The combination of penicillin plus streptomycin was empirically found to cure the patients who were not improving with penicillin alone and was subsequently shown to have synergistic bactericidal activity in vitro. The development of high resistance to streptomycin (which abolishes synergism) led to the use of gentamycin, an aminoglycoside for which resistance was rare at the time and showed similar results in terms of bactericidal effect and clinical efficacy. Treatment of enterococcal IE with the combination of penicillin plus streptomycin or gentamycin has been evaluated in many studies and became the standard of care many decades ago for patients with IE due to enterococci in the absence of HLAR (High Level Aminoglycoside Resistant) strains ^{[1][2][3][4][5][6]}[30,40,41,42,99,100].

Another option that is especially recommended in elderly people, patients with previous renal impairment, and specially, in IE caused by HLAR strains, is the ampicillin + ceftriaxone (A + C) regimen, which is synergistic in vitro and has also proven effective both in experimental studies and in real life. Its similar efficacy and lower toxicity have led to be included as an alternative regimen in the current guidelines ^[7][8][65,66].

In 1995, a French group described an unexpected in vitro synergy between amoxicillin and cefotaxime, an antimicrobial discovered in 1981 ^[9][101]. Enterococci are naturally resistant to cephalosporins, which act only on Peptide Binding Proteins (PBP) 2 and 3, triggering the production of more efficient PBPs 1, 4 and 5 under treatment. However, aminopenicillins (ampicillin and amoxicillin) and ureidopenicillins (piperacillin) act effectively on these other PBPs, which means that the joint use of both classes of drugs results in a complete blockage and synergy of action in inhibiting bacterial growth. These results were considered by a Spanish group that found identical synergy between ampicillin and another cephalosporin (ceftriaxone) discovered years later with a very favorable pharmacokinetic profile that allowed less frequent administration, due to its high plasma half-life. Gavaldá et al. in 1999 demonstrated a reduction of 1 to 4 dilutions in the MIC of ampicillin of 10 strains of HLRA E. faecalis when using the fixed dose of 4 mg/L of ceftriaxone by the double-disk technique and of at least one dilution when using micro dilution in Mueller-Hinton medium for its determination ^[10][102]. Using time-death curves, an ampicillin concentration of 2 mg/L and varying concentrations of 5–60 mg of ceftriaxone, they achieved a >2 log reduction of the initial inoculum at 24 h of incubation in all strains, and this effect increased to >3 log (synergy) in 7 of the 10 strains when 10 mg/L doses of ceftriaxone were used, and in six strains when the concentration was 5 mg/L. Similar results were reported much later, showing that even ampicillin concentrations at 1 mg/L + 2 mg/L ceftriaxone were synergistic ^[11][103]. Using a humanized model in the experimental animal, the authors found that by administering the equivalent of 2 g of IV ceftriaxone, drug concentrations at 12 h were around 50 mg/L and 20 mg/L at 24 h (antibiotic bound to proteins). As ceftriaxone bound to protein at 90%, the administration of 2 g IV/12 h. of ceftriaxone, together with the administration of ampicillin, could always achieve free drug concentrations of ceftriaxone above 2–4 mg/L, guaranteeing this synergistic effect during the entire dosing interval. These facts were effectively translated into a clear decrease in the colony count in the vegetations of the experimental animals treated with this regimen, and even the complete sterilization of the vegetations in some animals infected with certain strains.

The translation of this elegant experimentation on the animal model was published eight years later by the same group in a multicenter trial in 13 Spanish hospitals, in which 21 patients with HLRA strains and 22 with non-HLRA strains at high risk of nephrotoxicity were treated ^[12][104]. Cure was obtained in 100% of patients with HLRA strains who completed the protocol with this regimen. Due to the small sample size and the failures obtained in non-HLRA strains, the guideline was promptly considered but only for HLRA strains, due to the lack of existing alternatives. However, in 2003 the same group demonstrated, again in the experimental animal model, the efficacy of this pattern also in non-HLRA strains ^[13][105]. Again ten years later, the demonstration of its clinical efficacy in these non-HLRA strains compared to the “standard” treatment (ampicillin + gentamicin) came from a Spanish multicenter trial, in which 150 patients treated with the A + C regimen (ampicillin + ceftriaxone) were compared to 87 patients treated with A + G (ampicillin + gentamicin), showing equal mortality (22% vs. 21% during hospitalization and 8% vs. 7% at 3 months) and recurrences (3% vs. 4%), but with lower nephrotoxicity (23% vs. 0%; p < 0.01) ^[14][106]. Following these excellent results, the American and European guidelines included this regimen as “preferred” in HLRA strains and “alternative” in non-HLRA strains ^[7][8][65,66]. However, in Europe and especially in Spain, the A + C regimen progressively gained followers until it became the majority ^[15][107], and this was easily explained by its lower toxicity. The profile of the patient with enterococcal IE is often an elderly person, with abundant comorbidities and in many cases previously weakened by a previous hospitalization, and it is precisely in this group where the physician must be especially cautious about the side effects of treatment ^{[16][17][18][19][20]}[4,5,6,13,14].

One concern with ceftriaxone use is that is has been pointed as an independent risk factor for Clostridioides infection ^[21][108] although no such complication has been reported from Spain in which this guideline is prevalent. Another concern is that some clinical and observational studies implicate the use of ceftriaxone as major risk factor for occurrence of vancomycin-resistant E. faecium infection, including bacteremia ^[22][23][109,110]. In animal studies, ceftriaxone use promotes gastrointestinal colonization by VRE, probably due to the high biliary excretion of ceftriaxone that could select for drug-resistant enterococci living there ^[24][25][111,112]. Unlike ceftriaxone, other cephalosporins antibiotics, such as cefepime ^[24][111], and ceftaroline ^[26][113] do not appear to promote VRE colonization, and the combination of ampicillin plus ceftaroline have demonstrated efficacy similar to ampicillin plus ceftriaxone in several pharmacodynamic studies, although no clinical data are yet available ^[27][28][69,70]. Ceftobiprole have high affinity for enterococcal PBPs and have demonstrated efficacy against VanB-resistant E. faecalis in addition to synergy when used in combination with aminoglycosides, but this combination requires further exploration in human subjects ^[29][28].

Vancomycin is an alternative therapy recommended in European and American guidelines for patients unable to tolerate penicillin or ampicillin. Vancomycin reduced CFU/mL in vegetations significantly more than ampicillin monotherapy in the rabbit experimental model ^[30][82]. However, combinations of penicillin or ampicillin with gentamicin are preferable to combined vancomycin-gentamicin because of the potential increased risk of ototoxicity and nephrotoxicity with the vancomycin-gentamicin combination during six weeks. Moreover, combinations of penicillin or ampicillin and gentamicin are more active than combinations of vancomycin and gentamicin in vitro and in experimental models of IE ^[31][114].

Teicoplanin is particularly interesting due the in vitro data that demonstrate advantage over vancomycin against E. faecalis, with MIC₉₀ values usually lower than that for vancomycin ^[32][33][34][115,116,117]. Furthermore, its long-elimination half-life permits once-daily dosing and exhibit concentration-dependent activity with excellent results in experimental studies combined with gentamicin ^[35][36][118,119] and much lower toxicity than vancomycin ^[37][38][39][71,72,120]. Several observational studies (overall 56 patients) support the use of monotherapy with teicoplanin at doses of 6–10 mg/kg/d (two of them also introduced a loading dose), mainly as a continuation treatment for E. faecalis IE when adverse events have developed with standard treatments, or to facilitate outpatient treatments ^[40][41][42][73,74,75]. The largest study conducted supported the use of monotherapy with teicoplanin for treating E. faecalis IE as continuation therapy. The reported mortality related to IE was low (8%), although the population treated with teicoplanin suffered from less severe IE than the standard therapy group ^[41][74]. Within the patients treated with teicoplanin as a continuation or salvage therapy, 16 died (32%) in a minimal follow-up period of 3 months. Only three relapses were reported in these studies. Then, favorable results and very few toxicities lead reusearchers  to consider it as a reasonable alternative. Theoretically, teicoplanin has also activity against enterococci with VanB mediated resistance, but development of resistance during therapy is concerning ^[43][121] and cannot be a recommendation in this setting.

Although there are no prospective randomized-controlled studies evaluating the efficacy of daptomycin for the treatment of E. faecalis IE, several reports including a total of 26 patients were published shortly after its approval, within an “off-label” use ^[44][45][46][122,123,124]. The treatment scheme was considerably heterogeneous, included initial and salvage therapy, monotherapy and combined regimens, and the mean doses ranged between 8.5 and 10.125 mg/kg/day. Mortality rates reported were low (0–22%), although only one study ^[45][123] attained more than a one-month follow-up. In one study, the salvage treatment of five E. faecalis IE episodes was reported ^[44][122], of which four needed a treatment change due to treatment failure. Daptomycin patients had longer duration of bacteremia (6 versus 1 day) and greater need of therapy switch due to complications (66.7% versus 0%) compared with conventional antibiotic regimens (ampicillin or vancomycin ± gentamicin), although there were no differences regarding duration of hospital stay or mortality. So, the stated final conclusions differed, with two supporting daptomycin as an alternative treatment in this scenario ^[45][46][123,124], and one showing some concerns ^[44][122]. Among 22 patients with enterococcal IE treated with daptomycin in a European registry (18 E. faecalis), the success rate was 73%, but no information regarding dosage or combination therapy was given ^[47][125]. An observational prospective single center study found similar outcomes in patients with enterococcal endocarditis treated with daptomycin-based regimen versus standard regimens, although daptomycin was used in combination with another antibiotic (mostly a beta-lactam) an at high doses (>10 mg/kg/day) ^[46][124]. Microbiological failures of daptomycin were promptly reported when “standard” doses (6 mg/Kg/day, approved dose for S. aureus bacteremia and right-sided IE) were administered, and high doses (8–12 mg/Kg/day) are now recommended for enterococcal and S. aureus severe infections ^{[48][49][50][51]}[50,51,52,53]. It is important to note that the daptomycin MIC90 for enterococci is higher than that of staphylococci (4 mg/L and 0.5 mg/L, respectively), supporting the concept that higher doses of daptomycin may be needed for the management of enterococcal IE, and in vitro studies have demonstrated that a high percentage (33%) of E. faecalis incubated with daptomycin at a subinhibitory concentration (2 mg/L) can develop MIC ≥ 8 mg/L ^[52][126]. Daptomycin display a dose-dependent bactericidal effect and high-dose regimens have demonstrated an enhanced pharmacodynamic profile, and perhaps the most bactericidal regimen against VRE ^[53][127]. However, microbiological failures also have been described with high doses in patients with prior daptomycin exposures, prostheses, or immunocompromised patients with long hospitalization courses ^[51][54][55][53,128,129]. Therefore, this alternative could be considered in resistant isolates or when adverse events appear, but not to simplify antibiotic treatment. Taking also account the synergistic activity between daptomycin and beta-lactams ^[56][57][58][83,84,130] fosfomycin ^{[59][60][61][62][63][64][65]}[85,86,87,88,89,90,91] or tigecycline, a combination regimen with high doses seems to be preferable, whereas single therapy with this drug should be used with caution.

In vitro data have demonstrated synergy with fosfomycin in combination with ceftriaxone, rifampin, tigecycline, daptomycin and teicoplanin ^{[59][60][61][62]}[85,86,87,88]. Current oral fosfomycin use is limited to uncomplicated urinary tract infections due to limited absorption and intravenous formulation are yet unavailable in the USA. However, fosfomycin has demonstrated utility against MSSA and MRSA endocarditis in combination with daptomycin or imipenem ^{[63][64][65][66]}[89,90,91,131] and a study of in vitro and in vivo with the guinea pig model using intraperitoneal fosfomycin demonstrated promising activity against both planktonic and biofilm-forming E. faecalis when the drug was used in combination with gentamicin and daptomycin ^[67][132]. Thus, new therapeutic options with this drug could be considered in the future for E. faecalis IE.

Linezolid after a few promising studies has been recommended for the treatment of endocarditis as result of multi-drug resistant enterococci ^[68][133] and has been recommended in the USA for the treatment of Enterococcus species caused by strains resistant to penicillin, aminoglycosides, and vancomycin ^[7][65]. Regrettably, widespread use from the year 2000 has result in an emerging of linezolid-resistant VRE in 2001 ^[69][134] and increasing of these strains especially in hospitals from various countries (Denmark, Spain, Germany…) ^[70][135]. However, the use of linezolid is a matter of controversy because of the lack of bactericidal effect and the lack of randomized clinical trials or robust cohorts. Linezolid has displayed efficacy in the treatment of VR E. faecium bacteremia with an open-label nonrandomized, compassionate-use program reporting microbiological and clinical cure rates of 85.3% and 79% respectively with 10 out of 13 patients with VRE strains (76.9%) achieving clinical cure in the subgroup of endocarditis ^[71][136]. A systematic review attempted to evaluate the clinical efficacy of linezolid in the treatment of enterococcal IE. This study found that 7 out of 8 cases improved or were cured with linezolid: four of the included cases were caused by E. faecalis (two VRE) and the rest of them were cases of IE vancomycin-resistant E. faecium ^[72][137]. But clinical evidence is supported only by these case reports with heterogeneous results and numerous cases of enterococcal infections resistant to linezolid have been reported ^[73][74][75][138,139,140]. In a Danish cohort of consecutive IE patients 38 out of 550 patients were treated with Linezolid ^[76][141]. The authors retrospectively compared individuals who had received this antimicrobial with a control group, and no significant differences regarding in-hospital mortality or at one year of follow-up were detected. Some authors reported similar results in small single hospital cohorts ^[77][78][142,143] although they did not specify the time of initiation and duration of the linezolid therapy nor its effect on IE. Recently, an interesting study reported from the Spanish cohort (GAMES) retrospectively analyzed 295 consecutive IE treated with linezolid, 38 of them enterococci IE ^[79][144]. In this cohort, in-hospital mortality in patients treated with linezolid was higher than in controls, and as determined with the multivariate analysis, linezolid was an independent risk of mortality. One of the principal drawbacks is the need of a prolonged treatment (six weeks) of E. faecalis IE that usually occurs in elderly population, which is more likely to the myelotoxicity and neuropathy produced by this drug.

Gastrointestinal disorders and myelotoxicity are less frequent with tedizolid, and a favorable action against MRSA IE have been reported in experimental models (rats and rabbits). Against VRE tedizolid has a fourfold lower MIC when compared to linezolid and has activity against linezolid-resistant strains with a cfr mutation, probably due to additional interactions with the ribosomal ^{[80][81][82][83][84]}[95,96,145,146,147]. Thus, compared to linezolid, tedizolid has the potential to be a first-line agent for the treatment of serious VRE infections, but until now, no clinical data have been published in patients with IE.

Fluoroquinolones have been used in the treatment of some enterococcal infections such as chronic enterococcal prostatitis with relapsing bacteremia. Like the tetracyclines, these antibiotics have also been used as part of combination therapies in endocarditis. The combination of ampicillin plus ciprofloxacin was tested in an experimental model of rabbit endocarditis with E. faecalis and the regimen caused a significant decrease in bacterial counts compared to each compound alone, although it was less effective than the combination of beta-lactams and aminoglycosides ^[85][67], and this effect was previously reported in vitro ^[86][68]. Additionally, the use of ampicillin plus ofloxacin was shown to be also synergistic in vitro, achieving bactericidal activity, and to successfully clear the bacteremia in a patient with E. faecalis IE exhibiting HLAR ^[87][148]. Nonetheless, the lack of clinical experience and the increased rates of resistance to some of these compounds usually preclude the use of these antibiotics for E. faecalis IE, particularly as monotherapy.

Delafloxacin is a new quinolone active in vitro against MSSA, MRSA, CoNS and streptococci and interestingly retains activity against fluoroquinolone-resistant strains. Specific features in the delafloxacin molecule determines enhanced activity in acidic environment due to its anionic character, which eventually leads to improved activity ^[88][149]. Delafloxacin has been recently approved for acute bacterial skin and skin structure infections ^[89][150] and for the treatment of community-acquired bacterial pneumonia ^[90][151]. Delafloxacin can be given intravenously or orally due to its good bioavailability (60–70%) ^[88][149]. However, according to EUCAST, there is insufficient evidence that enterococci are a good target for therapy with delafloxacin and no clinical data have been published on the use of delafloxacin for IE.

Tigecycline is a broad-spectrum antibiotic derived from minocycline which is approved for skin and soft tissue infections, including those with vancomycin-susceptible E. faecalis. In the treatment of soft tissue infections (including those with vancomycin-susceptible E. faecalis), tigecycline sowed a microbiological eradication rate of 87.5%, similar to vancomycin plus aztreonam ^[91][152]. In complicated abdominal infections, tigecycline exhibit similar rates of microbiological curation for vancomycin-susceptible E. faecalis (78.8%) than imipenem ^[92][153]. Moreover, some in vitro models suggest that synergism of tigecycline with vancomycin, gentamicin and rifampin can be achieved for certain strains of E. faecalis and E. faecium ^[93][154] and successful therapy of endocarditis was reported with the combination of tigecycline plus daptomycin in several cases ^[94][95][96][92,93,94]. However, a serious drawback of the use of tigecycline monotherapy is the low levels obtained with this antibiotic ^[97][155] and the emergence of resistance during therapy has been reported in experimental studies ^[98][156]. Thus, the use of this compound as monotherapy for severe enterococcal infection is discouraged, although its role in combination therapies with bactericidal effects warrants further investigation.

Considered a subclass of the glycopeptide antibiotics, the new lipoglycopeptides have similar mechanisms of action of binding to the carboxyl terminal d-alanyl-d-alanine residue of the growing peptide chains but differ from their parent glycopeptides by the addition of lipophilic tails that allows prolonged half-lives, giving them unique dosing profiles.

Dalbavancin has a long-acting parenteral administration due to its high-protein binding (93%) and prolonged elimination half-life (14.4 days), that allows prolonged intervals between doses (7–14 days) ^[99][157] A promising activity against Gram-positive biofilms has also been reported ^[100][158].

Dalbavancin was approved in the USA and Europe to treat acute bacterial skin and skin structure infections caused by Gram-positive cocci isolates, including vancomycin-susceptible E. faecalis, but it must be remarked that it is inactive against VanA phenotypes. Although it has not been approved to treat patients with bloodstream infections or IE, there are in vitro studies showing a good susceptibility (MIC90: 0.06 mg/L) of most E. faecalis isolates (97.6%) collected from patients with a diagnosis of bacterial endocarditis ^[101][159]. Off-label utilization of dalbavancin was extensively done in patients with osteomyelitis, joint infections, and articular prostheses, and less in cardiovascular infections ^[102][76]. A retrospective cohort in Austria evaluated 27 adults with Gram-positive bacteremia with IE treated at least with one dose of dalbavancin with excellent results ^[103][77]: In most patients dalbavancin was used as sequential treatment after clearance of bacteremia to allow a promptly discharge with outpatient treatment, and the same scheme was used in a Spanish cohort that included 34 patients (three of them with E. faecalis IE) ^[104][78]. Two dosing strategies are used with similar results: a 1000 mg loading dose and the 500 mg/week or a 1500 mg loading dose and then 1000 mg every two weeks and in these cohorts, six patients were successfully treated. Thus, limited available evidence suggests that dalbavancin might be a good option to treat E. faecalis IE in the context of sequential outpatient therapy, but studies with full use (not only sequentially) of this drug throughout treatment are needed.

Oritavancin is an interesting drug, very active against Gram-positive cocci including enterococci, and that also retains some activity against VanA and VanB-mediated vancomycin resistance. Among two collections of more than 10,000 isolates, oritavancin showed potent in vitro activity against staphylococci (including MRSA), streptococci and enterococci ^[105][106][160,161]. Although higher MIC were registered against vancomicn-resistant E. faecalis (vanA phenotype) than against vancomycin-susceptible strains, all VanA- resistant E. faecalis were inhibited at 0.5 mg/L or less. Its high protein-binding (85–905) and the prolonged terminal half-life (200–300 h) permits the administration of a single dose of 1200 mg with good therapeutical levels beyond two weeks ^[107][162] and a good activity in biofilms ^[108][163]. After the initial dose of 1200 mg, sequentially doses of 800 mg can be administered weekly for infections that will require a more prolonged treatment such as osteomyelitis ^[109][164].

Elimination of oritavancin mainly occurs through the reticuloendothelial system and no adjustments of dosage are needed in the cases of renal or hepatic failure. Oritavancin is a weak inhibitor of CYP2C9 and CYP2C19, and an inducer of CYP3A4 and CYP2D6, thus drug-drug interactions (e.g., patients treated with warfarin) should always considered. Attention should be paid to the possible alterations of some coagulation tests after oritavancin administration because of its interaction with the phospholipid reagent. Prolonged prothrombin and active partial thromboplastin times have been reported and thus, the use of intravenous unfractionated heparin sodium is contraindicated for up to 5 days after oritavancin administration owing the inability to reliably monitor coagulation tests. However, the results of chromogenic factor Xa and the thrombin time assays are not affected, allowing the use of fractionated heparin.

Oritavancin was also approved in the USA and Europe to treat adults with acute bacterial skin and skin structure infections caused by Gram-positive cocci isolates, including vancomycin-susceptible E. faecalis, but several reports with its utilization in osteoarticular infections, bacteremia and very few endocarditis have been reported ^{[110][111][112][113]}[79,80,81,165].

In conclusion oritavancin seems also an important option for outpatient therapy and early discharge in patients with E. faecalis IE, but very limited number of papers are available, especially in this setting, and there is no experience with quantity and dosing schedule and duration of treatment. Thus, further studies are necessary for optimizing and refining its place in the treatment of IE.