Xu Qian, Fu Ying, Ji Jingshu, Du Xiaoxing, Yu Yunsong
Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310016, People's Republic of China.
Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang Province, 310016, People's Republic of China.
Infect Drug Resist. 2021 Mar 3;14:833-839. doi: 10.2147/IDR.S296233. eCollection 2021.
Antibiotics for treating infectious diseases caused by carbapenem-resistant Gram-negative pathogens (CR-GNOs) are very limited in clinical practice. We aim to provide supportive evidence by revealing the combined effect of aztreonam (ATM) and amoxicillin/clavulanic acid (AMC) against GNOs with carbapenem resistance mediated by metallo-β-lactamase (MBL).
All isolates were identified by the VITEK system and EDTA inhibitory assays. PCR followed by sequencing was conducted to confirm the genotypes of MBL and extended spectrum β-lactamase (ESBL). Time kill assay was performed to clarify the bactericidal effect of drug combination.
A total of 59 MBL-producing CR-GNOs (33 spp. isolates and 26 Pseudomonadales isolates) were identified and there found three MBL genes, namely, , and , with ratios of 76.2%, 11.8% and 11.8%, respectively. The spp. isolates were commonly positive for the ESBL genes, including (18 isolates), (20 isolates) and (8 isolates), while the isolates were positive for (11 isolates). The checkerboard microdilution assay was used to detect combination effect of ATM and AMC, which showed synergy (97.0%) and partial synergy (3.0%) in spp. isolates, and partial synergy (42.3%) and indifference (34.6%) in the Pseudomonadales isolates. Four spp. isolates were selected for a time-kill assay, and rapid bactericidal effects were observed in the combination groups compared to the control and mono-ATM groups; these effects began in the first hour and continued to the sixth hour, yielding a 5- to 7-fold reduction in Log10 CFU/mL.
The combination of ATM and AMC would be an available option to control infections caused by MBL-producing CR-GNOs, especially spp. isolates that coproduce ESBLs, and exhibit significant synergic effects in vitro.
在临床实践中，用于治疗由耐碳青霉烯革兰氏阴性病原体（CR-GNOs）引起的传染病的抗生素非常有限。我们旨在通过揭示氨曲南（ATM）和阿莫西林/克拉维酸（AMC）对具有金属β-内酰胺酶（MBL）介导的碳青霉烯耐药性的GNOs的联合作用，提供支持性证据。
所有分离株均通过VITEK系统和EDTA抑制试验进行鉴定。进行PCR测序以确认MBL和超广谱β-内酰胺酶（ESBL）的基因型。进行时间杀菌试验以阐明药物组合的杀菌效果。
共鉴定出59株产MBL的CR-GNOs（33株肠杆菌科分离株和26株假单胞菌目分离株），发现了3种MBL基因，即、和，比例分别为76.2%、11.8%和11.8%。肠杆菌科分离株的ESBL基因通常呈阳性，包括（18株）、（20株）和（8株），而假单胞菌目分离株的呈阳性（11株）。采用棋盘微量稀释法检测ATM和AMC的联合作用，结果显示在肠杆菌科分离株中表现为协同作用（97.0%）和部分协同作用（3.0%），在假单胞菌目分离株中表现为部分协同作用（42.3%）和无作用（34.6%）。选择4株肠杆菌科分离株进行时间杀菌试验，与对照组和单药ATM组相比，联合组观察到快速杀菌效果；这些效果在第1小时开始并持续到第6小时，使Log10 CFU/mL降低5至7倍。
ATM和AMC的联合使用可能是控制由产MBL的CR-GNOs引起的感染的一种可行选择，特别是同时产生ESBLs的肠杆菌科分离株，并且在体外表现出显著的协同作用。
