Lemaire Sandrine, Van Bambeke Françoise, Mingeot-Leclercq Marie-Paule, Tulkens Paul M
Unité de Pharmacologie cellulaire et moléculaire, Université catholique de Louvain, Brussels, Belgium.
J Antimicrob Chemother. 2005 Jun;55(6):897-904. doi: 10.1093/jac/dki094. Epub 2005 Apr 28.
Assessment of the activity of three beta-lactams [ertapenem (a carbapenem with a prolonged half-life), meropenem and ampicillin] against intraphagocytic Listeria monocytogenes and Staphylococcus aureus.
Quantitative measurements of cfu changes in broth and in THP-1 macrophages (post-phagocytosis) over time (5 and 24 h) at concentrations spanning from sub-MICs to C(max) (maximal concentration typically observed in patients' serum upon administration of conventional doses); morphological studies using an electron microscope; evaluation of drug stability (HPLC), protein binding (equilibrium dialysis) and measurement of drug cellular accumulation (microbiological assay).
Ertapenem was unable to control L. monocytogenes growth in THP-1 macrophages at all concentrations and times tested, even under conditions where ampicillin and meropenem were bactericidal. This behaviour could not be ascribed to drug instability, protein binding or lack of cell accumulation in comparison with ampicillin or meropenem. Ertapenem, ampicillin and meropenem were equally effective at reducing the post-phagocytosis inoculum of S. aureus ( approximately 1 log cfu), and caused conspicuous changes in the morphology of intracellular bacteria consistent with their lysis. These effects were obtained, however, only at large multiples (100-fold or more) of the MIC maintained over 24 h. Because of the high intrinsic antimicrobial potency of the beta-lactams studied, these concentrations were below the C(max).
Ertapenem will probably be ineffective against intraphagocytic forms of L. monocytogenes for reasons that remain to be discovered. Conversely, ertapenem could be an alternative to ampicillin and meropenem against intraphagocytic S. aureus since its longer half-life may allow high concentrations to be maintained for more prolonged times.
评估三种β-内酰胺类药物[厄他培南（一种半衰期延长的碳青霉烯类药物）、美罗培南和氨苄西林]对吞噬细胞内单核细胞增生李斯特菌和金黄色葡萄球菌的活性。
在从亚抑菌浓度到C(max)（给予常规剂量后患者血清中通常观察到的最大浓度）的浓度范围内，对肉汤中和THP-1巨噬细胞内（吞噬后）随时间（5小时和24小时）的cfu变化进行定量测量；使用电子显微镜进行形态学研究；评估药物稳定性（高效液相色谱法）、蛋白结合（平衡透析法）以及测量药物细胞内蓄积（微生物学测定法）。
在所有测试浓度和时间下，厄他培南均无法控制THP-1巨噬细胞内单核细胞增生李斯特菌的生长，即使在氨苄西林和美罗培南具有杀菌作用的条件下也是如此。与氨苄西林或美罗培南相比，这种行为不能归因于药物不稳定、蛋白结合或细胞内蓄积不足。厄他培南、氨苄西林和美罗培南在减少吞噬后金黄色葡萄球菌接种量方面同样有效（约1个对数cfu），并导致细胞内细菌形态发生明显变化，与其裂解一致。然而，这些效果仅在24小时内维持的MIC的大量倍数（100倍或更多）时才能获得。由于所研究的β-内酰胺类药物具有较高的内在抗菌效力，这些浓度低于C(max)。
厄他培南可能对吞噬细胞内形式的单核细胞增生李斯特菌无效，原因尚待发现。相反，厄他培南可能是氨苄西林和美罗培南针对吞噬细胞内金黄色葡萄球菌的替代药物，因为其较长的半衰期可能允许更长时间维持高浓度。
