Phenotypic and Genotypic Characteristics of Persistent Methicillin‐ResistantStaphylococcus aureusBacteremia In Vitro and in an Experimental Endocarditis Model

Abstract

Background Persistent MRSA bacteremia (PB) represents an important subset of Staphylococcus aureus infections and correlates with poor clinical outcomes. Methods We profiled relevant in vitro phenotypic and genotypic characteristics of MRSA isolates from 39 persons with bacteremia (21 had PB and 18 had resolving bacteremia [RB]). We also compared the intrinsic virulence and responsiveness to vancomycin of selected PB and RB strains in an experimental endocarditis model (IE). Results PB and RB isolates differed significantly with regard to several in vitro characteristics that are believed to impact endovascular infections. PB isolates exhibited significantly more resistance to the cationic defensin hNP-1, enhanced membrane fluidity, and substantially greater adhesion to fibronectin, fibrinogen, and endothelial cells. Genotypically, PB isolates had higher frequency of SCCmec II, CC30, and spa 16; and higher rates of agr type III, cap8, tst-1, and cna carriage. Finally, a prototypic PB strain was more resistant to vancomycin treatment in the infective endocarditis model than a RB comparator strain, despite equivalent virulence profiles. Conclusions Our findings indicate that PB isolates may have specific virulence signatures that distinguish them from RB isolates. These data suggest that methods might be developed to identify patients at higher risk for PB in real-time, thereby optimizing the effectiveness of anti-MRSA therapeutic strategies.

Identification of a distinctive phenotype for endocarditis-associated clonal complex 22 MRSA isolates with reduced vancomycin susceptibility

“…Most notably, the clonal group under analysis (CC22-high) had a strong epidemiological association with endocarditis derived from a large study [2]. The analysis included a CC30 comparator group with comparable V-MICs derived from the same collection, which has previously been associated with a small but significant increase in endocarditis [3,4]. This indicates that the CC22-high isolates analysed here, although uncommon (about 2 % of the MRSA BSI collection [2]), have a clear phenotype (30 % of cases developing endocarditis) and thus represent an important tool for investigating the pathogenesis of endocarditis.…”

“…There has been interest in understanding whether strains causing severe infections such as endocarditis have distinct genotypic or phenotypic characteristics [2][3][4][5][6]. Clonal complex (CC) 30 meticillin-resistant S. aureus (MRSA) [3,4] and other MRSA CCs [5] have been associated with endocarditis, whereas other studies have found no association between clones and endocarditis [6].…”

“…Vancomycin-intermediate S. aureus (VISA) (4-8 mg l À1 ) and heteroresistant [(h)VISA] isolates have also been associated with endocarditis [1][2][3]7]. VISA and hVISA isolates have multiple phenotypic and metabolic differences compared with susceptible isolates, such as reduced autolysis and gradual thickening of the cell wall, changes in global gene regulators including down-regulation of agr, increased expression of surface adhesins that bind fibrinogen and fibronectin, and attenuated virulence [3,[8][9][10][11][12][13].…”

“…VISA and hVISA isolates have multiple phenotypic and metabolic differences compared with susceptible isolates, such as reduced autolysis and gradual thickening of the cell wall, changes in global gene regulators including down-regulation of agr, increased expression of surface adhesins that bind fibrinogen and fibronectin, and attenuated virulence [3,[8][9][10][11][12][13]. There is also clinical evidence that VISA and hVISA isolates are less virulent, with lower acute mortality and less shock reported in some studies [14,15].…”

Infective Endocarditis

“…The most convincing data on the effect of biofilm formation in native valve IE comes from experimental studies in S. aureus IE. A series of studies over the past decade have linked the ability of S. aureus strains to produce biofilms in vitro and their ability to cause clinically 'persistent' methicillin-resistant S. aureus (MRSA) bacteraemia in humans (defined as >7 days of positive blood cultures despite presence of vancomycin-susceptible isolates and adequate vancomycin treatment regimens) 58,59 . Of interest, clinically-persistent MRSA bacteraemia strains produce significantly more biofilm in vitro when exposed to subinhibitory concentrations of vancomycin as compared to clinically-resolving MRSA isolates 58 .…”