuing its review. Has establishedsurveillance and data collection systems

Mexico Limited information suggests that Mexico does not currently restrict the use of these drugs in feed. Limited informationalso suggests that Mexico is developing a surveillance and data collection system

New Zealand Prohibits use of antibiotics in feed for growth promotion. Has established surveillance and data collection systemsSouth Korea Effective in 2011, prohibits ‘eight antibiotics (enramycin, tyrosine, virginiamycin, bacitracin methylene disalicylate,

bambermycin, tiamulin, apramycin, and avilamycin) and one antimicrobial agent (sulfathiazole) in animal feed as feedadditives,’ effective in 2011. Limited information is available on its surveillance and data collection systems

Thailand Some unconfirmed reports indicate that Thailand has increased or is considering increasing restrictions on antimicrobialuse in food animal production. Information is not available on its surveillance and data collection systems

United States Allows use in feed of some drug classes that are important in human medicine, but is reviewing its policies for approveduses. Has established surveillance and data collection systems

Source: Reproduced from Johnson, R., 2011. Potential trade implications of restrictions on antimicrobial use in animal production. Congressional Research Service Report 7−5700.

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Compared to most chemical coccidiostats, the situation ofcoccidial resistance against ionophores does not seem to be acause for alarm. However, following long-term application, aclear reduced efficiency of ionophore anticoccidial drugs hasbeen observed.

Besides their anticoccidial effect, ionophore antibiotics in-hibit the growth of Gram-positive bacteria and have beenshown to effectively reduce the numbers of Clostridium per-fringens, thus preventing necrotic enteritis. In this respect,ionophores seem to be able to substitute AGPs. The continueduse of ionophores in broiler feed, after the AGP ban inDenmark, is very likely the reason why the removal of AGPswas not being followed by increased problems with necroticenteritis, for example, increased mortality and liver condem-nation at slaughter.

The antibacterial property of ionophores is the reason whysome of these substances are also used as AGPs in animal feed.The ionophores salinomycin and monensin are applied as feedadditives in the production of pigs and cattle, respectively.However, when used as AGPs, the concentration allowed forthe use of salinomycin, for example, in pigs is lower (40 mgkg�1 feed), compared to the concentration allowed for use asan anticoccidial in broiler production (60 mg kg�1 feed).

Managing without ionophores will not be easy. Apart fromtheir efficiency, the low price of these compounds is an ad-vantage in favor of their continued use. A number of effortshave been made to prevent infection or to moderate intestinallesions related to coccidioses by dietary means. However, atthe present time the only real alternative to anticoccidial drugsin broiler feed seems to be the application of vaccines, which

are now commercially available. However, use of vaccines willnot solve the problems with necrotic enteritis caused by Clos-tridium perfringens. Despite these problems, the use of iono-phores as anticoccidials is being discussed in the EU, and theywill probably be phased out as feed additives by January 2012.

Impact on Resistance of Termination of the Use ofAntibiotic Growth Promotants

A continuous national monitoring program for antibiotic re-sistance has been carried out in Denmark since the ban ofAGPs in 1999. The data from this monitoring program showthat it is possible to reduce the occurrence of antibiotic-resistant bacteria in a national population of food animalswhen the selective pressure is removed. This observation issupported by investigations carried out in Germany, Holland,and Belgium.

The termination of AGP usage has resulted in a markedreduction in the presence of resistant bacteria in food animals,but resistant bacteria have not completely disappeared. Severalinvestigations have shown that, although the probability ofrandomly picking up an AGP-resistant enterococcus from ananimal or a food product has been reduced, the resistantstrains are still present in the farm environment, in the foodanimals, and even in the animal products. Removal of theselective pressure has thus reduced the population density ofresistant bacteria and accordingly the possibility for transfer ofresistant bacteria from animals to food, but the seeds of re-sistance remain in the farm environment for many years after

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the termination. A readmittance of antibiotics for growthpromotion would mean a quick increase in resistant strains topretermination levels.

Managing without Antibiotic Growth Promotants

So far, only a few studies have investigated the effect of ter-minating the use of AGPs on animal health and productivity.To investigate whether and how removal of AGPs affectedproduction results and mortality in Danish broiler flocks, datacovering the period before and after the termination of AGPswere extracted from a database administered by the DanishPoultry Council. This database provides information abouteach broiler flock including parental flock, stocking rate,mortality, and feed consumption. The results of this studyshowed no evidence of decreased productivity (kg broiler perm2) or increased mortality following the removal of AGPs.However, a minor increase in feed consumption was reportedcorresponding to 16 g feed per kg broiler. This decreased feedefficiency is, however, offset completely by saving the cost ofAGPs. Necrotic enteritis was at most a minor broiler healthproblem following the termination of AGPs in Denmark,probably because producers continued to use ionophores forprophylaxis against coccidiosis.

In Danish pig production, there was a significant increasein therapeutic antibiotic treatments for diarrhea in the post-weaning period following the complete elimination of AGPs.The termination of AGPs also resulted in some loss of prod-uctivity in weaners. In finishers, however, no effect of thetermination of AGPs was observed on productivity or feedefficiency. Similar results for pig production were observedearlier after elimination of the use of AGPs in other countries.

See also: Chemical Analysis: Sampling and StatisticalRequirements; Standard Methods. Foodborne Zoonoses. Growthof Meat Animals: Metabolic Modifiers. Microorganisms andResistance to Antibiotics, the Ubiquity of: Antibiotic Resistanceby Microorganisms. Residues in Meat and Meat Products: Feedand Drug Residues; Residues Associated with Meat Production

Further Reading

Aarestrup, F.M., Bager, F., Andersen, J.S., 2000. The association between the use ofavilamycin for growth promotion and the occurrence of resistance amongEnterococcus faecium. Microbial Drug Resistance 6, 71–76.

Aarestrup, F.M., Seyfarth, A.M., Emborg, A.-D., et al., 2001. Effect of abolishment ofthe use of antimicrobial agents for growth promotion on occurrence ofantimicrobial resistance in fecal enterococci from food animals in Denmark.Antimicobial Agents and Chemotherapeutics 45, 2054–2059.

Armstrong, D.G., 1986. Gut-active growth promoters. In: Buttery, P.J., Lindsay, D.B.,Haynes, N.B. (Eds.), Control and Manipulation of Animal Growth. London:Butterworths, pp. 21–37.

Atlef, M., Ramadan, A., Youseef, S.A.H., Abo El-Sooud, K., 1993. Kineticdisposition, systemic bioavailability and tissue distribution of salinomycin inchickens. Research in Veterinary Science 54, 254–268.

Borgen, K., Sorum, M., Wasteson, Y., Kruse, H., 2001. Van A-type vancomycin-resistant enterococci (VRE) remain prevalent in poultry carcasses 3 years afteravoparcin was banned. International Journal of Food Microbiology 64, 89–94.

Callesen, J., 2002. Effects of termination of AGP use on pig welfare andproductivity. In: Abstracts of the International Invitational Symposium: BeyondAntibiotic Growth Promoters in Food Animal Production, Foulum, Denmark, pp.42−45. Copenhagen: Danish Veterinary Institute and Tjele: Danish Institute ofAgricultural Science.

Cromwell, G.L., 2002. Why and how antibiotics are used in swine production.Animal Biotechnology 13, 7–27.

Dierick, N.A., Vervaeke, I.J., Decuypere, J.A., Hendericks, H.K., 1986. Influence ofthe gut flora and some growth promoting feed additives on nitrogen metabolismin pigs. II. Studies in vivo. Livestock Production Science 14, 177–193.

Emborg, H., Ersboll, A.K., Heuer, O.E., Wegner, H.C., 2001. The effect ofdiscountinuing the use of antimicrobial growth promoters on the productivity inthe Danish broiler production. Preventive Veterinary Medicine 50, 53–70.

Engberg, R.M., Petersen, J.S., 2005. Poultry production with and withoutquestionable feed additives and ingredients. Zootecnica International 5, 38–45.

Jensen, B.B., 1998a. The impact of feed additives on the microbial ecology of thegut in young pigs. Journal of Animal Feed Science 7, 45–64.

Jensen, B.B., 1998b. Effect of diet composition and virginiamycin on microbialactivity in the digestive tract of pigs. In: Proceedings of the 4th Symposium onDigestive Physiology in the Pig, pp. 392−400. Jublana, Poland: Institute ofAnimal Physiology and Nutrition, Polish Academy of Sciences, Poland.

Jensen, B.B., Mikkelsen, L.L., Christensen, D.N., 1998. Integration of ileumcannulated pigs and in vitro fermentation to quantify the effect of dietcomposition on microbial fermentation in the large intestine. In: Proceedings ofNJF Seminar No. 274 on Energy and Protein Evaluation for Pigs in the NordicCountries, pp. 106−110. Foulum, Denmark: Nordisk Jordbrugsforskning Nr.

Thonke, S., Elwinger, K., 1998. Growth promotants in feeding pigs and poultry. I.Growth and feed efficiency responses to antibiotic growth promotants. Annales deZootechnie 47, 85–92.

Wegner, H.C., 2003. Antibiotics in animal feed and their role in resistancedevelopment. Current Opinion in Microbiology 6, 439–445.

Wierup, M., 2001. The experience of reducing antibiotics used in animal productionin the Nordic countries. International Journal of Antimicrobial Agents 18,287–290.

Relevant Website

http://www.fas.org/sgp/crs/misc/R41047.pdfCongressional Research Service Report.