166 Chapter 8 microbiologic failure and persistent SAB [56]. These biomarkers were more predictive than clinical risk factors known to increase risk for persistence (age, steroid use, hemodialysis, non-removable infection foci, hospital vs. community onset, and MRSA vs. MSSA). Given the association of persistent SAB with mortality, it is unsurprising that elevated IL-17A and IL-10 levels were each associated with increased mortality in this study [13,56]. While these discoveries are exciting and show promise for future diagnostic options to stratify patient risk for persistence, the clinical utility at the present day is hampered by availability only in specific academic centers and reliance on external laboratories to perform the tests. Fast turnaround time will be the key to the realworld use of these tests to identify patients at risk of persistent SAB. This could allow for early detection of persistent SAB and subsequently altered therapeutic and diagnostic strategies that could potentially save lives. Pathogen-associated risk factors for persistent S. aureus bacteremia To survive and replicate in the bloodstream, S. aureus must avoid a barrage of host defenses while attempting to adhere to and proliferate upon an endothelial surface of the vasculature. The establishment of endovascular infection is a complex process requiring coordinated expression of multiple adhesins, exotoxins, and exoenzymes at various stages of infection. Meanwhile, S. aureus must resist or avoid phagocytosis by neutrophils and the resulting oxidative and non-oxidative burst, in addition to the circulating platelet-derived antimicrobial peptides. There is significant heterogeneity in the catalog of virulence factors produced by different S. aureus clinical isolates [57–60], the regulators mediating virulence factor expression [61– 64], and susceptibility to antimicrobial peptides [65–68]. This section discusses the key genetic and phenotypic characteristics of S. aureus that have been associated with persistent SAB. Accessory gene regulator dysfunction Virulence factor production is tightly controlled by a series of regulatory mechanisms including several two-component systems and SarA-family regulators [69]. One of the most well-characterized global regulators of virulence factor production is the two-component quorum-sensing accessory gene regulator (agr) system of S. aureus [70]. The agr system is a quorum-sensing system that mediates expression of exotoxins and exoenzymes [69]. The essentiality of agr to virulence in S. aureus infection depends on the type of infection [70]. Murine skin and soft tissue models have shown that agr deletion mutations are severely attenuated. However, agr-null S.
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