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Locally Delivered Polyclonal Antibodies Potentiate Intravenous Antibiotic Efficacy Against Gram-Negative Infections

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Abstract

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.

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REFERENCES

  1. H. C. Neu. The crisis in antibiotic resistance. Science 257:1064–1073 (1992).

    Google Scholar 

  2. H. S. Gold and R. C. Moellering. Antimicrobial-drug resistance. N. Engl. J. Med. 335:1445–1453 (1996).

    Google Scholar 

  3. S. Monroe and R. Polk. Antimicrobial use and bacterial resistance. Curr. Opin. Microbiol. 3:496–501 (2000).

    Google Scholar 

  4. W. Wong and D. L. Pompliano. In B. Rosen and S. Mobashery (eds.), Resolving the antibiotic paradox: progress in drug design and resistance, Plenum, New York, 1999, pp. 1–21.

    Google Scholar 

  5. D. T. Moir, K. J. Shaw, R. S. Hare, and G. F. Vovis. Genomics and antimicrobial drug discovery. Antimicrob. Agents Chemother. 43:439–446 (1999).

    Google Scholar 

  6. A. Persidis. Antibacterial and antifungal drug discovery. Nature Biotechnol. 17:1141–1142 (1999).

    Google Scholar 

  7. J. A. DeVito, J. A. Mills, V. G. Liu, A. Agarwal, C. F. Sizemore, Z. Yao, D. M. Stoughton, M. G. Cappiello, M. D. F. S. Barbosa, L. A. Foster, and D. L. Pompliano. An array of target-specific screening strains for antibacterial discovery. Nature Biotechnol. 20:478–483 (2002).

    Google Scholar 

  8. A. Casadevall. Antibody-based therapies for emerging infectious diseases. Emerg. Infect. Dis. 2:200–208 (1996).

    Google Scholar 

  9. R. H. Buckley and R. I. Schiff. The use of intravenous immune globulin in immunodeficiency diseases. N. Engl. J. Med. 325:110–117 (1991).

    Google Scholar 

  10. C. G. Gemmell. Does the appearance of drug resistance during therapy alter bacterial susceptibility to opsonophagocytosis? Drugs Exp. Clin. Res. 22:51–55 (1996).

    Google Scholar 

  11. A. Cometta, J. D. Baumgartner, and M. P. Glauser. Polyclonal intravenous immune globulin for prevention and treatment of infections in critically ill patients. Clin. Exp. Immunol. 97:69–72 (1994).

    Google Scholar 

  12. G. R. Siber. Immune globulin to prevent nosocomial infections. N. Engl. J. Med. 327:269–271 (1992).

    Google Scholar 

  13. K. N. Haque, C. Remo, and H. Bahakim. Comparison of two types of intravenous immunoglobulins in the treatment of neonatal sepsis. Clin. Exp. Immunol. 101:328–333 (1995).

    Google Scholar 

  14. F. Cafiero, M. Gipponi, U. Bonalumi, A. Piccardo, C. Sguotti, and G. Corbetta. Prophylaxis of infection with intravenous immunoglobulins plus antibiotic for patients at risk for sepsis undergoing surgery for colorectal cancer: results of a randomized, multicenter clinical trial. Surgery 112:24–31 (1992).

    Google Scholar 

  15. K. S. Lamp, M. J. Rybak, B. J. McGrath, and K. K. Summers. Influence of antibiotic and E5 monoclonal immunoglobulin M interactions on endotoxin release from Escherichia coli and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 40:247–252 (1996).

    Google Scholar 

  16. H. S. El-Zaim, A. K. Chopra, J. W. Peterson, M. L. Vasil, and J. P. Heggers. Protection against exotoxin A (ETA) and Pseudomonas aeruginosa infection in mice with ETA-specific antipeptide antibodies. Infect. Immun. 66:5551–5554 (1998).

    Google Scholar 

  17. J. E. Van Wye, M. S. Collins, M. Baylor, J. E. Pennington, Y. P. Hsu, V. Sampanvejsopa, and R. B. Moss. Pseudomonas hyperimmune globulin passive immunotherapy for pulmonary exacerbations in cystic fibrosis. Pediatr. Pulmonol. 9:7–18 (1990).

    Google Scholar 

  18. R. Malley, J. DeVincenzo, O. Ramilo, P. H. Dennehy, H. C. Meissner, W. C. Gruber, P. J. Sanchez, H. Jafri, J. Balsley, D. Carlin, S. Buckingham, L. Vernacchio, and D. M. Ambrosino. Reduction of respiratory syncytial virus (RSV) in tracheal aspirates in intubated infants by use of humanized monoclonal antibody to RSV F protein. J. Infect. Dis. 178:1555–1561 (1998).

    Google Scholar 

  19. L. B. Rice, E. C. Eckstein, J. DeVente, and D. M. Shlaes. Ceftazidime-resistant Klebsiella pneumoniae isolates recovered at the Cleveland Department of Veterans Affairs Medical Center. Clin. Infect. Dis. 23:118–124 (1996).

    Google Scholar 

  20. J. Wiener, J. P. Quinn, P. A. Bradford, R. V. Goering, C. Nathan, K. Bush, and R. A. Weinstein. Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA 281:517–523 (1999).

    Google Scholar 

  21. S. C. Lee, C. P. Fung, P. Y. Liu, T. C. Wang, L. C. See, N. Lee, S. C. Chen, and W. B. Shieh. Nosocomial infections with ceftazidime-resistant Pseudomonas aeruginosa: risk factors and outcome. Infect. Control Hosp. Epidemiol. 20:205–207 (1999).

    Google Scholar 

  22. A. Felts, D. W. Grainger, and J. B. Slunt. Locally delivered antibodies combined with systemic antibiotics confer synergistic protection against antibiotic resistant burn wound infections. J. Trauma 49:873–878 (2000).

    Google Scholar 

  23. N. A. Barekzi, K. A. Poelstra, A. G. Felts, I. A. Rojas, J. B. Slunt, and D. W. Grainger. Efficacy of locally delivered polyclonal immunoglobulin against Pseudomonas aeruginosa peritonitis in a murine model. Antimicrob. Agents Chemother. 43:1609–1615 (1999).

    Google Scholar 

  24. A. G. Felts, G. Giridhar, D. W. Grainger, and J. B. Slunt. Efficacy of locally delivered polyclonal immunoglobulin agains Pseudomonas aeruginosa infection in a murine burn wound model. Burns 25:415–423 (1999).

    Google Scholar 

  25. National Research Council. In N. Grossblatt (ed.), Guide for the Care and Use of Laboratory Animals, National Academy Press, Washington DC, 1996.

    Google Scholar 

  26. P. S. Hiemstra, J. Brands-Tajouiti, and R. van Furth. Comparison of antibody activity against various microorganisms in intravenous immunoglobulin preparations determined by ELISA and opsonic assay. J. Lab. Clin. Med. 123:241–246 (1994).

    Google Scholar 

  27. D. C. Straus. Production of an extracellular toxic complex by various strains of Klebsiella pneumoniae. Infect. Immun. 55:44–48 (1987).

    Google Scholar 

  28. M. S. Collins, R. F. Hector, R. E. Roby, A. A. Edwards, D. K. Ladehoff, and J. H. Dorsey. Prevention of gram-negative and gram-positive infections in rodents with three intravenous immunoglobulins and therapy of experimental polymicrobial burn wound sepsis with Pseudomonas immunoglobulin and ciprofloxacin. Infection 15:S51–S59 (1987).

    Google Scholar 

  29. K. A. Poelstra, N. A. Barekzi, A. M. Rediske, A. G. Felts, J. B. Slunt, and D. W. Grainger. Prophylactic treatment of grampositive and gram-negative abdominal implant infections using locally delivered polyclonal antibodies. J. Biomed. Mater. Res. 60:206–215 (2002).

    Google Scholar 

  30. A. Dalhoff. Synergy between acylureidopenicillins and immunoglobulin G in experimental animals. Am. J. Med. 76:91–100 (1984).

    Google Scholar 

  31. D. R. Absolom, C. J. van Oss, W. Zingg, and A. W. Neumann. Phagocytosis as a surface phenomenon: Opsonization by aspecific adsorption of Antibody as a function of bacterial hydrophobicity. J. Reticuloendothel. Soc. 31:59–70 (1982).

    Google Scholar 

  32. O. Mimoz, A. Jacolot, C. Padoin, J. Caillon, K. Louchahi, M. Tod, K. Samii, and O. Petitjean. Cefepime and amikacin synergy against a cefotaxime-susceptible strain of Enterobacter cloacae in vitro and in vivo. J. Antimicrob. Chemother. 39:363–369 (1997).

    Google Scholar 

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Authors and Affiliations

  1. Anthony G. Gristina Institute for Biomedical Research, (formerly Medical Sciences Research Institute), 520 Huntmar Park Drive, Herndon, Virginia, 20170

    Nazir A. Barekzi, Adrian G. Felts, Kornelis A. Poelstra & Jeffrey B. Slunt

  2. Department of Chemistry, Colorado State University, Ft Collins, Colorado, 80523

    David W. Grainger

Authors
  1. Nazir A. Barekzi
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  2. Adrian G. Felts
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  3. Kornelis A. Poelstra
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  4. Jeffrey B. Slunt
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  5. David W. Grainger
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Correspondence to David W. Grainger.

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Barekzi, N.A., Felts, A.G., Poelstra, K.A. et al. Locally Delivered Polyclonal Antibodies Potentiate Intravenous Antibiotic Efficacy Against Gram-Negative Infections. Pharm Res 19, 1801–1807 (2002). https://doi.org/10.1023/A:1021481122011

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