Potential for oxytetracycline administration by three routes to cause milk residues in lactating cows, as detected by radioimmunoassay (Charm II) and high-performance liquid chromatography test methods

Kevin L. Anderson From the Departments of Food Animal, and Equine Medicine (Anderson), and Anatomy, Physiological Sciences, and Radiology (Papich), College of Veterinary Medicine, and the Departments of Food Science (Rushing) and Animal Science (Wesen), College of Agricultural and Life Sciences, North Carolina State Unvesity, Raleigh, NC 27606, and Meat Science Research Laboratory (Moats), USDA Beltsville, MD 20705.

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William A. Moats From the Departments of Food Animal, and Equine Medicine (Anderson), and Anatomy, Physiological Sciences, and Radiology (Papich), College of Veterinary Medicine, and the Departments of Food Science (Rushing) and Animal Science (Wesen), College of Agricultural and Life Sciences, North Carolina State Unvesity, Raleigh, NC 27606, and Meat Science Research Laboratory (Moats), USDA Beltsville, MD 20705.

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John E. Rushing From the Departments of Food Animal, and Equine Medicine (Anderson), and Anatomy, Physiological Sciences, and Radiology (Papich), College of Veterinary Medicine, and the Departments of Food Science (Rushing) and Animal Science (Wesen), College of Agricultural and Life Sciences, North Carolina State Unvesity, Raleigh, NC 27606, and Meat Science Research Laboratory (Moats), USDA Beltsville, MD 20705.

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Donald P. Wesen From the Departments of Food Animal, and Equine Medicine (Anderson), and Anatomy, Physiological Sciences, and Radiology (Papich), College of Veterinary Medicine, and the Departments of Food Science (Rushing) and Animal Science (Wesen), College of Agricultural and Life Sciences, North Carolina State Unvesity, Raleigh, NC 27606, and Meat Science Research Laboratory (Moats), USDA Beltsville, MD 20705.

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Mark G. Papich From the Departments of Food Animal, and Equine Medicine (Anderson), and Anatomy, Physiological Sciences, and Radiology (Papich), College of Veterinary Medicine, and the Departments of Food Science (Rushing) and Animal Science (Wesen), College of Agricultural and Life Sciences, North Carolina State Unvesity, Raleigh, NC 27606, and Meat Science Research Laboratory (Moats), USDA Beltsville, MD 20705.

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SUMMARY

Milk antimicrobial residues are a serious concern for the dairy industry. Residues of the tetracycline family of antimicrobials have been reported in market milk by investigators, using radioimmunoassay and microbial receptor technology (hereafter referred to as the Charm II test). In response to these reports, an investigation was conducted to determine the potential of 3 extra-label routes of oxytetracycline (otc) administration to cause milk residues above the Food and Drug Administration safe value of 30 parts per billion (ppb). Lactating Holstein cows were administered otc once by use of 1 of 3 routes: iv at 16.5 mg/kg of body weight (n = 6); im at 11 mg/kg (n = 6); and intrauterine (iu) at 2 g in 500 ml of saline solution/cow (n = 6). Duplicate milk samples were collected at the milking prior to drug administration and for the next 13 milkings at 12-hour intervals. Concentrations of otc in milk samples were analyzed by use of the Charm II test for tetracyclines (lmit of otc detection, approx 5 ppb) and were compared with concentrations determined by use of a high-performance lquid chromatography (hplc) method (lower lmit of otc quantitation, approx 2 ppb).

The potential for milk otc residues above the Food and Drug Administration safe value of 30 ppb after treatment was considerably greater for the iv and im routes, compared with the iu route. Mean peak otc concentrations in milk at the first milking after treatment for the hplc and Charm II tests were approximately 3,700 to 4,200 ppb for the iv route, 2,200 to 2,600 ppb for the im route, and 186 to 192 ppb for the iu route, respectively.

Pharmacokinetic analysis, based on milk otc concentrations, indicated that the area under the curve (auc) and milk maximal concentration (Cmax) differed significantly (P < 0.001) among routes of administration. The auc was similar for iv and im administrations; values for both were greater than the auc for iu administration. The Cmax was greatest for iv, intermediate for im, and least for iu administration. There were significant (P ≤ 0.01) differences in auc between assay methods (Charm II vs hplc) for the iv route. Concentrations of otc in milk determined by the Charm II test were often greater than those determined by hplc.

Administration of otc to lactating cows via these routes is extra-label drug use. Failure to withhold the product from early milkings of cows administered otc by the iv or im route should be considered a potential cause of otc residues in market milk. Milk from nearly all cows contained otc (< 30 ppb), the Food and Drug Administration safe level, by 120 hours after otc administration. Use of appropriate withholding times and antibiotic residue testing is indicated to avoid otc residues.

SUMMARY

Milk antimicrobial residues are a serious concern for the dairy industry. Residues of the tetracycline family of antimicrobials have been reported in market milk by investigators, using radioimmunoassay and microbial receptor technology (hereafter referred to as the Charm II test). In response to these reports, an investigation was conducted to determine the potential of 3 extra-label routes of oxytetracycline (otc) administration to cause milk residues above the Food and Drug Administration safe value of 30 parts per billion (ppb). Lactating Holstein cows were administered otc once by use of 1 of 3 routes: iv at 16.5 mg/kg of body weight (n = 6); im at 11 mg/kg (n = 6); and intrauterine (iu) at 2 g in 500 ml of saline solution/cow (n = 6). Duplicate milk samples were collected at the milking prior to drug administration and for the next 13 milkings at 12-hour intervals. Concentrations of otc in milk samples were analyzed by use of the Charm II test for tetracyclines (lmit of otc detection, approx 5 ppb) and were compared with concentrations determined by use of a high-performance lquid chromatography (hplc) method (lower lmit of otc quantitation, approx 2 ppb).

The potential for milk otc residues above the Food and Drug Administration safe value of 30 ppb after treatment was considerably greater for the iv and im routes, compared with the iu route. Mean peak otc concentrations in milk at the first milking after treatment for the hplc and Charm II tests were approximately 3,700 to 4,200 ppb for the iv route, 2,200 to 2,600 ppb for the im route, and 186 to 192 ppb for the iu route, respectively.

Pharmacokinetic analysis, based on milk otc concentrations, indicated that the area under the curve (auc) and milk maximal concentration (Cmax) differed significantly (P < 0.001) among routes of administration. The auc was similar for iv and im administrations; values for both were greater than the auc for iu administration. The Cmax was greatest for iv, intermediate for im, and least for iu administration. There were significant (P ≤ 0.01) differences in auc between assay methods (Charm II vs hplc) for the iv route. Concentrations of otc in milk determined by the Charm II test were often greater than those determined by hplc.

Administration of otc to lactating cows via these routes is extra-label drug use. Failure to withhold the product from early milkings of cows administered otc by the iv or im route should be considered a potential cause of otc residues in market milk. Milk from nearly all cows contained otc (< 30 ppb), the Food and Drug Administration safe level, by 120 hours after otc administration. Use of appropriate withholding times and antibiotic residue testing is indicated to avoid otc residues.

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