The accessory gene regulator (agr) locus has been shown to be important for virulence in several animal models of Staphylococcus aureus infection. However, the role of agr in human infections, and specifically in antibiotic treatment, is controversial. Interestingly, agr dysfunction has been associated with reduced vancomycin responses.

Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (PB) (positive blood cultures after >7 days of therapy) represents a clinically challenging subset of invasive MRSA infections. In this investigation, we examined the potential correlation of specific virulence signatures with PB versus resolving MRSA bacteremia (RB) (negative blood cultures within 2 to 4 days of therapy) strains. Thirty-six MRSA isolates from patients enrolled in a recent multinational clinical trial were studied for (i) susceptibility to host defense cationic peptides (HDPs) (i.e., thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide 1 [hNP-1]); (ii) adherence to host endovascular ligands (fibronectin) and cells (endothelial cells); and (iii) biofilm formation. We found that PB isolates exhibited significantly reduced susceptibilities to tPMPs and hNP-1 (P < 0.001 and P ‫؍‬ 0.023, respectively). There was no significant association between the PB outcome and fibronectin binding, endothelial cell binding, or biofilm formation (P ‫؍‬ 0.25, 0.97, and 0.064 versus RB strains, respectively). However, multiple logistic regression analysis revealed that the PB outcome was significantly associated with the combination of reduced susceptibilities to HDPs and extent of biofilm formation (P < 0.0001). Similar results were obtained in a second analysis using days of bacteremia as a continuous outcome, showing that reduced HDP susceptibilities and increased biofilm formation cocontributed to predict the duration of bacteremia. Our data indicate that PB isolates have specific pathogenic signatures independent of conventional antimicrobial susceptibility. These combinatorial mosaics can be defined and used to prospectively distinguish PB from RB strains in advance and potentially to predict ultimate clinical outcomes.Staphylococcus aureus is a leading cause of bacteremia and infective endocarditis (IE) throughout the industrialized world (18,22,42,54). A growing proportion of these bloodstream infections are due to methicillin-resistant Staphylococcus aureus (MRSA), which is associated with worse clinical outcome, longer hospitalization, and higher net cost than similar infections caused by methicillin-susceptible S. aureus (MSSA) (3,6,14,15,26,49,52,60). Persistent-bacteremia (PB) outcomes comprise 20 to 30% of all episodes of MRSA bacteremia and are especially relevant to endovascular infections (13,22,23,31). Why some MRSA bacteremia strains persist while others resolve (RB) despite similar baseline clinical and microbiologic characteristics and identical medical and surgical therapeutic strategies is poorly understood.In two recent studies, we investigated S. aureus virulence factors that could potentially differentiate PB from RB strains in the context of endovascular infections (23, 56). We initially studied PB or RB isolates from the Duke University Medical Center and delineated several in vitro parameters that appeared to distinguish these two strain cohorts, including enhanced matrix ligand and e...

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