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This leads to a pro-inflammatory cytokine storm and the subsequent multiple organ damage and shock. Inbred mice are innately refractive to SAg-mediated responses. In this chapter, we discuss the versatility of the HLA-II transgenic mouse model that allowed the biological validation of known genetic associations to GAS NSTI. The combined utility of ARI-BXD and HLA-II mice as complementary approaches that offer clinically translatable insights into pathomechanisms driven by complex traits and host genetic context and novel means to evaluate the in vivo efficiency of therapies to improve outcomes of GAS NSTI are also discussed.Necrotizing skin and soft tissue infections (NSTIs) are severe life-threatening and rapidly progressing infections. Beta-hemolytic streptococci, particularly S. pyogenes (group A streptococci (GAS)) but also S. dysgalactiae subsp. equisimilis (SDSE, most group G and C streptococcus), are the main causative agents of monomicrobial NSTIs and certain types, such as emm1 and emm3, are over-represented in NSTI cases. An arsenal of bacterial virulence factors contribute to disease pathogenesis, which is a complex and multifactorial process. In this chapter, we summarize data that have provided mechanistic and immuno-pathologic insight into host-pathogens interactions that contribute to tissue pathology in streptococcal NSTIs. The role of streptococcal surface associated and secreted factors contributing to the hyper-inflammatory state and immune evasion, bacterial load in the tissue and persistence strategies, including intracellular survival and biofilm formation, as well as strategies to mimic NSTIs in vitro are discussed.Immunoglobulins are key effector molecules in the humoral immune response. Intravenous polyspecific immunoglobulin (IVIG) is a preparation of polyclonal serum immunoglobulins, typically IgG, from thousands of donors. It has been used as adjunctive therapy in critically ill patients with severe infections, i.e. see more sepsis, septic shock, and necrotizing soft tissue infections. IVIG has been used for patients with severe invasive group A streptococcal infection since the early nineties and off-label use of IVIG for necrotizing soft tissue infections is common. It is also used for a variety of autoimmune, inflammatory, and immunodeficiency diseases. A meta-analysis of the clinical studies available for IVIG use in group A streptococcal toxic shock syndrome indicates a survival benefit. A blinded, placebo-controlled clinical trial (INSTINCT) assessed the effect of IVIG in 100 intensive care unit patients with necrotizing soft tissue infections, including all bacterial etiologies. The study did not demonstrate any effect on self-reported physical functioning at 6 months. In this chapter, we review the mechanisms of action of IVIG and the clinical studies that are available for necrotizing soft tissue infections as well as severe group A streptococcal infections.Necrotizing soft tissue infections (NSTIs) are severe, life-threatening infections, and early therapeutic intervention is essential. Prompt administration of potent antimicrobial agents is pivotal, but inadequate empirical therapy is unfortunately common. Optimization of the antibiotic treatment strategy in NSTIs requires consideration of local epidemiology of causative pathogens and antimicrobial resistance patterns, knowledge on common pathogenetic mechanisms in NSTIs, and adaptations to pharmacokinetic and pharmacodynamic physiological changes in critically ill patients. In the present article we address all these issues, as well as review and compare contemporary guidelines for antimicrobial treatment of NSTIs from around the world.β-hemolytic streptococci are major causes of necrotizing soft tissue infections (NSTIs), Streptococcus pyogenes (group A streptococcus; GAS) in particular. NSTIs caused by Streptococcus dysgalactiae (SD) have also been reported. In the INFECT cohort of 409 NSTIs patients, more than a third of the cases were caused by GAS (31%) or SD (7%). Risk factors of streptococcal NSTIs compared to streptococcal cellulitis have previously been largely unknown. The INFECT study confirmed blunt trauma as an important risk factor. In addition, absence of pre-existing skin lesions and a lower BMI were associated with NSTIs. The study also confirmed that septic shock is more frequent in GAS cases than in other types of NSTIs. Septic shock was also among several predictors of mortality. The role of intravenous immunoglobulin (IVIG) in streptococcal NSTIs has been unclear. In the INFECT cohort, IVIG treatment was associated with increased survival. As in other studies, a significant microbial diversity was observed, but with predominance of a few emm types. Overall, the INFECT study gives a comprehensive and contemporary picture of the clinical characteristics and the microbes involved in streptococcal NSTIs. The reported severity of disease underscores the need for new efforts aimed at identifying novel diagnostic measures and improved treatment.Necrotizing soft tissue infections (NSTIs) are severe clinical conditions requiring swift therapeutic intervention, including surgical removal of infected tissue and administration of potent antibiotics. There is wide diversity in the microbial etiologic agents, and tailoring the antibiotic treatment to the offending pathogen is essential. However, the choice of empirical therapy is frequently inadequate, underlining the need for comprehensive and contemporary knowledge on causative pathogens and relevant antimicrobial resistance patterns in NSTIs. Also, studies of the pathogenic mechanisms in different NSTIs are needed, to improve handling of patients through developing patient stratification and tailored therapies. We review the current knowledge on microbial etiology and provide detailed characterizations of the predominant pathogens.The term necrotizing soft-tissue infection (NSTI) encompasses a heterogenous group of patients with necrotizing infections, involving any body part. NSTI is diagnosed by surgical exploration, where necrosis of the subcutaneous tissue and/or muscle tissue, undermining of the skin, thrombosis of the superficial veins, and deliquescent tissue can be seen. Patients can present with vague symptoms, and approximately half of patients experience severe pain. The clinical presentation and microbiological etiology vary according to affected body site, with NSTI located to the extremities being dominated by monomicrobial group A streptococcal infections, and NSTI located to the anogenital area dominated by polymicrobial infections. No set of diagnostic criteria exists, and suspicion of the diagnosis should come from careful clinical examination and signs of local or systemic severity. Laboratory blood values show no distinct pattern but resemble those of sepsis. Imaging can aid the diagnostic process but must not delay surgical intervention.