Skin and soft tissue infections (SSTIs) are among the most common infections worldwide. They range in severity from minor, self-limiting, superficial infections to life-threatening diseases requiring all the resources of modern medicine. Community (CA) and healthcare (HA) acquired SSTIs are most commonly caused by Staphylococcus aureus . They have variable presentations ranging from impetigo and folliculitis to surgical site infections (SSIs). Superficial SSTIs may lead to even more invasive infections such as bacteraemia and osteomyelitis. Here we describe the anatomical localization of the different SSTI associated with S. aureus, the virulence factors known to play a role in these infections, and their current epidemiology. Current prevention and treatment strategies are also discussed. Global epidemiological data show increasing incidence and severity of SSTIs in association with methicillin-resistant S. aureus strains (MRSA). CA-SSTIs are usually less morbid compared to other invasive infections caused by S. aureus, but they have become the most prevalent, requiring a great number of medical interventions, extensive antibiotic use, and therefore a high cost burden. Recurrence of SSTIs is common after initial successful treatment, and decolonization strategies have not been effective in reducing recurrence. Furthermore, decolonization approaches may be contributing to the selection and maintenance of multi-drug resistant strains. Clinical studies from the early 1900s and novel autovaccination approaches suggest an alternative strategy with potential effectiveness: using vaccines to control S. aureus cutaneous infections.

Authorship note: BL and RO contributed equally to this work. Conflict of interest: JBW has a financial agreement with Aridis Pharmaceuticals related to patents owned by the University of Chicago (US patent application 12/675,597, entitled "Methods and compositions related to immunizing against staphylococcal lung diseases and conditions").

Staphylococcus aureus is a leading pathogen in surgical site, intensive care unit, and skin infections, as well as healthcare-associated pneumonias. These infections are associated with an enormous burden of morbidity, mortality, and increase of hospital length of stay and patient cost. S. aureus is impressively fast in acquiring antibiotic resistance, and multidrug-resistant strains are a serious threat to human health. Due to resistance or insufficient effectiveness, antibiotics and bundle measures leave a tremendous unmet medical need worldwide. There are no licensed vaccines on the market despite the significant efforts done by public and private initiatives. Indeed, vaccines tested in clinical trials in the last two decades have failed to show efficacy. However, they targeted single antigens and contained no adjuvants and efficacy trials were performed in severely ill subjects. Herein, we provide a comprehensive evaluation of potential target populations for efficacy trials taking into account key factors such as population size, incidence of S. aureus infection, disease outcome, primary endpoints, as well as practical advantages and disadvantages. We describe the whole-blood assay as a potential surrogate of protection, and we show the link between phase III clinical trial data of failed vaccines with their preclinical observations. Finally, we give our perspective on how new vaccine formulations and clinical development approaches may lead to successful S. aureus vaccines.

Staphylococcus aureus alpha-toxin and Panton–Valentine leukocidin (PVL) have been reported to play critical roles in different animal models of skin infection. These models, however, do not completely recapitulate the human disease due to the host specificity of these toxins as well as the intrinsic anatomical and immunological differences between animals and humans. Human skin explants represent a valid alternative to animal models for studying skin infections. Herein, we developed a human skin explant wound model to study the pathogenic role of alpha-toxin and PVL; inflammatory responses elicited by these toxins; and the neutralizing ability of antibodies to mitigate skin damage. Different concentrations of alpha-toxin and/PVL were applied to superficial wounds on human skin explants. Treatment with alpha-toxin resulted in high tissue toxicity and loss of skin epithelial integrity. PVL induced a milder but significant toxicity with no loss of skin structural integrity. The combination of both toxins resulted in increased tissue toxicity as compared with the individual toxins alone. Treatment of the skin with these toxins also resulted in a decrease of CD45-positive cells in the epidermis. In addition, both toxins induced the release of pro-inflammatory cytokines and chemokines. Finally, antibodies raised against alpha-toxin were able to mitigate tissue toxicity in a concentration-dependent manner. Results from this study confirm the key role of α-toxin in staphylococcal infection of the human skin and suggest a possible cooperation of the two toxins in tissue pathology.