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Controlling the spread of vancomycin-resistant enterococci. Is active screening worthwhile?

  • H. Humphreys
    Correspondence
    Address: Department of Clinical Microbiology, The RCSI Education and Research Centre, Beaumont Hospital, PO Box 9063, Dublin 9, Ireland. Tel.: +353 1 8093710; fax: +353 1 8092871.
    Affiliations
    Department of Clinical Microbiology, Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin, Ireland
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Published:September 23, 2014DOI:https://doi.org/10.1016/j.jhin.2014.09.002

      Summary

      Vancomycin-resistant enterococci (VRE) are significant causes of healthcare-acquired infections. Active screening, i.e. the use of rectal swabs or faeces to detect carriage in at-risk patients, has been described as contributing to prevention by identifying previously unrecognized cases. The aim of this review was to determine the impact of screening for VRE on prevention and control, its cost-effectiveness and recent approaches to laboratory detection. A review of published studies in English from 2000 was undertaken. Whereas various guidelines were accessed and reviewed, the emphasis was on original reports and studies. It was determined that the patient groups who may need screening are those admitted to critical care units, haematology/oncology and transplant wards, patients on chronic dialysis and patients admitted to acute hospitals from long-stay units. Active screening is associated with reduced VRE colonization and infection and cost savings in some studies, even if these fall short of randomized trials. Selective media increase sensitivity and reduce the time to detection but the role of molecular methods remains to be determined. In conclusion, active screening contributes to VRE prevention probably by heightening awareness of control measures, including isolation. However, further studies are required to: better define high-risk groups that warrant screening; quantify the clinical and economic benefit; and determine the optimal laboratory methods in a range of different patient populations.

      Keywords

      Introduction

      Enterococci are part of the normal bacterial flora of the gastrointestinal tract of humans. The most important species are Enterococcus faecalis and Enterococcus faecium, which may cause significant infections including bloodstream infection (BSI).
      • Arias C.A.
      • Murray B.
      The rise of the Enterococcus: beyond vancomycin resistance.
      Enterococci are considered intrinsically resistant to some antibiotics such as the cephalosporins; consequently glycopeptides have been the mainstay of treatment as there are few other options for treatment. Vancomycin-resistant enterococci (VRE) were first isolated in the late 1980s and they have spread rapidly throughout the USA, Europe, and beyond.
      • Reik R.
      • Tenover F.C.
      • Klein E.
      • McDonald C.L.
      The burden of vancomycin-resistant enterococcal infections in US hospitals, 2003 to 2004.
      • Deshpande L.M.
      • Fritsche T.R.
      • Moet G.J.
      • Biedenbach D.J.
      • Jones R.N.
      Antimicrobial resistance and molecular epidemiology of vancomycin-resistant enterococci from North America and Europe: a report from the SENTRY antimicrobial surveillance program.
      Vancomycin-resistant enterococci are important causes of healthcare-associated infection (HCAI), often affect the most vulnerable patient groups, and cause considerable mortality with additional healthcare costs. Recent data from the National Healthcare Safety Network in the USA indicate that enterococci were the second most frequent cause of HCAIs after Staphylococcus aureus and that 89% of E. faecium isolates causing central line-associated BSI were vancomycin resistant.
      • Sievert D.M.
      • Ricks P.
      • Edwards J.R.
      • et al.
      Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010.
      In a recent European survey of >230,000 patients in nearly 1000 acute hospitals, enterococci were the third most common cause, of which 10% were VRE.
      • European Centre for Disease Prevention and Control Surveillance Report
      Point prevalence survey of healthcare-associated infections and antimicrobial use in European hospitals, 2011–2012.
      Patients with BSI due to VRE are more likely to die than are those with BSI caused by vancomycin-susceptible enterococci (VSE), vancomycin resistance is an independent predictor of mortality, the median duration of BSI is longer for VRE compared with VSE, and VRE acquisition is associated with a longer duration of hospital stay.
      • DiazGranados C.A.
      • Zimmer S.M.
      • Klein M.
      • Jernigan J.A.
      Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis.
      • DiazGranados C.A.
      • Jernigan J.A.
      Impact of vancomycin resistance on mortality among patients with neutropenia and enterococcal bloodstream infection.
      • Carmeli Y.
      • Eliopoulos G.
      • Mozaffari E.
      • Samore M.
      Health and economic outcomes of vancomycin-resistant enterococci.
      In Canada the mean total costs and length of stay (LOS) for patients with VRE have been calculated to be significantly higher compared to those for VRE-negative patients, i.e. C$46,924 and 34 days versus C$13,069 and 10.9 days, respectively.
      • Lloyd-Smith P.
      • Younger J.
      • Lloyd-Smith E.
      • Green H.
      • Leung V.
      • Romney M.G.
      Economic analysis of vancomycin-resistant enterococci at a Canadian hospital: assessing attributable cost and length of stay.
      The US Centers for Disease Control and Prevention have recently highlighted VRE as resistant bacteria of serious concern that require prompt and sustained action.
      • US Department of Health and Human Services, Centers for Disease Control and Prevention
      Antibiotic resistance threats in the United States.
      Whereas there has been a much-needed emphasis in recent years on the importance of Clostridium difficile infection and the threat posed by multidrug-resistant Gram-negative bacilli, such as carbapenem-resistant Enterobacteriaceae, VRE remain important. Hence it is opportune to review the indications for, and value of, screening for VRE. The purpose of screening is to identify carriers during outbreaks to assist in outbreak management, and in non-outbreak settings to prevent onward transmission, especially to vulnerable patient groups.

      Methods

      The scientific literature on the prevention and control of VRE published in English since 2000 until June 2014 was reviewed with searches conducted in PubMed, EMBASE, and CINAHL to access studies and other reports on VRE screening and the identification of risk factors that would inform screening strategies. Search terms used in addition to VRE included glycopeptide-resistant enterococci, antibiotic-resistant enterococci, including E. faecalis and E. faecium, epidemiology, clinical impact, risk factors, screening and surveillance, laboratory methods and diagnosis, individually as well as in combination. General terms such as infection prevention and control were also used. Emphasis was placed on sourcing and reviewing original papers describing controlled clinical trials or quasi-experimental studies involving screening, to prevent and control spread, and methods for laboratory detection. The reference list of papers obtained from the literature search was also reviewed to determine whether there were other relevant studies that should be assessed and included, but which were not detected in the original literature search. However, many reports describe multiple interventions during outbreaks and therefore it can be difficult to quantify or estimate the impact of screening compared with other measures, such as improved environmental hygiene and better antimicrobial stewardship.

      Risk factors for VRE

      Strategies to prevent and control VRE have been reviewed in the recent literature and in several guidelines and studies.
      • Muto C.A.
      • Jernigan J.A.
      • Ostrowsky B.E.
      • et al.
      SHEA guideline for preventing nosocomial transmission of multi-drug resistant strains of Staphylococcus aureus and Enterococcus.
      • Cookson B.D.
      • Macrae M.B.
      • Barrett S.P.
      • et al.
      Guidelines for the control of glycopeptide-resistant enterococci in hospitals.
      • Ofner-Agostina M.
      • Varia M.
      • Johnston L.
      • et al.
      Infection control and antimicrobial restriction practices for antimicrobial-resistant organisms in Canadian tertiary care hospital.
      • Tacconelli E.
      • Cataldo M.A.
      Vancomycin-resistant (VRE): transmission and control.
      • Armeanu E.
      • Bonten M.J.M.
      Control of vancomycin-resistant enterococci. One size fits all?.
      These recommend a multi-pronged approach that includes screening, improved professional practice such as hand hygiene, patient isolation, antibiotic stewardship, and enhanced environmental hygiene. Screening strategies should be devised to maximize the detection of carriers and should be informed by a knowledge of risk factors for VRE.

      Intrinsic and extrinsic patient factors

      Intrinsic risk factors associated with the patient include underlying illnesses, whereas extrinsic factors include exposure to a VRE-positive environment. However, many of these risk factors have been determined in studies that have varied considerably in size, population studied, and design. Nonetheless, some important and clinically relevant factors that predispose to VRE have been clearly recognized (Table I). As with other multidrug-resistant bacteria such as meticillin-resistant Staphylococcus aureus (MRSA), immunocompromised patients and those with significant underlying conditions are at greatest risk. A point prevalence survey of VRE, which detected vancomycin-resistant E. faecium in 32% of stool specimens, found that previous hospitalization, chronic renal failure, and length of hospital stay were associated with a patient being VRE positive.
      • Cohen M.J.
      • Adler A.
      • Block C.
      • et al.
      Acquisition of vancomycin-resistant enterococci in internal medicine wards.
      Screening of patients before admission to an intensive care unit (ICU) identified a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, having being resident in an acute or long-term care facility (LTCF), and previous antibiotic exposure as significant predictors of positive VRE status.
      • Pan S.-C.
      • Wang J.-T.
      • Chen Y.-C.
      • Chang Y.-Y.
      • Chen M.-L.
      • Chang S.-C.
      Incidence of and risk factors for infection or colonisation of vancomycin-resistant enterococci in patients in the intensive care unit.
      In a 15-month prospective cohort study from Australia, VRE was independently associated with being managed in a renal unit and the recent administration of ticarcillin–clavulanic acid or carbapenems.
      • Padiglione A.A.
      • Wolfe R.
      • Grabsch E.A.
      • et al.
      Risk factors for new detection of vancomycin-resistant enterococci in acute-care hospitals that employ strict infection control procedures.
      In a study that followed up 199 patients after hospital discharge, multivariate analysis indicated that a haematological malignancy was significantly associated with VRE infection.
      • Datta R.
      • Huang S.S.
      Risk of post discharge infection with vancomycin-resistant Enterococcus after initial infection or colonisation.
      In hospitalized children, screening identified 3% of the population screened as positive but 95% of these had underlying chronic illnesses.
      • Weddle G.
      • Jackson M.A.
      • Selvarangan R.
      Utility of a focused vancomycin-resistant enterococci screening protocol to identify colonisation in hospitalised children.
      The authors recommended an initial screening test in otherwise healthy children with a second screening test reserved only for high-risk groups, i.e. those with chronic illnesses.
      • Weddle G.
      • Jackson M.A.
      • Selvarangan R.
      Utility of a focused vancomycin-resistant enterococci screening protocol to identify colonisation in hospitalised children.
      Table IRisk factors for the acquisition of vancomycin-resistant enterococci
      Risk factorCommentReference
      Intrinsic
       ImmunosuppressionIncludes haematology/oncology conditions, solid organ transplantation, and neutropenia
      • Padiglione A.A.
      • Wolfe R.
      • Grabsch E.A.
      • et al.
      Risk factors for new detection of vancomycin-resistant enterococci in acute-care hospitals that employ strict infection control procedures.
      • Datta R.
      • Huang S.S.
      Risk of post discharge infection with vancomycin-resistant Enterococcus after initial infection or colonisation.
       Renal dialysisMay relate to underlying renal disease or regular healthcare contact
      • Cohen M.J.
      • Adler A.
      • Block C.
      • et al.
      Acquisition of vancomycin-resistant enterococci in internal medicine wards.
       Recent/current antibiotic useThird-generation cephalosporin, fluoroquinolones and β-lactam/β-lactamase inhibitors
      • Pan S.-C.
      • Wang J.-T.
      • Chen Y.-C.
      • Chang Y.-Y.
      • Chen M.-L.
      • Chang S.-C.
      Incidence of and risk factors for infection or colonisation of vancomycin-resistant enterococci in patients in the intensive care unit.
      • Padiglione A.A.
      • Wolfe R.
      • Grabsch E.A.
      • et al.
      Risk factors for new detection of vancomycin-resistant enterococci in acute-care hospitals that employ strict infection control procedures.
      • Carmeli Y.
      • Eliopoulos G.M.
      • Samore M.H.
      Antecedent treatment with different antibiotic agents as a risk factor for vancomcyin-resistant Enterococcus.
      • Hayakawa K.
      • Marchaim D.
      • Palla M.
      • et al.
      Epidemiology of vancomycin-resistant Enterococcus faecalis: a case–control study.
      • Stiefel U.
      • Paterson D.L.
      • Pultz N.J.
      • Gordon S.M.
      • Aron D.C.
      • Donskey C.J.
      Effect of the increasing use of piperacillin-tazobactam on the incidence of vancomycin-resistant enterococci in four academic medical centres.
      • Paterson D.L.
      • Muto C.A.
      • Ndirangu M.
      • et al.
      Acquisition of rectal colonisation by vancomycin-resistant Enterococcus among intensive care unit patients treated with piperacillin–tazobactam versus those receiving cefepime-containing antibiotic regimens.
       Chronic underlying disease, previous hospitalizationA variety of conditions cited but may reflect regular contact with healthcare and/or exposure to antibiotics
      • Cohen M.J.
      • Adler A.
      • Block C.
      • et al.
      Acquisition of vancomycin-resistant enterococci in internal medicine wards.
      • Weddle G.
      • Jackson M.A.
      • Selvarangan R.
      Utility of a focused vancomycin-resistant enterococci screening protocol to identify colonisation in hospitalised children.
      Extrinsic
       Intensive care unitMany studies on risk factors focus on intensive care unit rather than all hospital patients
      • Pan S.-C.
      • Wang J.-T.
      • Chen Y.-C.
      • Chang Y.-Y.
      • Chen M.-L.
      • Chang S.-C.
      Incidence of and risk factors for infection or colonisation of vancomycin-resistant enterococci in patients in the intensive care unit.
       Transfer from LTCFMay reflect underlying disease and lack of focused preventive measures in LTCF
      • Pan S.-C.
      • Wang J.-T.
      • Chen Y.-C.
      • Chang Y.-Y.
      • Chen M.-L.
      • Chang S.-C.
      Incidence of and risk factors for infection or colonisation of vancomycin-resistant enterococci in patients in the intensive care unit.
       Previous patient in single room, VRE positiveMay reflect inadequate terminal decontamination
      • Drees M.
      • Snydman D.R.
      • Schmid C.H.
      • et al.
      Prior environmental contamination increases the risk of vancomycin-resistant enterococci.
      • Zhou Q.
      • Moore C.
      • Eden S.
      • Tong A.
      • McGeer A.
      Factors associated with acquisition of vancomycin-resistant enterococci (VRE) in roommate contacts of patients colonized or infected with VRE in a tertiary care hospital.
       Prior hospitalization/transfer from another hospitalMany studies carried out in larger referral hospitals receiving patients from other institutions
      • Datta R.
      • Huang S.S.
      Risk of post discharge infection with vancomycin-resistant Enterococcus after initial infection or colonisation.
      LTCF, long-term care facility.
      The risk of acquiring VRE in a patient room is higher if the previous patient had been positive.
      • Drees M.
      • Snydman D.R.
      • Schmid C.H.
      • et al.
      Prior environmental contamination increases the risk of vancomycin-resistant enterococci.
      • Zhou Q.
      • Moore C.
      • Eden S.
      • Tong A.
      • McGeer A.
      Factors associated with acquisition of vancomycin-resistant enterococci (VRE) in roommate contacts of patients colonized or infected with VRE in a tertiary care hospital.
      In a 14-month study in two ICUs, multivariate analyses showed that a room previously colonized with a VRE patient in the last two weeks, and a previously positive environmental sample for VRE, were independent predictors of VRE acquisition.
      • Drees M.
      • Snydman D.R.
      • Schmid C.H.
      • et al.
      Prior environmental contamination increases the risk of vancomycin-resistant enterococci.
      In another study of patients who shared a room with a VRE-positive patient, 21% became positive and these patients were more likely to be exposed to the VRE-positive source patient for longer than VRE-negative contacts.
      • Zhou Q.
      • Moore C.
      • Eden S.
      • Tong A.
      • McGeer A.
      Factors associated with acquisition of vancomycin-resistant enterococci (VRE) in roommate contacts of patients colonized or infected with VRE in a tertiary care hospital.
      This emphasizes the need for effective decontamination of clinical areas occupied by VRE-positive patients after hospital discharge.

      Antibiotics

      Previous exposure to antibiotics has been the subject of several studies but there are variations in the findings of these.
      • Carmeli Y.
      • Eliopoulos G.M.
      • Samore M.H.
      Antecedent treatment with different antibiotic agents as a risk factor for vancomcyin-resistant Enterococcus.
      • Hayakawa K.
      • Marchaim D.
      • Palla M.
      • et al.
      Epidemiology of vancomycin-resistant Enterococcus faecalis: a case–control study.
      • Rice L.B.
      • Hutton-Thomas R.
      • Lakitcova V.
      • Helfand M.S.
      • Donskey C.J.
      Β-lactam antibiotics and gastrointestinal colonization with vancomycin-resistant enterococci.
      • Paterson D.L.
      • Stiefel U.
      • Donskey C.J.
      Effect of selective decontamination of the digestive tract regimen including parenteral cefepime on establishment of intestinal colonization and vancomycin-resistant Enterococcus spp. and Klebsiella pneumoniae in mice.
      • Stiefel U.
      • Paterson D.L.
      • Pultz N.J.
      • Gordon S.M.
      • Aron D.C.
      • Donskey C.J.
      Effect of the increasing use of piperacillin-tazobactam on the incidence of vancomycin-resistant enterococci in four academic medical centres.
      • Paterson D.L.
      • Muto C.A.
      • Ndirangu M.
      • et al.
      Acquisition of rectal colonisation by vancomycin-resistant Enterococcus among intensive care unit patients treated with piperacillin–tazobactam versus those receiving cefepime-containing antibiotic regimens.
      For example, in a matched case–control study of 880 inpatients, 233 with VRE, treatment with third generation cephalosporins, metronizadole, and fluroquinolones were positively identified as risk factors for VRE acquisition, but not treatment with vancomycin.
      • Carmeli Y.
      • Eliopoulos G.M.
      • Samore M.H.
      Antecedent treatment with different antibiotic agents as a risk factor for vancomcyin-resistant Enterococcus.
      Another study of vancomycin-resistant E. faecalis identified six independent risk factors, one being exposure to cephalosporins and fluoroquinolones in the previous three months.
      • Hayakawa K.
      • Marchaim D.
      • Palla M.
      • et al.
      Epidemiology of vancomycin-resistant Enterococcus faecalis: a case–control study.
      This suggests that the contribution of antibiotics to VRE acquisition is complex. However, many of the clinical studies were hampered by design, e.g. they were retrospective and not prospective, and a failure to allow for other variables.

      Screening strategies and their impact

      Classification of screening

      Passive screening refers to the detection of VRE from specimens routinely submitted to the microbiology laboratory for the diagnosis of active infection, e.g. wound swabs to diagnose surgical site infection. This is likely to miss a considerable proportion of VRE-positive patients who are asymptomatically colonized but who may transmit VRE to other patients. Active screening includes the regular or periodic screening of stool samples submitted for C. difficile analysis, as well as admission and subsequent regular screening of patients admitted to specific clinical areas such as ICUs, organ transplantation wards or haematology/oncology units. The samples taken to screen for VRE may be stool samples or rectal swabs; the frequency of sampling may vary, as may the laboratory methods. There is some evidence supporting the role of active screening in certain patient groups as an effective infection prevention and control measure, and such screening may be cost-effective (Table II).
      Table IIStudies demonstrating the impact and cost-effectiveness of active screening in preventing and controlling vancomycin-resistant enterococci (VRE)
      SettingDesignScreening strategyOutcomeComment/caveatsReference
      Kyoto Prefecture, JapanObservational study in response to outbreakScreened all hospital admissions and transfersNo. of faecal carriers rose from 0.71% to 1.2% but then fell to 0.17%78% of total beds in 177 hospitals; other measures introduced, e.g. hand hygiene
      • Matushima A.
      • Takakura S.
      • Yamamoto M.
      • et al.
      Regional spread and control of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in Kyoto, Japan.
      Tertiary care hospitals, USARetrospective review of VRE bloodstream infectionHospital A: no routine screening

      Hospital B: weekly rectal swabs in high-risk patients
      Higher VRE bloodstream infections in Hospital A with clonal isolates and longer hospital stayHospitals similar in location and patient categories but not a controlled trial
      • Price C.S.
      • Paule S.
      • Noskin G.A.
      • Peterson L.R.
      Active surveillance reduces the incidence of vancomycin-resistant enterococcal bacteremia.
      ICUs, USAMathematical model of three strategiesStandard precautions versus screening of known previously positive patients versus screening of all ICU patients on admission (active surveillance)Active surveillance annually prevented 46 cases of VRE in a 10-bed ICU. Passive surveillance only prevented five cases per yearActive surveillance recommended by most guidelines for ICU setting
      • Perencevich E.N.
      • Fisman D.N.
      • Lipsitch M.
      • Harris A.D.
      • Morris Lr J.G.
      • Smith D.L.
      Projected benefits of active surveillance for vancomycin-resistant enterococci in intensive care units.
      Cancer centre, USARetrospective review of VRE bloodstream infection ratesStool cultures from all patients admitted to ICU or who had leukaemia/bone marrow transplantIncidence of VRE bloodstream infection fell eight-foldNo decrease in vancomycin use and not a controlled trial
      • Hackem R.
      • Graviss L.
      • Hanna H.
      • et al.
      Impact of surveillance for vancomycin-resistant enterococci on controlling a bloodstream outbreak among patients with haematologic malignancy.
      Four US academic centres involving 14 adult ICUsMulticentre retrospective review of data from each centreAdmission and weekly rectal cultures in ICU82–88% compliance.

      Increased VRE detection by 2.2–17-fold.

      Only 13% of VRE-positive patients subsequently positive from clinical sample
      Probably provides truer range of VRE incidence
      • Huang S.S.
      • Rifas-Shiman S.L.
      • Pottinger J.M.
      • et al.
      Improving the assessment of vancomycin-resistant enterococci by routine screening.
      Medical ICU, USAProspective, single centre observational studyAdmission, weekly and discharge rectal swab for VRE compared with culture for VRE if stool sent for Clostridium difficile and detection of VRE from clinical samplesActive screening detected 91% of VRE, 8% detected from stool sent for C. difficile and only 1% from clinical specimens. Total cost savings from active screening were calculated to range from US$56,258 to US$303,334 per month due to reduced transmission and bloodstream infectionEstimated, not actual, cost savings. Only 53% and 41% of patients had discharge and one surveillance sample taken, respectively
      • Shadel B.N.
      • Puzniak L.A.
      • Gillespie K.N.
      • Lawrence S.J.
      • Kollef M.
      • Mundy L.M.
      Surveillance for vancomycin-resistant enterococci: type, rates, costs and implications.
      Two tertiary care hospitals, USAProspective observational study of active screening in one hospital compared with published data in another hospitalInpatients deemed high risk (e.g. in ICU more than four days, co-colonization with MRSA), screened weeklyReduced VRE bloodstream infections from 0.05 to 0.002% of patients. Approximately US$500,000 in savings from reduced infections, allowing for cost of screening/isolationComparison of two different hospitals
      • Muto C.A.
      • Giannetta E.T.
      • Durbin L.J.
      • Simonton B.M.
      • Farr B.M.
      Cost-effectiveness of perirectal surveillance cultures for controlling vancomycin-resistant enterococci.
      Adult oncology unit, USAReview of costs and savings using historical control dataAdmission and weekly rectal swabsReduced rates of VRE BSI from 2.1 patients per 1000 patients days to 0.45.

      Reduced BSI colonization and antibiotics led to cost savings of US$305,833
      Use of historical controls, single centre
      • Montecalvo M.A.
      • Jarvis W.R.
      • Uman J.
      • et al.
      Costs and savings associated with infection control measures that reduced transmission of vancomycin-resistant enterococci in an endemic setting.
      Ten intervention and eight control ICUs, USACluster-randomized trialVRE screening within two days of admission, then weekly and two days after discharge with stool or peri-anal swabsNo difference in rates of VRE colonization and infection in control (33.4/1000 patient-days at risk) and intervention ICUs (38.9)Use of gloves and hand hygiene compliance higher in intervention ICUs. Potential delays in screening patients on admission
      • Huskins W.C.
      • Huckabee C.M.
      • O’Grady N.P.
      • et al.
      Intervention to reduce transmission of resistant bacteria in intensive care.
      Thirteen European ICUsCluster-randomized trial in one of three phasesScreening within two days of admission, twice per week for three weeks and once per week afterwardsImproved hand hygiene and chlorhexidine body washes reduced VRE but no additional effect from screening and contact precautionsAbsence of screening of all patients at admission may have missed some cases. Increased length of stay during screening phase
      • Derde L.P.G.
      • Cooper B.S.
      • Goossens H.
      • et al.
      Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial.
      ICU, intensive care unit, MRSA, meticillin-resistant Staphylococcus aureus.

      Impact of active screening

      In a retrospective study of the monthly prevalence of VRE in four US academic medical centres, and where compliance with admission and weekly screening cultures was 82% and 83%, respectively, screening was associated with a 3.3-fold increased detection of VRE acquired from other institutions or acquired in the community. Whereas admission and weekly surveillance screens increased the number of patients requiring contact precautions, only 13% of these patients actively screened had subsequent positive clinical cultures for VRE during their hospital stay.
      • Huang S.S.
      • Rifas-Shiman S.L.
      • Pottinger J.M.
      • et al.
      Improving the assessment of vancomycin-resistant enterococci by routine screening.
      In a study of ICU patients, the negative predictive value of a rectal site was 99% and colonized patients were 42 times more likely to develop a VRE infection.
      • Hendrix C.W.
      • Hammond J.M.J.
      • Swoboda S.M.
      • et al.
      Surveillance strategies and impact of vancomycin-resistant enterococcal colonisation and infection in critically ill patients.
      In a comparison of two nearby hospitals in the USA, in one of which high-risk patients were screened – i.e. haematology, oncology, transplant, and intensive care patients – the rate of VRE BSI was lower in the hospital with active screening, and VRE in the hospital without active screening was clonal, suggesting cross-transmission.
      • Price C.S.
      • Paule S.
      • Noskin G.A.
      • Peterson L.R.
      Active surveillance reduces the incidence of vancomycin-resistant enterococcal bacteremia.
      However, this finding may also reflect other differences between the two hospitals such as the culture of compliance with standard precautions.
      Some studies assessing the role of active screening are confined to outbreak settings and where efforts are focused on detecting all cases to prevent onward transmission; others are designed to reduce ongoing unit or institutional rates of VRE colonization and infections. During an outbreak of VRE BSI in a haematology unit in Texas, USA, active stool surveillance cultures were associated with a decrease in the incidence density of VRE BSI by a factor of eight, and subsequently all isolates of VRE were non-clonal, suggesting random acquisition rather than cross-transmission.
      • Hackem R.
      • Graviss L.
      • Hanna H.
      • et al.
      Impact of surveillance for vancomycin-resistant enterococci on controlling a bloodstream outbreak among patients with haematologic malignancy.
      In a paediatric ICU, admission screening increased the detection of VRE by 63%.
      • Milstone A.M.
      • Maragakis L.I.
      • Carroll K.C.
      • Perl T.M.
      Targeted surveillance to identify children colonised with vancomycin-resistant Enterococcus in the paediatric intensive care unit.
      In a neonatal intensive care unit in the USA, screening was initiated after the identification of the first VRE patient and subsequently included rectal swabs on admission and weekly samples only from patients who were negative on admission.
      • Singh N.
      • Léger M.-M.
      • Campbell J.
      • Short B.
      • Campos J.M.
      Control of vancomycin-resistant enterococci in the neonatal intensive care unit.
      The prevalence ranged from 2% to 4%; there were three clusters and only 9% of cases with VRE would have been identified solely from clinical specimens.
      • Singh N.
      • Léger M.-M.
      • Campbell J.
      • Short B.
      • Campos J.M.
      Control of vancomycin-resistant enterococci in the neonatal intensive care unit.
      Perencevich et al. have developed a mathematical model of VRE transmission in ICU and, using data from an existing active surveillance programme, attempted to estimate the benefits of active surveillance.
      • Perencevich E.N.
      • Fisman D.N.
      • Lipsitch M.
      • Harris A.D.
      • Morris Lr J.G.
      • Smith D.L.
      Projected benefits of active surveillance for vancomycin-resistant enterococci in intensive care units.
      Passive surveillance was minimally effective according to this model whereas active surveillance was predicted to result in a 65% reduction in the number of cases of VRE colonization in an intensive care setting.
      • Perencevich E.N.
      • Fisman D.N.
      • Lipsitch M.
      • Harris A.D.
      • Morris Lr J.G.
      • Smith D.L.
      Projected benefits of active surveillance for vancomycin-resistant enterococci in intensive care units.
      In Japan following a large outbreak caused by a vanA E. faecium clonal complex 17, a major control programme was initiated including the screening of all admissions to hospital and hospital transfers.
      • Matushima A.
      • Takakura S.
      • Yamamoto M.
      • et al.
      Regional spread and control of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in Kyoto, Japan.
      Whereas initially the VRE carriage rate increased to 1.2% with increased detection, this subsequently fell to 0.17%.
      Screening for VRE in stool specimens submitted for other purposes, i.e. the detection of Clostridium difficile, has been used to monitor for the prevalence of VRE. From 200 stool samples submitted for C. difficile testing, five additional patients with VRE were detected in non-high-risk areas who would otherwise have gone undetected among a patient population that included haematology–oncology and bone marrow/solid organ transplant units, and surgical and medical ICUs.
      • Lee T.A.
      • Hacek D.
      • Stroupe K.T.
      • Collins S.M.
      • Peterson L.R.
      Three surveillance strategies for vancomycin-resistant enterococci in hospitalised patients: detection of colonisation efficiency and a cost-effectiveness model.
      In another study, 14% of stool samples sent for C. difficile testing were positive for VRE compared with 11% from rectal swabs, but, for some patients, stool samples were unavailable and in these patients VRE would have been missed in the absence of rectal swabs.
      • Hacek D.M.
      • Bednarz P.
      • Noskin G.A.
      • Zembower T.
      • Peterson L.R.
      Yield of vancomycin-resistant enterococci and multidrug-resistant Enterobacteriaceae from stools submitted for Clostridium difficile testing compared to results from a focused surveillance program.
      In a study from Los Angeles, VRE was detected in 19.8% of specimens taken to detect C. difficile and there was a strong association between VRE and C. difficile positivity with an odds ratio of 2.3.
      • Leber A.L.
      • Hindler J.F.
      • Kata E.O.
      • Bruckner D.A.
      • Pegues D.A.
      Laboratory-based surveillance for vancomycin-resistant enterococci: utility of screening stool specimens submitted for Clostridium difficile toxin assay.
      Therefore stools sent for the investigation of nosocomial diarrhoea and screened for VRE may provide some indication of the general prevalence of VRE. However, this is dependent on the likely prevalence of C. difficile locally, which may vary over time, the likelihood of stool samples being sent for C. difficile testing, and the category of patient, e.g. renal dialysis patients are a risk group for VRE. This form of screening is at best an indirect form of active screening, as the primary reason for taking the specimen is not to screen for VRE but to diagnose gastrointestinal infection.
      Recent literature reviews and studies have suggested the routine use of chlorhexidine in ICU patients to prevent colonization, infection and the transmission of multidrug-resistant bacteria (MDRB).
      • Derde L.P.G.
      • Dautzenberg M.J.D.
      • Bonten M.J.M.
      Chlorhexidine body washing to control antimicrobial-resistant bacteria in intensive care units: a systematic review.
      • Huang S.S.
      • Septimus E.
      • Kleinman K.
      • et al.
      Targeted versus universal decolonisation to prevent ICU infection.
      Some have exclusively focused on preventing MRSA but in a systematic review published in 2012, the authors concluded that the evidence supported the contention that chlorhexidine prevented both MRSA and VRE.
      • Derde L.P.G.
      • Dautzenberg M.J.D.
      • Bonten M.J.M.
      Chlorhexidine body washing to control antimicrobial-resistant bacteria in intensive care units: a systematic review.
      • Huang S.S.
      • Septimus E.
      • Kleinman K.
      • et al.
      Targeted versus universal decolonisation to prevent ICU infection.
      A recent systematic review and meta-analysis of VRE control measures included one study that involved screening and other measures in the ICU.
      • De Angelis G.
      • Cataldo M.A.
      • De Waure C.
      • et al.
      Infection control and prevention measures to reduce the spread of vancomycin-resistant enterococci in hospitalized patients: a systematic review and meta-analysis.
      However, this study did not confirm the benefit of screening combined with other measures in reducing MRSA or VRE rates.
      • Huskins W.C.
      • Huckabee C.M.
      • O’Grady N.P.
      • et al.
      Intervention to reduce transmission of resistant bacteria in intensive care.
      A multicentre study of 13 ICUs designed to assess the impact of different interventions in reducing MDRB in three phases found that improved hygiene but not screening reduced VRE rates.
      • Derde L.P.G.
      • Cooper B.S.
      • Goossens H.
      • et al.
      Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial.
      However, screening on admission to the ICU was not undertaken but was carried out subsequently. However, in the ICU there may be the capacity to isolate patients pre-emptively before VRE screening results are available, certain interventions may be applied to all patients such as body washing with chlorhexidine unlike in non-ICUs, and compliance with other interventions such as hand hygiene may be better there. Admission and subsequent regular inpatient screening, together with the isolation of VRE-positive patients, are necessary to maximize the impact of active screening.

      Laboratory methods

      For screening to contribute to VRE control, results should be available as quickly as possible so that interventions may occur to prevent onward spread. Recent improvements in laboratory methods have helped to provide more rapid results. A variety of studies have been conducted in recent years to compare different media and the use of enrichment in detecting VRE. The use of enrichment broth, while delaying the availability of a positive result, generally improves the sensitivity of testing. For example, in a study of 528 rectal swabs, a broth enrichment step led to a significantly greater number of VRE patients being detected.
      • Brown D.F.
      • Walpole E.
      Evaluation of selective and enrichment media for isolation of glycopeptide-resistant enterococci from faecal specimens.
      Many routine diagnostic laboratories now use chromogenic agar which greatly facilitates the identification of presumptive isolates of VRE. Stamper and colleagues compared a traditional culture medium such as bile-esculin-azide agar incorporating 6 μg/mL vancomycin with BBL CHROMagar using 517 swabs from high-risk patients such as those in ICU.
      • Stamper P.D.
      • Shulder S.
      • Bekalo P.
      • et al.
      Evaluation of BBL CHROMagar VanRE for detection of vancomycin-resistant enterococci in rectal swab specimens.
      The overall agreement between the two media was 95.7% but the CHROMagar detected more VRE and the overall sensitivity and specificity of the chromogenic agar was 99.1% and 94.8%, respectively.
      • Stamper P.D.
      • Shulder S.
      • Bekalo P.
      • et al.
      Evaluation of BBL CHROMagar VanRE for detection of vancomycin-resistant enterococci in rectal swab specimens.
      Hegstad et al. in a multicentre study found that EUCAST (European Committee on Antimicrobial Susceptibility Testing) and CLSI (Clinical and Laboratory Standards Institute) agar screening methods performed well in confirming vancomycin resistance among a diverse collection of VRE compared with an automated system, Vitex 2.
      • Hegstad K.
      • Giske C.G.
      • Haldorsen B.
      • et al.
      Performance of the EUCAST disk diffusion method, the CLSI agar screen method, and the Vitex 2 automated antimicrobial susceptibility testing system for detection of clinical isolates of enterococci with low- and medium-level vanB-type vancomycin resistance: a multicentre study.
      When faecal specimens were spiked with 18 VRE isolates, predominantly vanB, sensitivity was lower in liquid compared with solid media, at 24 h compared to 48 h, and when the minimum inhibitory concentration was <16 mg/L.
      • Wijesuriya T.M.
      • Perry P.
      • Pryce T.
      • et al.
      Low vancomycin MICs and fecal densities reduce the sensitivity of screening methods for vancomycin resistance in enterococci.
      Two main approaches are available via polymerase chain reaction (PCR) systems for the detection of VRE directly from patient specimens, i.e. the LightCycle and the BD Gene Ohm systems. The LightCyler (Roche, Mannheim, Germany) has been evaluated in a number of studies for the direct detection of VRE using multiplex real-time PCR. For example, Mak et al. evaluated this approach using 30,835 rectal samples collected over three years in Canada during outbreaks or from high-risk patients.
      • Mak A.
      • Miller M.A.
      • Chong G.
      • Momczak Y.
      Comparison of PCR and culture for screening of vancomycin-resistant enterococci: highly disparate results for vanA and vanB.
      The overall prevalence of VRE was 1.34% (vanA, 1.07%; vanB, 0.27%) but the specificity for vanB was much less, leading to a positive predictive value for vanB of 1.42%.
      • Mak A.
      • Miller M.A.
      • Chong G.
      • Momczak Y.
      Comparison of PCR and culture for screening of vancomycin-resistant enterococci: highly disparate results for vanA and vanB.
      The reasons for this poor specificity for vanB is felt to be due in part to the presence of vanB in six anaerobic bacteria including Clostridium spp. and Ruminococcus sp.
      • Ballard S.A.
      • Grabsch E.A.
      • Johnson P.D.R.
      • Grayson M.L.
      Comparison of three PCR primer sets for identification of vanB gene carriage in faces and correlation with carriage of vancomycin-resistant enterococci: interference by vanB-containing anaerobic bacilli.
      The Cepheid SmartCyler using the BDGeneOhm VanR also has poor specificity for the detection of vanB. In a study of 1027 peri-anal and rectal swabs in three different US sites, the sensitivity, specificity and positive and negative predictive values were 93.2%, 81.9%, 54.4% and 98.1%, respectively.
      • Usacheva E.A.
      • Ginocchio C.C.
      • Morgan M.
      • et al.
      Prospective, multicenter evaluation of the BD GeneOhm VanR assay for direct, rapid detection of vancomycin-resistant Enterococcus species in perianal and rectal specimens.
      Consequently, this assay may be best used for excluding VRE carriers and relying on culture when confirming positive VRE status. Gazin et al. compared the GeneOhm VanR, the Gene Expert System and culture with and without enrichment. Culture-based methods yielded VRE in 44% of samples and both the GeneOhm and GeneXpert assays were highly specific for vanA detection, i.e. 93% and 83%, respectively.
      • Gazin M.
      • Lammens C.
      • Goossens H.
      Evaluation of GeneOhm VanR and Xpert vanA/vanB molecular assays for the rapid detection of vancomycin-resistant enterococci.

      Cost issues

      The cost of screening has to be balanced against the cost savings from preventing VRE colonization and BSI. Many studies exclude the costs of screening or the cost savings. In others, costs are derived retrospectively and therefore may be crude estimates of the actual costs, such as only those incurred by the laboratory.
      In a prospective cohort of adult patients admitted to medical and surgical wards and actively screened, the prevalence of VRE was 6.3% and active screening for VRE cost US$77,275 compared with US$42,468 for targeted screening.
      • Morgan D.J.
      • Day H.R.
      • Furuno J.P.
      • et al.
      Improving efficiency in active surveillance for methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus at hospital admission.
      Shadel et al. assessed the effectiveness of active screening over a three-year period in an ICU and found that 91% of patients with VRE were detected by active screening compared with only 8% from routine laboratory diagnostic specimens, and that the cost savings from active screening ranged from US$56,258 to US$303,334 per month.
      • Shadel B.N.
      • Puzniak L.A.
      • Gillespie K.N.
      • Lawrence S.J.
      • Kollef M.
      • Mundy L.M.
      Surveillance for vancomycin-resistant enterococci: type, rates, costs and implications.
      In a US study, patients were evaluated weekly to identify those at increased risk of becoming VRE culture positive and from whom peri-rectal cultures were taken.
      • Muto C.A.
      • Giannetta E.T.
      • Durbin L.J.
      • Simonton B.M.
      • Farr B.M.
      Cost-effectiveness of perirectal surveillance cultures for controlling vancomycin-resistant enterococci.
      One case of VRE BSI was associated with 19 days of hospitalization and the overall cost of 28 cases of BSI was US$761,320 compared with US$253,099 for VRE infection prevention and control measures, including screening and patient isolation.
      • Muto C.A.
      • Giannetta E.T.
      • Durbin L.J.
      • Simonton B.M.
      • Farr B.M.
      Cost-effectiveness of perirectal surveillance cultures for controlling vancomycin-resistant enterococci.
      Finally, Montecalvo et al. assessed the costs of VRE BSI in an oncology unit that were associated with BSI, by matching VRE-positive with VRE-negative patients.
      • Montecalvo M.A.
      • Jarvis W.R.
      • Uman J.
      • et al.
      Costs and savings associated with infection control measures that reduced transmission of vancomycin-resistant enterococci in an endemic setting.
      Rates of VRE BSI were significantly reduced and the saving in one year from eight fewer VRE BSI patients was US$123,08; when allowing for the costs of infection prevention and control measures and other interventions, the net savings were US$189,318 for one year.
      • Montecalvo M.A.
      • Jarvis W.R.
      • Uman J.
      • et al.
      Costs and savings associated with infection control measures that reduced transmission of vancomycin-resistant enterococci in an endemic setting.
      Costs for laboratory detection vary according to the media used, whether an enrichment step is included, and whether molecular methods are used. The benefits of rapidity and high sensitivity using molecular methods have to be balanced against the increased laboratory costs of either the capital equipment, and/or consumables. In a study utilizing broth enrichment and the LightCycler, a laboratory-developed real-time PCR assay resulted in a saving of €7 per sample compared with a commercial kit-based method.
      • Fang H.
      • Ohlsson A.K.
      • Jiang G.-X.
      • Ulberg M.
      Screening for vancomycin-resistant enterococci: an efficient and economical laboratory-developed test.
      Therefore while better selective media have improved detection in terms of specificity and timeliness, the inevitable delays in using culture-based systems may lead to a failure to intervene earlier to prevent spread, especially from unexpectedly VRE-positive patients. PCR methods have the benefit of rapidity and high sensitivity, but with increased costs and poor specificity for VanB.

      Conclusion

      Enterococci remain important causes of HCAI and should remain a major focus of infection prevention and control practitioners notwithstanding other priorities. Whereas there are no effective methods to decolonize VRE-positive patients, active screening identifies additional VRE-positive patients and this is associated in some studies with reduced cases of VRE colonization, fewer VRE infections, and reduced costs. Those patients who should be actively screened include those admitted to high-risk units such as critical care, haematology/oncology and transplant wards, patients on renal dialysis, patients admitted from LTCF, and some patients previously on certain classes of antibiotics.
      There are various selective agar media specific for VRE which reduce the interval to detection, and PCR further reduces this time. Whereas molecular methods are more expensive and specificity for detecting vanB isolates is poor, when set against reduced time to detection and the opportunity to intervene to prevent onward transmission of vanA isolates, there may be some overall cost benefits. However, further research is required to: better define the factors responsible for the increase in VRE prevalence; quantify the benefits from active screening in different settings; and clarify the role of molecular testing as part of active screening.

      Acknowledgements

      I am grateful to B. Smith for assistance with the literature search, A. Shannon for secretarial support, and both Dr S. Corcoran and Professor E. Smyth for critically reviewing the manuscript.

      Conflict of interest statement

      The author has had in recent years research collaborations with Pfizer and has received lecture and other fees from Novartis, AstraZeneca, and Astellas.

      Funding sources

      None.

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