Analysis of Staphylococcal Toxins and Clinical Outcomes of Methicillin-Resistant <i>Staphylococcus aureus</i> Bacteremia

Abstract

It is well known that methicillin-resistantVancomycin (VCM) has been the standard treatment for MRSA infections for over 50 years. The area under the concentration-time curve [AUC/minimum inhibitory concentration (MIC) ratio] is a representative parameter of the pharmacokinetics-pharmacodynamics (PK-PD) of VCM.3) The Infectious Diseases Society of America recommends a target AUC/ MIC>400 for the treatment of severe MRSA infections. 4)However, this is often difficult to achieve for MRSA strains with high VCM MICs, thus increasing the risk of insufficient therapeutic response. Previous meta-analyses have attempted to address the association between MIC and clinical outcomes. [5][6][7] In contrast to these studies, a recent meta-analysis examining 8291 episodes reported no differences in the risk of death between patients with S. aureus high and low VCM MICs. 8) These results highlight the current lack of consensus regarding the relationship between VCM MICs and the prognosis of patients with MRSA infections.Our previous study measured MICs at 0.25 µg/mL intervals using the broth microdilution method and found that VCM MICs≥1.5 µg/mL affected the prognosis for MRSA bacteremia. 9) However, there were no significant differences in VCM AUC/MIC and clinical prognosis between the groups.The pathological mechanism of S. aureus infections includes infectious pathogenicity such as pneumonia, cellulitis, osteomyelitis, and infective endocarditis as well as toxic pathogenicity such as food poisoning and toxic shock syndrome.10,11) Several virulence factors have been reported to be associated with the clinical outcomes of MRSA infections. The expression of major virulence factors, such as Panton-Valentine leukocidin (PVL), is known to be correlated with higher mortality in community-associated MRSA infections. 12,13) We believe that toxic pathogenicity is closely associated with patient prognosis. S. aureus is known to produce various virulence factors, 14) such as toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxins (SEs), which are superantigenic toxins (SAgT) associated with severe infections. 11,15,16) A previous study reported that TSST-1 and SEC1 caused shock when intravenously injected into an animal model. 17) In addition, recent experimental study showed that SAgT play a critical role in the development and progression of S. aureus infective endocarditis and sepsis.18) However, the association between SAgT and the prognosis of patients with MRSA bacteremia has not been sufficiently studied. Therefore, here we aimed to examine the effects of staphylococcal virulence factors on the prognosis of patients with MRSA bacteremia.

Molecular epidemiology and virulence factors of methicillin‐resistant Staphylococcus aureus isolated from patients with bacteremia

“…Previous studies have reported the association between the virulence factors and mortality rate in patients with MRSAB. Masayuki et al reported the independent association between superantigenic toxins (SAgT) such as TSST‐1 and SEs and 30‐day mortality in MRSAB . Furthermore, Park et al reported that three staphylococcal superantigen genes ( sec , sel , and tst ) causing bloodstream infection were associated with mortality …”

“…[10][11][12][13] Methicillin-resistant Staphylococcus aureus is known to produce various virulence factors, including staphylococcal enterotoxins (SEs), toxic shock syndrome toxin-1 (TSST-1), leukocidins, hemolysins, and exfoliative toxins, and immune-modulatory factors. 14 Previous studies have reported the association between the virulence factors and mortality rate in patients with MRSAB. Masayuki et al reported the independent association between superantigenic toxins (SAgT) such as TSST-1 and SEs and 30-day mortality in MRSAB.…”

“…Masayuki et al reported the independent association between superantigenic toxins (SAgT) such as TSST-1 and SEs and 30-day mortality in MRSAB. 14 Furthermore, Park et al reported that three staphylococcal superantigen genes (sec, sel, and tst) causing bloodstream infection were associated with mortality. 15 The virulence genes harbored by each clone have been previously reported, [15][16][17] and studies have been performed to investigate whether the differences in the virulence genes among clones have any impact on mortality.…”

Different Types of Coagulase Are Associated With 28-Day Mortality in Patients With Staphylococcus aureus Bloodstream Infections

“…However, none of these additional factors demonstrated a significant impact on 28-day mortality when calculating a pathogen adapted Cox model. However, other prominent virulence factors like toxic shock syndrome toxin or staphylococcal enterotoxins, which were previously reported as independent risk factors for 30-day mortality, were not determined in the present study (Maeda et al, 2016). By using cluster analysis, which was previously used to study the effect of genetic and biofilm formation capacity characteristics on patients' outcomes, the present study investigated the sole impact of bacterial genetic factors on mortality in a cohort of SAB patients (Cremers et al, 2019;Seymour et al, 2019).…”

“…Considering the major impact of S. aureus on human coagulation, mediated by the vast amount of virulence factors interacting with fibrinogen, the influence of fibrinogen in that study might have been underestimated. Other studies investigating large collectives of patients with SAB did not include fibrinogen in their analysis or studies investigating sepsis in general did show a link between fibrinogen and mortality but did not state any causative pathogen (Fowler et al, 2005;Cagatay et al, 2007;Forstner et al, 2013;Maeda et al, 2016;Holmes et al, 2018;Guilamet et al, 2019;Xia et al, 2020).…”