鮑曼不動(dòng)桿菌流行及治療

1、鮑曼不動(dòng)桿菌流行及治療,,不動(dòng)桿菌是不發(fā)酵糖的革蘭陰性球桿菌至少分為16個(gè)基因種： ①鮑曼不動(dòng)桿菌（A baumanii） ②醋酸鈣不動(dòng)桿菌（A calcoacelicus） ③溶血性不動(dòng)桿菌（A haemolyticus） ④約翰遜不動(dòng)桿菌（A johnonii） ⑤洛菲不動(dòng)桿菌（A lwoffii） ⑥瓊氏不動(dòng)桿菌（A junii） ⑦耐放射性不動(dòng)桿菌（A radioresistens）,鮑曼不動(dòng)桿

2、菌、醋酸鈣不動(dòng)桿菌、未命名的基因種3、13TU表型十分接近，所以把它們統(tǒng)稱為鮑曼復(fù)合醋酸鈣不動(dòng)桿菌。 臨床標(biāo)本中分離到的不動(dòng)桿菌絕大數(shù)為鮑曼不動(dòng)桿菌，其它菌種引起的感染比較少見。,鮑曼不動(dòng)桿菌占ICU院內(nèi)獲得性肺炎病原菌的比例及對(duì)常用抗菌藥物的耐藥率,,Clin Infect Dis 2005: 41: 848-854,1994-2004年可分析的主要菌株數(shù)（NPRS）,,2008年CHINET耐藥監(jiān)測(cè)革蘭陰性菌菌種分布,Mult

3、idrug-resistant A. baumannii (MDRAB),Resistance to 3 or more than 3 kinds of antibioticsantipseudomonal cephalosporinsantipseudomonal carbapenemsβ-lactamase inhibitor combinationsantipseudomonal fluoroquinolonesamin

4、oglycosidesPandrug-resistant A. baumannii, PDRABresistance to all antibiotics but polymycin and tigecycline,“XDR”： extreme drug resistance,對(duì)抗綠膿的頭孢菌素抗綠膿的碳青霉烯類ß-內(nèi)酰胺抗生素復(fù)合制劑氟喹諾酮類氨基糖苷類替加環(huán)素多粘菌素,MDR-AB全球流行,從西班牙到挪威

5、，出現(xiàn)了令人擔(dān)憂的多重耐藥鮑曼不動(dòng)桿菌“入侵”現(xiàn)象 在駐阿富汗和伊拉克美軍和英軍的外傷士兵中流行，造成嚴(yán)重的公共衛(wèi)生問題,http://www.acinetobacter.org/,伊拉克美軍鮑曼不動(dòng)桿菌肺炎沿幼發(fā)拉底河、底格里斯河分布,http://www.acinetobacter.org/map/map.htm,伊拉克美軍帶回的鮑曼不動(dòng)桿菌在美國(guó)流行,http://www.leishmaniasis.us/Mapping.ht

6、ml,3個(gè)克隆在英國(guó)全國(guó)廣泛流行,6個(gè)主要克隆在6省市19家醫(yī)院播散(342株）,3 major pulse-clone spread in China Mainland,我國(guó)不同城市間出現(xiàn)相同克隆,國(guó)內(nèi)部分流行克隆株的ST分型及發(fā)現(xiàn)的新等位基因型,gltA：共30種，其中新型26種 gyrB：共39種，其中新型28種gdhB：共43種，其中新型33種 recA：共25種，其中新型17種

7、 cpn60：共39種，其中新型31種 gpi：共44種，其中新型32種 rpoD：共17種，其中新型9種,Diagram of clone complex 22 defined by eBURST,ST6：歐洲克?、颍嘀啬退幹?，在比利時(shí)、法國(guó)、德國(guó)、希臘、 波蘭、葡萄牙、西班牙、捷克及土耳其流行。ST4、ST53：意大利，多重耐藥株 ST33：葡萄牙，產(chǎn)OXA-40菌株ST22：截

8、至2009年，已有中國(guó)、中國(guó)香港、韓國(guó)、意大利報(bào)道ST22型　　　 鮑曼不動(dòng)桿菌,http://pubmlst.org/abaumannii/,,,,,,,,為什么鮑曼不動(dòng)桿菌會(huì)全球流行？,廣泛分布水、土壤、醫(yī)院環(huán)境和人體皮膚表面強(qiáng)大的環(huán)境生存能力和廣泛的耐藥性使其成為越來越重要的院感病原菌近年，多重耐藥鮑曼不動(dòng)桿菌（MDR-AB）已經(jīng)在全球各地出現(xiàn)甚至造成了爆發(fā)性流行，并且伴隨著耐藥性的不斷增強(qiáng),19,強(qiáng)大的環(huán)境生存能力,不動(dòng)

9、桿菌為不發(fā)酵糖的革蘭陰性 球桿菌、廣泛分布于水、土壤、 醫(yī)院環(huán)境和人體皮膚表面20℃-30℃環(huán)境下生長(zhǎng)良好， 抵抗力強(qiáng)，在干燥的物體表面 鮑曼不動(dòng)桿菌可存活25天， 遠(yuǎn)遠(yuǎn)超過其他革蘭陰性桿菌,,Jawad et al. JCM 1996;34:2881-87; Jawad et al. JCM 1998;36:1938-41,強(qiáng)大的耐藥基因獲得能力,Acinetobacter baylyi ADP1擁有比大腸桿菌

10、感受態(tài)細(xì)胞強(qiáng)大100倍的捕獲外源DNA能力錯(cuò)配修復(fù)系統(tǒng)mutS 的缺失增加了部分不動(dòng)桿菌的突變頻率,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 re

11、gion；17.2％ ORFs located in 28 foreign islands, suggested many acquired genes,GenBank: CP00521,Europe clone II ACICU:AbaR2,Michele I, et al. AAC. 2008, 52:2616-25,I類整合子結(jié)構(gòu)示意圖,I類整合子在鮑曼不動(dòng)桿菌中分布較廣，常同時(shí)攜帶多種抗菌藥物耐藥基因和消毒劑抗性基因，臨床工作

12、應(yīng)引起重視，減少對(duì)抗菌藥物、消毒劑雙重耐藥菌的篩選。,qacE△1 -sul1,qac家族有10 種亞型，表達(dá)多種化合物外排泵；qacE△1 由整合子介導(dǎo)，與sul1藕聯(lián)；qacE△1 -sul1可介導(dǎo)季銨類化合物(如苯扎溴銨、苯扎氯銨、度米芬) 、雙胍類化合物(氯己定) 、腙類化合物、堿性染料、磺胺類抗生素耐藥;鮑曼不動(dòng)桿菌(A. baumannii) qacE△1 -sul1基因的攜帶率達(dá)到80-90. 0%,消毒劑分類,季銨

13、鹽類：低效，抗性多；雙胍類：主要是醋酸氯己定，抗性普遍；酚類：酚可能造成環(huán)境污染，適用受限；醛類：主要在假單胞菌和腸桿菌科細(xì)菌有抗性報(bào)道,消毒劑分類,鹵素類：包括含氯消毒劑、含碘消毒劑和含溴消毒劑，對(duì)含碘消毒劑的抗性尚待確認(rèn)；醇類：常用消毒劑，抗性也有報(bào)道；氧化劑類：過氧乙酸、高錳酸鉀，是高效消毒劑；其他：如金屬離子消毒劑，已較少使用,Acinetobacter baumannii,未發(fā)現(xiàn)對(duì)消毒劑的抗性，也未發(fā)現(xiàn)抗生素耐藥與

14、消毒劑抗性之間的聯(lián)系,對(duì)目前使用消毒劑耐藥可能并不是目前鮑曼不動(dòng)感覺流行播散的最重要原因消毒措施偏差所導(dǎo)致的濃度和暴露時(shí)間減少可能導(dǎo)致院內(nèi)交叉感染的發(fā)生,4種主要消毒劑在有機(jī)干擾物存在的情況下殺菌活力顯著下降,Triclosan resistance in clinical AB from China mainland,MICs ranged between 0.015 and 16 mg/L and MIC90 was 0.5 mg

15、/L, extremely lower than the actual in-use concentration of triclosan (2000-20000 mg/L).,Factors leading to the emergence and transmission of MDRAB,Lisa L, et al. CID 2008, 46:1254-1263.,Contaminated surfaces increase cr

16、oss-transmission,X represents multi-drugs resistant pathogens culture positive sites,無處不在！,Highly refractory to both vigorouscleaning and to disinfectants!,alcohol-based hand rubs may make mattersworse rather than bett

17、er!!,Bernard Dixon. The Lancet Infectious Disease. 2008,8,alcohol or an alcohol-based hand rub provided the organism with an additional source of carbon,鮑曼不動(dòng)桿菌為什么多重耐藥？4 cluster of CHDLs in A. baumannii,Anton Y. Peleg, e

18、t al. CMR. 2008, 21:538–582.,Carbapenemases in Ab of China mainland,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,

19、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, China Mainland, et al.VEB-1: French、BelgianSHV-12、SHV-2:

20、 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,Amp

21、C in A. baumannii,Chromosomally encoded class C beta-lactamase: Acinetobacter-derived cephalosporinases (ADCs)～30 blaADC genes have been found We identified 60 ADCs-haboring isolates for 61 Acinetobacter spp. Includin

22、g: A. baumannii, Acinetobacter 13TU, Acinetobacter genus 3, A. calcoaceticus, A. haemolyticus,8 A. baumannii isolated from Wenzhou, producing ESBLs+AmpC,酶粗提液,酶粗提液+克拉維酸,酶粗提液+氯唑西林,酶粗提液+氯唑西林+拉維酸,16S rRNA methylase in A. bau

23、mannii,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

24、MDRAB,,,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, 21:538–582.,Susceptiblity of A

25、. baumannii: 1994-2004 (1874 isolates),Susceptibiligy(%),Year,2008年12家醫(yī)院3508株不動(dòng)桿菌屬(鮑曼不動(dòng)86.2%)細(xì)菌的耐藥率（%）,,,,,R,No S,How to treat infections caused by MDR A. baumannii,Sulbactam combinationsColistintigecycline,,,2007年浙醫(yī)

26、一院呼吸道標(biāo)本主要分離菌,,,鮑曼不動(dòng)桿菌菌在體液標(biāo)本中的分離率,,,FASS RJ, et al. Antimicrobial agents and chemotherapy 1990; 34(11): 2256-2259.,Activity of sulbactam to A. baumannii,鮑曼不動(dòng)桿菌體外藥敏,ampicillin/sulbactam to treat MDRAB infections,Levin et a

27、l. Int J Antimicrob Agents 2003;21:58-62,A case: burn patient,Admit 18d,CRAB治療-含舒巴坦制劑,對(duì)不動(dòng)桿菌具有固有的抗菌活性.根據(jù)體外藥敏實(shí)驗(yàn)結(jié)果選擇用藥.降低感染死亡率.國(guó)外報(bào)道對(duì)于嚴(yán)重感染者,舒巴坦的推薦劑量為6g/d,甚至在12g/d時(shí)仍有較好的安全性,但在治療效果上與9g/d組并無統(tǒng)計(jì)學(xué)差異.,Clin Microbiol Rev 2008: 21

28、: 538-582.Lancet Infect Dis 2008: 8: 751-762.Scand J Infect Dis 2007: 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的治療-多黏菌素,靜脈應(yīng)

29、用多黏菌素治療總有效率為57%~>80%.腎功能損害的發(fā)生率約為0~37%.霧化吸入有助于減少全身用藥的副作用,并在 局部組織達(dá)到較高的藥物濃度.仍需進(jìn)一步臨床對(duì)照研究證實(shí).,Clin Microbiol Rev 2008: 21: 538-582.,A case: PDRAB meningitis,Jian Li, et al. AAC, 2006, 50:2946–2950,Passage of ATCC 196

30、06 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小時(shí)，64mg/L * 48小時(shí),

31、High resistance to colistin of MDRAB from 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 K

32、young Parka, DMID 2009, 64:43-51,BIG BUG!,Colistin,Good outcome to MDR AB infection，including: bacteremia、pneumonia、urinary tract infection、wound infection、 meningitis,Only 10.8％ CRAB were resistant to colistin in China

33、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 (combinati

34、on 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

35、of Acinetobacte from a U.S. Military Hospital,Kevin S. Akers, AAC, 2009, accepted,,Susceptibility 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％）,Suscep

36、tibility of 43 IPM-S A. baumannii isolates to tigecycline,S:19 isolates（44.2％），I:6 isolates（14.0％），R:18 isolates（41.9％）,替加環(huán)素對(duì)中國(guó)部分地區(qū)亞胺培南耐藥鮑曼不動(dòng)桿菌體外抗菌活性差,Combinations of antibiotics demonstrating enhancedactivity against

37、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 spre