课件：革兰阴性菌感染治疗需关注ESBLs广州.ppt

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。,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,/Studies/,2011年CHINET耐药监测革兰阴性菌菌种分布,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 USA 5.3% 2.8% Latin America 27.6% 12.0% Northern Europe 5.2% 1.4% Southern/East. Europe 25.7% 6.6% China 37.3% 31.3% Australasia 4.6% 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,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,Antimicrob Agents Chemother. 2006 Jan;50(1):374-8.,Species Distribution of GNB Causing IAIs 2,292 Isolates, China, SMART, 2002-2007,Rates of ESBL-producing E. coli and K. pneumoniae from Community-onset (Data from SMART 48 h in China),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.No10,897904,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)*,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 2383%,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（46 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2448h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, MZali et al, ECCMID 2005,*Ten (62%) of the 16 patients ESBL+ on admission had been in hospital 48h,社区人群粪便携带产ESBLs菌株的危险因素,Turk J Med Sci 2007; 37 (1): 31-38,单变量分析,社区人群粪便携带产ESBLs菌株的危险因素,Turk J Med Sci 2007; 37 (1): 31-38,多变量分析,中国老年人中肠道定植 产ESBLs大肠埃希菌的分布,Can. J. Microbiol. 54: 781785 (2008),中国老年人中肠道定植产ESBLs大肠埃希菌比例：7.0% （19株） CTX-M-14 (11 strains) CTX-M-22 (3 strains) CTXM-79 (3 strains) CTX-M-24 (1 strain) CTX-M-24 CTX-M-79 (1 strain) 产ESBLs菌株没有克隆相关性,Can. J. Microbiol. 54: 781785 (2008),中国老年人中肠道定植 产ESBLs大肠埃希菌危险因素,Can. J. Microbiol. 54: 781785 (2008),临床病例,患者曹，女，70岁， 发热、呕吐伴腹泻2天，就诊肠道门诊 血常规：WBC 22.4*109/L，N 93.7% CRP:258.5mg/L；PCT：20.8ng/ml 肾功能：Bun 11.21mmol/L，Cr 236umol/L,大便常规,治疗及体温变化,AmpC 酶和ESBLs在阴沟肠杆菌中的 表达情况,单纯高产AmpC酶阴沟肠杆菌 的抗生素敏感性,单纯高产AmpC酶阴沟肠杆菌 的抗生素敏感性,同时高产AmpC酶和ESBLs阴沟肠杆菌 的抗生素敏感性,同时高产AmpC酶和ESBLs阴沟肠杆菌 的抗生素敏感性,耐药机制-内酰胺酶 表：碳青霉烯类抗生素不敏感PA中主要的 -内酰胺酶,SHV型：SHV-12（湖州、汕头、广州；荷兰）、SHV-5（纽约）；SHV-48、-56、-71（中国） TEM型：TEM-116（荷兰），TEM-92（意大利） CTX-M型：CTX-M-2（日本、玻利维亚、南充）、 CTX-M-9（广州） PER型：PER-1（土耳其、韩国、法国、中国