Bicarbonate modulates delafloxacin activity against MDR Staphylococcus aureus and Pseudomonas aeruginosa
Bicarbonate modulates delafloxacin activity against MDR Staphylococcus aureus and Pseudomonas aeruginosa
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DOI：
10.1093/jac/dkab421
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发表时间：
2021-12-10
影响因子：
5.2
通讯作者：
Dillon, Nicholas
中科院分区：
文献类型：
--
作者：
Holland, Mische;Bjanes, Elisabet;Dillon, Nicholas
目的 研究最近批准的德拉沙星和其他氟喹诺酮类药物在生理相关条件下对抗主要 MDR 细菌病原体的效用。方法在标准抗生素药敏试验培养基CAMHB、改良的Roswell-Park Memorial Institute组织培养基(RPMI+)或20%新鲜人全血中对金黄色葡萄球菌、铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌的MDR菌株进行MIC和MBC测定。在小鼠铜绿假单胞菌肺炎模型中进行了体外研究结果的体内相关性。通过改变培养基条件和已建立的氟喹诺酮积累测定，探索了这些发现的机制基础。结果 与 CAMHB 相比，RPMI+ 中所有四种 MDR 病原体的氟喹诺酮 MIC 均增加。具体而言，德拉沙星 MIC 与 MDR 金黄色葡萄球菌相比增加了 32 倍，与 MDR 铜绿假单胞菌相比增加了 8 倍。 20% 人全血和小鼠 MDR 铜绿假单胞菌肺炎模型的 MBC 测定均证实，德拉沙星活性在生理条件下降低。碳酸氢盐 (HCO3-) 是 RPMI+ 中发现的宿主生理学的关键成分，但 CAMHB 中不存在，它通过损害德拉沙星在细胞内的积累来决定 CAMHB 和 RPMI+ 中德拉沙星的敏感性。结论 标准体外抗生素敏感性测试条件高估了德拉沙星对抗 MDR 病原体的有效性，因为未能捕捉到生物缓冲剂 HCO3- 损害德拉沙星积累的作用。这项工作展示了我们当前抗生素敏感性测试范例的局限性，并强调了了解影响真实临床疗效的宿主微环境条件的重要性。
Objectives To investigate the utility of recently approved delafloxacin and other fluoroquinolones against leading MDR bacterial pathogens under physiologically relevant conditions. Methods MIC and MBC assays were conducted for MDR strains of Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae in the standard antibiotic susceptibility testing medium CAMHB, amended Roswell-Park Memorial Institute tissue culture medium (RPMI+) or 20% fresh human whole blood. In vivo correlation of in vitro findings was performed in a murine P. aeruginosa pneumonia model. Mechanistic bases for the findings were explored by altering media conditions and with established fluoroquinolone accumulation assays. Results Fluoroquinolone MICs were increased in RPMI+ compared with CAMHB for all four MDR pathogens. Specifically, delafloxacin MICs were increased 32-fold versus MDR S. aureus and 8-fold versus MDR P. aeruginosa. MBC assays in 20% human whole blood and a murine MDR P. aeruginosa pneumonia model both confirmed that delafloxacin activity was reduced under physiological conditions. Bicarbonate (HCO3-), a key component of host physiology found in RPMI+ but absent from CAMHB, dictated delafloxacin susceptibility in CAMHB and RPMI+ by impairing its intracellular accumulation. Conclusions Standard in vitro antibiotic susceptibility testing conditions overpredicted the effectiveness of delafloxacin against MDR pathogens by failing to capture the role of the biological buffer HCO3- to impair delafloxacin accumulation. This work showcases limitations of our current antibiotic susceptibility testing paradigm and highlights the importance of understanding host microenvironmental conditions that impact true clinical efficacy.