Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland.
Int J Antimicrob Agents. 2010 May;35(5):451-6. doi: 10.1016/j.ijantimicag.2009.12.022. Epub 2010 Feb 24.
Daptomycin is bactericidal against meticillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate-resistant S. aureus (GISA) and vancomycin-susceptible and -resistant enterococci. However, selection for daptomycin-resistant derivatives has occasionally been reported during therapy in humans. Here we evaluate whether selection for daptomycin-resistant S. aureus or enterococci could be prevented in vitro by combining daptomycin with amoxicillin/clavulanic acid, ampicillin, gentamicin or rifampicin. Six strains of S. aureus (four MRSA and two GISA) and four strains of enterococci (two Enterococcus faecalis and two Enterococcus faecium) were serially exposed in broth to two-fold stepwise increasing concentrations of daptomycin alone or in combination with a fixed concentration [0.25x minimum inhibitory concentration (MIC)] of either of the second agents. The daptomycin MIC was examined after each cycle. Exposure to daptomycin alone gradually selected for S. aureus and enterococci with an increased MIC. Gentamicin did not prevent the emergence of daptomycin-resistant bacteria. Rifampicin was also unable to prevent daptomycin resistance, although resistance was slightly delayed. In contrast, amoxicillin/clavulanic acid or ampicillin prevented or greatly delayed the selection of daptomycin-resistant mutants in S. aureus and enterococci, respectively. Addition of amoxicillin/clavulanic acid or ampicillin to daptomycin prevents, or greatly delays, daptomycin resistance in vitro. Future studies in animal models are needed to predict the utility of these combinations in humans.
达托霉素对耐甲氧西林金黄色葡萄球菌（MRSA）、糖肽中介耐药金黄色葡萄球菌（GISA）和万古霉素敏感和耐药肠球菌具有杀菌作用。然而，在人类治疗过程中，偶尔会有报道选择达托霉素耐药衍生物。在这里，我们评估了在体外联合使用达托霉素与阿莫西林/克拉维酸、氨苄西林、庆大霉素或利福平是否可以防止金黄色葡萄球菌或肠球菌对达托霉素产生耐药性。使用肉汤将 6 株金黄色葡萄球菌（4 株 MRSA 和 2 株 GISA）和 4 株肠球菌（2 株粪肠球菌和 2 株屎肠球菌）连续暴露于两倍逐步增加的达托霉素单独或与固定浓度[0.25x 最小抑菌浓度（MIC）]的任何第二种药物联合的浓度下。在每个周期后检查达托霉素 MIC。单独暴露于达托霉素会逐渐选择出具有更高 MIC 的金黄色葡萄球菌和肠球菌。庆大霉素不能防止产生达托霉素耐药菌。利福平也不能预防达托霉素耐药性，尽管耐药性略有延迟。相比之下，阿莫西林/克拉维酸或氨苄西林分别防止或大大延迟了金黄色葡萄球菌和肠球菌中达托霉素耐药突变体的选择。在达托霉素中添加阿莫西林/克拉维酸或氨苄西林可防止或大大延迟体外达托霉素耐药性。需要在动物模型中进行进一步的研究，以预测这些组合在人类中的应用。
