Activities of Antibiotic Combinations against Resistant Strains of Pseudomonas aeruginosa in a Model of Infected THP-1 Monocytes
Activities of Antibiotic Combinations against Resistant Strains of Pseudomonas aeruginosa in a Model of Infected THP-1 Monocytes
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DOI：
10.1128/aac.04011-14
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发表时间：
2015-01-01
影响因子：
4.9
通讯作者：
Van Bambeke, Franoise
中科院分区：
文献类型：
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作者：
Buyck, Julien M.;Tulkens, Paul M.;Van Bambeke, Franoise
抗生素组合通常用于治疗铜绿假单胞菌感染，但迄今为止尚未研究其对细胞内细菌的功效。我们研究了主要抗假单胞菌类（环丙沙星，美罗培南，妥布霉素和粘菌素）的代表组合对细胞内的铜绿假单胞菌在THP-1单核细胞的模型与肉汤中生长的细菌相比，使用参考菌株PAO 1和两个临床分离株（耐环丙沙星和美罗培南，分别）。通过棋盘滴定（仅细胞外模型）、杀伤曲线和使用最大效应分数（FME）方法评估药物之间的相互作用，该方法允许在剂量-效应关系不呈线性时研究联合用药的效应。对于单独使用的药物，简单的S形函数可以拟合所有的浓度-效应关系（细胞外和细胞内细菌），静态浓度接近（环丙沙星、粘菌素和美罗培南）或略高于（妥布霉素）的MIC和最大效力达到检测限肉汤，但只有1至1.5（粘菌素、美罗培南和妥布霉素）至2至3（环丙沙星）log（10）CFU的细胞内减少。在细胞外，通过棋盘滴定证明所有组合是加和的，但使用FME方法证明是协同的，并且在杀灭曲线测定中证明是更杀菌的。在细胞内，所有组合仅基于FME和杀伤曲线测定证明是加和的。因此，尽管组合似乎适度地改善了针对细胞内铜绿假单胞菌的抗生素活性，但它们不允许根除这些持续形式的感染。包括环丙沙星的组合是最有效的（甚至针对环丙沙星耐药菌株），这可能与这种药物在细胞内是最有效的单独药物的事实有关。
Antibiotic combinations are often used for treating Pseudomonas aeruginosa infections but their efficacy toward intracellular bacteria has not been investigated so far. We have studied combinations of representatives of the main antipseudomonal classes (ciprofloxacin, meropenem, tobramycin, and colistin) against intracellular P. aeruginosa in a model of THP-1 monocytes in comparison with bacteria growing in broth, using the reference strain PAO1 and two clinical isolates (resistant to ciprofloxacin and meropenem, respectively). Interaction between drugs was assessed by checkerboard titration (extracellular model only), by kill curves, and by using the fractional maximal effect (FME) method, which allows studying the effects of combinations when dose-effect relationships are not linear. For drugs used alone, simple sigmoidal functions could be fitted to all concentration-effect relationships (extracellular and intracellular bacteria), with static concentrations close to (ciprofloxacin, colistin, and meropenem) or slightly higher than (tobramycin) the MIC and with maximal efficacy reaching the limit of detection in broth but only a 1 to 1.5 (colistin, meropenem, and tobramycin) to 2 to 3 (ciprofloxacin) log(10) CFU decrease intracellularly. Extracellularly, all combinations proved additive by checkerboard titration but synergistic using the FME method and more bactericidal in kill curve assays. Intracellularly, all combinations proved additive only based on both FME and kill curve assays. Thus, although combinations appeared to modestly improve antibiotic activity against intracellular P. aeruginosa, they do not allow eradication of these persistent forms of infections. Combinations including ciprofloxacin were the most active (even against the ciprofloxacin-resistant strain), which is probably related to the fact this drug was the most effective alone intracellularly.