Enterococcal Infections

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Background

Enterococci are part of the normal intestinal flora of humans and animals. They have been long recognized as important human pathogens and are becoming increasingly so. The genus Enterococcus includes more than 17 species, although only a few cause clinical infections in humans. Since the beginning of the antibiotic era, they have posed major therapeutic challenges, including the need for synergistic combinations of antibiotics 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] E faecium is responsible for most vancomycin-resistant enterococci (VRE) infections.

Isolation of enterococci resistant to multiple antibiotics has become increasingly common in the hospital setting.[2] 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. Clonal spread is the dominant factor in the dissemination of multidrug-resistant enterococci in North America and Europe.[3] 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.[4, 3]

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.

Newer 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,[3] 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 newer cyclic lipopeptide antibiotic that acts on the bacterial cell membrane, has also been reported.[5]

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.

Three patients infected with vancomycin-resistant Staphylococcus aureus (VRSA) have been reported in the United States.[6, 7] 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 the first 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.[8, 9]

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 fourth most common cause of nosocomial bloodstream infections in the United States.

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 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.[10] Over the past 20 years, the incidence of multiply resistant E faecium has significantly increased; 35%-40% of enterococcal bloodstream infections involve this microorganism.[11]

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[8] and infection have been reported by hospitals in Europe[3] and have been associated with increased mortality rates.[9] 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.[12]

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.

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.[13] 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.[14]

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.[15]

History

Urinary tract infections

Bacteremia

Endocarditis

Intra-abdominal and pelvic infections

Other infections

Physical

Physical examination findings in patients with enterococcal infections vary widely and depend on the associated infectious syndrome; therefore, direct the examination according to the patient's symptoms and laboratory findings.

Evaluate the patient for suprapubic or flank tenderness if laboratory findings are consistent with enterococcal UTI.

If the patient has enterococcal bacteremia, carefully evaluate the patient for signs consistent with endocarditis, which include the following:

Examine the abdomen carefully for signs of organ tenderness, for peritoneal signs of peritonitis, and for ascites.

Examine prosthetic devices and the local skin (eg, orthopedic, cardiac, catheter insertion sites) for signs of infection, including erythema, swelling, tenderness, and/or warmth.

Laboratory Studies

The appropriate laboratory studies depend on the potential clinical syndrome present. Ideally, before administering empirical antibiotic therapy, obtain cultures from sites suspected to be infected, including blood, urine, peritoneal fluid, joint fluid, CSF, and/or pyogenic fluid collections in soft tissue.

Blood cultures are usually indicated in patients with possible infection who also require hospitalization. If endocarditis is suspected, obtain 3 sets of blood cultures over 1 hour or longer. A blood culture positive for Enterococcus species in a patient with a polymicrobial infection from an intra-abdominal source indicates the need for antimicrobial therapy, including activity against enterococci. A blood culture positive for Enterococcus species (especially if multiple cultures are positive) also warrants an evaluation for endocarditis if clinical features suggest this diagnosis. Echocardiography should be performed to help evaluate for cardiac vegetations.

Susceptibility testing is essential for all enterococcal isolates that require antimicrobial therapy.

Stool specimens, perirectal cultures that grow resistant Enterococcus, or both are the criterion standard for evaluating VRE colonization.

Imaging Studies

Echocardiography

Echocardiography should be performed when enterococcal endocarditis is suggested.

Transthoracic echocardiography is often performed as an initial screening test; if endocarditis is strongly suggested and the transthoracic echocardiography findings are negative, transesophageal echocardiography should be performed.

Abdominal CT scanning

A CT scan of the abdomen is indicated if symptoms or signs indicate a renal or gastrointestinal source of infection or if no clear focus of infection is evident elsewhere.

In elderly and/or immunocompromised patients, an intra-abdominal source of infection may manifest as minimal localizing signs or symptoms.

The scan may be ordered to include images of the pelvis in patients with suspected sigmoid or rectal disease, pelvic inflammatory disease (PID), or prostatic infection.

Ultrasonography

Ultrasonography of the kidneys, liver, and/or pelvis may be useful in determining whether an abscess is present and may be performed before CT scan or as an adjunct to CT scanning in selected cases.

Other Tests

Susceptibility testing

Blood isolates of enterococci should be tested for susceptibility. Routine testing should include penicillin or ampicillin, vancomycin, and high-level aminoglycosides. The Clinical and Laboratory Standards Institute (CLSI), formerly the National Committee for Laboratory Standards (NCCLS), recommends screening enterococci for high-level resistance to both gentamicin and streptomycin.

Urine isolates should be tested for susceptibility to ampicillin and nitrofurantoin.

For VRE isolates associated with infection, susceptibility testing should include a formal MIC determination for ampicillin and an assessment of beta-lactamase production in selected isolates. In addition, susceptibility testing should be requested for linezolid and may be considered for daptomycin, tigecycline, and quinupristin-dalfopristin, although not all of these antibiotics are FDA-approved for VRE infections. CLSI interpretive criteria are not available for non–FDA-approved indications or for certain organisms, so results must be interpreted using expert microbiological and clinical infectious-disease advice.

Procedures

Surgical incision and drainage of skin or soft-tissue abscesses or radiology-guided aspiration of abscess material may be required in certain enterococcal infections. In many cases, removal of prosthetic devices, such as vascular catheters, shunts, and prosthetic cardiac valves or orthopedic devices, is necessary to facilitate cure of the infection. Some vascular catheters may be exchanged over a wire and antibiotic lock therapy can be attempted, but the device should be permanently removed if failure occurs.

Medical Care

Antimicrobial therapy

Prior to treatment of enterococcal infections, all suspected intravenous lines, intra-arterial catheters, and urinary catheters should be removed, if possible, and abscesses drained. Infections that do not require bactericidal therapy are usually treated with a single antibiotic directed toward enterococci; these infections include UTIs, most intra-abdominal infections, and uncomplicated wound infections. Some studies find that monotherapy is adequate treatment in many patients with enterococcal bacteremia without evidence of endocarditis. In clinical practice, combination therapy with a cell wall–active agent and a synergistic aminoglycoside should be considered for treating serious enterococcal infections in critically ill patients and in those with evidence of sepsis, as well as in patients with endocarditis, meningitis, osteomyelitis, or joint infections.

Ampicillin is the drug of choice for monotherapy of susceptible E faecalis infection. For most isolates, the MIC of ampicillin is 2- to 4-fold lower than that of penicillin. For rare strains that are resistant to ampicillin because of beta-lactamase production, ampicillin plus sulbactam may be used. Vancomycin should be used in patients with a penicillin allergy or infections with strains that have high-level penicillin resistance due to altered PBPs. Nitrofurantoin is effective in the treatment of enterococcal UTIs, including many caused by VRE strains. As more experience is gained with the use of linezolid, daptomycin, and tigecycline, these drugs may be used more commonly to treat VRE infections.

Combination therapy with a cell wall–active agent (eg, ampicillin, vancomycin) and an aminoglycoside (eg, gentamicin, streptomycin) has long been regarded as the standard of care for E faecalis native valve endocarditis. This combination results in synergistic bactericidal activity against susceptible enterococcal strains. At least 4 weeks of combination therapy is recommended. Six weeks of combination therapy is recommended in patients with symptoms that persisted for more than 3 months before starting therapy, in patients who relapsed after shorter courses of therapy, and in patients with prosthetic valves. In sensitive E faecalis native valve endocarditis, consideration should be given to limiting the aminoglycoside component to 2 weeks in order to avoid nephrotoxic, vestibular, and ototoxic events. However, such limitations are not justified in treating prosthetic valve infections or those that are complicatedby large vegetations.

A recent study of ceftriaxone plus ampicillin in E faecalis valve endocarditis supported those of smaller earlier one. Gentamicin has always generated concern because of its significant rates of nephrotoxicity, ototoxicity, and vestibular toxicity, especially among older patients. For individuals at risk for these side effects, intravenous ampicillin 2 g every 4 hours plus intravenous ceftriaxone 2 g every 12 hours appears to provide a reasonable alternative. The combination has been shown to be effective in both gentamicin-resistant and gentamicin-sensitive isolates and in both native and prosthetic valve infections. This therapy is ineffective against E faecium.[20, 21]

Daptomycin has recently been demonstrated to be well tolerated and effective in patients with VRE UTI.[22]

If vancomycin is used in the course of treatment for endocarditis, a 6-week rather than 4-week course of therapy is recommended. Combination therapy is also recommended to treat enterococcal meningitis, usually for at least 2-3 weeks. Intravenous linezolid or intravenous plus intraventricular quinupristin-dalfopristin have also been used to successfully treat meningitis.

The emergence of enterococcal strains with multidrug-resistant determinants has significantly complicated the management of enterococcal infections. Vancomycin should be used to treat infections with strains that exhibit high-level resistance to ampicillin. Test strains with high-level gentamicin resistance for high-level streptomycin resistance. For gentamicin-resistant strains, the only alternative is streptomycin, as tobramycin and amikacin are not active. Treatment options are limited for endocarditis caused by strains that exhibit high-level resistance to all aminoglycosides. For E faecalis infection, prolonged therapy with high doses of ampicillin plus imipenem-cilastatin or ampicillin plus ceftriaxone may be considered.[23] For Efaecium infection, either linezolid or daptomycin may be effective, and quinupristin-dalfopristin or tigecycline could be considered. Surgical approaches may be necessary (see Surgical Care).

For VRE infections, base the treatment on infection severity and in vitro susceptibility of the strain to other antibiotics. Uncomplicated UTIs have been treated successfully with nitrofurantoin. Isolates that remain relatively susceptible to penicillin or ampicillin (MICs of 0.5-2 mcg/mL) may be treated with high doses of these agents. Doxycycline, chloramphenicol, and rifampin in various combinations have been used to treat VRE infections, but the newer antibiotic choices are also now available.[24, 25]

The streptogramin combination antibiotic quinupristin-dalfopristin targets the bacterial 50S ribosome and inhibits protein synthesis. It is available intravenously for the treatment of E faecium infections but is not effective against E faecalis strains.

Linezolid, an oxazolidinone antibiotic, is available orally and intravenously and is used to treat infections caused by E faecium and E faecalis strains, including VRE. Linezolid may be particularly useful in patients who require oral or outpatient therapy (when intravenous therapy is undesirable), who are intolerant to glycopeptides, or who have impaired renal function.[26] Linezolid has been FDA-approved for use in infants and children.[27] Unfortunately, linezolid-resistant VRE isolates have already been reported.[28, 29]

Daptomycin, a lipopeptide antibiotic that works by altering the bacterial membrane function, is indicated for the treatment of vancomycin-susceptible E faecalis– complicated skin infections. It became available in 2003, and, although it has in vitro activity against all strains of enterococci, the data regarding its use in E faecium and VRE infections are still somewhat limited, although encouraging.[30] Daptomycin may be the only drug with bactericidal activity against enterococci when used as sole antibiotic therapy.[25] However, resistance in VRE isolates has been reported.[5]

Recently, Arias and colleagues investigated the genetic basis for daptomycin resistance in enterococci. They found that resistance to daptomycin results from concomitant alterations in two genes encoding proteins that regulate the stress response to antimicrobial agents acting on the cell envelope and enzymes that are responsible for phospholipid metabolism in the cell membrane.[31] Daptomycin appears to provide optimal activity in serious enterococcal infections when administered at higher doses.[32] High-dose daptomycin (10 mg/kg/day) has been shown to be effective in treating penicillin-sensitive E faecalis left-sided endocarditis, many cases of which had failed previous regimens.[33] This strategy is not FDA-approved, may not prevent resistance from developing, and should be exercised only in consultation with expert advice.

Tigecycline, a glycylcycline antibiotic released in 2005, can be used to treat gram-positive, gram-negative, and anaerobic bacterial infections. It can be used to treat vancomycin-sensitive E faecalis infections, and, although it has in vitro activity against E faecium and VRE (including E casseliflavus and E gallinarum), as with daptomycin, clinical data are limited.

Teicoplanin is a glycopeptide that is used outside of the United States. It has demonstrated in vitro activity against E gallinarum and E casseliflavus, but not against the most common VanA, type VREF.

Telavancin is a novel lipoglycopeptide that is rapidly bactericidal against a broad spectrum of aerobic and anaerobic gram-positive pathogens, including many Enterococcus species.[34, 35] Telavancin was approved by the FDA on September 11, 2009, for the treatment of adult patients with complicated skin and skin structure infection due to numerous aerobic gram-positive organisms, including vancomycin-susceptible isolates of E faecalis. Although its activity against many vancomycin-resistant isolates of Enterococcus is good, especially against VanB strains of enterococci, it is currently not FDA-approved for the treatment of infections caused by vancomycin-resistant strains. Dalbavancin is a new lipoglycopeptide antibiotic that is structurally related to vancomycin and teicoplanin. It was approved by the FDA in May 2014 for gram-positive bacteria including Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant Staphylococcus aureus [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group (including S anginosus, S intermedius, S constellatus). It also has activity against non-VRE enterococci, but is not yet approved for this indication. It has a very long half-life that allows IV administration to be given as a 2-dose, once weekly regimen.

In August 2014, the FDA approved oritavancin for acute bacterial skin and skin structure infections (ABSSSI). Oritavancin is a lipoglycopeptide antibiotic. Susceptible gram-positive isolates include S aureus (including methicillin-susceptible S aureus and MRSA methicillin-resistant S aureus [MRSA] isolates), S pyogenes, S agalactiae, S dysgalactiae, S anginosus group (S anginosus, S intermedius, S constellatus), and E faecalis (vancomycin-susceptible isolates only). It is administered as an IV infusion over 3 hr as a one-time single-dose of 1200 -mg. Results from the SOLO I and II trials showed a single- dose of oritavancin was noninferior to twice daily vancomycin for 7-10 days for treating ABSSSI.[113]

Tedizolid, a newly approved oxazolidinone antibiotic, is indicated for skin and skin structure infections caused by susceptible isolates of gram-positive bacteria. Susceptible microorganisms include S aureus (including MRSA and methicillin-susceptible [MSSA] isolates), S pyogenes, S agalactiae, S anginosus group (including S anginosus, S intermedius, and S constellatus), and E faecalis. Its action is mediated by binding to the 50S subunit of the bacterial ribosome, resulting in inhibition of protein synthesis. It can be taken by mouth or IV qDay for 6 days. Approval for tedizolid was based on 2 clinical trials including more than 1300 participants that showed it to be noninferior to linezolid.[36, 37]

Surgical Care

Surgery may be indicated for the treatment of some enterococcal infections.

In patients with enterococcal endocarditis, valve-replacement surgery may be indicated for management of refractory congestive heart failure, failure of medical therapy to clear bacteremia, valve ring abscess, or development of septic emboli after initiation of therapy.

For enterococcal intra-abdominal infections, surgery may be indicated for cholecystitis or intra-abdominal abscess, among other conditions.

For enterococcal catheter-associated infections, removal of the line may be indicated.

Consultations

Consultation with an infectious diseases specialist should be considered for all patients with serious infections caused by Enterococcus species, particularly when multiresistant strains are isolated.

Consult with hospital infection control policy experts when treating patients with colonization or infection with VRE.

Diet

In patients who are persistently colonized with VRE, attempts are occasionally made to eradicate the bacteria. Enteral antibiotics such as bacitracin rarely achieve long-term success. In a small recent study, probiotic therapy (Lactobacillus rhamnosus GG in yogurt) was used to successfully clear VRE colonization and infection in renal patients.[38]

Medication Summary

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Ceftriaxone (Rocephin)

Clinical Context:  Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin binding proteins. Exerts antimicrobial effect by interfering with synthesis of peptidoglycan, a major structural component of bacterial cell wall. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.

Highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of dose excreted unchanged in urine, and remainder secreted in bile and ultimately in feces as microbiologically inactive compounds. Reversibly binds to human plasma proteins, and binding have been reported to decrease from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.

Ampicillin (Polycillin, Omnipen)

Clinical Context:  DOC if no penicillin allergy. Must be administered in combination with an aminoglycoside if bactericidal activity is required (eg, endocarditis).

Amoxicillin (Trimox, Amoxil)

Clinical Context:  Oral equivalent of ampicillin. PO therapy is appropriate for mild-to-moderate enterococcal infections and for continuing therapy after stabilization of patients with severe infections. PO therapy should not be used for treatment of endocarditis. Interferes with synthesis of cell wall mucopeptides during active multiplication.

Vancomycin (Vancocin, Lyphocin, Vancoled)

Clinical Context:  Used to treat enterococcal infections when ampicillin is contraindicated due to significant penicillin allergy and when strains are resistant to ampicillin but susceptible to vancomycin. Target levels of 30-50 mcg/mL (peak) and 10-15 mcg/mL (trough) for endocarditis and other serious infections.

Dalbavancin (Dalvance)

Clinical Context:  Dalbavancin is lipoglycopeptide antibiotic that prevents cross-linking by interfering with cell wall synthesis. It is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations observed in humans at recommended doses. It is indicated for treatment of acute bacterial skin and skin structure infections caused by Gram-positive bacteria including Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S aureus [MRSA]), S pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S anginosus, S intermedius, S constellatus).

Oritavancin (Orbactiv)

Clinical Context:  Oritavancin is lipoglycopeptide antibiotic that inhibits cell wall biosynthesis and disrupts bacterial membrane integrity that leads to cell death. It is indicated for treatment of acute bacterial skin and skin structure infections caused by gram-positive bacteria including S aureus (including methicillin-susceptible S aureus and MRSA), S pyogenes, S agalactiae, S dysgalactiae, S anginosus group (S anginosus, S intermedius, S constellatus) and E faecalis (vancomycin-susceptible isolates only).

Gentamicin (Garamycin, Gentacidin)

Clinical Context:  Aminoglycoside antibiotic administered in combination with ampicillin or vancomycin to provide bactericidal activity for treatment of enterococcal endocarditis and other serious enterococcal infections. Target levels of 3 mcg/mL (peak) and < 1 mcg/mL (trough). Drug levels should be drawn with third dose and then prn until target drug levels achieved. Thereafter, levels should be rechecked weekly during therapy or with any significant change in serum creatinine level.

Quinupristin/dalfopristin (Synercid)

Clinical Context:  Belongs to the group that includes macrolide, lincosamide, and streptogramin. Inhibits protein synthesis and is usually bacteriostatic. Effective against E faecium but not E faecalis strains. Option for treatment of vancomycin-resistant E faecium infections.

Linezolid (Zyvox)

Clinical Context:  Oxazolidinone antibiotic effective for treatment of both E faecalis and E faecium vancomycin-resistant enterococci (VRE) strains. Inhibits protein synthesis and is bacteriostatic. Has been effective in treating a variety of infections caused by VRE species, including a few cases of enterococcal endocarditis.

The FDA warns against the concurrent use of linezolid with serotonergic psychiatric drugs, unless indicated for life-threatening or urgent conditions. Linezolid may increase serotonin CNS levels as a result of MAO-A inhibition, increasing the risk of serotonin syndrome.[39]

Tedizolid (Sivextro)

Clinical Context:  Tedizolid is an oxazolidinone antibiotic indicated for skin and skin structure infections caused by susceptible isolates of Gram-positive bacteria including Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, S agalactiae, S anginosus Group (including S anginosus, S intermedius, and S constellatus), and Enterococcus faecalis. Its action is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis.

Nitrofurantoin (Macrodantin)

Clinical Context:  Effective for treatment of VRE urinary tract infections. Synthetic nitrofuran that interferes with bacterial carbohydrate metabolism by inhibiting acetylcoenzyme A. Bacteriostatic at low concentrations (5-10 mcg/mL) and bactericidal at higher concentrations.

Daptomycin (Cubicin)

Clinical Context:  Cyclic lipopeptide antibiotic that binds to components of the cell membrane and inhibits DNA, RNA, and protein synthesis; bactericidal in a concentration-dependent manner. Approved for vancomycin-sensitive E faecalis infections.

Tigecycline (Tygacil)

Clinical Context:  Used to treat complicated skin infections to include methicillin-resistant S aureus and vancomycin-sensitive E faecalis. Inhibits protein synthesis.

Telavancin (Vibativ)

Clinical Context:  Lipoglycopeptide antibiotic that is a synthetic derivative of vancomycin. Inhibits bacterial cell wall synthesis by interfering with polymerization and cross-linking of peptidoglycan. Unlike vancomycin, telavancin also depolarizes the bacterial cell membrane and disrupts its functional integrity. Indicated for complicated skin and skin structure infections caused by susceptible gram-positive bacteria, including Staphylococcus aureus (both methicillin-resistant and methicillin-susceptible strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis (vancomycin-susceptible isolates only).

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Further Outpatient Care

Patients with enterococcal endocarditis or other serious enterococcal infections may receive prolonged outpatient antibiotic therapy. These patients should receive regular follow-up care to assess complications from the infection or their medical therapy. Routine weekly follow-up care should include a CBC count and serum creatinine evaluation. The erythrocyte sedimentation rate and/or C-reactive protein level are monitored by some clinicians. The normalization or stabilization of these parameters may be used to help determine the total duration of antibiotic therapy. The need for monitoring vancomycin peak and trough levels has been questioned in recent years; however, if patients are to receive prolonged courses of vancomycin, routinely check at least one trough level. In patients with enterococcal endocarditis, especially when caused by drug-resistant organisms, peaks of 30-45 mcg/mL and trough levels of 10-15 mcg/mL are recommended.

The antibiotics used to treat enterococcal infections may be associated with various adverse effects that require monitoring. Aminoglycosides may cause renal insufficiency due to acute tubular necrosis or hearing loss due to ototoxicity. Ampicillin may cause thrombocytopenia or renal insufficiency due to interstitial nephritis. Vancomycin therapy is occasionally associated with neutropenia.

Linezolid can cause myelosuppression in patients receiving therapy for more than 2 weeks and therefore need at least weekly CBC counts while on therapy.

Daptomycin can cause significant myopathy and should be discontinued in patients with signs and symptoms of myopathy along with an increase in creatine kinase of greater than 5 times the upper limits of normal or in asymptomatic patients with an increase of greater than 10 times the upper limits of normal.

Transfer

When possible, patients with enterococcal endocarditis should be treated initially in or near a facility with personnel capable of performing open heart surgery.

Serious enterococcal infections such as endocarditis, meningitis, osteomyelitis, and prosthetic joint infections should be managed in conjunction with an infectious diseases specialist.

Deterrence/Prevention

To prevent endocarditis, antibiotics are prescribed to some at-risk cardiac patients prior to dental or invasive oral procedures. Enterococci are a rare cause of endocarditis following genitourinary tract or gastrointestinal tract procedures. Recently published guidelines advise that the administration of antibiotics solely to prevent endocarditis is not recommended in patients who undergo a genitourinary or gastrointestinal tract procedure.[40]

In addition to medical and surgical treatment, the management of enterococcal colonization and infection also includes measures to limit the spread of VRE. In 2006, the Healthcare Infection Control Practices Advisory Committee published guidelines on the management of multidrug-resistant organisms, including VRE, in healthcare settings. This resource can be found at the Centers for Disease Control and Prevention Web site.

In 1994, the US Centers for Disease Control Hospital Infection Control Practices Advisory Committee published recommendations for preventing and controlling the spread of vancomycin resistance. Specific recommendations were made for surveillance measures to identify patients colonized or infected with VRE, for isolation measures to prevent person-to-person transmission of VRE, and for the prudent use of vancomycin.

Surveillance measures to identify patients colonized or infected with VRE include the following:

Isolation measures to prevent person-to-person transmission include the following (also see the CDC’s Guideline for Isolation Precautions):[41]

The above isolation measures, in combination with surveillance cultures, have been effective in eliminating small VRE outbreaks caused by dissemination of single strains of VRE. These measures may not be as effective in the setting of large polyclonal VRE outbreaks. In a study from an ICU of a hospital experiencing a large polyclonal outbreak, the use of gloves and gowns was not more effective than the use of gloves alone in preventing rectal VRE colonization. In a neonatal ICU, however, control of transmission of multiclonal VRE strains was achieved through a multifaceted approach that included active surveillance cultures of all neonates, DNA fingerprinting of all isolates, contact isolation, staff education, use of waterless hand antiseptics, and removal of electrical thermometers.[42]

One large, cluster-randomized ICU study failed to demonstrate the effectiveness of enhanced infection control precautions to prevent transmitting VRE to other patients, possibly because adherence to barrier precautions was not 100%.[43] The authors advocate that good adherence to isolation precautions is important to reduce transmission of VRE in healthcare facilities, and that reducing body site density of organisms and environmental contamination may also be helpful.

Vancomycin restriction guidelines include the following:

Restriction of other antibiotics includes the following:

The risk of VRE acquisition in hospitalized patients is increased when environmental culture results are positive and/or when a room has been occupied by a patient with VRE colonization or infection.[46] Adequate environmental cleaning should be a priority. Simple educational interventions directed at the housekeeping staff can improve decontamination of environmental surfaces.[47]

Bathing of hospitalized patients should reduce the bacterial burden, including drug-resistant bacteria such as VRE. Daily bathing with chlorhexidine-impregnated bathing cloths was shown to reduce colonization of patients' skin, health care workers' hands, and environmental surfaces, as well as the incidence of VRE acquisition by other patients in one intensive care unit.[48]

In conclusion, active surveillance cultures for VRE, use of isolation for colonized and infected patients, appropriate antibiotic use, adequate patient care, and environmental cleaning are important interventions that should be implemented in order to control the transmission of VRE.[49]

Complications

Endocarditis may occur as a complication of enterococcal infection at a remote site if bacteremia occurs. For example, some cases of endocarditis are preceded by intravascular catheter infections or UTI or instrumentation.

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%.

Author

Susan L Fraser, MD, Chief, Infectious Diseases Service, Fort Belvoir Community Hospital; Chairman, Infection Control Committee; Associate Professor of Medicine, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

Coauthor(s)

Curtis J Donskey, MD, Chairman of Infection Control, Instructor, Department of Internal Medicine, Section of Infectious Diseases, Stokes Cleveland VA Medical Center, Case Western Reserve University

Disclosure: Nothing to disclose.

Julia Lim, MD, Associate Program Director, Internal Medicine Residency Program, Tripler Army Medical Center

Disclosure: Nothing to disclose.

Robert A Salata, MD, Chief and Clinical Program Director of Division of Infectious Diseases, Vice Chair for International Affairs, Professor, Department of Medicine, Case Western Reserve University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

David Hall Shepp, MD, Program Director, Fellowship in Infectious Diseases, Department of Medicine, North Shore University Hospital; Associate Professor, New York University School of Medicine

Disclosure: Gilead Sciences Salary Management position

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Disclosure: Nothing to disclose.

Chief Editor

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

Disclosure: Nothing to disclose.

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