is a leading cause of bacteremia and endocarditis in much of the industrialized world (4
). In the present study, we investigated associations between the genotypic and phenotypic characteristics of bloodstream S. aureus
isolates and the outcome of bacteremic patients. The results of this investigation demonstrate that bacterial genotypic properties differed by geographic region and were significantly associated with clinical characteristics, infection type, and outcome.
The predominant strain in this investigation, USA 300, accounted for approximately one-third of all MRSA bloodstream isolates from the United States. This finding is consistent with recent reports (12
) and confirms the emergence of the USA 300 strain type as an important cause of bacteremia, as well as skin infection. Although recent reports have documented an increasing incidence of USA 300 MRSA infections in European countries (14
), no isolates from this clone were identified in the European cohort. This finding may be due in part to the small sample size of our European cohort.
The distribution of putative virulence genes among S. aureus
isolates differed by geographic region. For example, all European isolates lacked the pvl
genes, suggesting that these genes remain relatively uncommon among S. aureus
bloodstream isolates from that region (8
). In contrast, all MRSA isolates and over three-quarters of MSSA isolates from European countries were positive for the tst
gene, an observation that is consistent with recent reports (28
). The presence of specific bacterial virulence genes among S. aureus
isolates from the same geographical region may reflect a rapid expansion of specific clones or horizontal transfer of mobile genetic elements among strains.
The severity of bacteremia due to USA 300 strains in our study was no greater than that observed in non-USA 300 strains and was significantly associated with better outcomes in certain clinical settings. For example, patients with right-sided MRSA endocarditis caused by USA 300 strains were significantly more likely to be cured of their infection than patients with right-sided MRSA endocarditis due to non-USA 300 strains. In addition, isolates from patients with persistent MRSA bacteremia were significantly less likely to contain the pvl
gene than isolates from patients with nonpersistent MRSA bacteremia. These findings are consistent with several recent reports. For example, Popovich et al. (24
) reported similar outcomes, including rates of persistent bacteremia, length of hospitalization, and hospital readmission rates, among patients with MRSA bacteremia due to “community genotype” strains and those infected with the “hospital genotype” strains. In another study evaluating the genotypic characteristics of U.S. and South African S. aureus
isolates from patients with skin and soft tissue infections, Campbell et al. reported that infections due to pvl
-constitutive S. aureus
isolates were significantly more likely to be cured than similar infections caused by S. aureus
isolates without the pvl
). Taken together, these findings suggest that the presence of pvl
, per se, does not confer a worse clinical course in all forms of infection caused by S. aureus
Although 8% of the MRSA bloodstream isolates, all from U.S. patients, exhibited the hGISA phenotype, no major associations with clinical outcomes, such as persistent bacteremia or treatment failure, were identified. This is in contrast to some prior reports regarding hGISA bacteremia. For example, Charles et al. observed significant differences in the outcomes of 5 patients with heterogeneously vancomycin-intermediate S. aureus
(hVISA) bacteremia compared to 47 patients with vancomycin-susceptible MRSA bacteremia (2
). hVISA bacteremia was associated with higher bacterial loads, longer duration of bacteremia, and treatment failure. However, this association between persistent bacteremia and hGISA isolates has not been observed in other studies. Khosrovaneh et al. evaluated the vancomycin susceptibilities of MRSA isolates obtained from 22 patients with persistent or recurrent bacteremia (11
). Three (13.6%) isolates were found to exhibit heteroresistance to vancomycin. However, most patients had other reasons for persistent infection, including inadequate removal of infected foci. Taken together, these findings suggest that the clinical relevance of vancomycin heteroresistance in defining the course and outcomes of bacteremic patients remains uncertain. Although our findings did not suggest any potential associations between the hGISA phenotype and clinical outcomes, this may in part be due to the small sample of hGISA patients and the high degree of variability in the clinical and genotypic characteristics of our cohort.
The clinical and microbiological data in the present study were highly accurate, having been collected as part of a registrational clinical trial on a well-defined cohort of patients with S. aureus
bacteremia and endocarditis from more than 40 centers in four countries. The present study was limited by the relatively small sample size of isolates from Europe. In addition, assessment of virulence determinants was based on the qualitative assessment by PCR. We did not evaluate quantitative expression of these genes or the presence of single nucleotide polymorphisms, which may influence the function of gene products (34
). Clinical outcomes may be correlated with in vivo gene expression, but that analysis is beyond available technology. Some genes, such as pvl
, were found to be highly clonal to USA 300 isolates and therefore associations with right-sided endocarditis might reflect a “hitchhiker effect” due to linkage disequilibrium between these genes and other virulence determinants rather than a causal association (23
). Finally, we were unable to assess the frequency of USA 300 isolates in patients with community-acquired versus hospital-acquired bacteremia due to the unavailability of relevant clinical data.
The present study documents several important findings, including the increasing incidence of USA 300 isolates among North American patients with S. aureus bloodstream infections and the higher incidence of tst gene-positive isolates causing S. aureus bacteremia in Europe than previously reported. The present study also suggests potential associations between S. aureus genotype and clinical outcomes. MRSA isolates positive for the pvl gene were associated with nonpersistent bacteremia, while USA 300 isolates were associated with right-sided endocarditis. In addition, right-sided endocarditis due to USA 300 strains of MRSA was associated with better treatment success rates compared to non-USA 300 MRSA isolates. Larger international collections of S. aureus isolates are required to fully characterize the geographic distribution of virulence factors and potentially validate the observations made in the present study.