Six rats (three males and three females) were fed a ration containing uniformly radiolabelled (14)C- avilamycin at a concentration of 550 mg/kg diet for 4.5 days. Urine and feces were collected during the dosing period, and livers were collected at zero withdrawal. Avilamycin A constituted approximately 19% of the fecal radioactivity. There were three major metabolites derived from the oligosaccharide and eurekanate portion of avilamycin in fecal samples. The most abundant metabolite in feces was flambic acid (metabolite B). Flambic acid was relatively unstable and readily converted to flambalactone (metabolite A).
The minimum inhibitory concentrations (MIC) of eight antibiotics and two anticoccidial agents were determined for Clostridium perfringens strains isolated from 26 commercial broiler farms and 22 commercial turkey farms. Isolates were obtained from the intestines of birds on the farm or as the processing plant using standard culture and identification techniques. The microbroth dilution test was used to determine the MIC for each compound. Most isolates from chickens had MICs in the range of 2-16 mg/L for tilmicosin, tylosin and virginiamycin, whereas the MICs for avilamycin, avoparcin, monensin, narasin and penicillin were < or = 1 mg/L. Most strains from chickens had high MICs (> or = 64 mg/L) and appeared to be resistant to bacitracin and lincomycin. Most turkey isolates had MICs in the range of 2-16 mg/L for bacitracin, tilmicosin, tylosin and virginiamycin, with strains exhibiting MICs < or = 1 mg/L for avilamycin, avoparcin, monensin, narasin and penicillin. Several turkey isolates had MICs > or = 64 mg/L to lincomycin. No attempt was made to associate farm usage of a particular antibiotic to the antibiograms.
... Nine crossbred pigs (five males and four females) weighing approximately 44 kg each were fed a ration containing 76.19 mg (14)C-avilamycin/kg in the diet (equivalent to 80 mg avilamycin activity/kg in the diet) at 12-hr intervals for 4, 7 or 10 days. ... One major metabolite observed in the extracts of both liver and excreta was flambic acid, which was formed as a result of cleavage of the ortho ester linking the C and D rings of avilamycin. Flambic acid represented 40-50% of the total radioactive residue in urine and feces and 15-20% of the residue in liver.
Avilamycin is poorly absorbed and is extensively metabolized in the gut of pigs. Only about 8% of total radioactivity in pig feces was attributable to parent avilamycin. Metabolites were found in liver, whereas they were not detected in other tissues. The primary metabolite is flambic acid, representing 40-50% of the total radioactive residue in urine and feces and 15-20% of the residue in liver. No microbiologically active residues were detected in liver. Avilamycin is unlikely to be persistent in the environment following excretion from treated animals, as it is highly metabolized or degraded in animals.
IDENTIFICATION AND USE: Avilamycin is an antibiotic mainly active against Gram-positive bacteria, including Bacillus spp., Clostridium spp., Corynebacterium bovis, Enterococcus spp., Lactobacillus spp., Listeria monocytogenes, Micrococcus luteus, Staphylococcus aureus and Streptococcus spp. Avilamycin is intended for use as a veterinary medicine in chickens, turkeys, pigs and rabbits to control bacterial enteric infections. HUMAN EXPOSURE AND TOXICITY: Avilamycin may be irritating to the eyes and may cause allergic reactions in those hypersensitive to avilamycin. ANIMAL STUDIES: The acute toxicity of avilamycin has been evaluated using various routes of administration in mice, rats and rabbits. The acute intraperitoneal toxicity of avilamycin was more severe than its oral or dermal toxicity. However, the deaths observed after intraperitoneal administration were mainly due to the inflammatory reactions to the unabsorbed avilamycin in the abdominal cavity rather than to the toxicity of avilamycin itself. Mice were fed avilamycin incorporated into the pelleted diet at levels of 0, 30, 300 or 3000 mg avilamycin activity/kg diet continuously for 28 days. There was a slight increase in feed intake and body weight of the males given 450 mg avilamycin activity/kg bw per day. In another study, rats received dietary doses of 0, 4, 6 or 10% dried fermentation product of avilamycin (14.9% avilamycin activity) for 2 weeks. The only treatment-associated finding was brown to black discoloration of the waste trays by urine, although urine was yellow in the bladder or when freshly voided. Avilamycin (mycelial cake form, activity 7.83%) was fed to pigs at levels of 0, 30, 300 and 3000 mg avilamycin activity/kg in the diet for 21 weeks, followed by a 4-week withdrawal period. Some blood biochemistry parameters, such as gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), sodium and inorganic phosphorus, were changed from control values, but those changes were weak and in the normal range In a 2-year experiment, male and female rat litters were fed avilamycin (derived from mycelial cake of 7% activity) at doses of 0, 30, 300 or 3000 mg avilamycin activity/kg in the diet and pure avilamycin at 3000 mg avilamycin activity/kg in the diet during the whole period of the study. The litters were from parent rats fed avilamycin at the same doses of 0, 30, 300 or 3000 mg avilamycin activity/kg in the diet for 1 week and then mated and maintained on their treatments during gestation and lactation. The mortality was 58-78%, with no difference between treatments. Clotting times were significantly decreased, with dose dependency in males at 15 and 150 mg avilamycin activity/kg bw per day, where avilamycin was derived from mycelial cake, on weeks 13, 26, 52 and 78. However, they recovered at the last two sampling times (weeks 104 and 112). There was a non-statistically significant increase in pancreatic exocrine adenomas in male rats that were fed avilamycin derived from mycelial cake at 15 and 150 mg avilamycin activity/kg bw per day. A higher incidence of thyroid parafollicular cell carcinoma was also observed in male rats treated with avilamycin derived from mycelial cake at 15 and 150 mg avilamycin activity/kg bw per day, without statistical significance. No thyroid parafollicular cell carcinoma was found at 1.5 mg avilamycin activity/kg bw per day for the mycelial cake and 150 mg avilamycin activity/kg bw per day for the pure form of avilamycin. Pregnant rabbits were administered a dried fermentation product of avilamycin (17.8% activity) by oral gavage in daily doses of 0, 250, 716 and 2000 mg/kg bw. Abortions occurred in two rabbits from the low dose group and one rabbit from both middle and high dose groups. All except one of these rabbits had diarrhea or were anorectic prior to abortion. The low incidence of abortions that occurred in all treatment groups was regarded as a secondary consequence of maternal toxicity. Avilamycin was not mutagenic in the reverse mutation assay with Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA1538, G46, C3076 and D3052 and Escherichia coli strains WP2 and WP2uvrA both with and without S9 activation. Also, avilamycin did not present any genotoxicity in a deoxyribonucleic acid (DNA) repair assay using primary cultures of adult rat hepatocytes, in a forward mutation assay using L5178Y mouse lymphoma cells and in a chromosomal aberration assay using Chinese hamster ovary cells both with and without S9 activation. Avilamycin was not mutagenic in sister chromatid exchange assays in bone marrow of Chinese hamsters that were orally administered avilamycin and in micronucleus tests with bone marrow of mice treated with avilamycin..
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. 3. replace fluid losses resulting from gastroenteritis with IV crystalloids. 4. Maintain steady urine flow with fluids to alleviate crystalluria from overdoses of sulfonamides, ampicillin, or amoxicillin. /Antibacterial agents/
(14)C-Avilamycin was fed to growing swine at a level of 60-80 ppm (1.5-2 times the recommended use level), and tissues were assayed for radioactivity (RA). At a practical zero withdrawal swine fed 60 ppm of uniformly labeled (U-14)C-avilamycin for 14 days had RA residues of 0.14, 0.66, 0.34, and 0.55 ppm in muscle, liver, kidney, and fat, respectively. Swine fed 80 ppm of (14)C-avilamycin labeled in the dichloroisoeverninic acid portion had residues 3-5 times lower, indicative that most of the residue was derived from the oligosaccharide portion of avilamycin. The primary metabolite in liver and feces was flambic acid. Most of the RA in fat from swine fed (U-14)C-avilamycin was in the fatty acids. (14)C-Avilamycin was excreted rapidly and nearly quantitatively by swine, with 5% of the dose in the murine and the remainder in feces. The excretion pattern and metabolic profile of (14)C-avilamycin in the rat were similar to swine.
Seven female and four to five male starter pigs weighing 7-12 kg were fed standard diets containing 20 mg avilamycin/kg in three different product forms (crystalline, micronized and non-micronized) for 6 days. The feces collected from pigs that were fed crystalline, micronized and non-micronized product had microbiologically active residues that represented 2.0%, 4.5% and 15.0%, respectively, of the residues of avilamycin and its degradation products, as determined by gas chromatographic assays. The faeces contained an average of 0.94, 2.28 and 8.45 ug of microbiologically active residues per gram for pigs fed crystalline, micronized and non-micronized avilamycin, respectively. The gas chromatographic assay, which determined the total residues of avilamycin plus any degradation products that hydrolyse to DIA, indicated that the faeces contained 43.3, 40.1 and 43.4 ug/g for pigs fed the crystalline, micronized and non-micronized product forms, respectively.
... Two crossbred female pigs weighing approximately 40 kg each received 0.9 kg of feed containing unlabelled avilamycin at 60 mg activity/kg in the diet twice daily for 7 days. After being fed the unlabelled drug, each pig received a one-time dose of 120 mg of (14)C-avilamycin (9.3 kBq/mg) incorporated into 450 g of diet. After the consumption of the diet containing (14)C-avilamycin, the animals were given an additional 450 g of unmedicated diet. The female pigs were then fed twice daily with 0.9 kg of unmedicated feed for the duration of the experiment. Most of the (14)C residues in both pigs were excreted in the first 4 days, with over 91% eliminated on days 2 and 3. The peak excretion of (14)C residues in urine occurred in the first 24-hr collection period, with 2.75% and 3.30% recovery for the two animals. During the 9-day collection period, the two pigs excreted 96.9% and 99.0%, respectively, of the total dose administered. An average of 93.4% of the excreted dose was found in the feces, and 4.54% was found in the urine.
Six male and six female 7-week-old broiler chickens (Hubbard-White Mountain Cross) were fed a standard broiler finishing ration containing 14.16 mg (14)C-avilamycin/kg diet (equivalent to 15 mg avilamycin activity/kg in the diet) for 4, 7 or 10 days. Medicated ration was provided ad libitum throughout the dosing phase. At the end of each dosing period, two birds of each sex were deprived of food and water for 6 h, and then samples of muscle, liver, abdominal fat, kidney and skin with subcutaneous fat were collected for radiochemical analysis. Radioactive residue levels in muscle and kidney were lower than the detection limits of 0.008 and 0.024 ug/g, respectively, at all sampling times. The mean peak level of 0.039 ug/g was attained in liver after 7 days of dosing. After 10 days of dosing, the mean total radioactive residues in skin, liver and fat, expressed as avilamycin equivalents, were 0.018, 0.022 and 0.024 ug/g, respectively. Steady-state concentrations of radioactivity were attained in all tissues within 4-7 days after the initiation of dosing.
