title: Improved treatment of systemic blood infections using antibiotics with extracorporeal opsonin hemoadsorption.
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.
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA; Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tohid F
authors.initials: TF
authors.lastname: Didar
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cartwright
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Rottman
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Graveline
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Nazita
authors.initials: N
authors.lastname: Gamini
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Watters
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA; Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Leslie
authors.affiliation: Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mammoto
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Rodas
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Joo H
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Waterhouse
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Seiler
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lombardo
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Elisabet I
authors.initials: EI
authors.lastname: Qendro
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Super
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA; Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard School of Engineering and Applied Sciences, Cambridge, MA 02139, USA. Electronic address: don.ingber@wyss.harvard.edu.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
mesh_terms: D000327:Adsorption; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005112:Extracorporeal Circulation; D006440:Hemofiltration; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D009895:Opsonin Proteins / Q000627:therapeutic use*; D017208:Rats, Wistar
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D009895:Opsonin Proteins
keywords: Bio-functional hollow fibers; Combined drug–device therapy for sepsis; Dialysis like treatment (DLT) of sepsis; Pathogen and LPS-endotoxin cleansgin; Sytematic blood infections