Sy Sherwin K B, Zhuang Luning, Beaudoin Marie-Eve, Kircher Philipp, Tabosa Maria A M, Cavalcanti Noely C T, Grunwitz Christian, Pieper Sebastian, Schuck Virna J, Nichols Wright W, Derendorf Hartmut
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
AstraZeneca, Waltham, MA, USA.
J Antimicrob Chemother. 2017 Apr 1;72(4):1109-1117. doi: 10.1093/jac/dkw535.
This study evaluated the in vitro pharmacodynamics of combinations of ceftazidime and the non-β-lactam β-lactamase inhibitor, avibactam, against ceftazidime-, piperacillin/tazobactam- and meropenem-multiresistant Pseudomonas aeruginosa by a quantitative time-kill method.
MICs of ceftazidime plus 0-16 mg/L avibactam were determined against eight isolates of P. aeruginosa . Single-compartment, 24 h time-kill kinetics were investigated for three isolates at 0-16 mg/L avibactam with ceftazidime at 0.25-4-fold the MIC as measured at the respective avibactam concentration. Ceftazidime and avibactam concentrations were measured by LC-MS/MS during the time-kill kinetic studies to evaluate drug degradation.
Avibactam alone displayed no antimicrobial activity. MICs of ceftazidime decreased by 8-16-fold in the presence of avibactam at 4 mg/L. The changes in log 10 cfu/mL at both the 10 h and 24 h timepoints (versus 0 h) revealed bacterial killing at ≥1-fold MIC. Significantly higher concentrations of ceftazidime alone, as compared with those of ceftazidime in combination, were required to produce any given kill. Without avibactam, ceftazidime degradation was significant (defined as degradation t 1/2 < 24 h), with as little as 19% ± 18% of the original concentration remaining at 8 h for the most resistant strain. In combination with avibactam, ceftazidime degradation at ≥ 1-fold MIC was negligible.
The addition of avibactam protected ceftazidime from degradation in a dose-dependent manner and restored its cidal and static activity at concentrations in combination well below the MIC of ceftazidime alone.
本研究采用定量时间杀菌法，评估头孢他啶与非β-内酰胺类β-内酰胺酶抑制剂阿维巴坦联合应用对头孢他啶、哌拉西林/他唑巴坦和亚胺培南多重耐药铜绿假单胞菌的体外药效学。
测定头孢他啶加0 - 16mg/L阿维巴坦对8株铜绿假单胞菌的最低抑菌浓度（MIC）。对3株菌研究了在0 - 16mg/L阿维巴坦存在下，头孢他啶浓度为各自阿维巴坦浓度下MIC的0.25 - 4倍时的单室24小时时间杀菌动力学。在时间杀菌动力学研究期间，通过液相色谱-串联质谱法（LC-MS/MS）测定头孢他啶和阿维巴坦浓度，以评估药物降解情况。
单独使用阿维巴坦无抗菌活性。在4mg/L阿维巴坦存在下，头孢他啶的MIC降低了8 - 16倍。在10小时和24小时时间点（与0小时相比）log10cfu/mL的变化显示，在≥1倍MIC时细菌被杀死。与联合使用时相比，单独使用头孢他啶需要显著更高的浓度才能产生任何给定的杀菌效果。在没有阿维巴坦的情况下，头孢他啶降解显著（定义为降解半衰期<24小时），对于最耐药菌株，在8小时时仅剩余19%±18%的原始浓度。与阿维巴坦联合使用时，在≥1倍MIC时头孢他啶的降解可忽略不计。
添加阿维巴坦以剂量依赖方式保护头孢他啶不被降解，并在联合浓度远低于头孢他啶单独MIC时恢复其杀菌和抑菌活性。
