Background Necrotizing soft-tissue infections (NSTI) are life-threatening conditions often caused by β-hemolytic streptococci, group A Streptococcus (GAS) in particular. Optimal treatment is contentious. The INFECT cohort includes the largest set of prospectively enrolled streptococcal NSTI cases to date. Methods From the INFECT cohort of 409 adults admitted with NSTI to 5 clinical centers in Scandinavia, patients culture-positive for GAS or Streptococcus dysgalactiae (SD) were selected. Risk factors were identified by comparison with a cohort of nonnecrotizing streptococcal cellulitis. The impact of baseline factors and treatment on 90-day mortality was explored using Lasso regression. Whole-genome sequencing of bacterial isolates was used for emm typing and virulence gene profiling. Results The 126 GAS NSTI cases and 27 cases caused by SD constituted 31% and 7% of the whole NSTI cohort, respectively. When comparing to nonnecrotizing streptococcal cellulitis, streptococcal NSTI was associated to blunt trauma, absence of preexisting skin lesions, and a lower body mass index. Septic shock was significantly more frequent in GAS (65%) compared to SD (41%) and polymicrobial, nonstreptococcal NSTI (46%). Age, male sex, septic shock, and no administration of intravenous immunoglobulin (IVIG) were among factors associated with 90-day mortality. Predominant emm types were emm1, emm3, and emm28 in GAS and stG62647 in SD. Conclusions Streptococcal NSTI was associated with several risk factors, including blunt trauma. Septic shock was more frequent in NSTI caused by GAS than in cases due to SD. Factors associated with mortality in GAS NSTI included age, septic shock, and no administration of IVIG.

Background: Skin and soft tissue infections (SSTIs) are increasing. Frequent over-and under-treatment has been reported, including non-purulent SSTIs where cases demanding surgery or broad-spectrum therapy often are hard to identify. Our aim was to measure the predictive power of a modified severity score and use it to identify areas of improvement in antimicrobial therapy of non-purulent SSTIs. Methods: We prospectively included adult patients admitted to hospital with non-purulent SSTIs. A modified Dundee score at admission was calculated retrospectively, and associations between severity and outcomes were analysed. We evaluated appropriateness of treatment in relation to severity scores, and assessed adverse effects of broad-spectrum therapy. Results: We included 200 cases with cellulitis and 19 cases with necrotising soft tissue infections (NSTIs). Thirty-two per cent were categorised as severity class I, 15% as class II, 28% as class III and 25% as class IV (most severe). In class I, 66 out of 69 cases did not have a complicated course. All but one NSTI case were identified by the class IV criteria. Over-treatment was common and mostly seen in class I. Broad-spectrum antibiotics or clindamycin use was associated with an increased risk of diarrhoea. Prolonged treatment (>14 days) was associated with age, severity and surgery. Conclusions: The modified Dundee score proved valuable in identifying those with the lowest risk of complication and the most severe infections, and could serve as a useful clinical tool in the emergency department. Frequent over-treatment and associated adverse effects were confirmed, underscoring the need for improved risk assessment.

Our findings indicate that BHS are the leading cause of facial cellulitis. Most patients exhibit sharply demarcated lesions and systemic symptoms. Narrow-spectrum β-lactam antibiotics and short hospital stay appear sufficient. Few complications and low recurrence rates were seen.

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These infections are infrequent, but are associated with a significant health burden due to high mortality and risk of severe long-term disability as a consequence of extensive tissue loss or amputations (3)(4)(5). The progression of the disease is rapid, and early identification is therefore pivotal for improving the prognosis of affected patients. Currently, the initial diagnosis of NSTI is challenging due to the often vague symptoms during early stages, a heterogeneous patient group, and lack of specific diagnostic tools (6), which lead to misdiagnoses of NSTI in many cases (7). Still, doctors are advised that in case of NSTI suspicion, patients should be referred to surgical evaluation immediately (8). Previous efforts to improve the diagnosis of NSTIs led to the proposal of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) CONCLUSIONS. This study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01790698.

Background Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection. A key driving force for this process is the bacterial Sda1 DNase. Methods Bacterial infiltration, immune cell influx, tissue necrosis and inflammation in patient´s biopsies were determined using immunohistochemistry. SpeB secretion and activity by GAS post infections or challenges with reactive agents were determined via Western blot or casein agar and proteolytic activity assays, respectively. Proteome of GAS single colonies and neutrophil secretome were profiled, using mass spectrometry. Results Here, we identify another strategy resulting in SpeB-negative variants, namely reversible abrogation of SpeB secretion triggered by neutrophil effector molecules. Analysis of NSTI patient tissue biopsies revealed that tissue inflammation, neutrophil influx, and degranulation positively correlate with increasing frequency of SpeB-negative GAS clones. Using single colony proteomics, we show that GAS isolated directly from tissue express but do not secrete SpeB. Once the tissue pressure is lifted, GAS regain SpeB secreting function. Neutrophils were identified as the main immune cells responsible for the observed phenotype. Subsequent analyses identified hydrogen peroxide and hypochlorous acid as reactive agents driving this phenotypic GAS adaptation to the tissue environment. SpeB-negative GAS show improved survival within neutrophils and induce increased degranulation. Conclusions Our findings provide new information about GAS fitness and heterogeneity in the soft tissue milieu and provide new potential targets for therapeutic intervention in NSTIs.

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Abstract Background Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. Methods In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. Results NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichia coli) and host genes. The host genes associated with S. pyogenes in this subnetwork were characterised by cellular response to cytokines. We further found several virulence factors including hyaluronan synthase, Sic1, Isp, SagF, SagG, ScfAB-operon, Fba and genes upstream and downstream of EndoS along with bacterial housekeeping genes interacting with the human stress and immune response in various subnetworks between host and pathogen. Conclusions At the population level, we found aetiology-dependent responses showing the potential modes of entry and immune evasion strategies employed by S. pyogenes, congruent with general cellular processes such as differentiation and proliferation. After stratifying the patients based on the subject-specific networks to study the patient-specific response, we observed different patient groups with different collagens, cytoskeleton and actin monomers in association with virulence factors, immunogenic proteins and housekeeping genes which we utilised to postulate differing modes of entry and immune evasion for different bacteria in relationship to the patients’ phenotype.