Targeting alpha toxin to mitigate its lethal toxicity in ferret and rabbit models of Staphylococcus aureus necrotizing pneumonia

Binh An Diep, Jamese J. Hilliard, Vien T.M. Le, Christine Tkaczyk, Hoan N. Le, Vuvi G. Tran, Renee L. Rao, Etyene Castro Dip, Eliane P. Pereira-Franchi, Paulyn Cha, Scott Jacobson, Rosemary Broome, Lily I. Cheng, William Weiss, Laszlo Prokai, Vien Nguyen, C. Ken Stover, Bret R. Sellman

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The role broad-spectrum antibiotics play in the spread of antimicrobial resistance, coupled with their effect on the healthy microbiome, has led to advances in pathogen-specific approaches for the prevention or treatment of serious bacterial infections. One approach in clinical testing is passive immunization with a monoclonal antibody (MAb) targeting alpha toxin for the prevention or treatment of Staphylococcus aureus pneumonia. Passive immunization with the human anti-alpha toxin MAb, MEDI4893, has been shown to improve disease outcome in murine S. aureus pneumonia models. The species specificity of some S. aureus toxins necessitates testing anti-S. aureus therapeutics in alternate species. We developed a necrotizing pneumonia model in ferrets and utilized an existing rabbit pneumonia model to characterize MEDI4893 protective activity in species other than mice. MEDI4893 prophylaxis reduced disease severity in ferret and rabbit pneumonia models against both community-associated methicillin-resistant S. aureus (MRSA) and hospital-associated MRSA strains. In addition, adjunctive treatment of MEDI4893 with either vancomycin or linezolid provided enhanced protection in rabbits relative to the antibiotics alone. These results confirm that MEDI4893 is a promising candidate for immunotherapy against S. aureus pneumonia.

Original languageEnglish
Article number02456-16
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number4
DOIs
StatePublished - Apr 2017

Keywords

  • Alpha toxin
  • Antibacterial
  • Antibiotic
  • Hemolysins
  • Monoclonal antibodies
  • Staphylococcus aureus

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    Diep, B. A., Hilliard, J. J., Le, V. T. M., Tkaczyk, C., Le, H. N., Tran, V. G., Rao, R. L., Dip, E. C., Pereira-Franchi, E. P., Cha, P., Jacobson, S., Broome, R., Cheng, L. I., Weiss, W., Prokai, L., Nguyen, V., Stover, C. K., & Sellman, B. R. (2017). Targeting alpha toxin to mitigate its lethal toxicity in ferret and rabbit models of Staphylococcus aureus necrotizing pneumonia. Antimicrobial agents and chemotherapy, 61(4), [02456-16]. https://doi.org/10.1128/AAC.02456-16