Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200 Brussels, Belgium.
Int J Antimicrob Agents. 2011 Jul;38(1):52-9. doi: 10.1016/j.ijantimicag.2011.03.002. Epub 2011 May 18.
Finafloxacin, an 8-cyano-substituted fluoroquinolone, expresses enhanced activity at acidic pH and is less susceptible to several fluoroquinolone resistance determinants. In this study, we compared finafloxacin and ciprofloxacin for (i) activity against ciprofloxacin-susceptible and -resistant Staphylococcus aureus as well as wild-type and Lde efflux-positive (Lde+) Listeria monocytogenes, (ii) accumulation in THP-1 macrophages and (iii) intracellular activity towards phagocytised S. aureus, L. monocytogenes and Legionella pneumophila (developing in acidic, neutral and mildly acidic environments, respectively), using a pharmacological approach assessing drug potencies and maximal relative efficacies (E(max)). Finafloxacin minimum inhibitory concentrations (MICs) were two-fold lower than those of ciprofloxacin against meticillin-susceptible S. aureus ATCC 25923, were only modestly increased in an isogenic strain overexpressing NorA and were ≤0.25 mg/L for community-acquired meticillin-resistant S. aureus. No loss of activity was seen in Lde+ L. monocytogenes. An acidic pH decreased the MIC of finafloxacin and increased that of ciprofloxacin both for S. aureus and L. monocytogenes, in parallel with corresponding changes in drug accumulation (tested with S. aureus ATCC 25923 only). Finafloxacin accumulated less than ciprofloxacin in THP-1 cells, but the situation was reversed by exposure of cells to acid pH. In S. aureus-infected cells, acid pH increased the potency of finafloxacin without change of E(max), whilst decreasing the potency and the maximal relative efficacy of ciprofloxacin (less negative E(max)). Finafloxacin was more potent and showed larger E(max) than ciprofloxacin against phagocytised L. pneumophila, but was less potent against phagocytised L. monocytogenes. Finafloxacin appears to be an acid-pH-favoured antibiotic that may find useful applications in infections where the local pH is low.
法氟沙星是一种 8-氰基取代的氟喹诺酮，在酸性 pH 下表现出增强的活性，并且对几种氟喹诺酮耐药决定因素的敏感性较低。在这项研究中，我们比较了法氟沙星和环丙沙星在以下方面的作用：（i）对环丙沙星敏感和耐药的金黄色葡萄球菌以及野生型和 Lde 外排阳性（Lde+）李斯特菌的活性，（ii）在 THP-1 巨噬细胞中的积累，以及（iii）吞噬后的金黄色葡萄球菌、李斯特菌和嗜肺军团菌（分别在酸性、中性和微酸性环境中生长）的细胞内活性，使用药理学方法评估药物效力和最大相对效力（E(max)）。法氟沙星的最低抑菌浓度（MIC）比环丙沙星对耐甲氧西林敏感的金黄色葡萄球菌 ATCC 25923 低两倍，在过表达 NorA 的同基因菌株中仅适度增加，对于社区获得性耐甲氧西林金黄色葡萄球菌，MIC 值≤0.25mg/L。Lde+李斯特菌的活性没有丧失。酸性 pH 降低了法氟沙星和环丙沙星对金黄色葡萄球菌和李斯特菌的 MIC，与药物积累的相应变化平行（仅用金黄色葡萄球菌 ATCC 25923 进行测试）。法氟沙星在 THP-1 细胞中的积累少于环丙沙星，但在细胞暴露于酸性 pH 时情况相反。在金黄色葡萄球菌感染的细胞中，酸性 pH 增加了法氟沙星的效力而不改变 E(max)，而降低了环丙沙星的效力和最大相对效力（E(max)更负）。法氟沙星对吞噬的嗜肺军团菌的效力比环丙沙星更强，E(max)更大，但对吞噬的李斯特菌的效力较低。法氟沙星似乎是一种酸性 pH 偏好的抗生素，在局部 pH 值较低的感染中可能有实用价值。
