Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages
Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages
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DOI：
10.1128/aac.50.3.841-851.2006
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发表时间：
2006-03-01
影响因子：
4.9
通讯作者：
Van Bambeke, F
中科院分区：
文献类型：
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作者：
Barcia-Macay, M;Seral, C;Van Bambeke, F
控制抗生素对细胞内金黄色葡萄球菌的活性的药效学性质在很大程度上仍未确定。7种不同药理学类别的16种抗生素（阿奇霉素和泰利霉素[大环内酯类];庆大霉素[一种氨基糖苷类];利奈唑胺[一种恶唑烷酮];青霉素V、萘夫西林、氨苄西林和苯唑西林[β-内酰胺类];替考拉宁、万古霉素和奥利万星[糖肽类];利福平[一种安莎霉素];和环丙沙星、左氧氟沙星、诺氟沙星和诺氟沙星[喹诺酮类]）已经检测了它们对沙门氏菌的活性。金黄色葡萄球菌（ATCC 25923）在人THP-1巨噬细胞（细胞内）与培养基（细胞外）中通过使用0至24小时的暴露时间和广泛的细胞外浓度（包括MIC至血清[C-max;总药物]或人中最大浓度的范围）进行比较。除大环内酯类外，所有分子均引起细菌计数的净减少，这是时间和浓度/MIC比率依赖性的（详细测试的四种分子[庆大霉素、苯唑西林、阿氟沙星和奥利万星]在24 h时显示出典型的S形剂量-反应曲线）。无论药物蓄积水平和药理学类别如何，最大细胞内活性始终低于细胞外活性。相对效力（50%有效浓度或固定的细胞外浓度/MIC比）也降低，但程度不同。在对应于它们在人体中的C（max）s（总药物）的细胞外浓度下，只有苯唑西林、左氧氟沙星、阿替诺沙星、阿替诺沙星和奥利万星具有真正的细胞内杀菌作用（如临床和实验室标准协会指南所定义的，2-log减少或更多）。抗生素对S.金黄色葡萄球菌（i）严重依赖于它们的细胞外浓度和细胞暴露于抗生素的持续时间（在0至24小时的时间范围内），以及（ii）总是低于可以在细胞外观察到的浓度。该模型可能有助于合理选择治疗链球菌的抗生素。金黄色葡萄球菌细胞内感染。
The pharmacodynamic properties governing the activities of antibiotics against intracellular Staphylococcus aureus are still largely undetermined. Sixteen antibiotics of seven different pharmacological classes (azithromycin and telithromycin [macrolides]; gentamicin [an aminoglycoside]; linezolid [an oxazolidinone]; penicillin V, nafcillin, ampicillin, and oxacillin [beta-lactams]; teicoplanin, vancomycin, and oritavancin [glycopeptides]; rifampin [an ansamycin]; and ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin [quinolones]) have been examined for their activities against S. aureus (ATCC 25923) in human THP-1 macrophages (intracellular) versus that in culture medium (extracellular) by using a 0- to 24-h exposure time and a wide range of extracellular concentrations (including the range of the MIC to the maximum concentration in serum [C-max; total drug] or humans). All molecules except the macrolides caused a net reduction in bacterial counts that was time and concentration/MIC ratio dependent (four molecules tested in detail [gentamicin, oxacillin, moxifloxacin, and oritavancin] showed typical sigmoidal dose-response curves at 24 h). Maximal intracellular activities remained consistently lower than extracellular activities, irrespective of the level of drug accumulation and of the pharmacological class. Relative potencies (50% effective concentration or at a fixed extracellular concentration/MIC ratio) were also decreased, but to different extents. At an extracellular concentration corresponding to their C(max)s (total drug) in humans, only oxacillin, levofloxacin, garenoxacin, moxifloxacin, and oritavancin had truly intracellular bactericidal effects (2-log decrease or more, as defined by the Clinical and Laboratory Standards Institute guidelines). The intracellular activities of antibiotics against S. aureus (i) are critically dependent upon their extracellular concentrations and the duration of cell exposure (within the 0- to 24-h time frame) to antibiotics and (ii) are always lower than those that can be observed extracellularly. This model may help in rationalizing the choice of antibiotic for the treatment of S. aureus intracellular infections.