头孢洛宁乳房注入剂(干乳期)在牛奶中的残留消除
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摘要
【目的】头孢洛宁为第一代半合成头孢菌素类抗生素,对革兰氏阳性菌和阴性菌均有良好的抗菌活性,临床以每个乳区250mg用于治疗亚临床感染引起的乳房炎。头孢洛宁通过与敏感菌的青霉素结合蛋白相结合,从而阻断细菌细胞壁的合成,达到抑制细菌生长的目的。笔者开展头孢洛宁乳房注入剂(干乳期)在牛奶中的残留消除规律研究,以期为该药的合理使用和乳品安全生产提供指导。【方法】选取20头进入干乳期的健康奶牛,每个乳区分别注入一支头孢洛宁乳房注入剂。平均干乳期为50 d,奶牛产犊开始泌乳后的6、12、24、36、48、60、72、96和120 h,将每头奶牛每次采集的4个乳区的奶混合。采用Phenomenex Luna C18(150mm×2.1mm,3.5μm)。以乙腈-0.1%甲酸水溶液为流动相,梯度洗脱程序洗脱,流速0.25 mL/min,柱温为35℃,进样量为5.0μL。头孢洛宁采用电喷雾离子源(ESI)离子化,正离子模式扫描,多反应监测模式(MRM),电喷雾电压(IS)为4k V,雾化气压力(GS1)为55psi,气帘气(CUR)为15 psi,辅助气流速(GS2)为35psi,离子源温度(TEM)为600℃;定量离子对为m/z→459.4/337.3。样品自然解冻,取5 g牛奶,置于50 mL离心管中,加入20 mL乙腈,涡旋混匀2min,在10℃条件下10 000 r/min离心10 min。将上清液用15 mL75%乙腈水溶液重复提取一次,合并两次的提取液,并加入10 mL乙腈饱和的正己烷,震荡1 min,弃掉正己烷,把提取液移至100 mL鸡心瓶中,在40℃用旋转浓缩仪旋转蒸发除去乙腈。向已除去乙腈的样品溶液中加入20 mL磷酸二氢钠缓冲溶液,然后用氢氧化钠溶液调节至p H8.5。将样品提取液以3 mL/min的流速通过HLB固相萃取柱,先用5 mL磷酸二氢钠缓冲溶液洗涤鸡心瓶并过柱,再用2 mL水洗柱。用2 mL乙腈洗脱,收集洗脱液于刻度样品管中,在40℃下用氮气浓缩仪吹干,用2 mL水溶解残渣,摇匀后,过0.22μm滤膜,取样供LC-MS/MS检测。【结果】头孢洛宁在2—200μg·kg~(-1)的范围内呈良好的线性关系,相关系数在0.991—0.997之间。该方法检测限为0.5μg·kg~(-1),定量限为2μg·kg~(-1)。头孢洛宁在2、20、40和200μg·kg~(-1)四个添加水平上的平均回收率为73.60%—103.52%,批内变异系数为1.85%—10.41%,批间变异系数为3.41%—8.97%。结果表明,该方法的回收率和变异系数满足残留检测定量分析要求。使用头孢洛宁干乳期乳房注入剂的初产奶牛,在产犊后96 h低于定量限。经产奶牛在产犊36 h低于定量限,24h均低于MRL。【结论】头孢洛宁乳房注入剂(干奶期)按推荐剂量4个乳区(250 mg/乳区)给药后,其产犊泌乳后牛奶中的弃奶期为24 h。
【Objective】Cefalonium is a first generation semi-synthetic cephalosporin with broad spectrum of activity against both Gram-positive and Gram-negative bacteria. The cefalonium is used intramammarily during the dry period of cattle at a recommended dose of 250 mg per quarter to treat existing sub-clinical infections and to prevent new infections. The bactericidal activity of cefalonium is a result of its inhibitory action on bacterial cell wall synthesis due to binding to one or more penicillin binding proteins located under the cell wall susceptible bacteria. The resulting high internal osmotic pressure leads to rupture of the cytoplasmic membrane. The objective of this study was to establish a withdrawal period for cefalonium in milk, following intramammary infusion treatment.【Method】Twenty healthy dairy cows in the dry period were injected with a cefalonium injection into each breast area. The average dry period was 50 days, and they were mixed with the samples of 4 milk areas collected per cow at 6, 12, 24, 36, 48, 60, 72, 96 and 120 h after the start of milking. Residues of cefalonium were detectable in milk for up to 6, 12, 24, 36, 48, 60, 72, 96 and 120 h post-treatment, respectively. Phenomenex Luna C18(150 mm×2 mm, 5 μm) was used. Acetonitrile-0.1% formic acid aqueous solution was used as the mobile phase. The gradient elution procedure was used. The flow rate was 0.25 m L·min~(-1), the column temperature was 35°C, and the injection volume was 5.0 μL. Phenomenex Luna C18(150 mm×2.1 mm,3.5 μm) was used. Acetonitrile-0.1% formic acid aqueous solution was used as the mobile phase. The gradient elution procedure was used. The flow rate was 0.25 mL/min, the column temperature was 35°C, and the injection volume was 5.0 μL. MS conditions of detection method: ESI ion source, positive ion scan, multiple reaction monitoring, ion spray voltage: 4kV, the pressure of GS1: 55 psi, the pressure of CUR: 15 psi, the pressure of GS2: 35 psi, TEM: 600℃, the quantitative ion is: cefalonium m/z→459.4/337.3. The sample was thawed naturally, 5g of milk was accurately pipetted into a 50 mL centrifuge tube, 20 mL of acetonitrile was added, vortexed and shaken for 2min, and centrifuged at 10 000 r/min for 10 min. The supernatant was extracted once with 15 mL of 75% acetonitrile aqueous solution, and the extracts were combined twice, and 10 mL of acetonitrile saturated n-hexane was added, shaken for 1 min, the n-hexane was discarded, and the extract was transferred to a 100 m L heart bottle. Acetonitrile was removed by rotary evaporation at 40 ° C using a rotary concentrator. To the above sample solution, 20 mL of a sodium dihydrogen phosphate buffer solution was added, followed by adjustment to pH = 8.5 with a sodium hydroxide solution. The sample was passed through the HLB solid phase extraction column, then the heart bottle was washed with 5 mL of sodium dihydrogen phosphate buffer solution and passed through the column, and the column was washed with 2 mL of water. It was eluted with 2 mL of acetonitrile, dried at 40 °C with a nitrogen concentrator, dissolved in 2 mL of water, shaken, passed through a 0.22μm microporous membrane, LC-MS/MS detection analysis.【Result】Cefalonium showed a good linearity in the concentration range of 2-200 μg·kg~(-1), with a correlation coefficient of 0.991-0.997, a detection limit of 0.5 μg·kg~(-1), and a limit of quantification of 2 μg·kg~(-1). The relative recovery rate of this method at the four levels of addition of 2, 20, 40 and 200 μg·kg~(-1) was 82.21%-89.08%. The coefficient of intra-assay coefficient of variation was 1.85%~(-1)0.41%, and the inter-assay coefficient of variation was 3.41%-8.97%. The experimental method has high sensitivity and simple operation, and can be used for the residue depletion study of cefalonium in milk. Milk samples from these cows after calving were analyzed for antibiotic residues by a liquid chromatography-mass spectrometry/mass spectrometry(LC-MS/MS) procedure. Primiparous dairy cows that used cefalonium intramammary infusion(dry cow) were below the limit of quantitation at 96 hours after calving. Dairy cows were below the limit of quantitation at 36 hours after calving.【Conclusion】After the cefalonium intramammary infusion(dry cow) was administered at the recommended dose of 4 milk areas(250 mg/milk area), the withdrawal period in milk was 24 h.
【Objective】Cefalonium is a first generation semi-synthetic cephalosporin with broad spectrum of activity against both Gram-positive and Gram-negative bacteria. The cefalonium is used intramammarily during the dry period of cattle at a recommended dose of 250 mg per quarter to treat existing sub-clinical infections and to prevent new infections. The bactericidal activity of cefalonium is a result of its inhibitory action on bacterial cell wall synthesis due to binding to one or more penicillin binding proteins located under the cell wall susceptible bacteria. The resulting high internal osmotic pressure leads to rupture of the cytoplasmic membrane. The objective of this study was to establish a withdrawal period for cefalonium in milk, following intramammary infusion treatment.【Method】Twenty healthy dairy cows in the dry period were injected with a cefalonium injection into each breast area. The average dry period was 50 days, and they were mixed with the samples of 4 milk areas collected per cow at 6, 12, 24, 36, 48, 60, 72, 96 and 120 h after the start of milking. Residues of cefalonium were detectable in milk for up to 6, 12, 24, 36, 48, 60, 72, 96 and 120 h post-treatment, respectively. Phenomenex Luna C18(150 mm×2 mm, 5 μm) was used. Acetonitrile-0.1% formic acid aqueous solution was used as the mobile phase. The gradient elution procedure was used. The flow rate was 0.25 m L·min~(-1), the column temperature was 35°C, and the injection volume was 5.0 μL. Phenomenex Luna C18(150 mm×2.1 mm,3.5 μm) was used. Acetonitrile-0.1% formic acid aqueous solution was used as the mobile phase. The gradient elution procedure was used. The flow rate was 0.25 mL/min, the column temperature was 35°C, and the injection volume was 5.0 μL. MS conditions of detection method: ESI ion source, positive ion scan, multiple reaction monitoring, ion spray voltage: 4kV, the pressure of GS1: 55 psi, the pressure of CUR: 15 psi, the pressure of GS2: 35 psi, TEM: 600℃, the quantitative ion is: cefalonium m/z→459.4/337.3. The sample was thawed naturally, 5g of milk was accurately pipetted into a 50 mL centrifuge tube, 20 mL of acetonitrile was added, vortexed and shaken for 2min, and centrifuged at 10 000 r/min for 10 min. The supernatant was extracted once with 15 mL of 75% acetonitrile aqueous solution, and the extracts were combined twice, and 10 mL of acetonitrile saturated n-hexane was added, shaken for 1 min, the n-hexane was discarded, and the extract was transferred to a 100 m L heart bottle. Acetonitrile was removed by rotary evaporation at 40 ° C using a rotary concentrator. To the above sample solution, 20 mL of a sodium dihydrogen phosphate buffer solution was added, followed by adjustment to pH = 8.5 with a sodium hydroxide solution. The sample was passed through the HLB solid phase extraction column, then the heart bottle was washed with 5 mL of sodium dihydrogen phosphate buffer solution and passed through the column, and the column was washed with 2 mL of water. It was eluted with 2 mL of acetonitrile, dried at 40 °C with a nitrogen concentrator, dissolved in 2 mL of water, shaken, passed through a 0.22μm microporous membrane, LC-MS/MS detection analysis.【Result】Cefalonium showed a good linearity in the concentration range of 2-200 μg·kg~(-1), with a correlation coefficient of 0.991-0.997, a detection limit of 0.5 μg·kg~(-1), and a limit of quantification of 2 μg·kg~(-1). The relative recovery rate of this method at the four levels of addition of 2, 20, 40 and 200 μg·kg~(-1) was 82.21%-89.08%. The coefficient of intra-assay coefficient of variation was 1.85%~(-1)0.41%, and the inter-assay coefficient of variation was 3.41%-8.97%. The experimental method has high sensitivity and simple operation, and can be used for the residue depletion study of cefalonium in milk. Milk samples from these cows after calving were analyzed for antibiotic residues by a liquid chromatography-mass spectrometry/mass spectrometry(LC-MS/MS) procedure. Primiparous dairy cows that used cefalonium intramammary infusion(dry cow) were below the limit of quantitation at 96 hours after calving. Dairy cows were below the limit of quantitation at 36 hours after calving.【Conclusion】After the cefalonium intramammary infusion(dry cow) was administered at the recommended dose of 4 milk areas(250 mg/milk area), the withdrawal period in milk was 24 h.
引文
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[3]DEB R,KUMAR A,CHAKRABORTY S,VERMA A K,TIWARI R,DHAMA K,SINGH U,KUMAR S.Trends in diagnosis and control of bovine mastitis:A Review.Pakistan Journal of Biological Sciences,2013,16(23):1653-1661.
[4]LEE J W,O'BRIEN C N,GUIDRY A J,PAAPE M J,SHAFER-WEAVER K A,ZHAO X.Effect of a trivalent vaccine against staphylococcus aureus mastitis lymphocyte subpopulations,antibody production,and neutrophil phagocytosis.Canadian Journal of Veterinary Research,2005,69(1):11-18.
[5]LEITNER G,LUBASHEVSKY E,TRAININ Z.Staphylococcus aureus vaccine against mastitis in dairy cows,composition and evaluation of its immunogenicity in a mouse model.Veterinary Immunology and Immunopathology,2003,93(3-4):159-167.
[6]DUFOUR S,DOHOO I R.Monitoring dry period intramammary infection incidence and elimination rates using somatic cell count measurements.Journal of Dairy Science,2012,95(12):7173-7185.
[7]Bradley A J.Bovine Mastitis:An Evolving Disease.The Veterinary Journal,2002,164(2):116-128.
[8]ROBERSON J R,FOX L K,HANCOCK D D,GAY J M,BESSER TE.Ecology of staphylococcus aureus isolated from various sites on dairy farms.Journal of Dairy Science,1994,77(11):3354-3364.
[9]SONG E,YU M,WANG Y,HU W,CHENG D,SWIHART M T,SONG Y.Multi-color quantum dot-based fluorescence immunoassay array for simultaneous visual detection of multiple antibiotic residues in milk.Biosensors&Bioelectronics,2015,72:320-325.
[10]WANG D,WANG Z,YAN Z,WU J,ALI T,LI J,LV Y,HAN B.Bovine mastitis staphylococcus aureus:antibiotic susceptibility profile,resistance genes and molecular typing of methicillin-resistant and methicillin-sensitive strains in China.Infection Genetics and Evolution,2015,31:9-16.
[11]王娟,黄秀梅,曲志娜,赵思俊,盖文燕,王玉东,王君玮.生鲜牛奶中金黄色葡萄球菌的分离及耐药性分析.中国人兽共患病学报,2014(12):1214-1217.WANG J,HUANG X M,QU Z N,ZHAO S J,GAI W Y,WANG Y D,WANG J W.Islation of staphylococcus aureus from raw milk and its drug resistance analysis.Chinese Journal of Zoonoses,2014(12):1214-1217.(in Chinese)
[12]吴天琪,吴艳涛,张小荣.牛奶源金黄色葡萄球菌耐药基因分布特征的研究.畜牧与兽医,2015(11):88-90.WU T Q,WU Y T,ZHANG X R.Study on distribution characteristics of staphylococcus aureus resistance gene in milk.Animal Husbandry&Veterinary Medicine,2015(11):88-90.(in Chinese)
[13]王娟,黄秀梅,刘书科,李玉清,赵思俊,曲志娜,王玉东,王君玮..牛奶中金黄色葡萄球菌的耐药性及其肠毒素分型研究.中国兽医杂志,2013(03):30-32.WANG J,HUANG X M,LIU S K,LI Y Q,ZHAO S J,QU Z N,WANG Y D,WANG J W.Study on drug resistance of Staphylococcus aureus in milk and its enterotoxin typing.Chinese Journal of Veterinary Medicine,2013(03):30-32.(in Chinese)
[14]PAPADOPOULOU C,DIMITRIOU D,LEVIDIOTOU S,GESSOULIH,PANAGIOU A,GOLEGOU S,ANTONIADES G.Bacterial strains isolated from eggs and their resistance to currently used antibiotics:is there a health hazard for consumers?Comparative Immunology,Microbiology and Infectious Diseases,1997,20(1):35-40.
[15]陈杖榴.兽医药理学.北京:中国农业出版社,2017:241-248.CHEN Z L.Veterinary Pharmacology.Beijing:China Agriculture Press,2017:241-248.(in Chinese)
[16]EMEA.Cefalonium Summary Report(1).http://www.ema.europa.eu/docs/en/2009/11/WC5000 11710.pdf
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