Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia.
Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Seri Kembangan, Malaysia.
Eur J Clin Microbiol Infect Dis. 2021 Sep;40(9):1943-1952. doi: 10.1007/s10096-021-04252-z. Epub 2021 Apr 22.
Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are commonly used. In this study, we explored the potential efficacy of meropenem-sulbactam combination (MEM/SUL) against CR-AB. The checkerboard method was used to screen for synergistic activity of MEM/SUL against 50 clinical CR-AB isolates. Subsequently, time-kill studies against two CR-AB isolates were performed. Time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Subsequently, Monte Carlo simulations were performed to estimate the probability of 2-log kill, 1-log kill or stasis at 24-h following combination therapy. The MEM/SUL demonstrated synergy against 28/50 isolates. No antagonism was observed. The MIC50 and MIC of MEM/SUL were decreased fourfold, compared to the monotherapy MIC. In the time-kill studies, the combination displayed synergistic killing against both isolates at the highest clinically achievable concentrations. At concentrations equal to the fractional inhibitory concentration, synergism was observed against one isolate. The PK/PD model adequately delineated the data and the interaction between meropenem and sulbactam. The effect of the combination was driven by sulbactam, with meropenem acting as a potentiator. The simulations of various dosing regimens revealed no activity for the monotherapies. At best, the MEM/SUL regimen of 2 g/4 g every 8 h demonstrated a probability of target attainment of 2-log kill at 24 h of 34%. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log reduction in bacterial burden demonstrated that MEM/SUL may potentially be effective against some CR-AB infections.
由于对碳青霉烯类耐药鲍曼不动杆菌（CR-AB）感染的治疗选择有限，通常会使用抗生素联合治疗。在这项研究中，我们探索了美罗培南-舒巴坦合剂（MEM/SUL）对 CR-AB 的潜在疗效。采用棋盘微量稀释法筛选 MEM/SUL 对 50 株临床 CR-AB 分离株的协同活性。随后，对两种 CR-AB 分离株进行了时间杀伤研究。使用半机械药代动力学/药效学（PK/PD）模型来描述时间杀伤数据。随后，进行了蒙特卡罗模拟以估计联合治疗 24 小时后 2-log 杀灭、1-log 杀灭或停滞的概率。MEM/SUL 对 28/50 株分离株表现出协同作用。未观察到拮抗作用。与单药治疗 MIC 相比，MEM/SUL 的 MIC50 和 MIC 降低了四倍。在时间杀伤研究中，组合在最高临床可达到的浓度下对两种分离株均表现出协同杀菌作用。在等于部分抑菌浓度的浓度下，对一株分离株观察到协同作用。PK/PD 模型充分描述了数据以及美罗培南和舒巴坦之间的相互作用。组合的作用由舒巴坦驱动，美罗培南作为增效剂。各种给药方案的模拟表明，单药治疗均无活性。在最佳情况下，MEM/SUL 方案为 2 g/4 g 每 8 小时，24 小时时目标达到 2-log 杀灭的概率为 34%。MIC 值的降低以及细菌负荷减少 2-log 的中度 PTA 的实现表明，MEM/SUL 可能对某些 CR-AB 感染有效。
