结核分枝杆菌对替比培南联用β内酰胺酶抑制剂的敏感性分析

In vitro susceptibility of Mycobacterium tuberculosis isolates to tebipenem alone or in combination with β-lactamase inhibitors

目的研究替比培南(TBM)及联用β-内酰胺酶抑制剂对结核分枝杆菌体外抑菌效果,分析菌株抗结核药物耐药表型和基因型与TBM药物敏感性的关联性。方法选取128株抗结核药物敏感(DS)和耐多药/广泛耐药(M/XDR)结核分枝杆菌临床分离株,其中96株(75.0%)属于北京家族,32株(25.0%)属于非北京家族。采用96孔微孔板显色法检测菌株药物敏感性(最小抑菌浓度)。采用χ2检验分析菌株对TBM及联用不同抑制剂组合物的耐药率差异。结果 TBM/克拉维酸(CLA)的抑菌活性最高(MIC90,2μg/ml),其次为TBM/阿维巴坦(AVI)(MIC90,4μg/ml),分别有2株和5株耐药。不同耐药类型菌株中,DS菌株的TBM,TBM/AVI和TBM/CLA耐药率均高于M/XDR菌株,但差异均无统计学意义(P>0.05)。不同基因型菌株中,北京基因型菌株TBM耐药率(60.4%)显著高于非北京基因型菌株(37.5%)(χ2=5.090,P=0.024),差异有统计学意义(P<0.05),而二者对TBM/AVI的耐药率差异无统计学意义(P>0.05)。结论 TBM联用CLA或AVI具有良好的体外抑制结核分枝杆菌效果,北京基因型与TBM耐药表型之间存在关联性,尚不能确定抗结核药物多重耐药表型与TBM耐药是否有相关性。

ObjectiveTo investigate the in vitro susceptibility of Mycobacterium tuberculosis isolates to tebipenem（TBM）alone or in combination with β-lactamase inhibitors,as well as the correlation between its anti TB drug resistant phenotype andgenotype and its susceptibility to tebipenem.MethodsA total of 128 clinical isolates of drug sensitive（DS）and multidrug/extensively drug-resistant（M/XDR）M. tuberculosis were collected,of which 96（75.0%）belonged to the Beijing family and 32（25.0%） belonged to non-Beijing family. The minimum inhibitory concentrations（MICs） were determined by the brothmicrodilution method based on Microplate Alamar Blue Assay（MABA）. The differences in drug resistant rate between single useand combined use of the antibiotic were analyzed with χ^2 test.ResultsTebipenem/clavulanate（TBM/CLA）showed the highestpotent activity against M. tuberculosis strains（MIC90,2 μg/ml）,followed by tebipenem/avibactam（TBM/AVI）（MIC90,4 μg/ml）. There were only 2 and 5 strains resistant to TBM/CLA and TBM/AVI,respectively. Among the different anti-TB drugresistance type strains,the resistant rates of DS strains to TBM,TBM/AVI and TBM/CLA were higher than those of M/XDRstrains,but there was no significant difference（P〉0.05）. Among the different genotype strains,the resistant rate of Beijingfamily strains to TBM（60.4%）was obviously higher than that of non-Beijing family strains（37.5%）（χ^2=5.090,P=0.024）,thedifference was significant（P〈0.05）. While the resistant rates to TBM/AVI of the two genotype strains had no significantdifference（P〉0.05）.ConclusionThe combined use of TBM and CLA or AVI showed excellent activity against M. tuberculosisclinical isolates in vitro and there was a correlation between the Beijing genotype and TBM resistance phenotype,while it was notpossible to determine whether the anti-TB drug resistance phenotype was associated with TBM resistance.