AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Enterococci are part of the normal intestinal flora of humans and animals but are also important pathogens responsible for serious infections. The genus Enterococcus includes more than 17 species, but only a few, Enterococcus faecalis and Enterococcus faecium, account for most clinical infections in humans. With increasing antibiotic resistance, enterococci are recognized as feared nosocomial pathogens that can be challenging to treat.

Enterococcus species are hardy, facultative anaerobic organisms that can survive and grow in many environments. 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) grow in 6.5% sodium chloride, (3) demonstrate pyrrolidonyl arylamidase and leucine aminopeptidase, and (4) react with group D antiserum. They were formerly known as group D streptococci until assigned their own genus.

E faecalis and E faecium are the most prevalent species cultured from humans, accounting for more than 90% of clinical isolates. E faecium represents most vancomycin-resistant enterococci (VRE). Isolation of enterococci resistant to multiple antibiotics has become increasingly common in the hospital setting. According to National Nosocomial Infections Surveillance (NNIS) data from January through December 2003, more than 28% of enterococcal isolates in ICUs of the more than 300 participating hospitals were vancomycin resistant.

Enterococci have both an intrinsic and acquired resistance to antibiotics, which make them important nosocomial pathogens. Intrinsically, these species 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 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. Mutations in the domain V of the 23S rRNA may be responsible for linezolid resistance, whereas resistance to quinupristin/dalfopristin may be the result of several mechanisms: modification of enzymes, active efflux, and target modification. Resistance of E faecalis to daptomycin, a newer cyclic lipopeptide antibiotic that acts on the bacterial cell membrane, has also been reported.

Six phenotypes of vancomycin resistance, termed VanA, VanB, VanC, VanD, VanE, and VanG are 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 Enterococcus gallinarum (VANC1) and Enterococcus casseliflavus (VANC2). These genes confer relatively low resistance levels to vancomycin and are not transferable. To date, the VanD, VanE, and VanG phenotypes are described in only a few strains of enterococci.

Three patients infected with vancomycin-resistant Staphylococcus aureus (VRSA) have been reported in the United States. 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 infections, endocarditis, bacteremia, wound infection, and intra-abdominal and pelvic infections. Many infecting strains originate from the patient's intestinal flora. From here, they can spread and cause urinary tract, intra-abdominal, and surgical wound infections. 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, and skin or soft tissue infections have also been reported.

Intestinal colonization with resistant enterococcal strains is more common than clinical infection; for example, in Cleveland, VRE stool isolates outnumber clinical isolates by a factor of 10 in hospitals in which active VRE surveillance is performed. If infection occurs, it usually develops in those who are previously colonized. Colonized patients are 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, which also contributes 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 are 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 infrequent, 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, and receipt of corticosteroids, chemotherapy, or parenteral nutrition.

Frequency

United States

According to recent NNIS surveys, enterococci remain in the top 3 most common pathogens that cause nosocomial infections. Enterococci frequently cause urinary tract infections, 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.

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 vancomycin-resistant Enterococcus 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 the rapid 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, and 12% were found to be carriers of VRE.

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.

Mortality/Morbidity

• 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 two weeks, and studies calculate an attributable mortality rate of up to 37% from these infections. However, critically ill patients, those with solid tumors, and some transplant patients may have mortality rates greater than 50%. VRE strains have shown a higher mortality rate compared to bacteremia due to vancomycin-susceptible strains. However, in general, enterococci have lower virulence compared to organisms such as S aureus.

Sex

• In general, enterococcal infections are distributed equally between the sexes.
• Although urinary tract infections 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 infection in neonatal ICUs are reported. VRE outbreaks have been reported in neonatal ICUs, but the overall percentage of enterococcal isolates with vancomycin resistance is lower in pediatric patients compared to adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Urinary tract infections
• • The most common type of infection caused by enterococci is usually nosocomial (associated with urinary tract catheterization or instrumentation).
  • Cystitis and pyelonephritis are common infections.
  • Occasionally, prostatitis and perinephric abscesses may develop.
  • Occasional infections may occur in young, healthy women ( <5%).
• Bacteremia
• • Sources of enterococcal bacteremia include the urinary tract, intra-abdominal foci, wounds, and intravascular catheters.
  • Community-acquired enterococcal bacteremia is more commonly associated with endocarditis (up to 36% of cases) than nosocomial bacteremia (0.8%).
  • Nosocomial enterococcal bacteremias may arise from a variety of sources. Polymicrobial bacteremias including enterococci and other bowel flora should increase the index of suspicion for an intra-abdominal source. Other sources may include surgical sites and burn wounds infections.
  • Blood cultures that grow enterococci may be positive because of contamination of the skin with these organisms. A positive blood culture result for Enterococcus species in the absence of evidence of ongoing infection should raise this possibility.
• Endocarditis
• • Enterococci cause 5-15% of all endocarditis cases.
  • This condition usually occurs in older patients.
  • Their presentation is typically subacute.
  • Usually, left-sided endocarditis and mitral valve involvement is more common than aortic involvement.
  • E faecalis causes most cases of endocarditis.
  • Risk factors include urinary tract infection or instrumentation.
• Intra-abdominal and pelvic infections
• • Infections include biliary tract infection, intra-abdominal abscess, spontaneous bacterial peritonitis, endometritis, and salpingitis.
  • Enterococci are usually part of mixed aerobic and anaerobic flora.
  • Antimicrobial regimens with minimal in vitro antienterococcal activity are effective for treating mixed infections; therefore, the pathogenicity of enterococci in this setting is questionable.
  • Antienterococcal bactericidal activity is recommended when blood culture results are positive for enterococci.
• Other infections
• • Wound infections often manifest as part of a mixed infection.
  • Meningitis is uncommon and is usually associated with neurosurgical procedures or anatomic defects, accounting for only 0.3-6% of cases.
  • Neonatal sepsis may occur.
  • Respiratory tract infections can develop. However, isolation of enterococci from respiratory secretions usually represents colonization rather than infection.
  • Other uncommon infections caused by enterococci include osteomyelitis and septic joint infections.

Physical

Physical examination findings 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 urinary tract infection.
• If the patient has enterococcal bacteremia, carefully evaluate the patient for signs consistent with endocarditis, which include the following:
• • Fever
  • Peripheral stigmata (Janeway lesions, Osler nodes, Roth spots, petechiae or splinter hemorrhages)
  • New or changing heart murmur (usually a regurgitant murmur)
  • Splenomegaly

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The possible clinical syndrome helps determines which laboratory studies to perform.
• Usually, blood cultures are indicated for patients with possible infection who also require hospitalization. If endocarditis is suspected, obtain 3 sets of blood cultures over 1 hour or longer.
• • A positive blood culture result 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 positive blood culture result for Enterococcus species (especially if multiple cultures are positive) also warrants an evaluation for endocarditis if clinical features suggest this diagnosis. An echocardiogram 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 determining 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 echocardiogram findings are negative, a transesophageal echocardiogram should be performed.
• Abdominal CT scan
• • A CT scan of the abdomen is indicated if symptoms or signs indicate a gastrointestinal source of infection or if no clear focus of infection is evident elsewhere.
  • In elderly or immunocompromised patients, an intra-abdominal source of infection may manifest with 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 liver or pelvis may be useful in determining whether 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 aminoglycosides. The Clinical and Laboratory Standards Institute (CLSI), formerly the National Committee for Laboratory Standards (NCCLS), recommends to screen 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. In addition, susceptibility testing should be requested for linezolid and quinupristin/dalfopristin and might be considered for daptomycin and tigecycline, although not all of these antibiotics are 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Antimicrobial therapy
• • Prior to any treatment of infections, all suspected intravenous lines, intra-arterial catheters, and urinary catheters should be removed and abscesses drained. Infections that do not require bactericidal therapy are usually treated with a single antibiotic directed toward enterococci; these infections include urinary tract, intra-abdominal, and uncomplicated wound infections. Some studies find that monotherapy is adequate treatment for many patients with enterococcal bacteremia when no evidence of endocarditis exists. In clinical practice, combination therapy with a cell wall–active agent and an 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.
  • For monotherapy of susceptible E faecalis, ampicillin is the drug of choice. Ampicillin MICs are 2- to 4-fold lower compared with penicillin MICs for most isolates. For rare strains that are resistant to ampicillin because of beta-lactamase production, ampicillin plus sulbactam may be used. For patients with a penicillin allergy or strains with high-level penicillin resistance due to altered PBPs, vancomycin should be administered. Nitrofurantoin is effective for the treatment of enterococcal urinary tract infections, 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 when VRE infections are encountered.
  • Combination therapy with a cell wall–active agent (eg, ampicillin, vancomycin) and an aminoglycoside (eg, gentamicin or streptomycin) is necessary to adequately treat patients with enterococcal endocarditis. This combination results in synergistic bactericidal activity against susceptible enterococcal strains. At least 4 weeks of combination therapy is recommended for the treatment of enterococcal endocarditis. Six weeks of combination therapy is recommended for patients with symptoms for more than 3 months before starting therapy, for patients who relapsed after shorter courses of therapy, and for patients with prosthetic valves.
  • 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 for the treatment of enterococcal meningitis, and treatment is usually administered for at least 2-3 weeks. Intravenous linezolid or intravenous plus intraventricular quinupristin-dalfopristin have also been used successfully for meningitis.
  • The emergence of strains with multidrug-resistant determinants has significantly complicated the management of enterococcal infections. Treat patients infected with strains that exhibit high-level resistance to ampicillin with vancomycin. Test strains with high-level gentamicin resistance for high-level streptomycin resistance. For gentamicin-resistant strains, the alternative is streptomycin. Treatment options are limited for patients with endocarditis who are infected with strains that exhibit high-level resistance to all aminoglycosides. For E faecalis, prolonged therapy with high doses of ampicillin plus imipenem/cilastatin or ampicillin plus ceftriaxone might be considered. For E faecium, either linezolid or quinupristin-dalfopristin may be effective, and daptomycin or tigecyline could be considered. Surgical approaches may be necessary.
  • For infections caused by VRE, base the treatment on infection severity and in vitro susceptibility of the strain to other antibiotics. Uncomplicated urinary tract infections 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 newer antibiotic choices have recently become available.
  • The streptogramin combination antibiotic quinupristin/dalfopristin targets the bacterial 50S ribosome and results in inhibited 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. However, their effectiveness in the treatment of prosthetic valve endocarditis is not entirely known.
  • Daptomycin, a new 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 or VRE infections are limited.
  • Tigecycline is a glycylcycline antibiotic that was released in 2005 and 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 been shown to have in vitro activity against E gallinarum and E casseliflavus, but not against the most common VanA, type VREF.
  • Dalbavancin is a new antibiotic that is structurally related to vancomycin and teicoplanin; however, it is not yet FDA approved. It will be marketed especially for MRSA infections but also has activity against non-VRE enterococci. It has a very long half-life, so weekly administration is possible.

Surgical Care

• Surgery may be indicated for the treatment of some enterococcal infections.
• • For patients with 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 occurrence of septic emboli after initiation of therapy.
  • For intra-abdominal infections, surgery may be indicated for cholecystitis or intra-abdominal abscess, among other conditions.
  • For catheter infections, removal of the line may be indicated.

Consultations

• Consultation with an infectious diseases specialist should be considered for all patients with serious infections from Enterococcus species, particularly when multiresistant strains are isolated.
• Consult with hospital infection control policy experts when treating patients with colonization or infection with VRE.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Antibiotics

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

Drug Name	Amoxicillin (Trimox, Amoxil)
Description	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.
Adult Dose	0.5-1 g PO q8h; not to exceed 3 g/d
Pediatric Dose	20-50 mg/kg/d PO divided q8h
Contraindications	Documented hypersensitivity
Interactions	Reduces efficacy of oral contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment

Drug Name	Vancomycin (Vancocin, Lyphocin, Vancoled)
Description	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.
Adult Dose	15 mg/kg per 12 h IV with normal renal function; adjust using peak/trough data for serious infections
Pediatric Dose	40-50 mg/kg/d IV divided tid/qid
Contraindications	Documented hypersensitivity
Interactions	Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal failure or neutropenia; red man syndrome is caused by IV infusion that is too rapid (dose given over a few min) but rarely happens when dose given IV over 2 h or PO or IP; red man syndrome is not an allergic reaction

Drug Name	Gentamicin (Garamycin, Gentacidin)
Description	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.
Adult Dose	1 mg/kg IV q8h; dose adjusted based on peak and trough levels; split-dose aminoglycosides preferred for treatment of enterococcal endocarditis; if >60 y, dose adjustments to q12h or q24h often required
Pediatric Dose	1 mg/kg IV q8h when used for bactericidal synergy against gram-positive organisms
Contraindications	Documented hypersensitivity; high-level resistance present
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy	D - Unsafe in pregnancy
Precautions	Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Name	Quinupristin/dalfopristin (Synercid)
Description	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.
Adult Dose	7.5 mg/kg IV q8h
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May decrease elimination and increase toxicity of cyclosporine A, midazolam, nifedipine, terfenadine astemizole, cisapride, alfentanil, alosetron, alprazolam, carbamazepine, delavirdine, diazepam, diltiazem, disopyramide, dofetilide, donepezil, erythromycin, ethinyl estradiol, felodipine, fexofenadine, indinavir, lidocaine, lovastatin, methylprednisolone, nevirapine, norethindrone, quinidine, ritonavir, saquinavir, simvastatin, tacrolimus, triazolam, trimetrexate, verapamil, vinblastine, and possibly other drugs
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Arthralgias and myalgias occur commonly but are not a concern; venous irritation common when administered through a peripheral line; administration through central venous line recommended; asymptomatic elevation of unconjugated bilirubin may occur

Drug Name	Linezolid (Zyvox)
Description	Oxazolidinone antibiotic effective for treatment of both E faecalis and E faecium 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.
Adult Dose	600 mg PO/IV bid; serum concentrations achieved with PO dosing equivalent to IV dosing; treat VRE endocarditis for >8 wk
Pediatric Dose	Neonates and infants: Not established Children and adolescents: Not established, but dosage of 10 mg/kg PO q8h used
Contraindications	Documented hypersensitivity; MAOI administration within 14 d
Interactions	May cause hypertension when used concomitantly with adrenergic agents including pseudoepinephrine, sympathomimetic agents, or vasopressor or dopaminergic agents (reduce dose of dopamine or epinephrine if concurrent use required); serotonin syndrome may occur if used concomitantly with serotonergic agents, including TCAs, meperidine, dextromethorphan, trazodone, venlafaxine, and selective serotonin reuptake inhibitors
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Nausea, vomiting, and diarrhea may occur; resistance may develop during therapy of VRE infections in the setting of unremoved prosthetic devices or inadequately drained abscesses; has mild MAOI properties and has potential to have same interactions as other MAOIs; caution in uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism and in patients who are at increased risk for bleeding, have preexisting myelosuppression, receive concomitant medications that may decrease blood counts, including platelet count or function, or who may require > 2 wk of therapy (monitor CBC count); unnecessary use may lead to development of resistance to drug

Drug Name	Nitrofurantoin (Macrodantin)
Description	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.
Adult Dose	100 mg/dose PO q12h
Pediatric Dose	>1 month: 5-7 mg/kg/d PO divided q6h; not to exceed 400 mg/d Long-term therapy: 1-2 mg/kg/d PO divided 12-24 h; not to exceed 100 mg/d
Contraindications	Documented hypersensitivity; renal insufficiency ( <60 mL/min CrCl), anuria, or oliguria
Interactions	Anticholinergics may delay gastric emptying and increase absorption, increasing bioavailability; antacids made of magnesium salts may decrease effects and absorption; concurrent high doses of probenecid decreases renal clearance and increases toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause severe and irreversible peripheral neuropathy that can be fatal; renal impairment, diabetes, electrolyte imbalance, anemia, and vitamin B deficiency increase risk for adverse effects; prolonged use of antibiotics may result in fungal or bacterial overgrowth of resistant or nonsusceptible organisms

Drug Name	Daptomycin (Cubicin)
Description	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.
Adult Dose	4 mg/kg/d IV
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with tobramycin slightly increase daptomycin Cmax and AUC and decreases tobramycin Cmax and AUC; may experience additive effects with other drugs causing myopathy (eg, HMG CoA reductase inhibitors)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Decrease dose or dose interval with renal function <30 mL/min; pseudomembranous colitis may occur; may cause muscle pain or weakness, monitor CPK levels and discontinue daptomycin with elevated CPK and unexplained myopathy, peripheral neuropathy, or marked CPK elevation (10-times upper limits of normal); not indicated for pneumonia (higher death rate in daptomycin-treated patients during phase III trials); not compatible with dextrose-containing solutions

Drug Name	Tigecycline (Tygacil)
Description	Used to treat complicated skin infections to include methicillin-resistant S aureus and vancomycin-sensitive E faecalis. Inhibits protein synthesis.
Adult Dose	100 mg IV (single dose), followed by 50 mg q12h
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity
Interactions	May cause decreased contraceptive efficacy, can increase the risk of pseudotumor cerebri, and cause a hypoprothrombinemic response when taken with warfarin
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with prior adverse reactions with tetracycline use; can cause fetal harm to include permanent discoloration of teeth in children aged 8 years and younger; requires dose adjustment in severe hepatic impairment

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients with 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 complete blood cell 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. For patients with 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 a variety of 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 may occasionally be 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, the initial management of patients with enterococcal endocarditis should occur 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 consultant.

Deterrence/Prevention

• In addition to medical and surgical treatment, the management of enterococcal colonization and infection also includes measures to limit the spread of VRE. 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
• • At hospitals where VRE has not been detected previously, periodic screening of clinical enterococcal isolates for vancomycin resistance should be performed.
  • Once VRE is identified in a medical facility, all clinical enterococcal isolates should be tested for vancomycin resistance. Some form of surveillance for intestinal colonization is recommended because most patients harboring VRE are not detected if only clinical samples are screened.
• Isolation measures to prevent person-to-person transmission
• • Handwashing with antimicrobial soaps and hand rubs with alcohol-based solutions is critical to prevent spread of organisms.
  • Place patients with VRE infections in private rooms or in rooms with other infected patients.
  • Wear gloves when entering a VRE-colonized or VRE-infected room, and wear a gown if substantial contact with patients or their environment is anticipated.
  • Remove gloves and gown before leaving the room, and wash with antiseptic soap.
  • Dedicate the use of items such as stethoscopes, blood pressure cuffs, and thermometers to a single patient (or group of patients) colonized or infected with VRE, and all room surfaces should be disinfected on a regular schedule.
• The above isolation measures, in combination with surveillance cultures, are 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.
• Vancomycin restriction
• • Limit use to situations in which vancomycin is clearly indicated.
  • Treat proven or possible serious infection due to susceptible pathogens in patients with serious beta-lactam allergies.
  • Treat proven or possible serious infections caused by beta-lactam–resistant, gram-positive organisms (eg, oxacillin-resistant S aureus [ORSA or MRSA] or methicillin-resistant Staphylococcus epidermidis).
  • Treat Clostridium difficile colitis that is severe or unresponsive to metronidazole therapy.
  • Use for single-dose surgical prophylaxis of patients with a high risk for MRSA or methicillin-resistant S epidermidis and occasionally for endocarditis prophylaxis, as recommended by the American Heart Association.
• Restriction of other antibiotics
• • In a prospective study of VRE-colonized patients, the authors have demonstrated that antianaerobic antibiotics promote persistent high-density stool colonization. Limiting the use of these agents in colonized patients may also help to limit the spread of VRE.
  • In a prospective cohort study, an enhanced infection control strategy including a program for reducing total antimicrobial use resulted in reduced VRE transmission for an oncology unit, in comparison to standard VRE infection control practices.
  • Compared with the standard infection control period, the use of vancomycin, imipenem-cilastatin, ceftazidime, ciprofloxacin, aztreonam, and gentamicin during the enhanced infection control period was significantly reduced.
  • The incidence of both VRE bloodstream infections and rectal colonization decreased significantly during the enhanced infection control period.

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 urinary tract infection 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%.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• VRE infections: Consultation with an infectious diseases specialist is recommended for all serious infections due to VRE strains. Due to coexisting resistance to multiple antibiotics, few effective therapeutic regimens may be available. Linezolid and quinupristin/dalfopristin are effective against many VRE strains, but resistance may develop during therapy with these agents, particularly if undrained foci of infection remain. Some new antibiotics and various combinations of antibiotics have been shown to have activity against VRE strains in vitro and in animal models, but these regimens should not be administered in clinical situations without expert guidance. Special laboratory testing may be required if such antibiotics or combinations are used.
• Enterococcal endocarditis: Consultation with an infectious diseases specialist is suggested for most patients with enterococcal endocarditis. These infections require prolonged courses of therapy with potentially toxic antimicrobial regimens. Infectious disease physicians are experienced in monitoring the course of treatment and in making appropriate therapeutic adjustments.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jul 5, 2006