头孢他啶/阿维巴坦单用或与氨曲南联用对碳青霉烯类耐药肠杆菌目细菌的体内、外抗菌活性的比较

Comparison of in vitro and in vivo antimicrobial activity of ceftazidime/avibactam alone or in combination with aztreonam against carbapenem-resistant Enterobacterales

摘要:

目的 了解头孢他啶/阿维巴坦(CZA)单用或与氨曲南(ATM)联合用药对耐碳青霉烯类肠杆菌目细菌(CRE)的体内、外抗菌活性,为临床抗感染治疗提供依据。方法 采用微量肉汤稀释法对某院2018—2022年临床分离的52株非重复CRE进行CZA及ATM最低抑菌浓度(MIC)测定,采用棋盘稀释法进行联合药敏试验。时间-杀菌曲线和大蜡螟感染模型检测CZA单用或与ATM联合使用的杀菌效果。结果 23株产KPC酶的CRE菌株中91.3%(21株)对CZA的MIC≤4 μg/mL,8.7%(2株)的菌株对CZA的MIC≥128 μg/mL。产NDM、IMP、KPC+IMP、KPC+NDM等酶型的29株CRE对CZA的MIC值均≥128 μg/mL。31株CZA耐药的菌株中93.5%(29株)的CZA与ATM联合FIC值＜0.5,6.5%(2株)的FIC在0~1。时间-杀菌曲线表明CZA对产KPC酶的菌株具有杀菌效果,CZA联合ATM对耐CZA菌株有杀菌效果。与单药组相比,CZA联合ATM处理组CRE感染大蜡螟生存率显著提高(中位生存时间120 h,P=0.001)。结论 CZA对产KPC酶的细菌有较好的抗菌作用。CZA与ATM联用对CZA耐药的菌株具有协同抑菌作用。

Abstract:

Objective To investigate the in vivo and in vitro antimicrobial activity of ceftazidime/avibactam (CZA) alone or in combination with aztreonam (ATM) against carbapenem-resistant Enterobacterales (CRE), and provide evidence for clinical anti-infective therapy. Methods The minimum inhibitory concentrations (MICs) of CZA and ATM against 52 clinically isolated non-repetitive CRE strains in a hospital from 2018 to 2022 were determined with microbroth dilution method, and the combined antimicrobial susceptibility testing was performed with the chessboard dilution method. Time-killing curve and Galleria mellonella infection model were used to test the bactericidal effect of CZA alone or in combination with ATM. Results Among the 23 KPC-producing CRE strains, 91.3% (n=21) had MIC ≤4 μg/mL for CZA, and 8.7% (n=2) had MIC ≥128 μg/mL for CZA. MIC of CZA to 29 CRE strains (strains producing NDM, IMP, KPC+IMP, and KPC+NDM) were all ≥128 μg/mL. Of the 31 CZA-resistant strains, 93.5% (n=29) strains had fractional inhibitory concentration (FIC) <0.5 for combination of CZA and ATM, while 6.5% (n=2) had FIC of 0-1. The time-killing curve showed that CZA had bactericidal effect on KPC-producing strains, and CZA combined with ATM had bactericidal effect on CZA-resistant strains. Compared with the monotherapy group, CZA combined with ATM treatment significantly improved the survival rate of CRE-infected Galleria mellonella (median survival time 120 hour, P=0.001). Conclusion CZA has good antimicrobial activity against KPC-producing bacteria. The combination of CZA and ATM had synergistic bacteriostatic effect on CZA-resistant strains.