Abstract：
OBJECTIVE: Enterobacteriaceae carrying mcr-9, in particularly those also co-containing metallo-β-lactamase (MBL) and TEM type β-lactamase, present potential transmission risks and lack adequate clinical response methods, thereby posing a major threat to global public health. The aim of this study was to assess the antimicrobial efficacy of a combined ceftazidime/avibactam (CZA) and aztreonam (ATM) regimen against carbapenem-resistant Enterobacter cloacae complex (CRECC) co-producing mcr-9, MBL and TEM.
METHODS: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model.
RESULTS: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups.
CONCLUSIONS: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms.
METHODS: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model.
RESULTS: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups.
CONCLUSIONS: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms.
摘要：
目的：携带mcr-9的肠杆菌科，特别是那些同时含有金属β-内酰胺酶（MBL）和TEM型β-内酰胺酶的肠杆菌，存在潜在的传播风险，缺乏足够的临床反应方法，从而对全球公共卫生构成重大威胁。这项研究的目的是评估头孢他啶/阿维巴坦（CZA）和氨曲南（ATM）联合方案对碳青霉烯耐药阴沟肠杆菌（CRECC）共同产生的mcr-9，MBL和TEM的抗菌功效。
方法：使用时间杀伤曲线测定法评估CZA加ATM的体外抗菌活性。此外，使用Galleriamellonella（G.Mellonella）感染模型。
结果：CRECC的所有8个临床菌株，共同携带mcr-9、MBL和TEM，对CZA和ATM表现出较高的抗性。体外时间-杀死曲线分析表明,CZA+ATM的组合疗法对mcr-9、MBL和TEM共产阴沟肠杆菌复合体(ECC)分离株具有显著的杀菌活性,在我们的研究中观察到100%的协同率。此外，使用共携带mcr-9，MBL和TEM的CRECC菌株感染的Galleriamelonella幼虫的体内存活测定显示，与单独药物治疗和未经治疗的对照组相比，CZA+ATM组合显着提高了存活率。
结论：据我们所知，这项研究是关于CZA加ATM对共同携带mcr-9，MBL和TEM的CRECC分离株的体外和体内抗菌活性的第一份报告。我们的发现表明，CZA+ATM的联合方案为临床医生解决临床微生物中观察到的日益复杂的抗生素耐药性情况提供了有价值的参考。
方法：使用时间杀伤曲线测定法评估CZA加ATM的体外抗菌活性。此外，使用Galleriamellonella（G.Mellonella）感染模型。
结果：CRECC的所有8个临床菌株，共同携带mcr-9、MBL和TEM，对CZA和ATM表现出较高的抗性。体外时间-杀死曲线分析表明,CZA+ATM的组合疗法对mcr-9、MBL和TEM共产阴沟肠杆菌复合体(ECC)分离株具有显著的杀菌活性,在我们的研究中观察到100%的协同率。此外，使用共携带mcr-9，MBL和TEM的CRECC菌株感染的Galleriamelonella幼虫的体内存活测定显示，与单独药物治疗和未经治疗的对照组相比，CZA+ATM组合显着提高了存活率。
结论：据我们所知，这项研究是关于CZA加ATM对共同携带mcr-9，MBL和TEM的CRECC分离株的体外和体内抗菌活性的第一份报告。我们的发现表明，CZA+ATM的联合方案为临床医生解决临床微生物中观察到的日益复杂的抗生素耐药性情况提供了有价值的参考。
