Demonstrating the Protective Efficacy of the Novel Fluoroquinolone Finafloxacin against an Inhalational Exposure to Burkholderia pseudomallei
Demonstrating the Protective Efficacy of the Novel Fluoroquinolone Finafloxacin against an Inhalational Exposure to Burkholderia pseudomallei
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DOI：
10.1128/aac.00082-17
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发表时间：
2017-07-01
影响因子：
4.9
通讯作者：
Harding, Sarah V.
中科院分区：
文献类型：
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作者：
Barnes, Kay B.;Hamblin, Karleigh A.;Harding, Sarah V.
假性伯克霍尔德菌是类鼻疽病的病原体，是东南亚和澳大利亚北部的一种严重的地方病。抗生素治疗时间长，而且经常复发。非那沙星是一种新型氟喹诺酮类药物，在酸性条件下具有更高的抗菌活性，而其他氟喹诺酮类药物在较低pH下的抗菌活性会降低。因此，非那沙星可能对假假芽孢杆菌有更好的抗菌效果，假假芽孢杆菌可以在局部pH为酸性的宿主细胞中存活。体外分析采用mic、最低杀菌浓度（MBCs）、时间杀伤法、持久性细胞法和巨噬细胞法。与ph7和ph5的环丙沙星相比，芬那沙星在ph5时的杀菌活性增加。BALB/c小鼠体内研究包括药代动力学研究，以确定合适的给药方案。在吸入性类鼻疽小鼠模型中评估非那沙星的疗效，在攻毒后6或24小时开始抗生素治疗并持续14天，小鼠观察63天。非那沙星、复方新诺明或环丙沙星治疗14天后的存活率，在6小时开始治疗时分别为80%、60%或0%，在24小时开始治疗时分别为60%、30%或0%。综上所述，与环丙沙星相比，非那沙星在体外酸性条件下增加了对假芽孢杆菌的杀菌活性，并提高了类meliosis小鼠模型的存活率。此外，与复方新诺明相比，非那沙星可以提高细菌清除率，这表明它可能是一种有效的暴露后预防假芽孢杆菌的药物。
Burkholderia pseudomallei is the causative agent of melioidosis, a serious disease endemic in Southeast Asia and Northern Australia. Antibiotic treatment is lengthy and relapse often occurs. Finafloxacin is a novel fluoroquinolone with increased antibacterial activity in acidic conditions in contrast to other fluoroquinolones which demonstrate reduced activity at a lower pH. Therefore, finafloxacin may have improved efficacy against B. pseudomallei, which can survive within host cells where the local pH is acidic. In vitro analysis was performed using MICs, minimal bactericidal concentrations (MBCs), time-kill assays, persister cell assays, and macrophage assays. Finafloxacin showed increased bactericidal activity at pH 5 in comparison to pH 7 and ciprofloxacin at pH 5. In vivo studies in BALB/c mice included pharmacokinetic studies to inform an appropriate dosing regimen. Finafloxacin efficacy was evaluated in an inhalational murine model of melioidosis where antibiotic treatment was initiated at 6 or 24 h postchallenge and continued for 14 days, and mice were observed for 63 days. The survival of infected mice following 14 days of treatment was 80%, 60% or 0% for treatments initiated at 6 h and 60%, 30% or 0% for treatments initiated at 24 h for finafloxacin, co-trimoxazole, or ciprofloxacin, respectively. In summary, finafloxacin has increased bactericidal activity for B. pseudomallei under acidic conditions in vitro and improves survival in a murine model of melioidosis compared with those for ciprofloxacin. Furthermore, finafloxacin improves bacteriological clearance compared with that of co-trimoxazole, suggesting it may offer an effective postexposure prophylaxis against B. pseudomallei.