1、临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology细菌耐药现状细菌耐药现状和抗菌药物合理应用和抗菌药物合理应用北京大学临床药理研究所北京大学临床药理研究所 北京大学第一医院北京大学第一医院 抗感染科抗感染科郑波郑波临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyIf you put a frog in
2、 boiling water,it is going to jump outIT WILL BOIL TO DEATH!If you put the frog in a pot of water,then slowly bring the water up to boil临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyK.pneumonia临临床床药药理理研研究究所所Peking
3、University Institute of Clinical PharmacologyLancet Infect Dis.Published online August 11,2010临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyAntimicrob Agents Chemother.2009,53(12):5046-54.临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking Unive
4、rsity Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyNDM-1全球分布情况全球分布情况Rolain JM.Clinical Microbiol.Infect.2010.0338
5、5.x临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology 细菌细菌 患者患者毒性毒性药代动力学药代动力学药效动力学药效动力学防御功能防御功能感染感染耐药耐药抗菌治疗三角抗菌药物抗菌药物临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology合理用药一般原则 5R原则：Right Drug to the Rig
6、ht Patient in the Right Dose by the Right Route at the Right Time.对适当的患者在恰当的时间按照正确的途径使用正确剂量的合适药物临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology抗菌药物作用靶位抗菌药物作用靶位临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology细菌耐药机制细菌耐药机制1 抗生素与细菌受体或靶部位结合的降低抗生素与细菌受体或靶部位结合的降低 -内酰胺类抗生
7、素内酰胺类抗生素糖肽类糖肽类夫西地酸夫西地酸喹诺酮类喹诺酮类2 产生破坏抗生素的酶产生破坏抗生素的酶-内酰胺类抗生素内酰胺类抗生素氯霉素氯霉素氨基糖苷类氨基糖苷类3 穿透细菌的能力降低穿透细菌的能力降低-内酰胺类内酰胺类喹诺酮类喹诺酮类氨基糖苷类氨基糖苷类4 泵出细菌将药物排出的能力增强泵出细菌将药物排出的能力增强四环素、喹诺酮类等四环素、喹诺酮类等 临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology爆破筒爆破筒：内装炸药的一段金属筒。由金属筒、炸药、导火索组成。碉堡：碉堡：军事上防守用的坚固建筑物，多用砖、石、
8、钢筋混凝土等建成。临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology黄继光黄继光 中国人民志愿军特级战斗英雄中国人民志愿军特级战斗英雄 临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyWhat are biofilms?Slimy matrix of bacteria that form in various aqueous environments临临床床药药理理研研究究所所Peking University Institute
9、 of Clinical PharmacologyBiofilm Formation临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyBiofilm Structure临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology生物膜(biofilm)形成临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology22.7%25.2%24.6%77.3%74.8%75.4
10、%0.0%20.0%40.0%60.0%80.0%100.0%200520082010G+G-临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyTop 5 Organisms0.0%4.0%8.0%12.0%16.0%20.0%2005 2008 2010 E.coliP.aeruginosaK.pneumoniaA.baummaniiS.aureus临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Pe
11、king University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyS.aureus临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyS.aureus临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyS.aureus临临床床药药理理研研究究所所Peking Univers
12、ity Institute of Clinical PharmacologyS.aureus临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologygrapeS.aureus临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyPenicillin 1941Methicillin 1959vancomycin 1958linezolid 2000PCase producing SA 1944MRSA 1961VRE 1986Palumbi,S
13、.R.,Science,293:1786-90,2001.VRSA 2002LRE 1999临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyMRSA在全球广泛流行Stefania Stefania.IJAA 2012 临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyMRSA 耐药机制 定义定义:头孢西丁头孢西丁 MIC 8ug/ml 对所有对所有 内酰胺类耐药内酰胺类耐药 mec 基因基因 葡萄球菌染色体基因盒葡萄球菌染色体基因
14、盒（staphylococcal chromosomal cassette，SCCmec)出现于所有出现于所有 MRSA 菌株中。菌株中。5种种 SCCmec 型型(I-V).I-III 型型 与医院感染相关与医院感染相关 IV,V 型型与社区感染相关与社区感染相关 mecA 编码编码PBP2a PBP2a可代替其他可代替其他 PBP功能生成肽聚糖功能生成肽聚糖.mecR1-mecI 调控调控mecA转录转录.临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology020406080100OXA FOXCZOCXAIM
15、P GEN AMK AZMCLI MNO LVXMXF VANTECRIF200520082010Antimicrobial Resistance in S.aureus临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology020406080100OXA FOXCZOCXAIMP GEN AMK AZMCLI MNO LVXMXF VANTECRIF200520082010Antimicrobial Resistance in S.epidermidis临临床床药药理理研研究究所所Peking University
16、Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyE.faecalis临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyE.faecalisE.faecalis临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyE.faecalis临临床床药药理理研研究究所所Peking Univers
17、ity Institute of Clinical PharmacologyE.faecalis临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyE.faecalis临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyPropotion of Enterococci in G+CocciMOHNARIN 临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology
18、55.947.847.847.736.641.142.742.30.020.040.060.080.0100.0Mohnarin 2005 Mohnarin 2007 Mohnarin 2009 Mohnarin 2010E.faecalisE.faeciumPropotion of E.faecalis and E.faecium in EnterococciMOHNARIN 临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyProminent Cause of Nosocomial Infections Se
19、cond most common bacterium isolated fromurinary tract infection and biliary infectionMOHNARIN,2010临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology0.0 20.0 40.0 60.0 80.0 100.0 AMPSAMERYTETMNOTGCLVXMFXLNZVANTECRIFCHLFOSNITGEHSTHE.faecalisE.faeciumComparison of Resistance in E.faeciu
20、m and E.faecalisMohanrin 2010临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology020406080100AMPMNOLVXERYRIFVANTEC200520082010Antimicrobial Resistance in E.faecalis临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology020406080100120AMPMNOLVXERYRIFVANTEC200520082010Antimicr
21、obial Resistance in E.faeciumMohanrin 2010临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology万古霉素耐药机制临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology美国院内感染中美国院内感染中VRE分离率分离率National Nosocomial Infections Surveillance(NNIS)System Data,1989-2007.临临床床药药理理研研究究所所Peking Uni
22、versity Institute of Clinical Pharmacology0.86.83.40.02.04.06.08.010.0GermanyGreeceIreland20052006200720082009欧洲万古霉素耐药欧洲万古霉素耐药粪肠球菌粪肠球菌分离率分离率www.rivm.nl/earss/database临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology42.515.337.80.020.040.060.080.0100.0GermanyGreeceIreland200520062007
23、20082009欧洲万古霉素耐药屎肠球菌分离率欧洲万古霉素耐药屎肠球菌分离率www.rivm.nl/earss/database临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology001.31.20.81.11.13.24.23.80246810SEANIR 2005CHINET 2006MOHNARIN 2007MOHNARIN 2009MOHNARIN 2010E.faecalisE.faecium我国临床VRE分离率临临床床药药理理研研究究所所Peking University Institute of Cl
24、inical Pharmacology万古霉素依赖肠球菌万古霉素依赖肠球菌vancomycin dependent enterococci临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology美国37.9%墨西哥27.5%德国16.2%西班牙35.3%加拿大14.0%法国53.9%日本77.2%中国73.9%全球肺炎链球菌对大环内酯的耐药形势全球肺炎链球菌对大环内酯的耐药形势Erythr
25、omycin resistant(MIC 1 mg/L).5、PROTEKT study HMR 3647A/v001-2000/2001.6、song AAC 2004临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology0.020.040.060.080.0100.0120.0PENAMX AMC CXMIMPCROFEPERYAZMCLILVXMFXVAN200520082010Antimicrobial Resistance in S.pneumonia 临临床床药药理理研研究究所所Peking Univer
26、sity Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyE.coli临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyE.coli临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyE.coli临临床床药药理理研研究究所所Peking University Institute of
27、Clinical Pharmacology0.020.040.060.080.0100.0AMX AMC PIPTZP CRO CZO CXM CAZ CFP CSL FEP IMP GEN AMK CIPLVX200520082010Antimicrobial Resistance in E.coli 临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology0.020.040.060.080.0100.0120.0AMX AMC PIPTZP CRO CZO CXM CAZ CFPCSLFEP IMP GEN AMK
28、 CIPLVX200520082010Antimicrobial Resistance in K.pneumonia临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology宿州眼球事件宿州眼球事件 2005年年12月月11日，宿州市立医院，为日，宿州市立医院，为10名患者名患者做白内障手术。结果做白内障手术。结果10名患者均出现感染情况名患者均出现感染情况，其中，其中9人的单眼眼球被摘除。
29、人的单眼眼球被摘除。临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyP.aeruginosa临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyP.aeruginosaP.aeruginosa临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyP.aeruginosaP.aeruginosa临临床床药药理理研研究究所所Peking University
30、Institute of Clinical PharmacologyP.aeruginosa临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology020406080100PIPTZPCAZCFPIMPCSLFEPAMKCIPLVX200520082010Antimicrobial Resistance in P.aeruginosa临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking Univers
31、ity Institute of Clinical Pharmacologyhttp:/www.acinetobacterbaumannii.org临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyA.baumannii临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyA.baumannii临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyA.baum
32、annii临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology7.0020406080100PIPTZPCAZCFPIMPCSLFEPAMKMNOCIPLVX200520082010Antimicrobial Resistance in A.baummanii临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology0.020.040.060.080.0100.0120.0AMPSAMPIPTZPCROCTXCAZCFPCSLFEPIMPME
33、MGENAMKTETMNOTGCPOLCIPLVXSMZIMP-SIMP-NSAntimicrobial Resistance in A.baummaniiMohanrin 2010临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyIMIPENEM0.0 10.0 20.0 30.0 40.0 50.0 60.0 E.coliE.cloacaeK.pneumoniaP.aeruginosaA.baumannii200520082010临临床床药药理理研研究究所所Peking University Institut
34、e of Clinical PharmacologyCiprofloxacin0.0 20.0 40.0 60.0 80.0 E.coliE.cloacaeK.pneumoniaP.aeruginosaA.baumannii200520082010临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology0.0 10.0 20.0 30.0 40.0 50.0 E.coliE.cloacaeK.pneumoniaP.aeruginosaA.baumannii200520082010Cefoperazone/sulbact
35、am临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyPiperacillin/tazobactam0.0 20.0 40.0 60.0 80.0 E.coliE.cloacaeK.pneumoniaP.aeruginosaA.baumannii200520082010临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology药物在人体中药物在人体中的吸收、分布、的吸收、分布、代谢和清除的代谢和清除的过程，是药物过程，是药物作用与抗菌效作用
36、与抗菌效果以及体外药果以及体外药代动力学参数代动力学参数与杀菌效果的与杀菌效果的关系关系药物在体内药物在体内发挥的作用，发挥的作用，涉及药物的涉及药物的浓度与药理浓度与药理作用、毒副作用、毒副反应之间的反应之间的关系关系血浆浓度血浆浓度-时时间曲线中的间曲线中的曲线下面积曲线下面积血浆中药物血浆中药物的峰浓度的峰浓度药物的半药物的半衰期衰期MIC药效动力学药效动力学(AUC)Cmax药代动力学药代动力学和药效动力学和药效动力学(PK&PD)及其参数及其参数TMIC药物血浆浓度药物血浆浓度高于高于MIC的时的时间比例间比例杀菌效应作用杀菌效应作用的时间的时间病原菌的病原菌的清除率清除率耐药菌的发
37、耐药菌的发生率生率药代动力学药代动力学临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology药代动力学和药效动力学(PK PD)最佳治疗方案最佳治疗方案最佳疗效最佳疗效减少耐药减少耐药最低毒性最低毒性PK微生物学微生物学PD临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyPK/PD对临床疗效评价的作用2.Pai AB et al.Advances in Chronic Kidney Disease,Vol 13,No 3(July),
38、2006:pp 259-270仅靠仅靠PK或或PD单方面无法全面地评价和估计抗生素的杀菌效应，单方面无法全面地评价和估计抗生素的杀菌效应，通常都将两者结合起来对药物进行考察，然后制定给药方案通常都将两者结合起来对药物进行考察，然后制定给药方案临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology杀菌效果与抗菌药物浓度关系0246864 x M IC16 x M IC4 x M IC1 x M IC0.25 x M ICControlTim e (hours)02460246Log10 cfu/mL23456789妥布
39、霉素妥布霉素环丙沙星环丙沙星替卡西林替卡西林临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology-内酰胺类体内试验Time Above MIC(%of Interval)020406080100Mortality(%)020406080100Cephalosporins PenicillinsCraig WA,Andes D.Inter J Antimicrob Agents 2002;19:261-8Craig WA,Andes D.Pediatr Infect Dis J 1996;15:255-9 Dagan
40、 R,et al.J Infect Dis.1997;176:1253-9Time Above MIC(%)020406080100Bacterial Eradication(%)020406080100PSSPPISP-PRSPH.influenza临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyCorrelation of PK/PD Parameters with Efficacy of Levofloxacin against Streptococcus pneumoniaein Thighs of N
41、eutropenic Mice 24-hr AUC/MIC101001000Log10 CFU/Thigh at 24 hours0246810Peak/MIC1101001000Time Above MIC0255075100Andes D,Craig WA.Int J Antimicrob Agents 2002;19:261-8临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology24-hour AUC/MIC and Mortality for Fluoroquinolones against Strepto
42、coccus pneumoniae in Non-Neutropenic Animal Models24-hour AUC/MIC12.510251002501000Mortality (%)020406080100Andes D.,Craig W.A.Int J Antimicrob Agents 2002;19:261-8临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology浓度依赖性抗生素(AUC/MIC)AUC/MICAUC/MIC有效有效率率%临临床床药药理理研研究究所所Peking University
43、Institute of Clinical Pharmacology抗菌药物的杀菌作用特性与抗菌药物的杀菌作用特性与PK/PD参数参数杀菌特征杀菌特征PAEPK/PD参数参数抗菌药物抗菌药物时间依赖短T MIC-内酰胺类短AUC/MIC利奈唑烷长AUC/MIC大环内酯类,林可霉素,四环素类长Cmax/MIC糖肽类浓度依赖短AUC/MIC多粘菌素长AUC/MIC氨基糖苷类,喹诺酮类,达托霉素Cmax/MIC链阳霉素,酮内酯类John Turnidge.Clin Micro Rev.2007临临床床药药理理研研究究所所Peking University Institute of Clinical
44、Pharmacology2株/十亿MIC200株/十亿20 000株/10亿免疫功能抑制既往感染既往抗生素使用突破免疫系统耐药突变的选择性扩增耐药突变的选择性扩增有效清除健康免疫系统急性感染/治疗失败时间Hansen&Blondeau 2002临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyMPC控制耐药突变的选择性扩增控制耐药突变的选择性扩增耐药突变的选择性扩增。在感染期间，敏感菌株和首步耐药突变菌株均存在，当药物剂量达到MPC水平时，则可通过药物溶解作用直接清除感染，或通过免疫系统促进清除感染。直接清除直接
45、清除感染感染在免疫系统帮助下在免疫系统帮助下控制和清除感染控制和清除感染控制耐药控制耐药突变株突变株MPC 野生型菌株耐药突变株临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology用药后时间血清或组织药物浓度MSW是介于MIC与MPC之间的范围MSW Mutation selection window，耐药选择窗药物浓度在该范围内时抗生素敏感菌株被抑制不能抑制发生第一步突变的菌株耐药菌株亚群选择性增殖临临床床药药理理研研究究所所Peking University Institute of Clinical Phar
46、macology200090807060504030Discovery and approval of new antibacterial agents in Japan per 5-year period from 1930 to 2005临临床床药药理理研研究究所所Peking University Institute of Clinical PharmacologyNathan,C.Antibiotics at the crossroads.,Nature,431:899-902,2004.临临床床药药理理研研究究所所Peking University Institute of Clin
47、ical Pharmacology抗菌药物的选择性压力Selective Pressure of Antibotics临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology嘿，我们只吃绿虫子！临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University I
48、nstitute of Clinical Pharmacology1敏感菌耐药菌死菌23临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology冰山现象冰山现象感染菌株感染菌株定植菌株定植菌株临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology病原体环境中存活时间病原体环境中存活时间临临床床药药理理研研究究所所
49、Peking University Institute of Clinical Pharmacology临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology总结 细菌耐药形式严峻 根据流行病学和临床资料临床资料估计可能病原体，应重视细菌培养细菌培养和和耐药监测耐药监测 根据病情严重程度严重程度、当地药敏资料药敏资料选择合适的抗菌药物 根据PK/PD特性及患者生理状况生理状况合理安排治疗方案临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology 细菌细菌 患者患者毒性毒性药代动力学药代动力学药效动力学药效动力学防御功能防御功能感染感染耐药耐药抗菌治疗三角抗菌药物抗菌药物临临床床药药理理研研究究所所Peking University Institute of Clinical Pharmacology谢 谢郑波郑波
