1. Introduction
Enterococcus, a gram-positive cocci occurring in chains, is a major pathogen in community and nosocomial infections. The infections caused by the
Enterococci spp. includes the genitourinary tract, intra-abdomen, bloodstreams, infective endocarditis, skin/soft tissue, rarely bone and joint, and central nervous system. The species that are clinically important and the cause of most infections are
E. faecalis and
E. faecium [
1]. However,
E. faecalis is a common cause of community and in-hospital infection, while most
E. faecium causes nosocomial infection. Additionally,
E. faecium is generally resistant to penicillin (with ampicillin being a drug of choice for treatment of enterococcal infection) by the production of beta-lactamase and point mutation in penicillin-binding proteins (PBPs); it is occasionally reported resistant to vancomycin (also called vancomycin resistant
Enterococci; VRE), by modifying pentapeptide precursors [
1,
2].
VRE isolates have been widely reported [
3]. As per data from the National Healthcare Safety Network from 2009 to 2010, around 1/3 of all enterococcal associated nosocomial infections are VRE. It is noteworthy that VRE is the second most common cause of nosocomial infections in the United States of America [
4,
5]. As per the National Antimicrobial Resistance Surveillance, Thailand data, an increased prevalence of VRE was reported, from 0.4% in 2012 to 6.4% in 2019, especially that of
E. faecium that is resistant to vancomycin, which was 7.2% in 2019 [
6].
Importantly,
Enterococci can cause serious infection in debilitated patients. Patients can acquire enterococcal infections from colonization and the hospital environment. Patients infected with enterococci had a mortality rate of 32%–66.7% [
7,
8,
9,
10,
11,
12,
13,
14] depending on their prognostic factors, such as underlying diseases, Charlson Comorbidity Index (CCI), illness severity (Acute Physiology and Chronic Health Evaluation; APACHE) II, Pitt bacteremia, Organ System Failure Index; OSFI), admission to the intensive care unit (ICU), shock, active drug against VRE, and particularly infection caused by vancomycin-resistant strains [
12,
14,
15,
16,
17].
However, several previous studies have shown that VRE infection is not associated with increased hospital deaths [
18,
19,
20,
21]. Whether the mortality among patients with VRE infection is higher than that among those with VSE remains a controversial issue. Additionally, certain studies described above gathered patient outcomes of
E. faecium mixed with
E. faecalis, and occasionally
E. gallinarum [
7,
8,
9,
16,
22]. Infection due to VR-
E. faecium was associated with greater than 2 fold-higher risk of mortality as compared with infections caused by VR-
E. faecalis [
16].
Owing to the growing prevalence of enterococcal infection, especially E. faecium, the controversial impact of vancomycin resistance on clinical outcomes, and the available data pertaining non-specifically to infections due to E. faecium, this study aimed to investigate the clinical outcomes of infection due to E. faecium and determine the risk factors associated with mortality, including the risk attributed to vancomycin resistance.
3. Discussion
Previously, several reports showed that patients with VRE versus those with VSE infection did not have a significantly greater risk of mortality [
19,
20,
21]. In contrast, our study reported 30-day and 90-day mortality rates for VR-
E. faecium infection patients of 57.7% and 69.2%, respectively; these values were obviously higher than those in patients with VS-
E. faecium infection cases (38.7% and 47.1%). These results were similar to previous studies indicating the clinical impact of VRE on patient outcomes and hospitalization duration [
14,
23].
Moreover, the median length of hospitalization was significantly longer in patients with VR-
E. faecium infection than in those with VS-
E. faecium (69 days vs. 36 days). Prematunge et al. performed a meta-analysis of VRE and VSE bacteremia outcomes among hospital patients in the era of effective VRE therapy [
24]. Among all the studies that were reviewed, the length of stay (LOS) was significantly longer in the VRE group than in the VSE group (mean difference, 5.01 days; 95% CI, 0.58–9.44]) [
24]. Similarly, we found an obvious increase in the duration of hospitalization among VR-
E. faecium infection patients. Considering only the patients infected with VR-E.
faecium, we also confirmed that VRE infection remained associated with an increased LOS. Therefore, the present study also conformed the influence of VR-
E. faecium infection on patients. However, due to variable findings across previous studies, the role for vancomycin resistance in clinical significance has to be further evaluated.
As per multivariate and cox-regression analyses, the mortality rate was higher in patients with severe illness based on the SOFA scores and VR-
E. faecium infection. A higher severity index score was a direct independent risk factor for mortality. Similar to previous reports [
8,
18,
20], we also found that the SOFA score increased the risk of poor outcome. Moreover, as for the type of infection, bone and joint infection was classified as decreasing the risk of death. Terpenning et al. [
25] indicated that the most common sites for
Enterococci isolation were the urinary tract, bone and soft tissue; however, the overall mortality rate in patients with bacteremia was as high as 71.4%.
To our knowledge, no previous study has revealed the association between
Enterococci bone and joint infection and death. Our result first documents this infection as a protective factor. However, certain evidence can explain this relationship. Thompson et al. [
26] reviewed the treatment outcomes in 55 patients with enterococcal prosthetic joint infections during a 5-year period. The overall cure rate was about 67%; however, in cases where cure was intended, the overall rate was 80% [
26]. Beyond the high cure rate for this type of infection, Fischbacher et al. [
27] also documented that the 1-year cumulative mortality was 5.5%, and the 2-year rate was only 7.3%. Thus, our findings confirmed bone and joint infection as a positive prognosis factor for
E. faecium infection. However, the patients with bone and joint infection in this study had a significantly longer duration of hospitalization than the patients with other infections (median 42 days vs. 12 days, respectively). The enterococcal bone and joint infection thus seems not to impact on mortality but to increase medical costs.
As described above, the present findings indicated that VRE and severe illness were risk factors for mortality. However, it is difficult to select effective agents against
Enterococci infection, especially in the VRE era, resulting in higher mortality [
28]. As per a recent meta-analysis, linezolid treatment or higher-dose daptomycin (≥9 mg/kg) for VRE bacteremia were comparable in terms of the mortality rate. However, linezolid and higher-dose daptomycin were independently associated with lower mortality as compared with lower-dose daptomycin [
29]. Therefore, the treatment of
Enterococci with appropriate antimicrobial regimens could significantly reduce mortality [
30].
Besides identifying effective agents against VRE infection, infection control in patients at risk of acquisition of VRE colonization is also important, especially immunocompromised patients, those with hematologic malignancy, organ transplantation, multiple comorbidities, prolonged hospitalization, staying in ICU, and close contact or staying on ward having patients with VRE colonization or infection [
31,
32]. Alevizakos et al. [
33] performed a meta-analysis on the importance of colonization with VRE and found that colonized patients were 24 times more likely to develop a VRE bloodstream infection than non-colonized patients.
The current study has several limitations. First, it is a retrospective study with a small number of patients, which makes it difficult to determine all previous significant factors related mortality and length of stay [
13]. Second, our findings were from a university-affiliated hospital, which might be dissimilar from those taken at other types of hospitals. Further studies with a larger and multi-center sample are required to investigate the clinical outcomes of VRE infection.
4. Materials and Methods
4.1. Study Design
This retrospective study of risk factors related to mortality and clinical outcomes in patients infected with
E. faecium was performed at the Phramongkutklao Hospital, a teaching hospital with 1200 inpatient beds for Phramongkutklao College of Medicine in Bangkok, Thailand, during the period from 2014 to 2018. The identification of
Enterococci was performed using conventional techniques. The results of in vitro antimicrobial susceptibility tests for ampicillin and vancomycin with a disk-diffusion method were interpreted based on the Clinical and Laboratory Standards Institute [
34]. The institutional review boards at Phramongkutklao College of Medicine and Phramongkutklao Hospital approved the study before its initiation (approval no. Q017b/61_Exp).
4.2. Participants
This study included participants (1) aged > 18 years; (2) with results for the first isolate of
E. faecium; and (3) diagnosed with infection based on the Centers for Disease Control and Prevention/National Healthcare Safety Network (CDC/NHSN) Surveillance Definitions for Specific Types of Infections [
35]. Patients who could not be followed up for treatment outcomes, those transferred to another hospital, and those with incomplete medical records were excluded.
4.3. Data Collection
The data of the enrolled study subjects were collected from medical records, and the subjects were concealed by coding. The following data were collected: (1) demographic data: gender, age, underlying diseases or comorbidity (malignant tumor, hematologic malignancy, chronic kidney disease, chronic liver function disease, diabetes, neutropenia [defined as neutrophil cell count being <500/mm], connective tissue disease, or cardiovascular disease), duration of admission, ward type when the patients had onset of infection, source of infections (based on CDC/NHSN), receiving anti-E. faecium therapy within 72 h from the onset of E. faecium infection, or septicemia. (2) Severity of illness: mechanical ventilator use, and Sequential Organ Failure Assessment (SOFA) score, mortality prediction score based on six organ dysfunction systems; SOFA score increased as mortality increased. (3) Mortality rate: in-hospital mortality, 30-day and 90-day mortality. In-hospital mortality was defined as death occurring during the hospital stay; 30- and 90-day mortality was defined as death occurring within 30 and 90 days of a diagnosis of infection.
4.4. Statistical Analyses
Descriptive statistics were used for depicting the participants’ characteristics, clinical status, and mortality rate related to E. faecium infection. The 1-sample Kolmogorov- Smirnov test was performed for testing the normality of the continuous variables. Chi-square or Fisher’s exact test were performed to analyze the relationship between the categorical variables. Mann Whitney U test (median with interquartile range was used as appropriate) or independent t-test (mean with standard deviation was used as appropriate) were used to compare the median or mean, respectively, of continuous variables. All significant variables in the univariate analysis were considered for the logistic regression analysis based on the backward stepwise (conditional) method. All significant univariate factors were entered first, then considered for elimination based on the probability criteria for stepwise entry and removal.
For the survival analysis, a Cox’s proportional hazard model for 90-day mortality among patients with E. faecium infection was employed. Cox’s regression analysis was used for determining the independent risk factors for mortality by selecting the independent variables, that is, those with p-values < 0.1 in the univariate analysis, to add into the final Cox’s regression model. The results were reported as hazard ratios with 95% confidence intervals. Data were analyzed with SPSS (IBM Corp., Armonk, NY, USA), and a p-value < 0.05 was considered statistically significant.
