革兰阴性菌感染治疗需关注ESBLs广州.pptx

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,#,革兰阴性菌感染治疗需关注,ESBLs,浙江大学医学院附属邵逸夫医院,感染科 俞云松,你认为该怎么办？,病人女性,81,岁,1,月,6,日：左腘窝疼痛，局部肿，压痛,WBC7.6*E9 N:77.2%,CRP65mg/L,1,月,20,日胸闷、气急,CTPA,：肺动脉栓塞,1,月,23,日出现发热,白细胞,WBC6.1*E9,N76%,CRP10.3mg/L,38.5,上升至,39.2,（罗氏芬）,1,月,26,日,改,舒普深,1,月,29,日体温,降到,38.5,度,2,月,1,日加,了,拜复乐,2,月,3,日,出现腹泻,右腘窝肿痛,停药，,4,、,5,号均,40,度,（这期间,CRP,最高,98mg/L,，后来在,60mg/L,左右）,超广谱,-,内酰胺酶（,extended spectrum,-lactamases,，,ESBLs,）,是一类由质粒介导的,2be,类,-,内酰胺酶，能水解氧亚氨基,-,内酰胺抗生素，大多数能被,-,内酰胺酶抑制剂如克拉维酸（,CA,）所抑制。,N,S,+NH,3,C,N,O,CH,3,C,NH,O,N,S,COO-,R,头孢噻肟,July 2004:Media,discovers,CTX-M,如何测出,ESBLs,头孢噻肟 克拉维酸,头孢噻肟,头孢他啶,头孢他啶 克拉维酸,ESBL,流行病学的改变,2010 AAC,www.lahey.org/Studies/,2011,年,CHINET,耐药监测革兰阴性菌菌种分布,细菌,株数,细菌,株数,大肠埃希菌,11860,27.96,摩根菌属,198,0.47,克雷伯菌属,6981,16.46,产碱杆菌,128,0.30,不动杆菌属,6723,15.85,少动鞘氨醇单胞菌,120,0.28,铜绿假单胞菌,6012,14.17,金杆菌属,208,0.49,肠杆菌属,2519,5.94,罗尔斯顿菌属,109,0.26,嗜麦芽窄食单胞菌,1889,4.45,气单胞菌属,106,0.25,变形杆菌属,1271,3.00,多源菌属,45,0.11,流感嗜血杆菌,830,1.96,普罗威登菌属,34,0.08,沙雷菌属,598,1.41,志贺菌属,154,0.36,其他假单胞菌,322,0.76,丛毛单胞菌,25,0.06,其他嗜血杆菌,211,0.50,奈瑟菌属,23,0.05,沙门菌属,655,1.54,博特菌属,37,0.09,柠檬酸杆菌属,424,1.00,黄杆菌属,23,0.05,伯克霍尔德菌属,455,1.07,其他,327,0.77,莫拉菌属,128,0.30,合计,42415,100.0,菌种分布：不动杆菌属铜绿假单胞菌；沙门菌属,；伯克霍尔德菌；,溶链（,A,、,B,组）和金葡菌,Common ESBL producers:,Klebsiella pneumoniae,Escherichia coli,Proteus mirabilis,Enterobacter cloacae,Non-typhoidal,Salmonella,(in some countries),First described in Germany(1983)and France(1985)among Klebsiella spp,Pseudomonas aeruginosa,Acinetobacter baumannii,PER-type and OXA-type enzymes are more common in Pseudomonas eruginosa and Acinetobacter spp.,ESBLs are rare in:,肠杆菌科细菌,临床关注的主要,-,内酰胺酶,超广谱,-,内酰胺酶,(ESBLs),高产头孢菌素酶,(AmpC,酶,),极少数菌株产碳青霉烯酶,(,碳青霉烯酶,KPC),MDR,XDR,or,PDR,Are ESBL producers associated with,higher mortality?,Meta-analysis of mortality from bacteremia with ESBL producers,Schwaber JAC Nov 2007,16 studies from 2000-2006,Crude mortality,：,34%(199/591)for ESBL producers vs.20%(216/1091)for non-ESBL,Pooled RR 1.85;95%CIs 1.39-2.47,Delay in effective therapy in up to 44%patients with ESBL producers,Schwaber JAC Nov 2007;Goff ICAAC 2006,产,ESBLs,菌株血行感染死亡率显著增加（,Meta,分析）,产,ESBLs,菌株与不产,ESBLs,菌株血行感染死亡率比较的,Meta,分析,包括,16,个研究,产,ESBLs,菌株菌血症死亡率显著增加,(pooled RR 1.85,95%CI 1.392.47,P 0.001,）,Mortality and delay in effective therapy associated with extended-spectrum b-lactamase production in Enterobacteriaceae bacteraemia:a systematic review and meta-analysis.Journal of Antimicrobial Chemotherapy(2007)60,913920,产,ESBLs,菌株血行感染发生率、死亡率、延误治疗的,meta,分析,Mortality and delay in effective therapy associated with extended-spectrum b-lactamase production in Enterobacteriaceae bacteraemia:a systematic review and meta-analysis.Journal of Antimicrobial Chemotherapy(2007)60,913920,Worldwide prevalence of ESBL producers,Kpn,E.coli,USA5.3%2.8%,Latin America27.6%12.0%,Northern Europe5.2%1.4%,Southern/East.Europe25.7%6.6%,China37.3%31.3%,Australasia4.6%1.6%,社区获得性产,ESBLs,菌株感染的定义,(1),入院后,48h,以内发生,(,最近,30,天内没有住过院,),(2),不符合,CDC,关于院内感染的标准,(3),不是转院或从护理院转入的患者,Am J Infect Control 2007;35:606-12,Guangzhou,Zhejiang,Shanghai,Beijing,Wuhan,Henan,Hong Kong,菌株来源,2002-2003,年,中国,7,个地区,社区获得性感染病人分离的革兰阴性菌共,2099,株,2099,株革兰阴性菌分布,Antimicrob Agents Chemother.2006 Jan;50(1):374-8.,主要肠杆菌科细菌耐药性,All,(1651),E.coli,(953),Klebsiella,(357),EnterobacterCitrobacter,Serratia(175),ESBL+,?,16,17,?,Imipenem,0,0,0,0,Ertapenem,0,0,0,0,Cefotaxime,14.7,14.4,15.4,25.1,Ceftazidime,(5.9),(2.7),(8.1),20.0,Pip/taz,9.5,7.1,13.2,21.7,Ciprofloxacin,40.8,50.6,25.2,22.9,Antimicrob Agents Chemother.2006 Jan;50(1):374-8.,Species Distribution of GNB Causing IAIs,2,2,92,Isolates,China,SMART,2002-200,7,Rates of ESBL-producing,E.coli,and,K.pneumoniae,from Community-onset,(Data from SMART 48 h in China),48hours,2002,2003,2004,2005,2006,2007,E.coli,65,66,65,60,121,97,ESBL,3,19,16,7,33,35,Precentage,5%,29%,25%,12%,27%,36%,K.pneumoniae,25,31,17,24,40,46,ESBL,4,5,5,2,7,7,Precentage,16%,16%,29%,8%,18%,15%,Emergence of High Levels of Extended-Spectrum-Lactamase-Producing Gram-Negative Bacilli in the Asia-Pacific Region,（,SMART 2007,）,Asia-Pacific Region,（,SMART 2007,）,ESBLs,an emerging problem,Glasswell,et al,Healthcare-associated Infection and Antimicrobial Resistance Dept&Antimicrobial Resistance Monitoring and Reference Laboratory,Health Protection Agency,Colindale,London,Community acquisition of ESBL-producing,Escherichia coli,:a growing concern,MJA,Volume 190 Number 1 5 January 2009,医院获得（,HA,）与社区获得（,CA,）产,ESBLs,大肠埃希菌分离率的比较,A review of microbiological isolates from clinical specimens taken from 2003 to 2007 at the Alfred Hospital,Melbourne,医院获得（,HA,）与社区获得（,CA,）产,ESBLs,大肠埃希菌的比较,Journal of Infection(2008)57,441e448,Healthcare associated community-onset ESBL-producing E.coli infections,Community acquired community-onset ESBL-producing E.coli infections,Journal of Infection(2008)57,441e448,医院获得（,HA,）与社区获得（,CA,）产,ESBLs,大肠埃希菌的比较,住院病人与门诊病人产,ESBLs,菌株,不同感染部位的分离情况,Extended spectrum beta-lactamases(ESBL)in,Escherichia coli,and,Klebsiella pneumoniae:,trends in the hospital and community settings,J Infect Dev Ctries,2009;3(4):295-299,医院获得（,HA,）与社区获得（,CA,）产,ESBLs,菌株感染特点比较,Lancet Infect Dis,2008;8:15966,基因型,感染部位,药敏,分子流行病学,危险因素,Prevalence of ESBLs,CHINET surveillance,China,2005-2009,中国,ESBL,的发生率,%,Wang H,Chen M.Diagnos Microbiol Infect Dis,2005,51,201-208,CMSS/SEANIR/CARES.,CMSS 2010,王辉等,中华检验医学杂志,2011,Vol34.No10,897,904,year,产,ESBLs,菌株血行感染：病死率增加,的危险因素之一,广谱头孢菌素的治疗,Bloodstream Infections Due to Extended-Spectrum,Beta,-,Lactamase-Producing,Escherichia coli,and,Klebsiella pneumoniae,:,Risk Factors for Mortality and Treatment Outcome,with Special,Emphasis on Antimicrobial Therapy.AAC.2004,48,(12),p.45744581,产,ESBLs,菌株感染：,头孢菌素的经验性治疗疗效判断,Bloodstream Infections Due to Extended-Spectrum,Beta,-,Lactamase-Producing,Escherichia coli,and,Klebsiella pneumoniae,:,Risk Factors for Mortality and Treatment Outcome,with Special,Emphasis on Antimicrobial Therapy.AAC.2004,48,(12),p.45744581,产,ESBLs,菌株血行感染：,头孢菌素的经验性治疗疗效判断,与,MIC,的相关性,Bloodstream Infections Due to Extended-Spectrum,Beta,-,Lactamase-Producing,Escherichia coli,and,Klebsiella pneumoniae,:,Risk Factors for Mortality and Treatment Outcome,with Special,Emphasis on Antimicrobial Therapy.AAC.2004,48,(12),p.45744581,Susceptible,：,MIC=8ug/ml,MICs=8 ug/ml,折点？,产,ESBLs,菌株感染：,头孢菌素的经验性治疗疗效判断,与,MIC,的相关性,头孢菌素治疗对其,敏感的,产,ESBLs,菌株的,严重感染,疗效仍差,DAVID L.PATERSON,et al.Outcome of Cephalosporin Treatment for Serious Infections Due to Apparently Susceptible,Organisms Producing Extended-Spectrum b-Lactamases:Implications for the Clinical Microbiology Laboratory.JCM 2001,39:2206-2212,失败,肠杆菌科对头孢类,氨曲南,新折点,(MIC,g/ml)*,Agents,CLSI-S19(2009),CLSI-S20(2010),S,It,R,S,I,R,Cefazolin,8,16,32,1,2,4,Cefotaxime,8,16-32,64,1,2,4,Ceftizoxime,8,16-32,64,1,2,4,Ceftriaxone,8,16-32,64,1,2,4,Ceftazidime,8,16,32,4,8,16,Aztreonam,8,16,32,4,8,16,CLSI M100-S20.Table 2A.,*CLSI,还改写了纸片扩散法的折点,评估了但不需要修改折点的药,头孢吡肟,头孢呋辛,Cefamandole,头孢孟多,Cefonicid,头孢尼西,Cefoperazone,头孢哌酮,Moxalactam,拉氧头孢,未被重新评估的折点,产,ESBLs,菌株感染：,不同抗菌药物经验性治疗疗效比较,头孢吡肟,体外往往敏感，但是,多个回顾性分析显示，,头孢吡肟失败率为,23,83%,尤其当产,ESBLs,菌株,MICs 1 mg/ml,.,一项随机单盲多中心试验显示，亚胺培南,/,西司他丁,(0.5 g q6h i.v.),明显由于头孢吡肟,(2 g q8h i.v.),用于治疗,ICU,患者的院内肺炎,加大剂量（,4,6 g administered as a continuous infusion or 2 g q6-8h with prolonged infusion,）或联合阿米卡星可改善疗效,头孢吡肟并不是治疗产,ESBLs,肠杆菌科细菌感染的最佳选择，尤其是严重感染,Current Opinion in Pharmacology 2007,7:459469,产,ESBLs,菌株感染：,头孢菌素的经验性治疗疗效判断,与,MIC,的相关性,DAVID L.PATERSON,et al.Outcome of Cephalosporin Treatment for Serious Infections Due to Apparently Susceptible,Organisms Producing Extended-Spectrum b-Lactamases:Implications for the Clinical Microbiology Laboratory.JCM 2001,39:2206-2212,失败,产,ESBLs,菌株的,严重感染,不适合选择头孢菌素作为起始经验性治疗！（即使药敏敏感）,产,ESBLs,菌株感染,不同抗菌药物经验性治疗疗效比较,内酰胺酶抑制剂复合制剂,临床医生需考虑酶抑制剂不能灭活的染色体介导的,AmpC,酶的存在,根据微生物学及临床数据分析，,内酰胺酶抑制剂复合制剂并不能作为产,ESBLs,肠杆菌科细菌,严重感染,的合适选择！,Current Opinion in Pharmacology 2007,7:459469,抗菌药物对产,ESBLs,菌抗菌活性,3.0 Q12h,3.0 Q8h,8,2,18,4,30,8,17%16,15%32,2%64,10%,耐药,产,ESBLs,菌株感染：,不同抗菌药物经验性治疗疗效比较,氟喹诺酮类,部分临床研究证实环丙沙星治疗产,ESBLs,菌株感染的有效性,但产,ESBLs,合并对氟喹诺酮类耐药菌株迅速增加！,中国台湾，,20%,的产,ESBL,肺炎克雷伯菌对环丙沙星耐药,亚洲其他地区的产,ESBLs,菌株环丙沙星耐药率很高,美国，产,ESBLs,合并环丙沙星耐药菌株的爆发流行，如,1999,年,15,家医院中的,34,肺克产,ESBLs,，其中仅,42,对环丙沙星敏感,尤其是中国大陆,Bell JM,et al.Prevalence of extended spectrum b-lactamase(ESBL)-producing clinical isolates in the Asia-Pacific region and South Africa:regional results from SENTRY Antimicrobial Surveillance Program(199899).Diagn Microbiol Infect Dis 2002;42:1938.,Yu WL,et al.Molecular epidemiology of extendedspectrum b-lactamase-producing,fluoroquinolone-resistant isolates of,Klebsiella pneumoniae,in Taiwan.J Clin Microbiol 2002;40:46669.,Quale JM,et al.Molecular epidemiology of a citywide outbreak of extended-spectrum b-lactamaseproducing,Klebsiella pneumoniae,infection.Clin Infect Dis 2002;35:83441.,产,ESBLs,菌株血行感染：,不同抗菌药物经验性治疗疗效比较,Clinical Infectious Diseases 2003;39:317,碳青霉烯类抗生素,产,ESBLs,菌株血行感染：,不同抗菌药物经验性治疗疗效比较,不同抗菌药物治疗方案,30,天,病死率,比较：,Thirty-day mortality rates,碳青霉烯类,12.9%(8 of 62),头孢菌素,26.9%(7 of 26),氨基糖苷类,26.9%(7 of 26),选择,碳青霉烯类抗生素,作为产,ESBLs,菌株感染的经验性治疗的合理性！,Bloodstream Infections Due to Extended-Spectrum,Beta,-,Lactamase-Producing,Escherichia coli,and,Klebsiella pneumoniae,:,Risk Factors for Mortality and Treatment Outcome,with Special,Emphasis on Antimicrobial Therapy.AAC.2004,48,(12),p.45744581,存活率,产,ESBLs,菌株血行感染：,不同抗菌药物经验性治疗疗效比较,ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,June 2007,p.19871994,Clinical Infectious Diseases 2010;50:408,血液来源产,ESBLs,大肠埃希菌对多种抗菌药物的药敏情况,Clinical Infectious Diseases 2001;32:116271,产,ESBLs,菌株感染：,抗菌药物的选择,产,ESBLs,菌株感染：非碳青霉烯类抗生素治疗病死率高于碳青霉烯类抗生素,头孢菌素治疗与产,ESBLs,菌株血行感染疗效较差,头孢菌素治疗对其敏感的产,ESBLs,菌株的严重感染疗效仍差,但起始选择头孢菌素，后根据药敏更改治疗方案并不影响病死率,更慎重的选择碳青霉烯类抗生素作为治疗产,ESBLs,菌株感染的起始治疗的合理性！,根据病人的疾病及病情,根据微生物的耐药性,Reference,：,Cheol-In Kang et al.Bloodstream Infections Due to Extended-Spectrum Beta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae:Risk Factors for Mortality and Treatment Outcome,with Special Emphasis on Antimicrobial Therapy.AAC.2004,48,(12),p.45744581,Schiappa et al.Ceftazidime-resistant,Klebsiella pneumoniae,and,Escherichia coli,bloodstream infection:a case-control and molecular epidemiologic investigation.J.Infect.Dis.1996.,174:,529536.,Wong-Beringer et al.Molecular correlation for the treatment outcomes in bloodstream infections caused by Escherichia coli and Klebsiella pneumoniae with reduced susceptibility to ceftazidime.Clin.Infect.Dis.2002.34:135146.,Lautenbach,E.,et al.Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae:risk factors for infection and impact of resistance on outcomes.Clin.Infect.Dis.2001.32:11621171.,DAVID L.PATERSON,et al.Outcome of Cephalosporin Treatment for Serious Infections Due to Apparently Susceptible Organisms Producing Extended-Spectrum b-Lactamases:Implications for the Clinical Microbiology Laboratory.JCM 2001,39:2206-2212,产,ESBLs,菌株感染的危险因素,Clinical Infectious Diseases 2001;32:116271,产,ESBLs,菌株感染的合并症,Clinical Infectious Diseases 2001;32:116271,产,ESBLs,菌株感染前的抗菌药物应用,Clinical Infectious Diseases 2001;32:116271,Clin Infect Dis.2010 Jan 1;50(1):40-8.,危险因素和预后,西班牙,13,家三甲医院,2004.102006.16000,，,000,病人,产,ESBL,大肠埃希菌引起社区发作性败血症危险因素的多变量分析,Clin Infect Dis.2010 Jan 1;50(1):40-8.,影响预后的因素,Clin Infect Dis.2010 Jan 1;50(1):40-8.,经验性治疗首先要覆盖,:,大肠埃希菌,肺炎克雷伯菌,关注是否产,ESBLs,社区革兰阴性菌感染,（包括败血症）,适当的经验性治疗,appropriate empiric therapy,感染患者起病,24,48h,之内选择适当的经验性治疗（,appropriate empiric therapy,）是影响预后的重要因素！,社区获得性,产,ESBLs,大肠埃希菌感染危险因素,ARCH INTERN MED/VOL 168(NO.17),SEP 22,2008,年龄,60,岁以上,女性,糖尿病,反复的尿路感染,卫生保健相关感染,之前抗菌药物的应用,特别的抗菌药物：氨基青霉素、头孢菌素、氟喹诺酮类,侵袭性泌尿道操作,ARCH INTERN MED/VOL 168(NO.17),SEP 22,2008,社区获得性产,ESBLs,大肠埃希菌感染危险因素,社区获得性产,ESBLs,大肠埃希菌感染危险因素,其中两大危险因素：,女性,老年人,Clinical Infectious Diseases 2004;38:173641,社区获得性产,ESBLs,大肠埃希菌感染危险因素,社区获得性产,ESBLs,大肠埃希菌感染的主要危险因素：,产,ESBLs,菌株定植,近期抗菌药物的使用：尤其是三代头孢，氟喹诺酮类,Am J Infect Control 2007;35:606-12,Group1,：社区产,ESBLs,菌株感染患者,Group2,：社区非产,ESBLs,菌株感染患者,社区获得性产,ESBLs,大肠埃希菌,菌血症,危险因素,J Microbiol Immunol Infect 2010;43(3):240248,年龄,性别,合并症,初始感染部位,临床表现,长期的照顾机构,社区获得性产,ESBLs,大肠埃希菌,菌血症,不同初始感染部位,J Microbiol Immunol Infect 2010;43(3):240248,尿路感染,社区获得（,CA,）产,ESBLs,大肠埃希菌,尿路感染,危险因素,Clin Microbiol Infect 2010;16:147151,复杂性尿路感染,尿路结石,前列腺疾病,最近一年发作,3,次,以上尿路感染,最近,3,个月应用抗菌,药物，尤其是,内酰胺类,肠道,定植的,产,ESBLs,菌株,重要的危险因素,粪便中产,ESBLs,菌株的分离情况,Fecal Carriage of Extended-Spectrum b-LactamaseProducing,Escherichia coli,and,Klebsiella pneumoniae,in Patients and Asymptomatic Healthy Individuals,Infect Control Hosp Epidemiol,2007;28:1114-1116,Rectal carriage,of ESBL-producing organisms on the General and Neurosurgical ICUs,Leeds General Infirmary,M,Zali,et al,ECCMID 2005,*,Ten(62%)of the 16 patients ESBL+on admission had been in hospital 256,米诺环素,-,-,32,128,黏菌素,0.5,98.4,1,1,对绿脓杆菌，美平比亚胺培南的敏感率更高,CMSS 2010,王辉等,中华检验医学杂志,2011,Vol34.No10,897,904,抗菌药物对鲍曼不动杆菌的敏感率,（,CMSS2010,）,抗菌药物,鲍曼不动杆菌（,180,株）,R%,S%,MIC50,MIC90,美平,62.8,35.6,16,64,亚胺培南,61.7,37.2,32,64,头孢吡肟,66.1,25,32,64,头孢他啶,72.2,25.6,64,256,头孢哌酮,/,舒巴坦,39.4,28.9,32,64,哌拉西林,/,他唑巴坦,71.1,24.4,256,256,环丙沙星,76.7,23.3,32,32,阿米卡星,64.4,35.6,256,256,米诺环素,32.2,47.8,8,16,黏菌素,2.2,97.8,1,1,CMSS 2010,王辉等,中华检验医学杂志,2011,Vol34.No10,897,904,抗菌药物对洋葱伯克霍尔德菌的敏感率,（,CMSS2010,）,抗菌药物,洋葱伯克霍尔德菌（,48,株）,R%,S%,MIC50,MIC90,美平,22.9,72.9,4,64,亚胺培南,-,-,32,64,头孢吡肟,-,-,8,64,头孢他啶,10.4,79.2,4,64,头孢哌酮,/,舒巴坦,35.4,31.2,32,256,哌拉西林,/,他唑巴坦,-,-,4,256,环丙沙星,-,-,2,32,阿米卡星,-,-,64,256,米诺环素,27.1,70.8,2,32,黏菌素,-,-,16,16,CMSS 2010,王辉等,中华检验医学杂志,2011,Vol34.No10,897,904,对,G-,菌的,MIC90,值对比,0.12,0.5,2,8,32,128,CMSS 2010,王辉等,中华检验医学杂志,2011,Vol34.No10,897,904,与亚胺培南相比，美平对革兰阴性菌的抗菌活性更强。,PK/PD parameters,（,g/mL）,Cmax,MIC,Time above MIC,BC,MIC,升高：,时间依赖性抗生素：,TMIC,明显缩短,Thank you for attention!,