Shi J, Zheng D W, Ma X G, Su R Y, Zhu Y K, Wang S H, Chang W J, Sun G Q, Sun D Y
Henan Province Center for Disease Control and Prevention, Zhengzhou 450016, China.
Zhonghua Jie He He Hu Xi Za Zhi. 2023 Aug 12;46(8):797-805. doi: 10.3760/cma.j.cn112147-20230111-00017.
To evaluate the activity of six β-lactams in combination with three β-lactamase inhibitors against mycobacterium tuberculosis(MTB) . A 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 six β-lactams (biapenem, meropenem, imipenem, doripenem, ertapenem and tebipenem) alone or in combination with β-lactamase inhibitors (clavulanic acid, avibactam and relebactam) was examined by minimum inhibitory concentration method (MICs) against 105 clinical isolates. Mutations of , and were analyzed by PCR and DNA sequencing. Chi-square test was used to compare the antimicrobial activities of different β-lactam drugs. Out of the β-lactams used herein, tebipenem was the most effective against MDR-TB and had an MIC value of 8 mg/L(χ=123.70,0.001). Besides, after the addition of β-lactamase inhibitors, the MICs of most β-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 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. Both avibactam and relebactam had better synergistic effects on β-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.
评估六种β-内酰胺类药物与三种β-内酰胺酶抑制剂联合对结核分枝杆菌（MTB）的活性。本研究纳入了2020年1月至9月来自河南省不同地区的105株耐多药结核病（MDR-TB）菌株。采用最低抑菌浓度法（MICs）检测六种β-内酰胺类药物（比阿培南、美罗培南、亚胺培南、多利培南、厄他培南和替比培南）单独或与β-内酰胺酶抑制剂（克拉维酸、阿维巴坦和雷利巴坦）联合对105株临床分离株的药物活性。通过PCR和DNA测序分析gyrA、rpoB和blaC基因的突变情况。采用卡方检验比较不同β-内酰胺类药物的抗菌活性。在本文使用的β-内酰胺类药物中，替比培南对MDR-TB最有效，MIC值为8 mg/L（χ=123.70，P<0.001）。此外，添加β-内酰胺酶抑制剂后，与克拉维酸相比，阿维巴坦和雷利巴坦存在时大多数β-内酰胺类药物的MICs降低更明显。特别是，雷利巴坦使替比培南的MIC50和MIC90均降低了16倍，并将23株（21.90%）和41株（39.04%）分离株的MIC分别稀释了32倍和16倍。此外，共有13.33%（14/105）的分离株blaC基因存在突变，有三种不同的核苷酸替换：AGT333AGG、AAC638ACC和ATC786ATT。对于BlaC中具有Ser111Arg和Asn213Thr替换的菌株，美罗培南-克拉维酸联合用药的MIC值与同义单核苷酸多态性（SNP）组相比降低。阿维巴坦和雷利巴坦对β-内酰胺类药物的协同作用均优于克拉维酸。替比培南和雷利巴坦联合用药对MDR-TB分离株显示出最强的活性。此外，BlaC的Ser111Arg和Asn213Thr替换可能与MDR-TB分离株在克拉维酸存在下对美罗培南敏感性增加有关。
