Enterococcal Infections Treatment & Management

Antimicrobial therapy

Before 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 and tedizolid, daptomycin, and tigecycline, as well as the newer tetracycline antibiotics, these drugs may be used more commonly to treat VRE infections, although in many cases off-label.

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 treated with ampicillin plus an aminoglycoside, 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 complicated by large vegetations.

Multiple studies of ceftriaxone plus ampicillin in E faecalis valve endocarditis supported those of smaller earlier ones. 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. ^[33] This therapy is ineffective against E faecium. ^{[34, 35]}

However, treatment with ceftriaxone may induce colonization with VRE owing to its high concentration in the bile. ^[36]

It appears that combining various beta-lactam antibiotics with daptomycin may result in synergy against vancomycin-resistant E faecalis and E faecium. Ceftaroline and ampicillin are the most promising of the beta–lactams. ^{[37, 38]} Combining various antibiotics with daptomycin may restore the effectiveness of daptomycin against enterococci that have become resistant to it.

When the MIC is unknown or greater than 0.25 mg/L, high-dose daptomycin (10-12 mg/kg) in the treatment of enterococcal endocarditis appears to reduce the development of daptomycin-resistant strains. In addition, this enhanced dose would deal with the relative resistance of enterococcal isolates that have been previously exposed to vancomycin. ^[39]

Daptomycin has been demonstrated to be well tolerated and effective in patients with VRE UTI. ^[40]

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. Intrathecal or intraventricular therapy can be considered in refractory cases.

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. ^[41] For Efaecium infection, either linezolid or daptomycin may be effective, and quinupristin-dalfopristin, tigecycline, omadacycline, eravacycline or oritavancin could be considered. Surgical approaches may be necessary.

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. Many enterococci that cause cystitis are also sensitive to fosfomycin. ^[42] 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. ^{[43, 44]}

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. ^[45] Linezolid has been FDA-approved for use in infants and children. ^[46] Unfortunately, linezolid-resistant VRE isolates have been reported. ^{[47, 48]}

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. ^[49] Daptomycin may be the only drug with bactericidal activity against enterococci when used as sole antibiotic therapy. ^[44] However, resistance in VRE isolates has been reported. ^[7]

Recent data indicate that daptomycin is associated with significantly better treatment outcomes, all-cause mortality, and microbiologic failure of VRE bacteremia than linezolid. ^[50]  

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. ^[51] Daptomycin appears to provide optimal activity in serious enterococcal infections when administered at higher doses. ^[52] 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. ^[53] 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. Newer tetracycline antibiotics that may be considered for enterococcal infections include omadacycline and eravacycline, although in many cases usage would be off-label.

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. ^{[54, 55]} 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. ^[56]

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 every day 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. ^{[57, 58]}

Table 1. Treatment Considerations for Enterococcal Infections. (Open Table in a new window)

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 or intravascular device may be indicated.

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.

Consult with pharmacy experts in the treatment of infections may be indicated, especially when treating resistant or refractory infections, and especially when using medications off-label.

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. ^[59]

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. ^[60]

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:

• At hospitals where VRE has not been detected previously, clinical enterococcal isolates should be periodically screened for vancomycin resistance.

• 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 identified when only clinical samples are screened.

Isolation measures to prevent person-to-person transmission include the following (also see the CDC’s Guideline for Isolation Precautions): ^[61]

• Hand washing 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 VRE-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 or with alcohol-based gel if the gloves are not visibly soiled.

• 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. In addition, all room surfaces should be disinfected on a regular schedule.

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. ^[62]

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%. ^[63]  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:

• 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 coagulase-negative staphylococci).

• Treat Clostridioides difficile colitis.

• Use for single-dose surgical prophylaxis in patients at high risk for MRSA or methicillin-resistant S epidermidis and occasionally for endocarditis prophylaxis, as recommended by the American Heart Association.

• Vancomycin-prescribing interventions do not always reduce VRE colonization and infection. ^[64]  Studies have shown that other infection-control measures in addition to vancomycin-prescribing restrictions are more likely to control VRE colonization and infection. ^[65]

Restriction of other antibiotics includes the following:

• 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 in an oncology unit compared with 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.

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. ^[66]  Adequate environmental cleaning should be a priority. Simple educational interventions directed at the housekeeping staff can improve decontamination of environmental surfaces. ^[67]

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. ^[68]

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. ^[69]

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 with WBC differential 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 trough levels. 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. Alternatively, vancomycin area under the curve can be calculated and used to adjust dosing, which is often optimally done in consultation with a pharmacist. A meta-analysis demonstrated that this strategy may result in a decreased risk for vancomycin-induced acute kidney injury.  ^[70]

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.

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

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