Avoparcin

1909.26

1745.558775 g/mol

253-466-4

White, amorphous solid

631 Ų

No definitive melting point

Soluble in water

LD50 in mice, rats, and chickens: >10000 mg/kg orally (Am. Cyanamid, company literature)

Maximum stability of aqueous solutions is at pH 4-8

Hygroscopic|The epimerization of avoparcin entities is discussed in some detail. The absolute stereochemistry of avoparcin is now known since the N-methyl terminal amino acid of the aglycone has been isolated & shown to exhibit negative optical rotation & hence has the R-configuration. The same amino acid has been isolated from an epimerized solution of avoparcin & found to have positive rotation & hence the S-configuration. A comparison is made of the CD curves of beta-avoparcin & epi-beta-avoparcin. Some discussion on the effect of protonation of the terminal N-methyl group on the antibacterial activity of avoparcin is included.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

IDENTIFICATION AND USE: Avoparcin is an antimicrobial antibiotic that has been widely used in feed for poultry, pigs, calves, cattle for fattening and lambs, due to its positive effects on animal growth. At the time since vancomycin was not widely used, there was little reason to be concerned about resistance problems in humans. Things changed, however, when vancomycin became critical in human medicine for treatment of methicillin-resistant Staphylococcus aureus (MRSA) and other serious infections. Resistance to vancomycin, especially among enterococci (VRE) became an important public health problem in many countries. Researchers identified VRE in animals exposed to avoparcin, where they were not found in animals in countries where avoparcin was not used as a growth promoter. Furthermore, the prevalence of VRE among non-hospitalized people in the community was much higher in countries that used avoparcin. There is evidence that VRE in food animals may have been a reservoir for resistance in humans, perhaps through exchange of genetic material between animal and human strains, or through transient colonization of the human gut by animal strains. Avoparcin was never approved for use in the United States and its use has been banned in the European Union since 1997.HUMAN EXPOSURE AND TOXICITY: A case of contact dermatitis in a 50 year old woman resulted from exposure to avoparcin. ANIMAL STUDIES: Studies have shown an association between the use of the glycopeptide antibiotic avoparcin as a growth promoter and the occurrence of Enterococcus faecium (VREF) with high-level resistance to vancomycin on poultry and pig farms. The investigations were conducted as retrospective cohort studies, where groups of farms exposed or not exposed to avoparcin were compared. In poultry, the association between the use of avoparcin and the occurrence of VREF was confounded by the use of broad-spectrum antibiotics. In pigs, the association had a similar magnitude. The similar findings in the two studies provide evidence in favor of a causal association between the use of avoparcin and the occurrence of VREF on farms, and suggest that food animals constitute a potential reservoir of infection for VREF in humans.

Avoparcin is a glycopeptide produced by Streptomyces candidus(1).

Avoparcin's production may result in its release to the environment through various waste streams; its use to increase feed conversion efficiency and promote growth in poultry, pigs, and cattle(1) may result in its direct release to the environment(SRC).|Avoparcin was never licenced in the US(1). It was banned from use in Sweden in 1986 (2), Norway in 1995(3) by the European Union between 1997 and 1999(4), and Taiwan in 2000(5).

Anti-Bacterial Agents|MEDICATION (VET): ... The European Commission has approved a directive banning, as a precautionary protective measure, all use of the additive "Avoparcin" in animal feed in the European Union. Avoparcin is an antimicrobial antibiotic widely used in feed for poultry, pigs, calves, cattle for fattening and lambs, due to its positive effects on animal growth.

/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/|/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/|For more Antidote and Emergency Treatment (Complete) data for AVOPARCIN (6 total), please visit the HSDB record page.

/CASE REPORTS/ A case of contact dermatitis resulting from exposure to avoparcin was described. A 50 year old housewife with a 15 month history of erythema and pruritus on the skin under her corset was examined at a Spanish dermatology clinic. Previous patch testing had yielded positive reactions to nickel and cobalt. Treatment with topical corticosteroids and oral antihistamines at the time had produced little improvement. Examination revealed erythema and pruritus with slight scaling and well defined borders on the skin under her brassiere. Further patch testing confirmed her allergies to nickel and cobalt. Since she had mentioned helping her husband with farm work, she was also patch tested with samples of animal feed and their components. This produced positive reactions to avoparcin, a veterinary antibiotic, and to cobalt. An atomic absorption spectrophotometric analysis of her corset and brassiere detected 70 parts per million cobalt. Analysis of a new brassiere of the same brand and type did not detect cobalt. Wearing the new brassiere while not doing farm work caused no skin problems. The authors conclude that sensitization to cobalt alone does not appear to be the cause of the dermatitis of the patient. Avoparcin may be an additional important factor in her dermatitis.|/OTHER TOXICITY INFORMATION/ With the exception of flavomycin & olaquindox, the antibiotics currently used in European countries as feed additives exert a Gram-positive spectrum of activity. Of these, tylosin & virginiamycin are known for cross-resistance to macrolides, lincosamidines & streptogramines, & avoparcin is known for cross-resistance to vancomycin & teicoplanin. The use of avoparcin in animal husbandry creates a potential reservoir of transferable, vanA-mediated glycopeptide resistance in enterococci. A study in a rural area in Germany where vancomycin-resistant enterococci (VRE) were not isolated from infected humans but found in animal husbandry has shown that VRE are disseminated via meat products & are also found in fecal samples of non-hospitalized humans. VRE of different ecological origin from Germany (hospitals, sewage, food, animal husbandry) are polyclonal as evidenced by macrorestriction patterns & multilocus enzyme electrophoresis, suggesting a wide dissemination of the vanA gene cluster. These results confirm earlier observations on the spread of the sat genes, which confer resistance to a streptothricin antibiotic which has only been used in animal feeding. The resistance determinants were later also found in Escherichia coli from human infections & had spread in the absence of selective pressure.|/OTHER TOXICITY INFORMATION/ Avoparcin is a glycopeptide antimicrobial in the same family as vancomycin. It was approved for use in many European countries as a growth promoter. At the time since vancomycin was not widely used, there was little reason to be concerned about resistance problems in humans. Things changed, however, when vancomycin became critical in human medicine for treatment of methicillin-resistant Staphylococcus aureus (MRSA) and other serious infections. Resistance to vancomycin, especially among enterococci (VRE) became an important public health problem in many countries. Researchers identified VRE in food animals exposed to avoparcin, where they were not found in animals in countries where avoparcin was not used as a growth promoter. Furthermore, the prevalence of VRE among non-hospitalized people in the community was much higher in countries that used avoparcin. There is evidence that VRE in food animals may have been a reservoir for resistance in humans, perhaps through exchange of genetic material between animal and human strains, or through transient colonization of the human gut by animal strains.

alpha-avoparcin

Never licenced in the US|... In countries using avoparcin ... as a growth promoter, vancomycin-resistant enterococci (VRE) are commonly found in the commensal flora of food animals, on meat from these animals and in commensal flora of healthy humans despite very limited use of vancomycin in hospitals. ...

A highly sensitive and selective method using LC-ESI-MS/MS and tandem-SPE was developed to detect trace amounts of avoparcin (AV) antibiotics in animal tissues and milk. Data acquisition using MS/MS was achieved by applying multiple reaction monitoring of the product ions of [M + 3H](3+) and the major product ions of AV-alpha and -beta at m/z 637 --> 86/113/130 and m/z 649 --> 86/113/130 in ESI(+) mode. The calculated instrumental LODs were 3 ng/mL. The sample preparation was described that the extraction using 5% TFA and the tandem-SPE with an ion-exchange (SAX) and InertSep C18-A cartridge clean-up enable us to determine AV in samples. Ion suppression was decreased by concentration rates of each sample solution. These SPE concentration levels could be used to detect quantities of 5 ppb (milk), 10 ppb (beef), and 25 ppb (chicken muscle and liver). The matrix matching calibration graphs obtained for both AV-alpha (r >0.996) and -beta (r >0.998) from animal tissues and milk were linear over the calibration ranges. AV recovery from samples was higher than 73.3% and the RSD was less than 12.0% (n = 5).|An analytical method was developed for determination of residual avoparcin in chicken muscle by measuring alpha- and beta-avoparcin, major components of the pharmaceutical preparation avoparcin, using HPLC with UV and amperometric detectors. The analytical HPLC was run on a Cosmosil 5C18-AR column (4.6 mm x 25 cm) with a gradient formed from A: 2.5% acetic acid, 0.01 mol/L sodium heptane sulfonic acid-acetonitrile (88.5:11.5) (pH 4.0) and B: 2.5% acetic acid-acetonitrile (10:90), using UV and amperometric detection (AMD) with glassy-carbon electrode (+900 mV). Avoparcin was extracted from chicken muscle by homogenization with methanol-0.2 mol/L sulfuric acid (6:4) followed by centrifugation after pH adjustment to 4 with 1 mol/L sodium hydroxide. The supernatant was evaporated to dryness, and the residue was dissolved in water. The aqueous layer was adjusted to pH 4 by adding 1 mol/L sodium hydroxide. Then it was purified on a Sep-Pak tC18 plus ENV cartridge. The cartridge was washed with water, and retained substances were eluted with 50% methanol. The eluate was evaporated to dryness under reduced pressure. The residue was dissolved in water and determined by HPLC. Recoveries of avoparcin spiked in chicken muscle were 73.1-88.1% at levels of 2-10 ug/g. The detection limits were 0.5 microgram/g (UV) and 0.2 ug/g (AMD).