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1、鲍曼不动杆菌的流行及治疗浙江大学医学院附属第一医院 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
2、曼不动杆菌占鲍曼不动杆菌占ICUICU院内获得性院内获得性肺炎病原菌的比肺炎病原菌的比例及对常用抗菌例及对常用抗菌药物的耐药率药物的耐药率Clin Infect Dis 2005: 41: 848-8541994-2004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 细菌细菌株数株数 细菌细菌株数株数大肠埃希菌大肠埃希菌651226.58 莫拉菌属莫拉菌属1410.58 铜绿假单胞菌铜绿假单胞菌403416.47 摩根菌属摩根菌属1360.56 克雷伯菌属克雷伯菌属371715.17 志贺菌属志贺菌属1300.53 不动杆菌属不动杆菌属350814.32 产
3、碱杆菌产碱杆菌1080.44 肠杆菌属肠杆菌属14165.78 沙门菌属沙门菌属990.40 嗜麦芽窄食单胞菌嗜麦芽窄食单胞菌12745.20 罗尔斯顿菌属罗尔斯顿菌属670.27 流感嗜血杆菌流感嗜血杆菌8123.31 气单胞菌属气单胞菌属660.27 变形杆菌属变形杆菌属6562.68 博特菌属博特菌属350.14 其他嗜血杆菌其他嗜血杆菌2140.87 普罗威登菌属普罗威登菌属290.12 其他假单胞菌其他假单胞菌3441.40 奈瑟菌属奈瑟菌属250.10 沙雷菌属沙雷菌属2711.11 多源菌属多源菌属200.08 柠檬酸杆菌属柠檬酸杆菌属2601.06 丛毛单胞菌丛毛单胞菌140.
4、06 伯克霍尔德菌属伯克霍尔德菌属2360.96 黄杆菌属黄杆菌属110.04 金杆菌属金杆菌属1660.68 其他其他1990.81 合计合计24500100.0Multidrug-resistant A. baumannii (MDRAB) Resistance to 3 or more than 3 kinds of antibioticspantipseudomonal cephalosporinspantipseudomonal carbapenemsp-lactamase inhibitor combinationspantipseudomonal fluoroquinolones
5、paminoglycosidesPandrug-resistant A. baumannii, PDRABlresistance to all antibiotics but polymycin and tigecyclineClin Microbiol Rev 2008; 21: 538-82N Engl J Med 2008; 358: 1271-81“XDR”: extreme drug resistance对抗绿脓的头孢菌素对抗绿脓的头孢菌素抗绿脓的碳青霉烯类抗绿脓的碳青霉烯类-内酰胺抗生素复合制剂内酰胺抗生素复合制剂氟喹诺酮类氟喹诺酮类氨基糖苷类氨基糖苷类替加环素替加环素多粘菌素多粘
6、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:/www.acinetobacter.org/伊拉克美伊拉克美军鲍曼不曼不动杆菌肺炎沿杆菌肺炎沿幼幼发拉底河、底格里斯河分布拉底河、底格里斯河分布 http:/www.acinetobacter.org/map/map.htm伊拉克美伊拉克美军带回的回的鲍曼不曼不动杆菌在美国流行杆菌在美国流行http:/www.leishmaniasis.us/Mapping.html3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
7、散(342株)3 major pulse-clone spread in China Mainland18 of 19 hospitals254 of 342 isolates(74.3%)我国不同城市间出现相同克隆国内部分流行克隆株的国内部分流行克隆株的ST分型及发现的新等位基因型分型及发现的新等位基因型Strain No.PFGE typeSTAllele No.gltAgyrBgdhBrecAcpn60gpirpoDB53A221332273N212A221332273ZF15B33(新型新型)13322113SH80B33(新型新型)13322113ZF12C221332273ZP13
8、C34(新型新型)1332226(新型新型)3ZY112D35(新型新型)15(新型新型)151312426(新型新型)2F20D35(新型新型)15(新型新型)151312426(新型新型)2gltA:共:共30种,其中种,其中新型新型26种种 gyrB:共:共39种,其中种,其中新型新型28种种gdhB:共:共43种,其中种,其中新型新型33种种 recA:共:共25种,其中种,其中新型新型17种种 cpn60:共:共39种,其中种,其中新型新型31种种 gpi:共:共44种,其中种,其中新型新型32种种 rpoD:共:共17种,其中种,其中新型新型9种种22A (1-3-3-2-2-28
9、-3)22B (1-3-3-2-2-11-3)(1-3-3-2-2-7-3)(1-4-3-2-2-3-3)(1-3-3-2-2-3-3)(1-12-3-2-2-3-3)(1-3-3-2-2-3-1)(1-4-3-2-2-7-3)(1-3-15-2-2-7-3)(1-12-3-2-2-7-3)Diagram of clone complex 22 defined by eBURSTST6:欧洲克隆欧洲克隆,多重耐药株,在比利时、法国、德国、希腊、,多重耐药株,在比利时、法国、德国、希腊、 波兰、波兰、葡萄牙、西班牙、捷克及土耳其流行。葡萄牙、西班牙、捷克及土耳其流行。ST4、ST53:意大利,多
10、重耐药株:意大利,多重耐药株 ST33:葡萄牙,产:葡萄牙,产OXA-40菌株菌株ST22:截至:截至2009年,已有中国、中国香港、韩国、意大利报道年,已有中国、中国香港、韩国、意大利报道ST22型型 鲍曼不动杆菌鲍曼不动杆菌http:/pubmlst.org/abaumannii/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 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
11、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 19Jawad et al. JCM 1996;34:2881-87; Jawad et al. JCM 1998;36:1938-41强大的耐药基因获得能力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获得性获得性天然天然染色体介导染色体介导OXA-51/69-likeOXA
12、-23OXA-64OXA-24OXA-65OXA-25OXA-66OXA-26OXA-68OXA-40OXA-70OXA-58OXA-71OXA-78质粒介导质粒介导OXA-79OXA-23OXA-80OXA-58OXA-82Perez F, et al. Antimicrob Agents Chemother 2007; 51: 3471-84. A. Baumannii ATCC179783,976,747bp,3,830 ORFs;GC: 38%,71 is coding region;17.2 ORFs located in 28 foreign islands, suggested
13、many acquired genesGenBank: CP00521GenBank: CP00521Europe clone II ACICU:AbaR2Michele I, et al. AAC. 2008, 52:2616-2553P1 P2attIattC(59bp)qacE1 sul1 P orfintl1Pint基因盒基因盒PI类整合子结构示意图I 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,和消毒剂抗性基因,临床工作应引起重视,减少对抗菌药物、消毒剂双重减少
14、对抗菌药物、消毒剂双重耐药菌的筛选。耐药菌的筛选。qacE1 -sul1qac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
15、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YearStrainsDisinfectantsCountryJournal20039antisepticsdisinfectantsSpainJ hosp Infection2007201-propanol;Idophor;Triclosan;CHXGermanyJ hosp Infection200814/283CHX;BZK;BZT;ADHJapanJACAcinetobacter baumannii未未发现对消毒消毒剂的抗性,也未的抗性,也
16、未发现抗生素耐抗生素耐药与消毒与消毒剂抗抗性之性之间的的联系系对目前使用消毒剂耐药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种主要消毒种主要消毒剂在有机干在有机干扰物存在的情况下物存在的情况下杀菌菌活力活力显著下降著下降Triclosan resistance in clinical AB from China mainlandMICs ranged between 0.015 and 16 mg/L and MIC90 was 0.5 mg/L, extremely lower than the actual in-use
17、 concentration of triclosan (2000-20000 mg/L).Triclosan MICs of 732 clinical ABClinic used concentration2000 Factors leading to the emergence and transmission of MDRABLisa L, et al. CID 2008, 46:1254-1263.Contaminated surfaces increase cross-transmissionX X represents multi-drugs resistant pathogens
18、 culture positive sites无处不在!无处不在!Highly refractory to both vigorouscleaning and to disinfectants!alcohol-based hand rubs may make mattersworse rather than better!Bernard Dixon. The Lancet Infectious Disease. 2008,8alcohol or an alcohol-based hand rub provided the organism with an additional source o
19、f carbon鲍曼不动杆菌为什么多重耐药?4 cluster of CHDLs in A. baumanniiAnton Y. Peleg, et al. CMR. 2008, 21:538582.Carbapenemases in Ab of China mainlandZhou H, et al. JCM. 2007, 45:4054-4057MBLs in AB is less than CHDLsIMP-like: IMP-1、2、4、5、6、11VIM-like: VIM-2SIM-1Usually class I integron encode, reported in Japa
20、n, Korea, Spain, England, Hongkong, et al.The quiet before a storm?ESBLs in ABPER-1: Turkey, Korea, France, Belgium, Bolivia, United States, China Mainland, et al.VEB-1: French、BelgianSHV-12、SHV-2: China MainlandCTX-M-3: China MainlandCTX-M-2: Japan, BoliviaLocated in a 55kb conjugative plasmidEasy
21、to conjugate and transform to E. coliCTX-M-3 in A. baumanniiAccquired from Accquired from EnterobacteriaceaeEnterobacteriaceae? ?conjugatorAmpC in A. baumanniiChromosomally encoded class C beta-lactamase: Acinetobacter-derived cephalosporinases (ADCs)30 blaADC genes have been found We identified 60
22、ADCs-haboring isolates for 61 Acinetobacter spp. Including: A. baumannii, Acinetobacter 13TU, Acinetobacter genus 3, A. calcoaceticus, A. haemolyticus8 A. baumannii isolated from Wenzhou, producing ESBLs+AmpC酶粗提液酶粗提液酶粗提液酶粗提液+克克拉维酸拉维酸酶粗提液酶粗提液+氯唑氯唑西林西林酶粗提液酶粗提液+氯氯唑西林唑西林+拉维拉维酸酸16S rRNA methylase in A. b
23、aumanniiarmA gene widely occurred in CRAB of China mainlandStrongly suggested to be located in chromosomeAlso in Korea、Japan、USAarmAso widely in China17 of 19 hospitalsMultidrug efflux systemplay important role in MDRAB101 isolates of MDRABMIC50MIC90IMP32128IMP+PAN832MEM1664MEM+PAN432Our unpublished
24、 dataOMPs(22、22.5、29、33、35、36、37、43、44、47KD)29-kD, also named carO was associated with carbapenems resistantwww.bio.davidson.eduAnton Y. Peleg, et al. CMR. 2008, 21:538582.Susceptiblity of A. baumannii: 1994-2004 (1874 isolates)Susceptibiligy(%)Year2008年年12家医院家医院3508株不动杆菌属株不动杆菌属(鲍曼不动鲍曼不动86.2%)细菌的耐药率
25、(细菌的耐药率(%)对头孢哌酮对头孢哌酮/舒巴坦耐药率较低。对其他药耐药率均较高。舒巴坦耐药率较低。对其他药耐药率均较高。两种碳青霉烯类耐药率均两种碳青霉烯类耐药率均48%,高于,高于2007年。年。RNo SHow to treat infections caused by MDR A. baumanniiSulbactam combinationsColistintigecycline20072007年浙医一院呼吸道标本主要分离菌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% ofinhibited isolates concentration of sulbactam
26、g/mlFASS 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 MDRAB infectionsbacteremia (13)pneumonia (12)Urinary infection(6)peritonitis (3)Wound infection(3)meningitis (2)sinusinfection(1)Effective%46
27、75100100670100Levin et al. Int J Antimicrob Agents 2003;21:58-62A case: burn patientcefuroximeadmitexcision of eschar、mechanical ventilation 3dSulperazon, amikacin6d8dBlood:AB(IMP:S,CPS:S)sputum:AB(IMP:S,CPS:I)Imipenem 0.5q6hT: 3940 Admit 18dcefuroxime 3dsulperazon, amikacin6d8dIMP:S,CPS:S/IT: 3940
28、11dskin grafting18d9dIMP:S14dPDRABPDR AB &Xanthomonas maltophiliaimipenemSORRY,no drug remain?excision of eschar、mechanical ventilation 3d6d8dABT: 3940 11d18d14dPDRABPDRABX. maltophiliaimipenemsulperazone2g q6h21d38.5 excision of eschar、mechanical ventilation skin graftingcefuroxime sulperazone, ami
29、kacinCRAB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 2007: 39: 38-43.High-dose ampicillin-sulbactam for MDRAB VAPScand J Infect Dis 2007: 39:
30、 38-43.0.7850.3030.5800.5680.936p valueCRAB的治疗的治疗- -多黏菌素多黏菌素静脉应用多黏菌素治疗总有效率为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雾化吸入有助于减少全身用药的副作用,并在并在 局部组织达到较高的药物浓度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仍需进一步临床对照研究证实.Clin Microbiol Rev 2008: 21: 538-582.A case: PDRAB meningitis cefoperazone/cefoper
31、azone/sulbactam sulbactam 35dPolymyxin EPolymyxin EJian Li, et al. AAC, 2006, 50:29462950Passage of ATCC 19606 in CAMHB with or without colistinHetero resistant to colistinpassages clinic AB in broth containing colistin increased the proportion of the resistant subpopulations from 10E-8 to 10E-4isol
32、atesMICBefore inductionAfter induction*6mg/L 8mg/L10mg/L6mg/L8mg/L10mg/L163011.5mg/L10E-610E-610E-610E-5 10E-5 10E-5163021.5mg/L10E-810E-810E-810E-410E-410E-4103051.5mg/L10E-710E-810E-810E-510E-510E-5*8mg/L * 48小时,小时,64mg/L * 48小时小时High resistance to colistin of MDRAB from Korea Considering theincre
33、asing 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, 64:43-51BIG BIG BUG!BUG!Colistin Good outcome to MDR AB infection,including: bacteremia、pneumonia、urinary tract infection、wound i
34、nfection、 meningitisOnly 10.8 CRAB were resistant to colistin in China MainlandTigecycline: 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 with other an
35、tibiotics in 28 patients) was effective in 32 cases In 3 cases, resistance to tigecycline developed during treatment Drosos EK, et al. JAC, 2008, 62:44-45Tetracycline Susceptibility Testing in Isolates of Acinetobacte from a U.S. Military HospitalKevin S. Akers, AAC, 2009, acceptedSusceptibility of
36、73 IPM-I or R A. baumannii isolates to tigecyclineS:6 isolatesS:6 isolates(8.28.2),),I: 6 I: 6 isolatesisolates(8.28.2),),R:61 R:61 isolatesisolates(83.683.6)Susceptibility of 43 IPM-S Susceptibility of 43 IPM-S Susceptibility of 43 IPM-S Susceptibility of 43 IPM-S A. baumanniiA. baumanniiA. baumann
37、iiA. baumannii isolates to isolates to isolates to isolates to tigecyclinetigecyclinetigecyclinetigecyclineS:19 isolatesS:19 isolates(44.244.2),),I:6 I:6 isolatesisolates(14.014.0),),R:18 R:18 isolatesisolates(41.941.9)替加环素对中国部分地区亚胺培南耐药鲍曼不动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杆菌体外抗菌活性差In vitro studiesAnima
38、l modelsClinical experienceMP+SAMMP+SAMRIF+COIP+SAMIP+SAMCO+*RIF+SAMIP+TOBRIF+POIP+RIFRIF+CORIF+TOB/COIP+RIF+PORIF+SAMIP+POFEP+SAMCombinations of antibiotics demonstrating enhancedactivity against CRAB*: IP, MP, SAM, TZP, FEP, quinolones, aminoglycosidesFederico P, et al. Antimicrob Agents Chemother. AcceptedHand HygineIsolation of patients (infected or colonized)environment sterilization Decrease clonal spreadThank you for your attention!