Anti-biofilm activity of bacteriophage-antibiotic combinations against MRSA

总结/摘要 由耐甲氧西林金黄色葡萄球菌（MRSA）引起的感染是有问题的 因为相关的治疗失败率高，死亡率高。葡萄球菌 包括MRSA是医疗器械感染（MDI）的主要原因， 形成生物膜的能力。这些细菌生物膜抵抗宿主免疫系统并导致 由于抗生素渗透有限、细菌耐受性和 抗生素耐药性万古霉素是MRSA MDI和达托霉素的推荐治疗药物 是万古霉素治疗这些感染的主要抗生素替代品;然而， 达托霉素耐药性的增加，尤其是万古霉素治疗后， 频率.虽然万古霉素或达托霉素与β-内酰胺类药物联合治疗 抗生素如头孢洛林已经在体外显示出改善的活性， 在葡萄球菌引起的MDI中没有显示出显著的增强。因此，由于 由于缺乏有效的MDI治疗，迫切需要新的抗菌选择。专性 裂解性噬菌体（Bacteriophage，简称噬菌体）感染细菌，在细胞内复制，裂解细胞，释放出它们的 繁殖并重新启动感染周期。这些抗生素根除了抗生素敏感和 耐药菌呈螺旋状和生物膜状。噬菌体和抗生素的结合 显示使先前的多重耐药细菌对抗生素重新敏感。协同和 噬菌体-抗生素组合中的拮抗相互作用高度依赖于 与噬菌体配对的抗生素的细菌抑制机制，细菌宿主状态（生物膜 相对于无菌的）和细菌生长年龄。在这里，我们提供了一个系统的调查， 噬菌体抗生素组合使用各种标准护理抗生素（SOC）来检查 上述参数。这项研究的意义重大，特别是由于缺乏 关于使用具有SOC抗生素的噬菌体对抗生物膜包埋的MRSA的信息 菌株我们的中心假设是噬菌体-抗生素的组合将减少 万古霉素和达托霉素暴露对生物膜包埋的MRSA有效性所需 并进一步防止抗生素耐药性的出现。我们将测试我们的中心假设， 首次评估生物膜包埋的MRSA对各种噬菌体抗生素的敏感性 组合，然后进行体外双室PK/PD生物膜模型， 人源化药代动力学以优化新型噬菌体-抗生素组合疗法。我们 我希望通过优化MRSA生物膜感染的治疗，我们将改善患者的护理 并延长万古霉素和达托霉素用于管理MRSA MDI的使用寿命。

Summary/Abstract Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are problematic because of the high associated treatment failures and elevated mortality rates. Staphylococci including MRSA are the major cause of medical device infections (MDIs) due to their strong capability to form biofilms. These bacterial biofilms resist host immune system and lead to antibiotic failure due to limited antibiotic penetration, bacterial tolerance and development of antibiotic resistance. Vancomycin is the recommended therapy for MRSA MDIs and daptomycin is the primary antibiotic alternative to vancomycin for these infections; however, the development of daptomycin resistance especially post vancomycin therapy has been reported with increasing frequency. Although combination therapy of vancomycin or daptomycin with beta-lactam antibiotics such as ceftaroline have demonstrated improved activity in vitro, these combinations have not shown significant enhancements in MDIs caused by Staphylococci. Therefore, due to the lack of effective MDI treatments, novel antibacterial options are critically needed. Obligately lytic bacteriophages (phages) infect bacteria, replicate within the cell, lyse the cell to release their progeny and reinitiate the infection cycle. These phages eradicate both antibiotic susceptible and resistant bacteria in planktonic and biofilm forms. The combination of phage and antibiotics have shown to re-sensitize previously multi-drug resistant bacteria to antibiotics. Synergistic and antagonistic interactions in phage-antibiotic combinations are highly dependent on the mechanism of bacterial inhibition of the antibiotic paired to the phage, bacterial host state (biofilm versus planktonic) and bacterial growth age. Here we are offering a systematic investigation of phage antibiotic combination using various standard of care antibiotics (SOC) to examine the aforementioned parameters. The proposed research is significant especially due to lack of information regarding the use of phage with SOC antibiotics against biofilm embedded MRSA strains. Our central hypothesis is that the combination of phage-antibiotic will reduce the vancomycin and daptomycin exposures required for efficacy against biofilm embedded MRSA and further prevent the emergence of antibiotic resistance. We will test our central hypothesis by first evaluating susceptibility of biofilm embedded MRSA to various phage-antibiotic combinations and then performing in vitro two-compartment PK/PD biofilm models with humanized pharmacokinetics to optimize novel phage-antibiotic combination therapies. We expect that through optimizing therapy of MRSA-biofilm infections, we will improve patient care and prolong the useful life of vancomycin and daptomycin for the management of MRSA MDIs.