致死性ST11型高毒力耐碳青霉烯肺炎克雷伯菌的宿主内耐药性进化
Within-host resistance evolution of a fatal ST11 hypervirulent carbapenem-resistant Klebsiella pneumoniae.
作者信息
Pu Danni, Zhao Jiankang, Lu Binghuai, Zhang Yulin, Wu Yongli, Li Ziyao, Zhuo Xianxia, Cao Bin
机构信息
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.
出版信息
Int J Antimicrob Agents. 2023 Apr;61(4):106747. doi: 10.1016/j.ijantimicag.2023.106747. Epub 2023 Feb 8.
OBJECTIVES
Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKp) has become a great threat to public health. This study reported an hv-CRKp-associated fatal infection and revealed its mechanisms of antimicrobial resistance and within-host evolution.
METHODS
A carbapenem-susceptible K. pneumoniae (CSKp) and 11 KPC-producing CRKp strains were isolated from a lung transplant recipient receiving continual antimicrobial therapy for 1.5 years. Pulsed-field gel electrophoresis (PFGE) separated two clusters between CSKp and CRKp.
RESULTS
Further whole genome sequencing analysis found that all 11 CRKp were ST11-KL64 clones, while the CSKp was ST412-KL57. Among these 11 CRKp strains, three and one were resistant to colistin and ceftazidime/avibactam (CAZ/AVI), respectively. Three different mechanisms were found to be responsible for the colistin resistance, including the insertions of two different IS (ISKpn74 and IS903B) into the same position of mgrB and one related to the efflux pump system. CAZ/AVI resistance was associated with bla mutation, and it was also found that increasing bla expression increased the MICs of CAZ/AVI, but not at the resistance level. All these 12 strains had iucABCDiutA virulence cluster and rmpA/rmpA2 genes, with higher siderophore production than a reference classic K. pneumoniae (cKp), which were thought to be hypervirulent K. pneumoniae (hvKp). However, only the CSKp showed higher mucoviscosity according to the mucoviscosity assay. Genomic analysis showed that the rmpA variation (interrupted by ISKpn26) existed in all CRKp strains except the CSKp strain, demonstrating that hypermucoviscous phenotype assays could not accurately identify hvKp.
CONCLUSION
This study depicted a rapid and diverse within-host evolution of resistance in hv-CRKp of ST11-KL64 clone.
目的
高毒力碳青霉烯耐药肺炎克雷伯菌（hv-CRKp）已对公共卫生构成重大威胁。本研究报告了1例与hv-CRKp相关的致命感染病例，并揭示了其耐药机制及宿主内进化情况。
方法
从1例接受了1.5年持续抗菌治疗的肺移植受者中分离出1株对碳青霉烯敏感的肺炎克雷伯菌（CSKp）和11株产KPC的CRKp菌株。脉冲场凝胶电泳（PFGE）将CSKp和CRKp分为两个簇。
结果
进一步的全基因组测序分析发现，11株CRKp均为ST11-KL64克隆，而CSKp为ST412-KL57。在这11株CRKp菌株中，分别有3株和1株对黏菌素及头孢他啶/阿维巴坦（CAZ/AVI）耐药。发现3种不同机制导致黏菌素耐药，包括两种不同的插入序列（ISKpn74和IS903B）插入mgrB的同一位置以及一种与外排泵系统相关的机制。CAZ/AVI耐药与bla突变有关，还发现bla表达增加会提高CAZ/AVI的最低抑菌浓度（MIC），但未达到耐药水平。这12株菌株均具有iucABCDiutA毒力簇和rmpA/rmpA2基因，与参考经典肺炎克雷伯菌（cKp）相比，其铁载体产量更高，被认为是高毒力肺炎克雷伯菌（hvKp）。然而，根据黏液黏稠度测定，只有CSKp表现出更高黏液黏稠度。基因组分析表明，除CSKp菌株外，所有CRKp菌株中均存在rmpA变异（被ISKpn26中断），表明高黏液黏稠表型检测无法准确鉴定hvKp。
结论
本研究描述了ST11-KL64克隆的hv-CRKp在宿主体内耐药性的快速且多样的进化。
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