g Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (⌬hla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented ⌬hla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893*, an anti-alphatoxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the ⌬hla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893* was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.

The role broad-spectrum antibiotics play in the spread of antimicrobial resistance, coupled with their effect on the healthy microbiome, has led to advances in pathogen-specific approaches for the prevention or treatment of serious bacterial infections. One approach in clinical testing is passive immunization with a monoclonal antibody (MAb) targeting alpha toxin for the prevention or treatment of Staphylococcus aureus pneumonia. Passive immunization with the human anti-alpha toxin MAb, MEDI4893*, has been shown to improve disease outcome in murine S. aureus pneumonia models. The species specificity of some S. aureus toxins necessitates testing anti-S. aureus therapeutics in alternate species. We developed a necrotizing pneumonia model in ferrets and utilized an existing rabbit pneumonia model to characterize MEDI4893* protective activity in species other than mice. MEDI4893* prophylaxis reduced disease severity in ferret and rabbit pneumonia models against both community-associated methicillin-resistant S. aureus (MRSA) and hospital-associated MRSA strains. In addition, adjunctive treatment of MEDI4893* with either vancomycin or linezolid provided enhanced protection in rabbits relative to the antibiotics alone. These results confirm that MEDI4893 is a promising candidate for immunotherapy against S. aureus pneumonia.

Introduction: Wounds can be colonized by methicillin-resistant Staphylococcus aureus (MRSA). Methods: We evaluated the prevalence of S. aureus and MRSA in the wounds of patients treated at Basic Health Units in Brazil and identifi ed risk factors associated with their presence. Results: The prevalence rates of S. aureus and MRSA were 51.5% and 8.7%, respectively. There was a correlation between the presence of S. aureus in wounds and nostrils (p<0.01). A positive association was detected between S. aureus infection and previous benzylpenicillin use (p=0.02). No associations were observed for MRSA. Conclusions: Multidrug-resistant pathogens are present in primary healthcare settings in Brazil.

Objective To evaluate the molecular epidemiology and to georeference Staphylococcus aureus isolated from wounds and nares of patients seen at Basic Health Units (BHUs) of a Brazilian city. Methods Observational, cross‐sectional study conducted from 2010 to 2013. A total of 119 S. aureus strains isolated from the wounds and nares of 88 patients were studied. The isolates were characterised by identifying virulence genes encoding enterotoxins A–E, haemolysins α, β and δ, exfoliatins A, B and D, biofilm production, Panton‐Valentine Leukocidin and toxic shock syndrome toxin 1, and by pulsed‐field gel electrophoresis (PFGE), multilocus sequence and spa typing. Results Eighteen methicillin‐resistant Staphylococcus aureus (MRSA) (6 SCCmec type II and 12 SCCmec type IV) and 101 (85%) MSSA were identified. PFGE typing resulted in the formation of eight clusters, with STs 1, 5, 8, 30, 188, 1176 and 1635 and spa type t002 being the predominant types among MSSA. The 18 MRSA belonged to STs 5, 8 and 1176 and spa types t002 and t062. Conclusion The results demonstrate widespread dissemination of MSSA and MRSA clones carrying haemolysin, biofilm and toxin genes. Kernel density estimation revealed the highest density of S. aureus in the 4, 5 and 8 BHUs.