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Increase in Bloodstream Infection Due to Vancomycin-Susceptible Enterococcus faecium in Cancer Patients: Risk Factors, Molecular Epidemiology and Outcomes

Increase in Bloodstream Infection Due to Vancomycin-Susceptible Enterococcus faecium in Cancer... We conducted a prospective study to assess the risk factors, molecular epidemiology and outcome of bloodstream infection (BSI) due to Enterococcus faecium in hospitalized cancer patients. Between 2006 and 2012, a significant increase in vancomycin-susceptible E. faecium BSI was observed among cancer patients. Comparison of 54 episodes of BSI due to E. faecium with 38 episodes of BSI due to E. faecalis showed that previous use of carbapenems was the only independent risk factor for E. faecium acquisition (OR 10.24; 95% CI, 1.35-77.66). All E. faecium isolates were susceptible to glycopeptides, whereas 97% showed high-level resistance to ampicillin and ciprofloxacin. All 30 isolates available for genotyping belonged to the hospital-associated E. faecium lineages 17, 18 and 78. After 2009, most of the isolates belonged to ST117 (lineage 78). Patients with E. faecium BSI were more likely to receive inadequate initial empirical antibiotic therapy than patients with E. faecalis BSI, and time to adequate empirical antibiotic therapy was also longer in the former group. No significant differences were found between the two groups regarding early and overall case-fatality rates. Independent risk factors for overall case-fatality were current corticosteroids (OR 4.18; 95% CI, 1.34-13.01) and intensive care unit admission (OR 9.97; 95% CI, 1.96-50.63). The emergence of E. faecium among cancer patients is a concern since there are limited treatment options and it may presage the emergence of vancomycin-resistant enterococci. A rationale approach that combines infection control with antimicrobial stewardship. Citation: Gudiol C, Ayats J, Camoez M, Domínguez MÁ, García-Vidal C, et al. (2013) Increase in Bloodstream Infection Due to Vancomycin-Susceptible Enterococcus faecium in Cancer Patients: Risk Factors, Molecular Epidemiology and Outcomes. PLoS ONE 8(9): e74734. doi:10.1371/journal.pone. Editor: Willem van Schaik, University Medical Center Utrecht, Netherlands Received June 5, 2013; Accepted August 2, 2013; Published September 19, 2013 Copyright: © 2013 Gudiol et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by research grant REIPI RD06/0008 from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Spanish Network for the Research in Infectious Diseases. MB is the recipient of a research grant from the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain. The funding sources had no role in the study design, the collection, analysis and interpretation of the data or the decision to submit the manuscript for publication. Only the authors had full access to the data files for the study. The authors do not have any relationship that may constitute a dual or conflicting interest. Competing interests: The authors have declared that no competing interests exist. * E-mail: cgudiol@iconcologia.net (CG); jcarratala@bellvitgehospital.cat (JC) Introduction changing worldwide, and a number of trends have been recognized, notably, the global emergence of enterococci as Enterococci are part of the normal human microbial flora. important nosocomial pathogens and the emergence of Historically, the majority of invasive enterococcal infections resistance to commonly used antimicrobial agents, including were caused by Enterococcus faecalis, followed by penicillins, aminoglycosides and glycopeptides [1]. Enterococcus faecium [1]. In recent decades, however, the An increase in the number of E. faecium strains in hospitals epidemiology of invasive enterococcal infections appears to be in different countries has been documented during the last PLOS ONE | www.plosone.org 1 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients decade [2-4]. These isolates had in common not only the identifying information of each patient in the electronic antibiotic resistance traits (to ampicillin, quinolones and to database was encrypted. Informed consent was waived by the glycopeptides in some cases) but also several virulence factors Clinical Research Ethics Committee because no intervention that might have contributed to the success of E. faecium as a was involved and no patient identifying information was leading nosocomial pathogen [4,5]. Although these strains included. were initially classified within a single clonal complex 17, it appears that the genetic diversity of this CC allows the Definitions classification of all isolates in three main lineages (17, 18, and Neutropenia was defined as an absolute neutrophil count 78), which is a more accurate representation of the recent <500/mm . Current corticosteroid therapy was recorded when a evolution of these isolates[6]. patient was receiving corticosteroids at the time of the BSI Management of severe infections due to resistant episode or in the previous month. Prior antibiotic therapy was enterococcal strains, especially E. faecium, has therefore defined as the receipt of any systemic antibiotic for >48 hours become a therapeutical challenge. However, most of the during the previous month. BSI was considered to be from an reported experiences regarding enterococcal infections endogenous source in those patients with neutropenia in whom concern the general, non-immunocompromised population, and they mainly involve vancomycin-resistant strains [7-12]. no other BSI sites were identified. In those patients without Additionally, the majority of the studies published to date have neutropenia, an unknown source was considered if an evident been carried out in the United States, where the origin of the infection was not identified [16]. Shock was epidemiological situation is very different from that occurring in defined as a systolic pressure <90 mmHg that was Europe [1,13]. Furthermore, information regarding bloodstream unresponsive to fluid treatment or which required vasoactive infection (BSI) due to E. faecium in immunosuppressed drug therapy. Empirical antibiotic therapy was considered patients with cancer is particularly scarce [10,11,14,15]. Given inadequate if the treatment regimen did not include at least one the above, the aim of the present study was to describe the antibiotic active in vitro against the infecting microorganism. incidence and risk factors for vancomycin-susceptible E. Early case-fatality rate was defined as death within 48 hours of faecium BSI in a large prospective cohort of cancer patients. the BSI episode. Overall case-fatality rate was defined as We also aimed to ascertain the clinical features, antimicrobial death by any cause within the first 30 days of the onset of BSI. susceptibility, genotypes and outcome of BSI due to E. faecium in this population. Microbiological studies Blood cultures were performed by standard methods. Two Materials and Methods sets of two blood samples were drawn from patients with suspected bloodstream infection. Blood samples were Setting, patients and study design processed by the BACTEC 9240 system (Becton Dickinson We conducted a prospective observational study in a 200- Microbiology Systems) with an incubation period of five days. bed cancer referral centre for adults in Barcelona, Spain. From Positive blood samples were sub-cultured onto chocolate agar. 1 January 2006 to 30 September 2012 all hospitalized cancer Identification and antibiotic susceptibility were performed using patients and haematopoietic stem cell transplant recipients with at least one episode of BSI were included in the study. commercially available plates (MicroScan, Siemens), following Information on baseline characteristics, clinical features, the manufacturer’s instructions. The antimicrobial susceptibility empirical antibiotic therapy and outcome was carefully of isolates was interpreted according to current Clinical recorded in a specific database. Laboratory Standard Institute criteria [17]. All episodes of BSI due to vancomycin-susceptible E. Thirty E. faecium strains isolated between 2006 and 2012 faecium were compared with those caused by vancomycin- from single bacteraemic patients were available for genotyping. susceptible Enterococcus faecalis in order to identify the risk Pulsed field gel electrophoresis (PFGE) was performed in all factors for ampicillin resistance acquisition and to assess strains after SmaI restriction of chromosomal DNA, as differences in clinical features and outcome. We also compared previously described [18]. PFGE patterns were interpreted both patients who died with those who survived in order to identify by visual inspection, using the criteria of van Belkum et al. and risk factors for mortality. by analysis with the FINGERPRINTING TM II software, version All BSI episodes at our hospital are reported and followed up 3.0 (BioRad Laboratories, Inc., Madrid, Spain) [19]. by an infectious disease physician. Changes in antimicrobial Dendrograms were constructed using Dice coefficients, with treatment and general management were advised when optimization and band position tolerance being set to 0.5% and necessary. 1% respectively. A similarity coefficient of 80% was selected to define the patterns. Ethics statement Multilocus sequence typing (MLST) was conducted on 17 This observational study was approved by the Institutional representative strains of each SmaI-PFGE type, as described Review Board Comité Ético de Investigación Clínica del by Homan et al. [20]. Sequence types (STs) were assigned Hospital Universitari de Bellvitge (Ethics Committee of Clinical according to the E. faecium MLST database (http:// Research-Hospital Universitari de Bellvitge), with the following reference number PR 232/10. To protect personal privacy, efaecium.mlst.net). PLOS ONE | www.plosone.org 2 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients Statistical analysis Table 1. Baseline and clinical characteristics of all episodes Continuous variables were compared by means of the Mann- of enterococal bacteraemia and risk factors for E. faecium Whitney U test and t-test. Qualitative variables were compared acquisition. using the chi-square test, and odds ratios and 95% confidence intervals were calculated. Multivariate conditional logistic regression analysis of factors potentially associated with E. E. faecalis E. faecium p Adjusted OR p faecium acquisition and mortality included all statistically Characteristic n=38 (%) n=54 (%) (95%CI) significant variables in the univariate analysis, sex and age, 1.70 Male sex 27 (71) 32 (59) 0.27 0.55 and all clinically important variables regardless of whether they (0.29-9.81) were statistically significant or not [21]. This analysis was Age (yrs, median, 0.99 61 (26-78) 59 (21-83) 0.15 0.98 performed with the stepwise logistic regression model of the range) (0.94-1.05) SPSS software package (SPSS v. 17). Underlying disease 0.074 Solid tumour 15 (39.5) 12 (22) Results Haematological 23 (60.5) 42 (78) malignancy During the study period 1287 consecutive episodes of BSI Haematopoietic stem 2 (5) 7 (13) 0.29 were recorded. Of the 550 (42.5%) episodes caused by Gram- cell transplant (HSCT) positive bacteria, 105 were due to enterococci (19%). Thirteen Type of HSCT episodes of enterococcal BSI were not included in the study Autologous 1 1 0.41 because they were caused by species other than E. faecium or Allogeneic 0 4 - E. faecalis (E. gallinarum 6, E. casseliflavus 2, E. avium 2, E. Dual 1 2 - hirae 1, E. durans and E. raffinosus 1). Thus, 54 episodes of Graft-versus-host 0 2 (4) 0.50 BSI caused by E. faecium and 38 by E. faecalis were finally disease included in the study. Four patients with two episodes of Comorbidities 16 (42) 21 (39) 0.83 enterococcal BSI were included since they were considered to Diabetes mellitus 6 (16) 8 (15) 1.00 present different episodes, separated by at least four weeks. Chronic obstructive 2 (5) 1 (2) 0.56 The incidence of E. faecium BSI increased significantly over pulmonary disease time (22 episodes/126610 admissions from 2006 to 2009 vs 32 Chronic heart 7 (18) 7 (13) 0.56 episodes/80586 admissions from 2010 to September 2012; disease p=0.002). By contrast, the incidence of E. faecalis BSI Chronic renal failure 1 (3) 3 (6) 0.64 remained stable over time (p=0.215). Chronic liver disease 2 (5) 1 (2) 0.56 Table 1 shows the baseline and clinical characteristics of Neutrophil count < 500 19 (50) 35 (65) 0.19 patients with enterococcal BSI compared by groups. Patients Previous days with 0.99 with BSI due to E. faecium were more likely to have received neutropenia (< 500) 8 (0-35) 11 (1-60) 0.028 0.95 (0.92-1.07) previous antibiotics (mainly carbapenems), previous antifungal (median, range) prophylaxis and previous blood transfusion. Likewise, they had MASCC ≥ 21 9 (56) 17 (55) 1.00 more prolonged neutropenia than did patients with E. faecalis Chemotherapy (within 23 (60.5) 41 (76) 0.16 BSI, and were more likely to have a concomitant infection. In 1 month) addition, there was a trend in the former group of patients Radiotherapy (within 1 1 (3) 4 (7) 0.40 towards haematological malignancy as the most frequent month) underlying disease, and for there to be a venous catheter in Corticosteroid therapy 18 (47) 19 (35) 0.28 place. The most frequent origin of BSI was an endogenous (within 1 month) source in 38% of cases (41% in the E. faecium group vs 34% 1.31 Antifungal prophylaxis 12 (32) 32 (59) 0.011 0.77 in the E. faecalis group), followed by catheter infection in 15% (0.20-8.35) of cases (15% vs 16%, respectively) and cholangitis in 13% Previous antibiotic 10.24 (15% vs 10.5%, respectively). BSI originating in the urinary therapy (within 1 24 (63) 52 (96) <.001 0.024 (1.35-77.66) tract tended to be more frequent in the group of E. faecalis, month) whereas neutropenic enterocolitis tended to be more frequent Carbapenems 3 (12,5) 27 (52) 0.001 in the E. faecium group. After applying a logistic regression β-lactam + β-lactam 5 (21) 18 (35) 0.28 inhibitor model the only variable found to be an independent risk factors Cephalosporin 14 (58) 29 (56) 1.00 for E. faecium acquisition was previous use of carbapenems Quinolone 2 (8) 12 (23) 0.20 (OR 10.24; 95% CI, 1.35-77.66). Aminoglycoside 1 (4) 1 (2) 0.53 Glycopeptide 5 (21) 10 (19) 1.0 Microbiological studies Severe mucositis All E. faecium isolates were vancomycin and teicoplanin 3 (8) 10 (18.5) 0.22 (grade III-IV) susceptible. Only two strains (2.9%) of the 54 isolates were Urinary catheter 10 (26) 11 (21) 0.61 ampicillin susceptible with MICs ≤1 µg/mL. During the study Venous catheter 28 (74) 48 (89) 0.058 period 97.1% of strains showed high-level resistance to PLOS ONE | www.plosone.org 3 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients Table 1 (continued). Table 2. Antibiotic therapy and outcome of patients with enterococal bacteraemia compared by groups. E. faecalis E. faecium p Adjusted OR p Central venous E. faecalis E. faecium p 15 (39.5) 28 (52) 0.29 catheter n=38 (%) n=54 (%) Previous hospital Empirical antibiotic therapy 35 (92) 49 (91) 1.00 admission (within 3 16 (42) 26 (49) 0.53 months) Inadequate empirical antibiotic therapy 9 (24) 24 (44) 0.041 Previous ICU β-lactam + β-lactam inhibitor 13 (37) 9 (18) 0.054 admission (within 3 5 (13) 7 (13) 1.00 Cephalosporin 11 (31) 13 (26.5) 0.63 months) Carbapenem 8 (23) 13 (26.5) 0.80 Previous episode of 10 (26) 20 (38) 0.27 bacteremia Glycopeptide 10 (29) 25 (51) 0.046 Previous blood Quinolone 1 (3) 2 (4) 1.00 transfusion (within 5 10 (28) 26 (51) 0.046 0.57 (0.12-2.6) 0.48 Aminoglycoside 5 (14) 5 (10) 0.73 days) Combination therapy 8 (23) 6 (12) 0.24 8.4 Concomitant infection 4 (11) 15 (29) 0.041 0.076 (0.80-88.33) Days to adequate empirical antibiotic 0 (0-6) 1 (0-4) 0.036 Axillary temperature ≥ therapy (median, range) 35 (92) 46 (85) 0.51 38 C 5 (13) 7 (13) 1.00 Intensive care unit admission Polymicrobial 9 (24) 11 (20) 0.79 2 (6) 4 (8) 1.00 Mechanical ventilation bacteraemia Persistent bacteraemia 4 (11) 7 (15) 0.75 Overall case-fatality rate (30 days) 10 (26) 16 (30) 0.72 Shock at presentation 4 (10.5) 2 (4) 0.22 Early case-fatality rate (48 hours) 1 (3) 3 (6) 0.64 Source of bacteraemia doi: 10.1371/journal.pone.0074734.t002 Endogenous source 13 (34) 22 (41) 0.66 Gastrointestinal tract 3 (8) 3 (6) 0.68 Antibiotic treatment and patient outcomes are detailed in Neutropenic 1 (3) 8 (15) 0.076 Table 2. The large majority of patients received empirical enterocolitis Cholangitis 4 (10.5) 8 (15) 0.75 antibiotic therapy (91%). The most frequently antibiotic used Urinary tract 5 (13) 1 (2) 0.078 was a glycopeptide (42% of cases), followed by third- and Catheter-related 6 (16) 8 (15) 1.00 fourth-generation cephalosporins (29%), β-lactam plus β- Unknown 5 (13) 3 (6) 0.26 lactam inhibitors (26%) and carbapenems (25%). More patients doi: 10.1371/journal.pone.0074734.t001 with E. faecalis BSI received a combination of a β-lactam plus β-lactam inhibitor empirically, whereas more patients in the E. ampicillin, and the rates of high-level resistance to streptomycin faecium group were given a glycopeptide. Patients with E. and gentamycin were 74.6% and 32.8%, respectively. faecium BSI were more likely to have received inadequate Quinolone resistance accounted for 88.8% of the isolates, with initial empirical antibiotic therapy than were patients with E. MICs ≥4 µg/mL. faecalis BSI, and time to adequate empirical antibiotic therapy Among 30 ampicillin-resistant E. faecium strains available for was also longer in the former group. No significant differences genotyping, 13 PFGE patterns were obtained corresponding to were found between the two groups regarding other outcomes 7 STs (Figure 1). ST117 was dominant, accounting for 16 such as early and overall mortality rates. isolates (53.3%) belonging to PFGE type D (n=10; 62.5%) and Risk factors associated with overall case-fatality in the cohort PFGE type A (n=6; 37.5%). Five isolates (16.7%) belonged to of patients with enterococcal BSI are shown in Table 3. The ST17 of PFGE type B (n=4) and H (n=1), three isolates (10%) use of current corticosteroids, shock at presentation, intensive belonged to ST 78, two (6.7%), to ST18, two (6.7%) to ST203 care unit (ICU) admission, mechanical ventilation and unknown and one to ST192. A single isolate belonged to a new ST844 source of BSI were the variables most frequently found in the (Table S1). Considering the new classification recently group of patients who died. However, after applying a logistic proposed by Willems and co-workers, 5 isolates belonged to regression model the only variables found to be independent lineage 17 (ST17), two isolates belonged to lineage 18 (ST18) risk factors for overall case-fatality were the current use of and 23 isolates belonged to lineage 78 (ST78, ST117, ST192, corticosteroids (OR 4.18; 95% CI, 1.34-13.01) and ICU ST203 and ST844) [6]. From 2006 to 2009, one isolate out of admission (OR 9.97; 95% CI, 1.96-50.63). BSI due to E. eight available for genotyping belonged to ST117 (year 2009). faecium was not identified as a risk factor for overall mortality. In contrast, from 2010 to 2012, 15 out of 22 isolates belonged to ST117, with PFGE patterns D (n=10) and A (n=5). The allelic profiles for all different STs are detailed in Table S1. PLOS ONE | www.plosone.org 4 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients Figure 1. Cluster analysis of Pulsed-field Gel Electrophoresis (PFGE) SmaI macrorestriction fragments of the 30 Enterococcus faecium strains followed by multilocus sequence typing (MLST) data. MLST was inferred in those strains that were marked with an asterisk. For dendrogram construction, optimization and band position tolerance were set at 0.5% and 1.0% respectively. The cut-off value to define the PFGE patterns was set at 80% similarity. doi: 10.1371/journal.pone.0074734.g001 published to date are retrospective studies [11,14,15,22]. Thus, Discussion our study is the first prospective analysis of a cohort of cancer We observed a dramatic increase in the incidence of patients with vancomycin-susceptible E. faecium BSI to be ampicillin-resistant, vancomycin-susceptible E. faecium BSI in conducted at a time when enterococcal infections are gaining patients with cancer over the study period. Historically, E. importance worldwide, both in terms of dissemination and faecalis was the responsible for the large majority of all clinical antimicrobial resistance. It is also the first study to describe enterococcal infections, with E. faecium being less frequently how vancomycin-susceptible E. faecium outnumbers E. isolated. However, in the late 1990s the ratio of E. faecalis to E. faecalis in this high-risk population of patients with BSI in our faecium infections in the United States shifted in favour of E. geographical area. faecium, while in Europe the first reports of increased numbers Although several studies have focused on risk factors for of infections due to E. faecium were published in the mid-1990s vancomycin-resistant enterococcal infection or colonization [1,9,13]. Despite this, information regarding BSI caused by [23,24], little is known about risk factors for BSI due to vancomycin-susceptible E. faecium in immunosuppressed vancomycin-susceptible E. faecium. In our study we identified cancer patients is scarce in the literature, and all the articles previous use of carbapenems as the only independent risk PLOS ONE | www.plosone.org 5 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients PFGE and MLST analysis of 30 available E. faecium isolates Table 3. Risk factors for overall mortality (30 days) in the showed that all isolates belonged to the three major recently cohort of patients with enterococcal bacteraemia. described hospital-associated E. faecium lineages (17, 18 and 78) [6]. Of note, the ST117 (lineage 78) was especially frequent in the last three years, which may explain, at least partially, the E. faecalis E. faecium p Adjusted OR p emergence of E. faecium in our centre. This finding is in line Characteristic n=38 (%) n=54 (%) (95%CI) with recent molecular epidemiological studies that have Male sex 43 (65) 16 (61.5) 0.81 1.23 (0.38-3.89) 0.72 identified these three lineages (formerly CC17) as being Age (yrs, median, 61 (26-78) 59 (21-83) 0.15 0.99 (0.95-1.03 0.65 responsible for the worldwide emergence of ampicillin-resistant range) E. faecium. These three lineages have adapted extremely well Underlying to the hospital environment, including the acquisition of haematological 49 (74) 16 (61.5) 0.30 ampicillin resistance and the esp virulence gene, which is disease associated with biofilm formation. Therefore, these lineages Neutropenia (<500) 40 (61) 14 (54) 0.64 have become the leading cause of hospital-acquired E. 4.18 Corticosteroids 20 (30) 17 (65) 0.004 0.013 faecium infections and outbreaks [2-4,28]. The partial (1.34-13.01) replacement of ampicillin-susceptible E. faecalis by hospital- 3.43 Shock at presentation 1 (1.5) 5 (19) 0.006 0.34 associated lineages of ampicillin-resistant E. faecium is (0.27-43.70) worrying, since it may set the stage for the emergence of Inadequate empirical 26 (39) 7 (27) 0.33 vancomycin-resistant E. faecium. antibiotic therapy There is controversy in the literature regarding the 9.97 Intensive care unit 3 (4.5) 9 (35) <.001 0.006 (1.96-50.63) association between E. faecium infection and mortality. Some admission authors have reported increased mortality in those patients with Mechanical 1 (2) 5 (22) 0.005 BSI due to ampicillin-resistant E. faecium [7,10,16]. However, it ventilation 3.99 is still unclear if the increase in mortality actually depends on Unknown source of 3 (4.5) 5 (19) 0.038 0.12 (0.68-23.40) infection or, rather, whether infection behaves as a marker of bacteraemia the severity of underlying diseases [29]. In our study, and in E. faecium 38 (58) 16 (61.5) 0.81 bacteraemia line with some previous reports, we found no association doi: 10.1371/journal.pone.0074734.t003 between E. faecium BSI and increased mortality [8,9,14,28]. Interestingly, some in vitro studies have suggested that enterococcal virulence determinants are more frequently found factor associated with E. faecium BSI. Since the early research in E. faecalis isolates than in E. faecium isolates [30]. On the of Boyce et al., which related ampicillin-resistant enterococci to other hand, some studies have reported that E. faecium is the use of imipenem, several authors have demonstrated the more often resistant to phagocytosis than is E. faecalis [31]. association of ampicillin-resistant enterococci with β-lactams Whether there is a clinically relevant difference in virulence [9-11,16,25]. Antibiotics may facilitate colonization and infection between vancomycin-resistant enterococci and vancomycin- by depleting the gastrointestinal tract of its normal anaerobic susceptible enterococci, or between different enterococcal flora and by selecting enterococci due to limited bactericidal species is unknown. activity against these organisms. The use of broad spectrum β- The only variables found to be independent risk factors for lactams (including carbapenems) in patients with cancer and mortality in our study were ICU admission and current frequently-associated febrile neutropenia is very common in corticosteroid therapy. ICU admission is associated with severe clinical practice. Furthermore, the emergence of multidrug- sepsis and shock, which are known to be risk factors for resistant organisms (especially extended-spectrum β- mortality in patients with BSI [7]. Patients receiving lactamase-producing Enterobacteriaceae) among cancer corticosteroid therapy mainly corresponded to debilitated patients in our centre often forces us to use carbapenems as patients with severe uncontrolled underlying disease, who are the treatment of choice [26]. A judicious use of antibiotics is known to be a risk group for poor outcome. therefore needed in order to avoid the development and Patients with E. faecium BSI in our study were more likely to dissemination of bacterial resistance. receive inadequate empirical antibiotic therapy. Inadequate Our study shows that all the enterococci isolates remained empirical antibiotic therapy has previously been reported to be susceptible to glycopeptides. Although vancomycin resistance associated with mortality, especially in patients with Gram- has become an emerging health problem worldwide, it is less negative BSI and in those with vancomycin-resistant important in Europe than in the United States, and as yet it enterococcal infections [32]. However, this association was not does not seem to be a problem in our geographical area [1,13]. observed in our study. A retrospective study by DiazGranados However, the emergence of E. faecium is of potential concern et al. identified vancomycin-resistance as a risk factor for as it is more commonly associated with vancomycin resistance mortality in neutropenic cancer patients. However, it was not than are the other enterococci [27]. The large majority of E. associated with inadequate empirical antibiotic therapy, but faecium isolates showed a high level of resistance to ampicillin, and only two strains were ampicillin susceptible. Notably, the rather was attributed to prolonged duration of BSI [15]. Factors two patients carrying the two susceptible strains had not influencing mortality among cancer patients are often difficult to received carbapenems previously. asses. PLOS ONE | www.plosone.org 6 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients The emergence of E. faecium in immunosuppressed patients was responsible for the large majority of E. faecium infections, with cancer is a concern, since there are limited therapeutic particularly in recent years. The emergence of E. faecium options for these organisms. Although new antimicrobials, such among immunosuppressed cancer patients is worrying since as linezolid, daptomycin and quinupristin/dalfopristin, have there are limited treatment options and it may presage the recently been developed to treat serious enterococcal emergence of vancomycin-resistant enterococci. Addressing infections, resistance to these agents has already emerged this trend for enterococci requires a rational approach that [33-35]. combines infection control with antimicrobial stewardship. This study has a number of strengths. It describes the incidence of E. faecium BSI in a large cohort of BSI episodes Supporting Information prospectively collected in a specific immunosuppressed high- risk population. Additionally, it provides information regarding Table S1. Allelic profiles among 17 E. faecium blood the E. faecium clonal complexes identified during the study isolates. period. However, it also has certain limitations. The small (DOC) number of patients in the two groups may have prevented us from identifying significant differences between them. Also, as Author Contributions this was a single-centre study the results may have been influenced by local epidemiological variables, thereby limiting Conceived and designed the experiments: CG JC. Performed their applicability to other settings. the experiments: CG JA MC MAD CA. Analyzed the data: CG In conclusion, we found a significant increase in vancomycin- CGV MO. Contributed reagents/materials/analysis tools: MB M. susceptible E. faecium BSI among cancer patients, especially Arnan M. Antonio. Wrote the manuscript: CG MAD FA JC. those treated previously with carbapenems. Clonal complex 17 References 1. Arias CA, Murray BE (2012) The rise of the Enterococcus: beyond de bacteriemia por enterococo: estudio de la epidemiología, vancomycin resistance. Nat Rev Microbiol 10: 266-278. doi:10.1038/ microbiología y evolución clínica. Enfer Infecc Microbiol Clin 25: nrmicro2761. PubMed: 22421879. 503-507. doi:10.1157/13109986. 2. Werner G, Coque TM, Hammerum AM, Hope R, Hryniewicz W et al. 13. 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CLSI Document M100-S20. Wayne, PA: Clinical and Restricted gene flow among hospital subpopulations of Enterococcus Laboratory Standards Institute. faecium. mBio 3: e00151-12. PubMed: 22807567. 18. Coque TM, Willems RJ, Fortún J, Top J, Diz S et al. (2005) Population 7. McBride SJ, Upton A, Roberts SA (2010) Clinical characteristics and structure of Enterococcus faecium causing bacteremia in a Spanish outcomes of patients with vancomycin-susceptible Enterococcus university hospital: setting the scene for a future increase in faecalis and Enterococcus faecium bacteremia: a five-year vancomycin resistance? Antimicrob Agents Chemother 49: 2693-2700. retrospective study. Eur J Clin Microbiol Infect Dis 29: 107-114. doi: doi:10.1128/AAC.49.7.2693-2700.2005. PubMed: 15980338. 10.1007/s10096-009-0830-5. PubMed: 19916034. 19. van Belkum A, Tassios PT, Dijkshoorn L, Haeggman S, Cookson B et 8. Suppola JP, Kuikka A, Vaara M, Valtonen VV (1998) Comparison of al. 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Hosmer DW, Lemeshow S (2000) Logistic regression: variable for and risk factors associated with vancomycin-resistant Enterococcus selection. In: DW HosmerS Lemeshow. Applied logistic regression. 2nd faecalis and vancomycin-resistant Enterococcus faecium bacteremia in ed. New York, NY: John Willey & Sons. cancer patients. Infect Control Hosp Epidemiol 28: 1054-1059. doi: 22. Cherif H, Kronvall G, Björkholm M, Kalin M (2003) Bacteremia in 10.1086/519932. PubMed: 17932826. hospitalised patients with malignant blood disorders: a retrospective 11. Conde-Estévez D, Grau S, Albanell J, Terradas R, Salvadó M et al. study of causative agents and their resistance profiles during a 14-year (2011) Clinical characteristics and outcomes of patients with period without antibacterial prophylaxis. Hematol J 4: 420-426. doi: vancomycin-susceptible Enterococcus faecalis and Enterococcus 10.1038/sj.thj.6200334. PubMed: 14671614. faecium bacteremia in cancer patients. Eur J Clin Microbiol Infect Dis 23. Pan SC, Wang JT, Chen YC, Chang YY, Chen ML et al. (2012) 30: 103-108. doi:10.1007/s10096-010-1029-5. PubMed: 20711795. Incidence of and risk factors for infection or colonization of vancomycin- 12. Martínez-Odriozola P, Muñoz-Sánchez J, Gutiérrez-Macías A, Arriola- resistant enterococci in patients in the intensive care unit. PLOS ONE Martínez P, Montero-Aparicio E et al. (2007) Análisis de 182 episodios 7: e47297. doi:10.1371/journal.pone.0047297. PubMed: 23071778. PLOS ONE | www.plosone.org 7 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients 24. Almyroudis NG, Lesse AJ, Hahn T, Samonis G, Hazamy PA et al. 30. Mundy LM, Sahm DF, Gilmore M (2000) Relationships between (2011) Molecular epidemiology and risk factors for colonization enterococcal virulence and antimicrobial resistance. Clin Microbiol Rev by vancomycin-resistant Enterococcus in patients with hematologic 13: 513-522. doi:10.1128/CMR.13.4.513-522.2000. PubMed: malignancies. 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PubMed: producing Escherichia coli (ESBL-EC) in cancer patients: clinical 16007529. features, risk factors, molecular epidemiology and outcome. J 33. Arias CA, Murray BE (2008) Emergence and management of drug- Antimicrob Chemother 65: 333-341. doi:10.1093/jac/dkp411. PubMed: resistant enterococcal infections. Expert Rev Anti Infect Ther 6: 19959544. 637-655. doi:10.1586/14787210.6.5.637. PubMed: 18847403. 27. Rice LB (2001) Emergence of vancomycin-resistant enterococci. 34. Mishra NN, Bayer AS, Tran TT, Shamoo Y, Mileykovskaya E et al. Emerg Infect Dis 7: 183-187. doi:10.3201/eid0702.010205. PubMed: (2012) Daptomycin resistance in enterococci is associated with distinct 11294702. alterations of cell membrane phospholipid content. PLOS ONE 7: 28. Top J, Willems R, van der Velden S, Asbroek M, Bonten M (2008) e43958. doi:10.1371/journal.pone.0043958. PubMed: 22952824. Emergence of clinal complex 17 Enterococcus faecium in the 35. Prystowsky J, Siddiqui F, Chosay J, Shinabarger DL, Millichap J et al. Netherlands. J Clin Microbiol 46: 214-219. doi:10.1128/JCM.01351-07. (2001) Resistance to linezolid: characterization of mutations in rRNA PubMed: 17977983. and comparison of their occurrences in vancomycin-resistant 29. Garbutt JM, Ventrapragrada M, Littenberg B, Mundy LM (2000) enterococci. Antimicrob Agents Chemother 45: 2154-2156. doi: Association between resistance to vancomycin and deaths in cases of 10.1128/AAC.45.7.2154-2156.2001. PubMed: 11408243. Enterococcus faecium bacteraemia. Clin Infect Dis 30: 46. PLOS ONE | www.plosone.org 8 September 2013 | Volume 8 | Issue 9 | e74734 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png PLoS ONE Pubmed Central

Increase in Bloodstream Infection Due to Vancomycin-Susceptible Enterococcus faecium in Cancer Patients: Risk Factors, Molecular Epidemiology and Outcomes

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Abstract

We conducted a prospective study to assess the risk factors, molecular epidemiology and outcome of bloodstream infection (BSI) due to Enterococcus faecium in hospitalized cancer patients. Between 2006 and 2012, a significant increase in vancomycin-susceptible E. faecium BSI was observed among cancer patients. Comparison of 54 episodes of BSI due to E. faecium with 38 episodes of BSI due to E. faecalis showed that previous use of carbapenems was the only independent risk factor for E. faecium acquisition (OR 10.24; 95% CI, 1.35-77.66). All E. faecium isolates were susceptible to glycopeptides, whereas 97% showed high-level resistance to ampicillin and ciprofloxacin. All 30 isolates available for genotyping belonged to the hospital-associated E. faecium lineages 17, 18 and 78. After 2009, most of the isolates belonged to ST117 (lineage 78). Patients with E. faecium BSI were more likely to receive inadequate initial empirical antibiotic therapy than patients with E. faecalis BSI, and time to adequate empirical antibiotic therapy was also longer in the former group. No significant differences were found between the two groups regarding early and overall case-fatality rates. Independent risk factors for overall case-fatality were current corticosteroids (OR 4.18; 95% CI, 1.34-13.01) and intensive care unit admission (OR 9.97; 95% CI, 1.96-50.63). The emergence of E. faecium among cancer patients is a concern since there are limited treatment options and it may presage the emergence of vancomycin-resistant enterococci. A rationale approach that combines infection control with antimicrobial stewardship. Citation: Gudiol C, Ayats J, Camoez M, Domínguez MÁ, García-Vidal C, et al. (2013) Increase in Bloodstream Infection Due to Vancomycin-Susceptible Enterococcus faecium in Cancer Patients: Risk Factors, Molecular Epidemiology and Outcomes. PLoS ONE 8(9): e74734. doi:10.1371/journal.pone. Editor: Willem van Schaik, University Medical Center Utrecht, Netherlands Received June 5, 2013; Accepted August 2, 2013; Published September 19, 2013 Copyright: © 2013 Gudiol et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by research grant REIPI RD06/0008 from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Spanish Network for the Research in Infectious Diseases. MB is the recipient of a research grant from the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain. The funding sources had no role in the study design, the collection, analysis and interpretation of the data or the decision to submit the manuscript for publication. Only the authors had full access to the data files for the study. The authors do not have any relationship that may constitute a dual or conflicting interest. Competing interests: The authors have declared that no competing interests exist. * E-mail: cgudiol@iconcologia.net (CG); jcarratala@bellvitgehospital.cat (JC) Introduction changing worldwide, and a number of trends have been recognized, notably, the global emergence of enterococci as Enterococci are part of the normal human microbial flora. important nosocomial pathogens and the emergence of Historically, the majority of invasive enterococcal infections resistance to commonly used antimicrobial agents, including were caused by Enterococcus faecalis, followed by penicillins, aminoglycosides and glycopeptides [1]. Enterococcus faecium [1]. In recent decades, however, the An increase in the number of E. faecium strains in hospitals epidemiology of invasive enterococcal infections appears to be in different countries has been documented during the last PLOS ONE | www.plosone.org 1 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients decade [2-4]. These isolates had in common not only the identifying information of each patient in the electronic antibiotic resistance traits (to ampicillin, quinolones and to database was encrypted. Informed consent was waived by the glycopeptides in some cases) but also several virulence factors Clinical Research Ethics Committee because no intervention that might have contributed to the success of E. faecium as a was involved and no patient identifying information was leading nosocomial pathogen [4,5]. Although these strains included. were initially classified within a single clonal complex 17, it appears that the genetic diversity of this CC allows the Definitions classification of all isolates in three main lineages (17, 18, and Neutropenia was defined as an absolute neutrophil count 78), which is a more accurate representation of the recent <500/mm . Current corticosteroid therapy was recorded when a evolution of these isolates[6]. patient was receiving corticosteroids at the time of the BSI Management of severe infections due to resistant episode or in the previous month. Prior antibiotic therapy was enterococcal strains, especially E. faecium, has therefore defined as the receipt of any systemic antibiotic for >48 hours become a therapeutical challenge. However, most of the during the previous month. BSI was considered to be from an reported experiences regarding enterococcal infections endogenous source in those patients with neutropenia in whom concern the general, non-immunocompromised population, and they mainly involve vancomycin-resistant strains [7-12]. no other BSI sites were identified. In those patients without Additionally, the majority of the studies published to date have neutropenia, an unknown source was considered if an evident been carried out in the United States, where the origin of the infection was not identified [16]. Shock was epidemiological situation is very different from that occurring in defined as a systolic pressure <90 mmHg that was Europe [1,13]. Furthermore, information regarding bloodstream unresponsive to fluid treatment or which required vasoactive infection (BSI) due to E. faecium in immunosuppressed drug therapy. Empirical antibiotic therapy was considered patients with cancer is particularly scarce [10,11,14,15]. Given inadequate if the treatment regimen did not include at least one the above, the aim of the present study was to describe the antibiotic active in vitro against the infecting microorganism. incidence and risk factors for vancomycin-susceptible E. Early case-fatality rate was defined as death within 48 hours of faecium BSI in a large prospective cohort of cancer patients. the BSI episode. Overall case-fatality rate was defined as We also aimed to ascertain the clinical features, antimicrobial death by any cause within the first 30 days of the onset of BSI. susceptibility, genotypes and outcome of BSI due to E. faecium in this population. Microbiological studies Blood cultures were performed by standard methods. Two Materials and Methods sets of two blood samples were drawn from patients with suspected bloodstream infection. Blood samples were Setting, patients and study design processed by the BACTEC 9240 system (Becton Dickinson We conducted a prospective observational study in a 200- Microbiology Systems) with an incubation period of five days. bed cancer referral centre for adults in Barcelona, Spain. From Positive blood samples were sub-cultured onto chocolate agar. 1 January 2006 to 30 September 2012 all hospitalized cancer Identification and antibiotic susceptibility were performed using patients and haematopoietic stem cell transplant recipients with at least one episode of BSI were included in the study. commercially available plates (MicroScan, Siemens), following Information on baseline characteristics, clinical features, the manufacturer’s instructions. The antimicrobial susceptibility empirical antibiotic therapy and outcome was carefully of isolates was interpreted according to current Clinical recorded in a specific database. Laboratory Standard Institute criteria [17]. All episodes of BSI due to vancomycin-susceptible E. Thirty E. faecium strains isolated between 2006 and 2012 faecium were compared with those caused by vancomycin- from single bacteraemic patients were available for genotyping. susceptible Enterococcus faecalis in order to identify the risk Pulsed field gel electrophoresis (PFGE) was performed in all factors for ampicillin resistance acquisition and to assess strains after SmaI restriction of chromosomal DNA, as differences in clinical features and outcome. We also compared previously described [18]. PFGE patterns were interpreted both patients who died with those who survived in order to identify by visual inspection, using the criteria of van Belkum et al. and risk factors for mortality. by analysis with the FINGERPRINTING TM II software, version All BSI episodes at our hospital are reported and followed up 3.0 (BioRad Laboratories, Inc., Madrid, Spain) [19]. by an infectious disease physician. Changes in antimicrobial Dendrograms were constructed using Dice coefficients, with treatment and general management were advised when optimization and band position tolerance being set to 0.5% and necessary. 1% respectively. A similarity coefficient of 80% was selected to define the patterns. Ethics statement Multilocus sequence typing (MLST) was conducted on 17 This observational study was approved by the Institutional representative strains of each SmaI-PFGE type, as described Review Board Comité Ético de Investigación Clínica del by Homan et al. [20]. Sequence types (STs) were assigned Hospital Universitari de Bellvitge (Ethics Committee of Clinical according to the E. faecium MLST database (http:// Research-Hospital Universitari de Bellvitge), with the following reference number PR 232/10. To protect personal privacy, efaecium.mlst.net). PLOS ONE | www.plosone.org 2 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients Statistical analysis Table 1. Baseline and clinical characteristics of all episodes Continuous variables were compared by means of the Mann- of enterococal bacteraemia and risk factors for E. faecium Whitney U test and t-test. Qualitative variables were compared acquisition. using the chi-square test, and odds ratios and 95% confidence intervals were calculated. Multivariate conditional logistic regression analysis of factors potentially associated with E. E. faecalis E. faecium p Adjusted OR p faecium acquisition and mortality included all statistically Characteristic n=38 (%) n=54 (%) (95%CI) significant variables in the univariate analysis, sex and age, 1.70 Male sex 27 (71) 32 (59) 0.27 0.55 and all clinically important variables regardless of whether they (0.29-9.81) were statistically significant or not [21]. This analysis was Age (yrs, median, 0.99 61 (26-78) 59 (21-83) 0.15 0.98 performed with the stepwise logistic regression model of the range) (0.94-1.05) SPSS software package (SPSS v. 17). Underlying disease 0.074 Solid tumour 15 (39.5) 12 (22) Results Haematological 23 (60.5) 42 (78) malignancy During the study period 1287 consecutive episodes of BSI Haematopoietic stem 2 (5) 7 (13) 0.29 were recorded. Of the 550 (42.5%) episodes caused by Gram- cell transplant (HSCT) positive bacteria, 105 were due to enterococci (19%). Thirteen Type of HSCT episodes of enterococcal BSI were not included in the study Autologous 1 1 0.41 because they were caused by species other than E. faecium or Allogeneic 0 4 - E. faecalis (E. gallinarum 6, E. casseliflavus 2, E. avium 2, E. Dual 1 2 - hirae 1, E. durans and E. raffinosus 1). Thus, 54 episodes of Graft-versus-host 0 2 (4) 0.50 BSI caused by E. faecium and 38 by E. faecalis were finally disease included in the study. Four patients with two episodes of Comorbidities 16 (42) 21 (39) 0.83 enterococcal BSI were included since they were considered to Diabetes mellitus 6 (16) 8 (15) 1.00 present different episodes, separated by at least four weeks. Chronic obstructive 2 (5) 1 (2) 0.56 The incidence of E. faecium BSI increased significantly over pulmonary disease time (22 episodes/126610 admissions from 2006 to 2009 vs 32 Chronic heart 7 (18) 7 (13) 0.56 episodes/80586 admissions from 2010 to September 2012; disease p=0.002). By contrast, the incidence of E. faecalis BSI Chronic renal failure 1 (3) 3 (6) 0.64 remained stable over time (p=0.215). Chronic liver disease 2 (5) 1 (2) 0.56 Table 1 shows the baseline and clinical characteristics of Neutrophil count < 500 19 (50) 35 (65) 0.19 patients with enterococcal BSI compared by groups. Patients Previous days with 0.99 with BSI due to E. faecium were more likely to have received neutropenia (< 500) 8 (0-35) 11 (1-60) 0.028 0.95 (0.92-1.07) previous antibiotics (mainly carbapenems), previous antifungal (median, range) prophylaxis and previous blood transfusion. Likewise, they had MASCC ≥ 21 9 (56) 17 (55) 1.00 more prolonged neutropenia than did patients with E. faecalis Chemotherapy (within 23 (60.5) 41 (76) 0.16 BSI, and were more likely to have a concomitant infection. In 1 month) addition, there was a trend in the former group of patients Radiotherapy (within 1 1 (3) 4 (7) 0.40 towards haematological malignancy as the most frequent month) underlying disease, and for there to be a venous catheter in Corticosteroid therapy 18 (47) 19 (35) 0.28 place. The most frequent origin of BSI was an endogenous (within 1 month) source in 38% of cases (41% in the E. faecium group vs 34% 1.31 Antifungal prophylaxis 12 (32) 32 (59) 0.011 0.77 in the E. faecalis group), followed by catheter infection in 15% (0.20-8.35) of cases (15% vs 16%, respectively) and cholangitis in 13% Previous antibiotic 10.24 (15% vs 10.5%, respectively). BSI originating in the urinary therapy (within 1 24 (63) 52 (96) <.001 0.024 (1.35-77.66) tract tended to be more frequent in the group of E. faecalis, month) whereas neutropenic enterocolitis tended to be more frequent Carbapenems 3 (12,5) 27 (52) 0.001 in the E. faecium group. After applying a logistic regression β-lactam + β-lactam 5 (21) 18 (35) 0.28 inhibitor model the only variable found to be an independent risk factors Cephalosporin 14 (58) 29 (56) 1.00 for E. faecium acquisition was previous use of carbapenems Quinolone 2 (8) 12 (23) 0.20 (OR 10.24; 95% CI, 1.35-77.66). Aminoglycoside 1 (4) 1 (2) 0.53 Glycopeptide 5 (21) 10 (19) 1.0 Microbiological studies Severe mucositis All E. faecium isolates were vancomycin and teicoplanin 3 (8) 10 (18.5) 0.22 (grade III-IV) susceptible. Only two strains (2.9%) of the 54 isolates were Urinary catheter 10 (26) 11 (21) 0.61 ampicillin susceptible with MICs ≤1 µg/mL. During the study Venous catheter 28 (74) 48 (89) 0.058 period 97.1% of strains showed high-level resistance to PLOS ONE | www.plosone.org 3 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients Table 1 (continued). Table 2. Antibiotic therapy and outcome of patients with enterococal bacteraemia compared by groups. E. faecalis E. faecium p Adjusted OR p Central venous E. faecalis E. faecium p 15 (39.5) 28 (52) 0.29 catheter n=38 (%) n=54 (%) Previous hospital Empirical antibiotic therapy 35 (92) 49 (91) 1.00 admission (within 3 16 (42) 26 (49) 0.53 months) Inadequate empirical antibiotic therapy 9 (24) 24 (44) 0.041 Previous ICU β-lactam + β-lactam inhibitor 13 (37) 9 (18) 0.054 admission (within 3 5 (13) 7 (13) 1.00 Cephalosporin 11 (31) 13 (26.5) 0.63 months) Carbapenem 8 (23) 13 (26.5) 0.80 Previous episode of 10 (26) 20 (38) 0.27 bacteremia Glycopeptide 10 (29) 25 (51) 0.046 Previous blood Quinolone 1 (3) 2 (4) 1.00 transfusion (within 5 10 (28) 26 (51) 0.046 0.57 (0.12-2.6) 0.48 Aminoglycoside 5 (14) 5 (10) 0.73 days) Combination therapy 8 (23) 6 (12) 0.24 8.4 Concomitant infection 4 (11) 15 (29) 0.041 0.076 (0.80-88.33) Days to adequate empirical antibiotic 0 (0-6) 1 (0-4) 0.036 Axillary temperature ≥ therapy (median, range) 35 (92) 46 (85) 0.51 38 C 5 (13) 7 (13) 1.00 Intensive care unit admission Polymicrobial 9 (24) 11 (20) 0.79 2 (6) 4 (8) 1.00 Mechanical ventilation bacteraemia Persistent bacteraemia 4 (11) 7 (15) 0.75 Overall case-fatality rate (30 days) 10 (26) 16 (30) 0.72 Shock at presentation 4 (10.5) 2 (4) 0.22 Early case-fatality rate (48 hours) 1 (3) 3 (6) 0.64 Source of bacteraemia doi: 10.1371/journal.pone.0074734.t002 Endogenous source 13 (34) 22 (41) 0.66 Gastrointestinal tract 3 (8) 3 (6) 0.68 Antibiotic treatment and patient outcomes are detailed in Neutropenic 1 (3) 8 (15) 0.076 Table 2. The large majority of patients received empirical enterocolitis Cholangitis 4 (10.5) 8 (15) 0.75 antibiotic therapy (91%). The most frequently antibiotic used Urinary tract 5 (13) 1 (2) 0.078 was a glycopeptide (42% of cases), followed by third- and Catheter-related 6 (16) 8 (15) 1.00 fourth-generation cephalosporins (29%), β-lactam plus β- Unknown 5 (13) 3 (6) 0.26 lactam inhibitors (26%) and carbapenems (25%). More patients doi: 10.1371/journal.pone.0074734.t001 with E. faecalis BSI received a combination of a β-lactam plus β-lactam inhibitor empirically, whereas more patients in the E. ampicillin, and the rates of high-level resistance to streptomycin faecium group were given a glycopeptide. Patients with E. and gentamycin were 74.6% and 32.8%, respectively. faecium BSI were more likely to have received inadequate Quinolone resistance accounted for 88.8% of the isolates, with initial empirical antibiotic therapy than were patients with E. MICs ≥4 µg/mL. faecalis BSI, and time to adequate empirical antibiotic therapy Among 30 ampicillin-resistant E. faecium strains available for was also longer in the former group. No significant differences genotyping, 13 PFGE patterns were obtained corresponding to were found between the two groups regarding other outcomes 7 STs (Figure 1). ST117 was dominant, accounting for 16 such as early and overall mortality rates. isolates (53.3%) belonging to PFGE type D (n=10; 62.5%) and Risk factors associated with overall case-fatality in the cohort PFGE type A (n=6; 37.5%). Five isolates (16.7%) belonged to of patients with enterococcal BSI are shown in Table 3. The ST17 of PFGE type B (n=4) and H (n=1), three isolates (10%) use of current corticosteroids, shock at presentation, intensive belonged to ST 78, two (6.7%), to ST18, two (6.7%) to ST203 care unit (ICU) admission, mechanical ventilation and unknown and one to ST192. A single isolate belonged to a new ST844 source of BSI were the variables most frequently found in the (Table S1). Considering the new classification recently group of patients who died. However, after applying a logistic proposed by Willems and co-workers, 5 isolates belonged to regression model the only variables found to be independent lineage 17 (ST17), two isolates belonged to lineage 18 (ST18) risk factors for overall case-fatality were the current use of and 23 isolates belonged to lineage 78 (ST78, ST117, ST192, corticosteroids (OR 4.18; 95% CI, 1.34-13.01) and ICU ST203 and ST844) [6]. From 2006 to 2009, one isolate out of admission (OR 9.97; 95% CI, 1.96-50.63). BSI due to E. eight available for genotyping belonged to ST117 (year 2009). faecium was not identified as a risk factor for overall mortality. In contrast, from 2010 to 2012, 15 out of 22 isolates belonged to ST117, with PFGE patterns D (n=10) and A (n=5). The allelic profiles for all different STs are detailed in Table S1. PLOS ONE | www.plosone.org 4 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients Figure 1. Cluster analysis of Pulsed-field Gel Electrophoresis (PFGE) SmaI macrorestriction fragments of the 30 Enterococcus faecium strains followed by multilocus sequence typing (MLST) data. MLST was inferred in those strains that were marked with an asterisk. For dendrogram construction, optimization and band position tolerance were set at 0.5% and 1.0% respectively. The cut-off value to define the PFGE patterns was set at 80% similarity. doi: 10.1371/journal.pone.0074734.g001 published to date are retrospective studies [11,14,15,22]. Thus, Discussion our study is the first prospective analysis of a cohort of cancer We observed a dramatic increase in the incidence of patients with vancomycin-susceptible E. faecium BSI to be ampicillin-resistant, vancomycin-susceptible E. faecium BSI in conducted at a time when enterococcal infections are gaining patients with cancer over the study period. Historically, E. importance worldwide, both in terms of dissemination and faecalis was the responsible for the large majority of all clinical antimicrobial resistance. It is also the first study to describe enterococcal infections, with E. faecium being less frequently how vancomycin-susceptible E. faecium outnumbers E. isolated. However, in the late 1990s the ratio of E. faecalis to E. faecalis in this high-risk population of patients with BSI in our faecium infections in the United States shifted in favour of E. geographical area. faecium, while in Europe the first reports of increased numbers Although several studies have focused on risk factors for of infections due to E. faecium were published in the mid-1990s vancomycin-resistant enterococcal infection or colonization [1,9,13]. Despite this, information regarding BSI caused by [23,24], little is known about risk factors for BSI due to vancomycin-susceptible E. faecium in immunosuppressed vancomycin-susceptible E. faecium. In our study we identified cancer patients is scarce in the literature, and all the articles previous use of carbapenems as the only independent risk PLOS ONE | www.plosone.org 5 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients PFGE and MLST analysis of 30 available E. faecium isolates Table 3. Risk factors for overall mortality (30 days) in the showed that all isolates belonged to the three major recently cohort of patients with enterococcal bacteraemia. described hospital-associated E. faecium lineages (17, 18 and 78) [6]. Of note, the ST117 (lineage 78) was especially frequent in the last three years, which may explain, at least partially, the E. faecalis E. faecium p Adjusted OR p emergence of E. faecium in our centre. This finding is in line Characteristic n=38 (%) n=54 (%) (95%CI) with recent molecular epidemiological studies that have Male sex 43 (65) 16 (61.5) 0.81 1.23 (0.38-3.89) 0.72 identified these three lineages (formerly CC17) as being Age (yrs, median, 61 (26-78) 59 (21-83) 0.15 0.99 (0.95-1.03 0.65 responsible for the worldwide emergence of ampicillin-resistant range) E. faecium. These three lineages have adapted extremely well Underlying to the hospital environment, including the acquisition of haematological 49 (74) 16 (61.5) 0.30 ampicillin resistance and the esp virulence gene, which is disease associated with biofilm formation. Therefore, these lineages Neutropenia (<500) 40 (61) 14 (54) 0.64 have become the leading cause of hospital-acquired E. 4.18 Corticosteroids 20 (30) 17 (65) 0.004 0.013 faecium infections and outbreaks [2-4,28]. The partial (1.34-13.01) replacement of ampicillin-susceptible E. faecalis by hospital- 3.43 Shock at presentation 1 (1.5) 5 (19) 0.006 0.34 associated lineages of ampicillin-resistant E. faecium is (0.27-43.70) worrying, since it may set the stage for the emergence of Inadequate empirical 26 (39) 7 (27) 0.33 vancomycin-resistant E. faecium. antibiotic therapy There is controversy in the literature regarding the 9.97 Intensive care unit 3 (4.5) 9 (35) <.001 0.006 (1.96-50.63) association between E. faecium infection and mortality. Some admission authors have reported increased mortality in those patients with Mechanical 1 (2) 5 (22) 0.005 BSI due to ampicillin-resistant E. faecium [7,10,16]. However, it ventilation 3.99 is still unclear if the increase in mortality actually depends on Unknown source of 3 (4.5) 5 (19) 0.038 0.12 (0.68-23.40) infection or, rather, whether infection behaves as a marker of bacteraemia the severity of underlying diseases [29]. In our study, and in E. faecium 38 (58) 16 (61.5) 0.81 bacteraemia line with some previous reports, we found no association doi: 10.1371/journal.pone.0074734.t003 between E. faecium BSI and increased mortality [8,9,14,28]. Interestingly, some in vitro studies have suggested that enterococcal virulence determinants are more frequently found factor associated with E. faecium BSI. Since the early research in E. faecalis isolates than in E. faecium isolates [30]. On the of Boyce et al., which related ampicillin-resistant enterococci to other hand, some studies have reported that E. faecium is the use of imipenem, several authors have demonstrated the more often resistant to phagocytosis than is E. faecalis [31]. association of ampicillin-resistant enterococci with β-lactams Whether there is a clinically relevant difference in virulence [9-11,16,25]. Antibiotics may facilitate colonization and infection between vancomycin-resistant enterococci and vancomycin- by depleting the gastrointestinal tract of its normal anaerobic susceptible enterococci, or between different enterococcal flora and by selecting enterococci due to limited bactericidal species is unknown. activity against these organisms. The use of broad spectrum β- The only variables found to be independent risk factors for lactams (including carbapenems) in patients with cancer and mortality in our study were ICU admission and current frequently-associated febrile neutropenia is very common in corticosteroid therapy. ICU admission is associated with severe clinical practice. Furthermore, the emergence of multidrug- sepsis and shock, which are known to be risk factors for resistant organisms (especially extended-spectrum β- mortality in patients with BSI [7]. Patients receiving lactamase-producing Enterobacteriaceae) among cancer corticosteroid therapy mainly corresponded to debilitated patients in our centre often forces us to use carbapenems as patients with severe uncontrolled underlying disease, who are the treatment of choice [26]. A judicious use of antibiotics is known to be a risk group for poor outcome. therefore needed in order to avoid the development and Patients with E. faecium BSI in our study were more likely to dissemination of bacterial resistance. receive inadequate empirical antibiotic therapy. Inadequate Our study shows that all the enterococci isolates remained empirical antibiotic therapy has previously been reported to be susceptible to glycopeptides. Although vancomycin resistance associated with mortality, especially in patients with Gram- has become an emerging health problem worldwide, it is less negative BSI and in those with vancomycin-resistant important in Europe than in the United States, and as yet it enterococcal infections [32]. However, this association was not does not seem to be a problem in our geographical area [1,13]. observed in our study. A retrospective study by DiazGranados However, the emergence of E. faecium is of potential concern et al. identified vancomycin-resistance as a risk factor for as it is more commonly associated with vancomycin resistance mortality in neutropenic cancer patients. However, it was not than are the other enterococci [27]. The large majority of E. associated with inadequate empirical antibiotic therapy, but faecium isolates showed a high level of resistance to ampicillin, and only two strains were ampicillin susceptible. Notably, the rather was attributed to prolonged duration of BSI [15]. Factors two patients carrying the two susceptible strains had not influencing mortality among cancer patients are often difficult to received carbapenems previously. asses. PLOS ONE | www.plosone.org 6 September 2013 | Volume 8 | Issue 9 | e74734 Enterococcus faecium Bacteremia in Cancer Patients The emergence of E. faecium in immunosuppressed patients was responsible for the large majority of E. faecium infections, with cancer is a concern, since there are limited therapeutic particularly in recent years. The emergence of E. faecium options for these organisms. Although new antimicrobials, such among immunosuppressed cancer patients is worrying since as linezolid, daptomycin and quinupristin/dalfopristin, have there are limited treatment options and it may presage the recently been developed to treat serious enterococcal emergence of vancomycin-resistant enterococci. Addressing infections, resistance to these agents has already emerged this trend for enterococci requires a rational approach that [33-35]. combines infection control with antimicrobial stewardship. This study has a number of strengths. It describes the incidence of E. faecium BSI in a large cohort of BSI episodes Supporting Information prospectively collected in a specific immunosuppressed high- risk population. Additionally, it provides information regarding Table S1. Allelic profiles among 17 E. faecium blood the E. faecium clonal complexes identified during the study isolates. period. However, it also has certain limitations. The small (DOC) number of patients in the two groups may have prevented us from identifying significant differences between them. Also, as Author Contributions this was a single-centre study the results may have been influenced by local epidemiological variables, thereby limiting Conceived and designed the experiments: CG JC. 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