Hospital Infection Control

Gram positive bacteria - Enterococcus

Gram positive bacteria - Enterococcus

What are Gram positive bacteria - enterococci?

Enterococci are ubiquitous gram-positive cocci, calatase-negative, non-spore-forming, facultative anaerobic organisms, that belong to the Lancefield group D streptococci.

Enterococci are normally present, as colonizers, in the intestinal tract of human beings and animals, and can be recovered from feces in large quantities. Enterococci may occasionally reside in the vagina and oral cavity. They also may be found in food and water.

The two predominant enterococcal species in humans are E. faecalis and E. faecium, while other species are occasionally found.

Enterococci may survive in adverse environmental conditions, such as high temperature, drying, and in some antiseptic agents. This property helps enterococci contaminate surfaces and medical equipment, enabling it to be transmitted to patients via healthcare workers, causing outbreaks.

Although enterococci have been considered a low-virulent pathogens, during the last decades they have become an important cause of a variety of infections that primarily affect debilitated and immunocompromised patients and are mainly hospital-acquired or healthcare associated infections.

High-level resistance in enterococci to antibiotics such as betalactams, aminoglycosides and glycopeptides has increased dramatically in the last three decades and the treatment of some enterococcal infections has become a challenge for clinicians.

The changing epidemiology of enterococcal infections necessitates that the microbiology laboratory identify enterococci at the species level because the enterococcal species may have different epidemiology and antibiotic resistant patterns.

Importantly, recent studies have disclosed the genomics of enterococci, particularly E. faecalis and E. faecium, providing new insights to better understand the biology of enterococci. Comparative genomic analyses have exhibited considerable intra-species genomic diversity also within clonally related strains, which is mainly linked to the variable presence of plasmids, phages, pathogenicity islands and conjugative elements.

Also, reports on experimental models in animals have evaluated the host immune response against enterococci and have given some insights about the increased vulnerability of immunocompromised and critically ill patients to enterococcal infections.

Most putative virulence determinants associated with E. faecalis(and less frequently with E. faecium) are involved in adherence to extracellular structures and biofilm formation, which appear to be important factors for colonization and infection. Mobile genetic elements such as plasmids and transposons are crucial to the spread of antibiotic resistance in enterococci and also to transfer resistance determinants to other bacteria such as Staphylococcus aureus.

With the next generation of sequencing approaches such as pyrosequencing, with lower cost and higher performance, many more enterococcal genomes will be sequenced, and our understanding of the enterococcal virulence determinants and enterococcal biology will increase.

However, little is known about the adaptive response mechanisms of enterococci to several conditions.

New advances in genomics including the knowledge of the enterococcal virulence determinants and the adaptive response mechanisms of enterococci to different conditions as well as a better understanding of the host immune response to these pathogens will be able to create new approaches for reducing colonization and infection as well as novel therapeutic alternatives for difficult-to-treat enterococcal infections.

Enterococcal infections

Enterococci are relatively low virulence organisms, but they can invade the debilitated and immunocompromised host and cause a variety of serious infections.

Although enterococci can produce community-acquired infections, in recent years there have been an increased number of enterococcal healthcare associated infections (HAI). Enterococci are often involved in mixed infections. Enterococcal healthcare associated infections are often preventable and cause poor outcomes and increased costs.

Enterococci can harbor intrinsic low-level antibiotic resistance. Moreover, in recent years, enterococci have developed an escalating process of acquiring high-level antibiotic resistance to aminoglycosides, beta-lactams and glycopeptides.

High-level resistance to gentamicin, streptomycin or both has been observed in the US and Europe, and may affect both E. faecalis and E. faecium. The main clinical consequence of high-level aminoglycoside resistance is the lost of synergistic effect when adding to ampicillin or vancomycin in endocarditis or other serious enterococcal infections.

High-level resistance to betalactams and glycopeptides is of special concern, and both resistance patterns are mainly concentrated in E. faecium.

Although the figures for high-level ampicillin resistant are quite similar in the US and Europe, there are clear differences in the epidemiology of glycopeptide resistance in enterococci

High-level glycopeptide resistance is most commonly associated with vanA gen cluster and generates resistance to vancomycin and cross-resistance to teicoplanin. A great problem in clinical practice is that glycopeptide resistance can be transmitted intra-species and inter-species.

To find the most appropriate therapeutic option for enterococcal infections with high-level resistance to ampicillin and vancomycin is a complicated issue and may requiere new agents.

Prevention of vancomycin-resistant enterococci (VRE)

The emergence of vancomycin-resistant enterococci (VRE) has become a major problem in many healthcare institutions and, therefore, control and prevention of infection and colonization with VRE have become imperative. Most preventive strategies for VRE are also applicable to other antibiotic-resistant enterococci.

Preventing VRE colonization of the intestinal tract is essential, since it usually precedes the infection. Patients receiving antibiotics may have increased density of VRE colonization and VRE in stools which may increase and facilitate their dissemination. VRE may spread from patient to patient through the healthcare workers (with poor hand hygiene practices and insufficient compliance with contact precautions) and may contaminate the surfaces and medical equipment.

In brief, several risk factors for infection and/or colonization with VRE have been identified. These include:

  • Patient characteristics and site of care

  • Prior antibiotics

  • Colonization pressure and

  • Environmental contamination.

One important issue for an infection control team is to prevent transmission of VRE in the healthcare settings. These strategies include:

  • Hand hygiene, contact/barrier precautions, and source control.

  • Cohorting of colonized/infected patients and/or healthcare workers such as nursing staff; use private rooms when possible.

  • Surveillance studies for detecting colonization.

  • Prudent use of antibiotics.

  • Environmental cleaning programs in hospitals to optimize cleaning of high touch surfaces and medical equipment.

Current controversies

There are several controversial issues and questions regarding enterococci that are not fully answered. These include:

  • What are the genetic and molecular mechanisms that really lead to an increased pathogenicity and virulence of enterococci?

  • What are the host response mechanisms effective in preventing enterococcal infection?

  • What is the role of genetic and molecular determinants that may cause and facilitate spreading antibiotic resistance in enterococci?

  • What is the best methodology for improving and evaluating the hand hygiene practices and barrier precautions compliance in different healthcare settings?

  • How can a health care institution really improve the prudent use of antibiotics?

  • What is the effectiveness of a program using active surveillance cultures and subsequent isolation of colonized patients to control VRE?

  • Can the administration of drugs suppress or diminish intestinal tract colonization with VRE and result in decreased VRE infections?

  • Does restriction of vancomycin and anti-anaerobic drugs produce a decreased colonization and infection with VRE?

  • Which is the best methodology to promote and evaluate better practices for environmental cleaning?

  • What are the best treatment options for infections caused by multidrug-resistant and VRE?

What types of infections do enterococci cause?

Background

Enterococci can produce infections at multiple anatomic sites. These include:

  • Bacteremia and vascular catheter-related bloodstream infections (BSIs)

  • Endocarditis

  • Urinary tract infections (UTIs)

  • Abdominal and pelvic infections

  • Skin and soft tissue infections

  • Joint and bone infections

  • CNS infections

  • Pulmonary infections

Over the past three decades there has been a dramatic increase in the rates of enterococcal infections, particular those associated with the healthcare system.

Although some enterococcal infections can be acquired in the community, most of them are nosocomial or healthcare associated infections. Enterococcal infections have a propensity to affect elderly, debilitated or immunocompromised patients whose mucosal barriers and normal flora have been altered by instrumental procedures and/or antibiotic therapy.

Enterococcal infections in humans are mainly caused by E. faecalis and E. faecium and less commonly by other enterococcal species.

Although E. faecalis had been the predominant enterococcal species, about 90% of clinical isolates, in recent years E. faecium has become an important cause of nosocomial and healthcare associated infections, and in many US hospitals it may represent more than 40% of all enterococcal isolates (Table I). Importantly, the increase in E. faecium infections has been associated with high-level antibiotic resistance (to ampicillin, aminoglycosides and vancomycin). The prevalence of vancomycin resistant E. faecium infections in Europe varies widely among countries and is still lower than in the US, but they are increasingly reported (Table II and Table III).

Table I.

Isolation of Enterococci from Healthcare Associated Infections (HAI) in the United States*

Table II.

High-level Antibiotic Resistant Enterococci in Patients with Healthcare Associated Infections (HAI) in the United States*

Table III.

Proportion of High-level Antibiotic Resistance in Enterococcus spp. Bacteraemia in England, Wales, and Northern Ireland (year 2009)

Importantly, molecular studies have suggested that the emergence of E. faecalis and E. faecium as predominant pathogens in hospitals and healthcare settings has resulted from the evolutionary development of specific lineages or clonal complexes, such as E. faecium clonal complex-CC17, with several antibiotic resistance determinants and virulence factors.

Enterococci are often involved in mixed infections, such as intraabdominal suppurative infections, surgical wounds, diabetic foot ulcers, pressure ulcers, and catheter-related BSIs. The pathogenic role of enterococci in mixed infections is difficult to interpret and often these infections can be resolved without effective anti-enterococcal drugs. Enterococcal infections have been associated with the Strongyloides hyperinfection syndrome.

Some descriptions of the main enterococcal infections are given below:

Bacteremia and cathether-related BSIs

Enterococci have become one of the leading causes of nosocomial and healthcare-associated bacteremia. A prospective study using the SCOPE database (from 1995 to 2002) showed that enterococci were responsible for approximately 9% of nosocomial bacteremia cases.

The sources or portal of entry of enterococcal bacteremia may include:

  • Intravascular catheter infections

  • Localized enterococcal infections

  • Intestinal translocation

Intravascular catheter infections

Intravascular catheter infections are a major cause of nosocomial and healthcare associated bacteremia being the most prevalent microorganisms Staphylococci and Enterococci, albeit with lesser extent. Among patients with nosocomial enterococcal bacteremia, an intravascular catheter infection may be the portal of entry in more than 20% of cases. Enterococcal catheter-related bacteremia occur mainly in ICU patients, severely immunocompromised or those with dialysis.

In general, the most important risk factors for, and the prevalence of, catheter-related bacteremia are mainly associated with type of catheter, catheter location and other factors.

Localized enterococcal infections

Bacteremia can be associated with localized enterococcal infections (secondary bacteremia), which is generally associated with worse outcomes than catheter-related bacteremia.

Intestinal translocation

Occasionally, enterococcal bacteremia may not have an apparent portal of entry and when it happens in severely ill or immunocompromised patients often with multiple antimicrobial treatments, a mechanism of intestinal translocation may occur. It has also been demonstrated in experimental models in animals.

Diagnosis

Sometimes, the clinical relevance of a positive blood culture for enterococci is difficult to interpret. Most clinicians agree that a confirmed diagnosis of enterococcal bacteremia should be made on the basis of two or more positive blood cultures or one positive blood culture with a positive culture from another sterile site. The clinical significance of a single positive blood culture for enterococci in a febrile patient, without signs of severe sepsis or other suppurative focus of infection, is often unclear, but clinicians should be aware of the presence of a severe immunosuppressive condition, preexisting valvular heart disease or prosthesis. Most patients with enterococcal bacteremia who have not preexisting valvular heart disease or prosthesis will not develop endocarditis.

Enterococci bacteremia is often a polymicrobial infection since enterococci grew together with other microorganisms in blood cultures. Septic shock may occur in the setting of enterococcal bacteremia but it is relatively infrequent and its presence should alert for a polymicrobial infection, particularly in association with a gram-negative bacteria

Endocarditis

Mortality associated with enterococcal bacteremia is difficult to assess. Some studies have suggested that bacteremia due to E. faecium may have a worse prognosis than E. faecalis, and it can be partially explained because of an increased resistance to antibiotics in E. faecium. However, it should be noted that the mortality rate in severely ill and immune compromised patients with enterococcal bacteremia may be very high, but it is often unclear whether patients died with or because of the bloodstream infection, and the crude mortality is sometimes confounded by the associated comorbidities. Nevertheless, some studies have suggested that the attributable mortality of enterococcal bloodstream infections is substantial. Patients without severe underlying conditions or endovascular lesions/prostheses are more likely to be able to clear enterococcal bacteremia spontaneously and it becomes an indolent disease.

Enterococci are responsible for 10% to 20% of endocarditis, and in recent series enterococci are the second or third agent causing endocarditis.

Enterococci, particularly E. faecalis and less frequently E. faecium or other enterococcal species, can cause community-acquired, nosocomial-acquired, and healthcare-associated endocarditis. Endocarditis caused by multidrug-resistant enterococci is increasingly reported.

Enterococcal endocarditis occurs more frequently in elderly patients and the source of enterococci is often not found. However, in many cases the portal of entry of enterococci has been a urinary tract infection or a gastrointestinal infection, with subsequent hematogenous spreading and infection of the cardiac valve. Often patients with enterococcal endocarditis have associated a malignant or inflammatory disease and have undergone genitourinary surgery or instrumentation or gastrointestinal instrumentation.

In the case of enterococcal bacteremia the presence of endocarditis should be kept in mind. When enterococcal bacteremia is originated outside the hospital the presence of endocarditis should always be ruled out. However, the presence of endocarditis in patients with nosocomial or healthcare associated enterococcal bacteremia has been very low. Thus, several reports have shown that among patients with a diagnosis of enterococcal bacteremia, the presence of endocarditis varies widely, but it was higher in community-acquired cases (up to 34%) than in hospital-acquired cases (about 1%). However, in recent years there has been an increase of nosocomial and healthcare associated enterococcal endocarditis. The estimated risk of developing endocarditis is higher in E. faecalis bacteremia than in E. faecium bacteremia.

Enterococci usually cause left side endocarditis (mitral or aortic valves) and can affect both native valves - previously damaged heart valve and rarely intact valves - and prosthetic valves. The presentation of enterococcal endocarditis is usually subacute but may be acute, with rapidly progressive valve destruction. Enterococcal endocarditis may display the common signs and symptoms of endocarditis. The most severe complications are heart failure, which may require valve replacement, and embolic events particularly in the brain.

Urinary tract infection

Urinary tract infection (UTI) is the most common infection caused by enterococci, and may present with different clinical syndromes.

Enterococcal UTIs occur rarely in adults without predisposing conditions. Most patients with enterococcal UTIs have some identifiable risk factors.

Although enterococcal UTIs may be community-acquired, most are hospital-acquired or healthcare associated infections. A recent study from the National Healthcare Safety Network shows that enterococci are the third more common organism causing UTIs in patients with urinary catheters.

Enterococcal UTIs may be complicated with bacteremia, but it seems to be relatively uncommon as compared with others pathogens causing UTIs such as Escherichia coli.

In clinical practice it is often difficult to differentiate enterococcal urinary tract colonization from enterococcal UTIs. Some patients (mainly those with urinary catheters) may have only enterococcal urinary tract colonization without symptoms of UTI. Urinary catheters should be removed as soon as possible since it may eradicate enterococci from the urine tract without requiring antibiotic therapy. Mortality due to enterococcal UTIs, in the absence of bacteremia, is very low. However, enterococcal UTIs have been associated with increased length of hospital stay and costs.

Intra-abdominal and pelvic infections

Enterococci have been implicated as an etiologic agent of several intra-abdominal and biliary tract infections as well as in pelvic infections.

There has been a controversy about the role of enterococci in intra-abdominal and pelvic infections since these are frequently mixed infections and enterococci are often associated with other bacteria such as Gram-negative bacilli or anaerobes, and often these patients may recover with surgery and antibiotic regimens that do not include effective anti-enterococcal agents.

However, recent data have shown that in some patients with intra-abdominal infections the isolation of enterococci from abdominal samples is associated with increased rates of postoperative infectious complications, higher number of treatment failures and an increased mortality rate. Thus, although enterococci may not require specific antibiotic coverage in the initial empirical therapy of peritonitis, most clinical authorities believe that those patients who are severely ill or immunocompromised or with factors predisposing to endocarditis as well as those who developed a postoperative peritonitis should receive appropriate treatment for enterococci.

Other infections

These include the following:

  • Skin and soft tissue infections

  • Joint and bone infections

  • CNS infections

  • Pulmonary infections

  • Pediatric infections

What kind of problems does antibiotic resistance in enterococci cause?

Antibiotic resistance in enterocococi

Enterococci may contain (intrinsic) or develop (acquired) resistance to multiple antibiotics, with the most important resistance profiles being to betalactams, aminoglycosides and glycopeptides. Thus, over the past four decades there has been a progressive acquired resistance to several antimicrobials.

Enterococci harbor intrinsic low-level resistance to several antimicrobials. Thus, almost all enterococcal strains are tolerant to betalactams and glycopeptides and resistant to low concentrations of aminoglycosides. Thus, combinations of a cell-wall active compound, a betalactam or glycopeptide, and an aminoglycoside are necessary to achieve consistent bactericidal activity for the treatment of endocarditis and other serious enterococcal infections.

Enterococci have also a remarkable ability to acquire resistance by several mechanisms, such as mutations or acquisition of new resistant genes transferred by plasmids or transposons. Thus, recent progress in genomics has produced new knowledge about distribution and genetic content of mobile genetic elements in enterococci, such as plasmids and transposons. These mobile genetic elements are essential for dissemination and persistence of antimicrobial resistance among enterococci and, even more importantly, to transfer resistant determinants to other bacterial species.

Enterococci are part of the normal bowel flora and it may be crucial for acquiring antibiotic resistance and spreading resistant strains. Thus, the antibiotic use may produce a selective pressure on the colonizing intestinal flora and may favor overgrow and spread of resistant strains and the intra-species or inter-species transmission of resistance genes.

Nowadays, in several hospital or healthcare settings some enterococci, particularly E. faecium, may harbor multiple antibiotic resistances including high-level resistance to ampicillin, aminoglycosides and vancomycin, making the treatment options for serious enterococcal infection a challenge for clinicians.

There are several differences in antibiotic resistance among enterococcal species and some resistances are difficult to detect using standard laboratory methods, and special tests may be required for detecting resistance in clinical isolates.

Beta-lactam resistance

Enterococci exhibit intrinsic resistance to betalactams with increased MICs and loss of their bactericidal activity, also called tolerance.

Enterococcal species may harbor different degrees of betalactam resistance. Thus, E. faecium usually shows a higher intrinsic resistance to betalactams than E. faecalis (e.g., the MICs of ampicillin for E. faecium are about 8 to 32 mcg/mL and for E. faecalis are about 1 to 4 mcg/mL).

Also, betalactam compounds may exhibit different degrees of resistance against enterococci. For instance, the most active betalactams showing the lowest degree of resistance include ampicillin, penicillin G, piperacillin, and imipenem; while those with limited or no activity showing the greatest degree of resistance include aztreonam, ertapenem, cephalosporins, methicillin and ticarcillin. Some new cephalosporins such as ceftobiprole and ceftaroline are active against E. faecalis strains but their activity is lower for most E. faecium strains.

Some enterococci, particularly E. faecalis, have acquired resistance by the ability to produce enzymes such as belactamases, but this resistance mechanism is rarely found and can be easily solved by using a betalactamase inhibitor together with the betalactam agent such as amoxicillin-clavulanic, ampicillin-sulbactam or piperacillin-tazobactam.

A more worrisome therapeutic problem is that some enterococci, particularly E. faecium, may harbor a high-level resistance to ampicillin (i.e., the MICs of ampicillin may be greater than 256 mcg/mL) that appears to be associated with alterations in the PBP5 or transpeptidation mechanisms. Data from the US and UK show that high-level ampicillin/amoxicillin resistance remains relatively low in E. faecalis, but it can reach about 90% in E. faecium (Table II and Table III).

Aminoglycoside resistance

Enterococci exhibit an intrinsic moderate level of resistance to aminoglycosides, with increased gentamicin and streptomycin MICs. The MICs of gentamicin are about 8 to 64 mcg/mL and for streptomycin are about 64 to 512 mcg/mL. The resistance mechanism seems to be a decrease in the permeability of the cell wall that diminishes the entrance of aminoglycosides.

Despite this moderate level of resistance, a synergistic effect, together with a better clinical outcome, can be obtained when adding gentamicin or streptomycin to a regimen with a cell wall active compound (e.g., penicillin, ampicillin or vancomycin). Interestingly, it has been shown that when adding a cell wall active compound that blocks peptidoglycan synthesis markedly increases the cell permeability and the uptake of these aminoglycosides.

In most cases, the synergistic effect cannot be achieved with other aminoglycosides such as tobramycin, kanamycin, and netilmicin since they usually exhibit a high-level resistance because of other resistance mechanisms.

During the last four decades there has been a worldwide dissemination of high-level aminoglycoside-resistant enterococci and there have been several reports showing enterococci with high-level resistance to streptomycin, gentamicin, or both. Then, when using streptomycin or gentamicin in combination with a cell wall active compound (e.g., ampicillin, penicillin or vancomycin), the synergistic effect is not achieved and consequently there is not an improvement of the bactericidal activity necessary for some difficult to treat enterococcal infections (e.g., endocarditis or meningitis). For this reason, the Clinical Laboratory Standards Institute has recommended screening of enterococci for high-level resistance to streptomycin and gentamicin.

According to the European Centre for Disease Prevention and Control 2009 report (www.ecdc.europa.eu/en/publications/Publications/1011_SUR_annual_EARS_Net_2009.pdf), the proportion of high-level aminoglycoside resistance in E. faecalis was above 50% in three countries (Greece, Cyprus and Hungary) and between 30% and 50% in the majority of other European countries. Among enterococcal bacteremia cases from the UK in 2009 the proportion of high-level gentamicin resistance was similar and was higher for E. faecium than for E. faecalis (Table III). The prevalence of enterococcal strains with high-level resistance to aminoglycosides may experience large variations over time due to outbreaks.

The treatment of endocarditis due to E. faecalis with high-level resistance to aminoglycosides has become a worrisome problem. However, it has been suggested that the combination of ceftriaxone or cefotaxime with ampicillin may be more effective than ampicillin alone, and this synergistic combination may be an alternative therapy for patients with aminoglycoside resistant E. faecalis endocarditis. However, the synergistic effect with these combination regimens was not observed with E. faecium

Glycopeptide resistance

There are some enterococcal species such as E. gallinarum and E. casseliflavus that harbor an intrinsic low-level resistance to vancomycin (MICs 8 to 16 mcg/mL). But the most important problem has been that Enterococci have developed low-level and high-level resistance to glycopeptides, cell wall acting compounds, such as vancomycin and teicoplanin, which has been associated with van gen clusters.

The Clinical and Laboratory Standards Institute (CLSI) has reported the following vancomycin breakpoints:

  • Susceptible (MIC ≤4 mcg/mL)

  • Intermediate (MIC 8 to 16 mcg/mL) and

  • Resistant (MIC ≥32 mcg/mL).

Importantly, sometimes there are difficulties in detecting vancomycin resistance in enterococci when using standard laboratory tests, that may require additional methods. Vancomycin therapy should not be recommended for patients with enterococcal isolates showing intermediate or high level vancomycin resistance.

High level resistance to vancomycin is an increasingly reported clinical and therapeutic problem, because it often appears in enterococcal strains, particularly E. faecium, that also harbor high-level resistance to ampicillin.

The increased vancomycin resistance in enterococci in the US has been associated with the increasing use of vancomycin for treating other infections such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci, and Clostridium difficile.

High-level vancomycin resistance in enterococci is usually encoded by resistant gene clusters such as vanA, vanB, and vanD, while low-level vancomycin resistance is usually encoded by gene clusters such as vanC, vanE, vanG, vanL, and vanN (Table IV). In clinical practice, high-level vancomycin resistance is most commonly associated with vanA and generate cross-resistance to teicoplanin. The origins of van gen clusters are not fully understood but homologs of van genes have also been found in the biopesticide Bacillus popilliae and bacteria colonizing the intestinal tract such as Clostridium inoculums which suggest that other bacteria could be a potential source of van gen homologs.

Table IV.

Proportion of high-level antibiotic resistance in Enterococcus spp. bacteraemia in England, Wales, and Northern Ireland (year 2009)

Some reports have demonstrated the intraspecies and interspecies transmission of vancomycin resistance and the vanA cluster can disseminate from enterococci to other prevalent nosocomial bacterial species such as methicillin-resistant Staphylococcus aureus (MRSA) and produce a great problem in the hospital setting.

According to the European Centre for Disease Prevention and Control 2009 report (www.ecdc.europa.eu/en/publications/Publications/1011_SUR_annual_EARS_Net_2009.pdf) regarding vancomycin resistance in E. faecium, three European countries reported resistance proportions above 25% (Ireland, Greece and Luxembourg) and five countries reported resistance proportions between 10% and 25% (UK, Portugal, Lithuania, Latvia and Cyprus), while the majority of countries reported resistance proportions between < 1% and 10%.

Other antibiotic resistances

Different degrees of resistance in enterococci that can be intrinsically or acquired are frequently found among antibiotics such as trimethoprim-sulfamethoxazole, macrolides, tetracyclines or fluoroquinolones which are not usually included in the armamentarium for treating enterococcal infections. In several US hospitals the prevalence of vancomycin resistant E. faecium is very high (Table II), while in Europe it varies widely among countries but, in general, has experienced an increase in the years 2000s.

Newer antibiotics such as linezolid, daptomycin, quinupristin-dalfopristin, tigecycline and lypoglycopeptides usually show good activity against multidrug-resistant enterococci; however, resistance to these agents has already been reported.

  • Linezolid resistance

  • Daptomycin resistance

  • Quinupristin-dalfopristin resistance

  • Tigecycline resistance

  • Lipoglycopeptides resistance

What is the epidemiology of vancomycin resistant enterococci?

Epidemiology of vancomycin resistant enterococci

Enterococci have become resistant to multiple antimicrobial agents (e.g., betalactams, aminoglycosides, glycopeptides) and as resistance increases, the control of emergence and spread of resistant enterococci becomes more imperative.

In recent years, control of vancomycin resistant enterococci (VRE) in the healthcare setting has become a real challenge for epidemiologists and clinicians. Most of infection control measures for preventing VRE are also applicable, in large, to other drug-resistant enterococci and other resistant bacteria.

Vancomycin resistant enterococci (VRE) can colonize the gastrointestinal tract, particularly the large bowel, and is an important cause of nosocomial and healthcare-associated infections. Isolation of VRE in person without prior hospitalization or without contact with the healthcare system is very rare.

Large differences exist among enterococcal species regarding resistance to vancomycin. Thus, the majority of VRE isolates are E. faecium and less frequently E. faecalis; for example, data from the NHSN (2006-2007) showed that 80% of E. faecium and 6.9% of E. faecalis were vancomycin resistant (see Table II).

VRE bowel colonization can contaminate the skin due to fecal shedding. Patients colonized with VRE serve as a reservoir and can transmit the strains to other patients through the healthcare workers and contaminated materials. Colonization with VRE usually anticipates infection, but not all colonized patients will become infected.

Infections caused by VRE have become a difficult to treat infection in patients admitted to hospitals, long-term care facilities, or in other healthcare settings.

Interestingly, several reports have demonstrated clear differences in the epidemiology of VRE between Europe and the U.S. Thus, VRE infections in humans were initially reported in Europe in the late 1980s and were associated to the widely use of avoparcin, a glycopeptide compound, as a food additive for growth promotion in animals (VRE could be recovered from the bowel flora of many animals such as chicken, fowl and pigs). Thus, in Europe there was an evident link between an animal source of VRE and subsequent transmission to humans.

Later on, VRE infections were detected in the U.S. hospitals, where these infections were associated with an increased use of vancomycin in hospitalized patients. However, in the U.S., where avoparcin was not used for growth promoting in animals, there was no clear evidence of an animal source of VRE as occurred in Europe. Recently, a report from Michigan showed an isolation of VRE from pigs.

In humans, some enterococcal species such as E. casseliflavus and E. flavescens harbor intrinsic low-level vancomycin resistance may colonize the intestinal tract, but enterococci with high-level vancomycin resistance are not usually seen as colonizers. Then, in humans the bowel colonization with high-level vancomycin resistant enterococci having van A or van B gene cluster may result from an animal source or by horizontal transfer within the hospital or other healthcare settings.

Several reports have shown that VRE infections have been detected worldwide but the prevalence of these infections varies widely among countries. Of note, in the last two decades (1990s and 2000s) the rates of VRE infections in the U.S. have steadily increased, while in Europe these rates have persisted relatively lower than in the U.S. However, in recent years VRE are increasingly reported in some European countries (e.g. U.K., Portugal, Greece) while in others their prevalence is persistently relatively low.

VRE have produced multiple outbreaks in hospitalized patients, particularly in severely ill or immunocompromised patients admitted to ICUs as well as in surgical wards and medical wards. In more recent years, VRE have become endemic in many hospitals and chronic care facilities.

Analyses with molecular techniques such as PFGF (pulsed-field gel electrophoresis) have been useful to clarify the epidemiology of VRE in the hospital setting. Thus, several reports have shown that a single VRE clone can spread within a hospital unit and produce outbreaks. On the other hand, however, VRE strains can also transfer resistance horizontally to unrelated enterococcal strains and then many different VRE clones (different PFGF profiles) can be found in a single hospital and, in these circumstances, VRE may become endemic.

The epidemiology of VRE is not fully understood, but the emergence and spread of VRE may be a consequence of a complex interaction among several factors such as:

  • The use of antibiotics in animals and human beings.

  • The persistence of VRE in colonized animals and humans as well as in environmental and dietary reservoirs.

  • The potential for the rapid spread within hospitals and healthcare facilities where debilitated and immune compromised patients are admitted.

Risk factors for vancomycin resistant enterococci

It is well known that patients with VRE colonization in the intestinal tract sever as a reservoir and it is the initial step for spreading VRE in a healthcare setting and cause VRE infections (see Table V).

Table V.

Major risk factors for vancomycin resistant enterococci

VRE bowel colonization is usually detected by the use of rectal or perirectal swab cultures or stool cultures. The sensitivity of rectal swab varies widely depending on the VRE density in stool. Patients with high stool densities, prior antibiotics and associated skin colonization are those with higher probability of having positive rectal swab cultures for VRE.

The lack of identification of carriers because of false-negative rectal swab cultures, which may avoid the implementation of contact precautions, may increase transmission of VRE. Transmission of VRE from colonized patients to non-colonized patients can occur directly by contaminated hands of healthcare workers or indirectly by contaminated environmental surfaces. It has been demonstrated that VRE can survive for several days in different environmental surfaces (e.g., bedrails, countertops) and medical devices (e.g., stethoscopes, thermometers).

Multiple reports have evaluated the risk factors associated with VRE and there are several identifiable risk factors for infection and/or colonization with VRE, such as:

Patient characteristics and site of care

Several characteristics of patients have been associated with high risk of VRE such as the presence of serious underlying diseases (e.g., malignant disease and neutropenia, organ transplant recipients, chronic renal failure) and the use of invasive devices (e.g., intravascular catheters or urinary catheters).

In addition, patients admitted to ICUs and those with a prolonged hospital stay are at high risk for VRE. Some reports have also demonstrated that patients admitted to long-term care facilities are at high risk of VRE, particularly if the colonized pressure is high in those facilities. Often these patients have debilitating and chronic underlying conditions, suffer from decubitus ulcer, and receive multiple antibiotic treatments. Patients from nursing homes carrying VRE often introduce the strains to acute care facilities.

Prior antibiotics

Antibiotics may modify the normal bowel flora and predispose to colonization with resistant organisms. Thus, the use of antibiotics seems to be an important risk factor for VRE and multiple studies have demonstrated an association between prior antibiotic therapy and colonization or infection with VRE. Thus, patients with VRE had often prior antibiotic therapy with vancomycin, cephalosporins, anti-anaerobic drugs or quinolones, often with prolonged courses of treatment. The antibiotic selection pressure, particularly with anti-anaerobic drugs, may change the normal balance of the bowel flora and increase density of colonization with VRE.

Colonization pressure

The daily point prevalence of VRE colonized patients in a specific hospital unit is a crucial risk factor for acquisition of VRE. Thus, the risk for hospitalized patients to be colonized with VRE is strongly correlated with the number of VRE carriers and/or infected patients admitted in the hospital unit.

Environmental contamination

It has been demonstrated that exposure of hospitalized patients to contaminated surfaces and medical equipment is associated with VRE colonization and outbreaks of VRE infections.

The inappropriate use of hand washing and gloves by healthcare workers may transfer VRE from contaminated surfaces to uncontaminated surfaces and to uncontaminated patients.

An appropriate compliance by the housekeeping staff of the cleaning protocols to avoid or diminish environmental contamination with VRE should be mandatory

Control of VRE

Multiple experiences and reports have confirmed the beneficial effect of several infection control measures for preventing colonization and infection with VRE (see Table IV). One important step in interrupting transmission of VRE is early identification of colonized and/or infected patients. Once VRE have disseminated in a hospital unit, their eradication may become a very difficult issue.

For an effective control of VRE several steps are mandatory:

  • First, the microbiology laboratory must play an active role in the control of VRE by classifying the enterococci at the species level and determining antimicrobial susceptibilities on clinical isolates using accurate methods.

  • Secondly, control of infection with VRE require of different approaches.

  • Thirdly, several strategies for prevention of transmission of VRE must be implemented.

Strategies for prevention of transmission of VRE include the following five items:

1. Hand hygiene, contact precautions, and source control

Hand hygiene is considered the most important measure of preventing spread of VRE from patient to patient through the hands of healthcare workers. The two recognized techniques for hand hygiene are hand washing with soap and water and hand rubbing with alcohol-based hand-rub formulations. Proper use of hand hygiene is considered a critical issue for the prevention of VRE, and it should be performed immediately before and after touching a patient or touching objects located in the patient’s room. Several factors may influence the efficacy of hand hygiene and these include a proper duration of hand washing (it should take > 20 seconds) and use of soap.

Contact/barrier precautions can reduce the spread of VRE. Thus, transmission of VRE may decrease when healthcare workers wear gloves properly and gown when taking care of their patients, putting them on when entering a patient room, and removing them prior to exiting. It has been demonstrated that the use of gloves and gown is more efficacious than the use of gloves alone. It is important to clarify precisely when and how patients with VRE should be placed on contact precautions. Each institution should have available routes of electronic information of contact/barrier precautions requirements and initiation of isolation.

Education targeted to healthcare workers, cleaning and food service staff and visitors may help correct nonadherent practices to contact/barriers precautions and isolation measures. Finally, regular monitoring of contact/barrier precautions and revising the design of planned interventions are important to ascertain whether the recommendations are being followed and have any impact. Also the leaders and/or healthcare workers and staff should have a regular feedback of the process and appropriate recommendations for changes in order to increase behavioral adherence.

Source control, defined as a regular bathing of patients with antiseptic agents such as chlorhexidine, can reduce the burden of skin colonization by VRE and MRSA, and is an effective measure for preventing bloodstream infections.

When can a colonized patient with VRE be removed from contact precautions?

It has been recommended that for removing a patient from contact precautions he/she should have at least three negative rectal/perirectal or stool cultures obtained at weekly intervals. Importantly, however, these patients may persist with VRE colonization for more than one year, and rectal/perirectal or stools cultures may become positive after a new course of antibiotic therapy.

2. Cohorting of patients and/or healthcare workers

In the setting of colonization with multidrug-resistant organisms including VRE, cohorting of patients and/or cohorting of healthcare workers (e.g., nursing staff that take care for colonized or infected patients should not care for other patients) may diminish the transmission of VRE. In addition, several experiences have shown that using private rooms or closing units during outbreaks can help to reduce transmission of multidrug-resistant organisms.

Certain items of medical equipment such as thermometers, blood pressure cuffs and stethoscopes should be confined to the isolation room and not used for other patients.

Roommates of patients infected or colonized with VRE should have rectal/perirectal or stool cultures obtained.

Patients who had been colonized or infected with VRE and are readmitted to the hospital should be placed in isolation until colonization can be ruled out (e.g., two negative rectal/perirectal/stool cultures obtained at least 48 hours apart).

3. Surveillance studies for detecting colonization

Active surveillance cultures facilitate identification of patients with VRE carriage to be placed on contact precautions to minimize VRE spread. The most common specimens obtained to detect VRE carriage are rectal/perirectal swabs and stool samples.

Several studies have shown that performance of active surveillance cultures, on admission and periodically during hospitalization, for VRE carriage and further implementation of other control measures in patients at high risk can reduce transmission of VRE. It may be particularly important in patients admitted to ICUs and hematology/oncology wards or during outbreaks of infections caused by VRE.

What patients need active surveillance cultures?

It is well known that patients colonized with VRE, particularly those severely ill or immunocompromised, are at higher risk for developing VRE infections.

Active surveillance cultures of hospitalized patients for VRE carriage can be an effective strategy to implement rational preventive measures and should be carried out in patients at high risk. However, legislation has been introduced in some states in the U.S. where all hospitalized patients (not only patients at high risk) need to have performed surveillance cultures for MRSA and/or VRE. However, different professional organizations such as the Society for Healthcare Epidemiology of America (SHEA) and the Association of Professionals in Infection Control and Epidemiology (APIC) have expressed some concerns regarding this legislation. Moreover, a recent study has prospectively evaluated the culture-based active surveillance for MRSA and VRE and the expanded use of barrier precautions in 10 ICUs, as compared with existing practice in 8 ICUs. And, the conclusion was that the intervention was not effective in reducing the transmission of MRSA and VRE, although the use of barrier precautions was not optimal.

It is important to know that patients who had an infection or were colonized with VRE may remain culture-positive for more than 1 year and therefore active surveillance cultures are not needed for most of these patients.

Several decolonization strategies have been used to eradicate VRE carriage. However, current data show that intestinal decolonization with nonabsorbable oral antibiotics has not proved to be consistently effective and most authorities are not currently recommended it.

4. Prudent use of antibiotics

Most authorities consider that a prudent use of antibiotics is a fundamental strategy to reduce problems with antimicrobial resistance in the healthcare setting.

Thus, antibiotics must be administered prudently, with appropriate doses and duration of treatment. Inappropriate and excessive use of antibiotics can lead to selection of resistant organisms. For example, the risk of MRSA colonization has been correlated with a long duration of prior antibiotic therapy and certain types of antibiotics such as quinolones.

Although the relevance of antibiotic restriction in controlling VRE has not been clearly established, most authorities agree that antibiotic restriction, particularly vancomycin, cephalosporins, and anti-anaerobic drugs, should be considered in the setting of a nosocomial outbreak of VRE. For example, vancomycin should be avoided for routine prophylaxis unless high rates of MRSA exist. Also, vancomycin should be avoided for the treatment of coagulase-negative staphylococci bacteremia growing in a single blood culture if contamination is likely.

5. Environmental cleaning

In many circumstances transmission of VRE is related to contamination of near-patient surfaces and medical equipment. Often the evaluation of environmental cleaning is difficult to ascertain and some reports have confirmed that most near patient surfaces are not being cleaned in accordance with existing hospital policies.

Housekeeping staff should be instructed to clean properly the patient’s room, particularly the high touch surfaces and equipments, on a daily basis. After the patient is discharged or transferred, the room should be accurately cleaned and disinfected.

The cleaning process could be improved with the use of new techniques such as saturated steam vapor disinfectant systems.

The CDC initiative clearly emphasizes the need for improving the environmental cleaning and encourages hospitals to implement programs for optimizing it (basic or Level I program and Level II program). The CDC initiative claims to dedicate resources for evaluating environmental hygiene by means of implementing objective monitoring methods (e.g., direct practice observation, swab cultures, agar slide cultures, fluorescence markers, ATP bioluminesence). However, the local hospital or healthcare institution should consider the advantages and limitations of these monitoring approaches (www.cdc.gov/HAI/toolkits/Evaluating-Environmental-Cleaning.html).

What are the treatment options for enterococcal infections?

Treatment of enterococcal infections remains a difficult issue. Most currently available data are derived from uncontrolled studies. Several considerations should be taken into account and these may include:

  • Enterococci may harbor intrinsic antimicrobial resistance and more importantly, they have developed an escalating process of acquiring new resistant determinants.

  • Enterococcal infections often occur in a debilitated host.

  • Enterococci are frequently cultured from mixed infections.

  • There are some controversies related to using monotherapy versus combination therapy in enterococcal infections.

  • Treatment options for cases with high-level resistance for both ampicillin (non-betalactamase producing strains) and vancomycin.

Table VII summarizes the antimicrobial agents for enterococci. Briefly, some specific treatment options for the most common enterococcal infections are summarized below:

Table VI.

Major infection control measures for the prevention of vancomycin-resistant enterococci

Table VII.

Antimicrobial Agents for the Treatment of Enterococcal Infections

Bacteremia and catheter-related BSIs

Treatment of enterococcal bacteremia may include intravenous ampicillin as the treatment of choice and vancomycin in cases with ampicillin resistance; linezolid or daptomycin can be used in cases resistant to ampicillin and vancomycin. Doubts exist as to whether it should be monotherapy or combination therapy, which may include ampicillin or vancomycin plus gentamicin or streptomycin, in order to obtain a synergistic effect. Most authorities favor monotherapy for most cases of enterococcal bacteremia and combination therapy in severe sepsis or critically ill patients or those with preexisting valvular disease. In general, antibiotic therapy should be given for 7 to 14 days, although the optimal duration of treatment has not been established.

In the case of catheter-related BSIs, catheter removal alone may cure the infection, and most of these patients resolve the infection after 7 days of antibiotic therapy. No randomized trials have evaluated the potential benefit of combination therapy versus monotherapy or the optimal duration of therapy. However, most clinicians believe that many patients with enterococcal catheter-related BSIs can be cured with monotherapy and in cases of severe sepsis or critically-ill patients or those with risk factors for endocarditis or in whom intravascular catheter remains in situ a combination therapy and/or a prolonged duration of treatment should be considered.

Endocarditis

The treatment of choice for enterococcal endocarditis is ampicillin or penicillin G plus gentamicin. The usual duration of treatment is 4 to 6 weeks; however, to avoid nephrotoxity and ototoxicity, a shorter course of aminoglycoside (2 weeks) may be recommended in some cases, e.g., small vegetarians or patients with native endocarditis without prosthetic valves. If strains are producing beta-lactamase, the use of ampicillin-sulbactam plus gentamicin or vancomycin plus gentamicin is usually recommended. In the setting of high-level penicillin resistance, the use of vancomycin plus gentamicin is recommended; if high-level gentamicin resistance is detected, streptomycin may be the alternative.

In the setting of aminoglycoside resistant E. faecalis, other combinations such as ampicillin plus imipenem or ampicillin plus ceftriaxone or ceftotaxime have been recommended. For multi-drug resistant E. faecium, linezolid or quinupristin-dalfopristin may be used. Daptomycin is generally not recommended for enterococcal endocarditis, although high-dose daptomycin combined with other agents such as gentamicin, rifampin, or tigecycline have cured some patients with vancomycin resistant enterococcal endocarditis. Importantly, in cases with multiple resistances the treatment success is usually lower and the duration of treatment should be prolonged at least of 8 weeks.

Urinary tract infections (UTIs)

Oral therapy for uncomplicated enterococcal UTIs may include amoxicillin, nitrofurantoin, or fosfomycin; the experience with linezolid or fluoroquinolones is limited. For complicated UTIs, intravenous ampicillin is considered the drug of choice; alternatives may include vancomycin for susceptible cases or linezolid for cases resistant to ampicillin and vancomycin.

Intra-abdominal infections

It has been suggested that empiric antibiotic therapy for most community-acquired intra-abdominal infections or peritonitis does not need to cover enterococci. However, enterococci should be covered in selected patients with peritonitis such as those with prior antibiotics, immunocompromised host, those with valvular disease or prosthesis, as well as those with postoperative peritonitis. Antibiotics with a potential activity against enterococci, which must be confirmed with susceptibility studies, may include ampicillin, piperacillin-tazobactam, imipenem, or vancomycin. The coverage of VRE and/or multidrug resistant enterococci should be considered in endemic or epidemic settings and may require new alternative agents.

Meningitis

Treatment of enterococcal meningitis is a difficult issue. Most clinicians agree that a combination of drugs to achieve synergistic therapy with systemic antibiotics (i.e., ampicillin or penicillin or vancomycin plus gentamicin or streptomycin) should be given for most cases of enterococcal meningitis. Some patients may require an intraventricular therapy (e.g., vancomycin or gentamicin). Experience with multi-resistant E. faecium meningitis is very limited and requires alternative agents given alone or in combinations, such as quinupristin-dalfopristin and rifampin. Other agents such as daptomycin and tigecycline have poor CNS penetration.

What national and international guidelines exist related to Gram positive bacteria - Enterococcus?

Guidelines to prevent transmission of VRE

There is a debate on optimal infection control strategies for preventing multidrug resistant organisms and VRE. In addition, most studies have been carried out in acute care institutions, and with lesser extent in non-acute care institutions or chronic care facilities.

There have been several organizations that reported guideline recommendations to prevent transmission of multidrug resistant organisms including VRE. These evidence-based guidelines include The Society for Healthcare Epidemiology of America (SHEA), the Hospital Infection Society and Infection Control Nurses Association in UK, and the Hospital Infection Control Practices Advisory Committee (HICPAC) of the CDC.

In brief, the SHEA guidelines include several recommendations based on the level of scientific evidence for each infection control measures that should be implemented for preventing multidrug resistant strains of Staphylococcus aureus and Enterococcus.

The U.K. guidelines also provide recommendations for the control of glycopeptides-resistant enterococci and categorized the preventive measures according to the level of scientific evidence.

The HICPAC guidelines present a two-tiered approach for control of multidrug resistant organisms including VRE. Tier-1 includes general recommendations for routine prevention and control of multidrug resistant organisms, and Tier-2 includes recommendations for intensified multidrug resistant organisms control efforts in special situations such as an outbreak or high incidence rates. Tier-1 and Tier-2 include seven categories of intervention.

  1. Administrative measures/adherence monitoring

  2. Multidrug resistant organisms education

  3. Judicious antimicrobial use

  4. Surveillance

  5. Infection control precautions to prevent transmission

  6. Environmental measures

  7. Decolonization

All three guidelines mostly agree regarding the main infection control strategies for prevention colonization/infection with multidrug resistant organisms and VRE. However, these guidelines differ regarding the use of active surveillance cultures for detecting colonization with VRE in patients at high risk. The UK guideline did not particularly mention active surveillance cultures as a recommended practice among the infection control measures for VRE. The SHEA guideline recommends the use of surveillance cultures in patients at high risk. The HICPAC guideline includes two-tiered set of recommendations.

All three guidelines agree that no recommendations can be made for decolonization of patients who carry VRE and the use of nonabsorbable oral antibiotics has been generally disappointing.

The guidelines emphasize that compliance with hand hygiene practices and contact/barrier precautions are critical for preventing the spread of multidrug resistant organisms and VRE, but implementation is a challenge at many healthcare institutions. It is clear that the infection control program should be a dynamic process that requires a systematic approach and have precise measures for entering or removing a patient from contact/barrier precautions to promote adherent practices.

Also, the infection control program should identify nonadherent practices. It is important to emphasize that despite publication of detailed recommendations and guidelines, compliance remains suboptimal in many institutions. For example, a report from three New York institutions showed that patient care staff had an adherence rates on room entry and exit of 22.4% and 59.0% for hand hygiene, 71.6% and 72.5% for gloves, and 71.0% and 83.9% for gowns. Another multicenter study, which includes several ICUs from the US, showed that after an intervention (using surveillance cultures and reinforcing barriers precautions) health care providers used gloves, gowns and hand hygiene less frequently than required.

In summary, the hospitals and healthcare institutions need to reinforce the major infection control strategies such as hand hygiene and contact/barrier precautions, use antibiotics prudently, and proper environmental cleaning. Compliance with the current evidence-based guidelines is mandatory in order to reduce colonization and infection with VRE.

What other consensus group statements exist and what do key leaders advise?

See above.

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Guidelines

Muto, CA, Jernigan, JA, Ostrowsky, BE. "SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus". Infect Control Hosp Epidemiol. vol. 24. 2003. pp. 362-86.

Cookson, BD, Macrae, MB, Barrett, SP, Brown, DF, Chadwick, C, French, GL, Hateley, P, Hosein, IK, Wade, JJ. "Combined Working Party of the Hospital Infection Society and Infection Control Nurses Association. Guidelines for the control of glycopeptide-resistant enterococci in hospitals". J Hosp Infect. vol. 62. 2006. pp. 6-21.

Siegel, JD, Rhinehart, E, Jackson, M, Chiarello, L. "Management of multidrug-resistant organisms in healthcare settings". Centers for Disease Control. 2006. http://www.cdc.gov/hicpac/pdf/MDRO/Pages1_3MDROGuideline2006.pdf.

Clock, SA, Cohen, B, Behta, M, Ross, B, Larson, EL. "Contact precautions for multidrug-resistant organisms: Current recommendations and actual practice". Am J Infect Control. vol. 38. 2010. pp. 105-11.

Huskins, WC, Huckabee, CM, O'Grady, NP, Murray, P, Kopetskie, H, Zimmer, L. "Intervention to reduce transmission of resistant bacteria in intensive care". N Engl J Med. vol. 364. 2011. pp. 1407-18.

Bearman, GM, Marra, AR, Sessler, CN, Smith, WR, Rosato, A, Laplante, JK, Wenzel, RP, Edmond, MB. "A controlled trial of universal gloving versus contact precautions for preventing the transmission of multidrug-resistant organisms". Am J Infect Control. vol. 35. 2007. pp. 650-5.

Mathai, E, Allegranzi, B, Kilpatrick, C, Bagheri Nejad, S, Graafmans, W, Pittet, D. "Promoting hand hygiene in healthcare through national/subnational campaigns". J Hosp Infect. vol. 77. 2011. pp. 294-8.

Tschudin-Sutter, S, Pargger, H, Widmer, AF. "Hand hygiene in the intensive care unit". Crit Care Med. vol. 38. 2010. pp. S299-305.

Siegel, JD, Rhinehart, E, Jackson, M, Chiarello, L. "2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings". http://www.cdc.gov/niosh/docket/archive/pdfs/NIOSH-219/0219-010107-siegel.pdf.

"Options for Evaluation Cleaning". http://www.cdc.gov/HAI/toolkits/Evaluating-Environmental-Cleaning.html.

"Enterococcus spp. bacteraemia in England, Wales, and Northern Ireland: 2005-2009". http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1284475800225.

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