鲍曼不动杆菌流行及治疗(俞云松).ppt

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1、鲍曼不动杆菌流行及治疗,浙江大学医学院附属第一医院 俞云松,不动杆菌是不发酵糖的革兰阴性球杆菌至少分为16个基因种：鲍曼不动杆菌（A baumanii）醋酸钙不动杆菌（A calcoacelicus）溶血性不动杆菌（A haemolyticus）约翰逊不动杆菌（A johnonii）洛菲不动杆菌（A lwoffii）琼氏不动杆菌（A junii）耐放射性不动杆菌（A radioresistens）,鲍曼不动杆菌、醋酸钙不动杆菌、未命名的基因种3、13TU表型十分接近，所以把它们统称为鲍曼复合醋酸钙不动杆菌。临床标本中分离到的不动杆菌绝大数为鲍曼不动杆菌，其它菌种引起的感染比较少见。,鲍曼不动杆

2、菌占ICU院内获得性肺炎病原菌的比例及对常用抗菌药物的耐药率,Clin Infect Dis 2005:41:848-854,1994-2004年可分析的主要菌株数（NPRS）,2008年CHINET耐药监测革兰阴性菌菌种分布,Multidrug-resistant A.baumannii(MDRAB),Resistance to 3 or more than 3 kinds of antibioticsantipseudomonal cephalosporinsantipseudomonal carbapenems-lactamase inhibitor combinationsantips

3、eudomonal fluoroquinolonesaminoglycosidesPandrug-resistant A.baumannii,PDRABresistance to all antibiotics but polymycin and tigecycline,“XDR”：extreme drug resistance,对抗绿脓的头孢菌素抗绿脓的碳青霉烯类-内酰胺抗生素复合制剂氟喹诺酮类氨基糖苷类替加环素多粘菌素,MDR-AB全球流行,从西班牙到挪威，出现了令人担忧的多重耐药鲍曼不动杆菌“入侵”现象 在驻阿富汗和伊拉克美军和英军的外伤士兵中流行，造成严重的公共卫生问题,http:/w

4、ww.acinetobacter.org/,伊拉克美军鲍曼不动杆菌肺炎沿幼发拉底河、底格里斯河分布,http:/www.acinetobacter.org/map/map.htm,伊拉克美军带回的鲍曼不动杆菌在美国流行,http:/www.leishmaniasis.us/Mapping.html,3个克隆在英国全国广泛流行,6个主要克隆在6省市19家医院播散(342株）,3 major pulse-clone spread in China Mainland,我国不同城市间出现相同克隆,国内部分流行克隆株的ST分型及发现的新等位基因型,gltA：共30种，其中新型26种 gyrB：共39种，

5、其中新型28种gdhB：共43种，其中新型33种 recA：共25种，其中新型17种 cpn60：共39种，其中新型31种 gpi：共44种，其中新型32种 rpoD：共17种，其中新型9种,Diagram of clone complex 22 defined by eBURST,ST6：欧洲克隆，多重耐药株，在比利时、法国、德国、希腊、波兰、葡萄牙、西班牙、捷克及土耳其流行。ST4、ST53：意大利，多重耐药株 ST33：葡萄牙，产OXA-40菌株ST22：截至2009年，已有中国、中国香港、韩国、意大利报道ST22型 鲍曼不动杆菌,http:/pubmlst.org/abaumannii

6、/,为什么鲍曼不动杆菌会全球流行？,广泛分布水、土壤、医院环境和人体皮肤表面强大的环境生存能力和广泛的耐药性使其成为越来越重要的院感病原菌近年，多重耐药鲍曼不动杆菌（MDR-AB）已经在全球各地出现甚至造成了爆发性流行，并且伴随着耐药性的不断增强,19,强大的环境生存能力,不动杆菌为不发酵糖的革兰阴性 球杆菌、广泛分布于水、土壤、医院环境和人体皮肤表面20-30环境下生长良好，抵抗力强，在干燥的物体表面 鲍曼不动杆菌可存活25天，远远超过其他革兰阴性杆菌,Jawad et al.JCM 1996;34:2881-87;Jawad et al.JCM 1998;36:1938-41,强大的耐药基

7、因获得能力,Acinetobacter baylyi ADP1拥有比大肠杆菌感受态细胞强大100倍的捕获外源DNA能力错配修复系统mutS 的缺失增加了部分不动杆菌的突变频率,OXA carbapenemases in A.baumannii,Perez F,et al.Antimicrob Agents Chemother 2007;51:3471-84.,A.Baumannii ATCC17978,3,976,747bp，3,830 ORFs；GC:38%，71 is coding region；17.2 ORFs located in 28 foreign islands,suggest

8、ed many acquired genes,GenBank:CP00521,Europe clone II ACICU:AbaR2,Michele I,et al.AAC.2008,52:2616-25,I类整合子结构示意图,I类整合子在鲍曼不动杆菌中分布较广，常同时携带多种抗菌药物耐药基因和消毒剂抗性基因，临床工作应引起重视，减少对抗菌药物、消毒剂双重耐药菌的筛选。,qacE1-sul1,qac家族有10 种亚型，表达多种化合物外排泵；qacE1 由整合子介导，与sul1藕联；qacE1-sul1可介导季铵类化合物(如苯扎溴铵、苯扎氯铵、度米芬)、双胍类化合物(氯己定)、腙类化合物、碱性染

9、料、磺胺类抗生素耐药;鲍曼不动杆菌(A.baumannii)qacE1-sul1基因的携带率达到80-90.0%,消毒剂分类,季铵盐类：低效，抗性多；双胍类：主要是醋酸氯己定，抗性普遍；酚类：酚可能造成环境污染，适用受限；醛类：主要在假单胞菌和肠杆菌科细菌有抗性报道,消毒剂分类,卤素类：包括含氯消毒剂、含碘消毒剂和含溴消毒剂，对含碘消毒剂的抗性尚待确认；醇类：常用消毒剂，抗性也有报道；氧化剂类：过氧乙酸、高锰酸钾，是高效消毒剂；其他：如金属离子消毒剂，已较少使用,Acinetobacter baumannii,未发现对消毒剂的抗性，也未发现抗生素耐药与消毒剂抗性之间的联系,对目前使用消毒剂耐药

10、可能并不是目前鲍曼不动感觉流行播散的最重要原因消毒措施偏差所导致的浓度和暴露时间减少可能导致院内交叉感染的发生,4种主要消毒剂在有机干扰物存在的情况下杀菌活力显著下降,Triclosan resistance in clinical AB from China mainland,MICs ranged between 0.015 and 16 mg/L and MIC90 was 0.5 mg/L,extremely lower than the actual in-use concentration of triclosan(2000-20000 mg/L).,Factors leading

11、 to the emergence and transmission of MDRAB,Lisa L,et al.CID 2008,46:1254-1263.,Contaminated surfaces increase cross-transmission,X represents multi-drugs resistant pathogens culture positive sites,无处不在！,Highly refractory to both vigorouscleaning and to disinfectants!,alcohol-based hand rubs may mak

12、e mattersworse rather than better!,Bernard Dixon.The Lancet Infectious Disease.2008,8,alcohol or an alcohol-based hand rub provided the organism with an additional source of carbon,鲍曼不动杆菌为什么多重耐药？4 cluster of CHDLs in A.baumannii,Anton Y.Peleg,et al.CMR.2008,21:538582.,Carbapenemases in Ab of China m

13、ainland,Zhou H,et al.JCM.2007,45:4054-4057,MBLs in AB is less than CHDLs,IMP-like:IMP-1、2、4、5、6、11VIM-like:VIM-2SIM-1Usually class I integron encode,reported in Japan,Korea,Spain,England,Hongkong,et al.,The quiet before a storm?,ESBLs in AB,PER-1:Turkey,Korea,France,Belgium,Bolivia,United States,Chi

14、na Mainland,et al.VEB-1:French、BelgianSHV-12、SHV-2:China MainlandCTX-M-3:China MainlandCTX-M-2:Japan,Bolivia,Located in a 55kb conjugative plasmid,Easy to conjugate and transform to E.coli,CTX-M-3 in A.baumannii,Accquired from Enterobacteriaceae?,conjugator,AmpC in A.baumannii,Chromosomally encoded

15、class C beta-lactamase:Acinetobacter-derived cephalosporinases(ADCs)30 blaADC genes have been found We identified 60 ADCs-haboring isolates for 61 Acinetobacter spp.Including:A.baumannii,Acinetobacter 13TU,Acinetobacter genus 3,A.calcoaceticus,A.haemolyticus,8 A.baumannii isolated from Wenzhou,produ

16、cing ESBLs+AmpC,酶粗提液,酶粗提液+克拉维酸,酶粗提液+氯唑西林,酶粗提液+氯唑西林+拉维酸,16S rRNA methylase in A.baumannii,armA gene widely occurred in CRAB of China mainlandStrongly suggested to be located in chromosomeAlso in Korea、Japan、USA,armAso widely in China17 of 19 hospitals,Multidrug efflux systemplay important role in MDR

17、AB,Our unpublished data,OMPs(22、22.5、29、33、35、36、37、43、44、47KD）,29-kD,also named carO was associated with carbapenems resistant,www.bio.davidson.edu,Anton Y.Peleg,et al.CMR.2008,21:538582.,Susceptiblity of A.baumannii:1994-2004(1874 isolates),Susceptibiligy(%),Year,2008年12家医院3508株不动杆菌属(鲍曼不动86.2%)细菌的

18、耐药率（%）,R,No S,How to treat infections caused by MDR A.baumannii,Sulbactam combinationsColistintigecycline,2007年浙医一院呼吸道标本主要分离菌,鲍曼不动杆菌菌在体液标本中的分离率,FASS RJ,et al.Antimicrobial agents and chemotherapy 1990;34(11):2256-2259.,Activity of sulbactam to A.baumannii,鲍曼不动杆菌体外药敏,ampicillin/sulbactam to treat MDR

19、AB infections,Levin et al.Int J Antimicrob Agents 2003;21:58-62,A case:burn patient,Admit 18d,CRAB治疗-含舒巴坦制剂,对不动杆菌具有固有的抗菌活性.根据体外药敏实验结果选择用药.降低感染死亡率.国外报道对于严重感染者,舒巴坦的推荐剂量为6g/d,甚至在12g/d时仍有较好的安全性,但在治疗效果上与9g/d组并无统计学差异.,Clin Microbiol Rev 2008:21:538-582.Lancet Infect Dis 2008:8:751-762.Scand J Infect Dis 2

20、007:39:38-43.,High-dose ampicillin-sulbactam for MDRAB VAP,Scand J Infect Dis 2007:39:38-43.,0.785,0.303,0.580,0.568,0.936,p value,CRAB的治疗-多黏菌素,静脉应用多黏菌素治疗总有效率为57%80%.肾功能损害的发生率约为037%.雾化吸入有助于减少全身用药的副作用,并在 局部组织达到较高的药物浓度.仍需进一步临床对照研究证实.,Clin Microbiol Rev 2008:21:538-582.,A case:PDRAB meningitis,Jian Li,

21、et al.AAC,2006,50:29462950,Passage of ATCC 19606 in CAMHB with or without colistin,Hetero resistant to colistin,passages clinic AB in broth containing colistin increased the proportion of the resistant subpopulations from 10E-8 to 10E-4,*8mg/L*48小时，64mg/L*48小时,High resistance to colistin of MDRAB fr

22、om Korea,Considering theincreasing use of colistin,independent but frequent emergence of colistin resistance inMDRAB is of great concern.,Kwan Soo Ko,JAC 2007,60:1163-7Young Kyoung Parka,DMID 2009,64:43-51,BIG BUG!,Colistin,Good outcome to MDR AB infection，including:bacteremia、pneumonia、urinary trac

23、t infection、wound infection、meningitis,Only 10.8 CRAB were resistant to colistin in China Mainland,Tigecycline:the saviour?,22 microbiological studies reporting data for 2384 Acinetobacter spp,90%isolates(including MDR and CRAB)were susceptible42 severely ill patients,tigecycline therapy(combination

24、 with other antibiotics in 28 patients)was effective in 32 cases In 3 cases,resistance to tigecycline developed during treatment,Drosos EK,et al.JAC,2008,62:44-45,Tetracycline Susceptibility Testing in Isolates of Acinetobacte from a U.S.Military Hospital,Kevin S.Akers,AAC,2009,accepted,Susceptibili

25、ty of 73 IPM-I or R A.baumannii isolates to tigecycline,S:6 isolates（8.2），I:6 isolates（8.2），R:61 isolates（83.6）,Susceptibility of 43 IPM-S A.baumannii isolates to tigecycline,S:19 isolates（44.2），I:6 isolates（14.0），R:18 isolates（41.9）,替加环素对中国部分地区亚胺培南耐药鲍曼不动杆菌体外抗菌活性差,Combinations of antibiotics demonstrating enhancedactivity against CRAB,*:IP,MP,SAM,TZP,FEP,quinolones,aminoglycosides,Federico P,et al.Antimicrob Agents Chemother.Accepted,Hand HygineIsolation of patients(infected or colonized)environment sterilization,Decrease clonal spread,Thank you for your attention!,