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

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.

Locally delivered polyclonal antibodies potentiate intravenous antibiotic efficacy against gram-negative infections.

PURPOSE: Comparison of the anti-microbial efficacy of locally delivered antibodies in tandem with conventional systemic administration of ceftazidime antibiotic therapy in two lethal gram-negative animal infection models. METHODS: Previously published lethal E. coli-induced closed peritonitis and Klebsiella-induced burn wound infections were generated in outbred female CF-1 mice cohorts. Pooled human polyclonal antibodies were injected locally into sites of infection in these mice simultaneously with intravenous infusions of the broad-spectrum antibiotic, ceftazidime. Mouse survival was compared in sham control cohorts vs. both ceftazidime-alone or antibody-alone systemically infused cohorts as well as local antibody-systemic ceftazidime combination therapy cohorts. Microbial burdens in blood and tissue samples (by agar plating), as well as interleukin-6 cytokine levels (using ELISA) correlated with sepsis, were monitored in sacrificed animals as a function of antimicrobial treatment regimen. RESULTS: Local delivery of human polyclonal antibodies to infection sites was shown to produce synergistic therapeutic efficacy in combination with systemic antibiotic administration in these lethal wound infection models in mice. Enhanced benefits of the unique combination therapy included host survival, bacterial burden both locally and systemically, and IL-6 levels in host serum. CONCLUSIONS: Commercial pooled human antibodies contain a broad spectrum of antimicrobial activity against gram-negative pathogens. Prevention of systemization of infection correlates with host survival in these models. Local control of infection using doses of local, high-titer polyclonal antibodies can enhance traditional approaches to curb systemic spread of infection using intravenous antibiotics. Antibodies provide antimicrobial efficacy independent of known pathogen resistance mechanisms.