Characterization of infecting strains and superantigen-neutralizing antibodies in Staphylococcus aureus bacteremia

Staphylococcus aureus superantigens (SAgs) are highly potent T cell mitogens. Antibodies against non-enterotoxin gene cluster (non-egc) SAgs are common in healthy adults, whereas neutralizing antibodies against egc SAgs are rare. We investigated the infecting S. aureus strains and the anti-SAg antibody response during S. aureus bacteremia (SAB). This prospective clinical study (www.clinicaltrials.gov, NCT00548002) included 43 injection drug users (IDUs) and 44 group-matched nonaddicts with SAB. spa genotypes and SAg gene patterns (multiplex PCR) of the S. aureus isolates were determined. The neutralizing capacities of sera obtained at the acute phase and the convalescent phase of SAB were tested against the SAg cocktail of the respective infecting strain and a panel of recombinant SAgs. The lineages CC59 and CC30 were more prevalent among bacteremia strains from IDUs than among strains from nonaddicts. SAg gene patterns in isolates from IDUs and nonaddicts were similar. At the acute phase of bacteremia, IDUs had more neutralizing antibodies against non-egc SAgs than did nonaddicts. Antibody titers frequently increased during infection. In contrast, there were no neutralizing antibodies against egc SAgs at disease onset and such antibodies were not induced by SAB. SAB triggers an antibody response only against non-egc SAgs. Preimmunization in IDU patients is probably due to previous exposure to the infecting strain.     

Staphylococcal superantigens: do they play a role in sepsis?

In Staphylococcus aureus, 19 different superantigens (SAgs) have been described. Their genes are all located on mobile genetic elements, such as pathogenicity islands, plasmids, and phages. SAgs bypass conventional antigen recognition by directly cross-linking major histocompatibility complex class II (MHCII) molecules on antigen-presenting cells with T cell receptors. This leads to massive T cell proliferation and cytokine release, which may end in toxic shock syndrome. The role of SAgs in other forms of sepsis is less well defined. In animal models, SAgs and lipopolysaccharide (LPS) very efficiently synergize in the induction of lethal shock, and on the basis of these observations a two-hit model of sepsis has been proposed: LPS or another monocyte stimulus hits first, then SAg or another T cell stimulus hits. In clinical studies, however, evidence for an involvement of SAgs in sepsis has been difficult to obtain. This may have a number of reasons: differences between humans and rodents in their response to LPS and SAg, heterogeneity of SAg combinations in S.aureus clinical isolates, lack of tools to analyze SAg effects in patients, blocking anti-SAg serum antibodies, and MHCII polymorphisms.     

Changes in Murine Jejunal Morphology Evoked by the Bacterial Superantigen Staphylococcus aureus Enterotoxin B Are Mediated by CD4+ T Cells

Bacterial superantigens (SAgs) are potent T-cell stimuli that have been implicated in the pathophysiology of autoimmune and inflammatory disease. We used Staphylococcus aureus enterotoxin B (SEB) as a model SAg to assess the effects of SAg exposure on gut form and cellularity. BALB/c, SCID (lacking T cells) and T-cell-reconstituted SCID mice were treated with SEB (5 or 100 μg intraperitoneally), and segments of the mid-jejunum were removed 4, 12, or 48 h later and processed for histochemical or immunocytochemical analysis of gut morphology and major histocompatibility complex class II (MHC II) expression and the enumeration of CD3⁺ T cells and goblet cells. Control mice received saline only. SEB treatment of BALB/c mice caused a time- and dose-dependent enteropathy that was characterized by reduced villus height, increased crypt depth, and a significant increase in MHC II expression. An increase in the number of CD3⁺ T cells was observed 48 h after exposure to 100 μg of SEB. Enteric structural alterations were not apparent in SEB-treated SCID mice compared to saline-treated SCID mice. In contrast, SEB challenge of SCID mice reconstituted with a mixed lymphocyte population or purified murine CD4⁺ T cells resulted in enteric histopathological changes reminiscent of those observed in SEB-treated BALB/c mice. These findings implicate CD4⁺ T cells in this SEB-induced enteropathy. Our results show that SAg immune activation causes significant changes in jejunal villus-crypt architecture and cellularity that are likely to impact on normal physiological processes. We speculate that the elevated MHC II expression and increased number of T cells could allow for enhanced immune responsiveness to other SAgs or environmental antigens.Evidence from clinical observations, animal models of disease, and studies with cell lines indicate an intimate association between bacteria (and bacterial products) and the pathophysiology of enteric inflammatory and secretory disorders (28, 30). Moreover, significant tissue damage and abnormal physiology can be attributed to aberrant immune reactions, where T cells have been identified as a key cell type (5). A novel group of bacterial products have been identified that cross-link major histocompatibility complex class II (MHC II) molecules with a variable portion of the β chain (Vβ) of the T-cell receptor, binding beyond the antigen-specific site. These molecules do not require classical antigen-processing and presentation and can polyclonally stimulate up to 25% of T cells based on Vβ specificity, hence their designation as superantigens (SAgs) (8, 14). Skewed expression of T-cell receptor Vβ usage has been used to implicate SAgs in the pathogenesis of autoimmune and inflammatory disorders such as rheumatoid arthritis and diabetes (7, 27). More recently it has been postulated that SAgs could be involved in the initiation or exaggeration of inflammatory bowel disease in some patients (13, 29).Delineation of the physiological and pathophysiological effects, and mechanisms thereof, of exposure to SAgs has lagged behind the elucidation of the immunomodulatory properties of bacterial SAgs. The enterotoxins of the gram-positive Staphylococcus aureus are prototypic SAgs, and S. aureus enterotoxin B (SEB) has been used extensively as a model SAg to define the effects of these bacterial products on immune cells (14). Many elegant studies have shown that the murine immune response to SAgs is biphasic: an initial activation phase characterized by T-cell proliferation, cytokine production, and enhanced cytotoxic activity (10, 17, 25) is followed by a period of anergy and/or depletion of the appropriate Vβ-expressing T cells (32, 34). In beginning to define the enteric physiological consequences of exposure to bacterial SAgs, the objective of the present study was to assess the impact of SEB treatment on jejunal structure and cellularity in immunocompetent (BALB/c) and T-cell-deficient (severe combined immunodeficient [SCID]) mice. Our data demonstrate that SEB treatment of normal but not T-cell-deficient mice evokes a self-limiting enteropathy that is characterized by altered villus-crypt architecture, various degrees of histopathology, increased MHC II expression, and an increase in CD3⁺ T cells. We suggest that these changes will disrupt normal enteric physiological and homeostatic processes and have the potential to predispose the host to enhanced immune responsiveness to other antigens that gain access to the mucosa and/or submucosa.     

Relationship between pathogenic,clinical, and virulence factors of <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> in infective endocarditis versus uncomplicated bacteremia: a case–control study

Pathogenic factors of Staphylococcus aureus (SA) in the development of infective endocarditis (IE) have not been sufficiently investigated. The purpose of this study was to analyze the pathogenesis and virulence factors of SA in patients with IE as compared to patients with uncomplicated bacteremia (un-BAC). This is a retrospective case–control study (2002–2014) performed at a tertiary hospital in Spain. Clinical and epidemiological factors were analyzed. We assessed the presence of toxin genes [toxic shock syndrome toxin 1 (tst-1) and enterotoxins A (etA), B (etB), and D (etD)] and the potential relationship between accessory gene regulator (agr) groups and the development of IE confirmed by polymerase chain reaction (PCR). Twenty-nine patients with IE were compared with 58 patients with uncomplicated S. aureus bacteremia (SAB). As many as 75.9 % of patients had community-acquired IE (p?<?0.005). Multivariate analysis revealed that there is a significant relationship between community-acquired infection and severe sepsis or septic shock and IE. Also, a minimum inhibitory concentration (MIC) of vancomycin?≥1.5 μg/ml was found to be associated with IE. The agr group I was prevalent (55.2 % vs. 31.0 %; p?=?0.030). No association was observed between toxin genes (tst-1, etA, etB, and etD) and IE. The superantigen (SAg) most frequently found in SA isolates was tst-1 (12.6 %). We found no association between toxin genes and IE, probably due to the small sample size. However, a direct relationship was found between agr I and the development of IE, which suggests that agr I strains may have more potential to cause IE.     

A quantitative real time PCR method to analyze T cell receptor Vβ subgroup expansion by staphylococcal superantigens

Background  

Staphylococcal enterotoxins (SEs), SE-like (SEl) toxins, and toxic shock syndrome toxin-1 (TSST-1), produced by Staphylococcus aureus, belong to the subgroup of microbial superantigens (SAgs). SAgs induce clonal proliferation of T cells bearing specific variable regions of the T cell receptor β chain (Vβ). Quantitative real time PCR (qRT-PCR) has become widely accepted for rapid and reproducible mRNA quantification. Although the quantification of Vβ subgroups using qRT-PCR has been reported, qRT-PCR using both primers annealing to selected Vβ nucleotide sequences and SYBR Green I reporter has not been applied to assess Vβ-dependent expansion of T cells by SAgs.     

Similar superantigen gene profiles and superantigen activity in norwegian isolates of invasive and non-invasive group a streptococci

Group A streptococcus (GAS) harbours several virulence factors, including M protein (coded by the emm gene) and superantigens (SAgs). SAgs are extracellular toxins that directly activate the immune system by cross-binding to the HLA class II molecule and T cell receptor (TCR), thereby causing activation of up to 30% of the T cells and subsequent massive secretion of cytokines. Forty-eight GAS strains isolated from patients at Norwegian hospitals between 1988 and 2004 were included in this study. Of these, 24 were invasive streptococcal toxic shock syndrome (STSS) or necrotizing fasciitis (NF) isolates and 24 were non-invasive pharyngitis isolates, matched for having the same T-type and year of isolation as the invasive isolates. The isolates were characterized by emm sequence typing, multilocus sequence typing (MLST) and SAg gene profiles. A correlation between T-type, emm type, sequence type and SAg gene profile was revealed. No difference between invasive and non-invasive isolates regarding serotype or genotype was demonstrated. Selected invasive and non-invasive isolates with identical SAg gene profiles were analysed for SAg activity in bacterial growth culture media with and without human cell culture media added. A human T cell proliferation assay was used as measurement for SAg activity and simultaneously we also measured the cytokine content in normal human peripheral blood leucocyte cell culture media. The results revealed that invasive and non-invasive isolates did not differ significantly in SAg activity as it is present in semipurified bacterial culture medium.     

Superantigens Subvert the Neutrophil Response To Promote Abscess Formation and Enhance Staphylococcus aureus Survival In Vivo

Staphylococcus aureus is a versatile bacterial pathogen that produces T cell-activating toxins known as superantigens (SAgs). Although excessive immune activation by SAgs can induce a dysregulated cytokine storm as a component of what is known as toxic shock syndrome (TSS), the contribution of SAgs to the staphylococcal infection process is not well defined. Here, we evaluated the role of the bacterial superantigen staphylococcal enterotoxin A (SEA) in a bacteremia model using humanized transgenic mice expressing SAg-responsive HLA-DR4 molecules. Infection with S. aureus Newman induced SEA-dependent Vβ skewing of T cells and enhanced bacterial survival in the liver compared with infection by sea knockout strain. SEA-induced gamma interferon, interleukin-12, and chemokine responses resulted in increased infiltration of CD11b⁺ Ly6G⁺ neutrophils into the liver, promoting the formation of abscesses that contained large numbers of viable staphylococci. Hepatic abscesses occurred significantly more frequently in S. aureus Newman-infected livers than in livers infected with the Newman sea knockout strain, promoting the survival of S. aureus in vivo. This represents a novel mechanism during infection whereby S. aureus utilizes SAgs to form a specialized niche and manipulate the immune system.     

Superantigens augment antigen-specific Th1 responses by inducing IL-12 production in macrophages.

Superantigens (SAg) are microbial proteins that mediate antigen-presenting cell (APC)-T cell interaction by cross-linking MHC class II molecules with subsets of TcRVbeta. SAgs are implicated in the pathogenesis of several infectious, inflammatory, and autoimmune diseases. In this study, we examined the influence of SEB on interleukin-12 (IL-12) production and the activation of antigen-specific Th1 responses. Addition of SEB augmented the antigen-induced proliferation of HS-17, a murine MBPp91-103 peptide-specific TcRVbeta6+ CD4+ Th1 clone. SEB augments HS-17 T cell proliferation through its interaction with IA(S) molecules on macrophages, but not with the TcRVbeta6 on HS-17 cells. On binding to IA(S), SEB induces IL-12 production in macrophages, which in turn augments antigen-induced proliferation of HS-17 T cells. Treatment with anti-IA(S) nmAb 10-3.6 inhibited the antigen- and SEB-induced IL-12 production and T cell proliferation. These results suggest that SAgs augment antigen-specific T cell responses by inducing IL-12 production in macrophages.     

Activation of Bovine Lymphocyte Subpopulations by Staphylococcal Enterotoxin C

Staphylococcus aureus is a major mastitis-causing pathogen in cattle. The chronic nature of bovine staphylococcal mastitis suggests that some products or components of S. aureus may interfere with the development of protective immunity. One class of molecules that could be involved are superantigens (SAgs). Although a significant number of mastitis isolates produce SAgs, the effect of these molecules on the bovine immune system is unresolved. To determine if immunosuppression caused by SAgs could play a role in pathogenesis, we monitored bovine lymphocytes exposed to staphylococcal enterotoxin C1 (SEC1). Activation of bovine lymphocytes by either SEC1 or concanavalin A (ConA) was influenced by the γδ/αβ T-cell ratio in the culture. Compared to ConA-induced stimulation, cultures stimulated with SEC1 generated small numbers of CD4⁺ αβ T cells expressing high levels of interleukin-2 receptor α chain (IL-2Rα) and major histocompatibility complex class II (MHCII), suggesting that SAg exposure does not lead to full activation of these cells. This state of partial activation was most pronounced in cultures with a high γδ/αβ ratio. In contrast, significant numbers of CD8⁺ αβ T cells expressed high levels of IL-2Rα and MHCII, regardless of the γδ/αβ ratio and the stimulant used. CD8⁺ blasts in cultures stimulated with SEC1 also expressed another activation marker, ACT3, previously detected predominantly on thymocytes and CD4⁺ T cells. Although γδ CD2⁻ and CD2⁺ T cells expressed MHCII and IL-2Rα following stimulation with SEC1, only a few cells increased to blast size, suggesting that they were only partially activated. The results suggest ways in which SAgs might facilitate immunosuppression that promotes the persistence of bacteria in cattle and contributes to chronic intramammary infection.Staphylococcus aureus is a prominent pathogen in bovine mastitis (24). This organism is frequently isolated from milk (2, 16, 40) and from cows with intramammary infection (IMI) (17). IMI caused by S. aureus tends to become chronic and may resist antibiotic therapy (49). It has been postulated that persistent infection with S. aureus is associated with an impairment of the immune response, mediated by factors produced by S. aureus (34). Thus far, however, no single factor has been clearly implicated.Bovine isolates of S. aureus frequently produce one or more pyrogenic toxins (PTs), especially types C and D staphylococcal enterotoxins (SEs) and toxic shock syndrome toxin (24). The staphylococcal PTs are prototype microbial superantigens (SAgs), characterized by the ability to bind to major histocompatibility complex class II (MHCII) molecules and to specific Vβ segments of αβ T-cell receptor (TCR) outside the binding groove associated with MHC-restricted immune system recognition of processed peptides. By bypassing antigenic specificity, SAgs stimulate abnormally large numbers of T cells and are able, at nanomolar concentrations, to induce T-cell proliferation (33). Few studies have been performed to investigate the effects of SAgs on the bovine immune system (53); most studies have involved other animals. In several species, SAgs exert wide-ranging and deleterious effects, including induction of shock (4), T-cell unresponsiveness and deletion (23), differential stimulation of CD4⁺ and CD8⁺ T-cell subsets (47), and B-cell differentiation (46). Thus, although largely unconfirmed, there is a clear potential for SEs, and other SAgs, to modulate immune responses and contribute to the virulence and persistence of S. aureus in cattle.The T-cell population consists of cells expressing either the αβ TCR (TCR2) or the γδ TCR (TCR1). While the roles of αβ T cells in immune responses of many species have been well characterized, the function of γδ T cells is less well understood (22). This is especially true in ruminants. Recent investigations have shown that the ruminant γδ T cells comprise two disparate subpopulations, characterized by constitutive expression of cell surface molecules. One subpopulation, similar in composition and tissue distribution to γδ T cells from other species, consists of cells that express CD2, CD5, and CD6 and are positive or negative for CD8 (10). These cells are present in low concentrations (3 to 5%) in peripheral blood and in high concentrations (35 to 40%) in spleen, gut epithelium, and mammary gland secretions (41). The second subpopulation, negative for CD2, CD6, and CD8, is unique and has been identified in only one other member of the Artiodactyla, swine (3, 28). This subpopulation is positive for CD5 and two lineage-restricted molecules, workshop cluster 1 (WC1) (32, 36, 50) and GD3.5 (21). The concentration of WC1⁺ GD3.5⁺ CD2⁻ CD6⁻ γδ T cells is high (30 to 50%) in the peripheral blood in young ruminants, decreasing with age, and is low (3 to 8%) in secondary lymphoid tissues and mammary gland secretions (41, 52). Definitive data on the function of either of these major subpopulations of γδ T cells have not been obtained. However, previous studies have suggested that they may be involved in regulating the proliferative response of CD4⁺ T cells to antigens (7).Park et al. (42) identified a subset of T cells, positive for CD2 and CD8, in mammary gland secretions of cows infected with S. aureus. These cells had the ability to inhibit the proliferative response of bovine CD4⁺ cells to staphylococcal antigens (42). Although the mechanisms by which these cells were induced and mediated their effect were not determined, they clearly have the potential to contribute to the pathogenesis of staphylococcal IMI. Although not all bovine staphylococcal isolates produce known SAgs, it is important to determine whether SAg production could induce these or other immunosuppressive subpopulations in cows and promote the development of some infections such as IMI. The objective of this study was to extend these initial observations. We examined the effect of a representative SAg (SEC1) on the major subpopulations of bovine αβ and γδ T cells.     

Vancomycin minimum inhibitory concentration,host comorbidities and mortality in Staphylococcus aureus bacteraemia

We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30-day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality.     

Interferon-alpha-induced endogenous superantigen. a model linking environment and autoimmunity.

We earlier proposed that a human endogenous retroviral (HERV) superantigen (SAg) IDDMK(1,2)22 may cause type I diabetes by activating autoreactive T cells. Viral infections and induction of interferon-alpha (IFN-alpha) are tightly associated with the onset of autoimmunity. Here we establish a link between viral infections and IFN-alpha-regulated SAg expression of the polymorphic and defective HERV-K18 provirus. HERV-K18 has three alleles, IDDMK(1,2)22 and two full-length envelope genes, that all encode SAgs. Expression of HERV-K18 SAgs is inducible by IFN-alpha and this is sufficient to stimulate V beta 7 T cells to levels comparable to transfectants constitutively expressing HERV-K18 SAgs. Endogenous SAgs induced via IFN-alpha by viral infections is a novel mechanism through which environmental factors may cause disease in genetically susceptible individuals.     

Variable-Number Tandem Repeat Analysis and Multilocus Sequence Typing Data Confirm the Epidemiological Changes Observed with Staphylococcus aureus Strains Isolated from Bloodstream Infections

Since 2000, our geographical region in France systematically surveys bloodstream infections (BSI) due to Staphylococcus aureus. This survey involves 39 health care institutions (HCIs) encompassing 6,888 short-stay beds and was performed during two 3-month periods during 2007 and 2008. The study periods of this survey identified 292 S. aureus isolates causing BSI. Extensive molecular characterization, including genotyping as well as toxin, agr, and staphylococcal cassette chromosome content determinations, allowed us to describe epidemiological evolution in comparison to that discussed in our previous study. Our main epidemiological observation shows that the incidence of BSI remained constant but that methicillin (meticillin)-resistant S. aureus strains with a wider variety of genetic backgrounds now harbor pyl, as has already been reported in different European countries. We noticed stable numbers of BSI episodes involving community-acquired methicillin-sensitive S. aureus (MSSA), whereas a drastic increase in the number of strains harboring the tst gene was recorded. The increase in the number of tst gene-harboring strains is related to known hospital-acquired MSSA isolates and appears related to epidemic episodes in specific HCIs. Monitoring the increase in prevalence of specific strains helps us understand where the standard precautions are not satisfactorily applied or do not efficiently prevent the spread of epidemic MSSA strains in these HCIs. The recent increases in incidence of these strains call for particular vigilance to avoid the spread of potentially virulent MSSA strains harboring the tst gene and for continuance of this strategy of BSI surveillance.Reporting of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) is often mandatory, and reduction of BSI rates is a performance target (2, 15, 16, 19, 22, 23). Since 2000, a prospective, longitudinal survey of BSI has been under way at a regional level in France. Results obtained during the first 7 years of surveillance have been reported (26, 27). After sustained and decreasing incidence rates of S. aureus BSI attributed to successful infection control efforts in participating health care institutions (HCIs), we reported in 2006 a sudden increase in incidence that involved two populations of S. aureus strains: one of methicillin-sensitive S. aureus (MSSA) strains and one of MRSA isolates.First, an increasing incidence of BSI was observed due to MSSA strains, including (i) strains associated with epidemic phenomena in HCIs and (ii) a genetically homogeneous population of tst-positive MSSA isolates, mostly associated with community-acquired (CA) BSI, suggesting clonal spread at a regional level.Second, we observed the emergence of BSI associated with genetically diverse nonmultiresistant staphylococcal cassette chromosome mec type IV (SCCmec IV) MRSA strains (named NORSA) that could not be related to any local outbreak in the participating HCIs.We report here data collected in 2007 and 2008 using exactly the same study design. Again, a large S. aureus population genetic study, including MSSA and MRSA isolates in parallel, was conducted. Strain characterization included antimicrobial susceptibility profiles; luk, tst, eta, and etb gene detection; and SCCmec and pulsed-field gel electrophoresis (PFGE) typing. In addition, and to better understand how populations evolved and interacted, characterization of the S. aureus strains was completed by accessory global regulator (agr) typing and multiple-locus variable-number tandem-repeat analysis (MLVA) and multilocus sequence typing (MLST) analysis.     

Prostaglandin E2 is variably induced by bacterial superantigens in bovine mononuclear cells and has a regulatory role for the T cell proliferative response

Signal transduction in antigen presenting cells via MHC class II molecules induces production of prostaglandin E2 (PGE2) known to possess immunoregulatory potential. Since Staphylococcus aureus superantigens (SAgs) utilize MHC class II molecules as primary ligands, we wanted to know whether PGE2 is induced after in vitro SAg stimulation of bovine blood mononuclear cells (boMNC), and whether this arachidonic acid metabolite modulates the preferential SAg-induced proliferative response of bovine CD8+ T cells. SEB as well as SEA induced maximal amounts of PGE2 on day 2 of culture (1-2.5 x 10(-8) mol/l per 2 x 10(5) boMNC). PGE2 production could be inhibited completely by indomethacin (10(-5) mol/l) causing enhanced proliferation of boCD4+ T cells (174%) as well as of boCD8+ T cells (122%) between day 4 and 6 of the in vitro culture, however, only in a subset of the tested animals. Notably, the striking preference of proliferation of boCD8+ over boCD4+ T cells following SAg stimulation remained largely unchanged after inhibition of endogenous PGE2 synthesis or after addition of exogenous PGE2. Higher concentrations of exogenously added PGE2 (> or = 10(-8) mol/l) inhibited the proliferation reaction, mainly due to an increased death rate of both CD4+ and CD8+ blasts. In contrast, lower PGE2 concentrations between 10(-8)-10(-9) mol/l even slightly enhanced the proliferation of both T cell subsets, depending on the individual cell donor. Summing up: These data show that SAgs, indeed, can induce PGE2 production in boMNC which can enhance or reduce the proliferative response of bovine CD4+ and CD8+ T cells.     

Epidemiology and clinical presentation of community-acquired Staphylococcus aureus bacteraemia in children under 5 years of age admitted to the Manhiça District Hospital,Mozambique, 2001–2019

Staphylococcus aureus bacteraemia (SAB) is one of the most common bloodstream infections globally. Data on the burden and epidemiology of community-acquired SAB in low-income countries are scarce but needed to define preventive and management strategies. Blood samples were collected from children < 5 years of age with fever or severe disease admitted to the Manhiça District Hospital for bacterial isolation, including S. aureus. Between 2001 and 2019, 7.6% (3,197/41,891) of children had bacteraemia, of which 12.3% corresponded to SAB. The overall incidence of SAB was 56.1 episodes/100,000 children-years at risk (CYAR), being highest among neonates (589.8 episodes/100,000 CYAR). SAB declined significantly between 2001 and 2019 (322.1 to 12.5 episodes/100,000 CYAR). In-hospital mortality by SAB was 9.3% (31/332), and significantly associated with infections by multidrug-resistant (MDR) strains (14.7%, 11/75 vs. 6.9%, 14/204 among non-MDR, p = 0.043) and methicillin-resistant S. aureus (33.3%, 5/15 vs. 7.6%, 20/264 among methicillin-susceptible S. aureus, p = 0.006). Despite the declining rates of SAB, this disease remains an important cause of death among children admitted to MDH, possibly in relation to the resistance to the first line of empirical treatment in use in our setting, suggesting an urgent need to review current policy recommendations.

     

Gender affects prognosis of methicillin-resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> bacteremia differently depending on the severity of underlying disease

We aimed to elucidate the potential impact of gender on prognosis of Staphylococcus aureus bacteremia (SAB). We analyzed SAB cases prospectively collected over an 8-year period at 11 hospitals in Korea. SAB-related mortality was pre-defined as a death within 30 days from the onset of SAB without other apparent cause of death. The effect of gender on SAB-related mortality was examined in the entire cohort and in subgroups stratified according to methicillin resistance and Charlson’s comorbidity-weighted index (CCWI) score. Those factors independently associated to SAB-related mortality were explored. Among 1974 eligible cases, SAB-related mortality rates in male and female were 21.2% (259/1224) and 21.9% (164/750), respectively (P?=?0.786). The SAB-related mortality rate was independently higher in male than that in female in CCWI score?≤?3 methicillin-resistant SAB (MRSAB) group (15.9 vs. 6.2%; aOR 3.65, 95% CI 1.46–9.13; P?=?0.006) while the association tended to be inverse when CCWI score rises. Interaction between CCWI score and gender to MRSAB-related mortality was significant in multivariate analysis (aOR 0.85, 95% CI 0.74–0.96; P?=?0.011). There was no significant interaction between gender and CCWI in entire SAB or methicillin-susceptible SAB cohorts. Gender may affect clinical outcomes of MRSAB differently depending on the severity of underlying disease.     

Impact of antimicrobial treatment duration on outcome of Staphylococcus aureus bacteraemia: a cohort study

ObjectivesTo assess the outcome of Staphylococcus aureus bacteraemia (SAB) according to factors associated with necessity for longer treatment in conjunction with the duration of treatment.MethodsWe prospectively collected the data of patients with SAB consecutively during 12 to 39 months from 11 hospitals. If multiple episodes of SAB occurred in one patient, only the first episode was enrolled. Factors associated with necessity for longer treatment were defined as follows: persistent bacteraemia, metastatic infection, prosthesis and endocarditis. If any of the factors were present, then the case was defined as longer antibiotic treatment warranted (LW) group; those without any factors were defined as shorter antibiotic treatment sufficient (SS) group. Poor outcome was defined as a composite of 90-day mortality or 30-day recurrence. Duration of antibiotic administration was classified as <14 or ≥14 days in the SS group and <28 or ≥28 days in the LW group.ResultsAmong 2098 cases, the outcome was analysed in 1866 cases, of which 591 showed poor outcome. The SS group accounted for 964 cases and the LW group for 852. On multivariate analysis, age over 65 years, pneumonia, higher Sequential Organ Failure Assessment (SOFA) score and chronic liver diseases were risk factors for poor outcome. Administration of antibiotics less than the recommendation was associated with poor outcome, but this significance was observed only in the LW group (adjusted odds ratio = 1.68; 95% confidence interval, 1.00–2.83; p 0.05).ConclusionsInappropriately short antibiotic treatment was associated with poor outcome in the LW group. Vigilant evaluation for risk factors to determine the duration of treatment may improve the outcome among patients with SAB.     

Association between treatment duration and mortality or relapse in adult patients with Staphylococcus aureus bacteraemia: a retrospective cohort study

ObjectivesThe aim was to evaluate the effect of duration of therapy (DOT) on mortality and relapse for patients with Staphylococcus aureus bacteraemia (SAB).MethodsWe performed a retrospective single-centre cohort study including adult patients with SAB. We determined the association between DOT (≤14 days versus >14 days) and mortality by adjusted hazard ratios (aHR) and 95% confidence intervals through Cox regression adjusted for immortal-time bias and confounding by indication, stratified by presence of complicated SAB (any of: endocarditis, implant, duration of SAB >2 days, fever >3 days). The primary outcome was 90-day all-cause mortality, and the secondary outcome was 90-day relapse.ResultsBetween January 2010 and December 2015, we included 530 patients, of whom 94 out of 530 (17.7%) had methicillin-resistant SAB and 305 out of 530 (57.6%) had complicated SAB. Ninety-day mortality was 27.0% (143/530), with no significant trend across the study period; median time to death was 17 days (interquartile range (IQR) 8–30) after onset of SAB. Median DOT was 20 days (IQR 13–39). Patients with complicated SAB had significantly reduced mortality with DOT >14 days (aHR 0.32, 95% CI 0.16–0.64). DOT was not associated with mortality in patients with uncomplicated SAB (aHR 0.85; 0.41–1.78). Eighteen (18/530) patients (3.4%) relapsed; on univariate analysis, DOT was not associated with relapse (HR 1.01; 0.97–1.06).ConclusionsDOT >14 days is associated with higher survival in patients with complicated SAB, but not for patients with uncomplicated SAB. No association was found for relapse, but 90-day relapse was very low in this cohort. Importantly, 90-day mortality remained high across the study period.     

A recommendation to perform a blood culture before the administration of intravenous antibiotics increased the detection of Staphylococcus aureus bacteremia

In 2004, the Surviving Sepsis Campaign was launched to increase awareness and improve the outcome of severe sepsis. Accordingly, in Jönköping County, Sweden, a strong recommendation to perform a blood culture before the start of intravenous antibiotic treatment was introduced in 2007. Moreover, a reminder was included in the laboratory report to consult an infectious disease specialist when Staphylococcus aureus was isolated from a blood culture. Retrospectively, patients with at least one blood culture growing S. aureus during 2002 through 2003 (pre intervention n?=?58) or during 2008 through 2009 (post intervention n?=?100) were included. Medical records were evaluated regarding clinical data and outcome. Blood culture isolates were characterized by antibiotic susceptibility testing (AST) and S. aureus protein A (spa) gene typing. The annual incidence of S. aureus bacteremia (SAB) increased from 28 per 100,000 inhabitants at the pre intervention period to 45 per 100,000 at the post intervention period (p?=?0.046). During post intervention, the SAB incidence was significantly higher in men (p?=?0.009). The mortality rate during hospital stay was 14 % during pre intervention and 18 % during post intervention (p?=?0.47). The most common spa types were t012 and t084. The Surviving Sepsis Campaign resulted in an increased number of detected cases of SAB. The mortality rate was the same before and after the intervention, and no spa type correlated to certain clinical manifestations or mortality.