中国血流感染相关产碳青霉烯酶肠杆菌的基因组及表型多样性——一项多中心流行病学、 微生物学和遗传学研究

Beiwen Zheng, Hao Xu, Lihua Guo, Xiao Yu, Jinru Ji, Chaoqun Ying, Yunbo Chen, Ping Shen, Huiming Han, Chen Huang, Shuntian Zhang, Tao Lv, Yonghong Xiao

工程(英文) ›› 2022, Vol. 12 ›› Issue (5) : 90-100.

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工程(英文) ›› 2022, Vol. 12 ›› Issue (5) : 90-100. DOI: 10.1016/j.eng.2020.10.015
研究论文
Article

中国血流感染相关产碳青霉烯酶肠杆菌的基因组及表型多样性——一项多中心流行病学、 微生物学和遗传学研究

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Genomic and Phenotypic Diversity of Carbapenemase-Producing Enterobacteriaceae Isolates from Bacteremia in China: A Multicenter Epidemiological, Microbiological, and Genetic Study

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摘要

产碳青霉烯酶肠杆菌(CPE)是对全球公共卫生产生最严重威胁的病原菌之一。然而,血流感染(BSI)中CPE分离株的种群结构和遗传特征在很大程度上尚不清楚。为解决这一认知差距,将具有临床意义的由CPE引起的BSI 患者纳入本研究,并且于2014—2015 年在中国26 家哨点医院招募相关患者。对CPE分离株进行微生物学和基因组学表征,包括耐药谱、分子分型、系统发育特征以及碳青霉烯酶编码基因的遗传背景分析。在采集的2569 株BSI 相关肠杆菌中,发现42 株(1.6%)为碳青霉烯酶阳性。此外,对2242株大肠埃希菌、肺炎克雷伯菌、奇异变形杆菌和产酸克雷伯菌进行了产超广谱β-内酰胺酶(ESBL)检测试验,发现1111 株(49.6%)产ESBL菌株。全基因组测序分析显示,在收集的菌株中,产肺炎克雷伯菌碳青霉烯酶(KPC)-2 的ST11 型肺炎克雷伯菌和产新德里金属β-内酰胺酶(NDM)-5 的ST167 型大肠埃希菌在中国存在克隆扩散现象。质粒分析显示碳青霉烯酶编码基因位于多种类型的质粒上。此外,观察到在肺炎克雷伯菌分离株中生物膜形成相关的3 型菌毛簇基因和耶尔森菌素相关毒力基因的分离率较高。本研究证明了产ESBL菌株在中国BSI 分离株中的高流行率及CPE菌株在其中的广泛传播,凸显了上述两类病原菌在临床中产生的威胁。此外,本研究首次全面表征了BSI CPE分离株的基因组特征。强调未来需密切监测产KPC-2 的ST11 型肺炎克雷伯菌和产NDM-5 的ST167 型大肠埃希菌克隆在中国的播散情况。

Abstract

Carbapenemase-producing Enterobacteriaceae (CPE) isolates are recognized as one of the most severe threats to public health. However, the population structure and genetic characteristics of CPE isolates among bloodstream infections (BSIs) are largely unknown. To address this knowledge gap, in this study, we included patients with clinically significant BSIs due to Enterobacterales isolates, recruited from 26 sentinel hospitals in China (2014–2015). CPE isolates were microbiologically and genomically characterized, including their susceptibility profiles, molecular typing, phylogenetic features, and genetic context analysis of carbapenemase-encoding genes. Of the 2569 BSI Enterobacterales isolates enrolled, 42 (1.6%) were carbapenemase-positive. Moreover, among the 2242 investigated isolates, 1111 (49.6%) extended-spectrum β-lactamase (ESBL)-producing isolates were identified in Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Proteus mirabilis (P. mirabilis), and Klebsiella oxytoca. Whole genome sequencing analysis showed the clonal spread of K. pneumoniae carbapenemase (KPC)-2-producing K. pneumoniae sequence type 11 (ST11) and New Delhi metallo-β-lactamase (NDM)-5-producing E. coli ST167 in our collection. Plasmid analysis revealed that carbapenemase-encoding genes were located on multiple plasmids. A high prevalence of biofilm-encoding type 3 fimbriae clusters and yesiniabactin-associated genes was observed in K. pneumoniae isolates. This work demonstrates the high prevalence of ESBLs and the wide dissemination of CPE among BSI isolates in China, which represent real clinical threats. Moreover, our findings first illustrate a more comprehensive genome scenario of CPE isolates among BSIs. The clonal spread of KPC-2-producing K. pneumoniae ST11 and NDM-5-producing E. coli ST167 needs to be closely monitored.

关键词

碳青霉烯酶 / 产碳青霉烯酶肠杆菌 / 质粒介导 / 中国 / 产超广谱β-内酰胺酶 /

Keywords

Carbapenemase / Carbapenemase-producing / Enterobacteriaceae / Plasmid-mediated / China / Extended-spectrum β-lactamase

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Beiwen Zheng, Hao Xu, Lihua Guo. 中国血流感染相关产碳青霉烯酶肠杆菌的基因组及表型多样性——一项多中心流行病学、 微生物学和遗传学研究. Engineering. 2022, 12(5): 90-100 https://doi.org/10.1016/j.eng.2020.10.015

参考文献

[1]
Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 2009;9(4):228–36.
[2]
Grundmann H, Glasner C, Albiger B, Aanensen DM, Tomlinson CT, Andrasevic´ AT, et al. Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study. Lancet Infect Dis 2017;17(2):153–63.
[3]
WHO. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics [Internet]. Geneva: WHO; 2017 [cited 2020 Nov 25]. Available from: https://www.who.int/medicines/ publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf?ua=1.
[4]
Cerqueira GC, Earl AM, Ernst CM, Grad YH, Dekker JP, Feldgarden M, et al. Multi-institute analysis of carbapenem resistance reveals remarkable diversity, unexplained mechanisms, and limited clonal outbreaks. Proc Natl Acad Sci USA 2017;114(5):1135–40.
[5]
Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev 2012;25(4):682–707.
[6]
Rojas LJ, Salim M, Cober E, Richter SS, Perez F, Salata RA, et al. Colistin resistance in carbapenem-resistant Klebsiella pneumoniae: laboratory detection and impact on mortality. Clin Infect Dis 2017;64(6):711–8.
[7]
Cheng VCC, Chen JHK, So SYC, Wong SCY, Chau PH, Wong LMW, et al. A novel risk factor associated with colonization by carbapenemase-producing enterobacteriaceae: use of proton pump inhibitors in addition to antimicrobial treatment. Infect Control Hosp Epidemiol 2016;37(12):1418–25.
[8]
Zheng B, Xu H, Lv T, Guo L, Xiao Y, Huang C, et al. Stool samples of acute diarrhea inpatients as a reservoir of ST11 hypervirulent KPC-2-producing Klebsiella pneumoniae. mSystems 2020;5(3):e00498–20.
[9]
Laupland KB, Church DL. Population-based epidemiology and microbiology of community-onset bloodstream infections. Clin Microbiol Rev 2014;27 (4):647–64.
[10]
Satlin MJ, Chavda KD, Baker TM, Chen L, Shashkina E, Soave R, et al. Colonization with levofloxacin-resistant extended-spectrum beta-lactamaseproducing Enterobacteriaceae and risk of bacteremia in hematopoietic stem cell transplant recipients. Clin Infect Dis 2018;67(11):11.
[11]
CDC. Antibiotic resistance threats in the United States, 2013 [Internet]. Atlanta: CDC; 2013 [cited 2020 Nov 25]. Available from: http://www. cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf.
[12]
White AR. The British society for antimicrobial chemotherapy resistance surveillance project: a successful collaborative model. J Antimicrob Chemother 2008;62(Suppl 2):ii3–14.
[13]
Zhang R, Liu L, Zhou H, Chan EW, Li J, Fang Y, et al. Nationwide surveillance of clinical carbapenem-resistant Enterobacteriaceae (CRE) strains in China. EBioMedicine 2017;19:98–106.
[14]
Xu A, Zheng B, Xu YC, Huang ZG, Zhong NS, Zhuo C. National epidemiology of carbapenem-resistant and extensively drug-resistant Gram-negative bacteria isolated from blood samples in China in 2013. Clin Microbiol Infect 2016;22 (Suppl 1):S1–8.
[15]
Zhang Y, Wang Q, Yin Y, Chen H, Jin L, Gu B, et al. Epidemiology of carbapenem-resistant Enterobacteriaceae infections: report from the China CRE network. Antimicrob Agents Chemother 2018;62(2): e01882–17.
[16]
Quan J, Zhao D, Liu L, Chen Y, Zhou J, Jiang Y, et al. High prevalence of ESBLproducing Escherichia coli and Klebsiella pneumoniae in community-onset bloodstream infections in China. J Antimicrob Chemother 2017;72(1):273–80.
[17]
Zheng B, Chen Y, Violetta L, Xiao Y, Li L. Bloodstream infections caused by Enterobacteriaceae in China. Lancet Infect Dis 2019;19(8):810–1.
[18]
CLSI. Performance standards for antimicrobial susceptibility testing. 27th ed. Wayne: Clinical and Laboratory Standards Institute; 2017.
[19]
Zheng B, Zhang J, Ji J, Fang Y, Shen P, Ying C, et al. Emergence of Raoultella ornithinolytica coproducing IMP-4 and KPC-2 carbapenemases in China. Antimicrob Agents Chemother 2015;59(11):7086–9.
[20]
Zerbino DR, Birney E. Velvet: algorithms for de novo short read assembly using de Bruijn graphs. Genome Res 2008;18(5):821–9.
[21]
Zankari E, Hasman H, Cosentino S, Vestergaard M, Rasmussen S, Lund O, et al. Identification of acquired antimicrobial resistance genes. J Antimicrob Chemother 2012;67(11):2640–4.
[22]
Darling ACE, Mau B, Blattner FR, Perna NT. Mauve: multiple alignment of conserved genomic sequence with rearrangements. Genome Res 2004;14 (7):1394–403.
[23]
Zheng B, Dong H, Xu H, Lv J, Zhang J, Jiang X, et al. Coexistence of MCR-1 and NDM-1 in clinical Escherichia coli isolates. Clin Infect Dis 2016;63(10):1393–5.
[24]
Antipov D, Hartwick N, Shen M, Raiko M, Lapidus A, Pevzner PA. plasmidSPAdes: assembling plasmids from whole genome sequencing data. Bioinformatics 2016;32(22):3380–7.
[25]
Delcher AL, Salzberg SL, Phillippy AM. Using MUMmer to identify similar regions in large sequence sets. Curr Protoc Bioinformatics 2003;Chapter 10: Unit 10.3.
[26]
Galata V, Fehlmann T, Backes C, Keller A. PLSDB: a resource of complete bacterial plasmids. Nucleic Acids Res 2019;47(D1):D195–202.
[27]
Carattoli A, Zankari E, García-Fernández A, Voldby Larsen M, Lund O, Villa L, et al. In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. Antimicrob Agents Chemother 2014;58 (7):3895–903.
[28]
Holt KE, Wertheim H, Zadoks RN, Baker S, Whitehouse CA, Dance D, et al. Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc Natl Acad Sci USA 2015;112(27):E3574–81.
[29]
Stamatakis A. RAxML version 8: a tool for phylogenetic analysis and postanalysis of large phylogenies. Bioinformatics 2014;30(9):1312–3.
[30]
Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Paño-Pardo JR, et al. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis 2017;17(7):726–34.
[31]
Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55(7):943–50.
[32]
Liu L, Feng Y, Long H, McNally A, Zong Z. Sequence type 273 carbapenemresistant Klebsiella pneumoniae carrying blaNDM-1 and blaIMP-4. Antimicrob Agents Chemother 2018;62(6):AAC.00160–18.
[33]
Zhao F, Zhang J, Fu Y, Ruan Z, Xie X. Dissemination of extensively drugresistant and KPC-2 producing Klebsiella pneumoniae isolated from bloodstream infections. J Infect Dev Countries 2015;9(9):1016–21.
[34]
Myat TO, Hannaway RF, Zin KN, Htike WW, Win KK, Crump JA, et al. ESBL- and carbapenemase-producing Enterobacteriaceae in patients with bacteremia, Yangon, Myanmar, 2014. Emerg Infect Dis 2017;23(5):857–9.
[35]
Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. ST11, the dominant clone of KPCproducing Klebsiella pneumoniae in China. J Antimicrob Chemother 2011;66 (2):307–12.
[36]
Shen P, Berglund B, Chen Y, Zhou Y, Xiao T, Xiao Y, et al. Hypervirulence markers among non-ST11 strains of carbapenem- and multidrug-resistant Klebsiella pneumoniae isolated from patients with bloodstream infections. Front Microbiol 2020;11:1199.
[37]
Zhou K, Xiao T, David S, Wang Q, Zhou Y, Guo L, et al. Novel subclone of carbapenem-resistant Klebsiella pneumoniae sequence type 11 with enhanced virulence and transmissibility, China. Emerg Infect Dis 2020;26 (2):289–97.
[38]
Huang Y, Yu X, Xie M, Wang X, Liao K, Xue W, et al. Widespread dissemination of carbapenem-resistant Escherichia coli sequence type 167 strains harboring blaNDM-5 in clinical settings in China. Antimicrob Agents Chemother 2016;60 (7):4364–8.
[39]
Zong Z, Fenn S, Connor C, Feng Y, McNally A. Complete genomic characterization of two Escherichia coli lineages responsible for a cluster of carbapenem-resistant infections in a Chinese hospital. J Antimicrob Chemother 2018;73(9):2340–6.
[40]
Cuzon G, Bonnin RA, Nordmann P. First identification of novel NDM carbapenemase, NDM-7, in Escherichia coli in France. PLoS One 2013;8(4): e61322.
[41]
Grönthal T, Österblad M, Eklund M, Jalava J, Nykäsenoja S, Pekkanen K, et al. Sharing more than friendship-transmission of NDM-5 ST167 and CTX-M-9 ST69 Escherichia coli between dogs and humans in a family, Finland, 2015. Euro Surveill 2018;23(27):1700497.
[42]
Paskova V, Medvecky M, Skalova A, Chudejova K, Bitar I, Jakubu V, et al. Characterization of NDM-encoding plasmids from Enterobacteriaceae recovered from Czech hospitals. Front Microbiol 2018;9:1549.
[43]
Giufrè M, Errico G, Accogli M, Monaco M, Villa L, Distasi MA, et al. Emergence of NDM-5-producing Escherichia coli sequence type 167 clone in Italy. Int J Antimicrob Agents 2018;52(1):76–81.
[44]
Sun J, Yang RS, Zhang Q, Feng Y, Fang LX, Xia J, et al. Co-transfer of blaNDM-5 and mcr-1 by an IncX3-X4 hybrid plasmid in Escherichia coli. Nat Microbiol 2016;1 (12):16176.
[45]
Schubert S, Cuenca S, Fischer D, Heesemann J. High-pathogenicity island of Yersinia pestis in Enterobacteriaceae isolated from blood cultures and urine samples: prevalence and functional expression. J Infect Dis 2000;182 (4):1268–71.
[46]
Lam MMC, Wick RR, Wyres KL, Gorrie CL, Judd LM, Jenney AWJ, et al. Genetic diversity, mobilisation and spread of the yersiniabactin-encoding mobile element ICEKp in Klebsiella pneumoniae populations. Microb Genom 2018;4 (9):e000196.
[47]
Gu D, Dong N, Zheng Z, Lin D, Huang M, Wang L, et al. A fatal outbreak of ST11 carbapenem-resistant hypervirulent Klebsiella pneumoniae in a Chinese hospital: a molecular epidemiological study. Lancet Infect Dis 2018;18 (1):37–46.
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