Mohd Sazlly Lim S, Heffernan A J, Roberts J A, Sime F B
UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Australia.
Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia.
Antimicrob Agents Chemother. 2023 May 1;65(5). doi: 10.1128/AAC.02472-20. Epub 2021 Mar 8.
Due to limited treatment options for carbapenem-resistant (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates.Synergism of FOS/SUL against 50 clinical CR-AB isolates were screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill and 2-log kill after 24-hours with combination therapy.The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC and MIC of FOS/SUL were decreased four- to eight-fold, compared to the monotherapy MIC and MIC In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate, at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam 4 g every 8 hours, demonstrated a probability of target attainment of 1-log kill at 24 h of ∼69-76%, as compared to ∼15-30% with monotherapy regimens at the highest doses.The reduction in the MIC values and the achievement of a moderate PTA of a 2-log reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.
由于耐碳青霉烯类鲍曼不动杆菌（CR-AB）感染的治疗选择有限，抗生素联合用药目前被视为治疗CR-AB的潜在疗法。本研究旨在探讨磷霉素-舒巴坦联合用药（FOS/SUL）治疗CR-AB分离株的效用。采用棋盘法筛选FOS/SUL对50株临床CR-AB分离株的协同作用。此后，对两株CR-AB分离株进行了时间杀菌研究。使用半机制药代动力学/药效学（PK/PD）模型描述时间杀菌数据。然后进行蒙特卡洛模拟，以估计联合治疗24小时后达到停滞、1个对数级杀灭和2个对数级杀灭的概率。FOS/SUL联合用药对74%的分离株显示出协同作用。未观察到拮抗作用。与单药治疗的最低抑菌浓度（MIC）相比，FOS/SUL的MIC降低了4至8倍。在时间杀菌研究中，在临床可达到的最高浓度下，该联合用药对两株分离株均显示出杀菌活性，对一株分离株显示出协同活性。我们的PK/PD模型能够描述磷霉素和舒巴坦之间的相互作用。细菌杀灭主要由舒巴坦驱动，磷霉素起增强作用。每8小时使用4克舒巴坦的FOS/SUL治疗方案，在24小时达到1个对数级杀灭的目标达成概率约为69%-76%，而最高剂量的单药治疗方案的目标达成概率约为15%-30%。MIC值的降低以及实现细菌负荷降低2个对数级的适度目标达成概率表明，FOS/SUL可能对某些CR-AB感染有效。
