Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China.
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
Int J Antimicrob Agents. 2021 Feb;57(2):106271. doi: 10.1016/j.ijantimicag.2020.106271. Epub 2020 Dec 23.
Polymyxin-based combination therapy is often used to treat carbapenem-resistant Acinetobacter baumannii (A. baumannii) infections. Although sulbactam is intrinsically active against A. baumannii, few studies have investigated colistin/sulbactam combinations against carbapenem-resistant A. baumannii.
Whole genome sequencing was undertaken on eight carbapenem-resistant (colistin-susceptible) isolates of A. baumannii from Chinese patients. Bacterial killing of colistin and sulbactam, alone and in combination, was examined with checkerboard (all isolates) and static and dynamic time-kill studies (three isolates). In the dynamic studies, antibiotics were administered in various clinically-relevant dosing regimens that mimicked patient pharmacokinetics.
The eight isolates consisted of ST195, ST191 and ST208 belonging to clonal complex 208, which is the most epidemic clonal type of A. baumannii globally. All isolates possessed Acinetobacter-derived cephalosporinase (ADC-61 or ADC-78) and seven of eight isolates contained the carbapenem-resistance gene bla. The colistin/sulbactam combination was synergistic against two of eight isolates in checkerboard studies. In time-kill studies, rapid bacterial killing of ca. 3-6 log CFU/mL was observed with colistin monotherapy, followed by steady regrowth. Sulbactam monotherapy was generally ineffective. Substantially enhanced bacterial killing was observed with colistin/sulbactam combinations in both static and dynamic models, especially with the higher sulbactam concentration (2 g) and/or longer sulbactam infusion time (2 hours) in the dynamic model.
This study was the first to use a pharmacokinetics/pharmacodynamics model to investigate synergistic activity of colistin/sulbactam combinations against A. baumannii. It showed that clinically-relevant dosing regimens of colistin combined with sulbactam may substantially improve bacterial killing of multidrug-resistant and carbapenem-resistant A. baumannii.
多黏菌素联合治疗常被用于治疗碳青霉烯类耐药鲍曼不动杆菌（A.baumannii）感染。虽然舒巴坦对鲍曼不动杆菌固有活性，但很少有研究调查多黏菌素/舒巴坦联合治疗碳青霉烯类耐药鲍曼不动杆菌。
对来自中国患者的 8 株耐碳青霉烯类（多黏菌素敏感）鲍曼不动杆菌进行全基因组测序。采用棋盘法（所有分离株）和静态及动态时间杀菌试验（3 株分离株）检测多黏菌素和舒巴坦单独及联合应用的杀菌效果。在动态研究中，抗生素以模拟患者药代动力学的各种临床相关剂量方案进行给药。
8 株分离株包括 ST195、ST191 和 ST208，属于克隆复合体 208，是全球最流行的鲍曼不动杆菌克隆类型。所有分离株均携带不动杆菌来源的头孢菌素酶（ADC-61 或 ADC-78），8 株中有 7 株含有碳青霉烯耐药基因 bla。棋盘试验中，多黏菌素/舒巴坦联合对其中 2 株分离株表现为协同作用。时间杀菌试验中，多黏菌素单药治疗可迅速杀灭约 3-6 对数 CFU/mL 的细菌，随后出现稳定的再生长。舒巴坦单药治疗通常无效。在静态和动态模型中，多黏菌素/舒巴坦联合治疗可显著增强细菌的杀菌效果，尤其是在动态模型中采用较高的舒巴坦浓度（2 g）和/或较长的舒巴坦输注时间（2 小时）。
本研究首次使用药代动力学/药效学模型研究多黏菌素/舒巴坦联合治疗对鲍曼不动杆菌的协同作用。结果表明，临床相关剂量方案的多黏菌素联合舒巴坦治疗可能显著提高对多重耐药和碳青霉烯类耐药鲍曼不动杆菌的杀菌效果。
