Synergistic effects of ceftazidime/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae

文献类型： 外文期刊

第一作者： Zheng, Mei

作者： Zheng, Mei;Li, Fu-Hao;Liu, Juan;Li, Wen-Jie;Yin, Ruo-Xi;Cai, Da-Tong;Zheng, Si-Lin;Sun, Jian;Liao, Xiao-Ping;Yu, Yang;Zheng, Mei;Li, Fu-Hao;Liu, Juan;Li, Wen-Jie;Yin, Ruo-Xi;Cai, Da-Tong;Zheng, Si-Lin;Sun, Jian;Liao, Xiao-Ping;Yu, Yang;Zheng, Mei;Li, Fu-Hao;Liu, Juan;Li, Wen-Jie;Yin, Ruo-Xi;Sun, Jian;Liao, Xiao-Ping;Yu, Yang;Andrey, Diego O.;Andrey, Diego O.;Gales, Ana C.;Zhang, Wan-Jiang

作者机构：

期刊名称：JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY （ 影响因子：5.2； 五年影响因子：5.4 ）

ISSN： 0305-7453

年卷期： 2024 年

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收录情况： SCI

摘要： Objectives The emergence and expansion of carbapenem-resistant Klebsiella pneumoniae infections is a concern due to the lack of 'first-line' antibiotic treatment options. The ceftazidime/avibactam is an important clinical treatment for carbapenem-resistant K. pneumoniae infections but there is an increasing number of cases of treatment failure and drug resistance. Therefore, a potential solution is combination therapies that result in synergistic activity against K. pneumoniae carbapenemase: producing K. pneumoniae (KPC-Kp) isolates and preventing the emergence of KPC mutants resistant to ceftazidime/avibactam are needed in lieu of novel antibiotics.Methods To evaluate their synergistic activity, antibiotic combinations were tested against 26 KPC-Kp strains. Antibiotic resistance profiles, molecular characteristics and virulence genes were investigated by susceptibility testing and whole-genome sequencing. Antibiotic synergy was evaluated by in vitro chequerboard experiments, time-killing curves and dose-response assays. The mouse thigh model was used to confirm antibiotic combination activities in vivo. Additionally, antibiotic combinations were evaluated for their ability to prevent the emergence of ceftazidime/avibactam resistant mutations of blaKPC.Results The combination of ceftazidime/avibactam plus meropenem showed remarkable synergistic activity against 26 strains and restored susceptibility to both the partnering antibiotics. The significant therapeutic effect of ceftazidime/avibactam combined with meropenem was also confirmed in the mouse model and bacterial loads in the thigh muscle of the combination groups were significantly reduced. Furthermore, ceftazidime/avibactam plus meropenem showed significant activity in preventing the occurrence of resistance mutations.Conclusions Our results indicated that the combination of ceftazidime/avibactam plus meropenem offers viable therapeutic alternatives in treating serious infections due to KPC-Kp.

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