Department of Pathology and Genomic Medicine, The Methodist Hospital Research Institute, Houston, TX, USA.
Antimicrob Agents Chemother. 2012 Dec;56(12):6192-200. doi: 10.1128/AAC.01525-12. Epub 2012 Sep 17.
Methicillin-resistant Staphylococcus aureus (MRSA) has emerged to be one of the most important pathogens both in health care and in community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin infections, bacteremia, and right-sided endocarditis caused by MRSA. Resistance to DAP (DAP(r)) has been reported in MRSA and is mostly accompanied by a parallel decrease in oxacillin resistance, a process known as the "seesaw effect." Our study provides evidence that the seesaw effect applies to other β-lactams and carbapenems of clinical use, including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC), and imipenem (IMP), in heterogeneous DAP(r) MRSA strains but not in MRSA strains expressing homogeneous β-lactam resistance. The antibacterial efficacy of DAP in combination with β-lactams was evaluated in isogenic DAP-susceptible (DAP(s))/Dap(r) MRSA strains originally obtained from patients that failed DAP monotherapy. Both in vitro (MIC, synergy-kill curve) and in vivo (wax worm model) approaches were used. In these models, DAP and a β-lactam proved to be highly synergistic against both heterogeneous and homogeneous clinical DAP(r) MRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge, reverting the increased repulsion provoked by DAP alone, an effect that may favor the binding of DAP to the cell surface. The ease of in vitro mutant selection was observed when DAP(s) MRSA strains were exposed to DAP. Importantly, the combination of DAP and a β-lactam prevented the selection of DAP(r) variants. In summary, our data show that the DAP-β-lactam combination may significantly enhance both the in vitro and in vivo efficacy of anti-MRSA therapeutic options against DAP(r) MRSA infections and represent an option in preventing DAP(r) selection in persistent or refractory MRSA infections.
耐甲氧西林金黄色葡萄球菌（MRSA）已成为医疗保健和社区获得性感染中最重要的病原体之一。达托霉素（DAP）是一种环状阴离子脂肽，推荐用于治疗由 MRSA 引起的皮肤感染、菌血症和右侧心内膜炎。已报道 MRSA 对 DAP（DAP(r)）具有耐药性，并且这种耐药性大多伴随着耐苯唑西林的平行降低，这一过程称为“跷跷板效应”。我们的研究提供了证据表明，这种跷跷板效应适用于其他临床使用的β-内酰胺类和碳青霉烯类药物，包括苯唑西林（NAF）、头孢噻肟（CTX）、阿莫西林克拉维酸（AMC）和亚胺培南（IMP），在异质 DAP(r)MRSA 菌株中，但在表达同质β-内酰胺耐药性的 MRSA 菌株中则不然。在最初从未能接受 DAP 单药治疗的患者中获得的异源 DAP 敏感（DAP(s))/Dap(r)MRSA 菌株中，评估了 DAP 与β-内酰胺类药物联合使用的抗菌效果。采用了体外（MIC、协同杀伤曲线）和体内（蜡虫模型）方法。在这些模型中，DAP 和一种β-内酰胺类药物对异质和同质临床 DAP(r)MRSA 菌株均显示出高度协同作用。从机制上讲，β-内酰胺类药物降低了细胞净正表面电荷，逆转了 DAP 单独引起的排斥增加，这一效应可能有利于 DAP 与细胞表面的结合。当 DAP(s)MRSA 菌株暴露于 DAP 时，观察到易于体外突变选择。重要的是，DAP 和β-内酰胺类药物的联合使用可防止 DAP(r)变体的选择。总之，我们的数据表明，DAP-β-内酰胺类药物联合治疗可能显著增强针对 DAP(r)MRSA 感染的抗-MRSA 治疗选择的体外和体内疗效，并代表了预防持续性或难治性 MRSA 感染中 DAP(r)选择的一种选择。
