title: Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a Staphylococcus aureus dermonecrosis model.
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. MEDI4893* postinfection 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, MEDI4893* resulted 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.
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Jamese J
authors.initials: JJ
authors.lastname: Hilliard
authors.affiliation: Department of Translational Science, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Vivekananda
authors.initials: V
authors.lastname: Datta
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hamilton
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sadowska
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Omari
authors.initials: O
authors.lastname: Jones-Nelson
authors.affiliation: Department of Translational Science, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Terrence
authors.initials: T
authors.lastname: O'Day
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szarka
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: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Suzich
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: C Kendall
authors.initials: CK
authors.lastname: Stover
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, Maryland, USA sellmanb@medimmune.com.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000276:immunology*; D000080908:Broadly Neutralizing Antibodies; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006460:Hemolysin Proteins / Q000276:immunology*; D000069349:Linezolid / Q000493:pharmacokinetics / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000188:drug therapy / Q000382:microbiology; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D014640:Vancomycin / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D000080908:Broadly Neutralizing Antibodies; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; C000600718:suvratoxumab; D014640:Vancomycin; D000069349:Linezolid