Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany.
J Antimicrob Chemother. 2019 Nov 1;74(11):3211-3216. doi: 10.1093/jac/dkz330.
The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro.
Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time-kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination.
The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time-kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival.
Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time-kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.
β-内酰胺/β-内酰胺酶抑制剂复合制剂头孢他啶/阿维巴坦对产 KPC 的肠杆菌科具有活性。在此，我们介绍了在体内和体外产生的产 KPC-3 肺炎克雷伯菌对头孢他啶/阿维巴坦耐药性的分子和表型特征。
对临床和体外产生的头孢他啶/阿维巴坦耐药性肺炎克雷伯菌分离株的 blaKPC-3 进行序列分析。采用时间杀菌动力学和大蜡螟感染模型评估头孢他啶/阿维巴坦和亚胺培南单独及联合应用的活性。
头孢他啶/阿维巴坦耐药的临床肺炎克雷伯菌分离株显示 KPC-3 中的氨基酸变化 D179Y。描述了体外选择的头孢他啶/阿维巴坦耐药分离株中 KPC-3 的 16 种新的突变变化。时间杀菌动力学显示，在亚胺培南或头孢他啶/阿维巴坦选择压力下出现耐药亚群。然而，联合亚胺培南加头孢他啶/阿维巴坦选择压力可防止耐药性的发展并导致杀菌活性。同样，大蜡螟感染模型表明，头孢他啶/阿维巴坦单药治疗容易在体内选择耐药性，而亚胺培南联合治疗可显著提高生存率。
头孢他啶/阿维巴坦是治疗 MDR 和碳青霉烯类耐药肠杆菌科的有价值的抗生素。基于时间杀菌动力学和体内感染模型，我们推测头孢他啶/阿维巴坦和亚胺培南联合治疗是防止体内产 KPC 肠杆菌科对头孢他啶/阿维巴坦耐药性发展的策略。
