兽用抗菌药物联合用药的PK-PD研究进展

doi:10.16431/j.cnki.1671-7236.2020.01.033

摘要/Abstract

摘要： 随着养殖业的迅速发展，兽用抗菌药物的应用越来越广泛，但由于抗菌药物的不合理选择与滥用导致细菌对抗菌药物的耐药率在逐渐提高，几乎所有细菌都获得耐药基因。目前，细菌耐药已成为一个全球性问题，并且临床上，疾病病因复杂，常表现为多种病原菌的继发感染和混合感染，单一用药往往难以有效控制疾病，严重危害养殖业发展。抗菌药物的联合用药可以提升药物的治疗效果，缓解或减少不良反应，降低细菌耐药性发生率，对混合感染或不能进行细菌学诊断的病例，联合用药还可扩大抗菌范围。而药物代谢动力学（PK）与药效学（PD）结合模型可以有效综合药物、机体和致病菌之间的相互关系，为临床提供合理用药方案。因此，作者通过介绍联合用药的优势与问题，抗菌药物PK/PD的分类及PK/PD对联合用药给药方案的优化与指导，总结现阶段兽药抗菌药物联合用药的PK-PD研究进展，以期促进兽医临床抗菌药物的合理使用。

关键词: 抗菌药物; 联合用药; PK/PD

Abstract: With the rapid development of the breeding industry,the application of veterinary antibacterial drugs is more and more extensive.However,due to the unreasonable selection and abuse of antimicrobial drugs,the resistance rate of bacteria to antimicrobial drugs is gradually increasing,and almost all bacteria have acquired resistance genes.At present,bacterial resistance has become a global problem,and clinically,the cause of the disease is complex,often manifested as a variety of pathogens secondary infection and mixed infection,single drug is often difficult to effectively control the disease,seriously endangering the development of aquaculture.The combination of antibiotics can improve the therapeutic effect of drugs,alleviate or reduce adverse reactions,reduce the incidence of bacterial resistance.For cases of mixed infection or unable to carry out bacteriological diagnosis,the combination of antibiotics can also expand the scope of antibacterial.The combination model of PK and PD can effectively integrate the relationship among drugs,organism and pathogenic bacteria,and provide a reasonable medication plan for clinical use.Therefore,by introducing the advantages and problems of the combination of drugs,the classification of PK/PD and the optimization and guidance of PK/PD on the combination of drugs,this paper summarizes the research progress of PK-PD on the combination of veterinary drugs and antibacterial drugs at present,in order to promote the rational use of veterinary clinical antibacterial drugs.

Key words: antibacterial drugs; combination drug; PK/PD

中图分类号:

S859

袁园园, 黄玲利, 郝海红, 刘振利, 谢长清, 袁宗辉, 彭大鹏. 兽用抗菌药物联合用药的PK-PD研究进展[J]. 中国畜牧兽医, 2020, 47(1): 282-289.

YUAN Yuanyuan, HUANG Lingli, HAO Haihong, LIU Zhenli, XIE Changqing, YUAN Zonghui, PENG Dapeng. Progress in PK-PD Research on the Combination of Veterinary Antibacterial Drugs[J]. China Animal Husbandry and Veterinary Medicine, 2020, 47(1): 282-289.

参考文献

[1] ENGEL E,RATEL J,BOUHLEL J,et al.Novel approaches to improving the chemical safety of the meat chain towards toxicants[J].Meat Science,2015,109:75-85.
[2] ASLAM B,WANG W,ARSHAAD M I,et al.Antibiotic resistance:A rundown of a global crisis[J].Infection and Drug Resistance,2018,11:1645-1658.
[3] JONES R N,PFALLER M A.Bacterial resistance:A worldwide problem[J].Diagnostic Microbiology and Infectious Disease,1998,31(2):379-388.
[4] AYUKEKBONG J A,NTEMGWA M,ATABE A N.The threat of antimicrobial resistance in developing countries:Causes and control strategies[J].Antimicrobial Resistance & Infection Control,2017,6,1:47.
[5] NIELSEN E I,FRIBERG L E.Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs[J].Pharmacological Reviews,2013,65(3):1053-1090.
[6] 李冰,张继瑜,李剑勇,等.PK-PD结合模型及其在兽用抗菌药研究中的应用[J].畜牧与兽医,2010,42(6):92-96. LI B,ZHANG J Y,LI J Y,et al.PK-PD combination model and its application in research on veterinary antibiotics[J].Animal Husbandry and Veterinary Medicine,2010,42(6):92-96.(in Chinese)
[7] TUNTLAND T,ETHELL B,KOSAKA T,et al.Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at novartis institute of biomedical research[J].Frontiers in Pharmacology,2014,5:174.
[8] HUGHES D,KARLEN A.Discovery and preclinical development of new antibiotics[J].Upsala Journal of Medical Science,2014,119(2):162-169.
[9] CUNHA C B,OPAL S M.Antibiotic stewardship:Strategies to minimize antibiotic resistance while maximizing antibiotic effectiveness[J].Medical Clinics of North America,2018,102(5):831-843.
[10] LEE C R,CHO I H,JEONG B C,et al.Strategies to minimize antibiotic resistance[J].International Journal of Environmental Research & Public Health,2013,10(9):4274-4305.
[11] OLIVER A,PEREZ-VAZQUEZ M,MARTINEZ-FERRER M,et al.Ampicillin-sulbactam and amoxicillin-clavulanate susceptibility testing of Escherichia coli isolates with different β-lactam resistance phenotypes[J].Antimicrob Agents Chemother,1999,43(4):862-867.
[12] LIMA T B,SILVA O N,DE ALMEIDA K C,et al.Antibiotic combinations for controlling colistin-resistant enterobacter cloacae[J].The Journal of Antibiotics,2017,7(2):122-129.
[13] 胡功政,苑丽,刘智明,等.氟苯尼考及其与多西环素联合的体外抗菌作用[J].中国兽医学报,2004,4:379-383. HU G Z,YUAN L,LIU Z M,et al.Antibacterial activity of florfenicol and it’s combinations with doxycycline in vitro[J].Chinese Journal of Veterinary,2004,4:379-383.(in Chinese)
[14] SUZUKI S,HORINOUCHI T,FURUSAWA C.Acceleration and suppression of resistance development by antibiotic combinations[J].BMC Genomics,2017,18(1):328.
[15] 孟思妤,孟长明,陈昌福.盐酸多西环素与氟苯尼考联合用药离体抗鮰爱德华菌的作用[J].渔业致富指南,2014,16:72-73. MENG S Y,MENG C M,CHEN C F.Benzene nicol,doxycycline hydrochloride and fluorine combination in vitro anti the role of Edward bacteria[J].Journal of Rich Fishing Guide,2014,16:72-73.(in Chinese)
[16] CHEESMAN M J,ILANKO A,BLONK B,et al.Developing new antimicrobial therapies:Are synergistic combinations of plant extracts/compounds with conventional antibiotics the solution?[J].Pharmacognosy Reviews,2017,11(22):57-72.
[17] BERTERA F M,MAYER M A,OPEZZO J A,et al.Pharmacokinetic-pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats:A microdialysis study[J].Journal of Pharmacological and Toxicological Methods,2007,56(3):290-299.
[18] 张英丰,董宇,朱晓新.中药复方药代动力学研究的方法与思考[J].中国天然药物,2008,5:321-324. ZHANG Y F,DONG Y,ZHU X X.Methods and thoughts on the study of pharmacokinetics of traditional Chinese medicine compounds[J].Chinese Natural Medicine,2008,5:321-324.(in Chinese)
[19] NIELSEN E I,CARS O,FRIBERG L E.Pharmacokinetic/pharmacodynamic (PK/PD) indices of antibiotics predicted by a semimechanistic PKPD model:A step toward model-based dose optimization[J].Antimicrobial Agents and Chemotherapy,2011,55(10):4619-4630.
[20] KINGWELL K.Antibacterial agents:New antibiotic hits gram-negative bacteria[J].Nature Reviews Drug Discovery,2018,17(11):785.
[21] LEVISON M E,LEVISON J H.Pharmacokinetics and pharmacodynamics of antibacterial agents[J].Infectious Disease Clinics of North America,2009,23(4):791-815.
[22] FINCH N A,ZASOWSKI E J,MURRAY K P,et al.A quasi-experiment to study the impact of vancomycin area under the concentration-time curve-guided dosing on vancomycin-associated nephrotoxicity[J].Antimicrobial Agents and Chemotherapy,2017,61(12):e01293-17.
[23] BLONDEAU J M,DEBOER D J,AFFOLTER V K,et al.New concepts in antimicrobial susceptibility testing:The mutant prevention concentration and mutant selection window approach[J].Veterinary Dermatology,2009,20(5-6):383-396.
[24] LEEKHA S,TERRELL C L,EDSON R S.General principles of antimicrobial therapy[J].Mayo Clinic Proceedings,2011,86(2):156-167.
[25] TOUTAIN P L,BOUSQUET-MELOU A,DAMBORG P,et al.En route towards European clinical breakpoints for veterinary antimicrobial susceptibility testing:A position paper explaining the VetCAST approach[J].Frontiers in Microbiology,2017,8:2344.
[26] 董凤勇.时间依赖性与浓度依赖性抗菌药物的比较[J].医学信息,2016,29(4):380-381. DONG F Y.Comparison of time-dependent and concentration-dependent antimicrobial agents[J].Medical Information,2016,29(4):380-381.(in Chinese)
[27] ROBERTS J A,NORRIS R,PATERSON D L,et al.Therapeutic drug monitoring of antimicrobials[J].British Journal of Clinical Pharmacology,2012,73(1):27-36.
[28] RYBAK M J.Pharmacodynamics:Relation to antimicrobial resistance[J].American Journal of Medicine,2006,34(5):S38-S45.
[29] FRIMODT-MOLLER N.How predictive is PK/PD for antibacterial agents?[J].International Journal of Antimicrobial Agehts,2002,19(4):333-339.
[30] SARKAR P,YARLAGADDA V,GHOSH C,et al.A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics[J].Medicinal Chemistry Communications,2017,8(3):516-533.
[31] KOHANSKI M A,DWYER D J,COLLINS J J.How antibiotics kill bacteria:From targets to networks[J].Nature Reviews Microbiology,2010,8(6):423-435.
[32] COUSSENS N P,MOLINARO A L,CULBERTSON K J,et al.Better living through chemistry:Addressing emerging antibiotic resistance[J].Experimental Biology and Medicine,2018,243(6):538-553.
[33] YAN L,XIE S,CHEN D,et al.Pharmacokinetic and pharmacodynamic modeling of cyadox against Clostridium perfringens in swine[J].Scientific Reports,2017,7(1):4064.
[34] 左儒楠,刘筱,王雅倩,等.复方庆大霉素注射液的质量控制及体外抑菌效果[J].中国兽医科学,2018,5:649-657. ZUO R N,LIU S,WANG Y Q,et al.Quality control and antibacterial activity in vitro of compound gentamicin injection[J].Chinese Veterinary Science,2018,5:649-657.(in Chinese)
[35] SHAH S,BARTON G,FISCHER A.Pharmacokinetic considerations and dosing strategies of antibiotics in the critically ill patient[J].Journal of the Intensive Care Society,2015,16(2):147-153.
[36] LEIGUE L,MONTIANI-FERREIRA F,MOORE B A.Antimicrobial susceptibility and minimal inhibitory concentration of Pseudomonas aeruginosa isolated from septic ocular surface disease in different animal species[J].Open Veternary Journal,2016,6(3):215-222.
[37] UPRETI V V,BARBOUR A M.Antibiotics development and the emergence of resistance:Clinical pharmacology to the rescue[J].Journal of Clinical Pharmacology,2018,58(4):409-411.
[38] COLAKOGLU E C,BORKU K,HAYDARDEDEOGLU A E,et al.Correlation between endoscopic and histopathological findings in dogs with chronic gastritis[J].Journal of Veterinary Research,2017,61(3):351-355.
[39] FAIR R J,TOR Y.Antibiotics and bacterial resistance in the 21st century[J].Perspectives in Medicinal Chemistry,2014,6(6):25-64.
[40] LAPPIN M R,BLONDEAU J,BOOTHE D,et al.Antimicrobial use guidelines for treatment of respiratory tract disease in dogs and cats:Antimicrobial guidelines working group of the international society for companion animal infectious diseases[J].Journal of Veterinary Internal Medicine,2017,31(2):279-294.
[41] HILLIER A,LLOYD D H,WEESE J S,et al.Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial guidelines working group of the international society for companion animal infectious diseases)[J].Veterinary Dermatology,2014,25(3):163-e43.
[42] COLE M R,HOBDEN J A,WARNER I M.Recycling antibiotics into GUMBOS:A new combination strategy to combat multi-drug-resistant bacteria[J].Molecules,2015,20(4):6466-6487.
[43] ONUFRAK N J,FORREST A,GONZALEZ D.Pharmacokinetic and pharmacodynamic principles of anti-infective dosing[J].Clinical Therapeutics,2016,38(9):1930-1947.
[44] HOUSMAN S T,KUTI J L,NICOLAU D P.Optimizing antibiotic pharmacodynamics in hospital-acquired and ventilator-acquired bacterial pneumonia[J].Clinics in Chest Medicine,2011,32(3):439-450.
[45] AZOULAY-DUPUIS E,MOHLER J,BEDOS J P,et al.Efficacy of cethromycin,a new ketolide,against streptococcus pneumoniae susceptible or resistant to erythromycin in a murine pneumonia model[J].Antimicrobial Agents And Chemotherapy,2006,50(9):3033-3038.
[46] TAMMA P D,COSGROVE S E,MARAGAKIS L L.Combination therapy for treatment of infections with gram-negative bacteria[J].Clinical Microbiology Reviews,2012,25(3):450-470.
[47] LAXMINARAYAN R,DUSE A,WATTAL C,et al.Antibiotic resistance-the need for global solutions[J].The Lancet Infectious Diseases,2013,13(12):1057-1098.
[48] WORTHINGTON R J,MELANDER C.Overcoming resistance to β lactam antibiotics[J].The Journal of Organic Chemistry,2013,78(9):4207-4213.
[49] LISTER P D.β-lactamase inhibitor combinations with extended-spectrum penicillins:Factors influencing antibacterial activity against Enterobacteriaceae and Pseudomonas aeruginosa[J].Pharmacotherapy,2000,20(9Pt2):213S-218S.
[50] VIANA M D A,MACHADO S E F,EBINUMA V C S,et al.Production of β-lactamase inhibitors by streptomyces species[J].Antibiotics,2018,7(3):61.
[51] HYATT J M,NIX D E,STRATTON C W,et al.In vitro pharmacodynamics of piperacillin,piperacillin-tazobactam,and ciprofloxacin alone and in combination against Staphylococcus aureus,Klebsiella pneumoniae,Enterobacter cloacae,and Pseudomonas aeruginosa[J].Antimicrobial Agents and Chemotherapy,1995,39(8):1711-1716.
[52] DRAWZ S M,BONOMO R A.Three decades of beta-lactamase inhibitors[J].Clinical Microbiology Reviews,2010,23(1):160-201.
[53] AL-HASAN M N,WILSON J W,LAHR B D,et al.β-lactam and fluoroquinolone combination antibiotic therapy for bacteremia caused by Gram-negative bacilli[J].Antimicrobial Agents and Chemotherapy,2009,53(4):1386.
[54] COLEMAN K,LEVASSEUR P,GIRARD A M,et al.Activities of ceftazidime and avibactam against β-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model[J].Antimicrobial Agents and Chemotherapy,2014,58(6):3366-3372.
[55] LEVISON,MATTHEW E.Pharmacodynamics of antimicrobial drugs[J].Infectious Disease Clinics of North America,2004,18(3):451-465.
[56] CZOCK D,MARKERT C,HARTMAN B,et al.Pharmacokinetics and pharmacodynamics of antimicrobial drugs[J].Expert Opinion on Drug Metabolism & Toxicology,2009,5(5):475-487.
[57] KARPIUK I,TYSKI S.Looking for the new preparations for antibacterial therapy Ⅲ.New antimicrobial agents from the quinolones group in clinical trials[J].Przeglad Epidemiologiczny,2013,67(3):455-460.
[58] DATTA R,WANG T,ZHU M,et al.Antimicrobial therapy for asymptomatic bacteriuria or candiduria in advanced cancer patients transitioning to comfort measures[J].Infection Control and Hospital Epidemiology,2019,40(4):1-3.
[59] LOUIE A,LIU W,FIKES S,et al.Impact of meropenem in combination with tobramycin in a murine model of Pseudomonas aeruginosa pneumonia[J].Antimicrobial Agents and Chemotherapy,2013,57(6):2788-2792.
[60] GUILLOU J M L,WOLFF M,FARINOTTI R,et al.In vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia[J].Journal of Antimicrobial Chemotherapy,2000,46(5):827-830.
[61] 吴波,段龙川,罗厚强.磺胺间甲氧嘧啶与恩诺沙星联合用药对黄羽肉鸡常见病原菌的药敏试验[J].养殖与饲料,2014,12:30-32. WU B,DUAN L C,LUO H Q.Susceptibility test of sulfamethoxazole combined with enrofloxacin on common pathogens of yellow-feathered broilers[J].Animals Breeding and Feed,2014,12:30-32.(in Chinese)
[62] 张巧艳,林晶,毛江昌,等.环丙沙星和磺胺间甲氧嘧啶联合用药在猪体内的血浆药动学[J].中国兽医学报,2014,34(4):601-605. ZHANG Q Y,LIN J,MAO J C,et al.Pharmacokinetics of ciprofloxacin and sulfamonomethoxine by combinational injection in swine[J].Chinese Journal of Veterinary Science,2014,34(4):601-605.(in Chinese)
[63] FU G,PENG J,WANG Y,et al.Pharmacokinetics and pharmacodynamics of sulfamethoxazole and trimethoprim in swimming crabs (Portunus trituberculatus) and in vitro antibacterial activity against Vibrio:PK/PD of SMZ-TMP in crabs and antibacterial activity against Vibrio[J].Environmental Toxicology & Pharmacology,2016,46:45-54.