sou · GLB3132d2 · 1998-01-01 00:00:00 — Chickens reared in traditional, low stocking density units, such as free range backyard flocks, usually become infected by coccidia but these birds seldom develop overt clinical coccidiosis as the number of oocysts in the environment will be comparatively low and immunity develops rapidly. Unprevented coccidiosis, even if subclinical, has a considerable impact on the economic profit in the broiler industry. The economic losses of a coccidiosis outbreak are substantial due to increased mortality, depressed growth, decreased feed efficiency, medication and increased work load. It has been shown that coccidial infection predisposes chickens to intestinal clostridial overgrowth (Dykstra, 1978; , 1988). Interaction between coccidia and various other avian bacterial and viral pathogens has also been described (, 1985; Ruff, 1989). Taken together, modern broiler production systems require preventive strategies for coccidiosis control, which today are synonymous with chemoprophylaxis. 7.1.2 Prevention and chemoprophylaxis Anticoccidial drugs are classified in the Classification system (ATCvet) as group QP51A, together with other antiprotozoal agents (NLN, 1995). Coccidiostats approved for use in poultry and other food-producing animals within the EU are listed in table 7.I. In most countries, coccidiostats are incorporated in the feed to commercially raised broiler chickens and during the growth period to many replacement pullets (future layers and breeders). The by far most widespread use of coccidiostats is in broiler chickens. Ideally, the drugs should show no adverse effects on growth, feed intake, feed conversion or health, and leave no residues in meat. Furthermore, coccidiostats should minimise coccidiosis, but allow some development of coccidia in order to stimulate immunity. The discovery in the early 1940s that the sulphonamides possessed anticoccidial activity made way for the development of the broiler industry in the . The rapid development of new and more drugs against coccidia as well as the development of efficient vaccines against many avian viral diseases, together with confinement rearing and genetic selection for improved growth rate, made the success of the broiler industry possible. The remarkable world-wide expansion of the poultry industry and the rapid development of coccidial resistance against coccidiostats have necessitated a continuous search for new, efficient coccidiostats (figure 7.I). sulphanilamide sulphaguanidine sulphadimidine roxarsone clopidol decoquinate monensin robenidine halofuginone lasalocid salinomycin arprinocid narasin Year of introduction of representative coccidiostats. &IGUR ) )NTRODUKTIONS¥R F¶R REPRESENTATIVA KOCCIDIOSTATIKA Coccidiostats approved within Union (Council directive 70/524) 4ABELL ) +OCCIDIOSTATIKA GODK¤NDA INOM DEN %UROPEISKA 5NIONEN2¥DSDIREKTIV (ratio 25:1.6) (ratio 1:1) chickens for laying, Anticoccidial substances include the antibiotic group polyether ionophores (ionophoric antibiotics/ionophores) and various chemically synthesised substances (table 7.I. The ionophoric antibiotics are fermentation products from various 3TREPTOMYCES spp. and !CTINOMADURA spp. Ionophores make complexes with mono- or divalent cations, forming lipid soluble compounds which facilitate transport of cations through the cell membrane of the parasite (Jeffers, 1989). The facilitated transport of K+, Na+, Ca2+ and Mg2+ ions across the cell membrane results in secondary toxic intracellular calcium concentrations and disrupts osmotic balance. Ionophores are effective against both asexual and sexual stages of the coccidia. Few of the chemotherapeutic coccidiostats have been sufficiently studied with respect to the mechanisms for anticoccidial activity. However, the quinolone coccidiostats are known to disrupt the electron transport in the mitochondrial cytochrome system of coccidia (, 1975; , 1993). Amprolium acts as a thiamine antagonist (VET., 1997). The mode of action for some other coccidiostats, such as halofuginone and diclazuril, is incompletely understood. Coccidia have, so far, developed resistance to all coccidiostats used. In some cases the resistance problems have emerged so rapidly that the market life of new products has been too limited to justify the costs of development of the drug. The development of resistance to the ionophorous anticoccidials has been comparatively slow. However, increasing ionophore resistance problems have been noticed in many countries (McDougald ET AL , 1986; Jeffers, 1989; , 1994). Therefore, various anticoccidial programmes including switch, rotation or shuttle application of anticoccidial agents are applied to counteract resistance problems in many countries. There has been some debate as to whether resistance to one ionophoric substance conveys cross-resistance to all other ionophores. Reported results have been contradictory (Jeffers, 1989) However, the general view is that resistance leads to cross-resistance to all ionophores (, 1993). Considering the efforts that are put into avoiding resistance problems, it is somewhat surprising that so is known about the modes of action and resistance mechanisms for various coccidiostats. Explanations for the mechanisms of resistance are either speculative or unavailable (, 1993). Such information is essential for understanding how to counteract resistance and what substances would be most effective in a given situation. Most polyether ionophores are not only against protozoa, but also against aerobic and anaerobic gram-positive bacteria, e.g. ,ACTOBACILLUS spp (, 1994), #LOSTRIDIUM PERFRINGENS (Dutta ET AL , 1983; , 1988; Kondo, 1988; Elwinger ET AL , 1992; , 1995; , 1997), %UBACTERIUM SPP , 0EPTOCOCCUS SPP 0EPTOSTREPTOCOCCUS SPP , 3TREPTOCOCCUS (Watanabe ET AL , 1981) as well as !CHOLEPLASMA and -YCOPLASMA SPP (Stipkovits ET AL , 1987). As is the case with coccidia, the mechanism for the inhibitory activity against bacteria is tthrough increased membrane cation permeability. Microbiological manipulation of the ruminal fermentation process and consequently of the ruminal volatile fatty acid concentrations is thought to be the basis for the improved feed efficiency in ruminants when the feed is supplemented with low concentrations of ionophores (Nagaraja ET AL , 1985; Chirase ET AL , 1988). The changes of the ruminal fermentation process include enhanced production of propionic acid by ruminal ionophore resistant bacteria, and decreased production of acetic acid, butyric acid, lactic acid and methane by ionophore sensitive bacterial species (Schelling, 1984; Nagaraja and , 1987). Several ionophores including monensin, narasin, salinomycin and lasalocid sodium have been shown to suppress growth of # PERFRINGENS. antibiotics are therefore considered to be important in the prevention of necrotic enteritis (NE) in broiler chickens (Elwinger ET AL , 1994). Together with the suppression of # PERFRINGENS a better performance has also been noted in ionophore-medicated chickens (Elwinger ET AL , 1992; Quarles ET AL , 1992; Elwinger ET AL , 1994; Elwinger ET AL , 1996; Waldenstedt ET AL , 1997). It is likely that the reduced immunological challenge in terms of reduced load of # PERFRINGENS in the intestines of chickens explains the increased growth rate of the medicated birds. Like other antimicrobial substances that are mainly against gram- positive bacteria, ionophores might be expected to facilitate salmonella colonisation (see chapter 4). Only one study has been found that investigates the effect of monensin in this respect (Manning ET AL , 1994). The authors of this study concluded that monensin did not influence salmonella colonisation. Further studies, on other ionophores as well, are needed to evaluate this matter. No information about bacterial resistance to ionophores has been found. Anticoccidial drugs include ionophoric antibiotics and chemoterapeutic substances. Coccidial drug resistance is an emerging problem in particular for chemoterapeutic substances but also for ionophores. information about modes of action and resistance mechanisms for various coccidiostats is needed. Most ionophores are against gram-positive bacteria. Several ionophores suppress growth of #LOSTRIDIUM PERFRINGENS the causative agent of necrotic enteritis in chickens. Coccidiostats are generally considered to be free from side effects and toxicity as long as they are used in their target species at the correct dosage. However, the ionophoric antibiotics and some of the chemotherapeutic coccidiostats have a narrow range of safety and there are many reports in the literature of accidental intoxications of target and non-target species with various anticoccidial drugs. However, most such events can be avoided if good manufacturing practices (GMP) are maintained. Intoxications with coccidiostats have been reported in association with poor mixing of the feed resulting in uneven cocccidiostat concentration, failure to properly dilute the coccidiostat concentrate, and in cases of incorrect identification of the product or the feed (Szancer, 1989; Novilla, 1992). The feed can become cross-contaminated at the feedmill and pet food has on occasion been shown to contain traces of coccidiostat (, 1980; Wheeler, 1996). Toxicity has also been noted when giving poultry feed containing coccidiostat to animal species for which the feed was not intended and when chicken manure has been used as a source of nitrogen in cattle feed (Muylle ET AL , 1981; , 1991; Perelman ET AL , 1993). Diagnosis of coccidiostat intoxication is sometimes difficult due to reversibility of clinical signs and/or the variability of pathological lesions associated with toxicity of coccidiostats of different chemical groups. Feed analysis is often not possible to perform because the feed has already been consumed and/or representative feed samples are not available. Many review articles on the toxic effects of ionophores in target and non- target species have been published during the last decades (among others and , 1979; Galitzer and W., 1984; Langston ET AL , 1985; Szancer, 1989; Novilla, 1992). The toxic effects of ionophores are directed mainly against skeletal and/or cardiac muscle. )N studies have shown that myopathy occurs as a consequence of disturbances in intracellular calcium homeostasis followed by increased intracellular Na+ concentration (Shier and Dubourdieu, 1992; Sandercock and , 1995). The LD50 values for the ionophores are generally low, often not higher than 2 to 3 times the recommended dosage in various species (, 1991). The diagnostic approach to ionophore intoxication relies on the combination of non-pathognomonic clinical signs, histopathological changes, recovery of the animals when the feed is changed, and analysis of potentially toxic levels of coccidiostats in the feed. There is no efficient, specific treatment for ionophore intoxication in any species (Langston ET AL , 1985). Withdrawal of the suspected feed and supportive treatment is recommended (Langston ET AL , 1985). Accidental intoxication with ionophores has been described in many different animal species, e.g. chickens, , ostriches, cattle, sheep, deer, pigs, horses, dogs and cats (Muylle ET AL , 1981; and Wobeser, 1983; Galitzer and W., 1984; Langston ET AL , 1985; , 1988; Novilla, 1992; , 1997). There is considerable species variation in susceptibility to ionophore toxicity (table 7.II). Horses are very susceptible to ionophores and great care is warranted at the feed mill to ensure that cross contamination of equine feed is avoided. Species and substance variation of toxicity following oral dosing of monensin and lasalocid (mg/kg body weight) (from Galitzer and W., 1984; , 1995) 4ABELL )) 6ARIATION I TOXICITET MELLAN ARTER OCH SUBSTANSER EFTER ORALT INTAG AV MONENSIN OCH LASALOCID MG KG KROPPSVIKT (från Galitzer and W., 1984; -ONENSIN ,$ -ONENSIN ,$ ,ASALOCID ,$ 35 (25-43) * data not available Ionophore toxicity in poultry Intoxication with ionophores is a well known problem in poultry (among others Howell ET AL , 1980; Hanrahan ET AL , 1981; Halvorson ET AL , 1982; Braunius, 1989; Dowling, 1992). The prevalence of ionophore toxicity in broiler chickens may be higher than what is generally considered, but hidden due to diagnostic difficulties. When exposed to sub-lethal toxic doses of ionophoric antibiotics chickens show growth depression and decreased feed intake (Langston ET AL , 1985). At higher doses clinical signs include anorexia, leg-weakness, incoordination, drowsiness, depression, diarrhoea and sometimes even deaths. Sternal recumbence with neck and hind legs outstretched may also be seen (Langston ET AL , 1985). Gross pathology lesions are often inconclusive. Pathological changes include emaciation, congestion, myocardial ventricular dilatation, pallor and streaking of skeletal and heart muscle, and ascites (Langston ET AL , 1985). Histopathological changes are variable. In many cases scattered foci of acute myonecrosis can be seen. In other cases severe muscle and myocardial degeneration and necrosis are observed (Langston ET AL , 1985). The clinical signs are reversible and usually disappear once the feed containing toxic levels of the ionophore is removed. Ionophores may also negatively interfere with reproduction in poultry. Reduced fertility (, 1990; Perelman ET AL , 1993), reduced or completely lost egg production (Howell ET AL , 1980; , 1995) and reduced hatchability (Howell ET AL , 1980; , 1990; Perelman ET AL , 1993) have been reported. This is not a problem in commercial production, since breeders and layers are not treated with ionophores during the egg- laying period. However, in cases when layer feed has been contaminated with ionophores reproductive disturbances have been reported (Perelman ET AL , 1993). Remarkable differences in toxicity may be seen within the group of ionophores, when used in the same animal species. For example, in , ionophore intoxication has been recorded when standard dosages of narasin and salinomycin have been used (, 1983; Horrox, 1984), while other ionophores, such as monensin, maduramicin and semduramicin, are better tolerated. Ionophore toxicity in other animal species As mentioned, ionophore toxicity has been described in many non-target species including ostriches (, 1997), sheep (Nation ET AL , 1982; Confer ET AL , 1983), captive white-tailed deer (and Wobeser, 1983), horses (Muylle ET AL , 1981; Kamphues ET AL , 1990), dogs (, 1988; Karsai and , 1990; Safran ET AL , 1993) and cats (Wheeler, 1996). with ionophores in non-target species can cause a variety of clinicopathological changes. Horses may develop hypovolemic shock and toxic tubular nephrosis, as well as cardial and skeletal muscle changes when given low doses of ionophores. As a lingering effect of ionophore toxicity in horses cardiac fibrosis has also been reported (Muylle ET AL , 1981). There are also clear indications that cats show remarkable sensitivity to ionophores. In 1996 an outbreak of feline neuropathy was linked to cat feed containing traces of salinomycin (detection limit 2 ppm Wheeler, 1996). Ionophore intoxication has also been described in cattle (Galitzer ET AL , 1986; Schlosberg ET AL , 1992). A primary cardiomyopathic syndrome has been described in beef cattle fed dried broiler manure containing ionophore residues (, 1991; Schlosberg ET AL , 1992). This syndrome is characterised by sudden death, exercise intolerance and subcutaneous oedema. There are also reports describing intoxication with ionophores in swine (, 1983). Interactions of ionophores with other medicinal substances Some ionophores interact with antibiotics and chemotherapeutic agents (Meingassner ET AL , 1978; Frigg ET AL , 1983; Umemura ET AL , 1984; , 1986; , 1990; , 1995 and others). The mechanism of interaction between ionophores and other chemically defined substances has not been fully clarified. However, in an IN study the elimination of monensin in rat liver was reduced by when tiamulin was added (Meingassner ET AL , 1978). In combination with the narrow safety for ionophores the reduced elimination of ionophores poses an increased risk of intoxication. Monensin, narasin and salinomycin can interact with antibiotics such as chloramphenicol, erythromycin and oleandomycin (Prescott and Baggot, 1993). Other examples of interaction include lasalocid with chloramphenicol, lasalocid and monensin with furaltadone and furazolidone, lasalocid with sulphadimethoxine, and monensin with sulphaquinoxaline, sulphamethazine and sulphadimethoxine (Frigg ET AL , 1983; , 1990). 7.3.2Toxicity of other coccidiostats Non-specific signs of toxicity, such as depressed growth rate, reduced feed intake, weakness and depression, have been observed in birds and mammals following exposure to some of the non-ionophoric substances (, 1995). Furthermore, more specific toxic signs are reported with certain substances. One such example of toxicity is the reduction of the skin tensile strength of broiler chickens by the interference of halofuginone with the collagen synthesis (, 1985; Granot ET AL , 1991; , As a consequence, the birds suffer skin tears during slaughter and processing. In a recent study it was also shown that halofuginone supplementation is associated with an increase in skin scratches and sores in the birds IN VIVO (Pinion ET AL , 1995). Unpublished Swedish observations when this product was used in the middle of the 80s are consistent with these findings. to problems with carcass quality that were put in connection with the use of halofuginone, the product was abandoned by the industry (, personal communication, 1997 1). The animal welfare aspect of halofuginone toxicity should also be considered. Halofuginone and arprinocid are known to be toxic for ducks and geese (, 1988). Robenidine, arprinocid and in particular halofuginone have been reported to be toxic to chicken embryos (, 1989; Granot ET AL , 1991; , 1994). Additionally, halofuginone is toxic to fish (, 1995). Nicarbazin interferes with the thermoregulatory balance at high ambient temperatures which can, in a dose dependent way, cause decreased weight gain and feed efficiency as well as increased mortality (Wienernusz and Teeter, 1995). At therapeutic dosage nicarbazin also interferes with the reproduction of hens by causing decreased egg production and hatchability (, 1990). To avoid residues of coccidiostats in meat, withdrawal periods before slaughter of the animals are assigned (table 7.I.). Eggs are, however, a special problem. Maximum age levels and restrictions on usage in layer feed may not always be enough to ensure that eggs are free of coccidiostats. Laying might commence shortly after, or even before, the maximum age is reached. Moreover, withdrawal right before laying starts may not be sufficient for substances that persist for a long time in the tissues of the animals. It has been suggested that residues of ionophores in food could cause adverse effects on the health of humans since these substances possess cardiovascular properties (Kabell ET AL , 1979; and , 1981). Monensin induces coronary vasodilatation in dogs and rabbits at low concentrations. Inotropic effects of lasalocid on human heart muscle has been demonstrated IN (and Inesi, 1974) but there are no reports in 1 , , , , the literature describing ionophore toxicity in humans associated with meat consumption. Ionophores are absorbed from the gut and may be found in various organs at zero withdrawal time (Davison, 1984; Donoho, 1984; , 1992; , 1993). However, if withdrawal times are respected, presence of toxic residues would not be expected. For narasin, passage into egg yolk has also been reported (Catherman ET AL , 1991). Some of the non-ionophoric coccidiostats are absorbed from the gut of the target animals. However, most substances appear to have low toxicity, why residues would not be expected to give rise to any toxic effects. Decoquinate is only absorbed to a small extent (Seman ET AL , 1989) and is reported to have very low toxicity (, 1995). Low toxicity is also reported for diclazuril (, 1995). Feeding of radiolabelled arprinocid at concentrations between 60 and 80 ppm has been reported to result in residues of 0.1-0.5 ppm in liver after 3-5 days withdrawal time (, 1982). In one study, meticlorpindol in chicken feed at 125 ppm for 34 days resulted in residues in liver and muscle of 0.5 ppm and 0.1 ppm, respectively, at 2 days withdrawal (, 1984). Thereafter, there was a slow decrease in residue concentrations, which were measured until 10 days after withdrawal. Low toxicity of meticlorpindol after oral intake is reported (, 1995). Amprolium, may be found in eggs up to 10 days after withdrawal from the feed (Kan ET AL , 1989). Amprolium is reported to be fairly atoxic, and it is not permitted in the feed after the beginning of egg laying, but no withdrawal time has been assigned for eggs. Passage of halofuginone into eggs has also been reported (and Blagburn, 1995). No withdrawal time for eggs has been established. For some substances, such as lasalocid, maduramicin, narasin and halofuginone, withdrawal times are shorter in Swedish national regulations than in EU regulations. As a conservative approach may be preferable in this case, it is advisable to adjust the Swedish withdrawal times to the EU regulations. Ionophores may cause irritation and allergic reactions in humans, and may thereby be an occupational hazard for feedmill workers and other people that come into contact with these substances on a daily basis (Mancuso ET AL , 1990; , 1995). Protective clothing and dust masks are recommended when handling ionophores. Dust formation might be reduced by changes in the galenic formulation used. For some coccidiostats the maximum dusting properties allowed when handling the substances, as determined by the Stauber Heubach method, have been fixed. Amprolium, meticlorpindol, robenidine and halofuginone may cause irritation of the skin and eyes by direct contact or through aerosols (Mancuso ET AL , 1990; , 1995) and care should be taken to avoid contact, by using masks and protective clothing while handling these substances. Clinical reports of allergic reactions to non-ionophoric coccidiostats appear to be less frequent. However, this does not necessarily mean that such reactions are rare. The toxicological safety of ionophores are comparatively narrow. Ionophores are toxic for many non-target species. Some ionophores interact with antibiotics and chemotherapeutics which may increase the risk of intoxication. Some non-ionophore coccidiostats are toxic for ducks, geese and fish. Halofuginone causes skin damage in the target species. This is unacceptable from an animal welfare point of view. Most coccidiostats are absorbed from the gut, and may be found in various tissues at zero withdrawal. It is therefore important that withdrawal times are respected. For some substances, withdrawal times for eggs should be considered. Ionophores, and some non-ionophores may cause irritation and/or allergic reactions in man. Since poultry manure is extensively used as fertilisers, coccidiostats and their degradation products are likely to reach soil and water. Therefore, it is important to identify potential effects on terrestrial and aquatic environments, including flora, fauna and microbes. However, very few studies have been published regarding the environmental fate of coccidiostats, which makes it difficult to evaluate their possible impact in this respect. 7.4.1Environmental aspects on ionophores Ionophores are excreted in poultry manure (Donoho, 1984; , 1991; Schlosberg ET AL , 1992). Biodegradation studies indicate that monensin is degradable, under aerobic conditions, in soil with or without manure (Donoho, 1984).