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Most of the anticoccidials used for the control of the coccidia proper in livestock and poultry are approved by government agencies for the prevention of coccidiosis in chickens (Table 1). Despite the use of anticoccidials in continuous medication programs global losses chiefly due to subclinical coccidiosis in broiler poultry is estimated at up to US$ 750 million. The enormous expansion of broiler production over the last 30 years has been reflected in the world market for anticoccidial drugs. In 1991 the total turnover per year was about US$ 450 million. This figure includes in-feed anticoccidials (~ 80% ionophores) at about US$ 370 million, in-water anticoccidials at US$ 30–40 million, and biologicals at US$ 25–30; the broiler market with about 80% of the total has been large enough to stimulate major screening and development programs in the American and European pharmaceutical industries. However, the rapid emergence of drug resistance can result in a short market life for some drugs (less than 6 months for buquinolate). However, high cost of obtaining government clearance (registration costs continue to rise and may come to US$ more than 20 million per drug), and the delays involved, have all discouraged pharmaceutical companies. Discovering, characterizing, developing, and registering a new drug may take 8–10 years. The risk of drug resistance may also jeopardize any hope of benefit from the high capital expenditure on registering a new anticoccidial. Several pharmaceutical companies have consequently taken a new approach and abandoned anticoccidial-screening programs although the use of novel high-throughput screening methods would permit large numbers of compounds to be investigated within short periods. In future the most promising alternative to controlling coccidia infections with chemotherapy may be immune prophylaxis. As a result of public pressure against continuous medication, drug resistance problems, and the high cost of drug clearance vaccines, which are able to induce sufficient immunity (both humoral and cellular response) and thus provide flock protection against morbidity and mortality, would be an appropriate alternative.
The application of any control methods, whether hygienic, chemotherapeutic or immunological, needs profound knowledge of the epizootiology of various coccidioses. The term coccidiasis is used to describe relatively nonpathogenic and usually mixed infections, whereas coccidiosis is a severe disease in the host. In papers related to human medicine the ending 'iasis', however, is used to indicate an acute phase of disease with severe clinical symptoms. Thus the parasitological literature may lead to confusion on the severity of the disease. Mixed infections, i.e., those where animals are infected with more than one species of coccidia, are very common and only some species are highly pathogenic. The severity of the disease is the result of the combined actions of the particular mixture of coccidia, the number of sporulated oocysts ingested with feed or water. However, it may be influenced also by the nutritional condition of the host, environmental and climatic factors (such as temperature, moisture, oxygen tension, and sunlight) and the management practices used. Crowding of animals due to intensive rearing, for example in the broiler industry where large numbers of chickens are kept in enormous houses, creates conditions favorable to sudden outbreaks of severe coccidiosis. Fecal debris may concentrate large numbers of oocysts, which can rapidly sporulate and become infective under warm and moist conditions. Severe coccidiosis is, therefore, mostly a “man-made” problem with domestic animals and is not a general problem in the wild or on pastures. When coccidiosis is suspected and oocysts are found, the species present should be identified. A periodic examination of feces for oocysts and a post mortem examination in a few animals will give valuable information on the status of infection.
Coccidiosis cannot be recognized clinically until tissue damage associated with second- or third-generation schizogony occurs. When the disease is present, the clinical signs are catarrhalic or hemorrhagic enteritis. The severity of disease is often complicated by the presence of secondary bacterial infections. Moderately affected animals show poor weight gain or weight loss, weakness, and emaciation, severely affected animals (chiefly young ones) may die very soon after the first clinical signs are seen. Since coccidia have a self-limiting life cycle, the acute phase of infection may have already passed before therapeutic treatment can be started. Thus, treatment is usually too late to prevent economic loss. All classes of domestic animals can be affected by coccidia, and losses due to coccidiosis in mammals (particularly in bovines: cattle, sheep, goats) are difficult to determine. The expenses of management practices and the cost of preventive or therapeutic drugs are the main points of consideration. Using suitable control measures can minimize symptoms of the disease. There should be strict sanitation to prevent feed and water being contaminated by feces, and feedlots, pens, cages, or hutches should be kept dry and well drained and be cleaned out regularly (preferably every day in rabbitries). When outbreaks occur in pasture, water holes and ditches should be fenced off. Crowding of young animals should be avoided.
Negative effects of intensive animal production are numerous. Thus manure/mineral (phosphate/nitrate) accumulation (used as fertilizer), ammonia emission, (one of main causes for acid rain), dead animal disposal, flies nuisance in densely populated areas, and availability of sufficient water of feed quality may increasingly lead to legislative restrictions and costs involved in preserving protection.
Anticoccidials (Table 1) used in poultry may affect stages of the parasite inducing immunity. Pullets intended as commercial layers must develop immunity to coccidiosis when they receive preventive drugs. However, anticoccidials, which are effective against second-generation schizonts, can seriously delay the development of immunity if they are given at the dose levels recommended for broilers. Therefore, they should be fed at the lowest possible dose level and for the shortest practical period that give sufficient anticoccidial protection and allow progressive development of immunity in replacement pullets. One of the effects of immunity is to reduce the biotic potential of the coccidia; each oocyst of the common chicken coccidium E. tenella is theoretically able to produce about 2.5 million second-generation merozoites although this maximum number may only occur in the case of initial infection. In partially immune animals, however, only some of the parasites complete their life cycle and produce variable oocysts. In completely immune animals a few or no oocysts are produced for prolonged periods of time; some of the parasites may persist in an asexual stage within the host and thus fail to get further than the initial stage of trophozoite or first-generation meront. As a result, immunity to a challenge inoculum usually leads to a reduction in the clinical signs and in parasite multiplication. The specificity of immunity to Eimeria spp. is well known, although there may be considerable strain variations in immunity in some species of coccidia in commercial poultry houses as has been shown with E. acervulina and the very immunogenic E. maxima. The duration of protective immunity is uncertain and depends on several factors like mode of immunization, inoculum dose, age of the host, as well as on Eimeria species and strain variation. It is not yet clear whether immunity is of the sterile or premunition type. It seems likely that immunological control of poultry coccidiosis is achievable. In the not too distant future it will replace chemoprophylaxis coming increasingly under public pressure because of drug residues in edible tissues and occasionally in eggs (Chemotherapy/Withdrawal Time of Drugs in Target Animals). Immunoprophylaxis with attenuated or precocious strains of Eimeria spp. will be therefore an attractive alternative for parasite control since it lacks residual problems. In general, anticoccidials do not adversely affect build up of immunity after vaccination programs against bacterial and viral infections.
The disease is responsible for considerable losses in the poultry industry. Rearing of thousands of birds on litter-covered floors in enormous houses may result in a tremendous and dangerous buildup of the oocyst population (Eimeria). A change from litter-covered floors to wire-floored pens greatly reduces the exposure to coccidia. Thus, outbreaks of coccidiosis in laying hens maintained in cages rarely occur. In general, the prophylactic use of anticoccidial drugs is not required if the cages are kept clean and the feces do not contaminate watering and feeding systems. However, discouraging results have been obtained from experiments to convert broiler and breeder flocks entirely to cage operations (the most obvious problems being high equipment and maintenance costs, breast blisters, leg problems, removal of droppings and dead birds, and housefly control). Today most poultrymen rely on floor rearing methods for broiler production or breeder flocks and use continuous medication programs. Poultry producers also attempt to control coccidiosis by employing good sanitary programs. Litters should be kept dry so that oocysts cannot sporulate – many outbreaks occur after leaks in roofs or waterers. Wet litter must be cleaned out and replaced with dry litter. When broiler houses are emptied for a new batch of chickens the litter should be piled up for about 24 h so that the heat generated can destroy the majority of oocysts. Disinfection is usually impractical since oocysts are resistant to disinfectants used against bacteria, viruses, or fungi. In parasitology laboratories where disinfection is needed, heat (30 min at 60°C) or “effective” fumigants such as ammonia and methyl bromide may be used.
Despite the use of continuous medication programs (see Drugs Acting on Coccidiosis of Domestic Fowl, Table 1), coccidiosis is still the most important parasitic disease in chickens. As a rule young birds are prone to mixed infections and older birds are carriers. In many outbreaks, however, clinical signs can be ascribed to one species or a combination of two or rarely three; signs of coccidiosis become apparent about 3 days after infection; chickens cease feeding and huddle together for warmth; on the 4th day of infection blood may appear in the feces.
The Eimeria species of the domestic fowl show marked differences in their pathogenicity. E. tenella is the most pathogenic and important species occurring in the epithelial cells and submucosa of the ceca; it may produce severe hemorrhagic enteritis, which leads to high mortality in young birds. E. necatrix is also a common and highly pathogenic species, which occurs in the small intestine (first- and second-generation schizonts) and in the ceca (third-generation schizont and gamonts). It tends to cause predominantly chronic enteritis in older birds but in acute cases severe submucosal hemorrhaging and even death may occur. E. acervulina (probably the most common species seen) occurs in the small intestine. The pathogenicity of E. acervulina strains may vary, and the clinical signs consist of weight loss and watery, whitish diarrhea. E. maxima is also common; it occurs in the small intestine and is moderately pathogenic causing numerous petechial hemorrhages and a marked production of mucus. E. brunetti is markedly pathogenic but relatively uncommon. In heavy infections, characteristic necrotic (hemorrhagic) enteritis is evident in the lower small intestine, colon, and tubular part of the ceca. E. mitis is common worldwide and occurs throughout the small intestine, even in the tubular part of the ceca. This species is slightly to moderately pathogenic; in severe infections numerous petechial hemorrhages may be present. E. mivati is fairly common in the USA and Canada (presumably worldwide) and seems to be more pathogenic than E. acervulina. It primarily occurs in the upper small intestine and has been included by several authors as a variant of E. acervulina. The pathogenicity of Eimeria spp. in particular that of E. acervulina and E. tenella seems to be reduced by intestinal digesta viscosity reducing enzymes as xylanases, glucanases and pectinases. These enzymes may improve the nutritional value of wheat- or maize-based diets but mechanisms involved in reducing growth depression in coccidial infections are not yet known and need to be elucidated.
Economic losses (see economic Importance) due to subclinical infection of avian coccidia are enormous and much more common than coccidiosis, and coccidiasis should be regarded as ubiquitous in commercially reared poultry. Because some species of coccidia are highly pathogenic while others are only slightly or moderately pathogenic the species present must be identified. Scrapings from the mucosal surface of the intestine of affected birds must be examined microscopically for oocysts and endogenous stages of the parasite; the location and type of lesions must be determined to establish a definite diagnosis.
The disease may cause heavy economic loss in the turkey industry; it is primarily a disease of young turkey poults (aged 3 to 10 weeks); older birds are carriers. Clinical signs are enteritis, watery or mucoid diarrhea, and anorexia. The most pathogenic and important coccidia are E. meleagrimitis (located in the jejunum) and E. adenoeides (located in the lower ileum, ceca, and rectum); several species (in particular E. innocua, E. subrotunda and E. meleagridis) are nearly nonpathogenic. Therefore, oocysts of the latter species must be differentiated from the pathogenic ones as well as those of E. gallopavonis (lower small intestine, ceca, and rectum) and E. dispersa (duodenum, jejunum, ileum) which are not so common, and only slightly or moderately pathogenic. The presence of oocysts (even large numbers) in the feces can only be a tentative diagnosis for coccidiosis; satisfactory diagnosis can only be made at post mortem.
The disease seems to be of relatively little importance although several homoxenous coccidia are known. Some of these may be associated with severe disease and even death. E. truncata is highly pathogenic to goslings, and occasionally causes up to 100% mortality within a few days; older birds are carriers. This species occurs in the kidney tubules; its endogenous stages destroy the epithelial cells, causing enlarged and light-colored kidneys. Other species (goose: E. anseris, E. nocens, E. truncata, E. kotlani, duck: E. kotlani, E. danailovi, Tyzzeria perniciosa) appear to be important in areas where crowding and poor sanitation are present. Thus, large numbers of sporulated oocysts in an unhygienic environment often lead to sporadic outbreaks of intestinal coccidiosis.
The terms coccidiostatics and coccidiocidals (coccidiocides) for drugs, which characterize actions on coccidia, are often used confusingly. Drugs with a coccidiostatic action, such as clopidol, decoquinate, buquinolate, methylbenzoquate (Table 1), arrest the development of certain parasite stages in a reversible way; thus withdrawal of the drugs leads to completion of the life cycle and possibly the appearance of clinical signs several days after medication is discontinued. Drugs with coccidiocidal action, such as arprinocid, halofuginone, polyether antibiotics, toltrazuril, diclazuril and clazuril (Table 1), kill or irreversibly damage most of certain parasite stages, and there is no evidence of clinical relapse after drug withdrawal. Some drugs (e.g., nicarbazin, amprolium) may have both coccidiostatic and coccidiocidal activity depending on how long the drugs and in which concentration they have been given in the feed or water. Continuous medication of these drugs for more than 48 h usually results in the majority of parasitic stages being damaged. Polyether antibiotics mainly affect asexual Eimeria stages as sporozoites, schizonts of the first and second generation. Flow cytometric analysis has been shown to be a reliable and sensitive technique for characterizing coccidiocidal effects on sporozoites exposed to various ionophores in vitro. Diclazuril acts against most stages of Eimeria spp. but this may vary between species (e.g. in E. maxima gamonts only); this is also true for clazuril. Prophylactic drugs may preferably act on early and/or late asexual stages in the life cycle, like polyether antibiotics, zoalen, decoquinate, clopidol, robenidin, nicarbazin, arprinocid, halofuginone, diclazuril, amprolium+ethopabate, methylbenzoquate+clopidol, and other combinations. A few therapeutic drugs used for treating outbreaks of coccidiosis may affect stages of second- and third-generation schizogony and to a certain degree gamonts (sexual stages) as well; drugs reducing clinical signs of coccidiosis are amprolium, sulfonamides, clazuril, toltrazuril and combinations of sulfonamides+dehydrofolate reductase inhibitors (Table 1). Toltrazuril administered in drinking water has brought substantial progress in treatment of coccidiosis in various animals. It has a broad spectrum of activity against various parasitic protozoa, and unlike other anticoccidials, it acts against schizonts and gamonts of various Eimeria and Isospora spp.
Today, chemoprophylaxis in continuous medication programs appears to be the only effective tool for controlling coccidiosis in floor-reared poultry although drug resistance in Eimeria spp. populations is a widespread problem in the broiler industry today. Strategic use of anticoccidials may thwart the development of resistance processes (see Measures Against Drug Tolerance in the Broiler Industry). However, neither improved sanitation nor vaccination of birds with pathogen species of live precocious oocysts (Paracox®, Livacox®) via drinking water or feed can sufficiently substitute continuous medication programs today. The prophylactic use of anticoccidials is based on the application of additives in-feed, i.e., drugs are added directly to bird feed in small quantities, usually in concentrations of a few ppm (part per million). Such anticoccidials are approved by governmental agencies for the use in growing birds (e.g. chickens, turkey, others). Thus, prescribed concentrations rations of these drugs can be fed to licensed table birds ad libitum from the beginning of their life (fattening/growing period) to a prescribed preslaughter withdrawal time, or age at first egg, or start of cage or battery keeping of pullets. Additives in-feed used worldwide for the prevention of poultry coccidiosis and therapeutic anticoccidials are listed in Table 1. There are (1) synthetic compounds (amprolium, clopidol, decoquinate, diclazuril, halofuginone, nicarbazin, robenidine, zoalene), (2) polyether antibiotics or ionophores (lasalocid, maduramicin, monensin, narasin, salinomycin, semduramicin) and (3) drug combinations (amprolium+ethopabate, clopidol+methylbenzoquate, narasin+nicarbazin, maduramicin+nicarbazin). Most continuous medication programs may last 35 to 40 days, i.e., from the beginning of the fattening period to a fixed time prior to slaughter of birds. Withdrawal times (Chemotherapy/Withdrawal Time of Drugs in Target Animals) for most prophylactically used anticoccidials may last 0 to 5 days and longer (e.g. nicarbazin, 9 days in Europe), or may exceed 5 days for other reasons, e.g. to minimize costs, or to promote “compensatory growth”. A withdrawal time longer than 5 days may lead to enhanced risk of coccidiosis at the end of fattening period, particularly if environmental hygiene is poor. The prophylactic use of anticoccidials in-feed in egg-laying birds is not permitted, although the occurrence of residues of anticoccidials in eggs has been widely proven; carry-over of medicated feed in the feedmill or elsewhere must be the cause. Sensitive and specific analytical assays, as spectophotofluorometry, liquid chromatography, high performance liquid chromatography (HPLC), the qualitative vanillin test and others, are available to detect the parent compound or their residues in feed, edible tissues, and eggs of target animals or non-target animals. In case of outbreaks of coccidiosis therapeutic drugs (amprolium, sulfonamides, dehyrofolate reductase inhibitors plus sulfonamides, toltrazuril) are preferably administered via drinking water for a 3- or 5-day treatment course; withdrawal periods between 14 and 28 days may be necessary. In practice, this means that medication towards the end of the growing life of birds is not economically possible, and this is also true for drugs used outside their product license; the latter may also require withdrawal periods up to 28-days or even longer. So often the medicines regulations how they relate to the withdrawal periods stipulated for therapeutic drugs and given to food animals withhold birds (meat chickens, ducks, turkeys) from the possibility of treatment for a significant part of their life.
Approved additives in feed, and maxima concentrations (EC directives) for prevention of coccidiosis in turkeys are shown in Table 1. Drugs may be Amprolium + ethopabate (133 ppm/withdrawal time 3 days); metichlorpindol + methylbenzoquate (110 ppm/5 days); (diclazuril, 1 ppm/5 days) halofuginone (3 ppm/5 days), lasalocid (125 ppm/5 days), monensin (100 ppm/3 days), and robenidine (36 ppm/5 days). The turkey industry (mainly found in the USA) has till now been rather small compared to that of chicken broilers; the total market for anticoccidials may come to ~US$ 30 million. The most suitable drug program is continuous medication but anticoccidial treatment covers only a part of the growing period of birds (till 12–16 weeks of age or 8–10 weeks of age if birds are moved to outside pastures or larger facilities). At this time acquired immunity may be established in most of the birds; however, some birds may still be susceptible to damaging infections 12 weeks after the growout start. Intermittent medication is used relatively often since continuous anticoccidial programs are not universally practiced with turkeys up to 8 weeks of age because of the high resulting costs. Concentrations in the feed are generally in the same range as those administered in chicken broiler rations. There is evidence from field experience that drug resistance in coccidia of turkeys may exist. Generally it seems not to be a major problem although monensin resistance has been demonstrated in E. meleagrimitis field isolates. Under experimental conditions a drug sensitive laboratory strain became resistant to the drug after 10 generations of selection. (see Therapeutic drugs used against outbreaks of coccidiosis: Drugs Acting on Coccidiosis of Domestic Fowl)
Bovine eimeriosis (the most pathogenic species are E. zuernii and E. bovis, Table 1) is primarily a disease in calves between the ages of 3 weeks and 6 months; older calves and adult animals are usually symptomless carriers. Crowding and lack of sanitation greatly increase outbreaks of disease. Coccidiosis in sheep and goats is often a disease of feedlot lambs, and often occurs in breeding flocks. Mixed infections build up to a peak that may last 1–4 weeks and then decline. E. ovina (sheep), E. ashata (sheep), E. ovinoidalis (sheep), E. arloingi (goat) and E. christenseni (goat) are of clinical importance. Batch rearing of lambs or calves in groups of similar ages may limit the build up and spread of oocycts to younger animals thereby targeting potential treatment measures. Little information is available on the eimeriosis of equines, mainly caused by E. leuckarti in the small intestine or Klossiella equi in the kidneys of foals. Coccidiosis in horses (including asses and mules) seems to be very rare. Beware of polyether antibiotics in-feed in environment of horse facilities; they are highly toxic to equines.
Most drugs used in cattle are approved for the prevention of coccidiosis in poultry. The demand for grain-fed beef has led to cattle rearing techniques (large feedlot complexes) that may encourage damaging infection pressure. Only a few drugs have been approved for treatment in cattle by some governments. Decoquinate is licensed in several countries for the treatment and prophylaxis of bovine coccidiosis. The tissues of treated calves that had been on continuous medication with decoquinate were free of schizonts, gamonts and oocysts. The drug apparently kills E. bovis sporozoites or arrests their further development if administered at 1.5 mg/kg body weight in the feed.
Coccidiosis in bovines is often wrongly considered to be a sporadic disease with the result that drugs have rarely been used for prophylaxis. Outbreaks of the disease are still handled by spot treatment using therapeutic drugs as sulfonamides, e.g., sulfaguanidine, sulfamethazine, and sulfadimidine or sulfaquinoxaline. Combinations of sulfonamides with trimethoprim are used in manifest coccidiosis in cattle, sheep and goats. Nitrofurans, e.g., nitrofurazone, or amprolium are moderately effective against bovine coccidia. Amprolium has been widely used in the USA for treatment of clinically ill calves and lambs. Toltrazuril in-water and diclazuril in-feed have been proved to be very effective against bovine coccidiosis at a single oral dosage of 20 mg/kg body weight in bovines. Preventive drugs as ionophorous antibiotics such as monensin, lasalocid, and salinomycin licensed for prevention of coccidiosis in poultry exhibit distinct activity against coccidiosis in ruminants. The doses of monensin, lasalocid, and salinomycin used for improving feed efficiency in feedlot and pasture cattle correspond to the doses reported to prevent coccidiosis; it is assumed that the anticoccidial “side effect” of these “growth promotors” may considerably reduce coccidiosis problems in feedlot cattle. Calves artificially infected with Eimeria bovis (88%) and E. zuernii were given lasalocid in-feed at 0.50, 0.75, or 1.0 mg/kg body weight, daily for 45 days. There were no dose-dependent effects but equal reduction rates in oocyst output and preventing clinical coccidiosis. Calves given lasalocid, decoquinate, or monensin in-feed at 33 ppm for 46 days had significantly fewer oocysts in feces and fewer clinical signs of coccidiosis than those given nonmedicated rations. Mixing lasalocid in milk replacer or fresh milk (1mg/kg body weight/day) is an effective method of protecting young calves against early infection with coccidia. Decoquinate used as a creep feed additive is licensed (e.g. in the UK) for the prevention of coccidiosis in lambs, and has also been evaluated in the USA as an anticoccidial against coccidiosis in goats. Ionophores in-feed such as monensin, lasalocid or salinomycin prove effective also in preventing coccidiosis in lambs, and goats; against caprine coccidia they are, however, only moderately active. Treatment of coccidiosis in lambs and kids is done with drugs used in cattle. Often animals are clinically ill when the disease is diagnosed. At this time the intestinal mucosa is already extensively damaged, and consequently treatment cannot lead to a radical cure. As a rule, all lambs and kids in a flock should be treated, as even those showing no symptoms are likely to be infected. Fluid therapy using either oral rehydration solutions or parenteral solutions, and appropriate anthelminthic treatment are indicated in severely affected animals.
Coccidiosis in rabbits is essentially restricted to the young (adults are carriers) and occurs particularly in breeding and rearing establishments (rabbitries) although outbreaks of coccidiosis in warrens or similar types of habitat are not uncommon. The most important species seems to be Eimeria stiedai, which is common, worldwide and occurs in the walls of the bile ducts in the liver causing hepatic coccidiosis. Other important and pathogenic species, which may occur in the intestine, are E. irresidua, E. magna, E. intestinalis, E. media, and E. perforans; mixed infections are the rule. The presence of parasites in a case of enteritis does not necessarily indicate the cause. Coccidia may be present in large numbers without any serious clinical signs. Therefore, the most satisfactory diagnosis is made at post mortem; only the presence of characteristic lesions are evident in the liver/or the intestine.
There are only a few additives in-feed approved for the prevention of rabbit coccidiosis in Europe or elsewhere. These are metichlorpindol or clopidol (125–200 ppm), meticlorpindol +methyl benzoquate (220 ppm), robenidine (50–66 ppm), salinomycin (20–25 ppm) and possibly diclazuril (1ppm). Preslaughter withdrawal times of these drugs may range between 5 and 7 days. Robenidine at 33 ppm and meticlorpindol at 200 ppm are somewhat erratic in their anticoccidial activity and prove only partially effective in controlling coccidiosis. Meticlorpindol has been found to be superior to a mixture of sulfaquinoxaline plus pyrimethamine, or sulfadimidine plus robenidine in suppressing oocyst output. Preventive administration of monensin and that of salinomycin in pelleted feed at 50 and 25 ppm may not only reduce markedly the oocyst production but lead to almost total inhibition of hepatic and intestinal „lesions as well. This is also true for the administration of toltrazuril in the drinking water at 10–„15 ppm. Several sulfonamides alone, or in combination with dehydrofolate reductase inhibitors (Table 1) can be used for therapy or prevention of coccidiosis. They may be given in various routes and dosage forms (in-feed, in-water, parenterally, and as injection). Their preslaughter withdrawal times range between 8 and 15 days. Sulfaquinoxaline (relatively cheap and water soluble) seems to be the most widely used sulfonamide for treating rabbit coccidiosis, and it has been found to be just as helpful in preventing coccidiosis when given in continuous medication programs in feed or water. Treatment with amprolium proved to be less effective than that with sulfonamides in reducing mortality in rabbits suffering from coccidiosis; there was no protection against hepatic coccidiosis at 0.02% amprolium in pelleted feed. The drug of choice for treatment of intestinal and hepatic coccidiosis appears to be toltrazuril (not licensed for rabbits). However, a proper management and good hygiene in rabbitries can markedly reduce long-term medication and treatment with anticoccidials.
Coccidiosis in swine is mainly restricted to young pigs; older pigs are carriers. E. debliecki and E. scabra are probably the most pathogenic species. Isospora suis has also been found to cause severe enteritis; however, intestinal disorders are so common in baby and young pigs and are caused by so many different pathogens that a diagnosis based only on fecal examination is not definite. Only a very large number of oocysts can indicate that coccidiosis is present. Isospora suis is an important causative agent of porcine neonatal diarrhea worldwide; it may occur on any farm with any type of management system and at any time of the year although feces samples of sows always proved negative. Most canine and feline coccidia are usually nonpathogenic or only moderately pathogenic; however, coccidiosis in dogs and cats may be an important cause of the diarrheic syndrome often associated with secondary infections in puppies and kittens. Affected animals are frequently seen in breeding kennels and runways where sanitation is poor. Diagnosis is not definite if it is only based on clinical signs (e.g., diarrhea with blood in the feces), or on the presence of large numbers of Isospora spp. oocysts in the feces; post mortem examination is the most adequate diagnosis method. Coccidial infections in dogs and cats may also be caused by heteroxenous genera (Sarcocystis spp. in dogs, and Sarcocystis spp. and Toxoplasma gondii in cats, see respective entries).
The most commonly used compounds for treatment of coccidiosis in dogs, cats (and piglets) are sulfonamides, toltrazuril (and amprolium) affecting mainly later asexual stages of the schizogony cycle and to a certain degree sexual stages (gamonts). There are only a few controlled studies with experimental infections and no reliable evidence of practical problems associated with Eimeria spp. in swine. In contrast, Isospora suis infections appear to have become an economically important diarrheal disease in young piglets during the last two decades, and modern production systems seem to encourage the disease. Mortality due to I. suis infections may reach 10%–20% in nursing pigs, and a similar percentage may be severely stunted. I. suis infections causing severe enteritis or even death in piglets have been treated successfully with amprolium; medication of sows with amprolium for 1–2 weeks before and after farrowing and of neonatal piglets may be helpful in reducing morbidity and mortality. There are no anticoccidials approved for the prevention of coccidiosis in swine. Prophylactic administration of toltrazuril in piglets (a single 1.0 ml dose: 20 to 30 mg/kg, orally between 3 and 6 days of age) has been shown to reduce the morbidity in piggeries. There was a significant reduction in the number of antibacterial treatments given to piglets, fewer piglets developing diarrhea, and a significant improvement in growth rate of piglets. I. suis was detected in 38% to 50% of fecal samples from several piggeries and in 93% of those from the experimental piggery. Supportive treatment with antibiotics (e.g., chlortetracycline or oxytetracyclines) may reduce secondary bacterial infections in the intestine of piglets with severe enteritis. Good sanitation can effectively reduce diarrhea caused by I. suis infection in neonatal piglets in large farrowing facilities.
A new successful drug should have competitive advantages over other available drugs, for example high potency and broad-spectrum activity. Furthermore, at the recommended doses the coccidia must not be allowed to develop resistance or to survive for a longer period. The reduction in coccidial sensitivity to any drug (partial drug resistance) encourages the development of subclinical or subacute coccidiosis. Low levels of infection usually cause a moderate drop in feed conversion and thus lead to considerable economic losses in the poultry industry.
The development of drug resistance may be evident if a change in the parasite can be demonstrated by comparing sensitivity before and after exposure to the anticoccidial. Possible causes for drug failure in the field may result from selection of resistant organisms, which rapidly become the dominant phenotype in broiler houses. Resistance is commonly believed to arise initially in the presence of “subtherapeutic” or lower than recommended drug concentrations. Contrary to that suggestion, it has been argued that resistance may occur more rapidly in the presence of higher drug concentrations as a result of a more rapid change in gene frequency caused by increasing the intensity of selection. Studies on the incidence of drug resistance in the field and in experimental investigations have shown that resistance among strains of coccidia to synthetic drugs such as 4-hydroxyquinolines (e.g., decoquinate, methylbenzoquate), arprinocid, meticlorpindol, and halofuginone is relatively high. The resistance may result from the selection of preexisting mutants in the parent population. Thus drug resistance appears to be a genetic trait and tends to remain in a coccidia population for some years. Recent investigations on intraspecific polymorphisms of Eimeria spp. due to drug resistance indicate that differences in drug sensitivity correlate with genetic differences and polymorphisms detected by random amplified polymorphic DNA (RAPD) might facilitate the selection of molecular markers for resistance genotyping.
In vitro studies on uptake of [14C] monensin by E. tenella sporozoites in primary chicken kidney cell cultures infected with ionophore-sensitive (IS) or ionophore-resistant (IR) isolates showed significant differences in [14C] monensin accumulation between IS and IR isolates. The latter isolates had decreased uptake of monensin and the amount of the drug required to inhibit development of E. tenella by 50% was 20–40 times higher for IR isolates of E. tenella which might reflect differences in membrane chemistry. Studies on an E. tenella field isolate that was resistant to monensin, salinomycin and lasalocid at double use level and resistant to narasin and maduramicin at normal use level showed good agreement between in vitro and in vivo results. Flowcytometric analysis of fluorescence after simultaneous exposure to fluorescein diacetate (FDA) and propidium iodide is a suitable indicator of cellular viability and proved to be a valuable technique in the study of sporozoite response to anticoccidials. Thus, various improved in vitro techniques in research programs have become increasingly important in recent years. They may be a supplement to and, occasionally, a substitute for in vivo experiments in certain fields of the basic research, as in the field of biotechnology of poultry and farm animals. A first practical approach to countering drug resistance in the field may be an increase in the drug concentration. Increasing the drug concentration to compensate drug tolerance of coccidia is not only uneconomical but can also lead to toxic problems since several anticoccidials (e.g., nicarbazine, halofuginone, and various ionophorous antibiotics) are used at doses which are close to toxicity levels in birds. With the exception of some ionophorous antibiotics, such as monensin, salinomycin and lasalocid, none of the synthetic drugs introduced have enjoyed prolonged marketability. The continuing success of the ionophorous antibiotics (monensin was introduced in the USA in 1971) is a result of their broad-spectrum activity, and possibly because resistance in coccidia may not be able to develop by the mechanisms known to occur for synthetic drugs. There have also been early reports that monensin “resistant” E. maxima strains may be present in the field. Later selected Eimeria spp. from broiler farms in USA and Europe revealed that control of some isolates to ionophorous drugs was poor although none of the isolates judged in sensitivity tests was found to be completely resistant to the ionophores tested. Thus, prolonged use of ionophores in poultry units for nearly 10 years led to a decrease in their anticoccidial activity. Salinomycin provided the best overall control, followed by lasalocid and monensin. The latter findings are in agreement with results obtained from field studies on the comparative efficacy of salinomycin and monensin in 17 controlled field trials. They included more than 2 million broilers and were carried out in several European countries, and Salinomycin at 60 ppm showed performance advantages over monensin at 100 ppm. Maduramicin proved to be more effective against ionophore-tolerant field isolates of broilers than monensin and narasin, but showed similar activity to salinomycin in reducing lesions and mortality and in protecting performance. Although side-resistance (co-lateral resistance) among related ionophores such as monensin salinomycin, and narasin may occur `cross-resistance' between maduramicin and not related ionophores has also been reported; it is believed by some investigators that maduramicin is effective against strains resistant to the other ionophores. Results from drug-sensitivity tests with isolates of coccidia from broiler chickens in the USA, Brazil, Argentina, and Europe suggested in many cases incomplete side resistance of coccidia to polyether ionophorous drugs. Some field isolates revealed even complete multiple cross-resistance to synthetic and polyether antibiotics including maduramicin, and semduramicin (latest ionophore introduced into the market). An E. acervulina laboratory strain, which was resistant to monensin by passaging the strain 14 times in the presence of the drug (100 ppm), was shown to be sensitive to lasalocid but not to maduramicin, narasin, and salinomycin. Cross-resistance between the latter ionophores may suggest a similar mode of action in coccidia. Thus, monensin, maduramicin, narasin, and salinomycin, preferentially form complexes with monovalent rather than divalent alkali metals (e.g., lasalocid), e.g., Rb+, Na+, K+, Cs+, which may mediate electrically neutral exchange diffusion cation transport across membranes. Contrarily, a monensin-resistant E. meleagrimitis strain exhibited cross-resistance to narasin and lasalocid and a field isolate of E.tenella showed cross-resistance between lasalocid and several ionophores preferentially forming complexes with monovalent cations. To slow down development of drug resistance in coccidia alternate use of anticoccidials is widely practiced in the poultry industry (Measures Against Drug Tolerance in the Broiler Industry).
As shown by epizootiological investigations, coccidial drug resistance poses a serious economic problem to intensive poultry farming both in the USA and in Europe. Today, there is therefore an increasing use of shuttle or dual programs (rapid rotations), i.e., the switching of anticoccidials during broiler growout. The drug(s) to be switched should belong to different chemical classes (e.g. ionophore/synthetic drug or vice versa during starter/final phase of production) and should be effective at different stages of the parasites' life cycles. Any resistant coccidia, which appear during the use of the first drug, should be affected by the second. In straight or slow rotation programs a single and often the same drug may be used for several broiler growouts (e.g. about 6 months; each fattening period may last 35–40 days or longer); it is then replaced by an alternative drug. Shuttle programs are still being discussed with regard to their value in delaying drug resistance. Although alternation of the drugs between crops may delay the appearance of resistance, it is likely that the outcome will be the acquisition of multiple resistance. There may also be the risk of underdosing or insufficient activity of drug mixtures resulting from switching the drugs. This might allow resistance to be developed faster. However, by switching the drug underdosing can be excluded if new and exactly medicated feed is poured onto remaining feed; then the two drug fractions at the base of the silo funnel must add up to 100% of any resulting mixture. Mixtures of ionophorous antibiotics were as effective in controlling drug-sensitive E. tenella and E. acervulina infections as a single antibiotic mixed in the feed at recommended prophylactic concentrations. However, such mixtures (e.g., monensin + narasin or salinomycin) may have limited additive action if there is already a partial resistance to one of the partners. In these experiments it was also shown that combinations of ionophorous antibiotics and synthetic drugs are complementary, even against field isolates with unknown drug response.
Drug combinations (Table 1) have commonly been used for synergism in order to minimize the occurrence of drug resistance (e.g., Lerbek® → methyl benzoquate +meticlorpindol), or to extend the species spectrum to all six pathogenic Eimeria spp. in chickens. Amprolium and dinitolamide which show activity against E. tenella and E. necatrix have been combined with ethopabate and organic arsenicals respectively, in order to expand their spectrum to include the upper intestinal species E. maxima, E. acervulina, and E. mitis. Joyner and Norton found the only experimental evidence of retardation of drug resistance by synergistic effects of drugs. They observed complete resistance to methyl benzoquate 10 ppm and meticlorpindol 125 ppm, respectively, after three passages of E. maxima, but not with a 8.35 and 100 ppm combination of the two drugs.
To keep up their competitive position with other anticoccidials, narasin and maduramicin have been combined with nicarbazin, an oldtimer among anticoccidials; these products, however, reveal no performance advantages over related mono-drugs.
Species of the genus Cryptosporidium are coccidian parasites that infect epithelial cells (extracytoplasmic) of the intestinal and respiratory tract of vertebrates (see Opportunistic Infections). Although immunocompetent hosts show no or only mild clinical signs after Cryptosporidium infections particularly young birds under stress may suffer from life-threatening watery diarrhea, or severe respiratory symptoms. Cryptosporidiosis in chickens, turkeys, quail, and pheasants is usually manifest as respiratory disease caused predominantly by C. baileyi or as enteritic disease (small intestine) caused by C. baileyi and C. meleagridis. The severity of infection depends on the immunocompetence of the host. Infections are due to aerosol transmission of infective oocysts coughed up by carrier (seeder) birds, or may be transmitted by feed or water supplies containing sporulated oocysts derived from feces of infected birds. Clinical signs in birds are coughing, mucoid discharge, dyspnoe, diarrhea, dehydration, weakness and weight loss.
Causal therapy and chemoprophylaxis of chicken cryptosporidiosis with ionophorous antibiotics is problematic. Many approaches to anticryptosporidial efficacy of commercial drugs have failed to improve symptoms in birds suffering from Cryptosporidium infections. Several other anticoccidials as sulfonamides, lasalocid sodium, halofuginone, and decoquinate, or other antibiotics (e.g., paromomycin) available as additives in-feed (Table 1), or as other dosage forms for oral administration have proved to be insufficiently effective in controlling or even eradicating Cryptosporidium infection in birds. The drugs may exhibit positive short-term effects such as improvement of watery diarrhea and reduction of oocyst output in feces due to their `static' rather than `cidal' action on cryptosporidia.
Coccidia that may cause clinical signs in humans are rare. Isospora belli, a single host species in the small intestine, may be responsible for mild intestinal symptoms in some cases. Infections due to heteroxenous species like Sarcocystis spp. (Sarcocystosis) or Toxoplasma gondii, and related protozoans with a two-host life cycle are seen more often, especially in areas where raw meat is eaten and human beings have contact with cats or other felines. Moreover, Isospora belli, Cryptosporidium parvum, Toxoplasma gondii, and Cyclospora spp. belong to the opportunistic protozoa associated with immunosuppression caused by HIV (AIDS), or other pathogens and pathogenic processes.
