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.
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.
Authors: N A Barekzi; K A Poelstra; A G Felts; I A Rojas; J B Slunt; D W Grainger Journal: Antimicrob Agents Chemother Date: 1999-07 Impact factor: 5.191