Invasive Group A Streptococcus Research Articles

Three sequential outbreaks of Group A Streptococcus over a two-year period at the Canadian Forces Leadership and Recruit School, St. Jean Garrison, Québec.

Since December 2016, the basic military training (BMT) facility for the Canadian Armed Forces (CAF) has experienced repeated outbreaks of Group A Streptococcus (GAS). In 2018, a voluntary mass antibiotic prophylaxis (MAP) program was implemented to interrupt GAS transmission among recruits. The objective of this study was to describe the epidemiology of three GAS outbreaks and a period of increased pharyngitis infections at the CAF BMT facility in Québec over a two-year span, and to detail the prevention and control measures implemented to mitigate the risk to recruit health. Descriptive data were collected on invasive and severe GAS cases along with laboratory data including genotyping of throat swabs from recruits presenting with pharyngitis. A laboratory-based acute respiratory infection surveillance system was used to aid in monitoring and decision-making. Close contacts of recruits were assessed for asymptomatic GAS carriage and MAP adverse events surveillance was conducted. Three distinct GAS outbreaks occurred at the Canadian Forces Leadership and Recruit School totaling eight invasive (iGAS) and 13 severe (sGAS) cases over two years. All iGAS/sGAS cases, apart from one instructor, were among recruits. The predominant strain in all three outbreaks was type emm6.4. A total of 11,293 recruits received MAP (penicillin G benzathine or azithromycin) between March 7, 2018 and November 18, 2019. There were eight reported serious adverse events related to penicillin administration. The CAF BMT facility experienced three GAS outbreaks over the course of two years, and despite the use of enhanced hygiene measures, only MAP has been effective in quelling these outbreaks.

Opportunistic Invasive Infection by Group A Streptococcus During Anti-Interleukin-6 Immunotherapy.

Invasive group A Streptococcus (GAS) in immunocompetent individuals is largely linked to hypervirulent strains. Congenital immunodeficiencies and those acquired from chronic disease or immunosuppressant drugs also increase risk of severe illness. We recovered GAS from the blood of a patient receiving a biologic inhibitor of interleukin 6 (IL-6). Growth of this serotype M4 isolate in human blood or a murine bacteremia model was promoted by interleukin 1 or IL-6 inhibition. Hyperinvasive M1T1 GAS was unaffected by IL-6 in both models. These findings based on a natural experiment introduce IL-6 signaling deficiencies as a risk factor for invasive GAS.

Cross-serotype protection against group A Streptococcal infections induced by immunization with SPy_2191

Group A Streptococcus (GAS) infection causes a range of diseases, but vaccine development is hampered by the high number of serotypes. Here, using reverse vaccinology the authors identify SPy_2191 as a cross-protective vaccine candidate. From 18 initially identified surface proteins, only SPy_2191 is conserved, surface-exposed and inhibits both GAS adhesion and invasion. SPy_2191 immunization in mice generates bactericidal antibodies resulting in opsonophagocytic killing of prevalent and invasive GAS serotypes of different geographical regions, including M1 and M49 (India), M3.1 (Israel), M1 (UK) and M1 (USA). Resident splenocytes show higher interferon-γ and tumor necrosis factor-α secretion upon antigen re-stimulation, suggesting activation of cell-mediated immunity. SPy_2191 immunization significantly reduces streptococcal load in the organs and confers ~76-92% protection upon challenge with invasive GAS serotypes. Further, it significantly suppresses GAS pharyngeal colonization in mice mucosal infection model. Our findings suggest that SPy_2191 can act as a universal vaccine candidate against GAS infections.

Investigating the functional relationship between streptokinase variants from Group A Streptococcus, and associated M-like proteins

Background: Streptokinase (SK) from Group A streptococcus (GAS) activates human plasminogen to generate plasmin, which degrades fibrin clots tofacilitate bacterial dissemination. Sequence variants of SK from diverse GAS strains form distinct evolutionary clusters.Unlike cluster 1 SK, cluster 2 variants have very little activity in solution and depend on co-factors (e.g. fibrin(ogen)).Cluster 2 SK variants also appear to correlate with cell-surface M-like proteins: SK2a with M1 (fibrinogen-binding) and SK2b with PAM (plasminogen-binding). Methods: Plasminogen activation by recombinant SKs (rSK2a, rSK2b) was investigated by chromogenic assay; nickel-coated microtiter plates were used to immobilise recombinant M proteins (rPAM and rM1) via a C–terminal His tag to mimic cell surface plasmin generation. Results: Plasminogen activation by rSK2b is stimulated ∼18-fold by rPAM in solution; when rPAM is immobilised stimulation exceeds 100-fold. Fibrin is the most potent stimulator of rSK2a activity (7-fold increase) compared to fibrinogen (4-fold); when rM1 was included, either in solution or immobilised, there was no further stimulation of rSK2a activity with fibrinogen. Discussion: Stimulation ofSK2b activity by plasminogen bound to immobilised PAM suggests an important role for cell-surface plasmin generation. SK2a activity appears to be independent of M1, targeting fibrin directly. SK variants are commonly associated with distinct disease manifestations with SK2b commonly expressed by invasive skin-tropic strains of GAS and SK2a by nasopharynx-tropic strains. An improved understanding of the molecular mechanism of action by GAS SK variants may help to identify potential novel therapeutic targets for the treatment of invasive GAS diseases.

Immunotherapy targeting the Streptococcus pyogenes M protein or streptolysin O to treat or prevent influenza A superinfection.

Viral infections complicated by a bacterial infection are typically referred to as coinfections or superinfections. Streptococcus pyogenes, the group A streptococcus (GAS), is not the most common bacteria associated with influenza A virus (IAV) superinfections but did cause significant mortality during the 2009 influenza pandemic even though all isolates are susceptible to penicillin. One approach to improve the outcome of these infections is to use passive immunization targeting GAS. To test this idea, we assessed the efficacy of passive immunotherapy using antisera against either the streptococcal M protein or streptolysin O (SLO) in a murine model of IAV-GAS superinfection. Prophylactic treatment of mice with antiserum to either SLO or the M protein decreased morbidity compared to mice treated with non-immune sera; however, neither significantly decreased mortality. Therapeutic use of antisera to SLO decreased morbidity compared to mice treated with non-immune sera but neither antisera significantly reduced mortality. Overall, the results suggest that further development of antibodies targeting the M protein or SLO may be a useful adjunct in the treatment of invasive GAS diseases, including IAV-GAS superinfections, which may be particularly important during influenza pandemics.

Group A streptococcal bacteremias in Southwest Finland 2007\u20132018: epidemiology and role of infectious diseases consultation in antibiotic treatment selection

The incidence of invasive group A streptococcal (GAS) infections has shown a fluctuating but increasing trend in Finland. The impact of infectious diseases specialist consultation (IDSC) on the antimicrobial therapy of GAS bacteremia has not been studied earlier. A retrospective study on adult GAS bacteremia in The Hospital District of Southwest Finland (HDSWF) was conducted from 2007 to 2018. Data on incidence of bacteremic GAS cases were gathered from the National Infectious Disease Register. Clinical data were obtained by reviewing the electronic patient records. The overall incidence of GAS bacteremia in HDSWF was 3.52/100,000, but year-to-year variation was observed with the highest incidence of 7.93/100,000 in 2018. A total of 212 adult GAS bacteremia cases were included. A record of IDSC was found (+) in 117 (55.2%) cases, not found (−) in 71 (33.5%) cases and data were not available in 24 (11.3%) cases. Among IDSC+ cases, 57.3% were on penicillin G treatment whereas in the group IDSC− only 22.5%, respectively (OR = 4.61, 95% CI 2.37–8.97; p < 0.001). The use of clindamycin as adjunctive antibiotic was more common among IDSC+ (54.7%) than IDSC− (21.7%) (OR = 4.51, 95% CI 2.29–8.87; p < 0.001). There was an increasing trend in incidence of GAS bacteremia during the study period. Narrow-spectrum beta-lactam antibiotics were chosen, and adjunctive clindamycin was more commonly used, if IDSC took place. This highlights the importance of availability of IDSC but calls for improved practice among infectious diseases specialists by avoiding combination therapy with clindamycin in non-severe invasive GAS infections.

Lancefield Whole Blood Killing Assay to Evaluate Vaccine Efficacy.

While the Lancefield whole blood killing assay is named after the renowned streptococcal researcher Rebecca Lancefield, the protocol was first described by Todd in 1927 (Br J Exp Pathol 8:1-5, 1927). Initially, the assay was used to identify novel Group A Streptococcal (GAS) serotypes through the supplementation of non-immune human blood (often from infants) with type-specific antisera prepared in rabbits (Lancefield, J Exp Med 106:525-544, 1957; Maxted, Br J Exp Pathol 37:415-422, 1956) and to demonstrate the impressive longevity of type-specific immunity in patients following invasive GAS infection (Lancefield, J Exp Med 110:271-292, 1959). The modern assay is routinely used to screen defined GAS mutants (Wessels, Bronze, Proc Natl Acad Sci U S A 91:12238-12242, 1994; Zinkernagel et al., Cell Host Microbe 4:170-178, 2008) or transposon libraries (Le Breton et al., Infect Immun 81:862-875, 2013) for enhanced susceptibility to opsonophagocytic killing or to screen vaccine antisera (Salehi et al., mSphere 3:e00617-e00618, 2018) or other serological preparations (Reglinski et al., Sci Rep 5:15825, 2015) for anti-streptococcal activity.

Effect of Phosphatase Activity of the Control of Virulence Sensor (CovS) on Clindamycin-Mediated Streptolysin O Production in Group A Streptococcus.

Severe manifestations of group A Streptococcus (GAS) infections are associated with massive tissue destruction and high mortality. Clindamycin (CLI), a bacterial protein synthesis inhibitor, is recommended for treating patients with severe invasive GAS infection. Nonetheless, the subinhibitory concentration of CLI induces the production of GAS virulent exoproteins, such as streptolysin O (SLO) and NADase, which would enhance bacterial virulence and invasiveness. A better understanding of the molecular mechanism of how CLI triggers GAS virulence factor expression will be critical to develop appropriate therapeutic approaches. The present study shows that CLI activates SLO and NADase expressions in the emm1-type CLI-susceptible wild-type strain but not in covS or control of virulence sensor (CovS) phosphatase-inactivated mutants. Supplementation with Mg2+, which is a CovS phosphatase inhibitor, inhibits the CLI-mediated SLO upregulation in a dose-dependent manner in CLI-susceptible and CLI-resistant strains. These results not only reveal that the phosphorylation of response regulator CovR is essential for responding to CLI stimuli, but also suggest that inhibiting the phosphatase activity of CovS could be a potential strategy for the treatment of invasive GAS infection with CLI.

Unexpected relationships between frequency of antimicrobial resistance, disease phenotype and emm type in group A Streptococcus.

Despite universal susceptibility to β-lactams, resistance to second-line antimicrobials (e.g. erythromycin) is increasingly common among group A Streptococcus (GAS). To better understand the frequency of regional GAS antimicrobial resistance, we screened a previously described GAS strain collection from Houston, TX, USA, for resistance to commonly used antimicrobials. A total of 100/929 (10.8 %) showed resistance to at least one antimicrobial. Tetracycline resistance was identified in 52 (5.6 %) GAS strains. The cumulative frequency of erythromycin and clindamycin resistance [macrolide (M) and macrolide-lincosamide-streptogramin (MLS) phenotypes] was greatest among invasive GAS strains (9.9 %) compared to that of strains derived from any other infection type (5.9 %, P=0.045). We identified emm types 11, 75, 77 and 92 as the only emm types with high (e.g. >50 %) within-emm type resistance and contributing to the majority (24/26; 92 %) of erythromycin/clindamycin resistance in invasive GAS. High-frequency resistance emm types were also significantly overrepresented in invasive GAS strains as indicated by invasive index. We performed whole-genome sequencing to define genetic elements associated with resistance among emm types 11, 75, 77 and 92. Diverse mobile elements contributed to GAS resistance including transposons, integrative conjugative elements, prophage and a plasmid. Phylogenetic analysis suggests recent clonal emergence of emm92 GAS strains. Our findings indicate that less frequently encountered GAS emm types disproportionately contribute to resistance phenotypes, are defined by diverse mobile genetic elements and may favour invasive disease.

453. High Burden of Invasive and Severe Group A Streptococcus Disease Among Native Americans on the White Mountain Apache Tribal Lands

BackgroundNative Americans are overrepresented in outbreaks of Group A Streptococcus (GAS) in the United States (US). In 2016, several invasive cases of GAS were detected at the Whiteriver Indian Health Service (IHS) Hospital in Arizona that primarily serves the White Mountain Apache (WMA) Tribe. The objective of this study was to determine the burden of invasive and severe GAS disease among Native Americans on the WMA Tribal lands.MethodsProspective population and laboratory-based surveillance for invasive and severe GASinfections was conducted for two years from March 2017 through February 2019. A case was defined as a Native American individual living on or around WMA Tribal lands with GAS isolated from a normally sterile body site (invasive) or from a non-sterile site (e.g., wound, throat, ear) requiring hospitalization (severe). Incidence rates were calculated using the IHS User Population as the denominators. Age-standardized incidence rates were calculated using US Census data from 2015 as the reference group.Results157 cases were identified (Year 1: 85; Year 2: 72), including 42 (27%) invasive and 115 (73%) severe cases. Most cases were adults (88.5%; median age: 40.5 years) and had ≥1 underlying medical condition (99.4%), including alcoholism (57.1%), hypertension (37.2%), and diabetes (34.0%). 47.8% of cases had a trigger in the past two weeks, including penetrating trauma (31.8%) and blunt force trauma (14.0%). For 72.9% of cases, a co-infection was detected (most commonly Staphylocccus aureus: 96.8%). 4.5% of cases required amputation and 1.9% died within 30 days of initial culture. The incidence of invasive and severe GAS was 460.9 per 100,000 persons (95% confidence interval: 394.3, 538.8), with no significant difference by year. The incidence was highest among adults ≥65 and lowest among children 5–17 years of age. Age-standardized incidence rates of invasive and severe GAS and invasive only GAS are presented in the Figure.ConclusionThe WMA community has experienced disproportionately high rates of invasive and severe GAS for over two years. Studies to determine the reservoirs for transmission are urgently needed, as are interventions to reduce the morbidity and mortality associated with these infections. Disclosures All authors: No reported disclosures.

1625. Risk of Invasive Group A Streptococcus, Group B Streptococcus, and Streptococcus pneumoniae Infection Among Adults Experiencing Homelessness—Anchorage, Alaska, 2002–2015

BackgroundPeople experiencing homelessness (PEH) have an increased risk of infectious disease. However, for many infections, this increased risk has not been clearly quantified. For example, the risk of invasive streptococcal infection has not been established among PEH in the United States.MethodsWe compared the incidence of detected cases of invasive group A Streptococcus (GAS) infection, group B Streptococcus (GBS) infection, and Streptococcus pneumoniae (pneumococcal) infection among adult PEH to that in the general adult population in Anchorage, Alaska from 2005 through 2015 using data from the CDC Arctic Investigations Program surveillance system, the US census, and the Anchorage Point in Time count (PIT [a yearly census of PEH]).ResultsDuring 2005–2015, the PIT counted a mean number of 970 adults (minimum 795, maximum 1486) in Anchorage who were homeless, which accounted for 0.4% of the total population. Compared with the general population, PEH were 53 times as likely to have invasive GAS infection (95% CI 47–61), 7 times as likely to have invasive GBS infection (95% CI 6, 8), and 36 times as likely to have invasive pneumococcal infection (95% CI 33, 40). Of all invasive GAS cases in Anchorage over the time period, 19% occurred within the homeless population, while 3% of invasive GBS cases and 14% of invasive pneumococcal cases were within the homeless population. Additionally, the predominant subtypes of GAS and pneumococcus differed among PEH compared with the general population.ConclusionA disproportionate burden of invasive streptococcal disease in Anchorage was detected among PEH, indicating a need for further focus on this high-risk group.Disclosures All authors: No reported disclosures.

473. Impact of Adjunctive Clindamycin in Invasive β-Hemolytic Streptococcal Infections: A Propensity Score-matched Analysis of 1956 β-lactam Treated Patients from 118 US Hospitals

BackgroundClindamycin suppresses invasive β-hemolytic streptococcal (iBHS) toxin production and its cidality, unlike β-lactams, is independent of bacterial inoculum. Evidence favoring the use of adjunctive clindamycin in iBHS is predominantly from in vitro and animal studies. Clinical studies, limited to single-center series or active surveillance, have yielded mixed results. Furthermore, its role in infections caused by non–group A or B β-hemolytic streptococci (NABS) remains poorly defined. Previously we were unable to demonstrate a clindamycin survival benefit in patients with group A streptococci (GAS) bacteremia. Here we examined the impact of adjunctive clindamycin on survival among patients with either invasive GAS or NABS infections from all sites.MethodsClinical characteristics, in vitro susceptibility and antibiotic therapy were examined for unique inpatient encounters with iBHS (GAS + NABS) infections in the Cerner HealthfactsTM Database. β-Lactam treated cases receiving clindamycin were matched 1:1 to non-clindamycin cases by propensity of receiving clindamycin using nearest neighbor propensity score matching with downstream adjustment using logistic regression. In-hospital mortality, length of stay (LOS) and Sequential Organ Failure (SOFA) score trajectory was compared based on the matched sample.ResultsOf 1,956 inpatients with iBHS infection treated with β-lactams at 118 hospitals between 2000 and 2015, 459 (23.5%) received adjunctive clindamycin. Propensity score matching generated 389 case-pairs with good covariate balance (Table 1, Figure 1). In-hospital mortality did not differ between matched clindamycin and non-clindamycin cases (7.2% vs. 8.0%, P = 0.66, aOR 0.88, [95% CI .49–1.57]) (Figure 2). Receipt of clindamycin early (within 24h vs. no clindamycin) also did not display a survival advantage (aOR 1.04 [0.51–2.14]). On day 4 of therapy Median SOFA score (P = 0.586) and SOFA delta (day 0–day 4) were similar between the two groups (P = 0.13; Figure 3). Amongst survivors, median [IQR] LOS was greater in the clindamycin group (8[5,12] vs. 6[4,9]; P = 0.001)ConclusionAdjunctive clindamycin was not associated with decreased mortality or degree of organ dysfunction among patients with iBHS infection already treated with β-lactams. Figure 2: Odds Ratio of In-Hospital Mortality Abbreviations: GAS: Group A Streptococcus , ICU: intensive care unit, iβHS: invasive β-Hemolytic streptococcus, NABS: Non group A β-Hemolytic streptococci , OR: odds ratioFigure 2 Legend: The figure reports the odds ratios (ORs) of in-hospital mortality and 95% confidence intervals in the unmatched and unadjusted analysis, matched and unadjusted analysis, and primary analysis of all propensity-matched pairs with downstream adjustment with logistic regression for proven ißHS, vasopressor use and ICU (within 24h of culture sampling), as well as sensitivity analyses on propensity matched pairs of 2:1 match and subgroup analysis on propensity matched pairs of (1) proven ißHS alone (2) probable ißHS alone (3) ICU admission (within 24h of culture sampling) (4) patients receiving vasopressor therapy (within 24h of culture sampling) (5) Group A ißHS alone (6) Non Group A ißHS alone. There was no statistically significant difference in the ORs for in-hospital mortality between clindamycin and propensity-matched non-clindamycin cases in the primary analysis (*) as well as all sensitivity and subgroup (†) analyses.Figure 3: SOFA Score Trajectory by Survival Status Abbreviations: B: Non-Clindamycin cases, BC: Clindamycin CasesFigure 3 Legend: SOFA score by day of therapy of clindamycin and non-clindamycin matched cases based on survival status from day zero (day prior to antibiotic therapy) to day four of therapy. The linear mixed models were used to assess the time trends and the clindamycin effect on the longitudinal SOFA scores. SOFA trajectory was examined for the post matching sample. Square root transformation was applied to the SOFA score to meet the normality assumption Mean Baseline SOFA scores prior to therapy were similar amongst clindamycin and non-clindamycin subjects (mean [standard deviation(SD)] SOFA score: 1.88[2.48] vs. 1.96[2.60]; p= 0.634). On day 4 of therapy SOFA scores were similar between remaining 310 clindamycin and 286 non-clindamycin hospitalized patients (mean[SD] SOFA score: 1.79[2.88] vs. 1.67 [2.49]; p=0.586). The SOFA delta (day 0 SOFA score - day 4 SOFA score) was similar between the two groups (p=0.1331). When examined amongst survivors only, SOFA scores on day 4 of therapy were similar between and 272 non-clindamycin and 310 clindamycin hospitalized patients (mean[SD] SOFA score: 1.45 [2.20] vs. 1.52 [2.44])This work was funded in part by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases.The opinions expressed in this abstract are those of the authors and do not represent any position or policy of the National Institutes of Health, the United States Department of Health and Human Services, or the United States government.Disclosures All authors: No reported disclosures.

A report on the first outbreak of emm89 group A streptococcus invasive infections in a burns unit in Tunisia.

Four group A streptococcus (GAS) bacteraemia occurred in a small burn unit within 2 weeks. The GAS patient isolates, characterized as emm89, shared the same PFGE pulsotype with two other strains isolated 2 months later. The outbreak investigation revealed that a nurse was the most likely source of GAS transmission, as she was confirmed to carry the same outbreak strain in her throat and had direct and regular contact with the six outbreak patients in the unit. The outbreak was controlled after the nurse had undergone eradication treatment. This report highlights the emergence of the emm89 clone and its capacity to elicit invasive GAS outbreaks.

The Secreted Virulence Factor NADase of Group A Streptococcus Inhibits P2X7 Receptor-Mediated Release of IL-1β.

The common human pathogen Group A Streptococcus (GAS) causes superficial as well as invasive, life-threatening diseases. An increase in the occurrence of invasive GAS infection by strains of the M1 and M89 serotypes has been correlated with increased expression of the genetically and functionally linked virulence factors streptolysin O (SLO) and β-NAD+-glycohydrolase (NADase). NADase affects host cells differently depending on its location: its SLO-dependent translocation into the cytosol can lead to cell death through β-NAD+ depletion, while extracellularly located NADase inhibits IL-1β release downstream of Nlrp3 inflammasome activation. In this study, we use a macrophage infection model to investigate the NADase-dependent inhibition of IL-1β release. We show that bacteria expressing a functional NADase evade P2X7 activation, while infection with a NADase-deficient GAS strain leads to a P2X7-mediated increase in IL-1β. Further, our data indicate that in the absence of NADase, IL-1β is released through both P2X7-dependent and -independent pathways, although the precise mechanisms of how this occur are still unclear. This study adds information about the mechanism by which NADase regulates inflammasome-dependent IL-1β release, which may in part explain why increased NADase expression correlates with bacterial virulence.

Decoding the molecular epidemiology of group A streptococcus - an Indian perspective.

Unlike western countries the knowledge of group A streptococcus (GAS) epidemiology in India remains patchy and incomplete. Typing is crucial for surveillance as well as in predicting the efficacy of multivalent M protein vaccine. The present study aimed to explore the emm types of 206 invasive and non-invasive GAS isolates from South India as well as reviewing all the published literature on GAS molecular epidemiology from India thereby generating a pan-Indian data to predict the conjectural coverage of the 30-valent M-protein vaccine in this population. emm typing and superantigen (SAg) profiling of GAS along with reviewing literatures on GAS molecular epidemiology from India. This study revealed a high diversity of emm types with emm 63, 82, 183, 85, 92, 169, 42, 44, 106, 74, 12 being frequently encountered, belonging to twenty emm clusters. The pan-Indian data on prevalent emm types further supports our study findings with 135 emm different types. Six clusters dominated accounting for 80 % of the GAS isolates: E3(26 %), E6(20 %), E2(11 %), E4(10 %), D4(7 %), E1(6 %). No significant association was noted between emm types and the nature of infection (P≥0.05) while a few SAg profiles were significantly associated with certain emm types. Pan Indian data revealed that only 16 % of the emm types encountered were included in proposed 30-valent M protein based vaccine. The coverage among the South Indian GAS isolates was 28.2 % which increased to only 46.6 % with the cross-opsonic effect, thus highlighting the importance of developing a specific multivalent vaccine including the prevalent emm types in India or considering the use of conserved C-repeat vaccines and non-M protein based vaccines.

Remarkable Genome Stability among emm1 Group A Streptococcus in Belgium over 19 Years.

During the last two decades, there has been a public health concern of severe invasive infections caused by Group A Streptococcus (GAS) of the emm1 genotype. This study investigated the dynamics of emm1 GAS during 1994–2013 in Belgium. emm1 GAS isolated from blood, tissue, and wounds of patients with invasive infections (n = 23, S1–S23), and from patients with uncomplicated pharyngitis (n = 15, NS1–NS15) were subjected to whole-genome mapping (WGM; kpn) (Opgen). Whole-genome sequencing was performed on 25 strains (WGS; S1–S23 and NS6–NS7) (Illumina Inc.). Belgian GAS belonged to the M1T1 clone typified by the 36-kb chromosomal region encoding extracellular toxins, NAD+-glycohydrolase and streptolysin O. Strains from 1994–1999 clustered together with published strains (MGAS5005 and M1476). From 2001 onward, invasive GAS showed higher genomic divergence in the accessory genome and harbored on average 7% prophage content. Low evolutionary rate (2.49E-008; P > 0.05) was observed in this study, indicating a highly stable genome. The studied invasive and pharyngitis isolates were no genetically distinct populations based on the WGM and core genome phylogeny analyses. Two copies of the speJ superantigen were present in the 1999 and 2010 study strains (n = 3), one being chromosomal and one being truncated and associated with phage remnants.This study showed that emm1 GAS in Belgium, compared with Canada and UK M1 strains, were highly conserved by harboring a remarkable genome stability over a 19-year period with variations observed in the accessory genome.

Sequential Sensing by TLR2 and Mincle Directs Immature Myeloid Cells to Protect against Invasive Group A Streptococcal Infection in Mice

Severe invasive group A Streptococcus (GAS) infection evades anti-bacterial immunity by attenuating the cellular components of innate immune responses. However, this loss of protection is compensated for by interferon (IFN)-γ-producing immature myeloid cells (γIMCs), which are selectively recruited upon severe invasive GAS infection in mice. Here, we demonstrate that γIMCs provide this IFN-γ-mediated protection by sequentially sensing GAS through two distinct pattern recognition receptors. Ina mouse model, GAS is initially recognized by Toll-like receptor 2 (TLR2), which promptly induces interleukin (IL)-6 production in γIMCs. γIMC-derived IL-6 promotes the upregulation of a recently identified GAS-sensing receptor, macrophage-inducible C-type lectin (Mincle), in an autocrine or paracrine manner. Notably, blockade of γIMC-derived IL-6 abrogates Mincle expression, downstream IFN-γ production, and γIMC-mediated protection against severe invasive GAS infection. Thus, γIMCs regulate host protective immunity against severe invasive GAS infection via a TLR2-IL-6-Mincle axis.

Pathogenesis of Hypervirulent Group A Streptococcus.

Group A Streptococcus (GAS) causes common pharyngitis and skin infections and occasional severe invasive infections. This review describes the recent progress on the pathogenesis of hypervirulent GAS. CovRS mutations are frequent among invasive GAS isolates and lead to hypervirulence. GAS CovRS mutants can be selected in vivo by neutrophils. The role of protease SpeB in source-sink dynamics of wild-type GAS and hypervirulent variants is discussed. Streptolysin S and PAF acetylhydrolase Sse critically and synergistically contribute to the inhibition of neutrophil recruitment by GAS CovS mutants. CovS mutations in emm3 GAS lead to the vascular invasion and enhance systemic GAS dissemination.

Characteristics of Intracranial Group A Streptococcal Infections in US Children, 1997-2014.

Few data on intracranial group A Streptococcus (GAS) infection in children are available. Here, we describe the demographic, clinical, and diagnostic characteristics of 91 children with intracranial GAS infection. Cases of intracranial GAS infection in persons ≤18 years of age reported between 1997 and 2014 were identified by the Centers for Disease Control and Prevention's population- and laboratory-based Active Bacterial Core surveillance (ABCs) system. Medical charts were abstracted using a active, standardized case report form. All available isolates were emm typed. US census data were used to calculate rates. ABCs identified 2596 children with invasive GAS infection over an 18-year period; 91 (3.5%) had an intracranial infection. Intracranial infections were most frequent during the winter months and among children aged <1 year. The average annual incidence was 0.07 cases per 100000 children. For 83 patients for whom information for further classification was available, the principal clinical presentations included meningitis (35 [42%]), intracranial infection after otitis media, mastoiditis, or sinusitis (34 [41%]), and ventriculoperitoneal shunt infection (14 [17%]). Seven (8%) of these infections progressed to streptococcal toxic shock syndrome. The overall case fatality rate was 15%. GAS emm types 1 (31% of available isolates) and 12 (13% of available isolates) were most common. Pediatric intracranial (GAS) infections are uncommon but often severe. Risk factors for intracranial GAS infection include the presence of a ventriculoperitoneal shunt and contiguous infections in the middle ear or sinuses.

STREPTOCOCCUS PYOGENES: A DEVASTATING CAUSE OF MENINGITIS IN A YOUNG ADULT

SESSION TITLE: Critical Care 1 SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Streptococcus pyogenes is a rare but aggressive cause of bacterial meningitis. CASE PRESENTATION: A 27-year-old healthy gentleman presented to the emergency department with a 3 day history of headache. His symptoms began with an upper respiratory infection and fever which had resolved. Vital signs were normal, but he appeared in mild distress. His neurologic exam was non-focal without nuchal rigidity. There was tenderness to palpation over the right maxillary sinus. A CT head showed paranasal mucosal thickening and air-fluid levels in the right maxillary sinus. He was treated with intravenous fluids, acetaminophen, and promethazine with improvement in his headache. He was discharged home with a diagnosis of sinusitis. Within 24 hours, he returned to the emergency room after he developed confusion and suddenly collapsed. On presentation, he was hypotensive and febrile. His mental status was obtunded. Laboratory studies were notable for a leukocytosis with 55% bands, lactic acidosis, and acute renal failure. A lumbar puncture was performed with an opening pressure of 57 cm of water and had 11,000 white blood cells with 98% neutrophils. He was given dexamethasone, vancomycin, and ceftriaxone. Gram stain of the cerebral spinal fluid revealed gram positive cocci in chains and later grew Streptococcus pyogenes. A repeat CT head showed progression of sinusitis and effacement of the sulci concerning for cerebral edema. In the intensive care unit, he had multiple episodes of cardiac arrest, septic shock requiring vasopressors, and acute respiratory distress syndrome with refractory hypoxemia. On exam, brainstem reflexes were absent and he passed away 34 hours after admission. DISCUSSION: Streptococcus pyogenes, or Group A Streptococcus (GAS), is a rare cause of bacterial meningitis in the United States. In 1985, the incidence of bacterial meningitis due to GAS was 0.2% (1). A review of the literature showed a prospective study in the Netherlands where GAS was the cause of 2% of cases of bacterial meningitis. Of the patients with GAS meningitis, 92% initially presented with otitis media or sinusitis, 52% of patients developed neurologic sequelae, and 19% of the patients died. The most common neurologic complications were subdural empyema and hearing loss, while the most common systemic complications were respiratory failure and septic shock (2). Of note, this patient had preceding upper respiratory symptoms and presented during influenza season. There are reports of increased invasive GAS co-infection with influenza in healthy patients, some of which resulted in death (3). CONCLUSIONS: Although GAS is a rare cause of meningitis, this invasive organism may present with benign features of otitis media or sinusitis, and develop aggressively to meningitis associated with high rates of morbidity and mortality. It is important to consider GAS infection especially during influenza season. Reference #1: Schleck, W. et al. “Bacterial Meningitis in the United States, 1978-1981.” JAMA. 1985; 253(12): 1749-1754. Reference #2: Marjolein, L. et al. “Group A Streptococcal meningitis in adults.” Journal of Infection. 2015; 71(1): 37-72. Reference #3: Jean, C. et al. “Invasive Group A Streptococcal Infection Concurrent with 2009 H1N1 Influenza.” Clinical Infectious Disease. 2010; 50(10): e59-e62. DISCLOSURES: No relevant relationships by Chloe Castro, source=Web Response No relevant relationships by Edward Warren, source=Web Response