sou · GLB3132d1 · 1998-01-01 00:00:00 — 4ABELL ))A %FFEKT AV DEN ANTIBAKTERIELLA FODERTILLSATSEN CARBADOX P¥ TILLV¤XT OCH FODERUTNYTTJANDE HOS GRISAR MED H¶G ELLER L¥G GRAD AV ANTIGEN EXPONERING !NPASSAD FR¥N 3TAHLY 'ROWTH AND FEED UTILISATION !NTIGEN Kg feed/ kg gain aNon-medicated control group. bPigs fed 55 ppm carbadox from 5 to body weight and then placed on the control diet without carbadox from 34 to body weight. a /MEDICINERAD KONTROLLGRUPP b 'RISAR SOM F¥TT PPM CARBADOX FR¥N TILL KG KROPPSVIKT OCH D¤REFTER FODER UTAN CARBADOX FR¥N TILL KG KROPPSVIKT Responses of chickens with a low or high level of antigen exposure to dietary antibacterial agents (streptomycin and penicillin) Adopted from Rour (1992) 4ABELL ))B %FFEKT AV DE ANTIBAKTERIELLA SUBSTANSERNA PENICILLIN OCH STREPTOMYCIN P¥ TILLV¤XT OCH FODERUTNYTTJANDE HOS SLAKTKYCKLING MED H¶G ELLER L¥G GRAD AV ANTIGENEXPONERING !NPASSAD FR¥N 2OUR G GAIN G FEED 1Sixty-four chickens were raised 14 days in each of the 2 different environments (clean or unsanitary) and fed diets either without antibiotic or with streptomycin (100 ppm) and penicillin (100 ppm); 2Means in a column with different superscript letters differ significantly (p<0.05). 3EXTIOFYRA KYCKLINGAR VISTADES DAGAR I OLIKA MILJ¶ER L¥G ELLER H¶G ANTIGENEXPONERING OCH GAVS FODER ANTINGEN UTAN ANTIBIOTIKA ELLER INNEH¥LLANDE STREPTOMYCIN PPM OCH PENICILLIN PPM -EDELV¤RDEN I EN KOLUMN MED OLIKA BOKSTAVSMARKERINGAR SKILJER SIG SIGNIFIKANT P The relationship between cytokines, immunologic stress and growth is complex. Responses in the brain and immune system are expressed as effector Mode of action and effects signals in the form of regulatory hormones from the hypothalamus and pituitary and as cytokines from the immune system. Several hormones including corticotrophin releasing hormone, prostaglandins, glucagon, insulin and corticosteroids are induced by cytokines (for ref. see Grunfeld ET AL , 1996). In this respect the release of corticotrophin releasing hormone and corticosteroids is of special interest since corticosteroids have a catabolic effect, thereby reducing muscle tissue. An activated immune system releases cytokines, that mediate the host response to infection and/or inflammation. Cytokines may also have direct effects on the brain, resulting in, for example, a decreased appetite. In summary, cytokines released as a consequence of a stimulated immune system mediate profound host responses including decreased appetite and a general catabolic effect. Many extrinsic stimuli such as bacterial toxins, yeast cell walls, silica particles, bacterial (gram-positive and gram-negative) or viral antigens have the capacity to elicit these responses (Mahé and Oppenheim, 1992; Degré, 1996). Two recently published studies report on the effects of on the immune system in relation to performance in clinically healthy animals. In one, avoparcin (having a gram-positive spectrum) was used and in the other carbadox (having a gram negative spectrum). In the study on avoparcin, Krinke and Jamroz (1996) compared some immunological parameters in avoparcin-fed chickens with a control group. In birds from the medicated group, most chickens had a suppressed reactive lymphoid tissue of the bursa of . This result indicates that there may be a lack of stimulation of the immune system in the antibiotic-treated birds. The effects of carbadox in a model using pigs with low or high level of chronic immune system activation was studied by Stahly (1996 see table 3.IIa). The magnitude of the performance enhancement induced by carbadox was greater in the pigs with high level of chronic immune system activation than in pigs with low level of immune system. Similar results were obtained for pigs fed tylosin at 110 ppm (Stahly ET AL , 1995). In chickens fed therapeutic levels of antibiotics (Table 3.IIb Roura ET AL , 1992), the effects of antibiotics on immune stressed animals was further confirmed. Mode of action and effects Growth rate of pigs in farrow to finish herds with different pathogen loads. denotes specific pathogen free pigs representing the lowest pathogen load, denotes conventional pigs reared from farrow to finish but applying an age segregated system representing an intermediate pathogen load; denotes conventional pigs reared from farrow to finish employing a continuos rearing system representing the highest pathogen load (, 1993b). &IGUR ) 4ILLV¤XT HOS GRISAR UPPF¶DDA I INTEGRERADE BES¤TTNINGAR MED OLIKA SMITT¤MNESTRYCK VISAR 30& GRISAR 3PECIFIC 0ATHOGEN &REE REPRESENTERANDE DET L¤GSTA SMITTRYCKET VISAR KONVENTIONELLA GRISAR INOM EN BES¤TTNING SOM TILL¤MPAR ¥LDERSSEKTIONERING REPRESENTERANDE ETT INTERMEDI¤RT SMITTRYCK VISAR KONVENTIONELLA GRISAR SOM TILL¤MPAR ETT KONTINUERLIGT UPPF¶DNINGSSYSTEM REPRESENTERANDE DET H¶GSTA SMITTRYCKET 7ALLGREN B improve growth rate and feed efficiency. The effects of are inversely related to animal health status. The poorer the health status the better the effect. Challenge of the immune system will reduce growth rate and feed efficiency. This response is mediated by cytokines. Cytokines have direct effects on the brain, inducing a decrease in appetite, and stimulate the release of catabolic hormones, reducing the mass of muscle tissue. , through their antimicrobial effects, will alleviate immune system challenges from the intestinal tract on the immune system. This appears to be the major effect of . Mode of action and effects 3.2Prophylactic and therapeutic effects of Most substances used as are also used, or have been used, for therapeutic purposes. For some the maximum dosage permitted for growth promotion is the same or nearly the same as what is recommended for prophylaxis and treatment of disease (table 3.III.). It has been pointed out that one expected consequence of abstaining from use of is increased animal health problems due to infectious diseases (McOrist, 1997; Viaene, 1997) Indeed, the Swedish experience from banning in 1986 was the emergence of clinical problems and disturbances of the health status of piglets and broilers which initially created a demand for antibiotic medicated feed at therapeutic dosages. The response to withdrawal of in 1986 on piglet health and performance in 220 Swedish piglet producing herds was statistically evaluated by and Lundeheim (1994 see chapter 2). Removal of was followed by a doubling of incidence of diarrhoea and number of treatments of post-weaning diarrhoea as well as by an increased mortality by about . The age at increased by 5-6 days. Since then, efforts have been made to improve the rearing and production systems e.g. sectioning between age groups and planned production. Production data of the pig herds from 1986 (and Lundeheim, 1994) have now been re-analysed comparing 1986 to 1995 (Wierup, 1996). The comparison revealed a drop in post-weaning mortality from in 1986 to in 1995 and a reduction of the age at by 1-2 days in 1995, as compared to 1986. This poses questions as to what degree , at their permitted dosages for growth promotion, also have therapeutic and/or prophylactic effects against certain economically important intestinal diseases in pigs and poultry. Mode of action and effects Recommended dosages of for treatment, prophylaxis and growth promotion in swine and poultry. ( Från , 1992; Prescott and Baggot, 1993; VET., 1997 and 70/524/EEC). Dosages have been converted to mg/kg and rounded off 4ABELL ))) 2EKOMMENDERADE DOSER AV !&4 F¶R BEHANDLING PROFYLAX OCH SOM TILLV¤XTBEFR¤MJARE HOS SVIN OCH FJ¤DERF¤ &R¥N !LLEN ET AL 0RESCOTT AND "AGGOT &!33 6%4 OCH %%# $OSERINGAR HAR R¤KNATS OM TILL MG KG OCH AVRUNDATS SD1, PPE2, bacterial SD, bacterial enteritis plasmosis, SD, PPE SD, other bacterial 2PPE= porcine proliferative enteropathy Mode of action and effects , some studies on therapeutic and/or prophylactic effects of on certain diseases have been reviewed. Studies on this subject where several antimicrobial treatments are administered simultaneously to the same animals have not been included, as they are impossible to evaluate. 3.2.2Necrotic enteritis in poultry Necrotic enteritis (NE) is an intestinal disease affecting poultry. It is associated with #LOSTRIDIUM PERFRINGENS Wicker and co-workers (1977) demonstrated a reduced mortality (p<0.01) due to NE in broiler chicks fed bacitracin at 11 ppm. In chickens with experimentally induced disease, a prophylactic effect of bacitracin administered in water at /gallon and a therapeutic effect at /gallon was demonstrated (Prescott ET AL , 1978). In a larger study, and co-workers (1992) induced NE by feeding chickens a diet high in . Virginiamycin given in feed at 20 ppm effectively prevented the disease. Another study by Elwinger and Teglöf (1991) showed similar results; virginiamycin at 20 ppm in feed notably reduced mortality due to necrotic enteritis in chickens (p<0.001) compared to non-medicated groups. Stutz and co-workers (1983a) showed that bacitracin, carbadox and virginiamycin, all at the level of 55 ppm in feed, reduced the amount of # PERFRINGENS in the intestines of chickens compared to non-medicated controls (p<0.05). The numbers of clostridia were inversely correlated with performance data. A similar reduction in numbers of clostridia and correlation with performance data was observed by Elwinger and co-workers in several studies using avilamycin at 10 ppm or avoparcin at 15 ppm (Elwinger ET AL , 1993; Elwinger ET AL , 1995; Elwinger ET AL , 1996). From the above, it is clear that some are effective against clostridia, both IN at the levels used for growth promotion, resulting in effective disease prevention. Prevention of subclinical NE is associated with performance enhancement. Swine dysentery (SD) is a contagious diarrhoeic disease in swine, caused by the spirochete 3ERPULINA HYODYSENTERIAE. Other forms of spirochetal diarrhoea in pigs are associated with other 3ERPULINA spp. Various studies have shown effects on SD by quinoxalines at growth promoting levels. Hunneman (1980) reported a notable decrease in outbreaks of SD in a region when carbadox was introduced as a feed additive for swine. These observations are supported by the results obtained in two clinical trials Mode of action and effects (Anonymous, 1980). Molnar and Magyar (1987) reported an attempt to eradicate SD from swine herds by the aid of carbadox. Complete eradication of clinically apparent SD failed but the course and the severity of the disease was altered. The author also noted that the performance of the trial herds had improved markedly. Successful eradication of SD using carbadox in feed has been reported by other authors (, 1986; , 1987). A swine dysentery model for evaluation of drug prophylaxis has been developed by Raynaud and co-workers (1980a; 1980b). Using this model, carbadox, and to some extent olaquindox, was found to prevent the outbreak of SD. This was substantiated in a large scale trial in commercial pig herds in , where 50 ppm carbadox was found to be sufficient for both prophylaxis and treatment of swine dysentery (Raynaud and Bretheau, 1973) Prevention of experimentally induced SD with carbadox or olaquindox at levels used for growth promotion has been reported by several other authors (and Libke, 1976; and , 1978; and Shively, 1978; , 1980a; , 1980b; and , 1980; Biehl ET AL , 1984; and Froe, 1985; Jacks ET AL , 1986). In one of these studies, olaquindox-resistant strains were also used as challenge (and Shively, 1978). In those trials, the disease was not prevented, but morbidity was lower than in the non-medicated control group. There seems to be a good correlation between values of 3 HYODYSENTERIAE for tylosin and therapeutic effect of this substance. and Shively (1978) found that tylosin at 100-110 ppm completely prevented SD induced by a tylosin-susceptible isolate of 3 HYODYSENTERIAE, while it was only partly effective against the disease induced by isolates with higher values for tylosin. Jacks and co-workers (Jacks ET AL , 1986) also prevented swine dysentery in pigs experimentally infected with a tylosin-susceptible strain, by feeding tylosin at 110 ppm. When a tylosin-resistant strain was used the disease was not prevented, although mortality was lower in the tylosin-medicated group than in the non medicated group. A new tylosin compound, 3-acetyl-4"-isovaleryl tylosin was also tested and found to be effective at 50 ppm. and co-workers (1972) studied the effect of different levels of virginiamycin and tylosin on pigs experimentally infected with 3 HYODYSENTERIAE. They found a good prophylactic effect of virginiamycin at about 25 ppm but only a moderate effect of tylosin even at about 100 ppm. The antimicrobial resistance pattern of the infecting strain was not presented, but presumably it was resistant to tylosin. and Shively (and Shively, 1978) fed virginiamycin at 50 to 100 ppm to experimentally infected pigs. Virginiamycin could not control the disease, although clinical signs were a less common in medicated pigs than in non-medicated animals. This was supported by the observations of Rønne and co-workers (1992) who investigated the effect of 20 ppm of virginiamycin. Mode of action and effects 3.2.4Porcine proliferative enteritis (PPE) Porcine proliferative enteritis (proliferative adenomatosis) is an intestinal disease of pigs characterised by thickening of the intestinal mucosa. ,AWSONIA INTRACELLULARIS (formerly )LEAL SYMBIONT INTRACELLULARIS) is the causative agent. For a long time, the cause of the disease was elusive and various causative agents have earlier been pointed out. Therefore, most of the research bearing to prophylaxis or therapy is recent. McOrist and co-workers (McOrist ET AL , 1997) evaluated the efficacy of orally administered tylosin for the prevention and treatment of experimentally induced PPE. They found that tylosin at therapeutic levels could prevent PPE in challenge exposed pigs and could also be used for the treatment of previously induced PPE. Even at growth promoting levels, tylosin was effective in preventing the development of PPE. and (1996) reported successful prevention of PPE by tylosin at about 100 ppm. and (1994) compared 0, 40 and 100 ppm of tylosin for the treatment and prevention of PPE. The higher level of tylosin was effective as treatment of PPE, while 40 ppm did not quite prevent the emergence of clinical signs. and co-workers (1996a; 1996b) found that in-feed bacitracin had a prophylactic effect against PPE in swine. The dosages used in this study were mostly substantially higher than what is used for growth promotion, and doses were changed over time. Even in the group receiving the lowest levels of bacitracin (50-200 ppm), a notable prophylactic effect could be seen. 3.2.5Other bacterial enteritis in swine Among bacterial enteric diseases in swine, weaning diarrhoea is one of the most important, both clinically and economically. %SCHERICHIA COLI has been implicated in the pathogenesis. Bertschinger (Bertschinger, 1976) found that olaquindox at low growth promoting dosages was effective for both prevention and treatment of experimentally induced % COLI-diarrhoea in piglets. (1989) studied the effect of avilamycin and olaquindox on stress-induced post-weaning diarrhoea. At 40 ppm avilamycin or 50 ppm olaquindox, mortality was reduced (p<0.05). The diarrhoea score was considerably lower compared to the control, but the difference was not significant. At 80 ppm avilamycin, both diarrhoea and mortality were reduced (p<0.05). (1994) found that prophylactic treatment with 122 ppm or 173 ppm olaquindox in commercial swine herds reduced (p<0.01) the incidence of post-weaning diarrhoea in all but one of the herds investigated. From the herd where olaquindox had no prophylactic effect, olaquindox-resistant % COLI were isolated. Mode of action and effects Troutt and co-workers (1974) found that carbadox at maximum dosage reduced clinical signs and intestinal lesions in pigs experimentally infected with 3ALMONELLA Cholerasuis Most are, or have been, used for therapeutic purposes and for some the maximum dosage permitted for growth promotion is the same or nearly the same as recommended for prophylaxis and treatment of disease. Most have prophylactic and/or therapeutic effects on enteric diseases, at permitted dosages. 3.3Growth and feed efficiency responses to in pigs and poultry were introduced in the early 1950s and have played a major role in the development of intensive and industrialised livestock production. There is a great variation in responses of animals to (, 1993 , see table 3.IV). When judging these promoting or enhancing effects one has to consider the age and type of animals, the duration of administration and the performance level of the control group. The major part of the research in this area with different animal species has been performed by the manufacturing and feed industries, whereas a relatively limited part has been performed by independent research bodies (Brenninkmeiyer, 1996). 3.3.1Growth and feed efficiency responses to in pigs The response of younger animals, piglets as well as broiler chickens and calves, to is superior compared to responses in older animals. In piglets the growth responses to varies between 9 and and the feed efficiency responses between 6 and , whereas for growing-finishing pigs the level of response is inferior (Thomke and Elwinger, 1997b). There has been a tendency to increase the level of with time (Rosen, 1995). Some studies indicate a decreasing effect of on daily weight gain and feed efficiency over time (, 1986). However, (1992) was unable to find differences in growth rate and feed efficiency for tylosin in growing-finishing pigs comparing the period of 1969/79 versus 1980/90. A general opinion is that growth and feed efficiency responses of pigs and broiler chickens to is lower under improved environmental conditions than in poorer environments. Rosen (1995) estimated the ratio in response between a very good and a poor environment to 1:2. Mode of action and effects Percentage responses in growth performance and feed efficiency as a result of usage in livestock production, compared with unsupplemented control diets, as reported by different authors (sources cit. by De Craene and Viaene, 1992; , 1993) 4ABELL )6 3AMMANST¤LLNING AV PROCENTUELL EFFEKT AV !&4 P¥ TILLV¤XT OCH FODERUTNYTTJANDE HOS OLIKA HUSDJUR J¤MF¶RT MED OBEHANDLAD KONTROLL ENLIGT VAD SOM RAPPORTERATS AV OLIKA F¶RFATTARE K¤LLOR CIT AV $E #RAENE AND 6IAENE 'ROWING PIGS KG &INISHING PIGS KG SLAUGHTER 'ROWING FINISHING PIGS Bickel (1983) Hudd (1983) Mordenti et al. Birzer and Gropp (1991) Hudd (1983) Mordenti et al. Birzer and Gropp (1991) Some discrepancy exists between different reports on the effect of on sow performance. Speer (1974) concluded that the farrowing rate was improved by the use of . However, others state had no effects on oestrus, mating behaviour or breeding efficiency (and Speer, 1973). and Speer (1975) reported improved weights at birth and at Mode of action and effects weaning This could not be corroborated by and co-workers (1974) under Swedish conditions. Based on the available literature data, Thomke and Elwinger (1997b) estimated the average response in growth rate to and in feed efficiency to , when piglet diets were supplemented with . Corresponding responses for growing-finishing pigs were inferior, and averaged for growth rate and for feed efficiency. Thomke and Elwinger (1997b) also tried to predict the responses on performance in the Swedish pig industry to a re-introduction of APE. They assumed a lower response level on performance as a result of changes in the animal welfare rules, the current rearing and production models and performance levels in . For the piglet sector they calculated a response to of for growth performance and feed efficiency. For growing-finishing pigs a lower level of responses to , of was estimated. 3.3.2Growth and feed efficiency responses to in poultry In broiler production the administration of can yield an effect in comparison with the unsupplemented control of between -1 and (Brenninkmeiyer, 1996). Swedish and Danish experiments, performed during the period 1967-76 with broiler chickens fed bacitracin have been reviewed by Elwinger (1976). This antibacterial improved growth rate on average by and feed efficiency by . There were no differences in mortality. Similar to the result for pigs, responses in broiler chickens to are superior in the first growth phase, as compared with the second. In a comprehensive review, Rosen (1996), arrived at responses in growth rate and feed efficiency of 2 and , respectively. It was also observed that were more effective with respect to live weight gains when used in diseased than in apparently healthy birds. When including anticoccidials, the growth-promoting effect of the themselves was clearly limited, due to the fact that some anticoccidials have antibacterial effects as well. Based on available literature data, Thomke and Elwinger (1997b) estimated the overall responses of broiler chickens to as regards growth rate and feed efficiency and found it to be on average 3.9 and , respectively. A re-introduction of into today's Swedish broiler chicken industry would induce responses in performance and feed efficiency at a lower level than those reported above. An explanation for this is that the Swedish broiler industry has introduced production models without , with a very high standard of hygiene and by the use of feeding programmes including a mixture of enzyme preparations. A tentative response level for performance and feed efficiency of may be assumed. Mode of action and effects In pigs the responses to in terms of growth performance and feed efficiency are higher in piglets than in growing pigs and for finishing pigs the effects seem to be minute. A re-introduction of into Swedish pig and broiler meat production would most likely lead to lower levels of responses for growth performance and feed efficiency than what is reported in the literature. This is because these production systems have adjusted to production without usage. Livestock performance and feed efficiency are closely interrelated with the qualitative and quantitative microbial load of the host animal, including the alimentary tract and the animal environment. Appropriate nutrient supply and choice of ingredients and their proper preparation with respect to the animals digestive capacity will minimise nutrient losses, overloading, disturbances and intestinal overcrowding by harmful microbial flora. , improvements in feed composition and feeding strategies is an alternative to usage of . Despite a vast body of information, details on the mode of action of both enzymes and probiotics are still lacking. Obviously, more research is needed to develop more efficient enzymes and to find out efficient combinations of enzyme preparations suitable for individual and compounded feedstuffs Supplementing feed with enzymatic preparations may improve the digestive capacity, particularly in young animals. Thereby, nutrient utilisation in the anterior part of the gastrointestinal tract may be improved, possibly limiting the incidence of intestinal perturbation. Some experiments demonstrate that the beneficial effects achieved by can at least partly be obtained by the inclusion of dietary enzymes affecting the physical properties of the ingested non-starch polysaccharides (Elwinger and Teglöf, 1991; Kronseder, 1993; , 1996; Vranjes and Wenk, Thomke and Elwinger (1997a) assessed the effects of various enzyme preparations on the nutrient digestibility and performance in pigs, based on available literature data, and arrived at a value for the average feed efficiency response of approximately in piglets and about in growing-finishing Mode of action and effects