Enterococcus faecalis Endocarditis and Outpatient Treatment: A Systematic Review of Current Alternatives

antibiotics Review Enterococcus faecalis Endocarditis and Outpatient Treatment: A Systematic Review of Current Alternatives Laura Herrera-Hidalgo 1, Arístides de Alarcón2, Luis E. López-Cortes 3, Rafael Luque-Márquez 2, Luis F. López-Cortes 2, Alicia Gutiérrez-Valencia 2,4,* and María V. Gil-Navarro 1,† 1Unidad de Gestión Clinica de Farmacia, Hospital Universitario Virgen del Rocío/CSIC/Instituto de Biomedicina de Sevilla (IBiS), 41009 Seville, Spain; [email protected] (L.H.-H.); mariav[email protected] (M.V.G.-N.) 2Unidad de Gestión Clinica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Roc í o/CSIC/Instituto de Biomedicina de Sevilla (IBiS), 41009 Seville, Spain; [email protected] (A.d.A.); [email protected] (R.L.-M.); [email protected] (L.F.L.-C.) 3Unidad de Gestión Clinica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena/CSIC/Instituto de Biomedicina de Sevilla (IBiS), 41009 Seville, Spain; [email protected] 4Infección por el VIH y farmacocinética de antivirals, Instituto de Biomedicina de Sevilla (IBiS), Antonio Maura Montaner Street s/n, 41009 Seville, Spain *Correspondence: [email protected]; Tel.: +34-649640732 †On behalf of Grupo para el Estudio de las Infecciones Cardiovasculares de la Sociedad Andaluza de Enfermedades Infecciosas. Received: 4 September 2020; Accepted: 29 September 2020; Published: 30 September 2020   Abstract: The selection of the best alternative for Enterococcus faecalis infective endocarditis (IE) continuation treatment in the outpatient setting is still challenging. Three databases were searched, reporting antibiotic therapies against E. faecalis IE in or suitable for the outpatient setting. Articles the results of which were identified by species and treatment regimen were included. The quality of the studies was assessed accordingly with the study design. Data were extracted and synthesized narratively. In total, 18 studies were included. The treatment regimens reported were classified regarding the main antibiotic used as regimen, based on Aminoglycosides, dual β -lactam, teicoplanin, daptomycin or dalbavancin or oral therapy. The regimens based on aminoglycosides and dual β -lactam combinations are the treatment alternatives which gather more evidence regarding their efficacy. Dual β -lactam is the preferred option for high level aminoglycoside resistance strains, and for to its reduced nephrotoxicity, while its adaptation to the outpatient setting has been poorly documented. Less evidence supports the remaining alternatives, but many of them have been successfully adapted to outpatient care. Teicoplanin and dalbavancin as well as oral therapy seem promising. Our work provides an extensive examination of the potential alternatives to E. faecalis IE useful for outpatient care. However, the insufficient evidence hampers the attempt to give a general recommendation. Keywords: Enterococcus faecalis; infective endocarditis; outpatient treatment; outpatient parenteral antibiotic treatment (OPAT); systematic review; treatment alternatives Antibiotics 2020,9, 657; doi:10.3390/antibiotics9100657 www.mdpi.com/journal/antibiotics Antibiotics 2020,9, 657 2 of 17 1. Introduction Infective endocarditis (IE) is a potentially fatal infectious disease, characterized by its elevated morbidity and mortality. In spite of being relative infrequent, it is considered one of the four most common life-threatening infection syndromes [ 1 ]. Excluding cases developed among injection drug users, Enterococcal species are the third most common cause of IE, 90–97% of them being produced by E. faecalis [ 1 , 2 ]. While IE incidence has remained constant in the last few decades [ 1 ], the rate of enterococcal IE has increased along with changes in patients’ characteristics [3,4]. Nowadays, E. faecalis IE treatment is still challenging [ 5 ]. Enterococcal antimicrobial resistance is a major problem involving not only the inner bacterial resistance mechanisms, but also antibiotic use in the clinical setting and veterinary medicine, which requires a coordinated multidisciplinary approach. E. faecalis is a common microorganism in human microbiota, and several protective, but also harmful, roles have been suggested, including a leading role in colorectal cancer [ 6 ]. The gold standard treatment for E. faecalis IE is a combination therapy with ampicillin plus gentamycin or plus ceftriaxone [ 1 , 2 ]. Nevertheless, the lack of antibiotics with bactericidal effects, the ability for biofilm formation and the increase in antibiotic resistance have hindered the attempts to find a commonly accepted treatment for this endocarditis [ 1 , 5 – 8 ]. Moreover, another demanding feature in its management is the length of treatment, for which a minimum of 4–6 weeks is usually recommended [ 1 , 2 ]. These patients experience an initial period which involves a high risk of complications, such as heart failure, perivalvular extension or systemic embolism. Then, patients should remain hospitalized during this period, usually for 10 to 21 days, according to the clinical condition and the infection characteristics [ 9 ]. Thereafter, the only reason for remaining hospitalized is to receive intravenous antibiotic therapy [10,11]. At this point, there are several alternatives for outpatient continuation treatment. Oral antibiotic therapy has been explored and strengthened by recent promising results [ 12 , 13 ]. Nevertheless, despite being an attractive alternative that should be contemplated, there is still a lack of solid evidence supporting a specific oral antibiotic regimen for E. faecalis IE continuation regimen. Another option in this scenario is outpatient parenteral antibiotic therapy programs (OPAT), which provide an opportunity for discharge, with well-known benefits for both the health-care systems and the patients [ 11 , 14 ]. Recommendations for patient’s requirements and antibiotic selection have been previously published, the latter being determined by the OPAT model and the pharmacokinetic drug’s properties, but also by solution’s stability and safety drug’s profile [ 11 , 14 , 15 ]. E. faecalis IE treatment via OPAT has not been usually recommended [ 10 , 14 – 17 ], and sometimes even discouraged [ 11 , 18 ]. Nevertheless, evidence supporting E. faecalis IE continuation treatment through OPAT has grown lately, including a variety of antibiotic options, with favorable results [19–25]. The purpose of this systematic review is to identify, critically appraise and synthesize the evidence from studies reporting different strategies appropriated for outpatient continuation therapy for E. faecalis IE. 2. Results 2.1. Search Results The chosen search strategy resulted in a total of 320 articles. Additionally, 11 records were identified through reference and citation searching of the included papers. From this selection, we reviewed 55 potentially eligible full-text articles, based on title and abstract evaluation. Following an in-depth reading, a total of 18 articles were finally included in this systematic review (Figure 1). Antibiotics 2020,9, 657 3 of 17 Antibiotics 2020, 9, x FOR PEER REVIEW 3 of 19 Figure 1. Study selection flowchart. 2.2. Overview of the Studies As shown in Table 1, the study designs of the 18 selected articles included randomized clinical trials (n = 1) [12], non-randomized clinical trials (n = 1) [26], prospective cohort studies (n = 2) [27,28], retrospective cohort studies (n = 9) [20,22,23,29–34] and case series studies (n = 5) [19,21,24,25,35]. Only 10 of them analyzed more than one treatment option [12,20,23,27–33]. The study clinical settings were outpatient (n = 4) [19,24,25,34], inpatient (n = 9) [26–33,35] and mixed (n = 5) [12,20–23], and the therapy indication included continuation therapy in nine studies [12,19–25,34]. The majority of studies included left- and right-sided endocarditis, with the exception of three studies treating only left-sided IE [12,28,33]. There were large variations regarding the follow-up period after the ending of the antimicrobial therapy, ranging between no follow-up [20] and one year after [29,30,33,34]. Mortality was the most common outcome measure, being described in all articles, while relapse incidences were reported in 13 studies [12,19,22–27,29–31,33,34] and treatment failure in only 11 studies [12,19–22,25,27,29–32]. Two articles presented data from the same study population; nevertheless, both were included because different aims and outcomes were assessed [26,27]. 2.3. Quality of the Studies The methodological quality of the studies included in this review was variable. Five studies were evaluated as good quality or low risk of bias, 11 studies were assessed as having some concerns or moderate risk of bias and 2 studies were reported as poor quality or serious risk of bias. The detailed results for the risk of bias assessment are summarized in Table 2. 2.4. Therapeutic Alternatives The therapeutic alternatives identified in the articles were grouped into six categories corresponding with the main antibiotic used. The study details are summarized in Table 1. Figure 1. Study selection flowchart. 2.2. Overview of the Studies As shown in Table 1, the study designs of the 18 selected articles included randomized clinical trials (n=1) [ 12 ], non-randomized clinical trials (n=1) [ 26 ], prospective cohort studies (n=2) [ 27 , 28 ], retrospective cohort studies (n=9) [ 20 , 22 , 23 , 29 – 34 ] and case series studies (n=5) [ 19 , 21 , 24 , 25 , 35 ]. Only 10 of them analyzed more than one treatment option [ 12 , 20 , 23 , 27 – 33 ]. The study clinical settings were outpatient (n=4) [ 19 , 24 , 25 , 34 ], inpatient (n=9) [ 26 – 33 , 35 ] and mixed (n=5) [ 12 , 20 – 23 ], and the therapy indication included continuation therapy in nine studies [ 12 , 19 – 25 , 34 ]. The majority of studies included left- and right-sided endocarditis, with the exception of three studies treating only left-sided IE [ 12 , 28 , 33 ]. There were large variations regarding the follow-up period after the ending of the antimicrobial therapy, ranging between no follow-up [ 20 ] and one year after [ 29 , 30 , 33 , 34 ]. Mortality was the most common outcome measure, being described in all articles, while relapse incidences were reported in 13 studies [ 12 , 19 , 22 – 27 , 29 – 31 , 33 , 34 ] and treatment failure in only 11 studies [ 12 , 19 – 22 , 25 , 27 , 29 – 32 ]. Two articles presented data from the same study population; nevertheless, both were included because different aims and outcomes were assessed [26,27]. 2.3. Quality of the Studies The methodological quality of the studies included in this review was variable. Five studies were evaluated as good quality or low risk of bias, 11 studies were assessed as having some concerns or moderate risk of bias and 2 studies were reported as poor quality or serious risk of bias. The detailed results for the risk of bias assessment are summarized in Table 2. 2.4. Therapeutic Alternatives The therapeutic alternatives identified in the articles were grouped into six categories corresponding with the main antibiotic used. The study details are summarized in Table 1. Antibiotics 2020,9, 657 4 of 17 2.4.1. Aminoglycosides Based Regimens The clinical outcomes of E. faecalis IE patients treated via an initial therapy with a gentamycin-based regimen were evaluated in six studies, comprising 343 episodes, none of which were in OPAT [ 27 – 31 , 33 ]. The main combination employed was ampicillin 2 g each 4 h plus gentamicin 3 mg/kg/day during 4–6 weeks of treatment, although vancomycin and penicillin G were alternatives to ampicillin in two cases [ 28 , 33 ]. Among the studies, adverse events rates were high, even superior to 40% [ 27 , 30 , 31 ], mostly due to renal toxicity. On the other hand, relapse and mortality rates oscillated between 3% and 11% and 17% and 35% respectively, after 6–12 months of minimal follow-up. One study limited patient inclusion based on IE type [ 33 ]. This study compared the efficacy and safety of short (2 weeks) and long (4–6 weeks) treatment with gentamycin 3 mg/kg/day combined in both cases with 4–6 weeks of ampicillin or penicillin. Renal toxicity observed was significantly lower when the gentamycin short-course was used irrespective of clinical efficacy, which remained similar in both groups (69% vs. 66% of 1 year event-free survival). Likewise, Fernandez-Hidalgo et al. [ 31 ] analyzed a large cohort of patients treated with ampicillin plus gentamycin for 4–6 weeks, in which the overall mortality after a median follow-up of 11 months was 25% and the side effects reported were 44%. 2.4.2. Dual β-Lactam Regimens Nine studies gathered clinical results about 337 E. faecalis IE episodes treated with dual β -lactam therapy [ 19 , 20 , 24 – 27 , 29 – 31 ], three of which were conducted in OPAT, and then collected data from 11 patients [ 19 , 24 , 25 ]. The follow-up comprised six months (n=6), three months (n=1), and another study referred no follow-up after treatment ending. The most common combination assessed was ampicillin 2 g each 4 h plus ceftriaxone 2 g each 12 h for 4–6 weeks as an initial therapy [ 26 , 27 , 29 – 31 ]. However, one study [ 19 ] adjusted it to their OPAT program, administering ceftriaxone 4 g in single daily dose, and another one [ 20 ] administered ampicillin at a dose of 2 g each 6 h. Two studies proffered penicillin G as an alternative to ampicillin in a small cohort (n=7) without any deaths or relapses [ 24 , 25 ]. Embracing all data reported, the mortality rate was between 20% and 30% in four studies [ 26 , 27 , 29 , 31 ], and lower than 20% in another four [ 19 , 24 , 25 , 30 ]. Only one study reported a mortality rate higher than 30% [ 20 ], maybe related to the lower dose of ampicillin administered. Regarding toxicity, the highest adverse events rate was reported by Pericas et al. [ 27 ], showing 34% of renal failure in the cohort, although only 3% of discontinuation due to toxicity. Suzuki et al. [ 24 ] described adverse effects in one of the four patients reported (25%), while the percentage of adverse events reported was lower than 20% in the other seven studies [ 19 , 20 , 25 , 26 , 29 – 31 ]. In the largest cohort evaluated in the field [ 31 ] (n=159), the overall mortality rate was 26%, along with a low adverse events rate (9%), despite poorer general conditions than in the comparator group. Across the studies, the main conclusion was that dual β -lactam therapy with ampicillin is a primary option for E. faecalis IE, while penicillin G could be an alternative. 2.4.3. Teicoplanin-Based Regimens A total of 56 patients treated with teicoplanin were reported [ 22 , 23 , 35 ], most of them (89%) as continuation or salvage therapy. Two studies compromised episodes treated in OPAT [ 22 , 23 ]. The largest study conducted embraced the use of monotherapy with teicoplanin for treating E. faecalis IE as continuation therapy. The reported mortality related to IE was low (8%), but the population treated with teicoplanin suffered from less severe IE than the standard therapy group [23]. Overall, the dose regimens were highly variable among the studies. Two of them introduced a loading dose, but the mean maintenance dose varied between 5.8 and 10 mg/kg/day [ 22 , 23 ], while in the other one, fixed doses were used [ 35 ]. 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. The comprehensive conclusion of the studies was that teicoplanin could be an alternative for the sequential treatment of this syndrome. Antibiotics 2020,9, 657 5 of 17 Table 1. Summary of the results. Ref Study Design/Setting Endocarditis Type and Definition Follow-Up Period Dose Regimen EFIE/Total Patients Surgical Treatment Adverse Events Clinical Outcomes Key Finding Mortality Relapses Others Aminoglycoside based regimen [28] Prospective cohort study with comparator/Inpatient LS-NVE 28/43 LS-PVE 15/43 Modified Duke criteria 6 months Initial therapy A/V plus G 43/149 26/43 (60.5%) ND Overall 15/43 (35%) In hospital 6/43 (14%) ND Days of bacteriemia 3.0 (1.5–5.0) b High-dose daptomycin may be a valid alternative to standard therapy for left-side E. faecalis IE [29] Retrospective cohort study with comparator/Inpatient NVE 9/9 Modified Duke criteria 1 year Initial therapy A 2 g/4 h plus G 3 mg/kg/day for 4 weeks 9/9 2/9 (22.2%) 2/9 (22%) 1-year 3/9 (33%) In hospital 3/9 (33%) 1/9 (11%) Discontinuation of AB therapy 2/9 (22%) The suitability of a short course of antibiotic treatment for uncomplicated E. faecalis IE should be readdressed. NVE 14/23 PVE 9/23 Modified Duke criteria Initial therapy A 2 g/4 h plus G 3 mg/kg/day for 6 weeks 23/23 14/23 (60.8%) 2/23 (8%) 1-year 7/23 (30%) In hospital 6/23 (26%) 1/23 (4%) Discontinuation of AB therapy 9/23 (39.1%) [33] Retrospective cohort study with comparator/Inpatient LSE ND 1 year Initial therapy PG/A for 4–6 weeks plus G 3 mg/kg/day for 2 weeks 43/43 15/43 eGFR change −1 (−13 to 4) b mL/min In hospital 2/43 (5%) 2/43 (5%) 1 year evento-free survival 27/43 (69%) G treatment for 2 weeks, rather than 4–6 weeks, seems adequate and preferable in susceptible E. faecalis IE Initial therapy PG/A plus G 3 mg/kg/day for 4–6 weeks 41/41 14/41 (34.1%) eGFR change −11(−25 to−3) b mL/min In hospital 4/41 (10%) 3/41 (7%) 1 year evento-free survival 27/41 (66%) [30] Retrospective cohort study with comparator/Inpatient All types (ND) Modified Duke criteria 1 year Initial therapy A 2 g/4 h plus G 3 mg/kg/day for 4–6 weeks 67/67 24/67 (35.8%) 20/67 (66%) 1-year 11/67 (17%) 3 months 9/67 (14%) 1/67 (3%) Fail to complete therapy 30/67 (49%) AC is a safe alternative to AG for treating E. faecalis IE [27] Retrospective cohort study with comparator/Inpatient NVE 20/30 PVE 9/30 CDRE 1/30 Modified Duke criteria 392 (118.5–792.0) bdays Initial therapy A 2 g/4 h plus G 3 mg/kg/day for 4–6 weeks 30/30 15/30 (50%) Renal failure 19/30 (64%) 1-year 9/30 (30%) In hospital 8/30 (27%) 2/30 (3%) Discontinuation due to toxicity 13/30 (43%) The efficacy of 6 weeks treatment with AC appears similar and safer than 4–6 weeks treatment with AG [31] Prospective cohort study with comparator/Inpatient NVE 57/87 PVE 30/87 Modified Duke criteria 11.1 (4.4–22.5) b months Initial therapy A 2 g/4 h plus G 3 mg/kg/day for 4–6 weeks 87/87 35/87 (40.2%) 38/87 (44%) Overall 22/87 (25%) During treatment 8/87 (21%) 3/87 (3.4%) Treatment change 2/87 (2%) AC combination was as effective as AG, with less adverse events. Dual β-lactam regimens [20] Retrospective cohort study with comparator/Inpatient and outpatient LS-NVE 10/21 LS-PVE 9/21 RSE 2/21 Modified Duke criteria During antibiotic therapy Initial treatment A 2 g/6 h +C 2 g/12 h 21/21 4/21 (19%) 0% 9/21 (43%) ND Treatment change 0/21 (0%) Days of bacteraemia 1 (1–6) b Daptomycin treatment for enterococcal endocarditis lead to worse outcomes than AC therapy [19] Case series study without comparator/Outpatient LS-NVE 4/4 ND 365 (221–406) b days Continuation therapy A 2 g/4 h plus C 4 g/24 h for 6 weeks antibiotic therapy 4/4 3/4(75%) 0/4(0%) 0/4 (0%) 0/4(0%) Treatment change 0/4(0%) A high single daily dose of C plus A could be an option as a continuation therapy in an OPAT program for E. faecalis IE. Antibiotics 2020,9, 657 6 of 17 Table 1. Cont. Ref Study Design/Setting Endocarditis Type and Definition Follow-Up Period Dose Regimen EFIE/Total Patients Surgical Treatment Adverse Events Clinical Outcomes Key Finding Mortality Relapses Others [29] Retrospective cohort study with comparator/Inpatient NVE 14/14 Modified Duke criteria 1 year Initial therapy A 2 g/4 h plus C2g/12 h for 4 weeks 14/14 3/14 (21.4%) 2/14 (14%) 1-year 3/14 (21%) In hospital 2/14 (14%) 2/14 (14%) Discontinuation of AB therapy 1/14 (7.1%) The suitability of a short course of antibiotic treatment for uncomplicated EFIE should be readdressed. NVE 14/32 PVE 18/32 Modified Duke criteria Initial therapy A 2 g/4 h plus C2g/12 h for 6 weeks 32/32 14/32 (43.7%) 1/32 (3%) 1-year 8/32 (25%) In hospital 8/32 (25%) 0/32 (0%) Discontinuation of AB therapy 1/32 (3.1%) [30] Retrospective cohort study with comparator/Inpatient All types (ND) Modified Duke criteria 1 year Initial therapy A 2 g/4 h plus C2g/12 h for 4–6 weeks 18/18 3/18 (16.6%) 1/18 (20%) 1-year 3/18 (17%) 3 months 3/18 (17%) 1/18 (14%) Fail to complete therapy 5/18 (28%) AC is a safe alternative to AG for treating E. faecalis IE [27] Retrospective cohort study with comparator/Inpatient NVE 25/39 PVE 13/39 CDRE 1/39 Modified Duke criteria 392 (118.5–792.0) bdays Initial therapy A 2 g/4 h plus C2g/12 h for 4–6 weeks 39/39 15/39 (39%) Renal failure 13/39 (34%) In-hospital 9/39 (23%) 1-year 10/39 (26%) 3/39 (8%) Discontinuation due to toxicity 1/39 (3%) The efficacy of 6 weeks treatment with AC appears similar and safer than 4–6 weeks treatment with AG [31] Prospective cohort study with comparator/Inpatient NVE 98/159 PVE 59/159 CDRE 2/159 Modified Duke criteria 11.1 (4.4–22.5) b months Initial therapy A 2 g/4 h plus C2g/12 h for 4–6 weeks 159/159 53/159 (33.3%) 14/159 (9%) Overall 42/159 (26%) During treatment 35/159 (22%) 3/159 (1.8%) Treatment change 2/159 (1%) AC combination was as effective as AG, with less adverse events. [26] Non randomized clinical trial without comparator/Inpatient All types(ND) Modified Duke criteria 3 months Initial therapy A 2 g/4 h plus C2g/12 h for 42 (5–48)bdays 43/43 7/43 (16.3%) 2/43 (4.6%) Overall 12/43 (28%) During treatment 10/43 (23%) 2/43 (4.6%) ND AC may be a treatment option for E. faecalis endocarditis [24] Case series study without comparator/Outpatient NVE 3/4 PVE 1/4 Modified Duke criteria 6 months Continuation therapy PG 24 million U PC/24 h plus C 2 g/12 h for 6–8 weeks antibiotic treatment 4/4 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) ND PG plus C would be effective in the treatment of E. faecalis IE [25] Case series study without comparator/Outpatient ND 3 months PG 18–24 million U PC/24 h plus C 2 g/12 h for 6 weeks antibiotic therapy 3/3 ND 0/3 (0%) 0/3 (0%) 0/3 (0%) Treatment change 0/3 (0%) PG plus C maybe an alternative for the treatment of E. faecalis IE Teicoplanin based regimens [22] Retrospective cohort study without comparator/ Inpatient and outpatient NVE 16/22 PVE 5/22 Non valvular E 1/22 Modified Duke criteria 3 months Firstline (1/14) Salvage therapy (13/14) LD +10 (10–10.8) b mg/kg/day for 43.5 (38.8–56.3) days b 14/22 3/14 (21.4%) 2/14 (14%) During treatment 1/14 (7.1%) 3 months 2/14 (14%) 0/14 (0%) Treatment change 2/14 (14%) Teicoplanin can be used in E. faecalis IE as a sequential treatment [23] Retrospective cohort study with comparator/Inpatient and outpatient NVE 21/37 PVE 16/37 Modified Duke criteria 783 (126–1227) b days Continuation therapy LD + 5.8 mg/kg/day 39 (25–34) b days antibiotic therapy 37/37 11/37 (30%) ND Global 14/37 (38%) IE-related 3/37 (8%) 3/37 (8%) Patients who did not die from E. faecalis IE or experience relapses 33/37 (89%) Teicoplanin sequential treatment appears to be effective in selected patients [35] Case series study without comparator/Inpatient All type ND 6 months Initial therapy 600 mg/day for 5–6 weeks 5/26 ND ND 0/5 (0%) ND ND Teicoplanin initial treatment was effective for E. faecalis IE Antibiotics 2020,9, 657 7 of 17 Table 1. Cont. Ref Study Design/Setting Endocarditis Type and Definition Follow-Up Period Dose Regimen EFIE/Total Patients Surgical Treatment Adverse Events Clinical Outcomes Key Finding Mortality Relapses Others Daptomycin based regimens [20] Retrospective cohort study with comparator/Inpatient and outpatient LS-NVE 4/6 LS-PVE 1/6 CDRE 1/6 Modified Duke criteria During antibiotic therapy Initial therapy (1/5) Salvage (4/5) 8.5 (6–10) mg/kg/day 5/6 3/6 (50%) 0% 1/6 (16.7%) ND Treatment change 4/5 (80%) a Days of bacteriemia 6 (1–13) b Daptomycin treatment for enterococcal endocarditis lead to worse outcomes than AC therapy [28] Prospective cohort study with comparator/Inpatient LS-NVE 7/9 RS-NVE 2/9 Modified Duke criteria 6 months Initial (8/9) or salvage (1/9) 8.3 (7.1–9.4) bmg/kg for 28.5 (22.0–42.5)balone or in combination 9/29 4/9 (44.4%) 0/9 (0%) Overall 2/9 (22%) In-hospital 1/9 (11.1%) ND Days of bacteriemia 2.0 (1.5–3.0) b High-dose daptomycin may be a valid alternative to standard therapy for left-side E. faecalis IE [32] Retrospective cohort study with comparator/Inpatient NVE 8/12 PVE 4/12 Modified Duke criteria 30 days First-line or salvage therapy with daptomycin-based regimen 10.125 (8–12) b mg/kg for 45 ±21.1 days 12/16 7/16 (43.7%) ND 30-days 0/12 (0%) 2/12 (0%) Treatment failure 0/12 (0%) Daptomycin could be an alternative treatment option for enterococcal NVE and PVE. Dalbavancin based regimen [21] Case series study without comparator/Inpatient and outpatient NVE 3/4 PVE 1/4 Modified Duke criteria 6 months Initial, salvage or continuation therapy LD (1000–1500 mg) plus 500–1000 mg once or twice weekly for 1 to >6 weeks 4/27 ND 0/4 (0%) 1/4 (25%) ND Treatment failure 1/4 (25%) Dalbavancin is effective and safe for prolonged treatment. [34] Retrospective cohort study without comparator/Outpatient NVE 2/3 PVE 1/3 Modified Duke criteria 1 year Continuation therapy 500–1500 mg between 1 and 4 doses 3/34 12/34 0/3 0/3 0/3Cure of infection 3/3 Dalbavancin is an effective consolidation antibiotic therapy in clinically stabilized patients with IE Oral therapy [12] Randomized clinical trial with comparator/Outpatient LSE Modified Duke criteria 6 months Continuation therapy with oral antibiotics with amoxicillin alone or plus moxifloxacin/ linezolid/rifampicin/ ciprofloxacin or moxifloxacin plus linezolid for 17 (14–25) days b 51/201 15/51 (29.4%) 10/201 (5%) All-cause 1/51 (1.9%) 3/51 (5.8%) AB route change 4/201 (1.9%) Composite endpoint c 4/51 (7.8%) Continuation therapy with oral antibiotics is non-inferior than intravenous therapy Legend—AB: Antibiotic. Ref: Reference. LD: Loading dose. A: Ampicillin. C: Ceftriaxone. G: Gentamycin. PG: Penicillin G. V: Vancomycin. All-type endocarditis included left-side (LSE) and right-side endocarditis (RSE), native (NVE) or prosthetic (PVE) valve endocarditis and cardiac device-related endocarditis (CDRE). ND: No data. a All changes in the daptomycin group were due to treatment failure. b [median (range)]. c Composite endpoint: all-cause mortality, unplanned cardiac surgery, clinically evident embolic events, or relapse of bacteremia. Antibiotics 2020,9, 657 8 of 17 Table 2. Quality assessment of the studies. Study Risk of Bias Due To Tool Confounding Selection of Participants Classification of Interventions Deviations from Intended Interventions Missing Data Measurement of Outcomes Selection of the Reported Result Overall Bias [20] Robins S L L M L M M S [21] S L L S M M L S [22] M L L L L L L M [23] M L L L M L M M [29] M L L NI L M M M [33] M L L L L L L M [28] M L L L NI L L M [30] M L L M L L L M [27] M L L M L L L M [26] L L L NI L L L L [31] M L L M L L L M [32] M L M NI NI L L M [34] M L M NI L L L M Study Tool Randomization Process Deviations from Intended Interventions Missing Data Measurement of Outcomes Selection of the Reported Result Overall Bias [12] ROB-2 L SC L L SC SC Study Tool Study Question Population Consecutive Cases Comparable Intervention Measurement of Outcomes Length of Follow Up Statistical Methods Results Overall [19] SQAT Y Y Y Y Y Y Y NA Y GOOD [35] Y Y NR Y Y Y Y NR Y GOOD [24] Y Y Y Y Y Y Y NA Y GOOD [25] Y Y Y Y Y N Y NA N POOR Legend: L =Low/M=Moderate/S=Serious/SC =Some concerns/Y=YES/N=NO/NA =Not applicable/NR =Not reported/NI=Not informed. Antibiotics 2020,9, 657 9 of 17 2.4.4. Daptomycin Based Regimens E. faecalis IE treatment with daptomycin was assessed in 3 studies, including 26 patients [ 20 , 28 , 32 ]. The treatment scheme was considerably heterogeneous, included initial and salvage therapy, monotherapy and combine 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 [ 28 ] attained more than a one-month follow-up. Ceron et al. [ 20 ] included OPAT treatment and described the salvage treatment of 5 E. faecalis IE episodes, of which four needed a treatment change due to treatment failure. So, the stated final conclusions differed, with two supporting daptomycin as an alternative treatment in this scenario [ 28 , 32 ], and one showing some concerns [20]. 2.4.5. Dalbavancin Regimens Two articles [ 21 , 34 ] disclosed the outcomes of seven E. faecalis IE patients treated with dalbavancin, six (86%) with OPAT. The dosage regimen and length of the therapy encompassed single and multiple variable doses for 1 to more than 6 weeks. In these cohorts, six patients were successfully treated with dalbavancin in OPAT, hence it was proposed as an alternative. 2.4.6. Oral Therapy Oral therapy has been evaluated in one large randomized clinical trial [ 12 ]. This study comprised 400 left-side IE episodes, but it should be noted that only 20% of patients screened were included. Among them, continuation treatment with outpatient oral therapy and inpatient intravenous therapy were settled on in 201 and 199 patients, respectively. In total, 51 E. faecalis left-side IE episodes were enclosed in the oral arm. The mean time from diagnosis until the beginning of continuation of oral therapy was 17 days. High variability was shown among the antibiotic selection against E. faecalis, with six different regimen options used. Amoxicillin was part of the treatment in 90% (46/51) of these oral regimens given. The primary outcome was a composite endpoint that encompassed all-cause mortality, unplanned cardiac surgery, clinically evident embolic events or relapse of bacteremia. Considering patients with IE caused by E. faecalis treated with oral therapy, it occurred in four (7.8%), comprising only one death (1.9%). 3. Discussion This review included treatment alternatives for E. faecalis IE suitable for the outpatient setting, including oral or OPAT treatment. To this end, little evidence was found to support optimal continuation treatment. In fact, outpatient treatment of these patients has been a matter of discussion, and there is no consensus regarding patient and treatment selection [ 9 ]. To the best of our knowledge, there is no previous work summarizing the current evidence related to E. faecalis IE treatment appropriate for outpatient care. The two main findings were the lack of randomized clinical trials and large observational studies, and the heterogeneity regarding methodology and follow-up period among the included studies. Despite this, the alternatives analyzed in this review provided a wide view on the outpatient continuation treatment for this infection. On the one hand, the use of aminoglycosides to synergize with cell wall-active agents in the initial treatment of E. faecalis IE has been the first choice treatment for decades, in defiance of the high rates of nephrotoxicity observed [ 1 , 2 ]. Lately, doubts about its clinical utility have been raised [ 36 ]. This review included six studies in which this treatment option has been used as standard therapy [ 27 – 31 , 33 ]. That said, the toxicity of prolonged treatment, and the subsequent need for drug monitoring, have been obstacles for OPAT incorporation [ 10 ]. 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