Improved treatment of systemic blood infections using antibiotics with extracorporeal opsonin hemoadsorption |
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| Institution: | 1. Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA;2. Vascular Biology Program, Boston Children''s Hospital and Harvard Medical School, Boston, MA 02115, USA;3. Harvard School of Engineering and Applied Sciences, Cambridge, MA 02139, USA;1. MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, United Kingdom;2. School of Chemical Engineering, University of Birmingham, Birmingham B15 2TT, United Kingdom;3. The Royal Orthopaedic Hospital NHS Foundation Trust, Bristol Road South, Birmingham B31 2AP, United Kingdom;1. RMS Foundation, Bischmattstrasse 12, CH-2544 Bettlach, Switzerland;2. Technical University Bergakademie Freiberg, Institute for Ceramic, Glass- and Construction Materials, Agricolastraße 17, 09596 Freiberg, Germany;3. Complex Materials, Department of Materials, ETH Zürich, 8093 Zürich, Switzerland;4. EMPA, Swiss Federal Laboratories for Materials Science and Technology, Laboratory for High Performance Ceramics, Ueberlandstrasse 129, 8600 Dübendorf, Switzerland;1. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6;2. Econous Systems Inc., 80 St. George Street, Toronto, Ontario, Canada M5S 3H6;3. Clinical Biochemistry, St. Michael''s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8;1. School of Metallurgy and Environment, Central South University, Changsha 410083, China;2. Hunan Key Laboratory of Nonferrous Metal Resources Recycling, Changsha 410083, China;3. Hunan Engineering Research Center of Nonferrous Metal Resources Recycling, Changsha 410083, China;4. Department of Urology, Affiliated Haikou Hospital of Xiangya School of Medicine, Central South University, Haikou 570208, China;5. Department of Hemodialysis, Affiliated Haikou Hospital of Xiangya School of Medicine, Central South University, Haikou 570208, China |
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| Abstract: | Here we describe development of an extracorporeal hemoadsorption device for sepsis therapy that employs commercially available polysulfone or polyethersulfone hollow fiber filters similar to those used clinically for hemodialysis, covalently coated with a genetically engineered form of the human opsonin Mannose Binding Lectin linked to an Fc domain (FcMBL) that can cleanse a broad range of pathogens and endotoxin from flowing blood without having to first determine their identity. When tested with human whole blood in vitro, the FcMBL hemoadsorption filter (FcMBL-HF) produced efficient (90–99%) removal of Gram negative (Escherichia coli) and positive (Staphylococcus aureus) bacteria, fungi (Candida albicans) and lipopolysaccharide (LPS)-endotoxin. When tested in rats, extracorporeal therapy with the FcMBL-HF device reduced circulating pathogen and endotoxin levels by more than 99%, and prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver and kidney when compared to controls. Studies in rats revealed that treatment with bacteriocidal antibiotics resulted in a major increase in the release of microbial fragments or ‘pathogen-associated molecular patterns’ (PAMPs) in vivo, and that these PAMPs were efficiently removed from blood within 2 h using the FcMBL-HF; in contrast, they remained at high levels in animals treated with antibiotics alone. Importantly, cleansing of PAMPs from the blood of antibiotic-treated animals with the FcMBL-hemoadsorbent device resulted in reduced organ pathogen and endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs compared to treatment with antibiotics alone. As PAMPs trigger the cytokine cascades that lead to development of systemic inflammatory response syndrome and contribute to septic shock and death, co-administration of FcMBL-hemoadsorption with antibiotics could offer a more effective approach to sepsis therapy. |
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| Keywords: | Sytematic blood infections Bio-functional hollow fibers Dialysis like treatment (DLT) of sepsis Combined drug–device therapy for sepsis Pathogen and LPS-endotoxin cleansgin |
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