Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Australia; Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia.
Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Australia; UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia.
Int J Antimicrob Agents. 2020 Oct;56(4):106115. doi: 10.1016/j.ijantimicag.2020.106115. Epub 2020 Jul 25.
Due to limited therapeutic options, combination therapy has been used empirically to treat carbapenem-resistant Acinetobacter baumannii (CRAB). Polymyxin-based combinations have been widely studied and used in the clinical setting. However, the use of polymyxins is often limited due to nephrotoxicity and neurotoxicity. This study aimed to evaluate the activity of non-polymyxin-based combinations relative to polymyxin-based combinations and to identify potential synergistic and bactericidal two-drug non-polymyxin-based combinations against CRAB. In vitro activity of 14 two-drug combinations against 50 A. baumannii isolates was evaluated using the checkerboard method. Subsequently, the two best-performing non-polymyxin-based combinations from the checkerboard assay were explored in static time-kill experiments. Concentrations of antibiotics corresponding to the fractional inhibitory concentrations (FIC) and the highest serum concentration achievable clinically were tested. The most synergistic combinations were fosfomycin/sulbactam (synergistic against 37/50 isolates; 74%), followed by meropenem/sulbactam (synergistic against 28/50 isolates; 56%). No antagonism was observed for any combination. Both fosfomycin/sulbactam and meropenem/sulbactam combinations exhibited bactericidal and synergistic activity against both isolates at the highest clinically achievable concentrations in the time-kill experiments. The meropenem/sulbactam combination displayed synergistic and bactericidal activity against one of two strains at concentrations equal to the FIC. Non-polymyxin-based combinations such as fosfomycin/sulbactam and meropenem/sulbactam may have a role in the treatment of CRAB. Further in vivo and clinical studies are required to scrutinise these activities further.
由于治疗选择有限，经验性地使用联合疗法来治疗碳青霉烯类耐药鲍曼不动杆菌（CRAB）。基于多黏菌素的联合治疗已广泛研究并用于临床。然而，由于肾毒性和神经毒性，多黏菌素的使用往往受到限制。本研究旨在评估非多黏菌素联合治疗相对于多黏菌素联合治疗的活性，并确定针对 CRAB 的潜在协同和杀菌的两药非多黏菌素联合治疗方案。使用棋盘法评估了 14 种两药组合对 50 株鲍曼不动杆菌分离株的体外活性。随后，在静态时间杀伤实验中研究了棋盘试验中表现最好的两种非多黏菌素联合治疗方案。测试了抗生素浓度相当于部分抑菌浓度（FIC）和临床可达到的最高血清浓度。协同作用最好的组合是磷霉素/舒巴坦（协同作用 37/50 株；74%），其次是美罗培南/舒巴坦（协同作用 28/50 株；56%）。没有观察到任何组合的拮抗作用。在时间杀伤实验中，磷霉素/舒巴坦和美罗培南/舒巴坦组合在最高临床可达到的浓度下均对两种分离株表现出杀菌和协同作用。美罗培南/舒巴坦组合在等于 FIC 的浓度下对两种菌株中的一种表现出协同和杀菌作用。非多黏菌素联合治疗方案，如磷霉素/舒巴坦和美罗培南/舒巴坦，可能在治疗 CRAB 方面发挥作用。需要进一步的体内和临床研究来进一步研究这些活性。
