title: Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia.
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 ofStaphylococcus aureuspneumonia. Passive immunization with the human anti-alpha toxin MAb, MEDI4893*, has been shown to improve disease outcome in murineS. aureuspneumonia models. The species specificity of someS. aureustoxins necessitates testing anti-S. aureustherapeutics 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-resistantS. 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 againstS. aureuspneumonia.
authors.affiliation: 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.
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Jamese J
authors.initials: JJ
authors.lastname: Hilliard
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Vien T M
authors.initials: VT
authors.lastname: Le
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Hoan N
authors.initials: HN
authors.lastname: Le
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Vuvi G
authors.initials: VG
authors.lastname: Tran
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Rao
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Etyene Castro
authors.initials: EC
authors.lastname: Dip
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Eliane P
authors.initials: EP
authors.lastname: Pereira-Franchi
authors.affiliation: Department of Applied Immunology and Microbiology, MedImmune, LLC, Mountain View, California, USA.
authors.forename: Paulyn
authors.initials: P
authors.lastname: Cha
authors.affiliation: Department of Applied Immunology and Microbiology, MedImmune, LLC, Mountain View, California, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Jacobson
authors.affiliation: Department of Applied Immunology and Microbiology, MedImmune, LLC, Mountain View, California, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Broome
authors.affiliation: Department of Translational Sciences, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Lily I
authors.initials: LI
authors.lastname: Cheng
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: William
authors.initials: W
authors.lastname: Weiss
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: Laszlo
authors.identifier: 0000-0002-4559-3458
authors.initials: L
authors.lastname: Prokai
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: Vien
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: C Ken
authors.initials: CK
authors.lastname: Stover
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA binh.diep@ucsf.edu sellmanb@medimmune.com.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology; D005289:Ferrets; D006460:Hemolysin Proteins / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000502:physiology; D000071067:Pneumonia, Necrotizing / Q000188:drug therapy* / Q000382:microbiology; D011023:Pneumonia, Staphylococcal; D011817:Rabbits; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D006460:Hemolysin Proteins
keywords: Staphylococcus aureus; alpha toxin; antibacterial; antibiotic; hemolysins; monoclonal antibodies