Barcia-Macay Maritza, Seral Cristina, Mingeot-Leclercq Marie-Paule, Tulkens Paul M, Van Bambeke Françoise
Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 7370 Avenue E. Mounier 73, B-1200 Brussels, Belgium.
Antimicrob Agents Chemother. 2006 Mar;50(3):841-51. doi: 10.1128/AAC.50.3.841-851.2006.
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] of 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.
抗生素针对细胞内金黄色葡萄球菌发挥作用的药效学特性在很大程度上仍未明确。研究了七种不同药理类别的16种抗生素（阿奇霉素和泰利霉素[大环内酯类]；庆大霉素[氨基糖苷类]；利奈唑胺[恶唑烷酮类]；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[安莎霉素类]；环丙沙星、左氧氟沙星、加雷沙星和莫西沙星[喹诺酮类]）在人THP-1巨噬细胞内（细胞内）和培养基中（细胞外）对金黄色葡萄球菌（ATCC 25923）的活性，采用0至24小时的暴露时间和广泛的细胞外浓度范围（包括人类血清中最低抑菌浓度至最大浓度[C(max)；总药物]的范围）。除大环内酯类外，所有分子均导致细菌数量净减少，这与时间以及浓度/MIC比值有关（详细测试的四种分子[庆大霉素、苯唑西林、莫西沙星和奥利万星]在24小时时呈现典型的S形剂量反应曲线）。无论药物蓄积水平和药理类别如何，最大细胞内活性始终低于细胞外活性。相对效力（50%有效浓度或在固定的细胞外浓度/MIC比值下）也有所降低，但程度不同。在相当于人类C(max)（总药物）的细胞外浓度下，只有苯唑西林、左氧氟沙星、加雷沙星、莫西沙星和奥利万星具有真正的细胞内杀菌作用（按照临床和实验室标准协会指南定义，细菌数量减少2个对数或更多）。抗生素对金黄色葡萄球菌的细胞内活性：(i) 严重依赖于其细胞外浓度以及细胞暴露于抗生素的持续时间（在0至24小时时间范围内），(ii) 始终低于在细胞外可观察到的活性。该模型可能有助于合理选择治疗金黄色葡萄球菌细胞内感染的抗生素。
