Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a staphylococcus aureus dermonecrosis model

Jamese J. Hilliard, Vivekana Datta, Christine Tkaczyk, Melissa Hamilton, Agnieszka Sadowska, Omari Jones-Nelson, Terrence O'Day, William Weiss, Szabolcs Szarka, Vien Nguyen, Laszlo Prokai, Jo Ann Suzich, C. Kendall Stover, Bret R. Sellmana

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30 Citations (Scopus)

Abstract

Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

Original languageEnglish
Pages (from-to)299-308
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number1
DOIs
StatePublished - 1 Jan 2015

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Linezolid
Staphylococcus aureus
Vancomycin
Monoclonal Antibodies
Anti-Bacterial Agents
Soft Tissue Infections
Immune Evasion
Skin
Neutrophil Infiltration
Therapeutics
Neutralizing Antibodies
Abscess
Virulence
Necrosis
Macrophages

Cite this

Hilliard, Jamese J. ; Datta, Vivekana ; Tkaczyk, Christine ; Hamilton, Melissa ; Sadowska, Agnieszka ; Jones-Nelson, Omari ; O'Day, Terrence ; Weiss, William ; Szarka, Szabolcs ; Nguyen, Vien ; Prokai, Laszlo ; Suzich, Jo Ann ; Stover, C. Kendall ; Sellmana, Bret R. / Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a staphylococcus aureus dermonecrosis model. In: Antimicrobial agents and chemotherapy. 2015 ; Vol. 59, No. 1. pp. 299-308.
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abstract = "Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.",
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Hilliard, JJ, Datta, V, Tkaczyk, C, Hamilton, M, Sadowska, A, Jones-Nelson, O, O'Day, T, Weiss, W, Szarka, S, Nguyen, V, Prokai, L, Suzich, JA, Stover, CK & Sellmana, BR 2015, 'Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a staphylococcus aureus dermonecrosis model', Antimicrobial agents and chemotherapy, vol. 59, no. 1, pp. 299-308. https://doi.org/10.1128/AAC.03918-14

Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a staphylococcus aureus dermonecrosis model. / Hilliard, Jamese J.; Datta, Vivekana; Tkaczyk, Christine; Hamilton, Melissa; Sadowska, Agnieszka; Jones-Nelson, Omari; O'Day, Terrence; Weiss, William; Szarka, Szabolcs; Nguyen, Vien; Prokai, Laszlo; Suzich, Jo Ann; Stover, C. Kendall; Sellmana, Bret R.

In: Antimicrobial agents and chemotherapy, Vol. 59, No. 1, 01.01.2015, p. 299-308.

Research output: Contribution to journalArticle

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T1 - Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a staphylococcus aureus dermonecrosis model

AU - Hilliard, Jamese J.

AU - Datta, Vivekana

AU - Tkaczyk, Christine

AU - Hamilton, Melissa

AU - Sadowska, Agnieszka

AU - Jones-Nelson, Omari

AU - O'Day, Terrence

AU - Weiss, William

AU - Szarka, Szabolcs

AU - Nguyen, Vien

AU - Prokai, Laszlo

AU - Suzich, Jo Ann

AU - Stover, C. Kendall

AU - Sellmana, Bret R.

PY - 2015/1/1

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N2 - Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

AB - Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

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