Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Abstract

c 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.

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

“…(50). Intranasal challenge of S. aureus leads to lung infection; both the associated disease mortality and the bacterial burden are increased in IL-12p35 Ϫ/Ϫ mice (51). Following intracerebral inoculation of staphylococci, the initial phases of brain abscess formation were not impacted by IL-12 (p35) deficiency; however, IL-12p35 Ϫ/Ϫ mice displayed fewer clinical disease symptoms and healed more rapidly than wild-type mice (52).…”

Targeting Surface Protein SasX by Active and Passive Vaccination To Reduce Staphylococcus aureus Colonization and Infection

“…In ongoing efforts to use these as vaccination targets, alpha-toxin toxoid, for example, has proven to represent a very promising vaccination agent in efforts to reduce S. aureus skin and lung infection (21). In addition, we believe that virulence determinants that are found to strongly impact colonization and virulence phenotypes in MRSA strains with considerable epidemiological importance, wide geographical distribution, and likely further spread, such as SasX, should also be analyzed as potential vaccine targets.…”

Alternatives to Antibiotics: Phage Lytic Enzymes and Phage Therapy

“…Pathogen-specific monoclonal antibodies are either used independently for disease prevention or in combination with antibiotics to treat bacterial infections [18]. Antibodies neutralize the effects of bacterial toxins [19][20][21][22]; they can also be directed against bacterial antigens [23][24][25] and quorum-sensing signals [26,27] inhibiting biofilm formation enhancing the effect of antibioticbased treatment and can be employed for combating persister cells insensitive to antibiotics [28,29].…”