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Synergy between Mecillinam and Ceftazidime/Avibactam or Avibactam against Multi-Drug-Resistant Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae
Antibiotics ( IF 4.8 ) Pub Date : 2022-09-20 , DOI: 10.3390/antibiotics11101280
Karoline Knudsen List 1 , Mette Kolpen 1 , Kasper Nørskov Kragh 2 , Godefroid Charbon 1, 3 , Stine Radmer 1 , Frank Hansen 4 , Anders Løbner-Olesen 3 , Niels Frimodt-Møller 1 , Frederik Boetius Hertz 1
Affiliation  

Background: Carbapenemase-producing Klebsiella pneumoniae and Escherichia coli have become a significant global health challenge. This has created an urgent need for new treatment modalities. We evaluated the efficacy of mecillinam in combination with either avibactam or ceftazidime/avibactam against carbapenemase-producing clinical isolates. Materials and methods: Nineteen MDR clinical isolates of K. pneumoniae and E. coli were selected for the presence of blaKPC, blaNDM, blaOXA or blaIMP based on whole-genome sequencing and phenotypic susceptibility testing. We tested the synergy between mecillinam and avibactam or ceftazidime/avibactam. We used time–kill studies in vitro and a mouse peritonitis/sepsis model to confirm the synergistic effect. We investigated avibactam’s impact on mecillinam´s affinity for penicillin-binding proteins with a Bocillin assay, and cell changes with phase-contrast and confocal laser scanning microscopy. Results: Mecillinam combined with ceftazidime/avibactam or avibactam substantially reduced MICs (from up to >256 µg/mL to <0.0016 µg/mL) for 17/18 strains. Significant log-CFU reductions were confirmed in time–kill and in vivo experiments. The Bocillin assay did not reveal changes. Conclusion: Mecillinam in combination with avibactam or ceftazidime/avibactam has a notable effect on most types of CPEs, both in vitro and in vivo. The mecillinam/avibactam combination treatment could be a new efficient antibiotic treatment against multi-drug-resistant carbapenemase-producing Gram-negative pathogens.

中文翻译:

美西林与头孢他啶/阿维巴坦或阿维巴坦对产碳青霉烯酶的多重耐药大肠杆菌和肺炎克雷伯菌的协同作用

背景:产生碳青霉烯酶的肺炎克雷伯菌大肠杆菌已成为重大的全球健康挑战。这迫切需要新的治疗方式。我们评估了美西林联合阿维巴坦或头孢他啶/阿维巴坦对产碳青霉烯酶临床分离株的疗效。材料和方法:根据bla KPC、bla NDM、bla OXA 或bla的存在,选择 19 株肺炎克雷伯菌大肠杆菌的 MDR 临床分离株基于全基因组测序和表型敏感性测试的IMP。我们测试了美西林和阿维巴坦或头孢他啶/阿维巴坦之间的协同作用。我们使用体外时间杀灭研究和小鼠腹膜炎/败血症模型来确认协同效应。我们通过波西林测定研究了阿维巴坦对美西林对青霉素结合蛋白的亲和力的影响,并通过相差和共聚焦激光扫描显微镜研究了细胞变化。结果:美西林联合头孢他啶/阿维巴坦或阿维巴坦显着降低了 17/18 菌株的 MIC(从高达 >256 µg/mL 到 <0.0016 µg/mL)。在时间-杀灭和体内实验中证实了显着的 log-CFU 减少。Bocillin 测定没有显示变化。结论:美西林与阿维巴坦或头孢他啶/阿维巴坦联用对大多数类型的 CPE 在体外和体内都有显着影响。美西林/阿维巴坦联合治疗可能是一种新的有效抗生素治疗方法,可对抗产生多重耐药性碳青霉烯酶的革兰氏阴性病原体。
更新日期:2022-09-20
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