INTRODUCTION — Enterococcal species can cause a variety of infections, including urinary tract infections, bacteremia, endocarditis, and meningitis. The antimicrobial agents available for treatment of enterococcal infection are reviewed here, followed by treatment approaches for clinical syndromes caused by enterococci. Other issues related to enterococci are discussed in detail separately. (See "Mechanisms of antibiotic resistance in enterococci" and "Vancomycin-resistant enterococci: Epidemiology, prevention, and control" and "Microbiology of enterococci".)
Infections due to Enterococcus faecalis tend to be more virulent than infections due to Enterococcus faecium. In addition, bacteremia due to E. faecalis is more likely to be associated with endocarditis than bacteremia due to E. faecium. Clinical isolates of E. faecalis tend to be considerably more susceptible to beta-lactam agents than clinical isolates of E. faecium. Isolates of E. faecalis are typically susceptible to ampicillin but resistant to quinupristin-dalfopristin, whereas most E. faecium isolates are resistant to ampicillin (minimum inhibitory concentration ≥16 mcg/mL) but susceptible to quinupristin-dalfopristin.
Approach to susceptible strains — Enterococci are relatively resistant to penicillin and ampicillin (compared with most streptococci); even when these cell wall–active agents inhibit enterococci, they often do not kill them; vancomycin is even less bactericidal. E. faecium clinical isolates are more resistant to penicillin than E. faecalis (minimum inhibitory concentration for 90 percent of strains [MIC90] >16 mg/mL versus 2 to 4 mcg/mL, respectively); MICs of ampicillin are usually 1 dilution lower than those of penicillin. Piperacillin activity is similar to that of penicillin, and imipenem generally is active against penicillin-susceptible E. faecalis. Cell wall-active agents with limited or no activity against enterococci include nafcillin, oxacillin, ticarcillin, ertapenem, most cephalosporins, and aztreonam.
Enterococci are also relatively impermeable to aminoglycosides, and the serum concentrations of aminoglycosides required for bactericidal activity are much higher than can be achieved safely in humans. However, the simultaneous use of a cell wall-active agent raises the permeability of the cell so that an intracellular bactericidal aminoglycoside concentration can be achieved . Bactericidal antimicrobial activity is warranted in clinical circumstances of life-threatening infection. (See 'Approach to specific infections' below.)
Enterococcal isolates are usually tested for susceptibility to ampicillin, penicillin, and vancomycin. The presence of beta-lactamase is very rare; it confers resistance to penicillin and ampicillin when large numbers of organisms are present (such as in the setting of a valvular vegetation), even though the organism may test susceptible using standard laboratory inocula. Thus, to rule out this possibility in patients with life-threatening enterococcal infection (such as meningitis or endocarditis), some experts recommend that the isolate be screened for beta-lactamase production with nitrocefin, a chromogenic cephalosporin, even if ampicillin susceptible. There are also rare reports of more highly penicillin- and/or imipenem-resistant isolates of E. faecalis with retained ampicillin susceptibility (albeit with higher-than-usual MICs) [2,3]; this has been associated with specific amino acid changes in the low-affinity penicillin-binding protein (PBP) of E. faecalis.
Traditionally, the standard of care for severe enterococcal infection (such as endocarditis) has been a cell wall-active agent combined with an aminoglycoside to generate synergistic bactericidal activity. A newer regimen, the combination of ampicillin and ceftriaxone, has yielded clinical cure rates equivalent to that of ampicillin plus gentamicin for E. faecalis endocarditis (albeit not in prospective, randomized, blinded studies); this includes isolates that did not have high-level aminoglycoside resistance . In general, we favor the combination of ampicillin and ceftriaxone as it avoids the toxicity of aminoglycosides .
For circumstances in which a regimen of a cell wall-active agent plus an aminoglycoside is used, the isolate should be tested for high-level resistance to gentamicin and streptomycin. If the organism is reported as susceptible to high levels of an aminoglycoside ("SYN-S" indicates "susceptible to synergism"), then it may be assumed that synergism will be achieved when that aminoglycoside is combined with ampicillin; an aminoglycoside should never be used alone for treatment of enterococcal infection. Strains that are resistant to high levels of gentamicin are resistant to synergism with tobramycin, netilmicin, and amikacin (in addition to gentamicin), but some of these strains lack high-level resistance to streptomycin and thus will still demonstrate synergism with that agent [5,6]. (See 'Approach to specific infections' below.)
Even for strains lacking high-level resistance to gentamicin, tobramycin, and, particularly, amikacin should be avoided. All E. faecium are resistant to synergism with tobramycin due to a species-specific aminoglycoside acetyl transferase, and the majority of E. faecium and E. faecalis fail to show synergism with amikacin.
For circumstances in which a regimen of a cell wall-active agent plus an aminoglycoside is used, ampicillin or penicillin are the preferred cell wall-active agents; vancomycin should be substituted only in the setting of high-level beta-lactam resistance or hypersensitivity with an inability to desensitize . Combinations of ampicillin or penicillin with gentamicin or streptomycin are preferable to vancomycin-aminoglycoside combinations since the latter pose a greater risk of nephrotoxicity. Gentamicin is more convenient since determination of serum gentamicin concentrations is more readily available than serum streptomycin levels. As mentioned above, amikacin and tobramycin are generally avoided, and laboratories do not test these aminoglycosides.
Antibiotic regimens and doses for treatment of bacteremia due to susceptible strains are outlined in the table (table 1).
Approach to resistant strains — The major categories of resistant enterococci include those with high-level penicillin and ampicillin resistance, those with high-level aminoglycoside resistance, and those with vancomycin resistance .
High-level penicillin resistance — Penicillin/ampicillin resistance is usually due to alterations in PBP-5, a low-affinity PBP of E. faecium. In addition, penicillin/ampicillin resistance (MIC ≥16 mcg/mL) generally indicates that the strain is E. faecium.
In the setting of infection due to such organisms when bactericidal therapy is needed (eg, endocarditis), vancomycin (or teicoplanin, where available), or daptomycin (8 to 10 mg/kg intravenously [IV] daily) could be used with an aminoglycoside. In the presence of high-level aminoglycoside resistance or concern for nephrotoxicity, high-dose daptomycin (10 to 12 mg/kg IV daily) may be used; daptomycin may also demonstrate synergism with or enhancement by other agents such as ampicillin. If resistance is due to beta-lactamase production, ampicillin-sulbactam may be used as the cell wall agent. Success with high-dose ampicillin and high-dose ampicillin-sulbactam (in conjunction with aminoglycosides) has been described in case reports (for strains resistant to ampicillin that did not produce beta-lactamase) [9,10].
Regimens and doses for treatment of bacteremia due to enterococci with high-level penicillin resistance are outlined in the table (table 2).
High-level aminoglycoside resistance — When using an aminoglycoside to achieve synergistic, bactericidal therapy (eg, in the setting of endocarditis), testing of enterococci should include high-level aminoglycoside-resistance testing for both gentamicin and streptomycin, since one agent may have activity even when the other does not. Aminoglycoside monotherapy should never be used, and a cell wall-active agent should only be combined with an aminoglycoside to which the organism is found to be "synergism susceptible." Aminoglycosides reported as "SYN-R" (for "resistant to synergism"; or as MIC ≥500 mcg/mL of gentamicin or ≥2000 mcg/mL of streptomycin) should not be used; other aminoglycosides should generally be avoided.
Combination beta-lactam therapy is an option for treatment of infective endocarditis (IE) due to E. faecalis with or without high-level aminoglycoside resistance to both gentamicin and streptomycin. Benefit from double beta-lactam combinations may be due to saturation of different penicillin-binding protein targets. The combination of ampicillin with ceftriaxone demonstrated efficacy in experimental endocarditis due to E. faecalis strains that were highly resistant to aminoglycosides and in treatment of E. faecalis endocarditis in humans. [4,11,12].
Regimens and doses for treatment of endocarditis and other infections due to enterococci with high-level aminoglycosides resistance are discussed in detail separately . (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Resistance to penicillin, aminoglycosides, and vancomycin'.)
Vancomycin resistance — The optimal approach for treatment of enterococcal infection due to vancomycin-resistant E. faecium is uncertain. One agent, linezolid, is US Food and Drug Administration (FDA) approved for treatment of infections caused by vancomycin-resistant enterococci (VRE; prior approval of quinupristin-dalfopristin has been removed). The utility of this agent for treatment of endocarditis is uncertain, although there are anecdotal cases suggesting some utility. The resistance profile of VRE isolates should be evaluated carefully in conjunction with infectious diseases expertise when selecting appropriate therapy for such organisms. The approach to treatment of such isolates should be assessed in each individual case. (See 'Approach to specific infections' below.)
Vancomycin-resistant E. faecium isolates often have concurrent high-level resistance to beta-lactams and aminoglycosides. In contrast, vancomycin-resistant E. faecalis are usually susceptible to beta-lactams, as are E. gallinarum and E. casseliflavus (which are intrinsically vancomycin resistant). The newer agents linezolid, daptomycin, and tigecycline have activity against both vancomycin-resistant E. faecalis and E. faecium, whereas quinupristin-dalfopristin has activity against E. faecium but not E. faecalis.
Regimens for treatment of bacteremia due to VRE are outlined in the table (table 2).
Approach to specific infections — Important infections due to enterococci include urinary tract and wound infections, bacteremia, endocarditis, and meningitis. Urinary tract infections (UTIs) generally do not require bactericidal therapy, and urinary catheter-associated bacteriuria often resolves with removal of the catheter. When therapy for enterococcal urinary tract isolates is indicated, monotherapy is sufficient. In the setting of invasive infections such as endocarditis, meningitis, and bacteremia (in the setting of valvulopathy and/or critical illness), bactericidal activity is warranted (although linezolid has been successful in vancomycin-resistant E. faecium meningitis). In such cases, synergistic activity of a cell wall-active agent in combination with gentamicin (or streptomycin), or ampicillin plus ceftriaxone (or cefotaxime), is generally required (E. faecalis). Testing for high-level resistance to gentamicin and streptomycin should be performed when combination therapy with an aminoglycoside is considered. (See 'Approach to susceptible strains' above.)
In general, determining the clinical significance of an enterococcus recovered from a patient should be tailored to individual patient circumstances, since isolation of an enterococcus does not necessarily require targeted therapy. Enterococci can also be colonizers (such as in respiratory specimens or urinary catheters) or part of a mixed infection (such as in polymicrobial cultures in the setting of intra-abdominal surgery or traumatic wounds) for which therapy is being administered for more virulent organisms. E. faecalis infections tend to be more virulent than E. faecium and therefore should command greater attention when the clinical significance of culture data is in question.
Depending on the nature of the illness, acute infection due to VRE should be treated to resolution, although in some cases colonization may persist indefinitely.
Urinary tract infection — The urinary tract is the most common site from which enterococci are recovered; manifestations can include urinary colonization, simple cystitis, complicated UTI including pyelonephritis, perinephric abscess, or prostatitis . Most enterococcal UTIs are nosocomial and/or associated with obstruction, urinary catheterization, or instrumentation [14-16]. In one study of uncomplicated cystitis in premenopausal women, growth of enterococci from a midstream urine culture was not predictive of bladder bacteriuria as assessed by a contemporaneously collected catheter urine sample . Thus, recovering enterococci from the urine of otherwise healthy young females reporting symptoms of cystitis may not necessitate treatment of this organism, especially if another uropathogen is present. Bacteremia in the setting of enterococcal UTI is relatively uncommon .
Management should include removal of urinary catheters if possible; this intervention alone has been observed to resolve enterococcal urinary catheter-associated infections/colonization in some cases . If susceptibility is documented, the best options for oral therapy of enterococcal lower UTIs are amoxicillin, nitrofurantoin, or fosfomycin; dosing is outlined in the table (table 3) . Nitrofurantoin achieves excellent therapeutic levels in the urine and renal parenchyma but is not adequate for treatment of pyelonephritis or enterococcal infection at other sites. Fosfomycin has FDA approval for treatment of uncomplicated UTIs caused by E. faecalis (as well as Escherichia coli), although many E. faecium strains are also susceptible to fosfomycin [21,22]. Intravenous ampicillin may also be considered (see below). Ceftaroline may also be a reasonable consideration for E. faecalis UTI if a patient needs this agent for another reason.
Alternative oral agents include linezolid or a fluoroquinolone, although data on their efficacy for the treatment of enterococcal UTIs are limited; the latter should not be used as monotherapy in the setting of bacteremia since achievable serum levels of fluoroquinolones are frequently close to the minimum inhibitory concentrations [23-31].
For patients with complicated UTI and for patients unable to tolerate oral therapy, the majority of strains are E. faecalis and ampicillin is the drug of choice. Aminopenicillins generally achieve high urinary concentrations with oral or intravenous administration ; an intravenous dose of 1 gram every 6 hours is reasonable for uncomplicated UTIs. Higher doses may be needed if there is evidence of pyelonephritis or concurrent bacteremia. Vancomycin is an appropriate alternative if the organism is susceptible.
For patients with lower urinary tract disease initially treated with a parenteral regimen with clinical improvement and whose isolate demonstrates beta-lactam susceptibility, completion of therapy with oral amoxicillin may be sufficient. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults", section on 'Directed antimicrobial therapy and duration'.)
For UTIs due to ampicillin- and vancomycin-resistant E. faecium strains, ampicillin may still be effective even for strains of E. faecium with ampicillin MIC >64 mcg/mL, since ampicillin is concentrated in the urine. In two small retrospective studies, cure rates for treatment of UTI due to ampicillin-resistant VRE with aminopenicillins and non-beta-lactams were similar (84 versus 88 percent, respectively) [33,34]. Linezolid (excreted approximately 30 percent unchanged in the urine) or daptomycin are other considerations. For UTI caused by vancomycin-resistant E. faecalis, ampicillin should suffice since vancomycin and ampicillin resistance have not been reported together in the same E. faecalis isolate.
There are no specific clinical data on the duration of therapy for enterococcal UTIs. For uncomplicated cystitis, we suggest 5 days of therapy. A longer duration of 7 to 10 days may be warranted for complicated infections, depending on patient circumstances and clinical response.
Bacteremia — Portals of entry for enterococcal bacteremia include the gastrointestinal tract, the urinary tract, intravascular catheters, and wounds (such as ulcers or burns) [13,35-39].
We believe that antimicrobial therapy for enterococcal bacteremia is warranted in the setting of two or more positive blood cultures, a single positive blood culture accompanied by signs of sepsis, or a single positive blood culture together with a positive enterococcal culture from another usually sterile site.
Many experts favor deferring antimicrobial therapy for enterococcal bacteremia in the setting of a single positive blood culture in the absence of clinical evidence for sepsis or in patients who have a polymicrobial infection and are improving on appropriate therapy for a more virulent organism [40,41]. For circumstances in which an intravascular catheter is the likely source of the bacteremia, catheter removal alone may be sufficient to cure the infection. However, if febrile, most patients should be empirically started on antibiotics after detection of enterococci and after additional cultures are obtained, while awaiting sensitivity results; such therapy can generally be discontinued after five to seven days if symptoms have resolved and no valvular abnormality is found.
Most cases of enterococcal bacteremia due to species other than E. faecalis are not associated with endocarditis [14,35,37,42-45]. The relative risk of endocarditis in patients with E. faecalis bacteremia is higher but still relatively low. Septic shock in the setting of enterococcal bacteremia is uncommon and should raise suspicion for a polymicrobial infection with accompanying gram-negative bacilli. (See "Intravascular non-hemodialysis catheter-related infection: Treatment".)
A bedside clinical score may be a useful tool for prediction of endocarditis and need for echocardiogram in some patients with enterococcal bacteremia. In one study describing such a tool (NOVA: number of positive blood cultures [3/3 or the majority if more than 3], 5 points; unknown origin of bacteremia, 4 points; prior heart valve disease, 2 points; auscultation of a heart murmur, 1 point), a cutoff score <4 points suggested a very low risk for enterococcal IE . The NOVA score may be useful for avoiding unnecessary transesophageal echocardiography among patients with enterococcal bacteremia; further validation is required .
A modification of this scoring system, DENOVA, added two new variables: duration of symptoms ≥7 days and embolization . The scoring system was also simplified, with each variable, including two positive blood cultures, counting as one point. A cutoff score of <3 was associated with a low probability of IE, with a sensitivity and specificity of 100 percent and 85 percent, respectively. The number needed to screen with an echo to identify one case of IE was 2.4 for DENOVA and 7 using the original NOVA score.
●For bacteremia due to ampicillin-resistant, vancomycin-susceptible E. faecium, reasonable therapeutic choices include vancomycin (or teicoplanin where available) or daptomycin (8 to 10 mg/kg/day); high-dose ampicillin may be used if the ampicillin MIC is ≤32 mcg/mL. (See 'Daptomycin' below.)
●For bacteremia due to ampicillin- and vancomycin-resistant E. faecium, daptomycin (8 to 10 mg/kg/day) or linezolid (administered orally or intravenously) are reasonable therapeutic choices; high-dose ampicillin may be used if the ampicillin MIC is ≤32 mcg/mL . We prefer daptomycin if a parenteral agent is needed; linezolid is a useful drug if a patient may be treated with oral therapy. (See 'Daptomycin' below.)
When therapy is deemed warranted, optimal duration of antimicrobial therapy for treatment of enterococcal bacteremia is uncertain. For uncomplicated infection, five to seven days of therapy is likely adequate if repeated blood cultures drawn at 24 hours are negative.
In the setting of suspected endocarditis or critical illness, combination therapy is warranted (table 1). For E. faecalis, we favor the regimen of ampicillin plus ceftriaxone since it avoids the toxicity of aminoglycosides; use of a cell wall-active agent in combination with a synergistically active aminoglycoside is also acceptable . For ampicillin-susceptible E. faecium, the combination of a cell wall-active agent plus an aminoglycoside (if no high-level resistance) may be preferred, since one in vitro study found that the combination of ampicillin plus ceftriaxone was not reliably active for all isolates, despite low ampicillin MICs ; on the other hand, demonstration of in vitro synergism can be concentration dependent. We feel that ampicillin plus ceftriaxone would still be a consideration if there is high-level resistance to all aminoglycosides, if there is high risk of aminoglycoside nephrotoxicity or if toxicity appears during aminoglycoside therapy. Data on combination regimens for treatment of enterococcal endocarditis are outlined in detail separately. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Enterococci'.).
The optimal approach for treatment of resistant enterococci is uncertain. Linezolid is the only drug approved by the FDA for treatment of bacteremia due to VRE, although it is a bacteriostatic agent and was approved in an era when relatively few treatment options were available. Daptomycin, a bactericidal agent, is FDA approved for vancomycin susceptible E. faecalis in skin and skin structure infections; there were insufficient vancomycin-resistant strains or E. faecium for FDA approval for these organisms. It has become an important agent for treatment of severe VRE infection based on its in vitro profile, despite limited clinical evidence . Some meta-analyses suggested a survival benefit of linezolid over daptomycin [54-56] but are limited by methodologic shortcomings of the underlying literature. A retrospective cohort study including 644 patients noted treatment with linezolid was associated with significantly higher treatment failure and greater 30-day all-cause mortality compared with daptomycin . Further study is needed.
In the setting of a prosthetic valve and sustained high-grade bacteremia, the duration should reflect presumed endocarditis/intravascular infection (even in the absence of echocardiographic evidence for vegetation); the approach is outlined separately. (See "Antimicrobial therapy of prosthetic valve endocarditis".)
Endocarditis — The approach to selection of antimicrobial therapy for treatment of enterococcal endocarditis is discussed in detail separately. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)
Patients with enterococcal endocarditis and unclear source of infection appear to warrant colonoscopy [58,59]. This was suggested in a retrospective study including 142 patients with IE due to E. faecalis who underwent colonoscopy; the overall rate of colorectal disease was 70.4 percent, and the prevalence of advanced adenomas and colorectal carcinoma was 14.8 percent . Since most patients with enterococcal endocarditis are also in an age group that should be considered for colonoscopy, this seems a reasonable approach.
Meningitis — Enterococci rarely cause meningitis in normal adults . Most cases of enterococcal meningitis occur in patients with head trauma, neurosurgery, intraventricular or intrathecal catheters, or anatomic defects of the central nervous system (CNS) [61,62]. Rarely, enterococcal meningitis can be a complication of high-grade bacteremia in patients with enterococcal endocarditis or immunodeficiency such as AIDS or hematologic malignancy [60,61]. Enterococcal meningitis is also seen in the setting of neonatal sepsis and has also been described in association with Strongyloides hyperinfection [63,64].
The optimal approach for treatment of enterococcal meningitis is not certain. Combination therapy is warranted; options for treatment of meningitis are outlined in the table (table 4) [60,61,65]. For infection due to E. faecalis, we favor treatment with ampicillin, ceftriaxone, and gentamicin (assuming high-level resistance to gentamicin is not present), despite the lack of clinical studies supporting this regimen. We favor once-daily aminoglycoside, for the theoretical possibility that higher peaks would favor greater cerebrospinal fluid penetration. For patients failing to respond to systemic antibiotics, addition of intraventricular antibiotics (vancomycin or daptomycin +/- gentamicin) may be reasonable. Daptomycin has poor CNS penetration; if used for treatment of CNS infection, daptomycin should be administered intraventricularly as well as intravenously . (See "Infections of cerebrospinal fluid shunts and other devices".)
Treatment of enterococcal meningitis caused by E. faecium strains resistant to penicillin, aminoglycosides, and vancomycin is a difficult challenge; we favor intravenous linezolid. If there is a lack of response, we favor daptomycin (intravenous and intraventricular). Quinupristin-dalfopristin (intravenous plus intraventricular) is an alternative choice although experience with intraventricular administration is limited [66-79]. Rifampin (if susceptible) may be a useful adjunctive agent, as might intraventricular gentamicin added to intraventricular daptomycin [80-82]. Chloramphenicol should not be used for treatment of enterococcal meningitis. Tigecycline has been used in case reports with either intraventricular daptomycin or intraventricular tigecycline .
The precise duration of therapy for enterococcal meningitis is uncertain. In concurrence with the Infectious Diseases Society of America clinical practice guidelines for health care associated ventriculitis and meningitis, we suggest treatment for at least 10 days . If multiple cultures are positive, it is reasonable to extend treatment for 10 to 14 days after the last positive culture.
Parenteral agents with VRE activity
Linezolid — Linezolid is a bacteriostatic, synthetic oxazolidinone antibiotic that is US Food and Drug Administration (FDA) approved for use in vancomycin-resistant enterococci (VRE) infections. It binds to the peptidyltransferase center of the 50S ribosome, preventing peptide bond formation and thus the addition of new amino acids . Resistance can emerge from mutations or by acquisition from other organisms; a mobile gene, cfr, encoding a methyltransferase that modifies 23S rRNA, which confers resistance to linezolid as well as clindamycin, chloramphenicol, pleuromutilins, and streptogramin A, has been found in staphylococci [86,87] and more recently in enterococci . Another plasmid-borne resistant determinant, optrA, encodes a ribosomal protection factor that leads to increased minimum inhibitory concentrations (MICs) for oxazolidinones (linezolid and tedizolid) and chloramphenicol .
Linezolid may be given orally or parenterally. It has high bioavailability after oral administration, and it achieves therapeutic levels in most tissues.
Early data on linezolid were obtained in the setting of compassionate use programs. One report describing its compassionate use in nearly 500 patients with a variety of VRE infections (46 percent bacteremia, 10 percent endocarditis, 31 percent catheter infection) reported a cure in 81 percent of cases . Another report describing its compassionate use in 85 solid organ transplant recipients with VRE infection (43 with bacteremia) demonstrated resolution of infection in 63 percent of cases . However, linezolid failure and resistance have also been reported [92,93].
Safety concerns limit the use of linezolid, particularly in the setting of prolonged use. Adverse effects include thrombocytopenia, anemia, lactic acidosis, peripheral neuropathy, and ocular toxicity. When administered with serotonergic agents (particularly selective serotonin reuptake inhibitors), linezolid can induce serotonin syndrome due to its inhibition of monoamine oxidase [94,95]. (See "Serotonin syndrome (serotonin toxicity)".)
Thrombocytopenia associated with linezolid use appears to occur more frequently in the setting of end-stage kidney disease and typically resolves after discontinuation of the drug . Neuropathy (peripheral and, less commonly, optic) as well as lactic acidosis are uncommon but important side effects of linezolid. Peripheral neuropathy can be severe and may not resolve after drug discontinuation [97-99].
Appropriate linezolid dosing is 600 mg every 12 hours orally or intravenously. Blood counts and serum chemistries should be monitored at least weekly during linezolid therapy.
Clinical use — Daptomycin is a bactericidal cyclic lipopeptide antibiotic that causes depolarization of the bacterial cell membrane . It was approved by the FDA for treatment of skin and skin structure infections, including those caused by vancomycin-susceptible E. faecalis. Daptomycin is likely efficacious for treatment of skin and skin structure infections due to vancomycin-resistant E. faecalis or E. faecium, although the number of isolates in the study was insufficient to support FDA approval. For some strains, including ones with decreased daptomycin susceptibility, daptomycin is potentiated by the addition of ampicillin and/or ceftaroline, even in the setting of resistance to these agents [101,102], and several anecdotal cases have reported using ampicillin plus daptomycin for E. faecalis endocarditis . Potentiation still occurs with strains that became nonsusceptible strains via the liaFSR pathway but not when the organism used the yyc pathway to become nonsusceptible [104,105].
Some favor the use of daptomycin for treatment of E. faecium infections that are resistant in vitro to ampicillin and vancomycin, particularly bloodstream infections, even though daptomycin has not been approved by the FDA for E. faecium [106-108]. The daptomycin MICs for E. faecium are higher than those for E. faecalis, which in turn are higher than those for staphylococci. Data suggest that many enterococcal strains with a daptomycin MIC of 3 to 4 mg/mL already have mutations that can eliminate the bactericidal activity of the antibiotic, yet were previously reported as susceptible [109-112]. (See 'Susceptibility breakpoints' below.)
The addition of ampicillin or ceftaroline (even in the setting of resistance to these agents) may enhance binding of daptomycin and increase its activity, as mentioned above [101,102,104,105]; some favor use of these combinations for severe infection including VRE endocarditis .
FDA approved daptomycin dosing for complicated skin and skin structure infections is 4 mg/kg intravenously once daily. Minimum dosing for bloodstream infections is 6 mg/kg intravenously once daily (the approved dose for staphylococcal bacteremia).
In the setting of enterococcal bloodstream infections, and particularly endocarditis, we favor higher daptomycin doses of 8 to 10 mg/kg/day. This is supported by data from a retrospective study of more than 900 patients with VRE bacteremia in the Veterans Affairs hospital system, in which high-dose daptomycin regimens (≥10 mg/kg/day) were associated with reduced 30-day mortality (risk ratio 0.83, 95% CI 0.74-0.94) compared with standard-dose (6 mg/kg/day) and medium-dose (8 mg/kg/day) regimens, respectively . Both medium- and high-dose regimens were also associated with improved rates of microbiologic clearance compared with standard dosing. A study of 112 patients from Taiwan reported similar results; higher dose regimens (≥9 mg/kg/day) associated with lower mortality (20 percent) compared with medium (7 to 9 mg/kg/day) and standard (<7 mg/kg/day) doses (33 and 50 percent, respectively) . Among the small number of patients treated with higher dose therapy, treatment appeared to be safe and no dose dependent association between daptomycin and creatine kinase elevation was seen.
Patients receiving daptomycin should be evaluated regularly for clinical evidence of myopathy . Serial measurements of serum creatine kinase should be obtained at least weekly (more often in the setting of renal insufficiency); the drug should be discontinued in patients with symptomatic myopathy and creatine phosphokinase (CPK) ≥5 times the upper limit of normal (ULN) or in asymptomatic patients with CPK ≥10 times ULN.
Susceptibility breakpoints — The original Clinical and Laboratory Standards Institute (CLSI) daptomycin breakpoints for enterococci considered strains with a daptomycin MIC of ≤4 mg/L as susceptible. In January 2019, the Enterococcus spp CLSI breakpoints were revised , although there is ongoing discussion regarding these breakpoints. As of March 2019, for E. faecium, CLSI lists no S category; an MIC of ≤4 mg/L is considered susceptible dose dependent based on a dose of 8 to 12 mg/kg/day, and an MIC of ≥8 mg/L is considered resistant. For other Enterococcus spp, an MIC of ≤2 mg/L is considered susceptible, an MIC of 4 mg/L is considered intermediate, and an MIC of ≥8 mg/L is considered resistant, based on a dose of 6 mg/kg/day. In August 2020, the FDA also revised their breakpoints to match the CLSI breakpoints for vancomycin-susceptible E. faecalis; however, these breakpoints are only for the FDA-approved indication of complicated skin and soft tissue infections at a dose of 4 mg/kg/day. The FDA has not recognized any breakpoints for E. faecium because of a paucity of data on E. faecium strains and dosing regimens.
The CLSI recommends only the broth dilution method with Mueller-Hinton broth adjusted to a final calcium ion concentration of 50 mg/L. However, data suggest that MIC determination for daptomycin by both broth microdilution and Etest is unreliable and with poor interlaboratory reproducibility . Due to the apparent inaccuracy of the tests, clinical judgment should be exercised when treating "daptomycin-susceptible" VRE bacteremia and other deep-seated infections with this antibiotic. (See "Mechanisms of antibiotic resistance in enterococci".)
Oritavancin — Oritavancin is a semisynthetic glycopeptide that inhibits cell wall synthesis and has in vitro bactericidal activity against staphylococci and enterococci, including vancomycin-resistant strains [118-120]. There are no trial data to support its use for VRE, although there have been anecdotal reports of successful use . Oritavancin was approved in 2014 for treatment of acute bacterial skin and skin structure infections due to susceptible organisms, including E. faecalis . The drug has a half-life of 100 hours, allowing for single-dose therapy for skin and skin structure infections.
Data on oritavancin are discussed further separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections", section on 'Dalbavancin, oritavancin, and telavancin'.)
Tigecycline — Tigecycline is a glycylcycline antibiotic derived from minocycline with in vitro bacteriostatic activity against many gram-positive pathogens (including methicillin-resistant S. aureus [MRSA], VRE, and penicillin-resistant Streptococcus pneumoniae), some gram negatives (important exceptions include Pseudomonas, Proteus, Providencia, and Morganella species), anaerobes, and atypical species.
Tigecycline does not have FDA approval for treatment of VRE, although it has been approved for treatment of complicated skin and skin structure infections and intra-abdominal infections, including infections in which vancomycin-susceptible E. faecalis were recovered. Many VRE test susceptible to tigecycline, based on in vitro and animal model data, and MICs of tigecycline are usually lower for E. faecium than for E. faecalis or staphylococci [123-125].
Given concerns regarding achieving adequate tigecycline serum drug concentrations, caution should be used with tigecycline for the treatment of patients with bacteremia . Approved tigecycline dosing is 100 mg intravenously (IV) once, followed by 50 mg IV every 12 hours [127,128]. Major adverse effects include nausea and vomiting. Tigecycline is difficult to use for outpatient therapy because of the instability of intravenous preparations.
Tigecycline may be useful for patients with VRE infection who are intolerant of other agents or when VRE are present along with other pathogens that are susceptible to tigecycline. In addition, tigecycline may also be useful when the biliary system is the source of bacteremia since the drug is eliminated via the hepatobiliary tree. Tigecycline may also be useful in the setting of renal insufficiency. Anecdotal reports have used tigecycline with daptomycin for VRE infections [79,129,130]. In 2010, the FDA issued a boxed warning of increased all-cause mortality in patients receiving tigecycline compared with that of other drugs used to treat a variety of serious infections.
Quinupristin-dalfopristin — Quinupristin-dalfopristin is a mixture of streptogramin antibiotics with in vitro activity against VRE; a previous FDA approval for the treatment of vancomycin-resistant E. faecium infections  was subsequently withdrawn. It has poor activity against E. faecalis due to a species-specific adenosine triphosphate (ATP)-binding protein [132,133]. Central venous access requirements and adverse effects limit the use of quinupristin-dalfopristin; these include metabolic interactions, severe myalgias, arthralgias, nausea, and hyperbilirubinemia. (See "Mechanisms of antibiotic resistance in enterococci".)
In a study of 396 patients with VRE infections treated with quinupristin-dalfopristin (including bacteremia, intra-abdominal infections, urinary tract infections, and skin infections), the overall efficacy of quinupristin-dalfopristin (both clinical and bacteriologic success) was 66 percent . Clinical response to quinupristin-dalfopristin is comparable with that of linezolid .
Teicoplanin — Teicoplanin is a glycopeptide that is not available in the United States . It has in vitro activity against E. gallinarum and E. casseliflavus (VanC VRE) as well as most VanB-type VRE, although it is rarely active against VanA-type VRE. Some VanB VRE mutant strains are constitutively resistant to teicoplanin and have emerged after drug exposure in vitro and in vivo [137,138]. (See "Mechanisms of antibiotic resistance in enterococci", section on 'Vancomycin resistance'.)
In countries where it is available, teicoplanin may be used for treatment of infections due to susceptible enterococci. For patients with normal renal function, it should be administered with loading doses of 6 mg/kg (12 mg/kg for serious infections) every 12 hours for three doses (up to five doses for serious infections) followed by 6 mg/kg (12 mg/kg for serious infections) every 24 hours. The addition of an aminoglycoside (gentamicin or streptomycin, in the absence of high-level resistance to one of these drugs) should be considered to reduce the emergence of VanB mutants resistant to teicoplanin.
Telavancin — Telavancin is a lipoglycopeptide approved for complicated skin and skin structure infections caused by susceptible gram-positive bacteria, including S. aureus and vancomycin-susceptible E. faecalis. There are no clinical data regarding use of telavancin for other enterococcal infections, but it is about fourfold more potent than vancomycin against enterococci (eg, the MIC for 90 percent of strains [MIC90] is 0.12 mcg/mL), with little to no increase in MICs against VanB strains; for VanA strains, the MIC90 has been reported as 4 to 16 mcg/mL in various studies (versus >256 mcg/mL for vancomycin) [139-141].
Combination therapy — Data on additional therapeutic combinations for treatment of infections due to VRE are limited. Options, depending on susceptibility, include:
Alternative agents — Fluoroquinolones may be useful for treatment of enterococcal urinary tract infections in some circumstances. There are several case reports of success with moxifloxacin (usually with amoxicillin given before or after) for enterococcal prostatitis caused by susceptible organisms [149,150]. We would also consider using moxifloxacin plus amoxicillin for enterococcal prostatitis; this combination was one of the step-down regimens for enterococcal endocarditis in the Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET) study. Combination therapy of a fluoroquinolone plus amoxicillin offers a theoretical advantage of decreasing the emergence of fluoroquinolone resistance. Whether concentrations of amoxicillin in the prostate are sufficient to achieve this effect is not known. Tetracycline and chloramphenicol may demonstrate in vitro activity against some strains of enterococci, but they are only bacteriostatic against these organisms [151,152]. Clinical success and failure with chloramphenicol has been described, but the toxicity of this agent limits its usefulness [153-155]. (See 'Urinary tract infection' above.)
Most enterococci in the United States are resistant to erythromycin and other macrolides. In addition, although some enterococcal isolates demonstrate in vitro susceptibility to trimethoprim-sulfamethoxazole (TMP-SMX), in vivo enterococci can use exogenous folic acid and bypass the block in folate synthesis induced by TMP-SMX . Therefore, TMP-SMX should not be used for treatment of enterococcal infections, even if in vitro susceptibility testing suggests sensitivity [156-158].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Vancomycin-resistant enterococci (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Enterococci are relatively resistant to the killing effects of cell wall-active agents (penicillin, ampicillin, and vancomycin) and are impermeable to aminoglycosides. Antibiotic regimens and doses for susceptible strains are outlined in the table (table 1). (See 'Approach to susceptible strains' above.)
●The major categories of resistant enterococci include those with high-level penicillin and ampicillin resistance and those with vancomycin resistance. Antibiotic regimens and doses for resistant strains are outlined in the tables (table 2). (See 'Approach to resistant strains' above.)
●Options for oral treatment of enterococcal urinary tract infections (UTIs) are outlined in the table (table 3). For patients with lower UTI caused by susceptible strains, we suggest treatment with amoxicillin, fosfomycin, or nitrofurantoin (Grade 2B). For patients Enterococcus faecalis with complicated UTI and for patients unable to tolerate oral therapy, we suggest parenteral ampicillin (Grade 2B). (See 'Urinary tract infection' above.)
●We recommend antimicrobial therapy for treatment of two or more positive blood cultures, a single positive blood culture accompanied by signs of sepsis, or a single positive blood culture together with a positive enterococcal culture from another usually sterile site (Grade 1B). Options for monotherapy and combination therapy are outlined in the tables (table 2). For uncomplicated infection, five to seven days of therapy is usually adequate. (See 'Bacteremia' above.)
●Treatment of bacteremia due to susceptible enterococci (in the absence of suspected endocarditis) consists of ampicillin. Reasonable therapeutic choices for treatment of bacteremia due to ampicillin-resistant, vancomycin-susceptible Enterococcus faecium or ampicillin- and vancomycin-resistant E. faecium are described above. (See 'Bacteremia' above.)
●For treatment of enterococcal bacteremia with suspected endocarditis or critical illness, we recommend combination antimicrobial therapy over monotherapy (Grade 1B). Of the combination antimicrobial regimens, we suggest ampicillin plus ceftriaxone for E. faecalis since it avoids the toxicity of aminoglycosides (Grade 2B); use of a cell wall-active agent in combination with a synergistically active aminoglycoside is also acceptable. (See 'Bacteremia' above.)
●The treatment of enterococcal endocarditis is discussed in detail separately. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)
●For treatment of enterococcal meningitis, we recommend combination antimicrobial therapy over monotherapy (Grade 1C). Of the combination antimicrobial regimens, we suggest ampicillin, ceftriaxone, and gentamicin (table 4) (Grade 2C). (See 'Meningitis' above.)