SLR - August 2022 - Reid Marion PGY-1
Reference: Christine, T., Omari, J.-N., Yue, S. Y., E., T. D., Lily, C., Tianhui, Z., … D., F. P. (2022). Neutralizing Staphylococcus aureus Virulence with AZD6389, a Three mAb Combination, Accelerates Closure of a Diabetic Polymicrobial Wound. MSphere, 0(0), e00130-22. https://doi.org/10.1128/msphere.00130-22Level of Evidence: III
Scientific Literature Review
Reviewed By: Reid Marion PGY-1
Residency Program: Puget Sound VA, Seattle WA
Podiatric Relevance: Diabetic foot ulcers are a frequent complex medical issue addressed by podiatrists. This article details a novel treatment for polymicrobial infections which may not be adequately addressed by standard wound care. The authors attempt to demonstrate the impact of polymicrobial colonization of wounds on wound healing, and potential treatment options using monoclonal antibodies to neutralize virulence factors. Building understanding of wound colonization and advanced wound management are important for complete diabetic foot care.
Methods: Researchers generated wounds of similar sizes in diabetic mice, then inoculated the wound sites subdermally with P.aeruginosa, S.aureus, S.pyogenes or combination of all three. Mice randomized to the treatment group were then inoculated with intraperitoneal Monoclonal antibody treatment at different time points and doses. Separate treatment groups were administered combinations of one, two, or all three mAbs. Skin lesion size and estimated bacterial burden on skin lesion sizes were measured at different time points and compared between groups at 22 days. The quantity three virulence factors, alpha toxin, clumping factor, and leukotoxin were measured. Inflammatory cytokines were also quantified as a measure of inflammatory phase duration
Results: Wounds demonstrated complete closure at 21 days only in the group treated with a combination of three mAb. None of the remaining placebo or mAb combinations were healed within the 22 day experiment duration. Skin lesions were unhealed only in the control group inoculated with all three bacterial cultures without mAb treatment. Statistically significant reduction in wound size and bacterial bioburden in four different S.aureus strains in treatment group compared to placebo. There were statistically significant decrease in inflammatory cytokines in the 3 mAb treatment group. Additionally, level of virulence factors were higher in the diabetic mice control population relative to the non-diabetic group.
Conclusions: The authors concluded that polymicrobial infections were statistically significant factor in reducing wound healing rate and administered mAb treatment led to measurable differences in wound size and bacterial bioburden at the wound site. The results support the above conclusions. In addition, there was significant differences in the wound healing rate and the bacterial bioburden between diabetic and non-diabetic mice with similar wounds, though the wounds were not on a weight-bearing surface. Additionally, the treatment only led to improved wound healing metrics when administered together, to address S.aureus associated virulence factors allowing polymicrobial growth. The mouse skin model and quantification of virulence factors demonstrated feasibility of mAb delivery and activity against polymicrobial skin infections in mammals. Research into the use of mAbs for use against infectious diseases have grown in recent years, however no human clinical trials for commercial use in the setting of diabetic foot ulcerations have been conducted yet. For challenging, chronic DFUs, understanding the effect of polymicrobial colonization and implementing future therapies based on mAbs may lead to faster wound healing and improved outcomes.