|Year : 2016 | Volume
| Issue : 1 | Page : 38-45
Prevalence, outcome and risk factor associated with vancomycin-resistant Enterococcus faecalis and Enterococcus faecium at a Tertiary Care Hospital in Northern India
A Tripathi1, SK Shukla2, A Singh1, KN Prasad1
1 Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
2 Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA-19104, USA
|Date of Submission||07-Feb-2014|
|Date of Acceptance||22-Jun-2015|
|Date of Web Publication||15-Jan-2016|
K N Prasad
Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow
Source of Support: ICMR and DBT, Conflict of Interest: None
Purpose: To determine the prevalence, genotype, risk factors and mortality in patients having vancomycin-resistant Enterococcus faecalis (VR E. faecalis) and Enterococcus faecium (VR E. faecium) infection or colonisation. Materials and Methods: A total of 1488 clinical isolates of E. faecalis and E. faecium were tested for vancomycin resistance by phenotypic (disk diffusion, E-test and broth micro-dilution test) and genotypic polymerase chain reaction methods. Records of all 1488 patients who had E. faecalis or E. faecium infection or colonisation were reviewed for the identification of host, hospital and medication related risk factors associated with VR E. faecalis and VR E. faecium. Results: Of 1488 isolates, 118 (7.9%) were vancomycin-resistant and their distributions were as follows: E. faecalis =72 (61%) and E. faecium =46 (39%). All 118 vancomycin-resistant isolates were vanA genotype (minimum inhibitory concentration [MIC] to vancomycin ≥64 μg/ml and MIC to teicoplanin ≥32 μg/ml) and none of the isolates was vanB genotype. Multivariate logistic regression analysis identified ventilator support and hospital stay for ≥48 h as independent risk factors associated with VR E. faecalis and VR E. faecium infection or colonisation. Hospital stay ≥48 h was the only independent risk factor for mortality in patients infected with vancomycin-resistant enterococci. Conclusions: Strategies to limit the nosocomial infection especially in patients on ventilator support can reduce VRE incidence and related mortality.
Keywords: Enterococcus, nosocomial pathogen, vancomycin resistance
|How to cite this article:|
Tripathi A, Shukla S K, Singh A, Prasad K N. Prevalence, outcome and risk factor associated with vancomycin-resistant Enterococcus faecalis and Enterococcus faecium at a Tertiary Care Hospital in Northern India. Indian J Med Microbiol 2016;34:38-45
|How to cite this URL:|
Tripathi A, Shukla S K, Singh A, Prasad K N. Prevalence, outcome and risk factor associated with vancomycin-resistant Enterococcus faecalis and Enterococcus faecium at a Tertiary Care Hospital in Northern India. Indian J Med Microbiol [serial online] 2016 [cited 2019 Sep 15];34:38-45. Available from: http://www.ijmm.org/text.asp?2016/34/1/38/174099
| ~ Introduction|| |
Vancomycin-resistant Enterococcus (VRE) has been recognised as a serious health care problem. Since first reported in 1988, VRE has rapidly become one of the leading causes of nosocomial infection and major growing problems in health care facilities globally. In nosocomial settings, Enterococcus faecium (E. faecium) accounts for majority of VRE infections and Enterococcus faecalis (E. faecalis) constitutes only 2–20% of VRE isolates, depending on geographical location and healthcare facility., Other species, including Enterococcus casseliflavus, Enterococcus durans and Enterococcus avium are occasionally isolated. Infection caused by VRE leads to poor outcome, and it remains a challenge with 60–70% mortality rate.
The epidemiology of VRE varies from one hospital to another, which depends on the hospital size, characteristics of the patient population, antibiotic usage patterns and geographic location. According to earlier reports, risk factors that increase the likelihood of VRE infection or colonisation can be divided into the following categories: Host factors, hospital-specific factors and antibiotic use. Several hospital-based studies have shown that infection with VRE is associated with prolonged hospitalisation, frequent exposure to antimicrobial agents particularly the use of vancomycin and third generation cephalosporins, decreased immunity or neutropenia, renal insufficiency, use of steroids and presence of an indwelling urinary catheter., VRE infection rates are highest among critically ill patients admitted in Intensive Care Units (ICUs) with limited treatment options.
There is paucity of information on increasing rate of VRE infections and/or colonisation and their clinical outcomes. E. faecalis and E. faecium are the most common nosocomial pathogens related to the disease severity in VRE positive patients. The aim of the present study was to determine the prevalence of vancomycin-resistant E. faecalis (VR E. faecalis) and VR E. faecium isolated from various clinical samples at a tertiary care centre in northern India. We also sought to determine the distribution of genes encoding acquired vancomycin resistance in clinical isolates of E. faecalis and E. faecium. In addition, an attempt was made to analyse the associated risk factors and outcome in this group of patients.
| ~ Materials and Methods|| |
The study was conducted at 800 bedded tertiary care facility located in North India. During April 2009 to December 2010, single isolate from patients who were infected or colonised with E. faecalis or E. faecium were included in this prospective cohort study. Infection or colonisation in patients with Enterococcus species (E. faecalis and E. faecium) was assessed following the criteria proposed by the Centres for Disease Control and Prevention. In brief, infection with enterococci was defined in the presence of clinical symptoms or signs of infection and enterococci isolated from clinical specimens obtained from sterile sites (such as blood, cerebrospinal fluid) and pus, tissue, or fluid obtained during surgery or needle aspiration. Patients with surgical wound infections were enrolled if they had fever (>38.8°C) and localised pain or tenderness, with enterococci isolated from cultures of discharge specimens obtained from the incision wound or closed drainage. A case of primary bloodstream infection due to enterococci was defined in the presence of fever, chills, or hypotension with enterococci being isolated from blood cultures without concurrent isolation of the pathogen from other sites. A case of urinary tract infection was defined in the presence of urinary urgency, frequency, dysuria, suprapubic tenderness, or pyuria with enterococci, the only isolate cultured from a urine specimen at a colony count of >105 colonies/ml. A case of colonisation with enterococci was defined when there was isolation of enterococci from the skin, mucous membranes, open wounds, or excretions or secretions, in the absence of relevant signs or symptoms in the patients. Data and information of patients including demographic characteristics, underlying illness, antimicrobial therapy and clinical outcome were obtained from the medical records. The study was approved by the ethics committee of our institute.
Clinical specimens like urine, blood, pus and other body fluids were collected and processed for isolation and identification of enterococci following standard protocols. Gram-positive and catalase negative cocci grown on MacConkey agar were presumptively identified as enterococci and confirmed by their growth on bile-esculin agar and in 6.5% NaCl broth, hydrolysis of esculin and pyrrolidonyl arylamidase activity. E. faecium and E. faecalis were differentiated based on mannitol fermentation, arginine hydrolysis, growth on potassium tellurite agar, sorbitol and arabinose fermentation.
Antibiotic susceptibility test
All isolates identified as enterococci were tested for antimicrobial susceptibility by the disc diffusion method using reference strain, E. faecalis ATCC 29212 as a control. Inocula were prepared from overnight growth on a blood agar plate by suspending seven to eight morphologically similar colonies in nutrient broth. Each inoculum was adjusted to 0.5 McFarland standards. The antibiotic susceptibility was carried out on brain heart infusion agar (Hi-media Mumbai, India). All strains were tested for susceptibility using ampicillin (10 µg), doxycycline (30 µg), erythromycin (15 µg), gentamicin (120 µg), vancomycin (30 µg), ciprofloxacin (5 µg), tigecycline (15 µg) norfloxacin (10 µg), nitrofurantoin (300 µg), linezolid (30 µg) disks. VRE was presumptively identified by disc diffusion and growth on VRE screen agar (with 6 µg/ml vancomycin) following Clinical and Laboratory Standards Institute guidelines and confirmed by minimum inhibitory concentration (MIC) to vancomycin and teicoplanin using E-test strips (bioMérieux, Marcy-l'Etoile, France) and broth micro-dilution method. Vancomycin broth MIC breakpoints were as follows: ≤4 µg/ml for sensitive, from 8 to 16 µg/ml for intermediate and ≥32 µg/ml for resistant. Interpretations of vancomycin disc diffusion test were as follows: Resistant if zone diameter ≤14 mm, intermediate if zone diameter 15–16 and resistant if zone diameter ≥17 mm. Susceptibility testing for tigecycline and linezolid was performed using Mueller-Hinton broth (Hi-media Mumbai, India), and results were interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST-2012; http://www.eucast.org) breakpoints. Tigecycline broth MIC breakpoints were as follows: ≤0.25 µg/ml for sensitive, 0.5 µg/ml for intermediate and >0.5 µg/ml for resistant.
Plasmid DNA was extracted from phenotypically confirmed VRE strains by plasmid extraction kit (Surespin mini kit, Nucleopore, India). Vancomycin-resistant genes, vanA and vanB were amplified using gene-specific primers: vanA forward 5'-GGGAAAACGACAATTGC-3', vanA reverse 5'-GTACAATGCGGCCGTTA-3' and vanB forward 5' - ACGGAATGGGAAGCCGA-3', vanB reverse 5'-TGCACCCGATTTCGTTC-3' which were synthesised by Sigma-aldrich, USA. The amplicon size of vanA and vanB gene was 732 bp and 647 bp respectively.E. faecium ATCC 51559 and E. faecalis ATCC 51299 were used as positive controls for vanA and vanB gene respectively. The negative control was performed for each set of polymerase chain reactions (PCRs) containing all reagents but no DNA template.
Comorbid conditions included in this study were cancer, diabetes mellitus, renal insufficiency (creatinine clearance of <60 mL/min), organ-transplantation, neutropenia (absolute neutrophil count of <500/mm 3), use of corticosteroids and surgical procedure in the preceding 30 days. Multiunit stay term was used for patients who were admitted into more than two units after hospitalisation prior isolation of enterococci. Previous hospitalisation was defined by group of patients who were hospitalised 1 or more times in 6 months before the date of sample collection. ICU admission was defined if the patients were admitted in ICU unit at the time of sample collection. Previous ICU admission was defined if the patients were admitted in ICU unit in 30 days before the day of sample collection. Use of indwelling catheters was defined as patients used ventilator, central venous line and urinary catheters within 30 days before the day of sample collection. Nosocomial infection was defined if infection occurred ≥48 h after admission to the hospital or in a patient who had been hospitalised within the previous 2 weeks. Antibiotic use was defined as exposure to vancomycin, metronidazole, quinolones (norfloxacin, ciprofloxacin, ofloxacin and levofloxacin), aminoglycosides (gentamicin, amikacin), third generation cephalosporins (cefoperazone, ceftazidime, cefotaxime, ceftriaxone) and fourth generation cephalosporins (cefepime, cefozopran) in 30 days before the day of sample collection. Multiple drug resistant Enterococcus was defined as the enterococcal isolates that were resistant to three or more antimicrobial classes. Mortality was defined as deaths documented to have occurred within 30 days after colonisation or infection with E. faecalis and E. faecium; death associated with E. faecalis and E. faecium infection in the same hospital stay was counted as attributable mortality.
The Chi-square test was used to compare categorical variables. Continuous variables were compared using Student's t-test. All the tests were two-sided, and statistical significance was set at P ≤ 0.05. We used logistic regression analysis to determine the independent effect of VR E. faecalis and VR E. faecium infection or colonisation on outcomes such as clinical response and mortality as appropriate. Univariate analysis was performed for patients' demographic and clinical characteristics to evaluate their predictive effects. Significant factors on univariate analysis were subjected to analysis by multiple logistic regression models. All statistical analyses were performed using SPSS software, version 18 (SPSS Inc., Chicago).
| ~ Results|| |
A total of 1488 enterococci (E. faecalis =1067 [71.7%] and E. faecium =421 [28.3%]) were isolated from various clinical specimens; in 32 specimens in addition to enterococci, other microorganisms were also detected and these were excluded from this study. The detail of these other microorganisms was as follows: Acinetobacter spp. 8 (25%), Escherichia More Details coli 8 (25%), Citrobacter spp. 6 (18.75%); Klebsiella pneumonia 5 (15.6%); coagulase-negative staphylococci 3 (9.4%) and methicillin-resistant Staphylococcus aureus 2 (6.25%).
The median age of patients was 54.69 (range, 4–91) years; 819 (56.25%) patients were male. The median duration of hospitalisation prior to isolation of Enterococcus species was 9 (range, 0–54) days. Locations of patients at the time of sample collection were as follows: Totally, 762 (52.33%) in medical units, 572 (39.26%) in surgical units and 122 (8.38%) in ICU. A total of 276 (18.9%) patients had undergone surgical procedures and 356 (24.5%) had a history of admission in ICU in the preceding 30 days. Two hundred and nine (14.4%) patients had cancer (malignancy) and 463 (31.8%) had diabetes mellitus. Clinical specimens collected were as follows: Pus 743 (51%), urine 355 (24.4%), blood 279 (19.2%) and other body fluids 79 (5.4%).
The isolation rate of vancomycin-resistant enterococci was 7.9% (118/1488). Of 118 strains, 72 (61.02%) were identified as VR E. faecalis and 46 (38.98%) as VR E. faecium. The details of E. faecalis and E. faecium in different clinical specimens are given in [Table 1]. Of 118 patients who were positive for VR E. faecalis and E. faecium, 86 (E. faecalis =62 and E. faecium =24) had infection and 32 (E. faecalis =10 and E. faecium =22) had colonisation. All the specimens collected from the infected and colonised patients were culture positive.
Antibiotic susceptibility pattern of vancomycin-resistant Enterococcus faecalis nterococcus faecium isolates
Of the 1488 clinical isolates, 118 (7.9%) were identified as vancomycin-resistant (screen positive) on the basis of disc diffusion test. All these isolates grew on vancomycin screen agar plates. Vancomycin resistance was more prevalent in E. faecium isolates (46 out of 421) than E. faecalis (72 out of 1067) with the incidence of 10.9% and 6.7% respectively. All the VR E. faecalis and VR E. faecium isolates expressed high level resistant to vancomycin (MIC ≥64 µg/ml) and teicoplanin (MIC ≥32 µg/ml). Multiple drug resistance was observed in 56.78% VRE (67/118) isolates. High resistance rate was recorded against ciprofloxacin, gentamicin followed by erythromycin and norfloxacin in VR E. faecalis and VR E. faecium isolates [Figure 1]. However, all VRE isolates were susceptible to linezolid. PCR results confirmed that all the VR E. faecalis and VR E. faecium strains had vanA gene; none of them had vanB gene [Figure 2].
|Figure 1: Prevalence of resistance to other antimicrobial agents among vancomycin resistance and vancomycin susceptible Enterococcus faecalis (a) and Enterococcus faecium (b) recovered from patients at a Tertiary Care Hospital (Northern India) from April 2009 through December 2010|
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|Figure 2: Panel A shows the 732 bp amplified product of vanA. Lane M, contains 1 kb ladder; lane 1, positive control; lanes 2–4, vancomycin-resistant Enterococcus strains and lane 5, negative control. Panel B shows the 647 bp amplified product of vanB. Lane M contains 100 bp ladder; lane 3, positive control; lane 2–4, vancomycin-resistant Enterococcus strains and lane 5, negative control|
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Factors associated with vancomycin-resistant Enterococcus faecalis and Enterococcus faecium infection or colonisation
The epidemiological and clinical data of the patients infected or colonised with VRE (VR E. faecalis and E. faecium) and VSE (vancomycin sensitive E. faecalis and E. faecium) are shown in [Table 2]. On univariate analysis, patient's age (≥50 years), gastrointestinal disorders, E. faecalis incidence, renal insufficiency, surgery, hospitalisation ≥48 h, ICU admission, use of invasive devices such as mechanical ventilator and central venous catheters were significantly associated with VRE infection or colonisation. Antibiotic therapy related data of patients showed that all 118 (100%) patients with VRE (VR E. faecalis and E. faecium) and 1327 (95.6%) of 1388 patients with VSE (vancomycin sensitive E. faecalis and E. faecium) infection/colonisation had received antibiotic therapy within 30 days of sample collection. Use of multiple antibiotics mostly vancomycin, third and fourth generation cephalosporins were significantly associated with VR E. faecalis and VR E. faecium infection or colonisation. Multivariate logistic regression analysis revealed that the use of ventilator (odds ratio [95% confidence interval] 4.11 [1.215–13.910]; P = 0.023) and hospital stay ≥48 h (2.151 [1.097–4.220]; 0.026) was the independent risk factors associated with VR E. faecalis and VR E. faecium infection or colonisation. The use of third generation cephalosporin was a protective factor [Table 3].
|Table 2: Univariate analysis of risk factors between VRE (VRE, (n=118) and VSE (VSE, (n=1338))|
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|Table 3: Independent risk factors associated with infection/colonisation by VRE (multivariate logistic regression)|
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Factors associated with mortality in patients having vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium infection
To determine the factors associated with mortality, the epidemiological and clinical data of live and died patients infected with VR E. faecalis or VR E. faecium were compared [Table 4]. Of 86 infected patients, 55 (63.95%) were live and 31 (36.05%) died at the time of hospital discharge. The mortality rate was significantly associated with VR E. faecalis group (40.3% [25/62]) in comparison to VR E. faecium group (25% [6/24]) (P = 0.002). The attribuatble mortality due to VR E. faecalis and VR E. faecium infection was 22.8% (22/118). Univariate analysis identified renal insufficiency, ICU admission, hospital stay ≥48 h and use of aminoglycosides as significant risks associated with death due to VR E. faecalis and VR E. faecium infection. On multivariate analysis, hospital stay ≥48 h (15.75 [3.33–74.35]; ≤0.001) was independent predictor of death among VR E. faecalis and VR E. faecium infected patients [Table 3].
|Table 4: Univariate analysis of risk factors associated with mortality in patients with VRE infection|
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| ~ Discussion|| |
Several reports investigated the risk factors associated with VRE infections and/or colonisation. However, these efforts were limited due to small numbers of patients or controls or cases only from specialty services., Earlier study from our centre reported that 1.4% of the enterococcal isolates were resistant to vancomycin, and the resistance was mediated by vanA. The current finding shows several folds increase in vancomycin resistance among enterococci during last few years (from 1.4% to 7.9%). E. faecalis incidence was more common in comparison to E. faecium in our patients. However, in our patient population, VR E. faecalis and VR E. faecium represented 61% and 39%, respectively of total VRE occurrence. This result was discordant to the other previous reports., Moreover, the present study included a large number of patients from various medical and surgical specialties (wards) and analysed broad range of underlying co-morbidities and patients characteristics that were associated with VR E. faecalis and VR E. faecium infection or colonisation.
In this study, we found that all clinical isolates of VRE were susceptible to linezolid. Studies conducted in Europe, the United States and Taiwan demonstrated similar findings. Linezolid non-susceptible enterococci may be an emerging clinical problem in other countries  but they were not identified in our study.
Analysis of data of National Nosocomial Infection Surveillance system demonstrated ICU as an epicentre of resistance within hospitals; 28.5% of nosocomial VRE were isolated from 300 U.S. hospitals in 2003. At our institution, of 57.6% of total nosocomial VRE, 34.7% (41/118) VRE were isolated from ICU admitted patient. The impact of nosocomial infections is enormous regarding morbidity, mortality and economic loss. According to the previous study, the risk of nosocomial infection increases from three major factors: (1) Intrinsic risk factors related to the need for intensive care, such as severe underlying disease, multiple illnesses and extremes of age; (2) invasive medical devices, such as endotracheal tubes for mechanical ventilation, intravascular catheters and urinary tract catheters; (3) animate reservoirs (e.g., colonised or infected patients), which increase the risk of cross-infection in the ICU. In our study comorbid conditions, old age, use of invasive devices and ICU admission were found to be significantly associated with VRE infection or colonisation by univariate analysis. Most of our ICU admitted patients received mechanical ventilation support, and it is used independently increased VR E. faecalis and VR E. faecium incidence. All these factors increase the risk of nosocomial infection which independently responsible for the risk of VRE and mortality in infected patients.
The role of antibiotic selection pressure in the pathogenesis of VR E. faecalis and VR E. faecium colonisation and subsequent infection has been well-documented in literature. In this study, we collected the detail of antibiotics which were given to the patients in our hospital. However, history of patient's previous antibiotic therapy was not known and due to this limitation of our study we found third generation cephalosporins protected against the isolation of VR E. faecalis and VR E. faecium.
The attributable mortality due to VR E. faecalis and VR E. faecium was calculated in this study and was higher ([22/118] 22.8%) in comparison to previous studies which reported 15.3% and 21.3% attributable mortality due to VRE infection.,E. faecalis infection was the major cause of death in VRE infected patients in comparison to E. faecium infection. On the other hand, the frequency of E. faecalis infection was not significantly associated with mortality in VR E. faecalis and VR E. faecium infected patients. The result was discordant with previous studies which reported E. faecium infection as life-threatening compared to E. faecalis. Higher frequencies of virulence traits in E. faecalis isolates in comparison to E. faecium can be responsible for the occurrence of invasive infection and disease severity. Recently, Matos et al. described the role of prophage of clinical isolate of E. faecalis (V583) in disease severity with the explanation for the correlation between antibiotic usage and E. faecalis success as a nosocomial pathogen. These are the possible reasons why the species of E. faecalis is more life-threatening than E. faecium.
In summary, we found that hospital stay ≥48 h was the common independent predictor of VR E. faecalis or VR E. faecium incidence and mortality in infected patients. However, use of mechanical ventilator was another independent predictor related to VR E. faecalis and VR E. faecium infection or colonisation. Careful attention on ventilator dependent patients who have heavy respiratory tract colonisation or infection, proper hand washing, isolation and disinfection are critical to prevent nosocomial transmission of resistant pathogens between patients via contaminated equipment or contaminated hands of health care providers. Although not reached in statistical senses, we should be still careful of the appropriate use of antibiotics such as vancomycin, third generation cephalosporin and multiple antimicrobial agents. Preventing the emergence and spread of VRE requires the adoption of a multifaceted approach.
| ~ Acknowledgment|| |
Aparna Tripathi and Avinash Singh acknowledge the financial assistance received from Indian Council of Medical Research, Government of India, New Delhi through Senior Research fellowship grant no. 80/625/2009-ECD-I and 80/675/10-ECD-I respectively. Sanket Shukla acknowledges the Department of Biotechnology (DBT), Government of India for Senior Research Fellowship grant no. (DBT-JRF)/09-10/634. Further, we confirm that all authors report no conflicts of interest relevant to this article.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]