sou · GLB3132d1 · 1998-01-01 00:00:00 — During the accession negotiations with Union, was granted a derogation from community legislation to maintain national legislation within the area of feed additives of the groups antibiotics, chemotherapeutics, coccidiostats and growth promoters. In , the use of such substances is restricted to the purpose of curing or preventing diseases, i.e. used as veterinary medicines according to the Feedingstuffs Act of 1985. The Swedish government has appointed a commission to evaluate the hazards and risks associated with use of antimicrobial feed additives in animal production. Our conclusions can be summarised as follows: ·Antibacterial feed additives have favourable economic effects on livestock production, but from a long term perspective these are questionable, especially regarding animal welfare and animal health. Antibacterial feed additives can, at levels permitted in feedingstuffs, be used for treatment or prevention of animal diseases, which is in violation of directive 70/524/EEC. ·The quinoxalines and the nitroimidazoles are potentially genotoxic and may be regarded as an occupational hazard. ·Halofuginone and the quinoxalines are toxic for target species. This is deleterious for animal well being. ·The risk of increased resistance associated with the general use of antibacterials as feed additives are far from negligible and the potential consequences are serious for both animal and human health. Antibacterials that are presently not used as therapeuticals in human or veterinary medicine are valuable templates for future drugs. As emergence of resistance is considered to be a threat to animal and human health, all should be restricted to and veterinary purposes. It is the conclusion of this commission that the benefits of antibacterial feed additives do not outweigh the risks. With regard to coccidiostats and other medicinal substances, they are specifically used to prevent disease and should therefore be treated as pharmaceutical specialities, i.e. as medicated feed. %XECUTIVE SUMMARY )NTRODUCTION 1.1 The Swedish derogation.......................................................................... Role of antibacterials in animal husbandry........................................... 2.2.1 Therapeutic and prophylactic use of antibacterials......................... 2.2.2 Chemoprophylaxis of protozoal diseases........................................ 2.2.3 Antibacterials as performance enhancers ....................................... 2.3.1 Antibiotics and growth promoters .................................................. 2.3.2 Coccidiostats and other medicinal feed additives........................... Current Swedish legislation .................................................................. 2.4.1 Antibiotics and growth promoters .................................................. 2.4.2 Coccidiostats and other antiprotozoals ........................................... 2.4.3 Antibacterials for use in therapy or prophylaxis............................. 2.4.4 Distribution of medicinal products ................................................. The Swedish ban .................................................................................. 2.5.1 The preambles................................................................................. 2.5.2 Effects on animal health ................................................................. of antibacterials for veterinary use in ............................. 2.6.1 Materials and methods .................................................................... 2.6.2 Total consumption .......................................................................... 2.6.3 Flock treatment ............................................................................... 2.6.5 Some comments on the Swedish consumption statistics ................ Prevalence of bacterial resistance ......................................................... 2.7.1 Zoonotic pathogens......................................................................... 2.7.2 Animal pathogens ........................................................................... 2.7.3 Animal commensals........................................................................ 2.7.4 Some comments on the resistance figures ...................................... 2.8 Summary comments.............................................................................. -AND EFFECTS OF ANTIBACTERIAL FEED ADDITIVES 3.1 Mode of action ...................................................................................... 3.1.2 Suggested main mode of action ...................................................... 3.2 Prophylactic and therapeutic effects of ........................................ 3.2.2 Necrotic enteritis in poultry ............................................................ 3.2.3 Swine dysentery .............................................................................. 3.2.4 Porcine proliferative enteritis (PPE) ............................................... 3.2.5 Other bacterial enteritis in swine .................................................... 3.3 Growth and feed efficiency responses to in pigs and poultry ...... 3.3.1 Growth and feed efficiency responses to in pigs ................... 3.3.2 Growth and feed efficiency responses to in poultry .............. 3.4 Alternatives to .............................................................................. 3.5 Addendum: A benefit cost analysis of reintroduction of in 3.5.1 Executive Summary........................................................................ 3.5.2 Introductory comments................................................................... 3.5.3 Gains if were to be used in ....................................... 3.5.4 The pig industry.............................................................................. 3.5.5 Egg production ............................................................................... 3.5.6 Production of poultry meat (broilers) ............................................. 3.5.7 A brief comment on an earlier report ............................................. -ICROBIOLOGICAL ASPECTS ON ANTIBACTERIAL FEED ADDITIVES Antibacterial activity of ............................................................... and development of resistance..................................................... 4.3.1 Prospective studies ......................................................................... 4.3.2 Retrospective studies ...................................................................... 4.3.3 Point-prevalence studies ................................................................. 4.3.4 Some comments on study design.................................................... Acquisition of resistance in bacteria..................................................... 4.4.1 Transfer of resistance genes ........................................................... 4.4.2 Bacterial interspecies transfer of resistance genes ......................... 4.4.3 Co-transfer of genes and multiresistance........................................ 4.4.4 Resistance genes and animal hosts ................................................. 4.4.5 The encumbrance of resistance for bacteria ................................. 4.4.6 Some remarks on horizontal transmission of genes ..................... Transfer of resistance between various host species .......................... 4.5.1 Transmission of bacteria............................................................... 4.5.2 Transfer of genes .......................................................................... 4.5.3 Routes of transmission - food as a vehicle ................................... 4.5.4 Likelihood of resistance being transferred from animals to man . Epidemiology of antibacterial resistance............................................ 4.6.1 Reservoirs - the gene pool ............................................................ 4.6.2 Risk factors for spread of resistance............................................. 4.6.3 Persistence of resistance ............................................................... 4.6.4 Some comments on epidemiology................................................ Effects of an increase in resistance ..................................................... Other effects on the microflora........................................................... 4.8.2 Other pathogens ............................................................................ 4.8.3 Other alterations of the microflora ............................................... 4.9 Summary comments............................................................................ 4OXICOLOGICAL AND RELATED EFFECTS OF ANTIBACTERIAL FEED ADDITIVES Toxicity for target species................................................................... Toxicity for non-target species ........................................................... Adverse effects in humans .................................................................. 5.4.1 Exposure to residues ..................................................................... %NVIRONMENTAL ASPECTS ON ANTIBACTERIAL FEED ADDITIVES Exposure of the environment to ................................................. Effects of on the environment.................................................... 6.3.1 Disruption of microecology .......................................................... 6.3.2 Decreased nutrient losses.............................................................. Antimicrobial resistance genes in the environment ............................ 6.4.1 Persistence of resistant bacteria in the environment ..................... 6.4.2 transfer in the environment.................................................. 6.4.3 Persistence of resistance genes in environmental bacteria ........... 6.4.4 Possible implications for the environment................................... 6.5 Summary comments............................................................................ 7.1.1 The parasite and the disease.......................................................... 7.1.2 Prevention and chemoprophylaxis................................................ 7.2.1 Parasitological aspects .................................................................. 7.2.2 Bacteriological aspects ................................................................. 7.3.1 Toxicity of ionophores.................................................................. 7.3.2 Toxicity of other coccidiostats...................................................... 7.4.1 Environmental aspects on ionophores .......................................... 7.4.2 Environmental aspects on other coccidiostats .............................. Alternatives to coccidiostats ............................................................... 7.5.1 Improved hygiene ......................................................................... 7.5.2 Genetic resistance to coccidiosis .................................................. Summary comments on coccidiostats ................................................. Addendum: dimetridazole, ipronidazole and ronidazole .................... 7.7.2 Histomoniasis - the parasite and the disease ................................ 7.7.3 Toxicological aspects on 5-nitroimidazoles ................................. 7.7.4 Summary comments on nitroimidazoles....................................... !SSESSMENT OF THE USAGE OF ANTIMICROBIAL FEED ADDITIVES Some comments on risk analysis ........................................................ Safety for animals and humans........................................................... 8.3.1 Increased resistance ...................................................................... 8.3.2 Suppression of pathogens ............................................................. 8.3.3 Favouring of enteric pathogens .................................................... 8.3.4 Toxicological aspects ................................................................... Safety for the environment ................................................................. Prophylactic effects of ............................................................... The risks and the benefits ................................................................... 8.6.1 The benefits .................................................................................. 8.6.2 Indirect long-term losses and animal welfare aspects .................. 8.6.3 The risks ....................................................................................... 8.6.5 Considerations for risk management decisions ............................ Mode of action and resistance mechanisms...................................... Development of resistance................................................................. Acquisition of resistance.................................................................... Impact of resistance on animal and human health ............................. Other effects on the microflora .......................................................... A.6.2 Other enteric pathogens ............................................................... Effects on specific animal diseases.................................................... A.10 Summary comments......................................................................... !NNEX " "ACITRACIN Mode of action and resistance mechanisms ...................................... Development of resistance ................................................................. B.3.1 Prospective studies....................................................................... B.3.2 Point-prevalence studies .............................................................. Acquisition of resistance .................................................................... Effects on specific animal diseases .................................................... Impact of resistance on animal and human health ............................. Other effects on the microflora .......................................................... B.7.1 Effects on salmonella colonisation .............................................. B.7.2 Other enteric pathogens ............................................................... B.8.1 Adverse effects in ruminants........................................................ B.10 Summary comments ......................................................................... !NNEX # &LAVOMYCIN Mode of action and resistance mechanisms ...................................... Development of resistance ................................................................. C.3.1 Prospective studies ....................................................................... C.3.2 Point-prevalence studies............................................................... Acquisition of resistance .................................................................... C.4.1 Influence on resistance against other antimicrobials ................... Effects on specific animal diseases .................................................... Impact of resistance on animal and human health ............................. Other effects on the microflora .......................................................... C.7.2 Other enteric pathogens................................................................ C.10 Summary comments ......................................................................... !NNEX$!RDACIN AND AVOPARCIN Mode of action and resistance mechanisms ...................................... Development of resistance ................................................................. Resistance genes and gene transfer .................................................... Effects on specific animal diseases .................................................... Impact of resistance on animal and human health ............................. Other effects on the microflora .......................................................... D.7.2 Other enteric pathogens ............................................................... D.10 Summary comments......................................................................... !NNEX % 3PIRAMYCIN TYLOSIN AND VIRGINIAMYCIN E.1.1 Macrolides (tylosin and spiramycin) ............................................ E.1.2 Streptogramins (virginiamycin).................................................... Mode of action and resistance mechanisms ...................................... Development of resistance ................................................................. E.3.1 Prospective studies ....................................................................... E.3.2 Retrospective studies .................................................................... E.3.3 Point-prevalence studies............................................................... Resistance genes and acquisition of resistance .................................. E.4.1 Target modification ...................................................................... E.4.2 Enzymatic inactivation................................................................. E.4.4 Co-transfer of resistance genes .................................................... E.4.5 Exposure to and resistance .................................................. Effects on specific animal diseases .................................................... Impact of resistance on animal and human health ............................. E.6.1 Consequences of MLS resistance................................................. E.6.2 Influence of usage ............................................................... Other effects on the microflora .......................................................... E.7.2 Other enteric pathogens................................................................ E.7.3 Other effects ................................................................................. E.8.3 Other immunological effects........................................................ E.10 Summary comments ......................................................................... !NNEX & #ARBADOX AND OLAQUINDOX Mode of action and resistance mechanisms ...................................... Development of resistance ................................................................. Acquisition of resistance .................................................................... Effects on specific animal diseases .................................................... Impact of resistance on animal and human health.............................. Other effects on the microflora .......................................................... F.8.1 Target species ............................................................................... F.8.2 Adverse effects in humans ........................................................... F.10 Summary comments ......................................................................... !NNEX ' "UGET SHEETS TO Budget sheets for piglet production ................................................... Budget sheets for pig meat production .............................................. Budget sheets for egg production ...................................................... Budget sheets for poultry meat production........................................ In 1986, the Swedish Parliament imposed a ban on antibacterial growth promoters. During the accession negotiations with Union was granted a derrogation from Community legislation concerning the use of antibiotics, chemotherapeutics, coccidiostats and growth promoters as feed additives. Before , 1998 the Commission shall decide on the applications for adjustment to be submitted by . These applications are to be accompanied by a detailed scientific report on motives for the applications. The decision shall be taken in accordance with the procedures laid down in article 7 of the directive 70/524/EEC concerning additives in feedingstuffs. In 1995 the appointed a Commission (Commission on Antimicrobial Feed Additives) to collect and review scientific data which are relevant for a decision on the above mentioned feed additives. Professor was appointed chairman of the commission and Laboratory Veterinary Officer was appointed scientific secretary. Laboratory Veterinary Officer was appointed assisting scientific secretary. The following experts have been appointed to deal with particular areas of the work of the commission: Professors and to conduct a scientific review for Chapter 3; Laboratory Veterinary Officer to undertake a similar review for Chapter 7 and Associate Professor to undertake the economic analysis in Chapter 3. The appointed Commission has gathered the scientific data which it has found appropriate in two reports, one in English (SOU 1997:132) and one in Swedish (SOU 1997:133). The Swedish report is an abstract the English report. Among the feed additives dealt with, the coccidiostats hold a specific position since they are used to prevent specific diseases and not as growth promoters. They are according to 705/524/EEC classified as medicinal substances. As the indications for use of these substances are specifically to prevent disease, they are treated separately. Chapters 3-7 of the report provides scientific documentation on hazards and risks of using antibiotics, chemotherapeuticals, coccidiostats and growth promoters as feed additives. In Annexes A-F is a case by case review of substances which are used as feed additives within Union. In chapter 8 the assessment of identified hazards is undertaken. Antimicrobials are probably the single most important discovery in the history of medicine. The antimicrobial era began in the 1930s when the first sulphonamides made their way into clinical use in human medicine. Penicillin, the first antibiotic, was discovered in 1929 but was not introduced for therapy until 1940. Shortly after its introduction into human medicine penicillin was used in animals for the treatment of different bacterial diseases. Since these early discoveries, a large number of antimicrobial substances have been discovered or developed. Although some of these drugs have been developed specifically for animal use, the substantial costs for development are often not covered by profits from the veterinary market alone. Some terms used and corresponding definitions 4ABELL ) .¥GRA ANV¤NDA TERMER OCH DESSAS DEFINITION Substance produced by a microorganism, with an inhibitory effect on other microorganisms Chemically synthesised substance with an inhibitory effect on microorganisms Antibiotic or chemically synthesised substance with an inhibitory or lethal effect on bacteria Antibiotic or chemically synthesised substance with an inhibitory or lethal effect on protozoa Substance with an antibacterial and/or Antiprotozoal with inhibitory or lethal effect on Anticoccidial used specifically for prevention of Antiprotozoal with inhibitory or lethal effect on Antibacterials used as feed additives for the purpose of performance enhancement (corresponds to antibiotics and growth promoters in Directive 70/524/EEC) Antimicrobials used as feed additive for the purpose of preventing a specific disease (corresponding to medicinal feed additives according to Directive 70/524/EEC) An antibiotic is defined as a substance produced by living micro-organisms that inhibits or kills other micro-organisms. Synthetic antimicrobial substances, such as the sulphonamides and the quinolones, are referred to as chemotherapeuticals. The word antimicrobial (as a noun) is often used to encompass any substance of natural, semi-synthetic or synthetic origin that kills or inhibits the growth of a microorganism. With respect to spectrum of activity, antimicrobial substances may be divided into antibacterial, antiprotozoal, antifungal and antiviral drugs.