Clinical Department of Medical, Surgical and Health Sciences, Trieste University, Piazza dell'Ospitale 1, 34129 Trieste, Italy.
Clinical Department of Medical, Surgical and Health Sciences, Trieste University, Piazza dell'Ospitale 1, 34129 Trieste, Italy.
Int J Antimicrob Agents. 2021 Jul;58(1):106362. doi: 10.1016/j.ijantimicag.2021.106362. Epub 2021 May 16.
Multidrug-resistant (MDR) Enterobacterales are a priority health issue with few treatment options. Recently, fosfomycin has been reconsidered for MDR bacterial infections. Zidovudine, licensed for the treatment of human immunodeficiency virus (HIV), has unexploited antibacterial properties and has been considered for drug repurposing. The aim of this study was to assess the effect of the combination of fosfomycin plus zidovudine against clinical MDR Enterobacterales isolates. Minimum inhibitory concentration (MIC) determination and checkerboard assays for 36 MDR Enterobacterales strains were performed. In addition, fosfomycin-resistant strains were evaluated using time-kill assay and in an in vivo Galleria mellonella infection model. Zidovudine and fosfomycin MICs ranged between 0.06 to >64 mg/L and 0.125 to >512 mg/L, respectively. A synergistic effect [fractional inhibitory concentration index (FICI) ≤0.5] was observed in 25 isolates and no antagonistic effect was observed in the remaining isolates. For 7 of 8 fosfomycin-resistant strains (MIC > 32 mg/L), zidovudine combination was able to restore fosfomycin susceptibility. These results were confirmed by time-kill assays. Fosfomycin + zidovudine presented greater larval survival (20-50%) than monotherapy. Synergistic activity was observed for fosfomycin + zidovudine in 69.4% of the tested strains. In vivo experiments confirmed the enhanced effectiveness of the combination. The zidovudine concentrations tested here can be reached in human serum using the actual licensed dosage, therefore this combination deserves further clinical investigation.
多药耐药（MDR）肠杆菌科是一个优先的健康问题，治疗选择有限。最近，磷霉素已重新用于治疗 MDR 细菌感染。齐多夫定（用于治疗人类免疫缺陷病毒（HIV））具有未被开发的抗菌特性，并被认为可用于药物再利用。本研究旨在评估磷霉素联合齐多夫定对临床 MDR 肠杆菌科分离株的疗效。对 36 株 MDR 肠杆菌科菌株进行了最低抑菌浓度（MIC）测定和棋盘试验。此外，还使用时间杀伤试验和体内家蚕感染模型评估了磷霉素耐药株。齐多夫定和磷霉素的 MIC 值范围分别为 0.06 至 >64mg/L 和 0.125 至 >512mg/L。在 25 株分离株中观察到协同作用（分数抑菌浓度指数（FICI）≤0.5），而在其余分离株中未观察到拮抗作用。对于 8 株磷霉素耐药株中的 7 株（MIC > 32mg/L），齐多夫定联合用药能够恢复磷霉素敏感性。这些结果通过时间杀伤试验得到证实。磷霉素+齐多夫定治疗组幼虫存活率（20-50%）高于单药治疗组。在 69.4%的受试菌株中观察到磷霉素+齐多夫定的协同活性。体内实验证实了联合用药的增强效果。此处测试的齐多夫定浓度可通过实际许可剂量在人血清中达到，因此该联合用药值得进一步临床研究。
