Мадурамицин инструкция по применению в ветеринарии

Maduramicin

Maduramicin was approved for chickens in 1989. Maduramicin ammonium is a polyether carboxylic ionophore agent that is authorized as a coccidiostat feed additive in the chicken and turkey for the control of E. adenoides, E. meleagrimitis, E. gallopavonis, and E. dispersa. Maduramicin can inhibit the growth of Gram-positive microorganisms. Maduramicin and/or its metabolites are rapidly eliminated in chickens. Steady state is observed after 3 days in the excreta, but after 6 days in plasma. Maduramicin is the main compound excreted (26%). O-Demethylation represents the main metabolic pathway of maduramicin in chickens. Maduramicin is the marker residue in all tissues tested. Tissue residue kinetics of total residues and marker residue indicate a rapid decline of residues in all tissues.

Ionophores

Salinomycin has been reported to induce toxicity to the nervous system in cats. Cats which were exposed to feed material containing salinomycin had acute onset of lameness and paralysis of the hind limbs and forelimbs. Microscopic findings include neuropathy, myelin degeneration of the sensory and motor nerves (van der Linde-Sipman et al., 1999). Diagnosis is by case history, chemical analysis of the feed and pathological findings.

Ionophores

Monensin, lasalocid, salinomycin, narasin, maduramicin, and semduramicin are some of the ionophore antibiotics used in poultry. Accidental or intentional off-label use has resulted in adverse reactions in adult poultry (laying hens), ostriches, and ornamental or game birds. In addition, interactions with other drugs used in target and nontarget species can occur. Various antibiotics have been reported to potentiate ionophore toxicity. The most frequently reported drug interaction is with the pleuromotilin derivative and tiamulin. This antibiotic interferes with the metabolic degradation of monensin in the liver, causing accumulation at toxic concentrations.

Excessive monensin exposure was reported in a 42-week broiler flock due to feed mixing error. There was high mortality and affected birds exhibited feed refusal, decreased water consumption, diarrhea and severe paralysis that ranged from abnormal gait to complete inability to move (Zavala et al., 2011). Another case report of monensin intoxication on a commercial ostrich farm in northern Greece described similar clinical signs along with elevated concentrations of serum aspartate aminotransferase, creatine kinase, and lactate dehydrogenase (Dedoussi et al., 2007). In layers, there will be a loss of egg production, hatchability, infertile eggs, early embryonic death, and weak ataxic chicks (Perelman and Smith, 1993). Reported cases of salinomycin intoxication in birds were associated with high mortality, signs of dyspnea, drowsiness, sternal recumbency with legs extended posteriorly, inability to stand, stiffness, and weakness (Andreasen and Schleifer, 1995). Gross postmortem findings may be absent or limited to hydropericardium, pale myocardium, hepatic congestion and enteritis. However, significant findings occur histologically and, include extensive fragmentation and necrosis of skeletal and myocardial muscle fibers (Dedoussi et al., 2007; Zavala et al., 2011).

Though avoidance of feed mixing errors and off-label use is the mainstay of prevention, results from few in vitro studies have been promising and show the protective effect of the herbal flavonolignan compound silybin from Silybum marinum against the toxicity of salinomycin, lasalocid, monensin and narasin in chicken hepatoma cell lines (Cybulski et al., 2015; Radko et al., 2013).

Concluding Remarks and Future Directions

Seven ionophores—monensin, lasalocid, salinomycin, narasin, maduramicin, laidlomycin and semduramicin—are marketed globally for use as anticoccidial drugs for poultry and/or growth promotants in ruminants. Off-label usage of ionophore products is known to occur since other uses continue to be investigated and applied in many countries. It is likely that basic and applied research on these versatile compounds could lead in the future to product line extensions to other target species and potential development of novel therapeutics for unmet needs in veterinary and human medicine.

Generally, these feed additives have been found to be safe and effective in target animal species, but toxic syndromes have resulted from overdosage, misuse, and drug interaction. Among the domestic species, horses are the most sensitive to ionophore toxicoses, poultry the least sensitive, and cattle intermediate. However, even for the horse, there is a threshold level of exposure below which no adverse effects are observed. Consumption of complete feed containing the maximum approved use levels of monensin, lasalocid, or laidlomycin is harmless. Dose and time factors influence the severity and outcome of the toxic exposure. Results of controlled studies and confirmed field reports of toxicity indicate that the greatest risk of intoxication is upon initial exposure to ionophore-containing feed or supplement. Following sublethal exposure, consumption of culprit feed or supplement is negligible because of anorexia. Animals that die acutely after high levels of exposure often will have few or no lesions. Those that die later have profound striated (cardiac and/or skeletal) muscle lesions and changes secondary to CHF in some animals that survive the acute toxic episode.

Confirmatory diagnosis requires efficient laboratory assays to determine the identity and amounts of the ionophore involved and a thorough consideration of differential diagnosis. These cannot be overemphasized. There is no known antidote or specific treatment for ionophore toxicoses and treatment is largely supportive. Judicious use, avoidance of overdosing, and adherence to species recommendation will enhance livestock production and help prevent the occurrence of adverse effects associated with this class of compounds.

Ionophore toxicosis

Ionophores used in agriculture are monensin, lasalocid, salinomycin, narasin, and maduramicin. Ionophores are compounds that alter membrane permeability to electrolytes by influencing transmembrane transport. In excess, all of these agents damage skeletal and cardiac muscle but horses are uniquely susceptible. Most reports of toxicosis involve monensin, an ionophore used widely for years.

Monensin, an antibiotic produced by the fermentation of Streptomyces cinnamonensis, has a growth-promoting effect in ruminants and is an efficient coccidiostat in birds and other animals. Monensin is produced commercially in very large quantities in North America and Europe, where it is added, as a concentrated premix, to pelleted or bulk feeds fed to cattle, sheep, and other ruminants. Toxicity develops when monensin is fed to monogastric animals, which have a much reduced tolerance for the drug, or when human or mechanical error leads to concentrations of monensin in the ration that are abnormally high for the species being fed. Toxic effects have been recorded in horses, donkeys, mules, zebras, cattle, sheep, dogs, wallabies, camels, blesbok, Stone sheep, turkeys, and chickens. Many episodes of monensin poisoning have been caused by mixing errors in packaged, pelleted, commercial animal feeds, either concentrates or final mix, which has put hundreds or thousands of animals at risk, sometimes over wide geographic areas. In North America alone, such mixing errors have been reported in horse, cattle, dog, and zoo feeds. Some indication of susceptibility of different species is provided by the estimated LD₅₀ for different animals. Horses and other equids that are sensitive have an LD₅₀ of 2-3 mg of monensin/kg body weight. LD₅₀ values for other species are: dogs, 5-8 mg/kg; sheep and goats, 12-24 mg/kg; cattle, 50-80 mg/kg; and various types of poultry 90-200 mg/kg. Pigs, which may be given the drug for its coccidiostatic properties or be exposed by mistake, have an LD₅₀ of 16-50 mg/kg body weight. The toxic effects of monensin or salinomycin are potentiated by the addition of tiamulin, triacetyloleandomycin, or sulfonamides to the ration, usually for therapeutic purposes.

Ingestion of maduramicin, an ionophore antibiotic used as a coccidiostat in poultry, has caused cardiotoxicity in cattle and sheep. Cases occurred in South Africa and Israel, where dried poultry litter was used as a source of protein for ruminants. The clinical and pathologic features of this toxicosis are similar to those of monensin cardiotoxicity.

When a single large toxic dose of an ionophore is fed to an animal, clinical signs of lethargy, stiffness, muscular weakness, and recumbency occur within 24 hours. Horses and other equids are likely, in the early stages, to show marked signs of colic, apprehension, shifting or fidgeting, sweating, myoglobinuria, and muscle tremors. Dogs show apprehension and progressive weakness. If sublethal doses are fed, the toxic effect will be cumulative, and the clinical onset may be delayed for 2-3 days to weeks depending on the total amount and the period over which it is fed, but the debility is likely to be more pronounced. Animals on low-level toxicity experiments often have delayed progression of the toxic signs because consumption of these feeds is reduced. These animals frequently scour and lose weight. At dose levels capable of inducing clinical signs of toxicity in a few days, many animals show evidence of progressive cardiac failure caused by a high incidence of myocardial lesions. Animals recovering from the acute disease may subsequently develop, within several months, signs of progressive cardiac insufficiency from myocardial fibrosis. Sometimes renal failure, in addition to poor growth or poor weight gain, occurs, although the signs referable to skeletal muscle injury may disappear.

Postmortem lesions of ionophore toxicity may be difficult to detect in acute cases dying within 24 hours. In horses, myocardial damage predominates, in sheep and swine the skeletal muscles are the main site of damage and myoglobinuria is generally present, and in cattle skeletal and cardiac muscle are about equally affected. Skeletal muscle may lack normal rigor, and ill-defined pale streaks may be visible in both myocardium and skeletal muscle. Later, the white streaking of affected skeletal muscles becomes more prominent. Hindlimb muscles may be the sites of major degenerative changes. Cases with terminal cardiac damage will have features of congestive heart failure including fluid accumulations in body cavities, pulmonary congestion and edema, and hepatic congestion.

Microscopic lesions of ionophore toxicity typically are multifocal monophasic necrosis by 48 hours after exposure and thus differ from the polyphasic lesions of nutritional myopathy. One of the earliest electron-microscopically visible lesions in muscle fibers is marked swelling and disintegration of mitochondria. Monensin is an ionophore that distorts membrane transport of sodium and potassium. This apparently leads to abnormalities of the electrolyte-modulated calcium gating mechanism and then mitochondrial failure, energy exhaustion, failure of calcium ion removal from the cytosol, and eventually myofibrillar hypercontraction and segmental degeneration. Both type 1 and type 2 fibers are involved with necrosis and macrophage infiltration. Satellite cell nuclei as well as endomysial cells apparently survive acute toxicity, and the early stages of regeneration are initiated during the first few days after exposure.

Myocardial lesions in monensin toxicity are not reparable and, particularly in a growing animal, the probability of lasting cardiac insufficiency is high.

Toxicities

Toxic myopathy – ionophore toxic syndrome

Ionophore toxic syndromes have resulted from overdosage, misuse, and drug interactions of feed additives, including formulations with monensin, lasalocid, salinomycin, narasin, maduramicin, laidlomycin, or semduramicin. Target organs damaged by toxic doses of ionophores were identified to include the heart and skeletal muscles in all species studied (reviewed by Novilla, 2012). The most important change is a toxic myopathy characterized by focal areas of degeneration, necrosis, and repair in cardiac and skeletal muscles with a variable inflammatory component (Novilla and Folkerts, 1986; Van Vleet et al., 1991). The development of muscle lesions varies among domestic species. The heart is primarily affected in horses, skeletal muscle in pigs and dogs, and there is about equal tissue predilection in rats, chickens, and cattle. In addition, neurotoxic effects have been reported for lasalocid (Shlosberg et al., 1985; Safran et al., 1993), narasin (Novilla et al., 1994), and salinomycin (Van der Linde-Sipman et al., 1999). Neuropathic changes occurred in peripheral nerves and the spinal cord. Focal swelling, fragmentation, loss of axons, and formation of digestion chambers filled with macrophages were observed in both sensory and motor nerves, and there was vacuolation with swelling, degeneration, and fragmentation of myelin sheaths and axons in the spinal cord.

It is not easy to diagnose ionophore toxicoses. Clinical signs and muscle lesions of monensin toxicoses are not pathognomonic. In the absence of proof of a gross feed mixing error with monensin (usually >5X), the diagnostic pathologist must go through a process of exclusion of potential causes of the lesion. Confirmatory diagnosis requires laboratory assays to determine the identity and amounts of the ionophore involved or concurrent use of an incompatible drug.

Polyether ionophores

The first report of an LC electrospray MS in ionophore analysis was published by Schneider et al. (1991). Another method, using HPLC–electro-spray MS for the detection of narasin, monensin, salinomycin and lasalocid was reported, with the advantage that only a single, quadruple MS system was needed (Harris et al., 1998). By adding ammonium acetate to the HPLC mobile phase, additional diagnostic ions could be produced to further confirm the identity of the analyte. However, no results of practical applications were presented in the study. Recently, two groups reported methods based on LC–electrospray tandem MS, using chicken eggs and liver as the sample matrices. One method was able to detect simultaneously narasin, monensin and salinomycin (Rosen, 2001) and the other lasalocid, narasin, monensin and salinomycin residues (Matabudul et al., 2002). The sample preparation in these studies was based on anhydrous sodium sulphate-acetonitrile extraction with SPE clean-up (Matabudul et al., 2002) or methanol extraction with automated SPE clean-up (Rosen, 2001). Both methods were very sensitive and had a high throughput. Therefore, they could be used for both screening and confirmatory purposes. Matabudul et al. (2000) also reported a two-tier testing system for lasalocid: an HPLC with fluorescence detection for screening and an LC–MS–MS for confirmation. A comprehensive review of the methods available for ionophore analysis was given by Elliott et al. (1998).

Several enzyme immunoassays for various ionophores have been described (Kennedy et al., 1995a,b, 1997; Muldoon et al., 1995; Shimer et al., 1996; Watanabe et al., 1998, 2001). In addition, immunoassays for monensin (Crooks et al., 1998b) and narasin/salinomycin (Peippo et al., 2004) that rely on the use of time-resolved fluorometry have been reported. The monensin immunoassay for poultry plasma samples described by Crooks et al. (1998b) utilised the dry chemistry assay concept, in which all the reagents needed for the assay were dry-coated in microtitre wells. Feeding experiments were also conducted to correlate the residue concentrations in plasma with those in liver. The narasin/salinomycin assay was used to screen residues from poultry muscle and eggs. The polyclonal antibody had a cross-reactivity of 100% for narasin and salinomycin, but less than 0.1% for other ionophores. The assay was very sensitive; the LOQ was 1.8 and 0.6 μg per kg for muscle and eggs, respectively.

Ionophore Toxicosis

Dietary addition of ionophores has been used to enhance food conversion efficiency and manage coccidial disease in production animals. Ionophores used include monensin, lasalocid, salinomycin, maduramicin, and narasin. Accidental overdoses have been reported in various species including cattle, sheep, horses, and swine. Ionophores have also been used as an experimental model of toxic myocardial injury and irreversible myocardial dysfunction. Toxicity manifests to varying degrees in both the myocardium and skeletal muscle. Susceptibility differs among species, with the horse being particularly sensitive.

Monensin is a sodium (Na⁺)-selective carboxylic ionophore derived from the bacterium Streptomyces cinnamonensis. Lipid-soluble cation complexes traverse the cardiomyocyte membrane to increase the intracellular Na⁺ concentration. This change is accompanied by a corresponding increase in intracellular Ca^2 + concentration, possibly via a transmembrane Na⁺/Ca^2 + exchanger. When increases in intracellular Ca^2 + exceed Ca^2 +-sequestering capacity, numerous enzymes are activated – phospholipases, proteases, ATPases, and endonucleases – resulting in decreased cellular function or death. Other mechanisms that could contribute to cardiomyocyte death include catecholamine toxicity and peroxidative membrane injury. In support of the latter, supplementation of vitamin E and selenium in both cattle and swine can modify the course of disease and may offer a degree of protection when given as dietary supplements.

Ionophore toxicity is dose-dependent. Pathological findings are characterized by degeneration and necrosis of myocardium and skeletal muscle. Grossly, white linear streaks can be identified in striated muscles representing myofiber death and mineralization. Histological changes of lesions include swelling, hyalinization, vacuolar degeneration, and eventually loss of myofibers (Virtual Microscopy Slide 4 eSlide: VM00272). Acute ultrastructural changes include lipid deposition and mitochondrial swelling with accumulation of matrix densities. Consistent with intracellular Ca^2 + accumulation, a short phase of hypercontraction may manifest morphologically as ‘contraction band’ necrosis. Macrophages infiltrate the necrotic myofiber tubes, followed by phagocytosis and activation of interstitial fibroblasts. In cattle, lesions are most apparent in the left ventricular myocardium. Selective atrial myocardial injury occurs in experimental models of porcine monensin intoxication.

3.6 Antibiotics

A number of antibiotics have been reported to possess antiprotozoal activities in humans and domestic animals. These include monensin (12) [100,101], salinomycin (13) [102,103], narasin (14) [104], maduramicin, (15) [105] lasalocid-A (16) [106], tetracycline (17a) [107,108], doxycycline (17b) [109], oxytetracycline (17c) [110], spiramycin (18) [111], amphotericin-B (19) [112], nystatin (20) [113], clindamycin (21) [114] and paromomycin (22) [115].