167 Persistent MRSA bacteremia 8 aureus strains are frequently isolated from the bloodstream of human subjects with SAB [16,61–63,71–73]. Several groups have shown that specific agr genotypes are associated with persistent MRSAB [16,74,75]. Fowler et al. discovered that isolates from patients with persistent MRSAB were predominantly (≈85%) of similar agr genotypes and lacked agr activity, as measured by δ-lysin production. The same study also noted that isolates from patients with persistent MRSAB were less susceptible to killing by thrombin-induced platelet microbicidal protein, an antimicrobial peptide produced by host platelets. Another study by Park et al. examined the agr genotype in MRSAB patients without retained foci of infection (e.g., prosthetic joint, intravenous catheter) [74]. They found that persistent MRSAB isolates more frequently possessed agr dysfunction compared to those from patients with resolving bacteremia (94% vs. 75%, p = 0.03). A third investigation by Kang et al. limited their investigation to 152 patients with persistent MRSAB and asked if infections due to isolates with agr dysfunction had worse clinical outcomes compared to agr positive strains [75]. They found significantly higher rates of in-hospital mortality in patients with persistent MRSAB if the bloodstream isolate had a dysfunctional agr system (68% vs. 49%, p = 0.029). The mechanism for the reciprocal relationship between agr activity and persistence remains unclear but is likely multifactorial. First, the reduction in cytotoxic leukocidin production in agr-null isolates may lead to decreased hostcell toxicity and increased bacterial survival [75]. Second, the agr operon also repressed adhesins such as fnbA, which are required for adhesion and invasion of endothelial cells. The lack of a functional agr would result in upregulated adhesins and potentially enhanced intracellular invasion, where it would be shielded from the effects of numerous antibiotics including vancomycin. Third, multiple studies have linked agr dysfunction with glycopeptide intermediate-resistance or vancomycin tolerance (discussed further in Section 3.4 The mechanism of increased antibiotic tolerance is thought to be due to altered autolysin activity, blunting the bactericidal effect of vancomycin [61,74]. These studies provide some compelling evidence that agr dysfunction can be a driver of persistent SAB. Variability in virulence factor production Despite several decades of mechanistic studies examining S. aureus virulence factor function and regulation, the field has been unable to pinpoint which specific virulence factors are responsible for microbial survival in bloodstream infections. It appears that no single virulence factor can dictate the pathophysiology, which points towards combinations that are likely expressed in different infectious niches. Few studies have examined virulence factor expression to specifically differentiate persistent MRSAB from resolving MRSAB isolates. Xiong et al. performed an in vitro analysis on isolates from patients with persistent MRSAB and resolving MRSAB to determine phenotypic characteristics that may distinguish the two isolates [76]. They found that
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