Phenotypic and Genotypic Characteristics of Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia In Vitro and in an Experimental Endocarditis Model

The persistent bacteremia (PB) syndrome is well represented in large clinical series of persons with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (PB prevalence, 20%–30%), and it is especially relevant to patients with endovascular infection [1, 2]. However, in up to one-third of cases, no readily identifiable cause of PB is identified, despite extensive clinical evaluation [3]. Therefore, understanding the molecular mechanisms and determinants of PB is essential to optimize prevention and therapy against life-threatening S. aureus infections. We hypothesize that S. aureus uses specific virulence determinants to persist in the bloodstream and cause PB in the context of endovascular infection. For example, the organism must avoid immediate killing by host-defense peptides liberated by platelets at sites of endovascular infection. Next, the organism must evade or survive phagocytosis and intracellular killing by neutrophil-associated oxidative and nonoxidative killing mechanisms (including those associated with antimicrobial peptides, such as α-defensins). During this phase, the pathogen must adhere to host cells and ligands to colonize vascular endothelium and avoid clearance by the reticuloendothelial system. Following adherence, the organism proliferates and invades tissues, creating reservoir foci. Finally, it deploys exotoxins and exoenzymes to reemerge from these reservoir sites, reenter the bloodstream, and hematogenously seed metastatic target organs (figure 1). Figure 1 Hypothesized life cycle of methicillin-resistant Staphylococcus aureus (SA) isolates that cause persistent bacteremia in the context of endovascular infection. AP, antimicrobial peptides; α-Tox, α-toxin; CM, cell membrane; FBG, fibrinogen; ... Because distinct infection foci are not synchronized, organisms are continuously reemerging into the bloodstream, accounting for persistent bacteremia. On the basis of this hypothesized life cycle of PB isolates, we investigated a cadre of in vitro phenotypic and genotypic characteristics considered to be involved in these phases of endovascular pathogenesis. In addition, we examined the in vivo virulence and antibiotic responsiveness of MRSA isolates associated with PB (hereafter, “PB isolates”) and those associated with resolving bacteremia (here-after, “RB isolates”) in a rabbit model of infective endocarditis.