PDF(Pubmed)
Abstract：
Antimicrobial resistance is emerging in clinical strains of Clostridioides difficile. Ibezapolstat (IBZ) is a DNA polymerase IIIC inhibitor that has completed phase II clinical trials. IBZ has potent in vitro activity against wild-type, susceptible strains but its effect on C. difficile strains with reduced susceptibility to metronidazole (MTZ), vancomycin (VAN), or fidaxomicin (FDX) has not been tested. The primary objective of this study was to test the antibacterial properties of IBZ against multidrug-resistant C. difficile strains. The in vitro activity, bactericidal, and time-kill activity of IBZ versus comparators were evaluated against 100 clinical strains of which 59 had reduced susceptibility to other C. difficile antibiotics. Morphologic changes against a multidrug resistance strain were visualized by light and scanning electron microscopy. The overall IBZ MIC50/90 values (µg/mL) for evaluated C. difficile strains were 4/8, compared with 2/4 for VAN, 0.5/1 for FDX, and 0.25/4 for MTZ. IBZ MIC50/90 values did not differ based on non-susceptibility to antibiotic class or number of classes to which strains were non-susceptible. IBZ bactericidal activity was similar to the minimum inhibitory concentration (MIC) and maintained in wild-type and non-susceptible strains. Time-kill assays against two laboratory wild-type and two clinical non-susceptible strains demonstrated sustained IBZ activity despite reduced killing by comparator antibiotics for IBZ and VAN non-susceptible strains. Microscopy visualized increased cell lengthening and cellular damage in multidrug-resistant strains exposed to IBZ sub-MIC concentrations. This study demonstrated the potent antibacterial activity of IBZ against a large collection of C. difficile strains including multidrug-resistant strains. This study highlights the therapeutic potential of IBZ against multidrug-resistant strains of C. difficile.
摘要：
艰难梭菌的临床菌株中出现了抗菌素耐药性。Ibezapolstat（IBZ）是一种DNA聚合酶IIIC抑制剂，已完成II期临床试验。IBZ对野生型具有有效的体外活性，敏感菌株，但其对艰难梭菌菌株的影响对甲硝唑（MTZ）的敏感性降低，万古霉素(VAN),或非达霉素（FDX）尚未测试。这项研究的主要目的是测试IBZ对多重耐药艰难梭菌菌株的抗菌特性。体外活性，杀菌,对100个临床菌株中59个对其他艰难梭菌抗生素的敏感性降低的菌株进行了IBZ与比较物的时间杀伤活性的评估。通过光学和扫描电子显微镜观察多药耐药菌株的形态变化。评估的艰难梭菌菌株的总体IBZMIC50/90值（µg/mL）为4/8，而VAN为2/4，FDX为0.5/1，MTZ为0.25/4。IBZMIC50/90值基于对抗生素类别的不敏感性或菌株对其不敏感的类别的数量而没有差异。IBZ杀菌活性与最低抑制浓度（MIC）相似，并在野生型和非易感菌株中保持不变。针对两种实验室野生型和两种临床非易感菌株的时间杀伤测定显示出持续的IBZ活性，尽管通过比较抗生素对IBZ和VAN非易感菌株的杀伤降低。显微镜观察到暴露于IBZ亚MIC浓度的多药耐药菌株的细胞延长和细胞损伤增加。该研究证明了IBZ对大量艰难梭菌菌株(包括多重耐药菌株)的有效抗菌活性。这项研究强调了IBZ对艰难梭菌多重耐药菌株的治疗潜力。
