State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
J Antimicrob Chemother. 2024 May 2;79(5):1069-1080. doi: 10.1093/jac/dkae074.
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.
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.
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.
Our results indicated that the combination of ceftazidime/avibactam plus meropenem offers viable therapeutic alternatives in treating serious infections due to KPC-Kp.
由于缺乏“一线”抗生素治疗选择，碳青霉烯类耐药肺炎克雷伯菌感染的出现和扩大令人担忧。头孢他啶/阿维巴坦是治疗碳青霉烯类耐药肺炎克雷伯菌感染的重要临床治疗方法，但治疗失败和耐药的病例越来越多。因此，需要联合治疗方案来对抗产碳青霉烯酶肺炎克雷伯菌（KPC-Kp）分离株，并防止对头孢他啶/阿维巴坦产生耐药性的 KPC 突变体的出现，以替代新型抗生素。
为了评估它们的协同活性，对 26 株 KPC-Kp 菌株进行了抗生素联合测试。通过药敏试验和全基因组测序研究了抗生素耐药谱、分子特征和毒力基因。通过体外棋盘试验、时间杀伤曲线和剂量反应试验评估抗生素协同作用。使用小鼠大腿模型在体内验证抗生素联合活性。此外，评估了抗生素联合用药预防头孢他啶/阿维巴坦耐药突变 blaKPC 的出现的能力。
头孢他啶/阿维巴坦联合美罗培南对 26 株菌株表现出显著的协同活性，并恢复了对两种联合抗生素的敏感性。头孢他啶/阿维巴坦联合美罗培南在小鼠模型中的显著治疗效果也得到了证实，联合组的大腿肌肉细菌负荷明显降低。此外，头孢他啶/阿维巴坦联合美罗培南在预防耐药突变的发生方面表现出显著的活性。
我们的研究结果表明，头孢他啶/阿维巴坦联合美罗培南为治疗 KPC-Kp 引起的严重感染提供了可行的治疗选择。
