Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA.
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
Antimicrob Agents Chemother. 2019 Mar 27;63(4). doi: 10.1128/AAC.01743-18. Print 2019 Apr.
Glycopeptides such as vancomycin have been used as the first-line therapy against MRSA infections for over half a century. Reduced susceptibility and emergence of resistance to first-generation glycopeptides has led to development of second-generation lipoglycopeptide derivatives such as dalbavancin which hold broader ranges of activity and enhanced pharmacokinetic properties. We evaluated the MIC values for a total of 100 isolates, including 25 methicillin-resistant (MRSA), 25 heterogeneus vancomycin-intermediate , 25 daptomycin nonsusceptible (DNS), and 25 vancomycin-intermediate strains against dalbavancin, ceftaroline, and vancomycin alone and in combination. Dalbavancin was highly active against hVISA, DNS, and MRSA strains, achieving 96 to 100% susceptibility and 72% susceptibility against VISA strains. The combination of dalbavancin plus ceftaroline reduced dalbavancin MICs 62.5-fold and demonstrated enhanced killing against all four phenotypes in pharmacokinetic/pharmacodynamic models. Four strains of the aforementioned phenotypes were randomly chosen for pharmacodynamic/pharmacokinetic simulation models. Of interest, while both dalbavancin and vancomycin in combination with ceftaroline demonstrated significant improvement in glycopeptide AUC/MIC values against these four phenotypes, the dalbavancin-ceftaroline combinations exhibited a 44- to 11,270-fold higher AUC/MIC value in comparison to vancomycin-ceftaroline combinations. In addition, the time to detection limit was reduced for this combination (24 to 32 h) versus the vancomycin-ceftaroline combination (24 to 72h). To our knowledge, this is the first comprehensive study of dalbavancin and vancomycin combinations with ceftaroline. These data provide a novel approach for combating recalcitrant MRSA infections.
糖肽类药物（如万古霉素）已被用作治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染的一线药物超过半个世纪。第一代糖肽类药物的敏感性降低和耐药性的出现，导致了第二代糖脂类衍生物如达巴万星的开发，后者具有更广泛的活性和增强的药代动力学特性。我们评估了总共 100 株分离株的 MIC 值，包括 25 株耐甲氧西林金黄色葡萄球菌（MRSA）、25 株异质性万古霉素中介金黄色葡萄球菌（hVISA）、25 株达托霉素不敏感（DNS）和 25 株万古霉素中介金黄色葡萄球菌菌株，分别针对达巴万星、头孢洛林和万古霉素单独及联合用药。达巴万星对 hVISA、DNS 和 MRSA 菌株具有高度活性，达到 96%至 100%的敏感性，对 VISA 菌株的敏感性为 72%。达巴万星联合头孢洛林降低了达巴万星 MIC 值 62.5 倍，并在药代动力学/药效学模型中对所有四种表型表现出增强的杀菌作用。随机选择了上述四种表型的四株菌株进行药代动力学/药效学模拟模型。有趣的是，虽然达巴万星联合头孢洛林与万古霉素联合头孢洛林均显著提高了针对这四种表型的糖肽类 AUC/MIC 值，但达巴万星联合头孢洛林的 AUC/MIC 值比万古霉素联合头孢洛林高 44 至 11,270 倍。此外，与万古霉素联合头孢洛林组合相比，该组合的检测限时间（24 至 32 小时）缩短。据我们所知，这是首次对达巴万星和万古霉素联合头孢洛林进行全面研究。这些数据为治疗耐药性 MRSA 感染提供了一种新的方法。
