预防抗生素附加损害优化抗感染经验治疗课件（可编辑）

预防抗生素附加损害优化抗感染经验治疗课件预防抗生素附加损害优化抗感染经验治疗内容抗生素的附加损害国内细菌耐药状况抗生素治疗选择原则抗生素干预试验总结抗生素应用带来的附加损害一种令人忧心的趋势附加损害定义指由抗菌药物治疗引起的细菌生态学损害及不良反应包括筛选出耐药菌株筛选出MDR菌株筛选出致病性增加的菌株促进定植以及增加感染菌株致病能力有关附加损害的文献报道抗生素附加损害的发生机理产ESBLS菌株与三代头孢菌素的相关性MRSA的发生率与三代头孢使用量的关系VRE与四代头孢菌素的相关性一项抗菌药物消费量与耐药趋势的相关性研究抗菌药物消费量的变化头孢他啶9600G99G头孢噻肟6314G732G头孢吡肟0G5396G结果VRE的检出率1926结论VRE检出率的增加与头孢吡肟使用量增加相关MDR绿脓杆菌与碳青霉烯类的相关性小结抗生素治疗的附加损害导致细菌耐药问题国内大规模细菌流行病学及耐药监测研究国内大型细菌耐药监测项目CMSS住友全国10家教学医院耐药监测SEANIR施贵宝全国院内G菌耐药监测CARES惠氏中国院内感染的抗生素耐药监测计划2006年SEANIR监测515株大肠杆菌CARES20062007284株大肠杆菌2006年SEANIR监测429株肺炎克雷伯菌CARES20062007149株肺克2006年SEANIR422株绿脓2006年SEANIR392株鲍曼CARES20062007122株鲍曼不动杆菌抗生素治疗选择原则起始适当抗感染经验治疗考虑因素下呼吸道感染的常见致病菌ICU获得性感染的常见致病菌金黄色葡萄球菌30铜绿假单胞菌29凝固酶阴性葡萄球菌19大肠杆菌13肠球菌12腹腔内感染常见致病菌致病菌检出率1大肠杆菌65变形杆菌属25克雷伯氏菌属20假单胞菌属15肠球菌15脆弱类杆菌80类杆菌属30梭状芽胞杆菌属65消化链球菌属25消化球菌属15梭状菌属20起始适当抗感染经验治疗考虑因素从所在医院细菌室的病原学数据及耐药数据革兰阴性菌超广谱B内酰胺酶ESBLS产I型酶AMPC酶克雷伯氏菌大肠杆菌绿脓杆菌肠杆菌属不动杆菌起始适当抗感染经验治疗考虑因素药代动力学药效学参数抗生素疗效的PKPD参数时间依赖性血药浓度高于MIC的时间浓度依赖性峰值浓度CMICAUCMICAUICTMIC的最大化增加每次给药量增加每日给药次数延长点滴时间或持续给药哌拉西林三唑巴坦间断VS持续给药临床疗效比较对付MDR绿脓延长给药效果起始适当抗感染经验治疗考虑因素2005年美国胸科协会ATS推荐的迟发或有耐药菌危险因素的HAPVAPHCAP的初始经验用抗生素可能致病菌早发型致病菌和下列多重耐药菌铜绿假单胞菌肺炎克雷伯菌ESBL不动杆菌早发型致病菌包括肺炎链球菌流感嗜血杆菌抗生素敏感的大肠肺克肠杆菌属等MRSA抗生素治疗方案抗铜绿假单胞菌的头孢类他啶吡肟或抗铜绿假单胞菌的碳氢酶烯类或抗铜绿假单胞菌的哌拉西林三唑巴坦加抗铜绿假单胞菌的氟喹诺酮类或氨基糖苷类加万古霉素或立奈唑烷2003年美国感染病学会IDSA腹腔内感染抗生素治疗指南治疗种类轻中度感染中重度感染单一用药内酰胺酶抑制剂氨苄西林舒巴坦哌拉西林三唑巴坦特治星复合制剂替卡西林克拉维酸碳青酶烯类厄他培南亚胺培南西司他丁美罗培南联合用药以头孢类为基础头孢唑林钠或34代头孢菌素头孢吡肟头孢呋新甲硝唑头孢他啶头孢塞肟头孢曲松甲硝唑以氟喹诺酮为基础环丙沙星或左氧沙星环丙沙星甲硝唑莫西沙星加替沙星甲硝唑以单环类为基础氨曲南甲硝唑起始适当抗感染经验治疗考虑因素预防抗生素附加损害抗生素对B内酰胺酶的诱导弱中度高度羧苄西林替卡西林头孢唑林头孢西丁头孢噻肟头孢哌酮头孢曲松头孢他啶亚胺培南克拉维酸盐舒巴坦三唑巴坦哌拉西林起始适当抗生素经验治疗改善严重感染患者预后的最重要措施减少细菌耐药的抗生素干预试验如何在选择预防感染的药物时避免附加损害如何在有效的经验治疗同时避免附加损害如何在选择目标治疗的药物时预防附加损害抗菌药物干预定义是指针对细菌耐药以治疗耐药菌感染控制耐药菌流行为目的策略性选择应用抗菌药物的临床用药方案抗菌药物干预策略主要包括采取减少三代头孢菌素的使用等措施有效地预防并减少ESBLS的发生和耐万古霉素肠球菌VRE的发生策略性选择应用抗菌药物的临床用药方案它的目的有两个就是把所治疗的感染控制下来而又不诱导细菌耐药的出现治病救人不扔垃圾西班牙巴塞罗那BELLVITGE医院抗生素干预策略的成效国外多项抗菌药物研究结果三代头孢是ESBLS和AMPC酶的强诱导剂目前细菌对哌拉西林三唑巴坦耐药的主要原因过度使用三代头孢菌素后诱导细菌产ESBLS和AMPC酶造成的多重耐药和交叉耐药而不是使用哌拉西林三唑巴坦引起产ESBL和AMPC酶细菌在不同病人间的交叉感染造成了耐药菌分离率高哌拉西林可能诱导青霉素酶的产生三唑巴坦对青霉素酶的抑制活性很强哌拉西林三唑巴坦的诱导性极低哌拉西林三唑巴坦使用三代头孢用量去除ESBLS和AMPC酶的诱导因素降低产ESBLS和AMPC细菌的分离率降低多重耐药菌分离率和交叉感染机会哌拉西林三唑巴坦耐药率降低三代头孢敏感性恢复抗生素干预替代三代头孢用药的选择总结9088212118B102B期627212427986期188ES2人群9388612114A105B期7676024240100期205ES1人群未获得例数率获得例数率例数研究阶段产超广谱内酰胺酶大肠埃希菌获得率中国医院使用哌拉西林三唑巴坦进行抗生素干预的结果赵宗珉陈佰义等中华内科杂志2007年第9期714717可评价人群集1ES1至少进行过2次直肠拭子检查的患者可评价人群集2ES2至少进行过2次直肠拭子检查且在筛查期间或住院期间至少有一次未检出ESBL的患者三代头孢菌素诱导细菌对哌拉西林三唑巴坦耐药的原因JANEPATTERSONETALINFECTIONCONTROLANDHOSPITALEPIDEMIOLOGYVOL21NO72000哌拉西林三唑巴坦用量增加耐药率降低的合理解释JANEPATTERSONETALINFECTIONCONTROLANDHOSPITALEPIDEMIOLOGYVOL21NO72000对厌氧菌活性抗生素干预使用文献报道降低ESBL发生率耐亚胺培南绿脓杆菌爆发耐亚胺培南药鲍曼不动杆菌爆发降低ESBL发生率恢复三代敏感性但引起VRE显著上升降低ESBLVREMRSACDAD发生率同时恢复三代敏感性药物本身耐药率以降低抗生素干预使用后结果重度感染中重度感染中重度感染临床疗效对绿脓杆菌活性对ESBL活性广包括厌氧菌肠球菌和难辨梭菌较广对厌氧菌肠球菌和难辨梭菌无效广包括厌氧菌肠球菌难辨梭菌抗菌谱亚胺培南头孢吡肟哌拉西林三唑巴坦RAHALETALJAMA1998280123337SMITHETAL1999CHESTKERRYMEMPEYETALPHARMACOTHERAPY22181872002国内细菌耐药状况堪忧抗生素治疗引起的附加损害越来越严重优化抗感染经验治疗是抗感染治疗的目标哌拉西林三唑巴坦替代三代头孢菌素可以有效减少三代头孢菌素引起的耐药未来抗微生物感染治疗的关键在于控制致病原的进化而不是只针对致病原的治疗药物本身最可能的部位病原菌借鉴治疗指南药物的PKPD预防抗生素附加损害细菌流行病学及耐药性科室单位地区G绿脓及其他假单胞菌大肠变形杆菌等G肺炎球菌MRSA医院获得性肺炎G肺炎链金葡化脓性链球菌G流感嗜血其他如厌氧菌等社区获得性肺炎同上支气管扩张合并感染G肺炎球菌葡萄球菌属溶血性链球菌属G肠杆菌科肺炎杆菌流感绿脓等急慢性支气管炎致病菌各种感染1GORVACHSLJANTIMICROBCHEMOTHER3167781993需氧菌厌氧菌多为需氧菌和厌氧菌的混合感染最可能的部位病原菌借鉴治疗指南药物的PKPD预防抗生素附加损害细菌流行病学及耐药性科室单位地区目前耐药致病菌趋势革兰阳性菌耐甲氧西林金葡菌MRSA耐万古霉素肠球菌VRE耐青霉素肺炎链球菌PRSP艰难梭菌耐喹诺酮淋球菌大肠杆菌绿脓杆菌ESBLS的数量种类在上升VRE日益增多艰难梭菌相关性腹泻CDAD发生率和死亡率日益增加最可能的部位病原菌借鉴治疗指南药物的PKPD预防抗生素附加损害细菌流行病学及耐药性科室单位地区时间小时数浓度最小抑制浓度0峰值最小抑制浓度氨基糖苷类曲线下面积最小抑制浓度氟喹诺酮类时间最小抑制浓度内酰胺类大环内酯类CRAIGWACLININFECTDIS261121998AMBROSEPGOWENSRCGRASELADMEDCLINNORTHAMERICAINPRESS时间依赖型抗生素PKPD内酰胺类大环内酯类克林霉素万古霉素决定抗生素疗效的主要参数是血药浓度高于MIC的时间即TMIC要求达到2次给药间隙时间的4060严格按照每日给药次数给药不应随意减少给药次数和延长给药间隔TMIC达到4050时细菌清除率可达85以上内酰胺类抗生素选择充足的用量安全性高的药物选择抗菌活性更为优异的抗菌药MIC值低的药物持续静脉点滴间断静脉点滴P值到不发热天数1208N172415N130012到白细胞计数正常天数2824N183922N130065临床治愈94820081微生物清除91750092GRANTEMETALPHARMACOTHERAPY20022247148389813724哌拉西林三唑巴坦45GQ6H243807564哌拉西林三唑巴坦45GQ8H50881841美罗培南2GQ8H67838771美罗培南1GQ8H27720693亚安培南1GQ8H48792744头孢吡肟2GQ8H41712671CEFEPIME1GQ8H延长输注30MINUTE输注杀菌累计分数杀菌累计分数CFR抗生素方案SIMULATED3HOURINFUSIONSFORIMIPENEMANDMEROPENEM4HOURINFUSIONSFORCEFEPIMEANDPIPERACILLINTAZOBACTAMBACTERICIDALTARGET40FTMICFORTHECARBAPENEMS50FTMICFORCEFEPIMEANDPIPERACILLINTAZOBACTAM5000SUBJECTMONTECARLOSIMULATIONVERSUS180PSEUDOMONASAERUGINOSAISOLATEDFROMHUNGARYLUDWIGEETALINTJANTIMICROBAGENTS200628433438头孢吡肟最可能的部位病原菌借鉴治疗指南药物的PKPD预防抗生素附加损害细菌流行病学及耐药性科室单位地区AMJRESPIRCRITCAREMED1713884162005SOLOMKINJSETALCLINICALINFECTIOUSDISEASE2003379971005发热中性粒细胞减少低危险性口服静脉需要万古霉素环丙沙星阿莫西林克拉维酸仅用于成年人单药治疗两种药物头孢吡肟头孢他啶碳青霉烯类抗假单胞菌青霉素或L内酰胺类特治星内酰胺酶抑制剂氨基糖苷类抗假单胞菌青霉素或内酰胺类内酰胺酶抑制剂特治星头孢吡肟头孢他啶碳青霉烯类头孢吡肟头孢他啶碳青霉烯类抗假单胞菌青霉素或内酰胺类内酰胺酶抑制剂氨基糖苷类万古霉素高危险性不需要万古霉素ADAPTEDFROMHUGHESWTARMSTRONGDBODEYGPETALCLININFECTDIS2002MARCH346730512003年美国血液协会感染抗生素治疗指南最可能的部位病原菌细菌流行病学科室单位地区借鉴治疗指南药物的PKPD预防抗生素附加损害选用低附加损害抗生素起始适当的经验治疗抗生素的干预起始适当抗感染经验治疗考虑因素哌拉西林三唑巴坦对常见病原菌总体敏感性达75以上兼顾厌氧菌低附加损害可作为经验治疗的首选更多地尝试疗效确切且低附加损害的药物是必然途径PENAETALANTIMOCROBAGENTSCHEMOTHER19984253893年18月ESBLS日益严重93年9月减少三代头孢菌素使用增加亚胺培南的使用94年1月特治星加入干预与亚胺培南同时使用94年5月开始增加特治星用量同时减少亚胺培南和三代头孢使用后ESBLS发生率才开始明显下降细菌对哌拉西林三唑巴坦的耐药率耐药性的比率病菌1994干预前1998干预后VRE发生率166阴沟杆菌6128产气杆菌6311不动杆菌属170粘质沙雷菌200MRSA发生率3423SMITHETAL1999CHEST美国印地安那州METHODIST医院使用哌拉西林三唑巴坦进行抗生素干预的结果A225B105哌拉西林三唑巴坦医院A71医院B27头孢他啶PATTERSON20003412氨苄西林舒巴坦哌拉西林三唑巴坦8966头孢噻肟头孢他啶LANDMAN19992014亚胺培南80所有头孢菌素RAHAL1998400哌拉西林三唑巴坦亚胺培南83三代头孢PENA19963010哌拉西林三唑巴坦50头孢他啶RICE1996177亚胺培南73头孢他啶MEYER1993ESBL阳性率降低幅度换用的药物被替换的头孢菌素的比例被替换药物作者年份中国医院使用哌拉西林三唑巴坦进行抗生素干预的结果研究单位中国医科大学附属第一医院感染性疾病科研究目的评价哌拉西林三唑巴坦替换三代头孢菌素对肠道产ESBLS大肠埃希菌的定植的影响直肠拭子取样离开病房前的48小时内作直肠拭子检查如果住院超过1周每7天1次基线期I期干预期IIA期3个月3个月3个月干预期IIB阶段常规方案直肠拭子PIPTAZ替换不取直肠拭子PIPTAZ替换直肠拭子赵宗珉陈佰义等中华内科杂志2007年第9期714717两阶段人口学特征之间没有统计学差异男女年龄岁身高CM体重KG第I阶段4753549181180890165886595112第II阶段5149577183190910166287604111第一次直肠拭子产ESBL大肠杆菌分离率基线分离率无统计学差异第I阶段27第IIB阶段22P0624中国医院使用哌拉西林三唑巴坦进行抗生素干预的结果赵宗珉陈佰义等中华内科杂志2007年第9期714717I期GIIB期GI期到IIB期的变化哌拉西林他唑巴坦3879438536989330总抗生素3055031879053849青霉素类10123598175302173500543006870头孢一代270000010000头孢二代220039007727头孢三代16860050400701122900307003406氨基糖苷类17604607386420029502976林可霉素类144012001667其它抗生素4681207436头孢菌素类抗菌药物通用名大环内酯类其它内酰胺类中国医院使用哌拉西林三唑巴坦进行抗生素干预的结果本研究中使用的三代头孢菌素主要有头孢哌酮头孢哌酮舒巴坦头孢哌酮舒巴坦的用量从基线的153200G减少到49200G即下降了6789中国医院使用哌拉西林三唑巴坦进行抗生素干预的结果赵宗珉陈佰义等中华内科杂志2007年第9期714717未来抗微生物感染治疗的关键在于控制致病原的进化而不是只针对病原体的治疗药物本身HOBANDJCLINICALCORNERSTONE200319THCENTURYNOANTIBIOTICS21STCENTURYTHEENDOFANTIBIOTICS20THCENTURYANTIBIOTICSASMIRACLEDRUGS193019401950196019701980199020002010磺胺类药内酰胺类氨基糖苷类氯霉素四环素大环类酯类万可霉素利福平氟喹诺酮类甲氧苄氨无新品种对现有药品进行改造利奈唑胺达托霉素替加环素青霉素耐药的金葡菌甲氧西林耐药金黄色葡萄球菌万可霉素耐药的肠球菌VISAIN7STATES耐万古霉素金葡菌利奈唑胺耐药的金葡菌半数的美国和日本公司停止了抗生素的研发BMSLILLYWYETHGSKPGETC多重耐药的假单胞菌属和不动杆菌属金属内酰胺酶类碳青霉烯酶CID20042003ANNALSOFINTERNALMEDICINE抗生素的附加损害由于附加损害三代头孢菌素和喹诺酮类都不适合作为医院感染的经验首选DRDAVIDLPATERSONCID200438SUPPL4S341尽管头孢他啶和头孢噻肟的使用量降低了万古霉素耐药肠球菌VRE感染率仍然增加这可能是由于头孢吡肟使用增加所致KERRYMEMPEYPHARMACOTHERAPY22181872002在不同的研究中亚安培南的使用被确定在当地是导致对碳氢霉烯耐药和BETA内酰胺耐药的铜绿假单胞菌主要相关因素DRLEPPERETALAACSEPT2002P29202925COLLATERALDAMAGE是指使用抗生素后出现的生态学副反应即由于抗生素的使用选择出耐药细菌继而发展成多重耐药菌的定植和临床感染酶抑制剂复合制剂氨基糖苷和大环内脂类有较低的附加损害DRDAVIDLPATERSONCOLLATERALDAMAGEFROMANTIBIOTICTHERAPYCID200438SUPPL4S341SWABNETHMAP2003减少耐药克隆是阻止耐药出现的关键步骤暴露抗生素控制感染控制敏感菌群耐药克隆爆发流行大流行筛选扩增三代头孢菌素的消费量与产ESBLS菌株的相关性研究OR178ASENSIOAETALCLININFECTDIS2000JAN3015560减少三代头孢菌素用量可显著降低产ESBLS菌株的出现KMEMPEYETALPHARMACOTHERAPY20022218187亚胺培南的使用不仅与铜绿假单胞菌对亚胺培南耐药显著相关同时与铜绿假单胞菌对哌拉三唑巴坦和头孢他啶的耐药显著相关PHILIPPMLEPPERETALANTIMICROBIALAGENTSANDCHEMOTHERAPYSEPT2002P29202925真菌的定植和感染MDR不动杆菌MDR铜绿假单胞菌难辨梭状芽孢杆菌VREMRSA产ESBLS菌株氟喹诺酮四代头孢菌素三代头孢菌素碳青霉烯类抗生素耐药菌极少数文献报道特治星的使用与上述耐药菌株的发生相关特治星可用于干预治疗减少耐药菌株的检出COLLATERALDAMAGE抗生素的使用与附加损害的相关性导致耐药菌株的产生1216中国10家教学医院大肠杆菌的敏感性变迁CMSSS200420032006SEANIRDATA2006S20042003中国10家教学医院克雷伯菌的敏感性变迁CMSS2006SEANIRDATA2006CMSS中国10家教学医院绿脓杆菌的敏感性变迁20042003S2006SEANIRDATA2006CARES20062007148株绿脓杆菌CMSS10家教学医院鲍曼不动杆菌的敏感性变迁20042003S2006小结对于大肠埃希菌和肺炎克雷伯菌哌拉西林三唑巴坦和头孢菌素相比具有更强的抗菌活性其抗菌活性接近亚胺培南等碳氢霉烯类抗生素对于绿脓杆菌哌拉西林三唑巴坦较头孢菌素以及碳青霉烯类具有更强的抗菌活性3对于鲍曼不动杆菌哌拉西林三唑巴坦与头孢菌素抗菌活性接近SHEET3SHEET2ECOSHEET12NUMBERRISMIC50MIC90L002G256药名美罗培南亚胺培南阿米卡星头孢他啶头孢吡肟头孢西叮米诺环素头孢噻肟头孢曲松左氧氟沙星环丙沙星莫西沙星药名美罗培南替加环素亚胺培南哌拉他唑阿米卡星头孢他啶哌酮舒巴坦头孢吡肟头孢西叮米诺环素头孢噻肟256哌酮舒巴坦256替加环素哌拉三唑000E00000E00000E00000E00000E00000E00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000E00000E00000E00000E00000E00000E0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000SHEET3SHEET2ECOSHEET12NUMBERRISMIC50MIC90L002G256G256药名美罗培南替加环素亚胺培南阿米卡星头孢他啶头孢吡肟头孢西叮米诺环素头孢噻肟头孢曲松左氧氟沙星环丙沙星莫西沙星药名美罗培南替加环素亚胺培南哌拉他唑阿米卡星头孢他啶哌酮舒巴坦头孢吡肟头孢西叮米诺环素头孢噻肟256哌拉他唑哌酮舒巴坦256哌酮舒巴坦哌拉三唑000E00000E00000E00000E00000E00000E0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000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