β-内酰胺类抗生素与β-内酰胺酶抑制剂联合对临床分离株的活性。
Activity of -Lactams in Combination with -Lactamase Inhibitors against Clinical Isolates.
机构信息
State Key Laboratory for Infectious Diseases Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.
Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China.
出版信息
Biomed Res Int. 2018 Jul 2;2018:3579832. doi: 10.1155/2018/3579832. eCollection 2018.
OBJECTIVES
Evaluating the activity of nineteen -lactams in combination with different -lactamase inhibitors to determine the most potent combination against (MTB) .
METHODS
Drug activity was examined by drug susceptibility test with 122 clinical isolates from China. Mutations of and drug targets , , and were analyzed by nucleotide sequencing.
RESULTS
Tebipenem (TBM) in combination with clavulanate (CLA) exhibited the highest anti-TB activity. The MIC of -lactam antibiotics was reduced most evidently in the presence of CLA, compared to avibactam (AVI) and sulbactam (SUB). Eight polymorphism sites were identified in , which were not associated with -lactams resistance. Interestingly, one strain carrying G514A mutation in was highly susceptible to -lactams regardless of the presence of inhibitors. The transpeptidase encoding genes, , , and , harboured three mutations, two mutations, and one mutation, respectively, but no correlation was found between these mutations and drug resistance.
CONCLUSION
The activity of -lactams against MTB and different synergetic effect of -lactamase inhibitors were indicated. TBM/CLA exhibited the most activity and has a great prospect in developing novel anti-TB regimen; however, further clinical research is warranted. Moreover, the resistance to the -lactam antibiotics might not be conferred by single target mutation in MTB and requires further studies.
目的
评估 19 种β-内酰胺类药物与不同β-内酰胺酶抑制剂联合使用的活性，以确定针对结核分枝杆菌（MTB）最有效的联合用药方案。
方法
采用药物敏感性试验检测来自中国的 122 株临床分离株，通过核苷酸测序分析和靶位 、 、 、 的基因突变情况。
结果
替比培南（TBM）与克拉维酸（CLA）联合使用时表现出最高的抗结核活性。与阿维巴坦（AVI）和舒巴坦（SUB）相比，CLA 存在时，β-内酰胺类抗生素的 MIC 降低最为显著。在 中发现了 8 个多态性位点，但与β-内酰胺类耐药无关。有趣的是，一株携带 中 G514A 突变的菌株对β-内酰胺类药物高度敏感，无论抑制剂的存在与否。转肽酶编码基因 、 、 、 分别携带 3 个、2 个和 1 个突变，但这些突变与耐药性之间没有相关性。
结论
β-内酰胺类药物对 MTB 的活性以及β-内酰胺酶抑制剂的协同作用不同。TBM/CLA 表现出最强的活性，在开发新型抗结核方案方面具有广阔的前景；然而，需要进一步的临床研究。此外，MTB 对β-内酰胺类抗生素的耐药性可能不是由单个靶位突变引起的，需要进一步研究。
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