sou · GLB3132d1 · 1998-01-01 00:00:00 — In the following, the term antibacterial will be used for antibiotics and chemically synthesised substances that have an inhibitory or lethal effect on bacteria. Terms used in the text are defined as shown in table 2.I. 2.2Role of antibacterials in animal husbandry A better understanding of many aspects of animal husbandry have resulted in a development towards improved productivity. Such factors include the combat of epizootic diseases, control of parasitism, improvements in animal nutrition, genetic improvements and the use of antimicrobials. Antimicrobial agents are used for three major purposes in domestic animals: 1Therapy, to treat an identified illness 2Prophylaxis, to prevent illness in advance 3Performance enhancement, to increase feed conversion, growth rate or yield 2.2.1Therapeutic and prophylactic use of antibacterials Therapy usually involves an individual animal or a defined group of diseased animals while prophylactic treatment involves the treatment of a herd or group of animals. The aim of the latter is to prevent diseases that might otherwise occur. A special form of prevention, also called metaphylaxis, is when all animals in a herd or group of animals are medicated, in situations when the proportion of animals diseased during a defined time period reaches a threshold value. In such situations, the probability of most, or all, of the animals getting infected is high. In both therapy and prophylaxis, the drug is administered over a defined, preferably short, period of time and in both instances the drug is used upon prescription by a veterinarian. The dosages used must be high enough so that concentrations that are inhibitory for the infectious agent are reached at the site of infection (e.g. the lung). The animal diseases currently requiring the most extensive use of therapeutic or prophylactic drugs are respiratory and enteric diseases of pigs and calves, and mastitis in dairy cattle. Prophylactic treatment is particularly common during periods when stress is imposed on the animal, e.g.. changes in diet and loss of maternal interaction at weaning, after transport and commingling. Although in recent years much emphasis has been placed on disease prevention through improved management and environmental conditions, intensive animal production systems still depend on antimicrobials, as shown by the continuously growing market for antibacterials. 2.2.2Chemoprophylaxis of protozoal diseases In the case of certain protozoal diseases, the probability of clinical outbreaks or production losses due to subclinical disease is so high that chemoprevention has become standard practice. The main diseases in question are coccidiosis of poultry and rabbits and histomoniasis of and pheasants. The appropriate drugs for prophylaxis are referred to as anticoccidials (coccidiostats) and antihistomonals. Anticoccidials and antihistomonals are medicinal substances preventing specific diseases with a high probability of occurrence. In that respect, they are by definition veterinary medicines. On the other hand, in most parts of the world they are used as standard feed additives and are, from a regulatory point of view, treated as such. 2.2.3 Antibacterials as performance enhancers The growth-promoting properties of antimicrobials for farm animals were discovered in the late 1940s. Trials where fermentation waste from tetracycline production were fed to chicken as a source of vitamin B12 revealed that the chickens fed the fermentation waste grew more rapidly than did the controls. It was soon found that this effect was not due to the vitamin content of the feed but to residual tetracycline (Stokestad and Jukes, 1949; Stokestad and Jukes, 1950). This growth promoting effect of tetracyclines was soon confirmed for other antibacterials and other animal species. Growth enhancement in children The findings of improved growth as an effect of administration of subtherapeutic doses of antibiotics led to investigations on possible similar effects in humans. In 1952, Snelling and reported lowered morbidity, increased growth rate and shortened hospital stay of premature infants following daily administrations of chlortetracycline. Similar results, from a controlled trial in twins and triplets, were also reported by (1952). MacDougall (1957) found that low doses of chlortetracycline given to hospitalised malnourished children resulted in, among other effects, improved weight gain. Positive effects on the weight gain of undernourished school children have also been reported (, 1956; , 1958). MacDougall (1957) concluded that chlortetracyclines could prove a valuable adjunct to dietary therapy in clinical practice under the conditions described. In contrast, both and co-workers (1956) and Guzmán and co-workers (1958) concluded that there was no justification for considering continued administration of antibacterials to children in underdeveloped areas. Subsequent research with focus on the relative impact of improved nutrition and control of infectious diseases on the growth of children demonstrated, among other things, the absolute necessity of maintaining adequate nutrition during weaning (, 1967; Behar ET AL , 1968). Growth enhancers in animal husbandry In animal husbandry, the early findings initiated an intensive area of research. The practice of feeding subtherapeutic doses of antibiotics was readily adopted and soon became an integrated part of the systems developed in the animal industry. Apart from increased growth rate and/or increased feed conversion, examples of other observed effects of antimicrobials at low doses are improved egg production in laying hens, increased size in sows and increased milk yield of dairy cows. When antimicrobials are used for the latter purposes the term yield promoters has been used. Alternative terms proposed for growth promoters such as growth permitters or digestive enhancers appear misleading. Growth permitters would imply that growth of animals is not permitted without these additives. The term digestive enhancers indicates that the effect of is primarily on the digestion of feed. This is not in line with the, admittedly scarce, knowledge on the mode of action of (see chapter 3). The various claimed benefits of antibacterial performance enhancers have been listed by () as: ·To improve feed utilisation ·To improve growth rate ·To improve carcass quality ·To improve rate of throughput of livestock ·To improve farm economics ·To permit economical redeployment of resources ·To help indebtedness of farmers ·To permit controlled production from fewer stock to achieve quotas ·To reduce energy consumption ·To conserve natural fuels ·To reduce environmental contamination ·To reduce livestock numbers and slurry disposal problems ·To improve the environment (Source: FEDESA 1994 cit. by Colegrave and , 1995) The exhaustive nature of this list is due partly to the fact that some effects have been duplicated using different phrasings, and partly to the listing of various secondary and tertiary effects. If feed utilisation and/or growth rate of the animals is improved, the throughput of animals on a specific premise will increase. The latter is equal to improved utilisation. From this follows an economic benefit, which, for indebted farmers certainly will mean an improvement. Improved use of and feed would, in certain situations, reduce energy consumption which normally is the same as conservation of natural fuels. Reduced waste, reduced slurry disposal problems, reduced environmental contamination and improvement of the environment also appear synonymous and are sequels to improved feed The statement improved carcass quality is doubtful. In some cases, a higher fat content of the carcass has been noted (FiemsET AL, 1995). A list encompassing only the primary effects attributed to of would read: 2.3.1 Antibiotics and growth promoters In the EU, feed additives (and MFA) are regulated separately from veterinary medicines (including medicated feed). Approval of feed additives is co-ordinated through Directorate General of Commission. The basic Council Directive concerning is 70/524/EEC, with amendments (especially 84/587/EEC and 96/51/EC). Certain provisions of the latest amendment will be in force on April 1 1998 and the remaining provisions by October 1 1999. When the 5th amendment (Council Directive 96/51/EC) takes force, some important changes will follow. Approvals of high technology additives will be brand-specific. The responsibilities of all involved parties have been clearly defined. Further, possibilities of periodical renewal of authorisations are provided. In article 3 of this Directive (formerly Article 7 of Directive 84/587/EEC) important conditions that must be fulfilled are listed. It should be noted that, although the phrasing of some of the conditions has been altered (cf. Article 7, 2A of 84/587/EEC), the spirit is essentially the same as in the directive presently in force. $IRECTIVE %%# AS AMENDED IN %# !RTICLE A A WHEN USED IN ANIMAL NUTRITION IT HAS ONE OF THE EFFECTS REFERRED TO IN !RTICLE A B TAKING INTO ACCOUNT THE CONDITIONS OF USE IT DOES NOT ADVERSELY AFFECT HUMAN OR ANIMAL HEALTH OR THE ENVIRONMENT BY ALTERING THE CHARACTERISTICS OF LIVESTOCK PRODUCTS C ITS PRESENCE CAN BE MONITORED AS AN ADDITIVE PER IN FEEDINGSTUFFS OR WHERE APPROPRIATE IN FEED MATERIALS D EXCLUDED THIS CONDITION DOES NOT APPLY TO ADDITIVES BELONGING TO THE GROUP OF COCCIDIOSTATS AND OTHER MEDICINAL SUBSTANCES E FOR SERIOUS REASONS CONCERNING HUMAN OR ANIMAL HEALTH ITS USE MUST NOT BE RESTRICTED TO OR VETERINARY PURPOSES )N ARTICLE OF THIS DIRECTIVE FAVOURABLE EFFECTS OF ADDITIVES ARE SPECIFIED According to Council Directive 95/69/EC, where are produced or mixed need specific approval. Council Directive 94/40/EEC (amending 87/153/EEC), presently under revision, fixes standard data requirements for dossiers used to support approval of additives, so called guidelines. Specified data with relevance for the conditions cited above are to be provided. After consulting the Member States in , and evaluation by () the Commission may, if the substance if found to meet the requirements of the directives, be authorised for use. If, as the result of new information or a reassessment of existing information, a has specific grounds for establishing that the use of one of the authorised additives (or its use in specified conditions) constitutes a danger to animal or human health or the environment, the may temporarily suspend or restrict the application (so called safe guard , Article 11 of Council Directive 70/524/EEC). The other Member States and the Commission shall immediately be notified and informed of the reasons for the decision. The Commission shall examine the grounds cited by the member state and consult the Member States. Commission shall then deliver its opinion and take appropriate measures. If any of the conditions laid down in the article cited above are no longer met, a regulation shall be adopted to withdraw the additive. Presently authorised (annex I or II of 70/524/EEC) are bacitracin, flavomycin, avoparcin, spiramycin, tylosin, virginiamycin, carbadox, olaquindox, monensin, salinomycin and avilamycin (table 2.II). Ardacin has been approved under but the authorisation is not expected to be prolonged. A number of additives have, since the original list in 1970, been withdrawn from the list of authorised additives because of a decision to restrict certain antibiotics to therapeutic use (e.g. penicillin, streptomycin and tetracyclines) . 2.3.2Coccidiostats and other medicinal feed additives The anticoccidial agents authorised for use in poultry within the EU (Council Directive 70/524/EC) are listed in Table 2.III. Apart from being used as anticoccidials in poultry some coccidiostats are also approved for the prevention of coccidiosis in rabbits. Some ionophores are also approved for growth promotion (see table 2.II). The other medicinal substances include the antihistomonals which are mainly used in . Antibacterial feed additives authorised for growth promotion, including most of the applications (Council Directive 70/524/EEC) 4ABELL )) !NTIBAKTERIELLA FODERTILLSATSER GODK¤NDA SOM TILLV¤XTBEFR¤MJANDE MEDEL SAMT FLERTALET GODK¤NDA APPLIKATIONER R¥DSDIREKTIV %%' !.4)")/4)#3 '2/74( 02/-/4%23 withdrawal time 28 days withdrawal time 28 days Coccidiostats and other medicinal substances authorised as feed- additives within Union (Council directive 70/524/EEC) 4ABELL ))) +OCCIDIOSTATIKA OCH ANDRA MEDICINSKA SUBSTANSER GODK¤NDA SOM FODERTILLSATSER INOM DEN %UROPEISKA 5NIONEN R¥DSDIREKTIV chickens for laying, /4(%2 -%$)#). !, 35"34!.#%3 2.4.1Antibiotics and growth promoters The basic Swedish legislation with relevance for and medicinal feed additives is the Feedingstuffs Act (SFS 1985:295), that came into force in 1986. According to this act, antibiotics and chemotherapeuticals may only be incorporated in animal feed for the purpose of preventing, alleviating or curing disease, i.e. not for growth or yield promoting purposes. 2.4.2Coccidiostats and other antiprotozoals In , as in other countries, the coccidiosis control in broilers relies primarily on coccidiostats. The drugs approved in for this purpose are listed in table 2.IV. In accordance with the Feedingstuffs Act, coccidiostats are available as pharmaceutical specialities (veterinary medicinal products), on veterinary prescription only. As a result of the legislative changes in 1986, some coccidiostats earlier approved as feed additives are today instead authorised for use as medicated feed. Coccidiostats approved as pharmaceutical specialities in 4ABELL )6 +OCCIDIOSTATIKA GODK¤NDA SOM L¤KEMEDEL I 3VERIGE #ONTENT IN FEED (ATCvet code) 125+8 in starter feed, 75+4.8 in grower feed (QP51A X59) (QP51A X08) (QP51 A H02) (QP51A X10) (QP51A H03) (QP51A H04) Ronidazole (Ridzola® vet.) and dimetridazole (Emtryl® vet.) were approved as pharmaceutical specialities for use against swine dysentery and, for dimetridazole, also against histomoniasis in poultry, until 1995. Ronidazole and dimetridazole were then withdrawn from the market in accordance with the provisions of (). Ipronidazole has never been approved in . 2.4.3Antibacterials for use in therapy or prophylaxis Antibacterials for use in animals are authorised by the . Withdrawal times, based on the maximum residue limits (MRL) fixed by the CVMP, are assigned by the . All antibacterials, including dermatological and other formulations, for use in animals are available on prescription only. Veterinary prescriptions are subject to the regulations of the . All veterinarians are under the supervision of , that also issue regulations pertinent to antibacterials. The general veterinary regulations of (LSFS 1982:43) state that the usage of medicinal products shall be well motivated. When choosing type and dosage of a medicinal product the risk of residues in food of animal origin shall be taken into account. Further, in the regulations for veterinarians with special reference to prescriptions of medicinal products (LSFS 1979:8), it is stated that prescribing and handing out medicinal products shall be done with great restrictivity and only when the need is apparent.... According to the same regulations, medicinal products may, on each occasion, be prescribed or handed out only after careful examination of the diseased animal or herd, on the premises, except in the case of general prophylactic measures other than antibiotics and chemotherapeuticals, or if other special circumstances are at hand. Regarding medicated feed, the provisions of Directive 90/167/EEC are implemented. Of the antibacterials authorised as feed additives in the EU, tylosin and virginiamycin are presently available in for use in medicated feed. Olaquindox was withdrawn from the market in 1997. Spiramycin is authorised for use in food animals for injections only. 2.4.4Distribution of medicinal products All prescriptions and deliveries of drugs are administered by the pharmacies which all belong to Apoteksbolaget (Pharmacies). This means that all prescriptions of drugs for therapeutic use, including those mixed by the feed mills, are handled by the Swedish pharmacies. From the above follows that veterinarians are not allowed to sell or dispense medicinal products but may, for practical reasons, hand out the products to the end-user. In such cases, the quantity delivered may only satisfy the need for treatment of the animal or group of animals in question. The manufacturing of animal feed is supervised by . As part of the supervision, annual statistics on quantities of feed delivered and on specifics such as medicated feed are gathered. All veterinarians are, as mentioned, subject to supervision by . On a regional level, the County veterinarian (an official employee) is in charge of supervision of the work of the veterinarians, animal welfare and disease control. Traditionally, most of the veterinarians in food animal practice are employed by . However, private practice in food animals is becoming more common. statistics of antibacterials for use in animals is an indirect way of control. As mentioned above, annual statistics on sales of medicated feed. has, based on data provided by Apoteksbolaget, calculated the total sales of antibacterials for veterinary use in (see 2.6). Recently, Apoteksbolaget has initiated yearly surveys of all veterinary prescriptions of medicated feed. By combining these three sources of statistics, the surveillance is maximised. Discrepancies or undesired trends may be detected and their causes found and corrected (see 2.6.5). Similar to the situation in other countries, some Swedish scientists viewed the practice of routine addition of antibacterials to animal feeds with scepticism. The knowledge of the transmissibility of resistance between bacteria through plasmids led to exhortations for a restrictive use of antibacterials in animals (, 1970). Following the recommendations of in the UK, a broader debate was initiated, which eventually led to a reassessment of the use of antibacterials as feed additives (LBS, 1977). A working group of concluded, among other things, that the use of entails a risk of increased resistance in bacteria but as the substances in use are mainly against gram-positive bacteria from which resistance is not transferred, the impact of such development is negligible. On the other hand, a negative attitude to all kinds of additives among consumers was noted by the group. The benefits, in terms of increased production and prevention of certain diseases, were also acknowledged (LBS, 1977). Legislative changes, especially in the requirements for approval, were proposed in order to mitigate possible risks. At the same time, the farmers were growing increasingly sceptical towards feed antibiotics. They were concerned that the continued use of antibiotics might harm consumer confidence. The () made a policy statement, declaring that Swedish agriculture aimed towards a more restricted and controlled use of antibiotics. In a letter to the in 1984, the LRF requested a ban on the use of antibacterials as feed additives. In response to the above, the drafted a new Feedingstuffs Act (Government 1984/85:146, Swedish Government). Among other things, the draft proposed that the use of antibacterials in feed should be restricted to treatment, prevention or cure of diseases, i.e. their use for growth promotion should not be allowed. The grounds cited for this amendment was the risk for increased resistance, especially the risk for cross-resistance to other substances and the risk of increased susceptibility of animals to salmonella and other enteric pathogens. The Feedingstuffs Act was accepted by the parliament in and came into force in January 1986 (SFS 1985:295). 2.5.2Effects on animal health The effects of the ban on on animal health has recently been reviewed by Wierup (1996). In essence, the following is based on his review. In the 60s and 70s different (bacitracin, flavomycin, oleandomycin, spiramycin) were used in concentrate and milk replacers for calves. However, the effect was considered doubtful and documented improvements in animal growth was not always seen in repeated experiments (e.g. and , 1973; WierupET AL, 1975). to this scepticism, the use of in calf rearing had more or less come to an end before the ban in 1986. Negative clinical or other effects as a consequence of the ban have not been reported. The antibacterial feed additive nitrovin came into use in the 70s and through this, existing problems with necrotic enteritis in broiler chickens were almost completely eliminated. Later, nitrovin was gradually replaced by avoparcin. Reports on an effect of avoparcin on salmonella colonisation and excretion (e.g. and , 1978; and , 1980) gave rise to concern, as the broiler production put considerable efforts into the salmonellosis control programme. This prompted a change from avoparcin to virginiamycin in the early 80s. In the autumn of 1985 (before the ban), outbreaks of necrotic enteritis were reported with increasing frequency. This was dealt with by increasing the dosage of virginiamycin from 10 to 20 ppm. At the time of the ban, the chicken producers identified the occurrence of clinical or subclinical necrotic enteritis as the main problem to tackle. A committee with representatives of the producers, the feed industry and veterinarians from animal health areas as well as from the meat inspection services was put together. The aim of the committee was to initiate studies and to suggest appropriate solutions to the problem. It was agreed that a transition period would be necessary and that virginiamycin would be prescribed during this period, in the dose of 20 ppm. Field trials where no medicated feed was used indicated that a number of factors needed correction. It was concluded that the construction and climate of stables, hygiene, management and feed composition all contribute to the occurrence of necrotic enteritis in broiler production. Further, it was found that coccidiostats of the ionophore type also prevent necrotic enteritis. Strong emphasis was placed on improving animal environment because many diseases, including necrotic enteritis, have a multifactorial background. A special bonus was given for good animal management and care which also led to improvements in the total level of quality of the production. In 1988, all prophylactic medications were abandoned and, in case of outbreaks, a two day treatment with phenoxymethyl penicillin in the drinking water was applied. The amount of substance of antibiotics which was used for treatment decreased from about of virginiamycin in 1987 to of phenoxymethyl penicillin in 1988 (expressed as substance, Wierup, 1989). Today the need for such treatment of necrotic enteritis is more or less completely eliminated. formal, scientific studies were also initiated to find alternative ways to control necrotic enteritis. Studies on animal feed included effects of enzymes and certain probiotics, the structure of the feed, different levels of protein and different sources of proteins and coccidiostats (Elwinger and Teglöf, 1991; Elwinger ET AL , 1992; Elwinger ET AL , 1994; Elwinger ET AL , 1996). The results indicated that additions of enzymes acting on carbohydrates and the addition of certain probiotics to develop an adequate intestinal bacterial flora reduced the incidence of necrotic enteritis. Dietary levels of protein were reduced and amino acids were added which also resulted in an improved hygiene and health. In retrospect the most important changes were related to feed, involving a reduction of protein content, a higher fibre content and supplementation with enzymes together with the utilisation of ionophores for prevention of coccidiosis.