Practice Essentials
Enterococcus faecalis and E faecium can cause a variety of infections including cystitis, pyelonephritis and catheter-associated UTI, endocarditis, and mixed-organism infections of the abdomen and pelvis.
Ampicillin and amoxicillin are the agents of choice for susceptible strains.
E faecalis is more frequently retrieved from sites of infection. E faecium is more likely to be resistant to commonly used antibiotics such as ampicillin.
Dual antibiotic therapy with a cell-wall active agent plus a synergistic agent is necessary when treating endocarditis or meningitis due to enterococci.
In case of resistant or refractory infections, antibiotic choices may be limited, meriting an infectious diseases consultation.
Background
Enterococci are part of the normal intestinal flora of humans and animals.The genus Enterococcus includes more than 17 species, although only a few cause clinical infections in humans. They are increasingly recognized as significant human pathogens and pose major therapeutic challenges, including the need for synergistic antibiotic combinations to successfully treat enterococcal infective endocarditis (IE).
Enterococcus species are facultative anaerobic organisms that can survive temperatures of 60°C for short periods and that grow in high salt concentrations. In the laboratory, enterococci are distinguished by their morphologic appearance on Gram stain and culture (gram-positive cocci that grow in chains) and their ability to (1) hydrolyze esculin in the presence of bile, (2) their growth in 6.5% sodium chloride, (3) their hydrolysis of pyrrolidonyl arylamidase and leucine aminopeptidase, and (4) their reaction with group D antiserum. Before they were assigned their own genus, they were classified as group D streptococci.
Enterococcus faecalis and Enterococcus faecium are the most prevalent species cultured from humans, accounting for more than 90% of clinical isolates. Other enterococcal species known to cause human infection include Enterococcus avium, Enterococcus gallinarum, Enterococcus casseliflavus, Enterococcus durans, Enterococcus raffinosus, and Enterococcus mundtii. [1] Enterococcus faecalis is more virulent or pathogenic, but E faecium is responsible for most of the vancomycin-resistant enterococci (VRE) infections. [2]
Isolation of enterococci resistant to multiple antibiotics has become increasingly common in the hospital setting. [3] According to National Nosocomial Infections Surveillance (NNIS) data from January 2003 through December 2003, more than 28% of enterococcal isolates in ICUs of the more than 300 participating hospitals were vancomycin-resistant. Six years later, 35.5% of enterococcal hospital-associated infections were resistant to vancomycin, ranking as the second most common cause of nosocomial infections in the United States. [4] Clonal spread is the dominant factor in the dissemination of multidrug-resistant enterococci in North America and Europe. [5] Virulence and pathogenicity factors have been described using molecular techniques. Several genes isolated from resistant enterococci (agg, gelE, ace, cylLLS, esp, cpd, fsrB) encode virulence factors such as the production of gelatinase and hemolysin, adherence to caco-2 and hep-2 cells, and capacity for biofilm formation. [5, 6]
Enterococci have both an intrinsic and acquired resistance to antibiotics, making them important nosocomial pathogens. Intrinsically, enterococci tolerate or resist beta-lactam antibiotics because they contain penicillin-binding proteins (PBPs); therefore, they are still able to synthesize some cell-wall components. They are intrinsically resistant to penicillinase-susceptible penicillin (low level), penicillinase-resistant penicillins, cephalosporins, nalidixic acid, aztreonam, macrolides, and low levels of clindamycin and aminoglycosides. They use already-formed folic acid, which allows them to bypass the inhibition of folate synthesis, resulting in resistance to trimethoprim-sulfamethoxazole.
Enterococci also have acquired resistance, which includes resistance to penicillin by beta-lactamases, chloramphenicol, tetracyclines, rifampin, fluoroquinolones, aminoglycosides (high levels), and vancomycin. The genes that encode intrinsic or acquired vancomycin resistance result in a peptide to which vancomycin cannot bind; therefore, cell-wall synthesis is still possible.
Unlike streptococcal species, enterococci are relatively resistant to penicillin, with minimum inhibitory concentrations (MICs) that generally range from 1-8 mcg/mL for E faecalis and 16-64 mcg/mL for E faecium. Therefore, exposure to these antibiotic agents inhibits but does not kill these species. Combining a cell wall–active agent such as ampicillin or vancomycin with an aminoglycoside may result in synergistic bactericidal activity against enterococci.
The acquisition of vancomycin resistance by enterococci has seriously affected the treatment and infection control of these organisms. VRE, particularly E faecium strains, are frequently resistant to all antibiotics that are effective treatment for vancomycin-susceptible enterococci, which leaves clinicians treating VRE infections with limited therapeutic options.
Less frequently used antibiotics (eg, quinupristin-dalfopristin, linezolid, daptomycin, tigecycline) with activity against many VRE strains have improved this situation, but resistance to these agents has already been described. A mutation (G2576U) in the domain V of the 23S rRNA is responsible for linezolid resistance, [5] whereas resistance to quinupristin-dalfopristin may be the result of several mechanisms: modification of enzymes, active efflux, and target modification. Resistance of E faecalis and E faecium to daptomycin, a cyclic lipopeptide antibiotic that acts on the bacterial cell membrane, has also been reported. [7] Recently approved antibiotics such as eravacycline may provide treatment options in refractory cases.
It appears that the beta-lactam antibiotics ceftaroline, ertapenem, ampicillin, cefepime, and ceftriaxone can increase the in vitro activity of daptomycin against vancomycin-resistant E faecalis and E faecium. Ceftaroline and daptomycin appeared to be the most effective combination. [8] In a study of synergistic combinations against isolates resistant to daptomycin, a combination of daptomycin and ampicillin appeared to be the most synergistic. [9] The unavailability of clinical synergistic data for a specific isolate limits treatment to the mainstays of therapy against resistant enterococci, linezolid and daptomycin.
Six phenotypes of vancomycin resistance, termed VanA, VanB, VanC, VanD, VanE, and VanG, have been described. The VanA and VanB phenotypes are clinically significant and mediated by 1-2 acquired transferable operons that consist of 7 genes in 2 clusters termed VANA and VANB operons. In 1988, these gene clusters first were reported in enterococcal strains. VanA is carried on a transposon Tn1546 that is almost always plasmid-mediated.
In the United States and Europe, the 3 major phenotypes include VanA, VanB, and VanD. VanA is the most common, and enterococcal isolates exhibit high-level resistance to both vancomycin and teicoplanin, while VanB isolates have variable resistance to vancomycin and remain susceptible to teicoplanin. The VanC phenotype is mediated by the chromosomal VANC1 and VANC2 genes, which are constitutively present in E gallinarum (VANC1) and E casseliflavus (VANC2). These genes confer relatively low resistance levels to vancomycin and are not transferable. To date, the VanD, VanE, and VanG phenotypes have been described in only a few strains of enterococci.
Thirteen patients infected with vancomycin-resistant Staphylococcus aureus (VRSA) have been reported in the United States. [10, 11, 12] The in vivo conjugative transfer potential of the vanA resistance gene from vancomycin-resistant E faecalis to methicillin-resistant S aureus(MRSA) was confirmed in all of these cases. This poses an emerging threat to patient safety. E faecium isolates with a complex-17 lineage have also emerged in hospital and community settings in 5 continents over just the past 2 decades. This continued global spread of resistant organisms and the creation of new, highly virulent pathogens from transfer of resistance genes underscore the importance of infection control and prevention, active surveillance, and use of appropriate antibiotics.
Pathophysiology
Infections commonly caused by enterococci include urinary tract infection (UTIs), endocarditis, bacteremia, catheter-related infections, wound infections, and intra-abdominal and pelvic infections. Many infecting strains originate from the patient's intestinal flora. From here, they can spread and cause UTI, intra-abdominal infection, and surgical wound infection. Bacteremia may result with subsequent seeding of more distant sites. For example, genitourinary tract infection or instrumentation often precedes the onset of enterococcal endocarditis. Meningitis, pleural space infections, and skin and soft-tissue infections have also been reported.
Intestinal colonization with resistant enterococcal strains is more common than clinical infection. In Cleveland, VRE stool isolates outnumber clinical isolates by a factor of 10 in hospitals in which active VRE surveillance is performed. Colonized patients are not only at risk of being infected but are also a potential source for the spread of organisms to the hands of health care workers, the environment, and other patients. Antibiotic-selective pressure facilitates the spread of resistant enterococcal strains by promoting overgrowth of these strains in the intestinal tract. Enterococci can survive for long periods on environmental surfaces, contributing to their transmission. VRE have been isolated from all objects and sites in health care facilities.
For colonization development and infection with VRE, antimicrobial and nonantimicrobial risk factors have been identified. Vancomycin use is associated with VRE colonization and infection, but prior exposure is not required for colonization. Third-generation cephalosporins, aminoglycosides, aztreonam, ciprofloxacin, imipenem, clindamycin, and metronidazole have been associated with VRE colonization. Nonantimicrobial risk factors (eg, increased duration of exposure to individuals colonized with VRE and close proximity to other colonized patients) increase the likelihood of VRE exposure.
Individuals at risk for colonization include critically ill patients who have received lengthy courses of antibiotics (particularly those in long-term care facilities), solid-organ transplant recipients and patients with hematologic malignancies, and health care workers. Unfortunately, spontaneous decolonization is uncommon, and antimicrobials are unlikely to eradicate VRE colonization. Identified risk factors for VRE bacteremia include prior intestinal colonization, prior long-term antibiotic use, increased severity of illness, hematologic malignancy, bone marrow transplant, mucositis, neutropenia, indwelling urinary catheters, corticosteroid treatment, chemotherapy, and parenteral nutrition. [13, 14]
The ability of enterococci to produce biofilms both protects the organism from the body's defenses and promotes exchange of genetic material with other pathogens. [15]
Epidemiology
Frequency
United States
According to recent NNIS surveys, enterococci remain in the top 3 most common pathogens that cause nosocomial infections. Enterococci frequently cause UTIs, bloodstream infections, and wound infections in hospitalized patients. Nosocomial enterococcal infections typically occur in very ill debilitated patients who have been exposed to broad-spectrum antibiotics. They are the third most common cause of nosocomial bloodstream infections in the United States. [16]
The increased prevalence of serious enterococcal infections has been associated with the rise of third-generation cephalosporins. These compounds have no activity against enterococci but do eradicate the aerobic and anaerobic competitive organisms that act as suppressors of overgrowth of these pathogens in various body sites. The development of VRE also appears to be tied into the use of third-generation cephalosporins. [17] Over the past 20 years, the incidence of multiply resistant E faecium has significantly increased; 35%-40% of enterococcal bloodstream infections involve this microorganism. [18]
In 1989, VRE was first reported in New York City; subsequently, VRE has spread rapidly throughout the United States. From 1989-1993, the NNIS surveys reported that the percentage of enterococcal isolates exhibiting vancomycin resistance increased from 0.3% to 7.9%, with a 34-fold rise seen in ICUs. In 2003, the percentage of nosocomial enterococcal isolates exhibiting vancomycin resistance in ICU patients increased to more than 28%—an increase of 12% compared with 1998-2002.
NNIS data reveal the pooled mean for VRE species from all ICUs, non-ICU inpatient areas, and outpatient areas were 13.9%, 12%, and 4.6%, respectively, from 1998 through June 2004. VRE was initially isolated mainly in large university hospitals, but subsequent reports demonstrate the presence of significant VRE epidemics in community hospitals and chronic care facilities, whereby a single clone can easily spread. VRE is isolated almost exclusively from hospitalized (or recently hospitalized) individuals.
International
In contrast, Europe appears to have a large community reservoir of VRE without as rapid an increase in incidence of hospital-associated infections seen in the United States. In European countries, VanA-type VRE has been isolated from various farm animals, chicken carcasses, other meat products, and wastewater samples from sewage treatment plants. In 1994, a German community screened 100 healthy people for VRE, and 12% were found to be carriers.
In Europe, the use of avoparcin, a glycopeptide antibiotic, as a growth promoter for farm animals has been proposed to explain the epidemiology of VRE. Until banned by the European Union in 1997, avoparcin had been used in several European countries and provided a selective pressure for the emergence and spread of vancomycin-resistant genes. This hypothesis is supported by a Danish study that found VanA-type VRE in chicken stool samples from farms using avoparcin but not in samples from farms not using avoparcin. Among the Saxony-Anhalt region in Germany, the prevalence of VRE fecal colonization in healthy individuals after discontinuing avoparcin use in animal husbandry decreased from 12% to 3%, concurrent with a similar decrease in the prevalence of VRE in German poultry products.
Several outbreaks of VRE colonization [13] and infection have been reported by hospitals in Europe [5] and have been associated with increased mortality rates. [14] A Korean study documented unexpectedly high levels of resistance in VRE isolates to daptomycin, linezolid, and tigecycline despite the rare use of these antibiotics in Korean hospitals. [19]
Mortality/Morbidity
In general, the virulence of enterococci is lower than that of organisms such as S aureus. However, enterococcal infections often occur in debilitated patients and as part of polymicrobial infections. These factors limit the ability of investigators to determine the independent contribution of enterococcal infections to mortality and morbidity. Clinical outcomes are related more to the underlying comorbidities of the patient than to the specific virulence of the infecting strain of E faecalis. Contributing factors include diabetes (36.4%), various types of cancer (30.3%), cirrhosis (6.1%), steroid therapy (19%), antecedent antibiotic treatment (60.6%), and central venous (21.2%), arterial (12.1%), and urinary catheters (63.6%). [20]
Vancomycin-resistant bacteremia increases the length of hospital stay by an average of 2 weeks, and studies calculate an attributable mortality rate of up to 37% from these infections. Mortality rates associated with enterococcal infections may exceed 50% in critically ill patients, those with solid tumors, and some transplant patients. Bacteremia caused by VRE strains carries higher mortality rates than does bacteremia due to vancomycin-susceptible strains. [21] Despite the availability of antimicrobial agents with greater potency against VRE, one study of 113 patients with VRE bacteremia reported that such agents did not significantly change clinical outcomes. [22]
Sex
In general, enterococcal infections are distributed equally between the sexes.
Although UTIs are more common in healthy women than in healthy men, enterococci are an uncommon cause of uncomplicated cystitis in this setting.
In published series of enterococcal endocarditis, men often outnumber women.
Age
Enterococcal infections are more common in elderly patients because of various associated factors that are more common in these patients. For example, urinary tract catheterization and instrumentation are more common in elderly populations. Abdominal surgery for diverticulitis or biliary tract disease is also performed more commonly in elderly persons. In a recent series, most cases of enterococcal endocarditis occurred in elderly individuals.
In neonates, enterococci occasionally cause bacteremia and meningitis. Outbreaks of enterococcal infections, including VRE infections, have been reported in neonatal ICUs, pediatric ICUs, and hematology/oncology units, but, overall, VRE infections are less common in pediatric patients than in adults. [23]
Prognosis
Enterococcal bacteremia tends to occur in very debilitated patients, making the exact contribution of the bacteremia to mortality difficult to determine. Nevertheless, studies have estimated the attributable mortality rate of enterococcal bacteremia to be 31-37%. Even with current therapeutic regimens, the mortality rate of enterococcal endocarditis remains approximately 20%.
Patient Education
Direct patients to the CDC Web site for answers to some frequently asked questions about VRE.
Tables
Critical Illness/Sepsis |
Endovascular Infection (eg, Infectious Endocarditis) |
Central Nervous System Infection |
Bone/Joint Infection |
Serious Organ Infection (eg, Intra-abdominal or Kidney) |
Uncomplicated Skin Infections |
Bladder Infections |
|
Penicillin-Susceptible Enterococci |
Ampicillin 2 g IV q4h plus gentamicin 1 mg/kg IBW q8h Penicillin 18-30 MU daily via continuous infusion or in divided doses plus gentamicin 1 mg/kg IBW q8h Ampicillin 2 g IV q4h plus ceftriaxone 2 g IV q12h [Ampicillin plus imipenem-cilastatin] |
Ampicillin 2 g IV q4h for 4-6 weeks plus gentamicin 1 mg/kg IBW q8h for 2-6 weeks (or streptomycin 7.5 mg/kg IBW IV or IM] Penicillin 18-30 MU daily via continuous infusion or in divided doses for 4-6 weeks plus gentamicin 1 mg/kg IBW q8h for 2-6 weeks [or streptomycin 7.5 mg/kg IBW IV or IM] Ampicillin 2 gm IV q4h plus ceftriaxone 2 g IV q12h for 6 weeks [Ampicillin plus imipenem-cilastatin for 6 weeks] |
Ampicillin 2 g IV q4h plus gentamicin 1 mg/kg IBW q8h for 2-3 weeks Penicillin 18-30 MU daily via continuous infusion or in divided doses for 4-6 weeks plus gentamicin 1 mg/kg IBW q8h for 2-3 weeks Ampicillin 2 g IV q4h plus ceftriaxone 2 g IV q12h for 2-3 weeks [Ampicillin plus imipenem-cilastatin for 2-3 weeks] |
Penicillin G 20-24 MU IV q24h in continuous dosing or divided q4h for 4-6 weeks Ampicillin 12 g IV q24h continuously or in 6 divided doses for 4-6 weeks (For both regimens above, synergistic aminoglycoside is optional) |
Penicillin G 20-24 MU IV q24h in continuous dosing or divided q4h Ampicillin 12 g IV q24h continuously or in 6 divided doses (For both regimens above, synergistic aminoglycoside is optional) |
Ampicillin 8 g IV daily in divided doses Penicillin G 12 MU IV divided q4-6h |
Amoxicillin (or IV ampicillin) (Other options may include oral doxycycline, linezolid, fosfomycin or chloramphenicol) |
Penicillin-Resistant Enterococci or Patient Unable to Tolerate Beta-lactams |
Vancomycin 15 mg/kg q12h plus either gentamicin 1 mg/kg/8h IV or IM or streptomycin 7.5 mg/kg IV or IM every 12 hours |
Vancomycin 15 mg/kg q12h plus either gentamicin 1 mg/kg IV or IM q8h or streptomycin 7.5 mg/kg IV or IM q12h for 6 weeks |
Vancomycin 15 mg/kg q12h plus either gentamicin 1 mg/kg IV or IM q8h or streptomycin 7.5 mg/kg IV or IM q12h for 6 weeks |
Vancomycin 15 mg/kg IV q12h for 4-6 weeks (Addition of aminoglycoside is optional) |
Vancomycin 15 mg/kg IV q12h (Addition of aminoglycoside is optional) |
Vancomycin 15 mg/kg IV q12h (Addition of aminoglycoside is optional) |
Nitrofurantoin Doxycycline Linezolid Chloramphenicol |
VRE |
Linezolid 600 mg IV or PO q12h Daptomycin 10-12 mg/kg once daily |
Linezolid 600 mg IV or PO q12h for a minimum of 6 weeks Daptomycin 10-12 mg/kg once daily for minimum of 6 weeks |
Linezolid 600 mg IV or PO q12h for 2-3 weeks |
Linezolid 600 mg IV or PO q12h for 4-6 weeks Daptomycin 6 mg/kg once daily for 4-6 weeks |
Linezolid 600 mg IV or PO q12h Daptomycin 6 mg/kg once daily |
Linezolid 600 mg IV or PO q12h Daptomycin 4-6 mg/kg once daily |
Nitrofurantoin Doxycycline Linezolid Daptomycin Chloramphenicol |
