Prophylactic treatment of gram-positive and gram-negative abdominal implant infections using locally delivered polyclonal antibodies

Abstract

The increasing clinical incidence and host risk of biomaterial-centered infections, as well as the reduced effectiveness of clinically relevant antibiotics to treat such infections, provide compelling reasons to develop new approaches for treating implanted biomaterials in a surgical context. We describe the direct local delivery of polyclonal human antibodies to abdominal surgical implant sites to reduce infection severity and mortality in a lethal murine model of surgical implant-centered peritoneal infection. Surgical implant-centered peritonitis was produced in 180 female CF-1 mice by the direct inoculation of surgical-grade polypropylene mesh disks placed in the peritoneal cavity with lethal doses of either methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. Mice randomly received a resorbable antibody delivery vehicle at the implant site: either a blank carboxymethylcellulose (CMC) aqueous gel or the same CMC gel containing 10 mg of pooled polyclonal human immunoglobulin G locally on the implant after infection, either alone or in combination with systemic doses of cefazolin or vancomycin antibiotics. Human antibodies were rapidly released (first-order kinetics) from the gel carrier to both peritoneal fluids and serum in both infection scenarios. Inocula required for lethal infection were substantially reduced by surgery and the presence of the implant versus a closed lethal peritonitis model. Survival to 10 days with two different gram-negative P. aeruginosa strains was significantly enhanced (p < 0.01) by the direct application of CMC gel containing antibodies alone to the surgical implant site. Human-equivalent doses of systemic vancomycin provided a significantly improved benefit (p < 0.01) against lethal, implant-centered, gram-positive MRSA infection. However, locally delivered polyclonal human antibodies in combination with a range of systemic vancomycin doses against MRSA failed to improve host survival. Successful antibody therapy against gram-negative, implant-centered infections complements the clinically routine use of systemic antibiotics, providing a mechanism of protection independent of antibiotic resistance.