Anthelmintic drugs and coccidiostats: anti-parasitic drug residues in meat

by Mariclare McGarrity, helminth infection include diarrhoea, weight major metabolite is 5-hydroxythiabenda - senior customer support scientist, loss, anorexia and insufficient weight gain. zole. The sum of unaltered thiabendazole Randox Food Diagnostics. Anthelmintic drugs are used to treat and 5-hydroxythiabendazole is estimated to helminth infection in cattle. Despite the represent 50-90% of total residues and are lobally, livestock play a vital role in prevalence and economic impact of the most persistent residues detected in the economy, which includes meat, helminth infection in the global livestock liver. Gmilk, eggs and fibre. Cattle and poul - industry, little attention is given to the devel - l Triclabendazole: try production are two of the most impor - opment of new anthelmintics. Triclabendazole is a benzimidazole tant agricultural industries worldwide. As The most widely successful drug over the anthelmintic used in food animals, where it incomes rise, people in both developed and last 20 years has been Ivermectin (an is mainly employed in the control of liver developing nations have an increased Avermectin) which has decreased research fluke in sheep and cattle. appetite for animal protein, and therefore into new drugs. Triclabendazole has a narrow spectrum of the demand on the industries to increase Below are some of the most commonly activity concentrated against a limited num - productivity is also intensifying. used veterinary anthelmintic drugs: ber of fasciolides. Triclabendazole is not This article will provide a brief overview of l Avermectins: active against nematodes some common infections being battled The avermectins are a group of chemically l Levamisole: throughout our worldwide cattle and poul - related compounds originally isolated from Levamisole is a synthetic imidazothiazole try industries and also the drive to keep our the actinomycete Streptomyces avermitilis. derivative that has been used extensively as meat and eggs drug-residue free. They are macrocyclic lactone derivatives an anthelmintic agent. The racemic mixture with potent anthelmintic activity, but lack tetramisole is also used as an anthelmintic, antibacterial or antifungal activity. although the anthelmintic activity is due to Helminth infection The avermectins also have insecticide levamisole. Levamisole is commonly used in activity and include the compounds iver - cattle, sheep, pigs, goats, and poultry to There has been a noted success in the last mectin, abamectin, doramectin, emamectin, treat nematode infections, but has no activ - 60 years in controlling helminth parasites in and eprinomectin. ity against flukes and tapeworms. It is cattle using anthelmintics. However, l Benzimidazoles: thought that its anthelmintic activity is helminth infection continues to be a looming Albendazole is a benzimidazole carbamate, achieved through interaction with the threat to our global livestock production which is used as an anthelmintic in veteri - nicotinergic acetylcholine receptor, prevent - with increased anthelmintic resistance. nary and human medicine. Albendazole is ing males from successfully copulating as Parasitic helminth infection affects food metabolised to albendazole sulphoxide and they lose their ability to control their repro - producing animals worldwide. The word albendazole sulphone; the carbamate moi - ductive muscles. ‘helminth’ is a general term meaning ‘worm’, ety is then cleaved to produce albendazole l Moxidectin: but there are many different types of 2-aminosulphone. Moxidectin is a semi-synthetic, macrocyclic worms. The most widely prevalent Albendazole binds strongly to tubulin in lactone, structurally similar to abamectin, helminths are the nematodes (round the cells of nematodes, especially intestinal ivermectin and milbemycin. Moxidectin is worms), which inhabit the gastro-intestinal cells, resulting in a loss of absorptive func - intended for the treatment of endo- and tract. Larvae for these parasites are most tion which causes starvation of the nema - ecto-parasites in cattle and sheep by oral or commonly ingested during grazing. todes. Albendazole-containing products are sub-cutaneous route and in horses by oral Usually the development time of these lar - available in liquid form or as pellets, both of administration. vae then depends on the specific type of which are administered orally. nematode and the conditions they inhabit. l Thiabendazole: Under optimal conditions the developmen - Thiabendazole is an anthelmintic, which is Residues and resistance tal phase takes up to 10 days. used in the treatment and control of gas - Most trichstrongyles (type of nematode) trointestinal roundworms in horses, cattle, In 2011 46 border rejections were raised in moult into adults three weeks after infec - goats and sheep, and for the control of lung - the EU for residues of veterinary medical tion. Eggs produced by female adults are worms in sheep. It is also used for the con - products, 25 of which were for the present in the faeces of infected animals. trol of fungal diseases affecting plants, anthelmintic drug Ivermectin. These rejec - In Brazilian Beef herds, Cooperia infection animals and man. tions have highlighted the need for a rapid has been found to be one of the most Thiabendazole binds strongly to tubulin in and reliable screening method for many bor - prevalent. The Cooperia species live in the the cells of parasitic worms, especially der inspection points and import authorities small intestine and can penetrate the intestinal cells, resulting in interference with as vigilance must be increased to ensure that mucosa during larval development causing absorptive function and starvation. foods containing these drugs are not changes similar to those of the intestinal Thiabendazole is rapidly metabolized and allowed to enter the food chain. species trichostrongylus. Symptoms of this excreted in cattle, pigs, sheep, goats; its Continued on page 8

International Meat Topics — Volume 4 Number 3 7 Continued from page 7 Poultry are generally raised in cramped, static in action and is most effective against Treatment of the infected animal with the overcrowded conditions which make coc - the sporozoite stage of Eimeria. It is the only wrong drugs, incorrect dosage or insufficient cidiosis infection easily spreadable. member of the pyridinol group to be com - withdrawal period of the drugs are con - Coccidiosis is usually characterised by mercially successful and is one of the few tributing to anthelmintic resistance as well as bloody droppings, weight loss and mortality drugs used to control coccidiosis in rabbits. residues of these compounds remaining in in young chickens. Unsanitary conditions It is administered in feed at a dose of the milk or tissue of treated animals. usually increase the prevalence of this infec - 200ppm for rabbits and 125ppm for chick - Maximum Residue Levels (MRLs) have tion in the poultry industry. ens, with a withdrawal period of five days. been established for the majority of these Clopidol is generally used in combination compounds. with nequinate and is also used with methyl - Anticoccidial drugs benzoquate in chickens and turkeys. The United States-Food and Drug Coccidiosis in poultry Coccidiostats are antiprotozoal agents that Administration (US-FDA) has also approved act upon coccidia parasites in livestock. The the use of clopidol in medicated feed in Just like helminth infection in the cattle EU has implemented testing guidelines (out - combination with bacitracin zinc and roxar - industries, coccidiosis is causing economic lined in group B2b of Annex 1 to Council sone. losses in the poultry industry. The most Regulation 2377/90) to test for veterinary l Decoquinate: common species of coccidia that are preva - medicines in food. This would encompass Decoquinate is a quinolone derivative, lent in chickens are Eimeria tenella and the treatment of coccidiosis – a protozoal active against eimeria and toxoplasma Eimeria necatrix which both cause bloody disease that can cause diarrhoea and dysen - species. The quinolones are a family of syn - intestinal coccidiosis. tery in the affected animal. thetic antibiotics structurally related to In chickens, a coccidia oocyst is excreted Control of coccidiosis is particularly nalidixic acid that inhibit the action of bacte - in the droppings and then develops into important in the poultry industry, where the rial DNA gyrase enzymes, although the what is called a sporulated oocyst, infecting prophylactic use of coccidiostats prevents exact mode of action is not understood. other chickens. This sporulated oocyst facili - the disease from developing, thus increasing Decoquinate inhibits the development of tates many offspring inside the cells of the the risk of drug residue carry over into meat coccidia in the small intestine in the early infected chicken and large amounts of and eggs. Maximum Residue Limits have part of the infective cycle, resulting in lower intestinal cells may be destroyed or dam - been set in place for a number of coccidio - morbidity and mortality. Decoquinate is aged. stat residues. administered in feed at 20-40ppm for the After the developmental phase, male and Below are some commonly employed coc - prevention of coccidiosis. Decoquinate is female cells are produced which enables cidiostats: also administered in combination with other production of an oocyst. This oocyst rup - l Clopidol: antimicrobials such as chlortetracycline or tures from the intestinal cell wall and is Clopidol is a member of the pyridinol group roxarsone and bacitracin methylene disalicy - excreted in droppings. of anti-coccidial compounds. It is coccidio - late.

8 International Meat Topics — Volume 4 Number 3 l Diclazuril: potent as a coccidiostat than other poly - intracellular development stages and is Diclazuril is a benzeneacetonitrile derivative ether antibiotics. thought to interfere with nuclear division used as an oral anticoccidial agent. Its mode l Monensin: and mitochondrial activity. Toltrazuril is of action is not known, although it interrupts Monensin is a polyether antibiotic and is the administered in drinking water at a dose of the life-cycle of parasites by blocking the major component of the antibiotic complex 10-25ppm in chickens, turkeys and rabbits. excretion of oocysts. Diclazuril is adminis - produced by Streptomyces cinnamonensis. tered as a medicated feed premix, at a rec - Monensin is used as a coccidiostat in poultry ommended dose of 1ppm, to major poultry and a growth promoter in cattle. Coccidiostat toxicity species, rabbits and lambs, although it is not l Nicarbazin: intended for use in laying hens. Nicarbazin is an antiprotozoal agent used in In recent years concerns of chemical l Halofuginone: veterinary medicine as a coccidiostat but residues in the food stream has become Halofuginone is derived from febrifugine and also as a feed additive in animal husbandry. very topical, and this includes concerns over is a member of the quinazolone group of Nicarbazin interferes with mitochondrial coccidiostats which may be present in poul - chemicals. The active form is trans-halofugi - metabolism and inhibits oocyst production. try tissue. It is thought feed contamination none and the cis- form is present as an It consists of a 1:1 molar mixture of N,N’- could also be a contributing factor. impurity. Halofuginone lactate is used for bis(4-nitrophenyl) urea and 4,6-dimethyl- The problems related to coccidiostats the prevention of diarrhoea due to 2(1H)-pyrimidinone and the complex is being present in our foodstuffs. Maximum Cryptosporidium parvum in non-ruminating essential for coccidiostatic properties. Residue Levels have been established for the calves, whereas halofuginone hydrobromide Nicarbazin is often administered in con - majority of these compounds. It is highly is used as an anticoccidial feed additive for junction with other coccidiostats or antimi - recommended that with these drugs, an broilers and turkeys. crobials for example narasin and bacitracin. appropriate withdrawal time is observed Halofuginone has a steep dose-response l Nifursol metabolite: prior to slaughter and consequently this curve and at high doses is a growth depres - Nifursol is an anti-protozoal agent used in should result in no risk of toxicity in the con - sant, which can cause difficulties when veterinary medicine. It belongs to the nitro - sumer. Testing for these compounds in administered in feed. Halofuginone hydro - furan group of compounds, which are foodstuffs should be carried out. bromide is also administered in combination thought to be genotoxic due to the pres - with other antimicrobials such as lincomycin ence of a 5-nitro group. and bambermycin. Nifursol was used as an approved feed Testing platforms l Imidocarb: additive in the European Union (EU), for the Imidocarb is a carbanilide derivative adminis - prevention of histomoniasis in chickens and Biochip array technology based on ELISA tered via a subcutaneous injection as the turkeys. However, its use has now been test principles allows for the simultaneous dipropionate salt to cattle and sheep for the prohibited in the EU. detection of multiple compounds of drugs treatment of anaplasmosis and babeiosis. l Robenidine: from a single sample. The anthelmintics test - l Lasalocid: Robenidine is administered to chickens in ing array can detect 25 anthelmintic com - Lasalocid is a polyether ionophore antibiotic medicated feed in combination with baci - pounds from a single sample detecting both produced by Streptomyces lasaliensis. tracin and roxarsone. parent and metabolite forms of the com - Lasalocid is a mixture of several closely l Salinomycin/narasin: pounds. related substances termed lasalocid A-E. Salinomycin is a polyether antibiotic pro - These include albendazole sulphoxide and Lasalocid A constitutes 90% of the active duced by Streptomyces albus and used in albendazole–2-aminosulphone, both of substance. Lasalocid is mainly active against veterinary medicine as antiprotozoal agent which are the main residues detected in tis - Gram positive micro-organisms and it is to treat and prevent coccidiosis. It disrupts sue matrices irrespective of whether animals used in veterinary medicine as antiprotozoal the growth and reproduction of certain were dosed with netobimin, albendazole or agent. intestinal bacteria and was the first licensed albendazole sulphoxide. Lasalocid is also administered as a med - growth promoting polyether in swine. It is The Evidence Investigator Coccidiostats icated feed additive, either alone or in con - used in broiler chickens at 50-70ppm in Array will quantitatively test for lasalocid, junction with other antimicrobials such as feed, with a five day withdrawal period. nicarbazin, imidocarb, toltrazuril, maduram - virginiamycin. Lasalocid sodium binds mono - Salinomycin is commonly administered in icin, nifursol metabolite, salinomycin, clopi - valent and divalent cation and alters ionic combination with other antimicrobials such dol, monensin, robenidine, decoquinate, transport across lipid membranes. Although as roxarsone and bacitracin, roxarsone and halofuginone and diclazuril simultaneously. the use of lasalocid in laying hens is prohib - bambermycins, roxarsone and chlortetracy - Data indicates applicability of this biochip ited in Europe, one in eight samples of eggs cline, and tylosin. array to the multiplex determination of coc - tested by UK government chemists are Narasin is a polyether ionophore isolated cidiostat and anthelmintic residues, which is reported to contain residues of lasalocid. as the major compound in an antibiotic relevant for the screening of these com - The contamination of eggs is thought to complex produced by Streptomyces aureo - pounds in foods to ensure compliance with occur due to poor cleaning systems at feed faciens. It is used in veterinary medicine as regulatory MRLs. This multiplex screening mills and the accidental use in layers of lasa - an antiprotozoal agent but also in animal approach reduces time and cost spent test - locid-medicated feed destined for young husbandry as a growth promoter. ing samples for these residues. birds. It is effective against all intestinal and caecal The biochip testing platform uses the l Maduramicin: coccidia if administered continuously in feed, world’s only multi-analyte semi-quantitative Maduramicin is a polyether ionophore but it should not be administered to laying drug residue analyser; the Evidence antibiotic produced by Actinomadura hens. It is administered in feed at doses Investigator. This multiplex platform is also yumaense. It is often confused with madu - between 27 and 72ppm, often in conjunc - available for an extensive list of antibiotics ramycin, a distinct compound isolated from tion with other antimicrobials such as nicar - and growth promoting compounds using Actinomadura rubra as reported by Fleck et bazin and bacitracin, or bambermycin and sample matrices including muscle, liver/kid - al. (1978). Maduramicin has been approved roxarsone. ney, seafood, milk, honey, urine and animal for use for the prevention of coccidiosis in l Toltrazuril: feed. broiler chickens caused by various Eimeria Toltrazuril is a triazinetrione derivative used The multiplex testing format will reduce strains. as a coccidiostat in food producing animals. cost, run time and labour requirements – all Maduramicin is administered in feed at a It is a suspected teratogen and has an of which guarantee a faster turnaround time dose of 5ppm, with a seven day withdrawal extended withdrawal period. for results along with a higher sample period. It is reported to be 12-24 fold more Toltrazuril is effective against Eimeria at all throughput. n

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