In this study, we found that the predisposing factors associated with E. faecium compared to E. faecalis in patients with BSI due to Enterococcus spp were different. Previous use of penicillins or carbapenems, hospital-acquired BSI and biliary-tract source were independently associated with E. faecium BSI, whereas congestive heart failure, cerebrovascular disease and urinary tract source were independent factors associated with E. faecalis BSI. We found an in-hospital mortality rate of approximately 21% in monomicrobial enterococcal BSI, with no differences between E. faecalis and E. faecium. We further observed that while in-hospital mortality in episodes caused by E. faecium was mostly predicted by clinical severity at the onset of BSI, several other factors, including the burden of comorbidities and age were associated with higher risk of death in episodes caused by E. faecalis. In addition, urinary or biliary source was identified as a protective factor only for E. faecalis. To the best of our knowledge, this is the only prospective multicentre cohort study on both predisposing and prognostic factors in E. faecium and E. faecalis BSI.

Overall, the enterococcal BSI population in this study was mainly elderly people with a high burden of comorbidities, as shown in previous studies [5, 20]. Regarding the enterococcal species causing BSI, the proportion of E. faecium was higher than in studies from the previous decade, also performed in Spain, which reported E. faecium rates of 26% and 12% [4, 20]. This increase reflects a trend, previously described, which has also been linked to the higher intrinsic antimicrobial resistance of E. faecium [1, 21].

Our study confirmed differences in the predominant sources of infection between E. faecalis and E. faecium that were already known [5, 6, 9, 11]. Urinary source and endocarditis were more prevalent in E. faecalis BSI, while abdominal and biliary source were predominant in E. faecium. There was a high prevalence of patients with unknown source of BSI, especially in monomicrobial enterococcal BSI, in agreement with previous retrospective studies [6, 22].

The multivariable models for the different predisposing factors for enterococcal species supported some of the predictors found in previous retrospective studies, such as the associations between E. faecium and hospital acquisition, previous use of antibiotics, especially penicillins and carbapenems, and a biliary tract source [4, 23, 24]. To our knowledge, the association between cerebrovascular disease or congestive heart failure with E. faecalis as opposed to E. faecium has not been previously reported, beyond the obvious association of E. faecalis with endocarditis and heart failure [6, 25].

Some studies have shown a higher CCI score for E. faecium BSI [5, 24]. In this study on the other hand and in a few others, the CCIs in patients with BSI were similar for both species [6, 23]. In addition, the reported average values of CCI vary widely between studies, probably reflecting considerable heterogeneity in the populations studied.

Overall, the significant differences in patient characteristics and sources of infection observed in this and previous studies indicate that BSI caused by E. faecium and E. faecalis are two distinct entities affecting different populations.

The observed in-hospital mortality rate of 20.8% for monomicrobial enterococcal BSI is consistent with previous studies [5, 7,8,9,10, 20, 22, 24, 26, 27]. In this study, we were unable to show a difference in in-hospital mortality between patients with E. faecium and E. faecalis. This is noteworthy, as multiple studies have shown higher fatality rates for E. faecium BSI. Two large population studies have shown mortality rates of 35% and 30% for E. faecium BSI vs 21% and 17% for E. faecalis BSI [5, 6]. Other, smaller studies have documented similar differences [9, 23, 27]. We hypothesise that this discrepancy could be due to multiple factors: firstly, unlike in some studies, average CCI scores were similar for patients with both species, a factor that is associated with mortality [28]; secondly, vancomycin-resistant E. faecium, which was previously shown as a negative prognostic factor,was rare in our population [7]. Of note, in Spain, the rate of vancomycin-resistant enterococci is low compared to other European countries [29]. However, some of the studies in which higher mortality was found for E. faecium cases also reported low vancomycin resistance rates [5, 6, 9, 27]. Importantly, active targeted antimicrobial therapy, a known protective factor for mortality, was higher in our cohort than in previous studies [1, 8, 22, 27], which might be related to the fact that most of the participating hospitals in our study had active bacteremia programs. Furthermore, congestive heart failure, a disease associated with a high mortality rate in the general population [30], was more prevalent among patients with E. faecalis. New studies, preferably prospective, are needed to determine whether mortality differs between the two species.

The analysis of mortality predictors confirmed some prognostic factors observed in earlier studies: age, CCI and clinical severity at BSI onset [5, 6, 9, 10, 20]. The association between urinary catheters and mortality has only been reported in a recent enterococcal BSI study [7]; interestingly, a strong association between urinary catheter use and in-hospital mortality has recently been shown for patients admitted to internal medicine wards, regardless of infection [31]. In our opinion, urinary catheter use would not have a direct causative role in mortality, but would be a surrogate variable related to the baseline condition of patients that is not captured by other variables. Further studies are warranted to assess this issue in patients with BSI.

Other studies have found that inappropriate targeted antimicrobial therapy is independently associated with mortality [8, 22, 27]. The association between active targeted therapy and mortality was also present in our bivariate analysis. Unfortunately, we could not include this into our multivariable model due to a substantial amount of missing data.

We found some differences in the prognostic factors for BSIs caused by E. faecalis and E. faecium. To our knowledge, the study by Pinholt et al. [6] is the only previously published study reporting species-specific independent predictors for mortality and showed conflicting results with our data. However, that study did not include some variables that were considered in our study, including specific comorbidities or severity of BSI. The fact that age or comorbidities were not associated with mortality in E. faecium BSI in our study may be due to lack of statistical power; however, the bivariate data suggest at least a lower impact of age and comorbidities compared to E. faecalis. In the E. faecalis group, urinary or biliary tract source was protective for mortality, as expected [32].

This study has several limitations that should be acknowledged. First, we did not include a control group without enterococcal BSI and therefore the predisposing factors studied are only useful to differentiate patients with one or the other species from those with enterococcal BSI. Second, to avoid the confounding effect of other bacteria in the mortality analyses, we had to exclude patients with polymicrobal bacteremia, which reduced the power of those analyses. Third, we used in-hospital mortality up to day 30 and may have missed some deaths that occurred after hospital discharge. Fourth, we did not perform molecular typing to characterize the molecular epidemiology of the isolates. Finally, this study only comprised Spanish hospitals. Consequently, the generalizibility to settings with different epidemiology and another level of access to healthcare is limited.

The strengths of the study are the large number of patients in the primary analysis and the prospective, multicenter design with cases from 26 hospitals in different regions of Spain, including community and university hospitals, which would make the study reasonably representative of the Spanish population. Finally, to our knowledge, this is one of the few studies that has analysed differences in predisposing and prognostic factors between patients with E. faecium and E. faecalis BSI.

In conclusion, BSI caused by E. faecium and E. faecalis are associated with different comorbidities and sources of infection. This study showed significant but similar in-hospital mortality rates for both pathogens, but while mortality in E. faecium BSI was associated only with severe BSI, E. faecalis BSI mortality was also associated with age, high comorbidity burden and source of infection. This study helps to understand the differences between these two pathogens in terms of patient population and prognostic factors and adds to the available data on enterococcal BSI.