Laboratory of Infection Biology, Department of Biomedicine, University and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Cardiovascular Centre of the University of Lisbon, Faculty of Medicine, Universidade de Lisboa, Av Prof. Egas Moniz, 1649-028 Lisbon, Portugal.
Int J Pharm. 2018 Oct 25;550(1-2):372-379. doi: 10.1016/j.ijpharm.2018.08.048. Epub 2018 Aug 25.
Daptomycin (DAP) is a cyclic lipopeptide antibiotic with potential clinical application in orthopedic infections caused by staphylococci. However, it failed to eradicate Staphylococcus aureus in vitro, in intracellular infection studies, as well as in vivo in an experimental model of implant-associated biofilm infections. In this study, the antimicrobial effect of DAP encapsulated in poly(methyl methacrylate)-Eudragit (PMMA-EUD) microparticles (DAP-MPs) on intracellular S. aureus was evaluated in human osteoblast cells using fluorescence in situ hybridization (FISH) analysis. Encapsulated DAP was able to reduce the amount of intracellular S. aureus by 73% compared to blank microparticles (MPs). Then, the advantage of treating with DAP-MPs versus free DAP was evaluated in a murine model of implant-associated biofilm infection. Free DAP showed a >3 log decrease in planktonic and adherent bacteria but failed to eradicate adherent methicillin-resistant S. aureus (MRSA), whereas DAP-MPs showed a clearance of planktonic MRSA, significantly reduced adherent MRSA by more than 3 log and cured the infection in 60%. This was linked to the prolonged higher DAP concentration within the tissue cage fluid compared to free DAP. To our knowledge, this study provides the first evidence for the high intracellular and in vivo anti-biofilm efficacy of DAP-MPs to target staphylococcal infections.
达托霉素（DAP）是一种环状脂肽抗生素，具有治疗葡萄球菌引起的骨科感染的临床应用潜力。然而，在体外、细胞内感染研究以及植入物相关生物膜感染的动物模型中，它均未能根除金黄色葡萄球菌。在这项研究中，采用荧光原位杂交（FISH）分析评估了包封于聚甲基丙烯酸甲酯-聚（甲基丙烯酸乙酯）共聚物（PMMA-EUD）微球中的达托霉素（DAP-MPs）对人成骨细胞内金黄色葡萄球菌的抗菌作用。与空白微球（MPs）相比，包封的 DAP 能够使细胞内金黄色葡萄球菌的数量减少 73%。然后，在植入物相关生物膜感染的小鼠模型中评估了用 DAP-MPs 治疗的优势。游离 DAP 对浮游菌和黏附菌表现出>3 对数减少，但未能根除黏附性耐甲氧西林金黄色葡萄球菌（MRSA），而 DAP-MPs 对浮游性 MRSA 具有清除作用，黏附性 MRSA 减少超过 3 对数，并使 60%的感染得到治愈。这与组织笼液中游离 DAP 相比，DAP-MPs 具有持续的更高的 DAP 浓度有关。据我们所知，这项研究首次提供了 DAP-MPs 针对葡萄球菌感染具有高细胞内和体内抗生物膜功效的证据。
