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

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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 - 1 Apr 2017

Fingerprint

Staphylococcal Pneumonia
Ferrets
Rabbits
Linezolid
Passive Immunization
Methicillin-Resistant Staphylococcus aureus
Staphylococcus aureus
Pneumonia
Monoclonal Antibodies
Anti-Bacterial Agents
Species Specificity
Microbiota
Vancomycin
Therapeutics
Bacterial Infections
Immunotherapy
Necrotizing Pneumonia
MEDI4893

Keywords

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

Cite this

Diep, Binh An ; Hilliard, Jamese J. ; Le, Vien T.M. ; Tkaczyk, Christine ; Le, Hoan N. ; Tran, Vuvi G. ; Rao, Renee L. ; Dip, Etyene Castro ; Pereira-Franchi, Eliane P. ; Cha, Paulyn ; Jacobson, Scott ; Broome, Rosemary ; Cheng, Lily I. ; Weiss, William ; Prokai, Laszlo ; Nguyen, Vien ; Stover, C. Ken ; Sellman, Bret R. / Targeting alpha toxin to mitigate its lethal toxicity in ferret and rabbit models of Staphylococcus aureus necrotizing pneumonia. In: Antimicrobial agents and chemotherapy. 2017 ; Vol. 61, No. 4.
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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 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 = "Alpha toxin, Antibacterial, Antibiotic, Hemolysins, Monoclonal antibodies, Staphylococcus aureus",
author = "Diep, {Binh An} and Hilliard, {Jamese J.} and Le, {Vien T.M.} and Christine Tkaczyk and Le, {Hoan N.} and Tran, {Vuvi G.} and Rao, {Renee L.} and Dip, {Etyene Castro} and Pereira-Franchi, {Eliane P.} and Paulyn Cha and Scott Jacobson and Rosemary Broome and Cheng, {Lily I.} and William Weiss and Laszlo Prokai and Vien Nguyen and Stover, {C. Ken} and Sellman, {Bret R.}",
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month = "4",
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doi = "10.1128/AAC.02456-16",
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Diep, BA, Hilliard, JJ, Le, VTM, Tkaczyk, C, Le, HN, Tran, VG, Rao, RL, Dip, EC, Pereira-Franchi, EP, Cha, P, Jacobson, S, Broome, R, Cheng, LI, Weiss, W, Prokai, L, Nguyen, V, Stover, CK & Sellman, BR 2017, 'Targeting alpha toxin to mitigate its lethal toxicity in ferret and rabbit models of Staphylococcus aureus necrotizing pneumonia', Antimicrobial agents and chemotherapy, vol. 61, no. 4, 02456-16. https://doi.org/10.1128/AAC.02456-16

Targeting alpha toxin to mitigate its lethal toxicity in ferret and rabbit models of Staphylococcus aureus necrotizing pneumonia. / Diep, Binh An; Hilliard, Jamese J.; Le, Vien T.M.; Tkaczyk, Christine; Le, Hoan N.; Tran, Vuvi G.; Rao, Renee L.; Dip, Etyene Castro; Pereira-Franchi, Eliane P.; Cha, Paulyn; Jacobson, Scott; Broome, Rosemary; Cheng, Lily I.; Weiss, William; Prokai, Laszlo; Nguyen, Vien; Stover, C. Ken; Sellman, Bret R.

In: Antimicrobial agents and chemotherapy, Vol. 61, No. 4, 02456-16, 01.04.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Targeting alpha toxin to mitigate its lethal toxicity in ferret and rabbit models of Staphylococcus aureus necrotizing pneumonia

AU - Diep, Binh An

AU - Hilliard, Jamese J.

AU - Le, Vien T.M.

AU - Tkaczyk, Christine

AU - Le, Hoan N.

AU - Tran, Vuvi G.

AU - Rao, Renee L.

AU - Dip, Etyene Castro

AU - Pereira-Franchi, Eliane P.

AU - Cha, Paulyn

AU - Jacobson, Scott

AU - Broome, Rosemary

AU - Cheng, Lily I.

AU - Weiss, William

AU - Prokai, Laszlo

AU - Nguyen, Vien

AU - Stover, C. Ken

AU - Sellman, Bret R.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

KW - Alpha toxin

KW - Antibacterial

KW - Antibiotic

KW - Hemolysins

KW - Monoclonal antibodies

KW - Staphylococcus aureus

UR - http://www.scopus.com/inward/record.url?scp=85016508394&partnerID=8YFLogxK

U2 - 10.1128/AAC.02456-16

DO - 10.1128/AAC.02456-16

M3 - Article

VL - 61

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 4

M1 - 02456-16

ER -