多黏菌素对头孢他啶/阿维巴坦与碳青霉烯共耐药铜绿假单胞菌的体外杀菌作用研究  

Antibacterial activity of colistin against Pseudomonas aeruginosa isolates coresistant to carbapenem and ceftazidime-avibactam in vitro

作　　者：陈玲霞 邹雪寒 张晓璠 李曦[2] 潘红英[1] Chen Lingxia;Zou Xuehan;Zhang Xiaofan;Li Xi;Pan Hongying(Center for General Practice Medicine,Department of Infectious Diseases,Zhejiang Provincial People's Hospital,Affiliated People's Hospital,Hangzhou Medical College,Hangzhou 310014;Laboratory Medicine Center,Department of Clinical Laboratory,Zhejiang Provincial People's Hospital,Affiliated People's Hospital,Hangzhou Medical College,Hangzhou 310014)

机构地区：[1]浙江省人民医院,杭州医学院附属人民医院,全科医学中心感染病科,杭州310014 [2]浙江省人民医院,杭州医学院附属人民医院,检验医学中心检验科,杭州310014

出　　处：《中国抗生素杂志》2024年第5期544-551,共8页Chinese Journal of Antibiotics

基　　金：国家自然科学基金项目(No.82172306);浙江省基础公益研究计划项目(No.LGD21H190001)。

摘　　要：目的 头孢他啶/阿维巴坦(CZA)是治疗碳青霉烯耐药铜绿假单胞菌(CRPA)的一种有效的替代抗生素,在临床上被广泛应用,然而CZA耐药CRPA菌株的出现使得治疗铜绿假单胞菌感染的难度不断增加。本研究旨在通过体外时间杀菌分析,探讨多黏菌素(COL)对携带不同碳青霉烯耐药基因的CZA耐药铜绿假单胞菌菌株的体外杀菌活性,为铜绿假单胞菌感染的临床治疗提供科学依据。方法 从浙江省的一家三甲医院收集了CZA耐药的铜绿假单胞菌菌株。通过聚合酶链反应(PCR)和全基因组测序筛选了携带不同碳青霉烯耐药基因的5株代表性铜绿假单胞菌菌株,包括携带bla_(KPC-2)的PA4696、携带bla_(KPC-90)的PA2207、携带bla_(KPC-33)的PA1308、携带bla_(VIM)的PA2070、携带bla_(IMP-45)的PA6227。通过微量肉汤稀释法确认了实验菌株的抗生素敏感性。对COL敏感的菌株进行重复的时间杀菌实验。结果 5株CRPA菌株均对CZA耐药(MIC≥16/4 mg/L),对COL敏感(MIC≤2 mg/L);其中携带bla_(IMP-45)的菌株PA6227表现出特殊的药敏表型(ISMR),对亚胺培南(IPM)敏感(MIC=2 mg/L)而对美罗培南(MEM)(MIC=128 mg/L)等其他碳青霉烯类药物耐药。时间杀菌曲线显示,5株CZA耐药的铜绿假单胞菌菌株在前2~8 h被不同浓度的COL完全抑制,但随后恢复生长。结论 COL对CZA耐药的CRPA菌株具有体外杀菌活性,但不能单独使用。不同类型的碳青霉烯耐药基因会影响CZA的作用效果,但与COL的杀菌活性无关,携带不同碳青霉烯耐药基因的分离株均在不同时间恢复生长。在治疗铜绿假单胞菌感染时,可以调整给药间隔或药物浓度,以维持COL的浓度,从而获得更好的治疗效果。同时应注意具有ISMR这一特殊药敏表型的CRPA在临床上的出现,避免抗生素的不合理应用。Objective Ceftazidime-avibactam (CZA) is an effective alternative antibiotic for the clinical treatment of carbapenem-resistant Pseudomonas aeruginosa (CRPA) strains.However,the emergence of CZA-resistant CRPA in clinics has increased the difficulty of treating P.aeruginosa infections.The objective of our study was to investigate the in vitro bactericidal activity of colistin (COL) against CZA-resistant P.aeruginosa isolates carrying different carbapenemase genes using time-kill analysis,which provided a scientific basis for the clinical treatment of P.aeruginosa infections.Methods CZA-resistant P.aeruginosa isolates were collected from a tertiary hospital in Zhejiang Province,China.Five representative P.aeruginosa isolates carrying carbapenemase genes,including P.aeruginosa PA 4696 carrying bla_(KPC-2),P.aeruginosa PA 2207 carrying bla_(KPC-90),P.aeruginosa PA 1308carrying bla_(KPC-33),P.aeruginosa PA 2070 carrying bla_(VIM),P.aeruginosa and PA 6227 carrying bla_(IMP-45) were selected by polymerase chain reaction (PCR) and whole genome sequencing.Antibiotic susceptibility was confirmed by broth microdilution.Time-kill experiments were performed in duplicates for each isolate.Results All five isolates were resistant to CZA (MIC≥16/4 mg/L) and sensitive to COL (MIC≤2 mg/L).And P.aeruginosa PA 6227,which carried bla_(IMP-45),showed a specific drug-sensitive phenotype (ISMR) and was sensitive to IPM (MIC=2 mg/L) but resistant to other carbapenems such as MEM (MIC=128 mg/L).Time-killing curves showed that the five CZA-resistant P.aeruginosa isolates were completely inhibited for the first 2~8 hours at different concentrations of COL,but then resumed regrowth.Conclusion COL had in vitro bactericidal activity against CZA-resistant CRPA isolates but could not be used alone.The presence of different carbapenem resistance genes affected the efficacy of CZA,but was not related to the bactericidal activity of COL,and isolates carrying different carbapenem resistance genes all showed regeneration at different times.In th

关 键 词：多黏菌素 头孢他啶/阿维巴坦 碳青霉烯耐药铜绿假单胞菌 时间杀菌曲线 

分 类 号：R978.1[医药卫生—药品]