Clinical characteristics and risk factors of enterococcal infections in Nagasaki, Japan: a retrospective study

This retrospective study analyzed the epidemiology, characteristics, and risk factors for vancomycin-susceptible enterococcal (VSE) infections compared with colonized control patients on the basis of medical records.

In the United States, enterococci are recognized as important causative pathogens of catheter-related bloodstream infections, urinary tract infections, and cellulitis [2, 9, 10].

The independent risk factors for vancomycin-resistant enterococcal (VRE) infection were reported previously. Kim et al. compared the VRE “infected” and “colonized” groups and reported combined infection with bacteria other than VRE, presence of a hemodialysis catheter, and duration of vancomycin use were the independent risk factors for VRE infection [13]. Olivgeris et al. reported that cortisone use, third- or fourth-generation cephalosporins, enteral nutrition, and VRE colonization were the risk factors for developing enterococcal infection in critical ill patients [14]. Zaas et al. reported that the use of vancomycin, gastrointestinal procedures, diabetes mellitus, and acute renal failure could be risk factors for enterococcal bloodstream infections in malignant patients who colonized VRE [15]. As shown in these reports, the risk factors of enterococcal infections, especially VRE, are variable depending on patient background. In addition, the risk factors for VSE infections, which are highly prevalent in Japan, remain unknown. In our study, structural abnormalities of the urinary tract, abdominal surgery, immunosuppressive agent use, male sex, hypoalbuminemia, and the use of in situ devices are the risk factors of VSE infections.

Moreover, Sugiura et al. reported that enterococci are the most common causative pathogens of intra-abdominal infections after pancreaticoduodenectomy [16] and recommend accounting for enterococcal infections when selecting antimicrobials for empirical treatment for intra-abdominal infections after abdominal surgery. Furthermore, Kim et al. report that liver transplantations are an independent risk factor for enterococci intra-abdominal infections [17]. A high incidence of enterococcal infection was also found in the current study, and 17 of the 42 liver transplantations performed during 2010–2011 at our hospital were complicated by enterococcal infections (which corresponds to a high complication incidence of 42 %). In addition, according to an analysis of isolates from intra-abdominal infections after liver transplantations, the isolation frequency of E. faecium (23.7 %) is higher than that of E. faecalis (2.8 %) (p < 0.001). Enterococci, particularly E. faecium, are considered important causative pathogens of infections in liver transplantation recipients. In cases in which healthcare-associated infections are suspected after liver transplantation, the intra-abdominal infection complication guidelines of the 2010 Surgical Infection Society and Infectious Diseases Society of America recommend selecting antimicrobial agents that cover enterococci (e.g., ampicillin, piperacillin/tazobactam, vancomycin) to treat infections in patients administered antibiotics that do not cover enterococci, such as cephalosporin; in immunocompromised patients; or patients with valvular heart disease, prosthetic heart valves, or artificial blood vessels [18]. In addition, the resistance to anti-MRSA drugs, especially the increasing prevalence of VRE present in nosocomial infections, has become a major problem in the United States and Europe [5]. Since VRE was first reported as a VanA type-resistant E. faecium in 1988 in the United Kingdom and France, and VanB type-resistant E. faecalis in 1989 [19, 20], its prevalence has been increasing annually; reports from the United States indicate that 62.3–82.6 % of E. faecium isolates detected in nosocomial infections are VRE [9]. In Europe, it is most prevalent in Ireland (44.0 %), followed by Portugal (23.3 %) and Greece (17.1 %) [5, 21]. In China, the prevalence of vancomycin-resistant E. faecium is 2.7 % while that of vancomycin-resistant E. faecalis is 6.5 % [22]; the detection rates in Asia, including Japan, are low [12, 23], and these species were not isolated in the present study.

Interestingly, E. faecalis was identified as the causative pathogen in all cases of enterococcal urinary tract infections in the present study. Enterococci are causative pathogens in complicated urinary tract infections and feature a high isolation frequency [24]. Urine from children with congenital urinary tract disorders shows a high frequency of E. faecalis isolation [25]; in the present study as well, nearly all cases involving E. faecalis isolated from the urine were accompanied by congenital and acquired urinary tract disorders. Moreover, the frequency of E. faecalis isolation in bacterial cultures from ureteral stents is reportedly high [26]; likewise, in the present study, cases with acquired urinary tract disorders and E. faecalis isolation coincided with the presence of artificial devices from procedures such as nephrostomies and stent placements. Many factors related to the onset of urinary tract infection by E. faecalis have been reported. For example, enterococcal polysaccharide antigen is reportedly involved in the onset of ascending urinary tract infections since it binds to epithelial cells followed by biofilm formation and/or resistance to phagocytosis by polymorphonuclear leukocytes [27]. On the other hand, fewer reports have examined the pathogenicity of E. faecium affecting the onset of urinary tract infection than those on E. faecalis [10], which may be related to the results of our present clinical study. Structural abnormalities of the urinary tract might be unique compared with the risk factors of VRE infections, mainly caused by E.faecium, indicating that we should closely monitor patients with primary or secondary urinary tract abnormalities, stent placement, and nephrostomy for VSE infections, especially E. faecalis.

The use of immunosuppressive agents was an independent risk factor for E. faecium infection. Unlike E. faecalis, E. faecium recognizes peptidoglycan differences and has different acid production mechanisms that result in growth rate differences [2]. The recently increasing incidences of collagen diseases, hematologic malignancies, and solid tumors are thought to be related to increases in the number of patients undergoing immunosuppressive therapy; these patients are more likely to receive penicillin and cephalosporin antibiotics. Consequently, increased E. faecium levels have been reported with changes in the gut microbiota of the large and small intestines [28].

Our present study identified male sex and hypoalbuminemia as independent risk factors of enterococcal infections. However, these are not specific to enterococcal infections. There have been several reports on the correlation between sex and infection prognosis. Angele et al. reported that men have poorer prognosis of septicemia than women, and the main reasons include its correlation with male sex steroids, X-chromosome mosaicism, etc. [29]. Hypoalbuminemia is also a known risk factor related to the onset of and mortality caused by various infections [30].

The mortality rates of enterococcal infections including VRE are high (25–50 %) since they often develop in compromised hosts [31–37]. Enterococci are not highly pathogenic per se, and their survival rates mainly depend on underlying disease severity. However, the mortality rates of enterococcal infections in the present study (8.2 %) were low compared to those of previous reports. The likely reasons for this are as follows: VRE was not detected in this study; anti-MRSA agents such as vancomycin were immediately administered against E. faecium, and treatment with appropriate antimicrobial agents was administered during the early stages of onset; and nearly all subjects were inpatients undergoing careful pathologic monitoring. Patients who contracted E. faecium infections from carriers had significantly longer hospital stays on univariate analysis. This is probably because of the increased condition severity of the patients with E. faecium infections as well as a high degree of drug resistance that necessitated long-term antimicrobial agent use [35–37].