Necrotising soft tissue infections. / Nekrotiserende bløtdelsinfeksjoner.

Necrotising soft tissue infections can affect the skin, subcutaneous tissue, superficial fascia, deep fascia and musculature. The infections are severe, they spread quickly and can result in extensive tissue loss. Although rare, morbidity and mortality rates are high. Early clinical identification is crucial for the outcome, and rapid infection control through surgery and targeted antibiotic treatment is needed to save lives. Few prospective clinical trials have been conducted for the treatment of this type of infection. Specific challenges include rapid identification of the condition and the uncertain efficacy of the various treatment options. In this clinical review article, we describe clinical characteristics, diagnostics and treatment.

A new pathway for penicillin delabeling in Norway.

Background: Penicillin allergy is self-reported by 3-10% of patients admitted to hospital. The label is wrong in 90% of the cases and has severe health implications. Penicillin-delabeling can reverse the negative effects of the label, and pathways adapted to local practice are needed. No tools are available in Norway for penicillin delabeling outside an allergy clinic. Objective: To create and validate the first penicillin delabeling pathway applicable outside an allergy clinic in Norway. Methods: An interdisciplinary taskforce created a penicillin allergy delabeling program (PAD) adapted to the Norwegian health care system. This was validated in a prospective, single-center study. Very low-risk and low-risk patients underwent a direct oral penicillin challenge and high-risk patients were referred for allergologic evaluation. Results: One-hundred forty-nine patients declaring penicillin allergy were included. Seventy-four (50%) were very-low- and low risk patients suitable for a direct oral penicillin challenge resulting in only 1 mild reaction. Sixty high-risk patients were eligible for an oral penicillin challenge after allergologic evaluation; 3 patients reacted non-severely. Conclusion: We have created and demonstrated feasibility of the first penicillin delabeling program (PAD) applicable in a hospital setting outside an allergy clinic in Norway. Our data suggest this is safe and beneficial, with 49% patients delabeled through a direct oral penicillin challenge, performed without any serious adverse events, and an overall 87% delabeling rate.

Genomic epidemiology of Streptococcus dysgalactiae subsp. equisimilis strains causing invasive disease in Norway during 2018.

Background: Streptococcus dysgalactiae subspecies equisimilis (SDSE) is an emerging global pathogen, yet the epidemiology and population genetics of SDSE species have not been extensively characterized. Methods: We carried out whole genome sequencing to characterize 274 SDSE isolates causing bloodstream infections obtained through national surveillance program in 2018. We conducted multilocus sequence typing (MLST), emm-typing, core genome phylogeny, as well as investigated key features associated with virulence. Moreover, comparison to SDSE from other geographic regions were performed in order to gain more insight in the evolutionary dynamics in SDSE. Results: The phylogenetic analysis indicated a substantial diversity of emm-types and sequence types (STs). Briefly, 17 emm-types and 58 STs were identified that formed 10 clonal complexes (CCs). The predominant ST-types were ST20 (20%), ST17 (17%), and ST29 (11%). While CC17 and CC29 clades showed a substantial heterogeneity with well-separated emm-associated subclades, the CC20 clade harboring the stG62647 emm-type was more homogenous and the most prevalent in the present study. Moreover, we observed notable differences in the distribution of clades within Norway, as well as several disseminated CCs and also distinct geographic variations when compared to data from other countries. We also revealed extensive intra-species recombination events involving surface exposed virulence factors, including the emm gene important for phylogenetic profiling. Conclusion: Recombination events involving the emm as well as other virulence genes in SDSE, are important mechanisms in shaping the genetic variability in the SDSE population, potentially offering selective advantages to certain lineages. The enhanced phylogenetic resolution offered by whole genome sequencing is necessary to identify and delimitate outbreaks, monitor and properly characterize emerging strains, as well as elucidate bacterial population dynamics.

Streptococcus dysgalactiae Bloodstream Infections, Norway, 1999-2021.

Streptococcus dysgalactiae increasingly is recognized as a pathogen of concern for human health. However, longitudinal surveillance data describing temporal trends of S. dysgalactiae are scarce. We retrospectively identified all ß-hemolytic streptococcal bloodstream infections reported in Bergen, in western Norway, during 1999-2021. To explore S. dysgalactiae disease burden in a broader context, we mapped the incidence of all microbial species causing bloodstream infections during 2012-2021. We found S. dysgalactiae incidence rates substantially increased during the study period; by 2021, S. dysgalactiae was the fifth most common pathogen causing bloodstream infections in our region. We noted genotypic shifts and found that the rising trend was related in part to the introduction and expansion of the stG62647 emm-type. S. dysgalactiae is among the most common causes of bloodstream infections in western Norway, and increased surveillance and unambiguous species identification are needed to monitor the disease burden attributable to this pathogen.

Case Report: Whole-Genome Sequencing of Serially Collected Haemophilus influenzae From a Patient With Common Variable Immunodeficiency Reveals Within-Host Evolution of Resistance to Trimethoprim-Sulfamethoxazole and Azithromycin After Prolonged Treatment With These Antibiotics.

We report within-host evolution of antibiotic resistance to trimethoprim-sulfamethoxazole and azithromycin in a nontypeable Haemophilus influenzae strain from a patient with common variable immunodeficiency (CVID), who received repeated or prolonged treatment with these antibiotics for recurrent respiratory tract infections. Whole-genome sequencing of three longitudinally collected sputum isolates during the period April 2016 to January 2018 revealed persistence of a strain of sequence type 2386. Reduced susceptibility to trimethoprim-sulfamethoxazole in the first two isolates was associated with mutations in genes encoding dihydrofolate reductase (folA) and its promotor region, dihydropteroate synthase (folP), and thymidylate synthase (thyA), while subsequent substitution of a single amino acid in dihydropteroate synthase (G225A) rendered high-level resistance in the third isolate from 2018. Azithromycin co-resistance in this isolate was associated with amino acid substitutions in 50S ribosomal proteins L4 (W59R) and L22 (G91D), possibly aided by a substitution in AcrB (A604E) of the AcrAB efflux pump. All three isolates were resistant to aminopenicillins and cefotaxime due to TEM-1B beta-lactamase and identical alterations in penicillin-binding protein 3. Further resistance development to trimethoprim-sulfamethoxazole and azithromycin resulted in a multidrug-resistant phenotype. Evolution of multidrug resistance due to horizontal gene transfer and/or spontaneous mutations, along with selection of resistant subpopulations is a particular risk in CVID and other patients requiring repeated and prolonged antibiotic treatment or prophylaxis. Such challenging situations call for careful antibiotic stewardship together with supportive and supplementary treatment. We describe the clinical and microbiological course of events in this case report and address the challenges encountered.

Analysis of host-pathogen gene association networks reveals patient-specific response to streptococcal and polymicrobial necrotising soft tissue infections.

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.

Invasive group A streptococcal disease in pregnant women and young children: a systematic review and meta-analysis.

BACKGROUND: The incidence of invasive disease caused by group A streptococcus (GAS) has increased in multiple countries in the past 15 years. However, despite these reports, to the best of our knowledge, no systematic reviews and combined estimates of the incidence of invasive GAS have been done in key high-risk groups. To address this, we estimated the incidence of invasive GAS disease, including death and disability outcomes, among two high-risk groups-namely, pregnant women and children younger than 5 years. METHODS: We did a systematic review and meta-analyses on invasive GAS outcomes, including incidence, case fatality risks, and neurodevelopmental impairment risk, among pregnant women, neonates (younger than 28 days), infants (younger than 1 year), and children (younger than 5 years) worldwide and by income region. We searched several databases for articles published from Jan 1, 2000, to June 3, 2020, for publications that reported invasive GAS outcomes, and we sought unpublished data from an investigator group of collaborators. We included studies with data on invasive GAS cases, defined as laboratory isolation of Streptococcus pyogenes from any normally sterile site, or isolation of S pyogenes from a non-sterile site in a patient with necrotising fasciitis or streptococcal toxic shock syndrome. For inclusion in pooled incidence estimates, studies had to report a population denominator, and for inclusion in pooled estimates of case fatality risk, studies had to report aggregate data on the outcome of interest and the total number of cases included as a denominator. We excluded studies focusing on groups at very high risk (eg, only preterm infants). We assessed heterogeneity with I2. FINDINGS: Of the 950 published articles and 29 unpublished datasets identified, 20 studies (seven unpublished; 3829 cases of invasive GAS) from 12 countries provided sufficient data to be included in pooled estimates of outcomes. We did not identify studies reporting invasive GAS incidence among pregnant women in low-income and middle-income countries (LMICs) nor any reporting neurodevelopmental impairment after invasive GAS in LMICs. In nine studies from high-income countries (HICs) that reported invasive GAS in pregnancy and the post-partum period, invasive GAS incidence was 0·12 per 1000 livebirths (95% CI 0·11 to 0·14; I2=100%). Invasive GAS incidence was 0·04 per 1000 livebirths (0·03 to 0·05; I2=100%; 11 studies) for neonates, 0·13 per 1000 livebirths (0·10 to 0·16; I2=100%; ten studies) for infants, and 0·09 per 1000 person-years (95% CI 0·07 to 0·10; I2=100%; nine studies) for children worldwide; 0·12 per 1000 livebirths (95% CI 0·00 to 0·24; I2=100%; three studies) in neonates, 0·33 per 1000 livebirths (-0·22 to 0·88; I2=100%; two studies) in infants, and 0·22 per 1000 person-years (0·13 to 0·31; I2=100%; two studies) in children in LMICs; and 0·02 per 1000 livebirths (0·00 to 0·03; I2=100%; eight studies) in neonates, 0·08 per 1000 livebirths (0·05 to 0·11; I2=100%; eight studies) in infants, and 0·05 per 1000 person-years (0·03 to 0·06; I2=100%; seven studies) in children for HICs. Case fatality risks were high, particularly among neonates in LMICs (61% [95% CI 33 to 89]; I2=54%; two studies). INTERPRETATION: We found a substantial burden of invasive GAS among young children. In LMICs, little data were available for neonates and children and no data were available for pregnant women. Incidences of invasive GAS are likely to be underestimates, particularly in LMICs, due to low GAS surveillance. It is essential to improve available data to inform development of prevention and management strategies for invasive GAS. FUNDING: Wellcome Trust.

Molecular detection and genotype characterization of Streptococcus dysgalactiae from sheep flocks with outbreaks of infectious arthritis.

Outbreaks of infectious arthritis in young lambs are a growing concern for the Norwegian sheep industry. In other countries, Streptococcus dysgalactiae subspecies dysgalactiae (SDSD) is a frequent cause of such outbreaks. The objectives of this study were to investigate the causes of outbreaks of infections arthritis in Norwegian sheep flocks, and describe the sources, colonization patterns and genetic diversity of SDSD in affected and healthy sheep flocks. Almost 2000 samples from joints, animal body sites and the indoor environment were analysed by qPCR and culturing for SDSD, which was detected in 27 of 30 flocks. The proportion of positive samples was greater in outbreak flocks compared to healthy flocks. Altogether, SDSD was detected in 48 % of the samples from lambs, 27 % of the samples from ewes and 48 % of environmental samples. A relatively high proportion (67 %) of ear tag wounds were SDSD positive. These wounds may provide a port of entry for SDSD. Whole genome sequencing revealed a clonal distribution of SDSD-isolates, and identified four different multi locus sequence types (STs), among which two STs, ST454 and ST531, dominated. These STs were found in geographically distant flocks. ST454 was almost exclusively found in outbreak flocks. The current study points to skin, wounds and mucous membranes of animals as the main reservoir of SDSD in sheep flocks. However, a significantly higher proportion of SDSD-positive environmental samples in outbreak flocks compared to healthy flocks suggests that also indirect transmission may play a role.

Whole genome sequencing reveals possible host species adaptation of Streptococcus dysgalactiae.

Streptococcus dysgalactiae (SD) is an emerging pathogen in human and veterinary medicine, and is associated with several host species, disease phenotypes and virulence mechanisms. SD has traditionally been divided into the subspecies dysgalactiae (SDSD) and subsp. equisimilis (SDSE), but recent molecular studies have indicated that the phylogenetic relationships are more complex. Moreover, the genetic basis for the niche versatility of SD has not been extensively investigated. To expand the knowledge about virulence factors, phylogenetic relationships and host-adaptation strategies of SD, we analyzed 78 SDSD genomes from cows and sheep, and 78 SDSE genomes from other host species. Sixty SDSD and 40 SDSE genomes were newly sequenced in this study. Phylogenetic analysis supported SDSD as a distinct taxonomic entity, presenting a mean value of the average nucleotide identity of 99%. Bovine and ovine associated SDSD isolates clustered separately on pangenome analysis, but no single gene or genetic region was uniquely associated with host species. In contrast, SDSE isolates were more heterogenous and could be delineated in accordance with host. Although phylogenetic clustering suggestive of cross species transmission was observed, we predominantly detected a host restricted distribution of the SD-lineages. Furthermore, lineage specific virulence factors were detected, several of them located in proximity to hotspots for integration of mobile genetic elements. Our study indicates that SD has evolved to adapt to several different host species and infers a potential role of horizontal genetic transfer in niche specialization.

Risk Factors and Predictors of Mortality in Streptococcal Necrotizing Soft-tissue Infections: A Multicenter Prospective Study.

BACKGROUND: Necrotizing soft-tissue infections (NSTI) are life-threatening conditions often caused by ß-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.

Identification of Streptococcus dysgalactiae using matrix-assisted laser desorption/ionization-time of flight mass spectrometry; refining the database for improved identification.

Matrix-assisted laser desorption/ionization time of flight (MALDI-ToF) has revolutionized bacterial identification. However, the phylogenetic resolution is still insufficient for discerning several ß-haemolytic streptococcal species. We aimed to improve the diagnostic performance of MALDI-ToF through manual curation of the reference spectra in Brukers Compass Library DB-7854. Before intervention, only 133 out of 217 (62%) Streptococcus dysgalactiae isolates were successfully identified to the species level, 83 isolates were identified to the genus level as either S. dysgalactiae, S. pyogenes or S. canis, and one S. dysgalactiae isolate was wrongly identified as S. canis. All 109 S. canis isolates were successfully identified to the species level. Removal of three reference spectra from the database significantly improved the identification of S. dysgalactiae to 94%, without compromising identification of S. canis. This illustrates the advantage of refinement of the reference database in order to improve the analytic precision of MALDI-ToF.

Beta-Hemolytic Streptococci and Necrotizing Soft Tissue Infections.

ß-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.

Treatment of Necrotizing Soft Tissue Infections: Antibiotics.

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.

Microbiological Etiology of Necrotizing Soft Tissue Infections.

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.

Emerging Threat of Antimicrobial Resistance in ß-Hemolytic Streptococci.

Highly variable resistance rates to erythromycin and clindamycin have been reported in the ß-hemolytic streptococcal species Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae, depending on geographic and temporal context. In the present study we aimed to examine the longitudinal trends of antimicrobial resistance in these three species in a northern European setting. Furthermore, we used whole genome sequencing to identify resistance determinants and the mobile genetic elements involved in their dissemination, as well as elucidate phylogenetic relationships. All cases of invasive ß-hemolytic streptococcal diseases in Health Region Bergen, western Norway, in the period 2004 to 2018 were retrospectively identified, comprising 271, 358, and 280 cases of S. pyogenes, S. agalactiae, and S. dysgalactiae, respectively. Antimicrobial susceptibility testing revealed a gradual but significant increase in erythromycin and clindamycin resistance for S. agalactiae and S. dysgalactiae during the study period. Whole genome sequencing of the erythromycin and clindamycin resistant bacterial population revealed a substantial phylogenetic diversity in S. agalactiae and S. dysgalactiae. However, the mobile genetic elements harboring the resistance determinants showed remarkable intra- and interspecies similarities, suggesting a dissemination of antimicrobial resistance predominantly through conjugative transfer rather than clonal expansion of resistant strains in these two species. Conversely, antimicrobial resistance in S. pyogenes remained low, apart from a transient outbreak of a clindamycin and erythromycin resistant emm11/ST403-clone in 2010-2012. Increased epidemiological attentiveness is warranted to monitor the emerging threat of antimicrobial resistance in ß-hemolytic streptococci, particularly in S. agalactiae and S. dysgalactiae.

Non-purulent skin and soft tissue infections: predictive power of a severity score and the appropriateness of treatment in a prospective cohort.

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.

Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections.

Analyses of plasma collected pre- and postadministration of intravenous immunoglobulin (IVIG) from patients with group A Streptococcus necrotizing soft tissue infections demonstrated a negative correlation between IVIG dose and toxin-triggered T-cell proliferation (r = -.67, P < .0001). One 25-g IVIG dose was sufficient to yield plasma-neutralizing activity against streptococcal superantigens. Clinical Trials Registration. NCT01790698 and NCT02111161.

Exploring the arthritogenicity of Streptococcus dysgalactiae subspecies equisimilis.

BACKGROUND: During the past decades, Streptococcus dysgalactiae subspecies equisimilis (SDSE) has been increasingly recognized as an important human pathogen. Osteoarticular infections is one of the predominant disease manifestations of SDSE, but the pathogenetic rationale for its arthritogenicity has yet to be unravelled. We aimed to explore if the rising incidence of osteoarticular infections caused by this pathogen in our region emanated from clonal expansion of strains with enhanced tropism for bone and joint tissue components or orthopaedic implants. RESULTS: Twenty-nine SDSE-isolates associated with osteoarticular infections were retrospectively identified. Their genomic content and affinity for fibronectin, collagen and stainless steel were compared to 24 temporally and geographically matched SDSE blood culture isolates obtained from patients without bone or joint infections. Despite a thorough genetic and phenotypic dissection, neither the presence or absence of any single gene, nor the binding abilities of the SDSE isolates, were predictive of clinical entity. SNP analysis revealed a heterogenous population, and a correlation between phylogenetic relationships and disease manifestation was not evident. However, we identified a strong concordance between phenotypic binding abilities and genetic variations in the pilus-region, also denoted as the FCT-region (Fibronectin binding, Collagen binding and T-antigen). This observation could be related to the ample and varied repertoire of putative adhesins residing within this region, including proteins predicted to adhere to fibronectin and collagen, as well as fibrinogen. CONCLUSIONS: SDSE strains associated with osteoarticular infections do not emanate from subpopulation characterized by distinct genetic or phenotypic traits. The genetic architecture of the pilus region was predictive of the adhesive properties of the SDSE-isolates, but its role in tissue tropism needs further investigation. To the best of our knowledge, this is the first comprehensive characterization of the genetic landscape of the SDSE pilus region.

Emergence of a Streptococcus dysgalactiae subspecies equisimilis stG62647-lineage associated with severe clinical manifestations.

Increasing incidence rates of invasive Streptococcus dysgalactiae subspecies equisimilis (SDSE) infections have been reported worldwide, but the evolutionary mechanisms underlying this development remain elusive. Through prospective surveillance of invasive SDSE infections in western Norway, we observed the emergence of a novel and virulent SDSE genotype, stG62647. This emm-type, rarely encountered as a cause of invasive disease during 1999-2012, emerged in 2013 as the predominant SDSE-genotype. The stG62647-infections were associated with an aggressive clinical course, including the occurrence of streptococcal toxic shock syndrome, necrotizing soft-tissue infections and endocarditis. All the invasive stG62647-isolates were subjected to whole genome sequencing, attempting to explore the genetic events underpinning its epidemicity. Although 10% of the genomes was unique for stG62647-genotype, notably 18 out of 19 isolates contained a disrupted streptococcal invasive locus (sil) due to the insertion of a transposase, IS1548, into the silB-gene. We postulate that the virulence of stG6267-isolates could be partly attributable to the abrogation of the attenuating control normally exerted by this regulon, although experimental verification was not performed. To the best of our knowledge, this is the first study employing large scale whole genome sequencing to illuminate the genetic landscape of epidemic lineages in SDSE.

Clinical and molecular characteristics of infective ß-hemolytic streptococcal endocarditis.

Streptococcus pyogenes (S. pyogenes) and Streptococcus dysgalactiae subspecies equisimilis (SDSE) cause considerable morbidity and mortality, and show similarities in disease manifestations and pathogenic mechanisms. Their involvement in infective endocarditis, however, has not been well described. Invasive S. pyogenes and SDSE infections in Health Region Bergen, Norway, in the period 1999-2013 were reviewed, and sixteen cases of endocarditis were identified. The median duration of symptoms was 2.5days, the frequency of embolic events 50%, 38% received valve replacement and the 30-day mortality was 25%. In S. pyogenes, a significant correlation was observed between the repertoire of fibronectin-binding genes, phenotypic binding ability to fibronectin and disease manifestations. Conversely, no associations between phenotypic and genotypic characteristics were detected in SDSE. S. pyogenes and SDSE endocarditis is characterized by rapid and severe clinical manifestations. The pathogenesis is multifactorial, but our results infer a potential role of fibronectin binding in the development of S. pyogenes endocarditis.