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Antimicrob Agents Chemother. 2017 Mar 24;61(4). pii: e02456-16. doi: 10.1128/AAC.02456-16. Print 2017 Apr.

Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia.

Author information

1
Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA binh.diep@ucsf.edu sellmanb@medimmune.com.
2
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
3
Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
4
Department of Applied Immunology and Microbiology, MedImmune, LLC, Mountain View, California, USA.
5
Department of Translational Sciences, MedImmune, LLC, Gaithersburg, Maryland, USA.
6
Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
7
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA binh.diep@ucsf.edu sellmanb@medimmune.com.

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.

KEYWORDS:

Staphylococcus aureus; alpha toxin; antibacterial; antibiotic; hemolysins; monoclonal antibodies

PMID:
28115346
PMCID:
PMC5365647
DOI:
10.1128/AAC.02456-16
[Indexed for MEDLINE]
Free PMC Article

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