β-内酰胺酶抑制剂联合不同β-内酰胺类抗生素对耐多药结核分枝杆菌临床菌株体外活性研究  

In vitro activity ofβ-lactamase inhibitors combined with differentβ-lactam antibiotics against multidrug-resistant Mycobacterium tuberculosis clinical strains

作　　者：石洁[1] 郑丹薇 徐吉英[1] 马晓光[1] 苏茹月 朱岩昆[1] 王少华[1] 常文静 孙定勇[1] SHI Jie;ZHENG Dan-wei;XU Ji-ying;MA Xiao-guang;SU Ru-yue;ZHU Yan-kun;WANG Shao-hua;CHANG Wen-jing;SUN Ding-yong(Tuberculosis Reference Laboratory,Tuberculosis Prevention and Control Institute,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结核病防治所结核病参比实验室,河南郑州450016

出　　处：《中国感染控制杂志》2024年第9期1091-1097,共7页Chinese Journal of Infection Control

基　　金：河南省自然科学基金项目(232300420290);河南省科技攻关项目(222102310726)。

摘　　要：目的体外评估5种β-内酰胺类抗生素和不同β-内酰胺酶抑制剂组合对耐多药结核分枝杆菌(MDR-TB)活性的影响,以期发现针对耐多药结核病最有效的β-内酰胺类抗生素和β-内酰胺酶抑制剂组合。方法选取2021年河南省耐药监测项目收集的MDR-TB菌株,使用最小抑菌浓度(MIC)法测定5种β-内酰胺类抗生素或联合β-内酰胺酶抑制剂对临床MDR-TB的MIC值,并采用聚合酶链式反应(PCR)和DNA测序法分析菌株的bla C突变情况。结果共纳入105株MDR-TB,MIC检测结果显示,多尼培南对MDR-TB抗菌活性最高,其MIC 50值为16μg/mL。与β-内酰胺酶抑制剂联合后,大部分β-内酰胺类抗生素的MIC值明显下降。共有13.33%(14株)的菌株存在bla C基因的突变,主要为3种核苷酸替代突变,分别为AGT333AGG、AAC638ACC、ATC786ATT。BlaC蛋白Ser111Arg和Asn213Thr与同义单核苷酸突变相比,增强了克拉维酸/舒巴坦与美罗培南对MDR-TB的协同作用。结论多尼培南和舒巴坦组合对MDR-TB具有最强的抗菌活性。而BlaC蛋白Ser111Arg和Asn213Thr的替代突变使MDR-TB对美罗培南的敏感性在克拉维酸/舒巴坦协同时增强。Objective To evaluate the in vitro effect of combinations of 5β-lactam antibiotics with differentβ-lactamase inhibitors on the activity of multidrug-resistant Mycobacterium tuberculosis(MDR-TB),and identify the most effective combination ofβ-lactam antibiotics andβ-lactamase inhibitors against MDR-TB.Methods MDR-TB strains collected in Henan Province Antimicrobial Resistance Surveillance Project in 2021 were selected.The minimum inhibitory concentrations(MIC)of 5β-lactam antibiotics or combinations with differentβ-lactamase inhibitors on clinically isolated MDR-TB strains were measured by MIC detection method,and the bla C mutation of the strains was analyzed by polymerase chain reaction(PCR)and DNA sequencing.Results A total of 105 strains of MDR-TB were included in the analysis.MIC detection results showed that doripenem had the highest antibacterial activity against MDR-TB,with a MIC 50 of 16μg/mL.MIC values of mostβ-lactam antibiotics decreased significantly after combined withβ-lactamase inhibitors.A total of 13.33%(n=14)strains had mutations in bla C gene,mainly 3 nucleotide substitution mutations,namely AGT333AGG,AAC638ACC and ATC786ATT.BlaC proteins Ser111Arg and Asn213Thr enhanced the synergistic effect of clavulanic acid/sulbactam and meropenem on MDR-TB compared with synonymous single-nucleotide mutation.Conclusion The combination of doripenem and sulbactam has the strongest antibacterial activity against MDR-TB.Substitution mutations of BlaC protein Ser111Arg and Asn213Thr enhances the sensitivity of MDR-TB to meropenem through the synergy with clavulanic acid/sulbactam.

关 键 词：结核分枝杆菌 Β-内酰胺类 Β-内酰胺酶抑制剂 耐多药结核分枝杆菌 

分 类 号：R969.3[医药卫生—药理学]