The most efficacious antimicrobial therapy to aid in the successful elimination of resistant S. aureus infections is unknown. In this study, we evaluated varying phenotypes of S. aureus against dalbavancin (DAL), vancomycin (VAN), and daptomycin (DAP) alone and in combination with cefazolin (CFZ). The objective of this study was to observe whether there was a therapeutic improvement in adding a beta-lactam to a glycopeptide, lipopeptide, or a lipoglycopeptide. We completed a series of in vitro tests including minimum inhibitory concentration testing (MIC) of the antimicrobials in combination, time-kill analysis (TKA), and a 168 h (7-day) one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model on two daptomycin non-susceptible (DNS), vancomycin intermediate S. aureus strains (VISA), D712 and 6913. Results from our MIC testing demonstrated a minimum 2-fold and a maximum 32-fold reduction in MIC values for DAL, VAN, and DAP in combination with CFZ, in contrast to either agent used alone. The TKAs completed on four strains paralleled the enhanced activity demonstrated via the combination MICs. In the one-compartment PK/PD models, the combination of DAP plus CFZ or VAN plus CFZ resulted in a significant (p < 0.001) improvement in bactericidal activity and overall reduction in CFU/ml over the 7-day period. While the addition of CFZ to DAL improved time to bactericidal activity, DAL alone demonstrated equal and more sustained overall activity compared to all other treatments. The use of DAL alone, with or without CFZ and the combinations of VAN or DAP with CFZ appear to result in increased bactericidal activity against various recalcitrant S. aureus phenotypes.

中文翻译：

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在药代动力学/药效学模型中，达巴万星，万古霉素和达托霉素单独使用以及与头孢唑林合用对金黄色葡萄球菌的耐药表型

有助于成功消除耐药性金黄色葡萄球菌感染的最有效的抗菌疗法尚不清楚。在这项研究中，我们评估了单独和与头孢唑林（CFZ）结合使用的达巴万星（DAL），万古霉素（VAN）和达托霉素（DAP）对金黄色葡萄球菌的不同表型。这项研究的目的是观察在将β-内酰胺添加到糖肽，脂肽或脂糖肽中是否有治疗上的改善。我们完成了一系列体外测试，包括组合使用的抗菌剂的最低抑菌浓度测试（MIC），时间杀伤分析（TKA）和168小时（7天）单室药代动力学/药效学（PK / PD）两个不敏感达托霉素（DNS）万古霉素金黄色葡萄球菌的模型菌株（VISA），D712和6913。我们的MIC测试结果表明，与单独使用的任何一种药物相比，DAL，VAN和DAP与CFZ结合使用时，MIC值至少降低了2倍，最大降低了32倍。在四个菌株上完成的TKA与通过组合MICs证实的增强活性平行。在一室PK / PD模型，DAP加CFZ或VAN加CFZ的组合产生了显著（p<0.001）在7天内提高了杀菌活性，并降低了CFU / ml。尽管在DAL中添加CFZ可以改善杀菌活性的时间，但与所有其他处理方法相比，仅DAL表现出相同且更持久的总体活性。单独使用DAL（带有或不带有CFZ）以及将VAN或DAP与CFZ结合使用似乎会提高针对各种顽固性金黄色葡萄球菌表型的杀菌活性。