Comparative intracellular (THP-1 macrophage) and extracellular activities of β-lactams, azithromycin, gentamicin, and fluoroquinolones against Listeria monocytogenes at clinically relevant concentrations
Comparative intracellular (THP-1 macrophage) and extracellular activities of β-lactams, azithromycin, gentamicin, and fluoroquinolones against Listeria monocytogenes at clinically relevant concentrations
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DOI：
10.1128/aac.46.7.2095-2103.2002
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发表时间：
2002-07-01
影响因子：
4.9
通讯作者：
Tulkens, PM
中科院分区：
文献类型：
--
作者：
Carryn, S;Van Bambeke, F;Tulkens, PM
测定氨苄西林、美罗培南、阿奇霉素、庆大霉素、环丙沙星和莫西沙星对人THP-1巨噬细胞内溶血素阳性单核细胞增多性李斯特菌的抑制活性，并与发酵液中观察到的胞外活性进行比较。所有的细胞外浓度都被调整，以探索在常规治疗下临床上可以在人血清中达到的范围。在肉汤中，氨苄西林、美罗培南和阿奇霉素仅具有抑菌作用，而庆大霉素、环丙沙星和莫西沙星具有强烈的杀菌作用，且呈浓度依赖关系。在细胞中，氨苄西林、美罗培南、阿奇霉素和环丙沙星有轻微的杀菌作用(0.3-0.8logCFU减少)，莫西沙星有很强的杀菌作用(2.1logCFU减少)，庆大霉素几乎没有活性。莫西沙星和环丙沙星在细胞内的疗效差异并不是由于细胞内蓄积水平的差异(6.96+/-1.05比7.75+/-1.03)，而只是部分解释了MIC的差异(0.58+/-0.04比1.40+/-0.17 mg/L)。进一步的分析表明，莫西沙星仅表达了胞外细菌活性的约1/7，环丙沙星仅表达了胞外细菌活性的1115。庆大霉素不能增加其他受试抗生素的细胞内活性。这些数据表明：(I)莫西沙星可能对根除单核细胞增多性李斯特菌具有潜在的意义，(Ii)抗生素在细胞内的积累并不是其细胞内活性的唯一决定因素(对于氟喹诺酮类药物，就活性而言，这实际上是一个弄巧成拙的过程)，以及(Iii)需要考虑药效学(活性与浓度的关系)来建立对细胞内细菌的疗效，正如它们对于建立对细胞外感染的效果一样。
The activities of ampicillin, meropenem, azithromycin, gentamicin, ciprofloxacin, and moxifloxacin against intracellular hemolysin-positive Listeria monocytogenes were measured in human THP-1 macrophages and were compared with the extracellular activities observed in broth. All extracellular concentrations were adjusted to explore ranges that are clinically achievable in human serum upon conventional therapy. In broth, ampicillin, meropenem, and azithromycin were only bacteriostatic, whereas gentamicin, ciprofloxacin, and moxifloxacin were strongly bactericidal in a concentration-dependent manner. In cells, ampicillin, meropenem, azithromycin, and ciprofloxacin were slightly bactericidal (0.3- to 0.8-log CFU reductions), moxifloxacin was strongly bactericidal (2.1-log CFU reduction), and gentamicin was virtually inactive. The difference in the efficacies of moxifloxacin and ciprofloxacin in cells did not result from a difference in levels of accumulation in cells (6.96 +/- 1.05 versus 7.75 +/- 1.03) and was only partially explainable by the difference in the MICs (0.58 +/- 0.04 versus 1.40 +/- 0.17 mg/liter). Further analysis showed that intracellular moxifloxacin expressed only approximately 1/7 of the activity demonstrated against extracellular bacteria and ciprofloxacin expressed only 1115 of the activity demonstrated against extracellular bacteria. Gentamicin did not increase the intracellular activities of the other antibiotics tested. The data suggest (i) that moxifloxacin could be of potential interest for eradication of the intracellular forms of L. monocytogenes, (ii) that the cellular accumulation of an antibiotic is not the only determinant of its intracellular activity (for fluoroquinolones, it is actually a self-defeating process as far as activity is concerned), and (iii) that pharmacodynamics (activity-to-concentration relationships) need to be considered for the establishment of efficacy against intracellular bacteria, just as they are for the establishment of efficacy against extracellular infections.