Staphylococcus aureus skin infections represent a significant public health 
threat because of the emergence of antibiotic-resistant strains such as 
methicillin-resistant S. aureus (MRSA). As greater understanding of protective 
immune responses and more effective antimicrobial therapies are needed, a S. 
aureus skin wound infection model was developed in which full-thickness scalpel 
cuts on the backs of mice were infected with a bioluminescent S. aureus 
(methicillin sensitive) or USA300 community-acquired MRSA strain and in vivo 
imaging was used to noninvasively monitor the bacterial burden. In addition, the 
infection-induced inflammatory response was quantified using in vivo 
fluorescence imaging of LysEGFP mice. Using this model, we found that both IL-1α 
and IL-1β contributed to host defense during a wound infection, whereas IL-1β 
was more critical during an intradermal S. aureus infection. Furthermore, 
treatment of a USA300 MRSA skin infection with retapamulin ointment resulted in 
up to 85-fold reduction in bacterial burden and a 53% decrease in 
infection-induced inflammation. In contrast, mupirocin ointment had minimal 
clinical activity against this USA300 strain, resulting in only a 2-fold 
reduction in bacterial burden. Taken together, this S. aureus wound infection 
model provides a valuable preclinical screening method to investigate cutaneous 
immune responses and the efficacy of topical antimicrobial therapies.