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(Chest. 2003;123:504S-518S.)
© 2003 American College of Chest Physicians

Vancomycin-Resistant Enterococci*

A Road Map on How To Prevent the Emergence and Transmission of Antimicrobial Resistance

Sylvain DeLisle, MD, MBA and Trish M. Perl, MD, MSc

* From the US Veterans Administration Medical Center (Dr. DeLisle), Departments of Internal Medicine and Physiology, Division of Pulmonary and Critical Care, University of Maryland, Baltimore; and Departments of Hospital Epidemiology and Medicine (Dr. Perl), Johns Hopkins Medicine and the Bloomberg School of Public Health and Hygiene, Johns Hopkins University, Baltimore, MD.

Correspondence to: Sylvain DeLisle, MD, MBA, 3D-122 VA Medical Center, 10 N. Greene St, Baltimore MD 21201; e-mail: sdelisle{at}umaryland.edu


   Abstract
TOP
 Abstract
Introduction
 The Problem
 How Did We Get...
 Is There a Way...
 Conclusion
 References
 
Nosocomial acquisition of microorganisms resistant to multiple antibiotics represents a threat to patient safety. Here we review the mechanisms that have allowed highly resistant strains belonging to the Enterococcus genus to proliferate within our health-care institutions. These mechanisms indicate that decreasing the prevalence of resistant organisms requires active surveillance, adherence to vigorous isolation, hand hygiene and environmental decontamination measures, and effective antibiotic stewardship. We suggest how to tailor such a complex, multidisciplinary program to the needs of a particular health-care setting so as to maximize cost-effectiveness.

Key Words: antibiotic control • antibiotic management • antibiotic stewardship • enterococcus • infection control • resistance • review • surveillance • vancomycin • vancomycin-resistant enterococci


   Introduction
TOP
 Abstract
 Introduction
The Problem
 How Did We Get...
 Is There a Way...
 Conclusion
 References
 
Many pathogenic microorganisms can now defy antibiotics to which they were previously susceptible. Examples abound: resistance to methicillin among Staphylococcus aureus and coagulase-negative species; resistance to third-generation cephalosporins among Escherichia coli, Klebsiella pneumonia, and Enterobacter species; imipenem, fluoroquinolone, and aminoglycoside resistance among Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter species. By putting patients at risk for longer hospital stays and increased mortality,1 2 3 4 these organisms may add over $4 billion to yearly US health-care expenditures.5

One of the most extreme examples of antibiotic resistance is observed in the Enterococcus genus, in which some strains are now resistant to almost all available antibiotics. In this work, we use vancomycin-resistant enterococci (VRE) as prototypes to review the mechanisms by which resistant microorganisms can become endemic in a hospital. These mechanisms then provide a framework to discuss the variety of measures that may limit the proliferation of resistance within a health-care environment.


   The Problem
TOP
 Abstract
 Introduction
 The Problem
How Did We Get...
 Is There a Way...
 Conclusion
 References
 
High-level resistance to glycopeptide antimicrobials, vancomycin and teicoplanin, was first reported in Europe in 19866 7 and in the United States in 1987.8 Since that time, VRE have been isolated from patients in Asia, Australia,9 South America,10 11 and Africa.12 Between 1989 and 1993, the rate of vancomycin resistance reported in the United States by the National Nosocomial Infections Surveillance system increased from 0.3% to 7.9%,13 with a 34-fold rise observed in ICUs.14 The increase in VRE prevalence also extends to patients hospitalized on medical, pediatric,15 and surgical wards. Prevalence is highest in hospitals with > 500 beds, particularly in those with university affiliation.14 16 17 As of December 2000, 26.3% of the ICU enterococcal isolates reported to the National Nosocomial Infections Surveillance system were resistant to vancomycin, an increase of 31% compared with data averaged for the years 1995 to 1999.18 Enterococci represent the third-most-common cause of nosocomial infections in ICU patients,19 contributing approximately 9% of all bloodstream and 12% of all urinary tract infections.19

VRE first colonize the GI tract.3 20 21 Once colonized, the patient is at an increased risk of acquiring a VRE surgical wound,19 or urinary tract or other intra-abdominal/pelvic infection. Enterococci can also cause eye or CNS shunt infections but are not believed to be respiratory tract pathogens. While it is true that enterococcal wound and urinary tract infections may heal without antibiotics, VRE bacteremia increases hospital length of stay by an average of 2 weeks22 23 and has an attributable mortality approaching 30%.13 22 23 24 25 26 27


   How Did We Get There?
TOP
 Abstract
 Introduction
 The Problem
 How Did We Get...
Is There a Way...
 Conclusion
 References
 
The leaf diagram in Figure 1 summarizes the main mechanisms by which antimicrobial resistance proliferates within a population. Resistance emerges when native microorganisms are exposed to antibiotics or when they acquire genetic resistance factors from neighboring organisms. Once resistant, microorganisms can spread through the population via human, environmental, or animal reservoirs. Beginning with the resistance properties intrinsic to the bacteria, we shall review how each of the mechanisms shown in Figure 1 contribute to the current prevalence of VRE.



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  		Figure 1.. Mechanisms leading to the proliferation of resistant microorganisms. Emergence of resistance is fueled mainly by antibiotics pressure and genetic transfers among organisms (left side of diagram). Transmission of resistant strains is facilitated by the existence of ecological reservoirs (right side of diagram). Measures aimed at interrupting the vicious circle leading to resistance are outlined in italic.

 
Intrinsic Resistance: the Native Organism
Enterococci are facultative anaerobic Gram-positive cocci that share their morphology and Lancefield antigenicity with group D streptococci. The genus Enterococcus includes at least 17 species, distinguished on the basis of pigment production, motility, and ability to produce acids from various carbohydrates. Nosocomial infections are caused mainly by two species: Enterococcus faecium (85 to 90%) and Enterococcus faecalis (5 to 10%).28 Most VRE are E faecium strains.

In the 1940s, clinicians observed that the response to penicillin was worse among patients with enterococcal endocarditis than among those individuals with streptococcal disease.29 30 We now know why: ß-lactam antibiotics bind only weakly to enterococci penicillin-binding proteins (PBPs) and may not prevent bacterial cell wall synthesis even when they do so.31 While most isolates of E faecalis can be inhibited by concentrations of penicillin achievable in the plasma (minimal inhibitory concentration [MIC] of 1 to 8 µg/mL), this is usually not the case with E faecium (MIC of 16 to 64 µg/mL). Higher-level resistance in E faecium has been attributed to overproduction of the low-affinity PBP-5, a protein that can take over the function of all other PBPs.32 33 34

Enterococci exhibit intrinsic resistance to antibiotics other than ß-lactams. Macrolides, for example, cannot stop protein synthesis because they face modified ribosomal targets. Enterococci can also bypass the block of folic acid synthesis due to trimethoprim-sulfamethoxazole by extracting folinic acid derivatives directly from their environment.35 Enterococci exhibit low level resistance to all aminoglycosides (MIC of 8 to 256 µg/mL), which cannot efficiently cross their cell wall. Aminoglycoside uptake is enhanced when enterococci are exposed to ß-lactams.36 This synergy underlies the long-standing practice of combining both classes of antibiotics to treat serious enterococcal infections.37

Emergence of Resistance: Antibiotic Exposure
The observation that changes in the incidence of bacterial resistance often mirror prior changes in exposure to antibiotics24 38 39 40 41 42 43 has withstood experimental, epidemiologic, and mathematical scrutiny in both animals and humans.44 45 Hence, there is an enduring consensus that antibiotic exposure lies at the root of the complex mechanisms through which resistance emerges.44 46 47

The evidence linking antibiotic exposure to resistance is particularly strong for VRE. Most healthy human noncarriers administered a glycopeptide antibiotic (vancomycin or teicoplanin) orally will become colonized with VRE.48 49 There is also a consistent association between previous use of vancomycin, the VRE carrier state, and VRE bacteremia.16 50 51 52 53 While VRE colonization rates are twofold to ninefold higher in patients who have received vancomycin,51 54 55 56 prior exposure to this drug is neither required nor sufficient for colonization: third-generation cephalosporins,54 55 56 57 aminoglycosides,52 aztreonam,16 ciprofloxacin, imipenem and the anti-anaerobe antimicrobials clindamycin58 and metronidazole20 have all been independently associated with the VRE carrier state. Antibiotic exposure can cause the emergence of VRE by inducing the expression of resistance genes and by selecting strains already expressing these genes. By altering the competing microbial flora in the GI tract, thereby increasing VRE concentration in the stools, antibiotic exposure can also facilitate the transmission of VRE.59 60

Emergence of Resistance: Genetic Transfers
Enterococci show a remarkable ability to acquire genetic material that confer antimicrobial resistance. Transfer of antibiotic resistance from enterococci to more aggressive pathogens, including S aureus, has been accomplished in vitro.61 62 63 Unfortunately, the prediction that such a transfer would occur in vivo has probably been realized: a gene cluster that confers vancomycin resistance, vanA, was recovered from both patient isolates of vancomycin-resistant S aureus [MIC >= 32 µg/mL] reported to date.64 65 The following acquired resistance mechanisms are now at play in a growing proportion of enterococci isolates.

ß-Lactams: Enterococci, almost exclusively strains of E faecalis, can express ß-lactamase enzymes that confer high level resistance against imipenem and against all penicillins, except those combined to ß-lactamase inhibitors (sulbactam or clavulanate).66 In addition, enterococci have acquired further modified PBPs with very low affinity for all ß-lactams antibiotics. Together, these two mechanisms can produce quite high resistance levels (MIC of > 256 µg/mL).

Aminoglycosides: Enterococci have acquired enzymes that modify ribosomes, thereby decreasing the binding and bacteriocidal activity of aminoglycosides (MIC > 500 µg/mL). The most commonly reported such enzymes include a dual function 2'-phosphotransferase/6'-acetyltransferase, a 3'-phosphotransferase, a 4'- and a 6'-adenylyltransferase. Although no single enzyme can inactivate all available aminoglycosides, 30% of VRE strains can produce multiple enzyme types and are thus highly resistant to all known aminoglycosides.

Glycopeptides: Vancomycin and teicoplanin inhibit cell wall synthesis by binding to the D-alaninyl-D-alanine terminus of a pentapeptide cell wall precursor.67 Glycopeptide resistance takes five different phenotypes, VanA to VanE (Table 1 ). Because the VanC phenotype is mainly manifested in species that do not yet pose a significant clinical threat68 69 and because little is known about VanD and VanE mechanisms of resistance,70 71 72 we will limit this discussion to vanA and vanB gene clusters.


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  		Table 1.. VRE Species and Phenotypes*

 
The vanA gene cluster has been reported in several enterococci species (E faecium,73 E faecalis,73 E avium,74 E casseliflavus,69 E gallinarum,69 and E durans75 76 ) and in the above-mentioned vancomycin-resistant S aureus isolates.64 65 vanA is encoded by a transposon, Tn1546, which is either integrated on the bacterial chromosome or located on a plasmid.77 vanA contains a resolvase and a transposase, two enzymes that regulate the integration of Tn1546 into foreign DNA, as well as seven other genes (vanS, vanR, vanH, vanA, vanX, vanY, and vanZ).78 vanS is implicated in sensing vancomycin while vanR induces at least some of the other Tn1546-encoded genes.79 The vanH dehydrogenase produces D-lactate that is attached to D-alanine by the vanA ligase. The resulting D-ala-D-lactate depsipeptide substitutes for the D-alaninyl-D-alanine moiety of the cell wall precursor, thereby inhibiting vancomycin binding and restoring cell wall synthesis. vanX and vanY cleave the remaining D-alaninyl-D-alanine termini, ensuring even higher levels of vancomycin resistance.80

The VanB phenotype is encoded in a complex of genes (vanB) whose products have both high sequence and functional homology to vanA except for the presence of the gene vanW, whose function remains unclear. Like vanA, vanB can be located on a conjugative plasmid, or can be transmitted to another microorganism as part of a large chromosomal element.81

Despite their genetic similarities, VanA and VanB isolates exhibit a distinct pattern of glycopeptide resistance. VanA isolates are highly resistant to both vancomycin and teicoplanin whereas VanB enterococci are variably resistant to vancomycin and sensitive to teicoplanin (Table 1) . Curiously, some VanA and VanB strains require vancomycin for growth.82 83 84 Although the mechanisms for vancomycin dependence have not been elucidated, one hypothesis is that while exposed to vancomycin, these strains have stopped the wasteful production of the D-alaninyl-D-alanine-containing cell wall precursor and are relying exclusively on the vanA/B gene products for cell wall synthesis. With the removal of vancomycin, vanA/B gene expression stops and so does cell wall synthesis.

Transmission of Resistant Organisms: Human Reservoir
The ecological niche of enterococci is the GI tract. Hence, the stool and perirectal/rectal cultures that grow organisms represent the "gold standard" for VRE colonization.85 VRE colonization typically persists for 1 to 2 months, but has been documented up to 1 year following discontinuation of antibiotics.86 87 88 89 90 Longitudinal genotyping data indicate that patients remain colonized this long either by retaining the same VRE strain or by serially acquiring new ones.91 Colonized patients contaminate themselves (38% of colonized patients have a positive culture finding at another body site92 ) and each other.90 As has been recognized for well over a century,93 94 most patient-to-patient VRE transfers probably occur through the hands of health-care workers: (1) enterococci are recovered on the hands in 10 to 43% of workers caring for colonized patients95 ; (2) VRE survives on gloved or ungloved hands for at least 60 min after inoculation96 ; (3) several case control studies have shown that exposure to health-care workers caring for VRE-colonized patients increases the risk of acquiring VRE.89 97

VRE strains are most often isolated from immunocompromised patients and in patients with severe medical illnesses, such as hematologic malignancies, respiratory failure, or chronic renal failure requiring dialysis.20 23 45 52 98 99 100 101 102 Because most of those patients have received long courses of antibiotics45 50 51 103 and/or have been in proximity with other VRE carriers,89 97 we do not yet know if these underlying diseases contribute per se to the emergence of VRE. Risk factors for VRE colonization are summarized in Table 2 .


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  		Table 2.. Risk Factors for Acquiring Vancomycin-Resistant Enterococcus

 
Transmission of Resistant Organisms: Environmental Reservoir
Hospital areas most likely to harbor VRE-colonized patients include ICUs,51 104 and organ transplant,23 99 oncology,20 56 dialysis101 102 and AIDS units. During outbreaks, 7 to 30% of environmental surface cultures in such areas may be positive for VRE. Environmental contamination, as measured by rates of environmental cultures where VRE is isolated, increases as patients grow VRE from multiple body sites,92 when they have diarrhea,105 or when VRE density rises above 104 organisms per gram of stool.60 The highest contamination rates occur on bed rails, bedside tables, objects near the patients,105 and on multiple hospital fabrics.106 107 VRE is a successful environmental contaminant at least in part because it survives for long periods of time on dry surfaces: 60 min on gloves, telephones, and stethoscopes; 24 h on bedrails; and up to 7 days on countertops.108 Contaminated fomites linked with VRE outbreaks include electronic thermometers,88 ear oxymeters,109 and bronchoscopes.110 Hospital pagers111 and computer keyboards112 should be considered highly suspect and decontaminated regularly. Anecdotally, we are aware of outbreaks where VRE strains originated from dirty utility rooms, ventilator tubing, and patient call bells.

Transmission of Resistant Organisms: Animal Reservoir
VRE were first found outside health-care settings in 1993, when E faecium was isolated in sewage treatment plant waste water in England and Germany. Since then, VRE have been isolated from pig and poultry feces and from uncooked chicken in Europe,113 114 but not in the United States. Because European livestock feeds were supplemented with the glycopeptide antibiotic avoparcin,115 116 investigators have hypothesized that the use of avoparcin selected for VRE.45 114 This hypothesis has been supported by epidemiologic studies documenting an association between avoparcin-containing feeds and VRE recovery from animals.114 The genetic similarity of the strains isolated from animals and workers indicates that VRE can be transmitted from animals to humans.81 113 117 118 Together, these observations have led to a European ban on the use of avoparcin.119 Despite this ban, VRE prevalence in some farm animals has remained high.120 In the United States, VRE strains have been isolated in animal feeds.121 Thus far, however, small community-based prevalence studies that have excluded persons in health-care settings have not documented VRE colonization.114


   Is There a Way Out?
TOP
 Abstract
 Introduction
 The Problem
 How Did We Get...
 Is There a Way...
Conclusion
 References
 
Figure 1 provides a functional overview of the many approaches that may be taken to limit the emergence and spread of resistant organisms within a health-care environment. These approaches are likely to be most effective when used in combination, as part of a comprehensive program that involves multiple hospital systems.122

Preventing Emergence of Resistance: Antimicrobial Stewardship
Vancomycin use, which has increased > 100-fold in the last 20 years,123 is often inappropriate.124 A strict vancomycin restriction policy can decrease the use of vancomycin by as much as 50%,16 125 and has reduced the prevalence of VRE.16 126 Table 3 reproduces the vancomycin usage guidelines in use at one of our own institutions. In institutions where VRE is endemic, simultaneous restriction of multiple antibiotics may be necessary to reduce VRE prevalence.17 126 127 128 129 130


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  		Table 3.. The Johns Hopkins Hospital Guidelines for Vancomycin Use

 
Any comprehensive strategy to limit the occurrence of resistant pathogens must seek to optimize antibiotics utilization.124 131 132 133 134 135 By "optimal use," we mean prescribing antibiotics only when they are needed, and then employing the narrowest spectrum of activity for the shortest possible treatment course. Optimally used antibiotics are also delivered in accurate amounts to the right patient, at the right time, using the safest route. They are adjusted as soon as the sensitivity of the offending microorganisms to antibiotics is known.136 By this definition, optimal use of antibiotics not only can minimize resistance, it can also reduce medication errors, adverse drug reactions, and unnecessary costs.

The many potential components of an antimicrobial stewardship program can perhaps best be conceptualized using a process-based framework where antibiotics are first chosen, prescribed, delivered, and then re-evaluated.136 Possible components include the following: (1) Practice guidelines may help providers choose appropriate prophylactic or empiric antimicrobial therapy; guidelines may be disease or drug specific, and have been notoriously difficult to operationalize. (2) The hospital formulary may exclude some antimicrobials and/or may restrict antibiotics to a group of practitioners, to an area of the hospital, and to specific clinical conditions. Formulary restrictions may also impose time limits to empiric or prophylactic use of antibiotics,137 or rotate preferred antibiotics as a function of time (antibiotic cycling). Obtaining restricted antibiotics involves a justification process that ranges from making a simple phone call, to filling out paper or computerized order forms, to obtaining a written infectious diseases consultation. (3) After antibiotics are prescribed, streamlining measures may suggest/impose alternate dosage, drug class, route of administration, and/or may focus on ensuring that therapy is adjusted according to culture results. Streamlining measures may be implemented through the hospital pharmacy, through an electronic patient record/order entry system, or with the help of clinical pharmacologist rounding with the care delivery team. The efficacy of the above components, taken either alone on in combination, has been reviewed elsewhere.135 136 138 Antibiotic cycling has thus far failed to reduce acquisition of VRE in the ICU.139 Antibiotic stewardship interventions that have lowered VRE prevalence are summarized in Table 4 .


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  		Table 4.. Managing Antibiotics to Lower VRE Prevalence*

 
Preventing Transmission of Resistance: Eradication
Treatment for VRE infections is a great challenge: the evidence supporting most current recommendations is either anecdotal or stems from small case series and uncontrolled clinical trials.71 Assessing the efficacy of therapy is likely to remain difficult because VRE is often associated with severe underlying illnesses and can be part of a polymicrobial infection. VRE eradication begins with abscess drainage and with the removal of suspected IV, intra-arterial, or urethral catheters. The latter may be all that is needed to treat urinary tract infections.

Antimicrobial therapy should be guided by microbial susceptibilities. We recommend using agents that are bacteriocidal and that exhibit synergy.141 In general, the drug concentrations that can be achieved in the bloodstream (or urinary tract, etc) should exceed the MIC reported by the laboratory. VRE is frequently moderately susceptible to ampicillin.141 If the MIC is <= 32 µg/mL, ampicillin doses of 10 to 12 g/d may be effective and should be attempted with an aminoglycoside for patients with endocarditis. If the VRE strain is highly resistant either to ampicillin (MIC >= 64 µg/mL) or to both gentamicin and streptomycin, then no drug regimen will be uniformly useful.71 Although successes with monotherapy (chloramphenicol, tetracycline,141 142 teicoplanin143 144 145 ) have been reported, two to three antibiotics are commonly recommended for VRE bloodstream infections. These combinations include penicillin or ceftriaxone plus vancomycin plus gentamicin, novobiacin plus ciprofloxacin, ampicillin plus imipenem, ampicillin plus gentamicin plus ciprofloxacin, and teicoplanin plus gentamicin. Even when a single agent or a combination of agents show in vitro activity against a particular VRE strain, overall therapeutic efficacy may be < 70%.142

The recently introduced semisynthetic streptogramin, quinupristin/dalfopristin, and the oxazolidinone, linezolid, are primarily bacteriostatic against VRE.146 Quinupristin/dalfopristin has been used successfully to treat patients with bacteremia, peritonitis, endocarditis, and meningitis.147 148 149 150 151 152 153 154 155 156 Its activity is equivalent to and may synergize with that of ampicillin against macrolide-susceptible VRE strains.157 Synergy of quinupristin/dalfopristin with ampicillin-sulbactam and doxycycline has also been reported.158 Linezolid is bioavailable both in the IV and oral form, but its utility against serious infections remains to be determined. Resistance to both agents has already emerged.147 159 160 Development of quinupristin/dalfopristin resistance could perhaps be slowed by adding doxycycline to the antibiotic regimen.147

Experimental agents with in vitro activity against VRE include glycopeptides (LY19145, LY307599, LY333328, ramoplanin), clinafloxacin, minocyline, ketolides, glycylcyclines, evernimomycin, and new tetracycline derivatives. Some of these agents are now being examined for safety and clinical efficacy.45 71 Ramoplanin was found to suppress VRE in 81 to 86% of asymptomatic GI carriers.161 Suppression, however, was temporary: 21 days after stopping therapy, VRE carriage returned in many patients.

Preventing Transmission of Resistance: Infection Control Measures
Measures aimed at preventing bacterial transmission are probably the most important aspect of a program that aims to reduce antimicrobial resistance rates. Patient safety requires US health-care systems to have a proactive strategy to control VRE. Table 5 ,5A outlines the potential elements of a multidisciplinary VRE prevention and control program based on the Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines. Responsibilities that such a program entails are outlined in Table 6 . Even though a comprehensive program can reduce the prevalence of VRE,97 110 122 163 its cost-effectiveness27 164 165 will be maximized if it is tailored to the size, patient mix, and VRE prevalence of the hospital.9 14


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  		Table 5.. VRE Prevention and Control Program: Elements

 

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  		Table 5A.. Continued

 

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  		Table 6.. VRE Prevention and Control Program: Responsibilities

 
Surveillance
How To Screen for Vancomycin Resistance: Accurate and early detection of VRE is a key element of a control program. Indeed, mathematical models argue that VRE endemicity requires a constant introduction of colonized patients.134 166 Screening with commercially available standard broth or agar dilution tests or with the antibiotic gradient method (E test) will detect most strains of VRE.167 Several disk diffusion systems may misclassify isolates as intermediately susceptible to vancomycin.9 To prevent this, the plates should incubate for 24 h before the size of the inhibitory zone can be related to vancomycin susceptibility according to the revised National Committee for Clinical Laboratory Standards definition.9 Once suspected, based on a screening method, vancomycin resistance should be confirmed using a different method.

What, Where, and When To Screen for VRE: In hospitals where no VRE has been documented, clinical samples submitted for culture probably do not need to be continually screened. Rather, point-prevalence studies (stool, rectal, or perirectal cultures) should be performed periodically on high-risk inpatient (ICU, hematology, bone marrow, solid-organ transplant)56 and outpatient (hemodialysis101 102 ) units. Because VRE colonization rates in a unit is a strong predictor of VRE acquisition rate,59 consider screening all patients admitted to wards where the VRE prevalence is > 20%, especially if these patients are immunocompromised or are likely to receive antibiotics. Once a colonized patient is identified and isolated, the search for other cases should expand to the patient’s original roommates and preferably to all patients on the ward. We would highly recommend screening all patients transferred from other hospitals or from nursing homes; such an active strategy can decrease VRE prevalence not only locally, but also throughout an entire geographic regions.122

In hospitals with a high VRE prevalence, we recommend that periodic point-prevalence surveys be performed on all wards. The frequency of the surveys depends on the previous prevalence, whether the ward houses high-risk patients, and whether the VRE prevalence has recently changed. In the ICU, for example, performing VRE rectal swabs on admission and then twice weekly identifies the vast majority of VRE-attributable hospital stay.168 Clinical specimens submitted for culture should also be continually screened for vancomycin resistance. Because only 45 to 50% of VRE are isolated from normally sterile clinical specimens (blood, urine, bile, etc),9 screening should also include specimens from nonsterile sources (stools, wounds, sputum, skin, catheter tips, etc).

Why and When To Use Molecular Typing: Molecular typing of enterococci can determine whether strains arise from a single or from multiple clones. This information helps define the epidemiology of an organism within an institution; when a single clone is found, nosocomial transmission from hands or from the environment is probable; when multiple clones are found, strains might have arisen randomly, through antibiotic pressures. Typing can begin with the polymerase chain reaction, using probes targeted at genes within vanA, vanB, or vanC. Because these genes may be found in different enterococcal clones, discriminating between strains requires additional technique(s): plasmid analysis, pulse-field gel electrophoresis of chromosomal DNA, or ribotyping. Of these, we and others84 91 have found that pulse-field gel electrophoresis discriminates well among different strains.

Isolation and Barrier Precautions
Isolation and barrier precautions are critical in interrupting nosocomial VRE transmission.97 122 169 170 171 HICPAC guidelines recommend that colonized/infected patients be placed in single rooms. In hospitals where VRE is endemic, colonized patients may be kept in the same room/ward and be taken care of by the same staff cohort.97 163 169 172 Health-care workers should wear both gloves and gown on entry into the patient’s room.162 170 173 Two clinical trials139 162 in ICUs have shown this strategy to be superior to gloves alone. Gowns can also increase compliance to other isolation/barrier precautions.171 Gloves and gowns should be discarded before leaving the isolation room.

While some hospitals continue to isolate patients if they remain at high risk for recolonization, most will attempt to stop patient isolation and barrier precautions when these measures are believed to be no longer necessary. In the absence of data on which protocol is the best, it is reasonable to adopt the HICPAC recommendations and discontinue precautions when three consecutive stool, perirectal, or rectal cultures, obtained 1 week apart, do not grow VRE. In addition, other body sites known to have been previously colonized with VRE should be re-cultured and proven negative. Patients who remain VRE positive at hospital discharge should be electronically "flagged" so as to accelerate their identification on readmission. Also, the institution to which they are transferred should be contacted so that appropriate precautions can be instituted.

Hand Hygiene
Hand hygiene by health-care workers, visitors, and patients is clearly an important measure to decrease VRE transmission and nosocomial infections.173 174 Unfortunately, compliance with hand hygiene is poor, particularly so in the ICUs,175 with physicians and health-care extenders often being the worst offenders. Compliance can improve following an extensive program to increase awareness,173 174 but even then remains far from ideal. Hand washing with soap and water is unreliable and will not remove tenacious organisms like VRE.96 Hands can be better cleaned with antiseptic soaps,96 174 175 176 and data favoring hand-rubbing with an alcohol-based solution is rapidly accumulating.176 177 Workers should disinfect their hands even after glove removal; despite wearing gloves, 5 of 17 health-care workers acquired their patients’ VRE strain on their hands.178 Following hand hygiene, great care must be exercised to avoid touching potentially contaminated surfaces, such as door knobs, bed rails, or countertops.96

Environment Decontamination
Every hospital should develop a detailed policy for cleaning of the environment (for an example, see www.hopkins-heic.org/prevention/vre.html). Cleaning is required after patients are discharged from a hospital room,179 or after a patient is seen in the outpatient clinic.180 If a dedicated "VRE" clinic room is provided, cleaning at the end of the day may suffice. Medical equipment, such as stethoscopes, blood-pressure cuffs, glucose monitors, oxymeters, and scales must be dedicated to VRE patients. In high-risk settings, fabrics and surfaces should be selected based on how easy they are to clean.107 110 With the exception of hydrogen peroxide (3%), most disinfectants (isopropyl alcohol, sodium hypochlorite, phenolic and quaternary ammonium compounds) are effective against VRE.181 To improve the efficacy of cleaning procedures, we have cultured the environment and shared the culture results with housekeepers.


   Conclusion
TOP
 Abstract
 Introduction
 The Problem
 How Did We Get...
 Is There a Way...
 Conclusion
References
 
The mechanisms underlying the emergence and transmission of VRE provide a road map on how to reduce the overall prevalence of resistant organisms within health-care systems. Because treatment options are limited, institutions should focus on a comprehensive prevention and control program that combines effective use of infection control measures and antibiotic stewardship. When properly adapted to a particular health-care setting, these labor-intensive efforts will prove cost-effective at improving overall patient safety.


   Footnotes
 
Abbreviations: HICPAC = Hospital Infection Control Practices Advisory Committee; MIC = minimal inhibitory concentration; PBP = penicillin-binding protein; VRE = vancomycin-resistant enterococci


   References
TOP
 Abstract
 Introduction
 The Problem
 How Did We Get...
 Is There a Way...
 Conclusion
 References
 

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  3. Beezhold, DW, Slaughter, S, Hayden, MK, et al Skin colonization with vancomycin-resistant enterococci among hospitalized patients with bacteremia. Clin Infect Dis 1997;24,704-706
  4. Richards, MJ, Edwards, JR, Culver, DH, et al Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System. Crit Care Med 1999;27,887-892
  5. Office of Technology Assessment.. Impacts of antibiotic-resistant bacteria. 1995 Government Printing Office. Washington, DC:
  6. Leclercq, R, Derlot, E, Duval, J, et al Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 1988;319,157-161
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