Anti-Clumping Factor A Immunoglobulin Reduces the Duration of Methicillin-ResistantStaphylococcus aureusBacteremia in an Experimental Model of Infective Endocarditis

Abstract

SA-IGIV is a human polyclonal immunoglobulin containing elevated levels of antibodies specific for the fibrinogen-binding MSCRAMM protein clumping factor A (ClfA). In vitro, SA-IGIV specifically recognized ClfA that was expressed on the surface of Staphylococcus aureus and inhibited bacterial adherence to immobilized human fibrinogen by >95%. Moreover, SA-IGIV efficiently opsonized ClfA-coated fluorescent beads and facilitated phagocytosis by human polymorphonuclear leukocytes. To determine its potential therapeutic efficacy, SA-IGIV was evaluated in combination with vancomycin in a rabbit model of catheter-induced aortic valve infective endocarditis (IE) caused by methicillin-resistant S. aureus (MRSA). The combination therapy was more effective than vancomycin alone in sterilizing all valvular vegetations when used therapeutically during early (12-h) IE. The combination therapy resulted in clearance of bacteremia that was significantly faster than that of vancomycin alone in animals with well-established (24-h) IE. Therefore, in both early and well-established MRSA IE, the addition of SA-IGIV to a standard antibiotic regimen (vancomycin) increased bacterial clearance from the bloodstream and/or vegetations.

Characterization of the fibrinogen-binding surface protein Fbl of Staphylococcus lugdunensis

“…It is encouraging to note that antibodies generated against bothFbl A domain and ClfA A domain recognize the heterologous proteins, thus indicating that common antigenic epitopes must be present on each protein allow antibodies (including those in pooled human IgG) to inhibit fibrinogen binding by Fbl. This suggests that polyclonal human IVIG Veronate (Vernachio et al, 2003) is likely to protect against S. lugdunensis as well as S. aureus infections.…”

Sortases and the Art of Anchoring Proteins to the Envelopes of Gram-Positive Bacteria

“…ClfA and ClfB are structurally related and comprise a large N-terminal A domain and a repeat domain (R domain) which is composed exclusively of serineaspartate repeats (69,90). The ligand binding sites of ClfA and ClfB have been mapped to residues 220 to 559 (125), which assume an immunoglobulin G (IgG)-like fold (37,125,153,209). An elegant molecular mechanism of fibrinogen substrate binding, coined "dock, lock, and latch," has recently been demonstrated for SdrG, a fibrinogen binding Staphylococcus epidermidis MSCRAMM that also encompasses repeat domains (156).…”

The Staphylococcus aureus “superbug”

“…A number of companies are developing products intended for active or passive immunization against S. aureus infections, including a capsular polysaccharide vaccine that has been subjected to a clinical trial with hemodialysis patients (24), a monoclonal antibody (25), and human immunoglobulin that is enriched for antibodies that recognize clumping factor A (26).…”