Abstract
Alpha toxin (Hla) is a major virulence factor of Staphylococcus aureus that targets platelets but clinical data on Hla pathogenesis in bacteremia (SAB) is limited. We examined the link between in vitro Hla activity and outcome. Study isolates obtained from 100 patients with SAB (50 survivors; 50 non-survivors) were assessed for in vitro Hla production by Western immunoblotting in a subset of isolates and Hla activity by hemolysis assay in all isolates. Relevant demographics, laboratory and clinical data were extracted from patients’ medical records to correlate Hla activity of the infecting isolates with outcome. Hla production strongly correlated with hemolytic activity (rs = 0.93) in vitro. A trend towards higher hemolytic activity was observed for MRSA compared to MSSA and with high-risk source infection. Significantly higher hemolytic activity was noted for MRSA strains isolated from patients who developed thrombocytopenia (median 52.48 vs. 16.55 HU/mL in normal platelet count, p = 0.012) and from non survivors (median 30.96 vs. 14.87 HU/mL in survivors, p = 0.014) but hemolytic activity of MSSA strains did not differ between patient groups. In vitro Hla activity of MRSA strains obtained from patients with bacteremia is significantly associated with increased risk for thrombocytopenia and death which supports future studies to evaluate feasibility of bedside phenotyping and therapeutic targeting.
Highlights
Among those who developed thrombocytopenia at onset of S. aureus bacteremia (SAB), a greater proportion had sources of infection associated with high risk for death such as endovascular and lower respiratory tract infections (50% vs. 24%, p = 0.022) and had MRSA as a causative pathogen (53% vs. 31%, p = 0.048) when compared to those who did not, though the groups did not differ in age or comorbid conditions except for liver cirrhosis (24% vs. 8%, p = 0.059)
We found that MRSA bloodstream isolates had higher overall hemolytic activity and that high Hla-producing MRSA strains are significantly associated with thrombocytopenia and death in S. aureus bacteremia but the association between high hemolytic activity and poor outcome was not observed with MSSA strains
In conclusion, our findings show that patients with MRSA bacteremia are more likely to be infected with high Hla-producing strains and are at a higher risk for developing thrombocytopenia and death
Summary
Staphylococcus aureus is a leading cause of bloodstream infection, affecting an estimated 50 in 100,000 people annually with an overall mortality rate of up to 57% in adults [1]. Wuescher et al found reduced survival rate with increased cytokine storm and higher bacterial load in kidneys of platelet-depleted mice infected with USA300 causing bacteremia compared to wild-type (WT) mice without platelet depletion [5]. High Hla production was shown to increase severity and reduce survival of infection in numerous experimental models of pneumonia [9,10], sepsis [6], peritonitis [11], and brain abscesses [12]. Administration of a novel anti-alpha toxin monoclonal antibody developed to target and neutralize Hla was shown to provide survival benefit in multiple animal models of infection, including pneumonia [13,14], skin and soft-tissue infections [15,16] and bacteremia [17]
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