兽用抗菌增效剂制剂的研究进展

doi:10.16431/j.cnki.1671-7236.2021.05.033

摘要/Abstract

摘要： 抗菌增效剂属于人工合成的二氨基嘧啶类药物，此类药物与抗菌药物联合使用时会以特定的机制来增强抗菌药的药物活性。近年来，由于抗生素的广泛使用甚至滥用导致细菌耐药的问题日益显现，通过加入抗菌增效剂而研制出的新制剂可以提高抗菌药在动物体内的利用率、降低药物用量、增强药物疗效、降低兽药残留及减少细菌耐药性。文章分析了近年来甲氧苄啶、二甲氧苄啶和艾地普林与各类抗生素的联合使用制备的制剂产品，发现其对疾病的治疗效果普遍优于单独使用抗生素。同时，配合中药的使用对细菌耐药的问题有显著改善，为后期抗菌增效剂的研究打开新的局面。随着对兽药制剂的研究，其不再局限于简单的剂型，通过运用新技术、新材料研制出的制剂，针对不同的给药部位和给药途径可以对病患进行更精准的治疗，减少药物达到靶部位的时间，增加患病部位的药量，此思路可为后续的研发方向提供支持和参考。文章将对抗菌药-抗菌增效剂联用制剂的研发情况进行综述。

关键词: 抗菌增效剂; 制剂; 兽药残留; 耐药性

Abstract: Antibacterial synergist is a kind of synthetic diaminopyrimidine drugs.When these drugs are used in combination with antibacterial agents,they will strengthen the activity of antibacterial agents through a specific mechanism.In recent years,the problem of bacterial resistance has become increasingly apparent due to the widespread use and even abuse of antibiotics.New preparations developed by adding antibacterial synergists can improve the utilization rate of antibiotics in animals,reduce drug dosage,enhance drug efficacy,reduce veterinary drug residues and reduce bacterial resistance.The preparation products prepared by the combination of TMP,DVD and ADP with various antibiotics were analyzed in recent years.It is found that the therapeutic effect of these preparations is generally better than those antibiotics alone.Besides,with the use of traditional Chinese medicine,the problem of bacterial resistance has been significantly improved,which opens a new prospect for the research direction of antibacterial synergist in the later study.With the research of veterinary drug preparation,it is no longer limited to simple dosage forms.Through the use of new technologies and new materials,the preparation developed can provide more accurate treatment for patients according to different drug delivery sites and routes,reduce the time for drugs to reach the target site,and increase the dosage of patients.This idea can provide support and reference for the follow-up research and development direction.In this paper,the research and development of the combination of antibiotics and antibacterial synergists are reviewed.

Key words: synergist for antibiotic drug; preparations; veterinary drug residues; drug resistance

中图分类号:

S859.5

黎欣, 王志霞, 潘源虎, 谢书宇, 袁宗辉, 黄玲利, 瞿玮. 兽用抗菌增效剂制剂的研究进展[J]. 中国畜牧兽医, 2021, 48(5): 1816-1824.

LI Xin, WANG Zhixia, PAN Yuanhu, XIE Shuyu, YUAN Zonghui, HUANG Lingli, QU Wei. Progress Research on Antibacterial Synergist Preparation for Animals[J]. China Animal Husbandry and Veterinary Medicine, 2021, 48(5): 1816-1824.

参考文献

[1] 陈杖榴.兽医药理学[M].第3版.北京:中国农业出版社,2015. CHEN Z L.Veterinary Pharmacology[M].3rd Edtion.Beijing:China Agriculture Press,2015.(in Chinese)
[2] 聂巧.磺胺氯吡嗪钠-甲氧苄啶可溶性粉在鸡体内的残留消除研究[D].扬州:扬州大学,2017. NIE Q.Study on the residues elimination of sulfachloropyrazine sodium-trimethopriom soluble powder in broilers[D].Yangzhou:Yangzhou University,2017.(in Chinese)
[3] 董梦晓,瞿玮,谢书宇,等.兽用抗菌药复方注射剂研制进展[J].中国抗生素杂志,2017,42(10):880-890. DONG M X,QU W,XIE S Y,et al.The development of compound injections for veterinary antibacterial agents[J].Chinese Journal of Antibiotics,2017,42(10):880-890.(in Chinese)
[4] 吕凤霞,陈玲,刘道中,等.高效抗球虫药磺胺氯吡嗪钠甲氧苄啶可溶性粉的制备工艺及抗球虫效果研究[J].黑龙江畜牧兽医,2018,21:188-191. LYU F X,CHEN L,LIU D Z,et al.Study on preparation technology of sulfaclopyrazine sodium trimethoprim soluble powder and its effect against coccidioides[J].Heilongjiang Animal Husbandry and Veterinary,2018,21:188-191.(in Chinese)
[5] 刘洋,赵修华,祖元刚,等.氟苯尼考PEG-6000固体分散体的无溶剂熔融法制备与分析[J].中国兽药杂志,2012,46(4):40-43. LIU Y,ZHAO X H,ZU Y G,et al.Preparation and analysis of florfenicol-polyethyleneglycol 6000 solid dispersion made by solvent-free hot-melt method[J].Chinese Journal of Veterinary Medicine,2012,46(4):40-43.(in Chinese)
[6] 薛润天.复方恩诺沙星颗粒剂的质量控制及药效学研究[D].杨凌:西北农林科技大学,2017. XUE R T.Study on the quaiity control and pharmacodyanmicsof compound enrofloxacin granules[D].Yangling:Northwest A&F University,2017.(in Chinese)
[7] 宋美英,张承欢,只勇,等.头孢噻呋单用及联合甲氧苄啶对致病性牛源大肠杆菌防突变浓度的研究[J].黑龙江畜牧兽医,2017,5:11-14. SONG M Y,ZHANG C H,ZHI Y,et al.Study on the mutant prevention concentrations of ceftiofur alone and in combination with trimethoprim against pathogenic Escherichia coli from cattle[J].Heilongjiang Animal Husbandry and Veterinary,2017,5:11-14.(in Chinese)
[8] DRLICA K.The mutant selection window and antimicrobial resistance[J].The Journal of Antimicrobial Chemotherapy,2003,52(1):11-17.
[9] 张佩.阿米卡星与三种抗菌药物单独及联合应用对奶牛乳房链球菌耐药突变选择窗的影响[D].哈尔滨:东北农业大学,2018. ZHANG P.The effect of amikacin alone and in combination with other three antibiotics on the MIC of streptococcus separated from cattle with mastitis[D].Harbin:Northeast Agricultural University,2018.(in Chinese)
[10] 郭丽华.复方海南霉素钠溶液制备方法及其对鸡球虫感染的治疗效果观察[J].畜牧与饲料科学,2016,1:40-41. GUO L H.Preparation of compound hainanmycin sodium solution and its therapeutic efficacy on chicken coccidiosis[J].Animal Husbandry and Feed Science,2016,1:40-41.(in Chinese)
[11] 黄晶晶.氟苯尼考明胶纳米药物制备及初步评价[D].泰安:山东农业大学,2019. HUANG J J.Preparation of florfenicol gelatin nanoparticles and its pharmacokinetics preliminary evaluation[D].Tai'an:Shandong Agricultural University,2019.(in Chinese)
[12] 张洁.复方恩诺沙星溶液剂的研制及药效学研究[D].杨凌:西北农林科技大学,2015. ZAHNG J.Preparation and pharmacodynamics study on compound enrofloxacin solution[D].Yangling:Northwest A&F University,2015.(in Chinese)
[13] 郑星星,欧阳五庆.琥乙红霉素纳米乳的制备及其体外抑菌活性研究[J].安徽农业科学,2016,13:183-185. ZHENG X X,OUYANG W Q.Preparation of erythromycin nanoemulsion and determination of its bacteriostatic activity in vitro[J].Journal of Anhui Agricultural Sciences,2016,13:183-185.(in Chinese)
[14] 苏士佳.二甲氧苄啶对Wistar大鼠的毒理学研究[D].武汉:华中农业大学,2011. SU S J.Toxieology of diaveridinein Wistar rats[D].Wuhan:Huazhong Agricultural University,2011.(in Chinese)
[15] 王曦岩.磺胺氯吡嗪钠-二甲氧苄啶可溶性粉在鸡体内的药代动力学研究[D].长春:吉林大学,2017. WANG X Y.Studies on pharmacokinetics of sulfamethoxazole sodium-diaveridine soluble powder in chickens[D].Changchun:Jilin University,2017.(in Chinese)
[16] 栾明娜,陈大健,韩薇.磺胺氯吡嗪钠二甲氧苄啶溶液质量标准研究[J].中兽医医药志,2016,1:22-24. LUN M N,CHEN D J,HAN W.Study on the quality standard of sulfachloropyrazine sodium and diaveridine solution[J].Chinese Journal of Veterinary Medicine,2016,1:22-24.(in Chinese)
[17] 徐维,曾振灵,权丹,等.磺胺对甲氧嘧啶和二甲氧苄啶在肉鸡体内的残留消除[J].动物医学进展,2016,8:49-56. XU W,ZENG Z L,QUAN D,et al.Study on residue depletions of sulfametoxydiazine and diaveridine in chickens[J].Advances in Animal Medicine,2016,8:49-56.(in Chinese)
[18] 郭京超,孙亚奇,刘振利,等.兽用二氨基嘧啶类抗菌增效剂毒理学研究进展[J].中国兽药杂志,2019,53(1):77-84. GUO J C,SUN Y Q,LIU Z L,et al.Advances in research on toxicology of veterinary antibacterial synergists[J].Chinese Journal of Veterinary Medicine,2019,53(1):77-84.(in Chinese)
[19] CHENG G Y,XU Y M,ZHU X D,et al.The antibacterial activities of aditoprim and its efficacy in the treatment of swine streptococcosis[J].Scientific Reports,2017,7:41370.
[20] 徐亚妹.艾地普林及其代谢物的抗菌活性研究[D].武汉:华中农业大学,2016. XU Y M.The antibacterial activity of aditoprim and its main metabolites[D].Wuhan:Huazhong Agricultural University,2016.(in Chinese)
[21] YUAN Z H,HUANG L L,DU X,et al.Veterinary aditoprim(ADP)-sulfamethoxazole(SMZ) compund injection and preparation method there of:Espacenet,103417552[P].2013-12-04.
[22] 郝智慧,孙伟之,赵永达.巴喹普林的研究进展及其临床应用[J].安徽农业科学,2013,41(6):2503-2504. HAO Z H,SUN W Z,ZHAO Y D.Research advance of baquiloprim and clinical application[J].Anhui Agricultural Science,2013,41(6):2503-2504.(in Chinese)
[23] KOSOFF R E,CHEN C Y,WOOSTER G A,et al.Sulfadimethoxine and ormetoprim residues in three species of fish after oral dosing in feed[J].Journal of Aquatic Animal Health,2007,19(2):109-115.
[24] 翟贯星,陆璐,陈代杰,等.中药化合物的抗菌及增效作用[J].中国抗生素杂志,2019,44(12):1366-1370. ZHAI G X,LU L,CHEN D J,et al.Antimicrobial and synergisicm effects of traditional Chinese medicine compounds[J].Chinese Journal of Antibiotics,2019,44(12):1366-1370.(in Chinese)
[25] 刘家男,陈祥帅,周钰奇,等.穿心莲与复方磺胺间甲氧嘧啶联合用药对鸡球虫感染的预防作用研究[J].黑龙江畜牧兽医,2016,14:160-162. LIU J N,CHEN X S,ZHOU Y Q,et al.Study on the preventive effect of andrographis paniculata combined with compound sulfamethazine on coccidioides infection in chickens[J].Heilongjiang Animal Husbandry and Veterinary,2016,14:160-162.(in Chinese)
[26] QUIROZ-CASTANEDA R E,DANTAN-GONZALEZ E.Control of avian coccidiosis:Future and present natural alternatives[J].BioMed Research International,2015,2015:430610.
[27] 杜爱芳.鸡球虫病的中药防治与DNA疫苗研究[D].杭州:浙江大学,2004. DU A F.Prevention and treatment of coccidiosis with herbal medicine and the DNA vaccine[D].Hangzhou:Zhejiang University,2004.(in Chinese)
[28] 苗明三.实用中药毒理学[M].上海:第二军医大学出版社,2007. MIAO M S.Toxicology of Practical Chinese Medicine[M].Shanghai:Second Military Medical University Press,2007.(in Chinese)
[29] 陈永亮,刘丹丹,汪飞燕.青蒿素与二甲氧苄啶联合抗鸡球虫的试验研究[J].家畜生态学报,2020,41(4):65-68. CHENG Y L,LIU D D,WANG F Y.Research on artemisinin combining with DVD on chickens coccidiosis infected by etenella[J].Acta Ecologae Animalis Domastici,2020,41(4):65-68.(in Chinese)
[30] 王宇彤,邵钰柔,陈利娜,等.青蒿素抗疟作用机制研究进展[J].世界科学技术-中医药现代化,2018,20(8):1357-1363. WANG Y T,SHAO Y R,CHEN L N,et al.Research progress on anti-malarial mechanism of action of artemisinin[J].World Science and Technology-Modernization of Traditional Chinese Medicine,2018,20(8):1357-1363.(in Chinese)
[31] 牛彪,秦文文,郭文柱,等.青蒿散抗鸡球虫药效研究[J].中国畜牧兽医,2018,45(6):1683-1691. NIU B,QIN W W,GUO W Z,et al.Study on anticoccidial efficacy of artemisia annua powder[J].China Animal Husbandry & Veterinary,2018,45(6):1683-1691.(in Chinese)
[32] DIBNER J J,RICHARDS J D.Antibiotic growth promoters in agriculture:History and mode of action[J].Poultry Science,2005,84(4):634-643.
[33] 李智,李静,汪以真.美国兽用抗生素管控措施的评价及思考[J].农业经济问题.2018,6:137-144. LI Z,LI J,WANG Y Z.Evaluation and reflection on the control measures of veterinary antibiotics in the United States[J].Agricultural Economics,2018,6:137-144.(in Chinese)
[34] PRESCOTT J F.Veterinary antimicrobial stewardship in North America[J].Australian Veterinary Journal,2019,97(7):243-248.
[35] SIMJEE S.The urgent need for harmonised definitions in addressing antimicrobial resistance in veterinary medicine[J].Australian Veterinary Journal,2019,7:249-251.
[36] 王鹤佳,沈昕,张晶,等.我国兽用抗菌药物使用调查分析[J].中国兽药杂志,2019,53(5):80-85. WANG H J,SHEN X,ZHANG J,et al.Investigation and analysis on the use of veterinary antibiotics in China[J].Chinese Journal of Veterinary Medicine,2019,53(5):80-85.(in Chinese)
[37] EMILY A F H,DYFRIG A H.Challenges for economic evaluation of health care strategies to contain antimicrobial resistance[J].Antibiotics,2019,8(4):166.
[38] 孙灵灵,袁宗辉,李梅,等.抗菌增效剂药动学与残留消除研究进展[J].中国畜牧兽医,2016,43(12):3141-3148. SUN L L,YUAN Z H,LI M,et al.Research progress on pharmacokinetics and residue elimination of antibacterial synergist[J].China Animal Husbandry & Veterinary,2016,43(12):3141-3148.(in Chinese)
[39] MATTHEW I H,ANDREW W T,BARRIE W.Antibiotics:Past,present and future[J].Current Opinion in Microbiology,2019,51:72-80.
[40] 王明艳,朱亚丽,张广智,等.浅谈兽用抗生素应用现状及益生菌的替代潜能[J].现代畜牧兽医,2019,7:36-41. WANG M Y,ZHU Y L,ZHANG G Z,et al.A brief discussion on the application status of veterinary antibiotics and the potential replacement by probiotics[J].Modern Journal of Animal Husbandry and Veterinary Medicine,2019,7:36-41.(in Chinese)
[41] DING Z Y,XIAO J J,ZHANG Y,et al.Pharmacokinetics and liver uptake of three Schisandra lignans in rats after oral administration of liposome encapsulating β-cyclodextrin inclusion compound of Schisandra extract[J].Journal of Liposome Research,2019,29(2):121-132.
[42] 时念秋,张勇,冯波,等.不同制备工艺制得姜黄素固体分散体的性质比较研究[J].中国药学杂志,2016,51(10):821-826. SHI N Q,ZHANG Y,FENG B,et al.Comparison of the properties of curcumin solid dispersions prepared by different technologies[J].Chinese Journal of Pharmacy,2016,51(10):821-826.(in Chinese)
[43] RICHARD J V,MATTEO B,CORNELIUS J C,et al.Combating resistance while maintaining innovation:The future of antimicrobial stewardship[J].Future Microbiology, 2019,14(15):1331-1341.
[44] 房诗薇,黄玲利,谢书宇,等.兽用抗菌药耐药判定标准的研究进展[J].中国抗生素杂志,2019,44(6):667-673. FANG S W,HUANG L L,XIE S Y,et al.Study progress on breakpoints of veterinary antibiotics[J].Chinese Journal of Antibiotics,2019,44(6):667-673.(in Chinese)
[45] 罗怡婧,黄桂婷,郑琴,等.药物固体分散体技术回顾与展望[J].中国药学杂志,2020,55(17):1401-1408. LUO Y J,HUANG G T,ZHENG Q,et al.Review and prospect of drug solid dispersion preparation technology[J].Chinese Journal of Pharmacy,2020,55(17):1401-1408.(in Chinese)
[46] YI P P,WANG Y F,ZHANG S H,et al.Stimulative nanogels with enhanced thermosensitivity for therapeutic delivery via β-cyclodextrin-induced formation of inclusion complexes[J].Carbohydrate Polymers,2017,166:219-227.
[47] YAKINDRA P T,TAIWO O,AKANBI K,et al.Complex coacervation:Principles,mechanisms and applications in microencapsulation[J].International Journal of Biological Macromolecules,2019,121:1276-1286.
[48] 邢桂英,邵林军.纳米载体在中药制剂经皮给药应用中的研究进展[J].华西药学杂志,2020,35(1):101-105. XING G Y,SHAO L J.Recent advance of nanocarriers in transdermal drug delivery of traditional Chinese medicine[J].West China Journal of Pharmacy,2020,35(1):101-105.(in Chinese)