Carryn Stéphane, Van Bambeke Françoise, Mingeot-Leclercq Marie-Paule, Tulkens Paul M
Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Brussels, Belgium.
Antimicrob Agents Chemother. 2002 Jul;46(7):2095-103. doi: 10.1128/AAC.46.7.2095-2103.2002.
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 1/15 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.
在人THP-1巨噬细胞中测定了氨苄西林、美罗培南、阿奇霉素、庆大霉素、环丙沙星和莫西沙星对细胞内溶血素阳性单核细胞增生李斯特菌的活性，并与肉汤中观察到的细胞外活性进行了比较。调整了所有细胞外浓度，以探索常规治疗后人体血清中可达到的临床浓度范围。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则以浓度依赖性方式具有强烈的杀菌作用。在细胞中，氨苄西林、美罗培南、阿奇霉素和环丙沙星具有轻微的杀菌作用（CFU减少0.3至0.8个对数），莫西沙星具有强烈的杀菌作用（CFU减少2.1个对数），而庆大霉素实际上无活性。莫西沙星和环丙沙星在细胞中的疗效差异并非源于细胞内积累水平的差异（分别为6.96±1.05和7.75±1.03），且仅部分可由MIC的差异解释（分别为0.58±0.04和1.40±0.17mg/L）。进一步分析表明，细胞内莫西沙星的活性仅约为其对细胞外细菌活性的1/7，环丙沙星的活性仅为其对细胞外细菌活性的1/15。庆大霉素并未增强所测试的其他抗生素的细胞内活性。这些数据表明：（i）莫西沙星对于根除单核细胞增生李斯特菌的细胞内形式可能具有潜在意义；（ii）抗生素的细胞内积累并非其细胞内活性的唯一决定因素（就氟喹诺酮类而言，就活性而言这实际上是一个适得其反的过程）；（iii）建立针对细胞内细菌的疗效时需要考虑药效学（活性与浓度关系），就像建立针对细胞外感染的疗效时一样。
