中国部分地区鲍曼不动杆菌多位点序列分型及碳青霉烯类抗生素耐药机制研究
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摘要
碳青霉烯类抗生素耐药鲍曼不动杆菌(Carbapenem-resistant Acinetobacter baumannii, CRAB)在我国各地的广泛出现和流行,给临床治疗带来了极大的困难。应用分子分型技术对我国各个地区的CRAB进行系统全面的分子流行病学研究,阐明我国CRAB的流行分布情况,将为制订科学、有效的预防和控制措施提供理论依据。
本研究第一部分收集了2005年中国16个城市24家三级医院的分离的226株非重复的鲍曼不动杆菌,包括152株CRAB菌株和74株碳青霉烯类抗生素敏感鲍曼不动杆菌(Carbapenem-susceptible Acinetobacter baumannii, CSAB),应用多位点序列分型(Multilocus sequence typing, MLST)技术对这些菌株进行分子分型,并将结果与细菌分子分型技术的“金标准”脉冲场凝胶电泳(Pulsed-field gel electrophoresis, PFGE)结果进行比较,分析MLST技术应用于鲍曼不动杆菌分子流行病研究的可行性；应用eBURST软件对MLST数据进行分析,推测菌株的进化关系,并与国外鲍曼不动杆菌MLST分型结果进行比较分析；测定了11种抗菌药物的体外敏感性试验；应用PCR检测了菌株携带的碳青霉烯类抗生素耐药基因。
MLST结果显示,CRAB菌株的遗传背景相对单一,包含8个序列型(Sequence type, ST),其中ST92及其单个位点变异型(Single locus variant, SLV) ST90和ST75为主要流行ST型,其次为ST91型。CSAB菌株具有更多样性的遗传背景,包含36个ST型,ST92也是CSAB菌株中最主要的ST型。
PFGE将226株鲍曼不动杆菌分为44个脉冲型。整体上看,PFGE与MLST的结果具有较好的一致性,但是在对ST92及其SLVs菌株的区分上,PFGE和MLST存在部分的差异。与PFGE相比,MLST对菌株同源性的判定更为保守,可以反映菌株较长时间内的进化关系。
将MLST数据与鲍曼不动杆菌网络数据库Pubmlst (http://pubmlst.org/abaumannii/)中数据进行对比分析,发现ST92及其SLVs属于克隆复合体92(Clonal complex92, CC92,原名CC22),是目前数据库中最主要克隆复合体,其菌株来源包括了亚洲、欧洲、大洋洲和美洲的多个国家,证实CC92存在世界性的广泛流行,且中国流行的CRAB菌株与国外流行的菌株在进化上来自于相同的祖先。
CC92和ST91型鲍曼不动杆菌对碳青霉烯类、第三和第四代头孢菌素、氨基糖苷类、米诺环素和氟喹诺酮的耐药性均要高于其他ST型鲍曼不动杆菌(P<0.001)。ST92-CRAB与ST92-CSAB相比,除碳青霉烯类抗生素以外,对以上其他抗菌药物的耐药率无统计学差异,提示多重耐药是ST92型菌株的重要特征。
blaOXA-23是CRAB菌株携带的最主要的获得性的碳青霉烯酶基因。ST91型CRAB菌株同时携带了blaOXA-23和blaOXA-58。CSAB菌株中均未检测到获得性的碳青霉烯酶基因。blaOXA-23阳性的ST92型CRAB菌株对亚胺培南的最小抑菌浓度(Minimal inhibitory concentration, MIC)是blaOXA-23阴性的ST92型CSAB菌株的32-128倍,提示blaOXA-23是造成ST92型鲍曼不动杆菌对碳青霉烯类抗生素耐药的关键因素。
本研究第一部分应用了MLST分型技术对国内多个城市的鲍曼不动杆菌进行分子流行病学研究,发现克隆复合体CC92是我国甚至全球流行范围最广的CRAB克隆,且具有很强的耐药性。OXA-23型碳青霉烯酶基因是介导CC92对该类抗生素耐药的重要因素。CC92在国内的出现和播散是我国鲍曼不动杆菌对碳青霉烯类抗生素耐药率不断升高的重要原因。
具有碳青霉烯类抗生素水解能力的D类p-内酰胺酶(Carbapenem hydrolyzingclass D β-lactamase, CHDL)是介导鲍曼不动杆菌对碳青霉烯类抗生素耐药的最重要机制。blaOXA-58是一种呈全球分布的CHDL基因。本研究第一部分发现ST91型CRAB同时携带了blaOXA-23型和blaOXA-58型碳青霉烯酶基因。第二部分在此基础上,对携带blaOXA-58基因的不动杆菌的遗传背景特征、质粒特征及blaOXA-58基因的周围结构与耐药表型间的联系进行了深入研究。
第二部分研究收集了13株携带blaOXA-58基因的非重复的不动杆菌,来自自国内6个城市的7家三级医院,包括了2株pittii不动杆菌(即不动杆菌基因种型3),3株nosocomialis不动杆菌(即不动杆菌基因种型13TU)和8株鲍曼不动杆菌(其中两株浙江金华的鲍曼不动杆菌来自在第一部分研究)。应用PFGE和MLST对这些菌株进行分子流行病学研究；测定所有菌株对13种抗菌药物的MIC值；应用Southern杂交确定blaOXA-58的基因定位；应用质粒抽提和电转化确定携带blaOXA-58质粒的可传播性；应用限制性酶切、克隆技术分析blaOXA-58的基因周围序列；应用基于PCR的鲍曼不动杆菌质粒复制子分型法(Acinetobacter baumannii PCR-based replicon typing, AB-PBRT)对不同菌株中携带blaOXA-58的质粒进行分型研究。
PFGE分型发现,2株pittii不动杆菌属于同一个脉冲型(分别来自浙江杭州和浙江台州),3株nosocomialis不动杆菌分属于2个脉冲型(均来自浙江温州),8株鲍曼不动杆菌可分为3个脉冲型。8株鲍曼不动杆菌可分为3个ST型。其中ST91在浙江金华和湖北武汉的医院出现,且浙江金华中心医院2004年和2009年均分离到了ST91型产OXA-58型碳青霉烯酶的鲍曼不动杆菌,提示其存在地方性流行。
13株不动杆菌表现出不同的碳青霉烯类抗生素敏感性表型。pittii不动杆菌和nosocomialis不动杆菌均为碳青霉烯类抗生素敏感。而鲍曼不动杆菌中仅有一株为碳青霉烯类抗生素敏感,其余均为耐药。同时,鲍曼不动杆菌对第三代和四代头孢菌素、含p-内酰胺酶抑制剂的复合制剂、氨基糖苷类、米诺环素和环丙沙星的耐药性均要高于pittii不动杆菌和nosocomialis不动杆菌。
Southern杂交结果显示,13株不动杆菌中blaOXA-58基因均定位于质粒上,质粒大小范围在52kb-305kb之间。除了305kb的质粒外,其余质粒均可通过电转化转移到碳青霉烯类抗生素敏感的鲍曼不动杆菌受体菌中。应用AB-PBRT分型法发现,这些质粒不属于已知的质粒复制子分型。确认了2株pittii不动杆菌,3株nosocomialis不动杆菌和2株鲍曼不动杆菌中携带blaOXA-58基因的质粒属于一种新的质粒复制子分型,命名为Acil0。
对blaOXA-58基因的周围序列进行分析发现,在blaOXA-58基因的上游存在类似插入序列(Insertion sequence, IS)ISAba3的ISAba3-like结构。部分菌株的ISAba3-like结构被IS6家族的插入序列打断,形成IS6family-△ISAba3-like-blaOXA-58的特殊结构。该结构仅出现在7株碳青霉烯类抗生素耐药的鲍曼不动杆菌和1株碳青霉烯类抗生素敏感的nosocomialis不动杆菌中,且具有此结构的质粒通过电转化转入鲍曼不动杆菌受体菌后介导了受体菌对碳青霉烯类抗生素的耐药或中介其余碳青霉类抗生素敏感的不动杆菌中blaOXA-58基因的上游的ISAba3-like结构未被其他IS序列打断。启动子分析发现,IS6family-△ISAba3-like结构为下游blaOXA-58的表达提供了强启动子,在介导碳青霉烯类抗生素耐药中起了重要作用。部分菌株blaOXA-58基因的周围序列中发现了重组位点序列,提示blaOXA-58基因的转移可能和重组事件有关。ST91型鲍曼不动杆菌blaOXA-58基因的下游同时发现了携带氨基糖苷类磷酸转移酶基因aphA6的复合转座子TnaphA6。aphA6随blaOXA-58基因进行传播使受体菌同时获得对碳青霉烯类抗生素和氨基糖苷类抗生素的耐药能力。
本研究第二部分发现blaOXA-58基因可存在于pittii不动杆菌、nosocomialis不动杆菌和鲍曼不动杆菌中,且均定位于质粒上,可以通过电转化的方式转移到受体菌中。pittii不动杆菌、nosocomialis不动杆菌和部分鲍曼不动杆菌中携带blaOXA-58基因的质粒具有相同的质粒复制子分型,提示质粒在不动杆菌间的传播也是造成鲍曼不动杆菌对碳青霉烯类抗生素耐药率迅速上升的重要原因。IS6家族插入序列△ISAba3-like-blaOXA-58的特殊结构为下游blaOXA-58的表达提供了强启动子,与碳青霉烯类抗生素耐药密切相关。
The carbapenem-resistant Acinetobacter baumannii (CRAB) has widely spread in China, which resulting in dilemma in clinical anti-infectious thrapy. Therefore, it is urgent to elucidate the distribution of CRAB in our country using molecular typing method. The results will be useful for prevention and control this pathogen.
In Part Ⅰ of this study,226non-duplicated A. baumannii were collected from24tertiary hospitals of16cities in2005, including152CRAB and74carbapenem-susceptible A. baumannii. Multilocus sequence tying (MLST) was used as the method of molecular typing. The results of MLST were compared with those of the "golden standard" of bacterial molecular typing, pulsed-field gel electrophoresis (PFGE) to confirm the availability of MLST in molecular epidemiological study of A. baumannnii. eBURST was used to analyze the data of MLST and infer the evalutionary descent. The susceptibility testing of11antimicrobial agents were determined. PCR was used to detected the presence of carbapenemase genes.
MLST revealed that the genetic background of CRAB was relatively simple, including8sequence types (STs). ST92and its single locus variants (SLVs), ST90and ST75were the dominant STs, followed by ST91. The genetic background of CSAB was more diverse, including36STs. ST92was also the major ST of CSAB.
44pulsotypes were identified in226A. baumannii by PFGE. In generally, the results of MLST and PFGE were consistent. However, there were some disparities about the genotypes of ST92and its SLVs. MLST was more conservative in the interpreting of bacterial genetic relatedness, and could reveal the bacterial evolutionary descent in long term period.
We compared our data with those in the MLST website database of A. baumannii (Pubmlst, http://pubmlst.org/abaumannii/). ST92and its SLVs were all grouped as clonal complex (CC)92(formerly named CC22), which is the largest CC in the database. The origins of CC92isolates were covered many countries of Asian, Europe, Oceania and Americas, confirming the worldwide spread of CC92. The CC92CRAB of China and other countries may evolve from a same progenitor.
CC92and ST91were more resistant to carbapenems, third-and forth-generation cephalosporins, aminoglycosides, minocycline and fluoroquinolones than the other STs (P<0.001). There were no statistical difference between antibiotics resistance of ST92-CRAB and ST92-CSAB. The results implys multidrug resistance is an important feature of ST92.
blaOXA-23was the main acquired carbapenemase gene of CRAB. ST91co-carried blaOXA-23and WaOXA-58.None of carbapenemase gene was detected in CSAB. The imipenem minimal inhibitory concentrations (MICs) of blaOXA-23-positive ST92-CRAB were32to128times to those of blaOXA-23-negative ST92-CSAB, implying blaOXA-23was an critical determinant of carbapenem resistance in ST92A. baumannii.
In Part Ⅰ of this study, MLST was used for molecular epidemiological investigation of A. baumannii from multiple cities of China. CC92was the most prevalent CRAB clone of China, as well as the worldwide spread clone, and showed greater antibiotics resistance than the other STs. OXA-23-type carbapenemase was an resistance mechanism of CC92against carbapenems. The emergence and dissemination of CC92in China accounted for the increasing carbapenem resistance inA baumannii.
The carbapenem hydrolyzing class D β-lactamases are the most important factors mediating carbapenem resistance in A. baumannii. blaOXA-58is a worldwide distributed CHDL gene. In Part Ⅰ of this study, we found the ST91CRAB co-carried blaOXA-23and blaOXA-58.On that basis, in Part Ⅱ of this study, we further studied the genetic background of blaOXA-58-harboring Acinetobacter spp., the feature of blaOXA-58-harboring plasmids, as well as the relationship between genetic contexts of blaOXA-58and susceptibility testing profiles
13blaOXA-58-harboring non-duplicated Acinetobacter spp. were collected from seven tertiary hospitals of six cities, including two Acinetobacter pittii (formerly Acinetobacter genomic species3), three Acinetobacter nosocomialis (formerly Acinetobacter genomic species13TU) and eight A. baumannii (two A. baumannii isolates from Jinhua, Zhejiang Province were present in Part Ⅰ of this study). PFGE and MLST were used for the molecular epidemiological investigation. The MICs of13antimicrobial agents were determined. The genetic location of blaOXA-58was determined by Southern hybridization. The genetic contexts of blaOXA-58were acquired through restricted digestion and cloning experiments. The blaOXA-58-harboring plasmids were typed by A. baumannii PCR-based replicon typing method (AB-PBRT).
PFGE identified the two A. pittii belonged to a same pulsotype (from Hangzhou and Taizhou respectively), and the three A. nosocomialis belonged to two pulsotypes (all from Wenzhou). Three pulsotypes were identified in eight A. baumannii, corresponding to three STs using MLST. ST91were detected in Jinhua, Zhejiang Province and Wuhan, Hubei Province, and recovered from Jinhua Center Hospital both in2005and2009, implying endemic prevalent in this hospital.
The13Acinetobacter spp. displayed various carbapenem susceptibility testing profiles. All A. pittii and A. nosocomialis were carbapenem susceptible. However, the A. baumannii were almostly carbapenem resistance, except one showed carbapenem susceptible. Moreover, A. baumannii were more resistant to third-and forth-generation cephalosporins, β-lactams combination with β-lactamase inhibitor, aminoglycosides, minocycline and ciprofloxacin than A. pittii and A. nosocomialis.
The plasmid location of blaOXA-58in13Acinetobacter spp. were confirmed by Southern hybridization, and the sizes of plasmid were ranged from ca.52kb to ca.305kb. All plasmids could transfer to carbapenem-susceptible recepient through electrotransformation except for the largest one. The plasmids did not belong to any known plasmid replicon typing. Aci10, a novel plasmid replicon typing was identified in the blaOXA-58-harboring plasmids of two A. pittii, three A. nosocomialis and two A. baumannii.
An ISAba3-like element was identified upstream of blaOXA-58, and the element was disrupted by insertion sequence of IS6family in partial isolates, named IS6family-AISAba3-like-blaOXA-58structure. The special structure was present in seven carbapenem-resistant A. baumannii and one carbapenem-susceptible A. nosocomialis, and their transformants showed carbapenem resistant or mediated. In remaining carbapenem-susceptible isolates, the ISAba3-like element was intact. The special IS6family-△ISAba3-like-blaOXA-58structure provided strong promoter for transcription of blaOXA-58, which played an important role in the carbapenem resistance. Recombination sites around blaOXA-58were identified in partial isolates, implying the acquisition of blaOXA-58was associated with recombination events. An aminoglycoside O-phosphotransferases gene, aphA6, was identified downstream of blaOXA-58of ST91A. baumannii, and which located in a composite transposon named TnaphA6. The co-transfer of aphA6and blaOXA-58, resulted in the recepient developed carbapenem and aminoglycoside resistance at the same time.
The part Ⅱ of this study demonstrated the plasmid-location of blaOXA-58in A.pittii, A. nosocomialis and A. baumannii, and the plamids could transfer to recepient by electrotransformation. A same plasmid replicon typing was identified in blaOXA-58-harboring plasmids of A. pittii, A. nosocomialis and partial A. baumannii, suggesting the transfer of plamids among Acientobacter spp. was involved in the rapid increasing of carbapenem resistant rate in this pathogen. The special IS6family-△ISAba3-like-blaOXA-58structure contributed to the carbapenem resistance through providing strong promoter for the transcription of blaOXA-58.
本研究第一部分收集了2005年中国16个城市24家三级医院的分离的226株非重复的鲍曼不动杆菌,包括152株CRAB菌株和74株碳青霉烯类抗生素敏感鲍曼不动杆菌(Carbapenem-susceptible Acinetobacter baumannii, CSAB),应用多位点序列分型(Multilocus sequence typing, MLST)技术对这些菌株进行分子分型,并将结果与细菌分子分型技术的“金标准”脉冲场凝胶电泳(Pulsed-field gel electrophoresis, PFGE)结果进行比较,分析MLST技术应用于鲍曼不动杆菌分子流行病研究的可行性；应用eBURST软件对MLST数据进行分析,推测菌株的进化关系,并与国外鲍曼不动杆菌MLST分型结果进行比较分析；测定了11种抗菌药物的体外敏感性试验；应用PCR检测了菌株携带的碳青霉烯类抗生素耐药基因。
MLST结果显示,CRAB菌株的遗传背景相对单一,包含8个序列型(Sequence type, ST),其中ST92及其单个位点变异型(Single locus variant, SLV) ST90和ST75为主要流行ST型,其次为ST91型。CSAB菌株具有更多样性的遗传背景,包含36个ST型,ST92也是CSAB菌株中最主要的ST型。
PFGE将226株鲍曼不动杆菌分为44个脉冲型。整体上看,PFGE与MLST的结果具有较好的一致性,但是在对ST92及其SLVs菌株的区分上,PFGE和MLST存在部分的差异。与PFGE相比,MLST对菌株同源性的判定更为保守,可以反映菌株较长时间内的进化关系。
将MLST数据与鲍曼不动杆菌网络数据库Pubmlst (http://pubmlst.org/abaumannii/)中数据进行对比分析,发现ST92及其SLVs属于克隆复合体92(Clonal complex92, CC92,原名CC22),是目前数据库中最主要克隆复合体,其菌株来源包括了亚洲、欧洲、大洋洲和美洲的多个国家,证实CC92存在世界性的广泛流行,且中国流行的CRAB菌株与国外流行的菌株在进化上来自于相同的祖先。
CC92和ST91型鲍曼不动杆菌对碳青霉烯类、第三和第四代头孢菌素、氨基糖苷类、米诺环素和氟喹诺酮的耐药性均要高于其他ST型鲍曼不动杆菌(P<0.001)。ST92-CRAB与ST92-CSAB相比,除碳青霉烯类抗生素以外,对以上其他抗菌药物的耐药率无统计学差异,提示多重耐药是ST92型菌株的重要特征。
blaOXA-23是CRAB菌株携带的最主要的获得性的碳青霉烯酶基因。ST91型CRAB菌株同时携带了blaOXA-23和blaOXA-58。CSAB菌株中均未检测到获得性的碳青霉烯酶基因。blaOXA-23阳性的ST92型CRAB菌株对亚胺培南的最小抑菌浓度(Minimal inhibitory concentration, MIC)是blaOXA-23阴性的ST92型CSAB菌株的32-128倍,提示blaOXA-23是造成ST92型鲍曼不动杆菌对碳青霉烯类抗生素耐药的关键因素。
本研究第一部分应用了MLST分型技术对国内多个城市的鲍曼不动杆菌进行分子流行病学研究,发现克隆复合体CC92是我国甚至全球流行范围最广的CRAB克隆,且具有很强的耐药性。OXA-23型碳青霉烯酶基因是介导CC92对该类抗生素耐药的重要因素。CC92在国内的出现和播散是我国鲍曼不动杆菌对碳青霉烯类抗生素耐药率不断升高的重要原因。
具有碳青霉烯类抗生素水解能力的D类p-内酰胺酶(Carbapenem hydrolyzingclass D β-lactamase, CHDL)是介导鲍曼不动杆菌对碳青霉烯类抗生素耐药的最重要机制。blaOXA-58是一种呈全球分布的CHDL基因。本研究第一部分发现ST91型CRAB同时携带了blaOXA-23型和blaOXA-58型碳青霉烯酶基因。第二部分在此基础上,对携带blaOXA-58基因的不动杆菌的遗传背景特征、质粒特征及blaOXA-58基因的周围结构与耐药表型间的联系进行了深入研究。
第二部分研究收集了13株携带blaOXA-58基因的非重复的不动杆菌,来自自国内6个城市的7家三级医院,包括了2株pittii不动杆菌(即不动杆菌基因种型3),3株nosocomialis不动杆菌(即不动杆菌基因种型13TU)和8株鲍曼不动杆菌(其中两株浙江金华的鲍曼不动杆菌来自在第一部分研究)。应用PFGE和MLST对这些菌株进行分子流行病学研究；测定所有菌株对13种抗菌药物的MIC值；应用Southern杂交确定blaOXA-58的基因定位；应用质粒抽提和电转化确定携带blaOXA-58质粒的可传播性；应用限制性酶切、克隆技术分析blaOXA-58的基因周围序列；应用基于PCR的鲍曼不动杆菌质粒复制子分型法(Acinetobacter baumannii PCR-based replicon typing, AB-PBRT)对不同菌株中携带blaOXA-58的质粒进行分型研究。
PFGE分型发现,2株pittii不动杆菌属于同一个脉冲型(分别来自浙江杭州和浙江台州),3株nosocomialis不动杆菌分属于2个脉冲型(均来自浙江温州),8株鲍曼不动杆菌可分为3个脉冲型。8株鲍曼不动杆菌可分为3个ST型。其中ST91在浙江金华和湖北武汉的医院出现,且浙江金华中心医院2004年和2009年均分离到了ST91型产OXA-58型碳青霉烯酶的鲍曼不动杆菌,提示其存在地方性流行。
13株不动杆菌表现出不同的碳青霉烯类抗生素敏感性表型。pittii不动杆菌和nosocomialis不动杆菌均为碳青霉烯类抗生素敏感。而鲍曼不动杆菌中仅有一株为碳青霉烯类抗生素敏感,其余均为耐药。同时,鲍曼不动杆菌对第三代和四代头孢菌素、含p-内酰胺酶抑制剂的复合制剂、氨基糖苷类、米诺环素和环丙沙星的耐药性均要高于pittii不动杆菌和nosocomialis不动杆菌。
Southern杂交结果显示,13株不动杆菌中blaOXA-58基因均定位于质粒上,质粒大小范围在52kb-305kb之间。除了305kb的质粒外,其余质粒均可通过电转化转移到碳青霉烯类抗生素敏感的鲍曼不动杆菌受体菌中。应用AB-PBRT分型法发现,这些质粒不属于已知的质粒复制子分型。确认了2株pittii不动杆菌,3株nosocomialis不动杆菌和2株鲍曼不动杆菌中携带blaOXA-58基因的质粒属于一种新的质粒复制子分型,命名为Acil0。
对blaOXA-58基因的周围序列进行分析发现,在blaOXA-58基因的上游存在类似插入序列(Insertion sequence, IS)ISAba3的ISAba3-like结构。部分菌株的ISAba3-like结构被IS6家族的插入序列打断,形成IS6family-△ISAba3-like-blaOXA-58的特殊结构。该结构仅出现在7株碳青霉烯类抗生素耐药的鲍曼不动杆菌和1株碳青霉烯类抗生素敏感的nosocomialis不动杆菌中,且具有此结构的质粒通过电转化转入鲍曼不动杆菌受体菌后介导了受体菌对碳青霉烯类抗生素的耐药或中介其余碳青霉类抗生素敏感的不动杆菌中blaOXA-58基因的上游的ISAba3-like结构未被其他IS序列打断。启动子分析发现,IS6family-△ISAba3-like结构为下游blaOXA-58的表达提供了强启动子,在介导碳青霉烯类抗生素耐药中起了重要作用。部分菌株blaOXA-58基因的周围序列中发现了重组位点序列,提示blaOXA-58基因的转移可能和重组事件有关。ST91型鲍曼不动杆菌blaOXA-58基因的下游同时发现了携带氨基糖苷类磷酸转移酶基因aphA6的复合转座子TnaphA6。aphA6随blaOXA-58基因进行传播使受体菌同时获得对碳青霉烯类抗生素和氨基糖苷类抗生素的耐药能力。
本研究第二部分发现blaOXA-58基因可存在于pittii不动杆菌、nosocomialis不动杆菌和鲍曼不动杆菌中,且均定位于质粒上,可以通过电转化的方式转移到受体菌中。pittii不动杆菌、nosocomialis不动杆菌和部分鲍曼不动杆菌中携带blaOXA-58基因的质粒具有相同的质粒复制子分型,提示质粒在不动杆菌间的传播也是造成鲍曼不动杆菌对碳青霉烯类抗生素耐药率迅速上升的重要原因。IS6家族插入序列△ISAba3-like-blaOXA-58的特殊结构为下游blaOXA-58的表达提供了强启动子,与碳青霉烯类抗生素耐药密切相关。
The carbapenem-resistant Acinetobacter baumannii (CRAB) has widely spread in China, which resulting in dilemma in clinical anti-infectious thrapy. Therefore, it is urgent to elucidate the distribution of CRAB in our country using molecular typing method. The results will be useful for prevention and control this pathogen.
In Part Ⅰ of this study,226non-duplicated A. baumannii were collected from24tertiary hospitals of16cities in2005, including152CRAB and74carbapenem-susceptible A. baumannii. Multilocus sequence tying (MLST) was used as the method of molecular typing. The results of MLST were compared with those of the "golden standard" of bacterial molecular typing, pulsed-field gel electrophoresis (PFGE) to confirm the availability of MLST in molecular epidemiological study of A. baumannnii. eBURST was used to analyze the data of MLST and infer the evalutionary descent. The susceptibility testing of11antimicrobial agents were determined. PCR was used to detected the presence of carbapenemase genes.
MLST revealed that the genetic background of CRAB was relatively simple, including8sequence types (STs). ST92and its single locus variants (SLVs), ST90and ST75were the dominant STs, followed by ST91. The genetic background of CSAB was more diverse, including36STs. ST92was also the major ST of CSAB.
44pulsotypes were identified in226A. baumannii by PFGE. In generally, the results of MLST and PFGE were consistent. However, there were some disparities about the genotypes of ST92and its SLVs. MLST was more conservative in the interpreting of bacterial genetic relatedness, and could reveal the bacterial evolutionary descent in long term period.
We compared our data with those in the MLST website database of A. baumannii (Pubmlst, http://pubmlst.org/abaumannii/). ST92and its SLVs were all grouped as clonal complex (CC)92(formerly named CC22), which is the largest CC in the database. The origins of CC92isolates were covered many countries of Asian, Europe, Oceania and Americas, confirming the worldwide spread of CC92. The CC92CRAB of China and other countries may evolve from a same progenitor.
CC92and ST91were more resistant to carbapenems, third-and forth-generation cephalosporins, aminoglycosides, minocycline and fluoroquinolones than the other STs (P<0.001). There were no statistical difference between antibiotics resistance of ST92-CRAB and ST92-CSAB. The results implys multidrug resistance is an important feature of ST92.
blaOXA-23was the main acquired carbapenemase gene of CRAB. ST91co-carried blaOXA-23and WaOXA-58.None of carbapenemase gene was detected in CSAB. The imipenem minimal inhibitory concentrations (MICs) of blaOXA-23-positive ST92-CRAB were32to128times to those of blaOXA-23-negative ST92-CSAB, implying blaOXA-23was an critical determinant of carbapenem resistance in ST92A. baumannii.
In Part Ⅰ of this study, MLST was used for molecular epidemiological investigation of A. baumannii from multiple cities of China. CC92was the most prevalent CRAB clone of China, as well as the worldwide spread clone, and showed greater antibiotics resistance than the other STs. OXA-23-type carbapenemase was an resistance mechanism of CC92against carbapenems. The emergence and dissemination of CC92in China accounted for the increasing carbapenem resistance inA baumannii.
The carbapenem hydrolyzing class D β-lactamases are the most important factors mediating carbapenem resistance in A. baumannii. blaOXA-58is a worldwide distributed CHDL gene. In Part Ⅰ of this study, we found the ST91CRAB co-carried blaOXA-23and blaOXA-58.On that basis, in Part Ⅱ of this study, we further studied the genetic background of blaOXA-58-harboring Acinetobacter spp., the feature of blaOXA-58-harboring plasmids, as well as the relationship between genetic contexts of blaOXA-58and susceptibility testing profiles
13blaOXA-58-harboring non-duplicated Acinetobacter spp. were collected from seven tertiary hospitals of six cities, including two Acinetobacter pittii (formerly Acinetobacter genomic species3), three Acinetobacter nosocomialis (formerly Acinetobacter genomic species13TU) and eight A. baumannii (two A. baumannii isolates from Jinhua, Zhejiang Province were present in Part Ⅰ of this study). PFGE and MLST were used for the molecular epidemiological investigation. The MICs of13antimicrobial agents were determined. The genetic location of blaOXA-58was determined by Southern hybridization. The genetic contexts of blaOXA-58were acquired through restricted digestion and cloning experiments. The blaOXA-58-harboring plasmids were typed by A. baumannii PCR-based replicon typing method (AB-PBRT).
PFGE identified the two A. pittii belonged to a same pulsotype (from Hangzhou and Taizhou respectively), and the three A. nosocomialis belonged to two pulsotypes (all from Wenzhou). Three pulsotypes were identified in eight A. baumannii, corresponding to three STs using MLST. ST91were detected in Jinhua, Zhejiang Province and Wuhan, Hubei Province, and recovered from Jinhua Center Hospital both in2005and2009, implying endemic prevalent in this hospital.
The13Acinetobacter spp. displayed various carbapenem susceptibility testing profiles. All A. pittii and A. nosocomialis were carbapenem susceptible. However, the A. baumannii were almostly carbapenem resistance, except one showed carbapenem susceptible. Moreover, A. baumannii were more resistant to third-and forth-generation cephalosporins, β-lactams combination with β-lactamase inhibitor, aminoglycosides, minocycline and ciprofloxacin than A. pittii and A. nosocomialis.
The plasmid location of blaOXA-58in13Acinetobacter spp. were confirmed by Southern hybridization, and the sizes of plasmid were ranged from ca.52kb to ca.305kb. All plasmids could transfer to carbapenem-susceptible recepient through electrotransformation except for the largest one. The plasmids did not belong to any known plasmid replicon typing. Aci10, a novel plasmid replicon typing was identified in the blaOXA-58-harboring plasmids of two A. pittii, three A. nosocomialis and two A. baumannii.
An ISAba3-like element was identified upstream of blaOXA-58, and the element was disrupted by insertion sequence of IS6family in partial isolates, named IS6family-AISAba3-like-blaOXA-58structure. The special structure was present in seven carbapenem-resistant A. baumannii and one carbapenem-susceptible A. nosocomialis, and their transformants showed carbapenem resistant or mediated. In remaining carbapenem-susceptible isolates, the ISAba3-like element was intact. The special IS6family-△ISAba3-like-blaOXA-58structure provided strong promoter for transcription of blaOXA-58, which played an important role in the carbapenem resistance. Recombination sites around blaOXA-58were identified in partial isolates, implying the acquisition of blaOXA-58was associated with recombination events. An aminoglycoside O-phosphotransferases gene, aphA6, was identified downstream of blaOXA-58of ST91A. baumannii, and which located in a composite transposon named TnaphA6. The co-transfer of aphA6and blaOXA-58, resulted in the recepient developed carbapenem and aminoglycoside resistance at the same time.
The part Ⅱ of this study demonstrated the plasmid-location of blaOXA-58in A.pittii, A. nosocomialis and A. baumannii, and the plamids could transfer to recepient by electrotransformation. A same plasmid replicon typing was identified in blaOXA-58-harboring plasmids of A. pittii, A. nosocomialis and partial A. baumannii, suggesting the transfer of plamids among Acientobacter spp. was involved in the rapid increasing of carbapenem resistant rate in this pathogen. The special IS6family-△ISAba3-like-blaOXA-58structure contributed to the carbapenem resistance through providing strong promoter for the transcription of blaOXA-58.
引文
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