β-内酰胺酶抑制剂阿维巴坦和瑞来巴坦联合不同β-内酰胺类药物对耐多药结核分枝杆菌体外活性研究  

In vitro activity ofβ-lactamase inhibitors avibanvctam and relebactam in combination withβ-lactams against multidrug-resistant Mycobacterium tuberculosis and mutations of resistance genes

作　　者：石洁[1] 郑丹薇 马晓光[1] 苏茹月 朱岩昆[1] 王少华[1] 常文静 孙国清[1] 孙定勇[1] Shi Jie;Zheng Danwei;Ma Xiaoguang;Su Ruyue;Zhu Yankun;Wang Shaohua;Chang Wenjing;Sun Guoqing;Sun Dingyong(Henan Province Center for Disease Control and Prevention,Zhengzhou 450016,China)

机构地区：[1]河南省疾病预防控制中心,郑州450016

出　　处：《中华结核和呼吸杂志》2023年第8期797-805,共9页Chinese Journal of Tuberculosis and Respiratory Diseases

摘　　要：目的体外评估6种β-内酰胺类药物和3种β-内酰胺酶抑制剂组合对耐多药结核分枝杆菌(MTB)的抗菌活性,以期发现针对耐多药结核病最有效的β-内酰胺类药物和β-内酰胺酶抑制剂组合。方法本研究自2020年1—9月共纳入来自河南省不同地区的105株耐多药MTB分离菌株,使用最低抑菌浓度(MIC)法测定6种β-内酰胺类药物(比阿培南、美罗培南、亚胺培南、多尼培南、厄他培南、泰比培南)单独或联合β-内酰胺酶抑制剂(克拉维酸、阿维巴坦、瑞来巴坦)对105株临床菌株的体外抗菌活性,使用PCR法和DNA测序分析blaC、ldt_(mt1)和ldt_(mt2)的突变情况。使用卡方检验比较不同β-内酰胺类药物的抗菌活性。结果在本研究使用的几种β-内酰胺类药物中,泰比培南对耐多药MTB最为有效,MIC50值为8 mg/L(χ^(2)=123.70,P=0.001)。阿维巴坦和瑞来巴坦与克拉维酸相比,可使大部分β-内酰胺类药物的MIC值明显降低。其中瑞来巴坦使泰比培南MIC50和MIC90均稀释了16倍,使23(21.90%)和41(39.04%)株的MIC稀释了32倍和16倍。共有13.33%(14/105)的菌株存在blaC基因的突变,主要为3种替代突变,AGT333AGG、AAC638ACC和ATC786ATT。与同义突变组相比,克拉维酸-美罗培南组合对BlaC蛋白Ser111Arg和Asn213Thr突变菌株的MIC值明显降低。结论阿维巴坦和瑞来巴坦对β-内酰胺类药物协同作用均优于克拉维酸。泰比培南-瑞来巴坦组合对耐多药MTB具有最强的抗菌活性。BlaC蛋白Ser111Arg和Asn213Thr的突变可能增强了耐多药MTB对克拉维酸-美罗培南组合的敏感性。ObjectiveTo evaluate the activity of sixβ-lactams in combination with threeβ-lactamase inhibitors against mycobacterium tuberculosis(MTB)in vitro.MethodsA total of 105 multidrug-resistant tuberculosis(MDR-TB)strains from different regions of Henan province from January to September 2020 were included in this study.Drug activity of sixβ-lactams(biapenem,meropenem,imipenem,doripenem,ertapenem and tebipenem)alone or in combination withβ-lactamase inhibitors(clavulanic acid,avibactam and relebactam)was examined by minimum inhibitory concentration method(MICs)against 105 clinical isolates.Mutations of blaC,ldt_(mt1)and ldt_(mt2)were analyzed by PCR and DNA sequencing.Chi-square test was used to compare the antimicrobial activities of differentβ-lactam drugs.ResultsOut of theβ-lactams used herein,tebipenem was the most effective against MDR-TB and had an MIC50 value of 8 mg/L(χ^(2)=123.70,P=0.001).Besides,after the addition ofβ-lactamase inhibitors,the MICs of mostβ-lactam drugs were reduced more evidently in the presence of avibactam and relebactam compared to clavulanic acid.Especially,relebactam decreased both the MIC50 and MIC90 of telbipenem by 16-fold,and diluted the MIC of 23(21.90%)and 41(39.04%)isolatesby 32-fold and 16-fold.In addition,a total of 13.33%(14/105)of isolates harbored mutations in the blaC gene,with three different nucleotide substitutions:AGT333AGG,AAC638ACC and ATC786ATT.For the strains with Ser111Arg and Asn213Thr substitution in BlaC,the MIC values of the meropenem-clavulanate combination were reduced compared with a synonymous single nucleotide polymorphism(SNP)group.ConclusionsBoth avibactam and relebactam had better synergistic effects onβ-lactams than clavulanic acid.The combination of tebipenem and relebactam showed the most potent activity against MDR-TB isolates.In addition,the Ser111Arg and Asn213Thr substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem in the presence of clavulanate.

关 键 词：分枝杆菌 结核 结核 抗多种药物性 Β-内酰胺酶 阿维巴坦 瑞来巴坦 

分 类 号：R965[医药卫生—药理学]