New Antimicrobials and New Therapy Strategies for Endocarditis: Weapons That Should Be Defended

The overall low-quality evidence concerning the clinical benefits of different antibiotic regimens for the treatment of infective endocarditis (IE), which has made it difficult to strongly support or reject any regimen of antibiotic therapy, has led to a discrepancy between the available guidelines and clinical practice. In this complex scenario, very recently published guidelines have attempted to fill this gap. Indeed, in recent years several antimicrobials have entered the market, including ceftobiprole, ceftaroline, and the long-acting lipoglycopeptides dalbavancin and oritavancin. Despite being approved for different indications, real-world data on their use for the treatment of IE, alone or in combination, has accumulated over time. Furthermore, an old antibiotic, fosfomycin, has gained renewed interest for the treatment of complicated infections such as IE. In this narrative review, we focused on new antimicrobials and therapeutic strategies that we believe may provide important contributions to the advancement of Gram-positive IE treatment, providing a summary of the current in vitro, in vivo, and clinical evidence supporting their use in clinical practice.


Introduction
Infective endocarditis (IE) is a potentially lethal disease that always poses new diagnostic and therapeutic challenges.The yearly incidence is about 3-10 cases per 100,000 people, with an overall mortality of about 30% [1].In 2019, the estimated incidence of IE was 13.8 cases per 100,000 subjects per year, and IE accounted for over 66,000 deaths worldwide [2].The aetiological agents of IE can be Gram-positive or Gram-negative bacteria or, less frequently, fungi.Among them, Gram-positive staphylococci, streptococci, and enterococci represent 80-90% of all IE causes [3].
Notably, 2023 has been an incredible and singular year for scientific advancements in IE management, witnessing the proposal of new revised Duke criteria to help diagnose endocarditis [4] and the recent publication of the new official European guidelines for IE that update the old version published eight years ago [5,6].
Between the publication of the 2015 guidelines and the new ones, new antibiotic molecules such as ceftaroline, ceftobiprole, dalbavancin, and oritavancin were approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) to meet the needs of tailored therapy and, accordingly, new antibiotic strategies were investigated.Indeed, despite being approved for indications other than IE, real-world data on their use, alone or in combination, for the treatment of IE has accumulated over time, providing clinical evidence on their possible therapeutic benefits over traditional regimens [7][8][9][10][11].
Furthermore, these molecules are characterised by high bactericidal activity towards the majority of microorganisms that commonly cause IE and, most importantly, exhibit a high safety profile in comparison with glycopeptides, which still represent the recommended option for methicillin-resistant Staphylococci.Fosfomycin, an old antibiotic discovered in 1969, has gained renewed interest in this setting thanks to (i) its broad activity against both Gram-positive and Gram-negative pathogens, including resistant ones, (ii) its high anti-biofilm activity, and (iii) its ability to synergise with several antimicrobials.
After the publication of the 2015 guidelines, the only relevant published randomised clinical trial (BACSARM) on IE treatment explored the combination of daptomycin and fosfomycin for the treatment of S. aureus IE [10]; however, only a few IE cases were included (approximately 8-10% for each arm).
Given that the complexity of endocarditis renders it difficult to set up a randomised controlled clinical trial to investigate the efficacy and safety of new drugs and antibiotic strategies, the evidence from the literature comes almost exclusively from observational retrospective studies [12].Thus, the collection of clinical evidence concerning the efficacy and tolerability of new therapeutic strategies is highly needed to address the incertitude in the most recent guidelines and in current clinical practice [5].
Furthermore, the evolution of antibiotic therapy is moving more and more towards treatment individualization and shortening.In this context, the possibility of step-down oral treatments or replacement with long-acting antibiotics represent the new therapeutic frontiers in selected and eligible patients [13,14].
To build this narrative review, we focused on new antimicrobials and therapeutic strategies that we believe may provide important contributions to the advancement of Gram-positive IE treatment, providing a summary of the current in vitro, in vivo, and clinical evidence supporting their use in the clinical practice.Some of these strategies are also recommended in the new guidelines, such as the use of a combination of daptomycin and fosfomycin or ceftaroline for the treatment of staphylococci-or enterococci-induced IE [5].
Since several other antimicrobials retain fundamental roles in the treatment of IE caused, for instance, by streptococci or susceptible E. faecalis, our review does not aim to substitute these consolidated and effective regimens with the new drugs.Rather, we attempted to summarise the potential therapeutic weapons we currently possess for the treatment of IE, such as ceftaroline, ceftobiprole, fosfomycin, dalbavancin, and oritavancin, and their most relevant therapeutic associations.
We consciously decided not to include daptomycin alone in the new therapeutic strategies.Indeed, it has earned a place as an "established treatment" for IE in recent years, a role confirmed in recently published guidelines.

Materials and Methods
We discussed the main topics of the narrative review in several meetings.In the first round of discussion, the following topics were identified to be addressed in this review: (i) new antimicrobials and new strategies for the management of IE caused by the most common Gram-positive pathogens, which included: ceftobiprole, ceftaroline, dalbavancin, oritavancin in monotherapy, ceftobiprole or ceftaroline in combination with daptomycin, and fosfomycin in combination with ß-lactams or daptomycin; (ii) the in vitro activity and synergism of the new antimicrobials recognised; (iii) animal studies; (iv) clinical evidence concerning the efficacy of the selected antimicrobials, alone or in combination, in the treatment of IE due to Gram-positive pathogens.
Afterwards, we retrieved scientific evidence supporting the proposals of the review by means of a PubMed-MEDLINE literature search up to July 2023.The following search strategy and key terms were adopted: "endocarditis" or "infective endocarditis" or "bacteraemia" or "bloodstream infection" or "synergism" or "in vitro activity" or "experimental model" AND the name of each single antimicrobial were searched.The antimi-crobials searched were "ceftobiprole" or "ceftaroline" or "fosfomycin" or "dalbavancin" or "oritavancin".
We selected all available categories of articles, including randomised controlled trials (RCTs), multicentre or single-centre prospective observational studies, multicentre or singlecentre retrospective observational studies, case series, case reports, and in vivo/in vitro preclinical studies.
During the subsequent shared discussions, we reviewed the articles' relevance based on the authors' opinions and the quality of evidence, established according to a hierarchical scale of study designs.Guidelines, systematic reviews, and meta-analyses were also consulted to address our proposals.
We excluded abstracts or articles not written in English.We did not consider any timeline limitations, but we mainly focused our research on studies published in the last 10 years.
In the final round of discussion, the last version of the manuscript was approved by all authors.
BPR is currently approved by the European Medicines Agency (EMA) for the treatment of community-acquired pneumonia (CAP), non-ventilator-associated hospital-acquired pneumonia (HAP), and acute bacterial skin and skin structure infections (ABSSSIs), including diabetic foot infections.

Clinical Evidence in Infective Endocarditis
The evidence available in the literature concerning the use of BPR in IE consists of a double-blinded, randomised, controlled non-inferiority study and observational and retrospective studies, case series, and case reports [7,[35][36][37][38][39][40] (Table 1).improvement with resolution of all signs and symptoms of infection during BPR treatment or at the end of therapy.Microbiological cure was defined as negative follow-up blood cultures after the index-positive blood culture at some point during treatment and a negative valve culture in patients who underwent surgery.Notes: * all the ERADICATE study results were published at the end of September 2023 and were not included in the review.As for the results published in 2022, the study confirmed the non-inferiority of BPR compared to DAP.
The recent ERADICATE study, a randomised double-blind trial, compared the efficacy of BPR versus daptomycin ± aztreonam in the treatment of S. aureus bacteraemia (SAB) (n = 390), including ABSSSI, osteomyelitis, and native-valve IE (8.5%).Daptomycin (DAP) was administered at a dosage ranging from 6 mg/Kg to 10 mg/Kg q24h, while BPR was given at a dosage of 500 mg q6h from Day 1 to Day 8 and 500 mg q8h from Day 9 onwards, with dose adjustments according to renal function.The study showed the non-inferiority of BPR compared to DAP in terms of mortality rates, microbiological eradication, and the occurrence of new complications associated with bacteraemia (overall clinical success: 69.8% in BPR-regimen vs 68.7% in DAP-regimen) [39,41].
In a recent Italian multicentre observational study on the real-life use of BPR, seven cases of IE were described: two from MRSA and five from methicillin-resistant coagulasenegative staphylococci (MR-CoNS).BPR was always used in combination with DAP (n = 6) and linezolid (n = 1).In this study, only two out of seven patients with IE achieved clinical success, with a mortality rate of 28.6%, while overall microbiological and clinical success was obtained in 29% of patients [7].
Tascini et al. described the use of BPR in 12 patients with EI caused by Staphylococcus spp., including MRSA (n = 4).Three patients had polymicrobial IE.The majority of patients (83%) were switched to BPR due to the failure of previous antimicrobial regimens, mostly represented by DAP.BPR was administered in combination with DAP in 11/12 patients, while in one patient, BPR was administered as monotherapy.The cure rate was 83% (10/12 patients).Notably, the addition of BPR resulted in a rapid microbial clearance in all the three patients with persistently positive blood cultures under previous treatments [37].
Taking into account BPR's pharmacokinetic-pharmacodynamic (PK-PD) profile, its microbial activity against E. faecalis by means of a high level of enterococcal PBP saturation, its synergism in combination with amoxicillin, and its enhanced activity against biofilms, Giuliano et al. investigated the use of BPR in combination with ampicillin (AMP) in a case series of 21 patients hospitalised for infections due to E. faecalis, including IE (n = 13).Clinical success was reached in 81% patients, with a microbiological cure obtained in 86% of patients.In the EI subgroup, clinical and microbiological success was reached in 69% and 77% of patients, respectively [40].Experiences from case reports and case series in the literature also suggest the effectiveness of BPR as a monotherapy or as a combination regimen with DAP in achieving the microbiological eradication of MRSA EI [35,36,38].
Overall, we recorded 70 IE episodes caused mostly by Staphylococcus aureus (both methicillin-resistant and susceptible (MSSA)) and 13 cases of left-side IE due to AMP-S E. faecalis.The cases occurred in both native and prosthetic valves.Notably, the RCT ERADICATE included mostly right-sided IE.The outcomes were frequently favourable, with a good percentage of cases ending in microbiological and clinical cure.

Mechanism of Action and Indication
Ceftaroline (CPT) is an intravenous fifth-generation cephalosporin which inhibits the bacterial cell wall by irreversibly binding PBPs.As in the case of ceftobiprole, its molecular structure confers an increased binding affinity to PBP-2a, improving its activity against MRSA [42].CPT also exhibits in vitro activity against CoNS, streptococci (including S. pneumoniae and S. pyogenes), Moraxella catarralis, Haemophilus influentiae, and Gram-negative bacteria including Klebsiella spp.and Escherichia coli.Notably, the in vitro activity includes vancomycin-intermediate S. aureus (VISA) and cephalosporine-resistant S. pneumoniae [43].In contrast, CPT seems to have no activity against E. faecium and a variable activity against E. faecalis [44].
CPT is currently approved by the FDA and EMA for the treatment of ABSSSI and CAP caused by susceptible microorganisms including MRSA.It is also approved in case of ABSSSI and CAP with intercurrent bacteriemia due to susceptible microorganisms with caution in MRSA bacteriemia in course of CAP [63].

Clinical Evidence in Infective Endocarditis
Several studies investigating the treatment of bacteriemia due to MRSA consider CPT an option even in IE populations.However, the results in IE were often not reported or were discussed separately, although two multicentre observational retrospective studies and one case series reported results only for IE.Relevant clinical studies and case reports on the use of CPT in IE are summarised in Table 2.
Only one RCT enrolling patients with MRSA bloodstream infection (BSI) (n = 40) included IE (n = 7) and randomised patients in combination therapy with CPT + DAP (600 mg/8 h or adjusted for renal function) or DAP/VAN monotherapy.The IE patients were randomised as follows: three were in the combination group vs. four in the monotherapy group (3 VAN and 1 DAP).Overall, the study showed that combination therapy was associated with a significantly lower in-hospital mortality rate (0% vs. 26%; p = 0.029), which was also reflected in the IE subgroup; the excess mortality observed in the monotherapy arm during the interim analysis led the investigators to stop the study early [8].The study was a pilot clinical trial which did not reach an appropriate sample size; consequently, the results did not provide any strong evidence and no definitive conclusions could be drawn.
Brandariz-Nunez and colleagues described 70 IE cases caused by different pathogens (MSSA, MRSA, MS and MR CoNS, AMP-S E. faecalis, Streptococcus spp.), all of which were CPT in vitro susceptible, with a 30% overall in-hospital mortality rate and a 38.6% treatment failure ate at 42 days.CPT was used in combination, mostly with DAP, at a dosage of 600 mg every 8 h or 12 h (or adjusted based on renal function) [64].
The CAPTURE study, a multicentre observational retrospective cohort, reported 55 IE cases due to different Gram-positive bacteria, mostly MRSA (80%), with an overall clinical success of more than 70% and a high success rate when CPT was administered as a first, second, or later line therapy.CPT was used in 32 patients as a combination therapy, mostly with DAP or vancomycin (VAN) [65].
Three multicentre retrospective studies including patients with various Staphylococcal infections and treated with CPT both in combination or monotherapy reported data on IE patients' outcomes: clinical success was observed in 69.7% and 78% of cases in two studies [56,66], with mortality rates of 22.9%, 7%, and 11%, respectively [56,66,67].
Zasowski and colleagues observed in both MRSA BSI and IE populations that CPT monotherapy was not inferior to DAP in terms of composite failure, expressed in terms of 30 d mortality, persistent bacteraemia > 7 d, and 60 d BSI recurrence [68].
In a large multicentre retrospective study, there was no significant difference in terms of the mortality rate, hospital readmission, or BSI recurrence between combination therapy with DAP plus CPT (with no data reported on dosage) and the standard of care monotherapy (mostly VAN) in the treatment of 171 patients with MRSA BSI, of which 70 had IE [69].
While the majority of studies described the use of CPT in combination, mostly with DAP but also with VAN, some studies investigated CPT use in monotherapy versus combination therapy.In 2017, Zasowski [93] and colleagues showed no statistical differences in mortality, microbiological cure, and clinical success between CPT monotherapy [most common dose 600 mg (61.8%) and frequency every 8 h (58.4%)] and combination therapy in 126 patients with MRSA BSI included in the efficacy population group, with 31 cases of IE.Likewise, a recent study observed no statistically significant differences in the composite outcomes of inpatient infection-related mortality, 60 day readmission, and 60 day BSI recurrence in MRSA BSI patients treated only with combination therapy (DAP + CPT) versus de-escalation to monotherapy (DAP/CPT/VAN) after a start with DAP + CPT [94].
Overall, the safety profile of CPT seemed to be similar to that of other beta-lactams also used in prolonged treatment for IE.In a recent systematic review, authors found 9% (83 out of 933) of adverse events were related to the use of CPT, mostly gastrointestinal events, rashes, and neutropenia [95].In our review, we also found several cases of C. difficile infections, eosinophilia, and thrombocytopenia and a few cases requiring CPT withdrawal (Table 2).
Overall, we recorded 677 IE cases caused mostly by MRSA and involving both native and prosthetic valves (right and left sides) as well as CIEDs.The outcomes, when reported, were frequently positive, with microbiological and clinical cure.

Mechanism of Action and Indication
Dalbavancin (DAL) is a semisynthetic lipoglycopeptide derived from teicoplanin which is characterised by a unique PK profile with a prolonged half-life, lasting just over two weeks [96].Similar to glycopeptides, DAL binds the C-terminal D-alanyl-D-alanine motif of peptidoglycan, inhibiting wall biosynthesis [97].DAL exhibits excellent in vitro activity against the main Gram-positive pathogens, including vancomycin-susceptible enterococci, VanB E. faecalis, and VanB E. faecium, although it is inactive against VanAphenotype enterococci [98].This second-generation lipoglycopeptide exhibits potential penetration of and activity against the established biofilm produced by Gram-positive bacteria [99].
Currently, DAL is approved for ABSSSI in adults by the FDA and the EMA.Recently, the approval was extended to pediatric ABSSSI [104,105].In fact, the off-label application of this antibiotic in more deep-seated infections commonly caused by Gram-positive bacteria and requiring prolonged antimicrobial treatment is supported by an ever-growing body of evidence, and it can be used in conditions including osteomyelitis, prosthetic joint infections, endovascular device infections, BSI, and IE [96].

Clinical Evidence in Infective Endocarditis
The available evidence in the literature concerning the application of DAL in IE is still mainly represented by observational and retrospective studies, case series, and case reports.No prospective randomised trial is available yet.Moreover, many data are only available in aggregate form because IE cases were a subgroup of larger studied populations.DAL prescription has been reserved primarily for the consolidation or completion phase of treatment in patients with already cleared bacteraemia.Published relevant clinical studies and cases on the use of DAL in IE are summarised in Table 3.
In a two-year retrospective cohort study, 27 patients with Gram-positive IE received primary or sequential DAL.The majority (88.9%) were previously treated with another with another antimicrobial and gaining bacteremia clearance antimicrobial agent for bacteraemia clearance.DAL was administered as a twice-weekly regimen [1500 mg loading dose (LD), then 1000 mg] in 63.0% of cases, with a median duration of 6 weeks.Failure was described in one patient with incomplete surgical control of cardiac device-related MRSA IE who received 30 weekly DAL infusions.Importantly, all cases received at least one DAL dose in hospital, but 23 continued DAL as OPAT [14].
The Italian multicentric study DALBITA retrospectively enrolled 206 patients treated with DAL, of which six had IE.In the whole cohort, MRSA (32%), CoNS (29%), and methicillin-susceptible S. aureus (MSSA) (18%) were the most frequent isolates, and 77.8% of patients received prior therapy for a median of 15 days.Clinical success was recorded in 83.3% of the IE subgroup [106].[65,66].Clinical failure was defined as inadequate response or resistance to CPT therapy, worsening of the clinical conditions during the treatment, or new recurrent signs and symptoms at the end of CPT therapy [66].Microbiological success/cure was defined as a documented negative blood culture result or BC clearance.Duration of bacteraemia was calculated as the number of days between the first positive blood culture and the first negative blood culture without subsequent positive cultures.Bacteraemia recurrence was defined as at least one positive blood culture for MRSA after an initial microbiological cure.
Notes: § Clinical success was defined as BSI clearance and cessation of BSI signs and symptoms (i.e., fever and leukocytosis) by the end of therapy or discharge and living patients at hospital discharge; § § Clearance of bloodstream infection was defined as a series of two consecutive negative blood cultures.* Patients with persistent bacteraemia for ≥5 days or deemed to be failing clinically on the regimen selected by the randomization process.+MRSAB-related mortality was defined as death prior to blood culture clearance or within 2 weeks following blood culture clearance using the date of the first positive blood culture as Day 1.
• Treatment failure was defined as any of the following: (i) persistent signs and symptoms of infection at the end of CPT therapy; (ii) persistent MRSAB defined as >7 days; (iii) recurrent MRSAB after the end of CPT therapy; (iv) death that could be attributed to ongoing infection (defined as MRSA-positive blood cultures at the time of death, death occurring before resolution of the signs and symptoms of MRSAB, or autopsy finding indicating MRSA infection as a cause of death); and (v) adverse drug reaction requiring cessation of CPT treatment.# Treatment success was defined as the absence of microbiologic or clinical recurrence at least 6 weeks after the end of therapy; ## treatment failure was defined as recurrence of MRSA infection after completion of CPT therapy or death related to MRSA infection.
In a system-wide retrospective analysis of 56 people receiving long-acting lipoglycopeptides, five had IE.Forty received DAL, fourteen received oritavancin, and two received both, but the outcomes of the two agents were not distinguishable.The success rate was 100% among the three IE cases included in the success/failure analysis [107].
A national cohort included 19 IE cases (nine native valve and ten prosthetic) among 75 patients.In the whole cohort, the main isolates were S. aureus (51.4%) and CoNS (44.4%); prior therapy was received in 98.7% of cases.DAL dosing for IE was a 1500 mg single or double dose, with a cure rate of 72.2%.Here, DAL was largely used as a rescue treatment, justifying the high failure rate [108].
In a retrospective multicentre study on real-life DAL use, 25 out of 101 subjects had IE.All received other antimicrobials before DAL and 64% received concomitant antibiotics while on DAL.The success rate was 92% among IE patients [109].
DALBACEN is a multicentre retrospective Spanish cohort that included 124 elderly, predominantly male patients with major comorbidities who received DAL for IE (46.8% native valve, 43.6% prosthetic valve, and 9.6% pacemaker lead IE).CoNS (38.7%),MSSA (22.6%),E. faecalis (19.4%), and Streptococcus spp.(9.7%) were the most isolated pathogens.Almost all patients (98.4%) received prior antibiotic treatment for a median of 9.5 days, followed in 60.5% of cases by a second regimen for a median of 24.5 days.DAL usually represented a sequential or consolidation therapy in hospitalised patients, with a single 1500 mg dose being the most frequent regimen.Surgery was undergone in 45.9% of cases, usually before DAL.The main reason for prescription was to accelerate the rate of discharge (95.2%), resulting in a median fourteen-day reduction in hospital stay.Overall clinical success in patients who completed the one-year follow-up was 95.9% [9].
An observational study enrolled 22 patients treated with DAL after previous antimicrobials, of whom three had IE.Overall, S. aureus and CoNS were the most isolated pathogens, and the success rate was 95% [110].
A single-centre retrospective experience described 10 IE cases (three native valve, five prosthetic, and two CIED IE) mainly caused by staphylococci and enterococci.A median of 2.5 DAL doses were administered after at least 2 weeks of antimicrobials.Microbiological cure was obtained in 70% of cases, but long-term mortality was high (60%) and two patients relapsed [111].
Another retrospective analysis included 102 individuals, 14 (13.7%) of them with IE.All received antibiotics before DAL for a median of 18.5 days.S. aureus was isolated in 70.6% of cases.IE patients had a DAL LD of 1500 mg followed by a range of one to six 1500 mg doses.Overall, 93.7% reached clinical and microbiological success, and hospitalization was reduced by a median of 14 days (range 7-84) [112].
Several other studies investigated DAL in poorly compliant people with IE including homeless people, people who inject drugs (PWID), and people with alcohol disorders.In the majority of cases, patients were treated with previous intravenous antimicrobial regimens and were unsuitable for OPAT.Overall, the clinical success of DAL use was high, ranging from 66% to 100% [113][114][115][116][117][118][119][120].However, the number of patients lost at follow-up was not negligible.
Finally, several cases and case series have described prolonged DAL treatment in patients with IE, with conflicting results [121][122][123][124][125][126][127].Among the seven individuals with IE included in the study of real-life experience by Bouza et al., DAL was mainly used as a targeted therapy and only one failure was recorded [128].
Some authors reviewed the clinical efficacy of DAL for IE, with an overall success rate ranging from 68% to 95% [129,130], but acknowledged that most of the evidence came from retrospective studies and that there was a huge heterogeneity in the population included (PWID, cardiac device-related IE), the definition of outcomes, the quality of studies, the indications, and the dosing strategies.Notably, only three cases of DAL resistance were detected [96].Our search confirmed this landscape.
Overall, we analyzed 313 cases of IE treated with DAL (the most-used regimen was a 1500 mg single or repeated dose), caused mostly by S. aureus (with a slight predominance of MSSA), followed by CoNS.Native valves of the right side were predominantly involved but cases involving the left side, prosthetic valves, and CIEDs were reported as well.Previous antibiotic treatment before DAL was almost universal.Clinical and microbiological outcomes were generally positive although there was an elevated rate of patients lost to follow-up and the data are difficult to interpret because of high heterogeneity.

Mechanism of Action and Indication
Oritavancin (ORI) is a second-generation semisynthetic lipoglycopeptide with an extensive tissue distribution, a high binding affinity for plasma proteins, and a long terminal half-life (393 h).With its concentration-dependent bactericidal action, it disrupts the membranes of Gram-positive bacteria causing depolarization and inhibits the production of cell wall peptidoglycan by binding either to D-Ala-D-Ala or to D-Ala-D-Lac residues [131].This bactericidal action through multiple mechanisms is considered to confer a low probability of resistance development [130].ORI acts against streptococci, as well as S. aureus and S. epidermidis, regardless of susceptibility to methicillin.Differently from DAL and telavancin, ORI retains activity against both VanA-and VanB-phenotype enterococci.In addition, it is active against VISA and vancomycin-resistant S. aureus (VRSA) [132].
ORI maintains activity inside the biofilms of MSSA, MRSA, and vancomycin-susceptible and resistant enterococci [133].Notably, the activity of ORI is not limited to the extracellular environment but concentrates in lysosomes and effectively addresses pathogens persisting intracellularly, as occurs with the SCV phenotype [134].
In 2014 and 2015, ORI was approved by the FDA and EMA, respectively, for ABSSSI [140].Similar to DAL, given its optimal spectrum, tissue penetration, prolonged half-life, and side effect profile, ORI was explored for multiple off-label indications in invasive Gram-positive infections [141].

Clinical Evidence in Infective Endocarditis
Presently, data on ORI off-label use are limited, as shown in Table 4 [142].In the multicentre retrospective cohort studied by Morrisette et al., 40 patients were treated with DAL, 14 were treated with ORI, and two were treated with both.In the whole cohort, five people had IE; however, unfortunately, it is not possible to distinguish how many received ORI.The success rate was 100% among the three IE cases analyzed [107].
A multicentre retrospective analysis was conducted among four hospitals and several clinics.Out of 75 patients receiving ORI, four had IE.The most common pathogens were MSSA and MRSA, and 13.3% of the population were PWID.In the whole cohort, the main reasons for ORI use were IV-line placement avoidance (61.3%) and social/insurance barriers (46.7%).Three patients with IE achieved clinical cure, the fourth was readmitted due to chest pain during the second infusion, subsequently attributed to cocaine use [11].
A retrospective single-centre analysis was performed on a very complex population (100% PWID, 70% with psychiatric illness, 67% homeless) treated with ORI.Two out of 23 patients had tricuspid IE.The first patient had MSSA and received 30 days of prior therapy followed by a single 1200 mg ORI dose and obtained clinical cure.The second had MRSA IE and, after 47 days of inpatient treatment, received two 1200 mg doses of ORI one week apart, but was finally recorded as a clinical failure [143].Two single cases of IE treated with ORI reported clinical and microbiological success obtained after valve replacement surgery [144,145].In a case series, after inpatient antibiotic therapy, five PWID with IE (two due to MSSA, two due to MRSA, one due to group A/F Streptococcus) were selected for ORI due to active illicit drug use and risk for IV-line manipulation.Clinical success was achieved by three patients, while two were lost to follow-up [146]      Abbreviations: ABSSSI: acute bacterial skin and skin structure infection; AE: adverse event; BC: blood cultures; BSI, bloodstream infection; CIED: cardiovascular implantable electronic device; CoNS: coagulase-negative staphylococci; DAL: dalbavancin; IE: infectious endocarditis; IM: intramuscular; LD: loading dose; LVAD: left ventricular assist device; MRSA: methicillin-resistant S. aureus; MSSA: methicillin-susceptible S. aureus; N/A: not applicable; NVE: native valve endocarditis; OD: once daily; OPAT: outpatient parenteral antibiotic therapy; ORI: oritavancin; PVE: prosthetic valve endocarditis; PWID: people who inject drugs; SCV: small colony variant; SOC: standard of care.Definitions: Clinical cure/success was defined, unless otherwise specified, as resolution of clinical signs of infection; as absence of clinical signs of infection [107]; as no further evidence of infection or microbiological evidence of infection control (clearance of cultures) [106]; as improvement in lesions and resolution of signs and symptoms at end of treatment [105]; as completed treatment course without change or addition of antibiotic therapy, and with no additional antibiotics commenced within 48 h of discontinuation of the targeted antimicrobial therapy [109]; as no clinical, laboratory, or microbiological evidence of persistent or recurring infection during a 90 day follow-up [108]; as resolution of signs and symptoms of IE with negative BCs after end of therapy [110]; and as no need for additional therapy, and no additional positive cultures at 90 days [113].Microbiological cure was defined as a documented negative blood culture result or BC clearance, unless otherwise specified.Overall, we retrieved only 13 IE cases of various types that were treated with ORI 1200 mg single or repeated doses, which were caused by staphylococci for the most part and frequently affected people with reduced compliance.Results were commonly good.
3.5.Old Antibiotics with a Renewed Interest: Fosfomycin 3.5.1.Mechanism of Action and Indication Fosfomycin (FOS) is a broad-spectrum bactericidal agent, with activity against several Gram-negative and Gram-positive pathogens, that enters the bacterial cell through the L-alpha-glycerophosphate and the hexose-6-phosphate transporter systems and acts by interfering with the formation of the peptidoglycan precursor uridine diphosphate N-acetylmuramic acid (UDP-MurNAc) [147].This feature makes cross-resistance with other antibiotics highly uncommon [148].
Although discovered more than four decades ago, its use has only recently been repurposed for the treatment of severe infections caused by Gram-negative MDR [147,[149][150][151] or Gram-positive pathogens such as MSSA/MRSA and VRE, showing promising results in terms of clinical efficacy and safety [10,148,152].
Indeed, its unique mechanism of action, along with its high level of in vitro synergism and its extensive tissue distribution, even in difficult-to-reach areas, renders FOS a very promising combination partner for the treatment of several infections, including IE [147,148].
Studies investigating FOS in vitro synergisms and experimental models of IE are shown in Supplementary Material, Sections S5.1 and S5.2 .
Current drug indications for FOS, namely infections for which no other antibiotics may be recommended, include complicated urinary tract infections, IE, bone and joint infections, pneumonia, skin and soft tissue infections, intra-abdominal infections, and meningitis, with or without bacteraemia [178].

Clinical Evidence in Infective Endocarditis
Clinical experience concerning the possible role of FOS-containing combinations for the treatment of Gram-positive IE has accumulated over time.Translating from in vitro and in vivo experiments, the most studied combinations were DAP and FOS and imipenem and FOS (Table 5).
The first report concerning the combination of imipenem and FOS dates back to 1994 [179].Subsequently, Del Rio et al. performed a clinical trial including adults receiving appropriate antibiotic therapy for MRSA bacteraemia or IE but who needed imipenem and FOS as rescue therapy because of persistent bacteraemia, unacceptable side effects of antibiotics, or relapse.Among the 16 patients included, 12 suffered from IE. Overall, the primary outcome (defined as negative blood cultures 72 h after the first dose) was reached in all the patients, with no breakthrough episodes of MRSA bacteraemia and an overall clinical success rate of 91.6% [180].
In 2018, Pericas et al. performed an RCT comparing patients receiving imipenem and FOS with VAN for the treatment of MRSA BSI, among whom eight had IE (four in each regimen).The primary endpoint was persistent bacteraemia at seven days while secondary endpoints were the clearance of blood cultures at 72 h after the initiation of study treatment, relapse of bacteraemia, and mortality.Persistent bacteraemia was absent and blood cultures at 72 h were negative in all patients receiving imipenem and FOS, while cure rates were similar between the two regimens (4/8 vs. 3/7 imipenem and FOS vs. VAN, respectively) [181].
Subsequently, Pujol and colleagues performed an RCT comparing DAP (10 mg/kg/ 24 h) and FOS (2 g every 6 h) with DAP alone (10 mg/kg/24 h) for the treatment of MRSA BSI.Of the 155 patients included, 112 underwent echocardiography and 18/112 (11.6%) had left-side IE.Combination therapy achieved treatment success in a higher number of patients, although it was not statistically significant (54.1% vs. 42%).Notably, microbiological failure was significantly lower in the combination arm than in the monotherapy arm (0% vs. 11.1%).After stratification for patients with or without IE, no differences were observed.On the other hand, side effects were higher in patients receiving DAP and FOS than those receiving DAP alone [10].
A post hoc analysis of the INSTINCT prospective cohort study, including 578 patients with S. aureus bacteraemia, among whome 129 had IE, evaluated combination therapy with either rifampin (n = 242) or FOS (n = 58) versus monotherapy.The authors found that combination therapy was associated with a better outcome than monotherapy, and this was also observed in the subgroup of patients with IE.No differences between the rifampin of FOS combinations were observed for 90 day mortality [182,183].The DAP or VAN and FOS combination was also reported in the case reports and case series [184][185][186].
Overall, we analyzed 294 IE episodes, mostly caused by MRSA and treated mainly with FOS in combination with different ß-lactams or DAP/VAN.When the data were reported, the native or prosthetic valves of the left side were predominantly involved.Clinical and microbiological outcomes were generally positive, leading the DAP and FOS regimen to be included in the recent guidelines [5].Self-limited hypokalaemia Abbreviations: CIED-EI: cardiovascular implantable electronic device endocarditis; IE: infective endocarditis; FOS: fosfomycin; DAP: daptomycin; MRSA: methicillin-resistant S. aureus; MRSE: methicillin-resistant S. epidermidis; VAN: vancomycin; AMK: amikacin; IMI: imipenem; BC: blood culture; ITT: intention-to-treat; BSI: bloodstream infection; INSTINCT: invasive stapyhlococcus aureus infection; CohorT; SAB: S. aureus bacteraemia; MSSA: methicillin-susceptible S. aureus; FLU: flucloxacillin; TEC: teicoplanin; LNZ: linezolid; PVE: prosthetic valve endocarditis; MRSAB: methicillin-resistant S. aureus bacteraemia.Definitions: Clinical success was defined as clinical improvement with resolution of all signs and symptoms of infection during treatment or at the end of therapy unless otherwise specified.Notes: § : Treatment was classified as clinically successful when the patient was alive, lacked signs or symptoms of infection, and had sterile blood cultures at the test-of-cure visit.Failure was defined as death, positive blood cultures, or discontinuation of FOS plus IMI because of persistent bacteraemia or AEs; *: Between 2001 and 2005, all patients received VAN as initial therapy; this was continued, and FOS and IMI were added.After 2006, FOS and IMI were administered instead of the initial antibiotic regimen, which included either DAP at 6-10 mg/kg or VAN; • : Treatment success was considered when patient was alive and had resolution of clinical manifestations of infection and negative blood cultures at test-of-cure after completion of therapy; • • : Microbiological failure was considered in the case of persistent bacteraemia, recurrent bacteraemia, and the emergence of resistance to study drugs during treatment.

Oral Strategies
There has been great interest in oral step-down strategies for the treatment of IE; however, most of the evidence comes from old trials or retrospective and observational studies, with controversial results [187][188][189][190][191].
It is only with the recent multicentre unblinded non-inferiority POET trial that the longlasting paradigm of treating IE always (and only) with prolonged intravenous treatment has changed.Indeed, this trial was able to show that, in stable patients with Streptococcus spp., E. faecalis, S. aureus, or CoNS left-side IE, changing to oral antibiotics after an initial phase of at least 10 days of intravenous treatment was not inferior to continued intravenous antibiotic treatment [192].However, it should be noted that only 22% of the enrolled patients had S. aureus IE, only a small percentage of patients with IV drug use was included, and, although it was not an exclusion criterion, no patients with MRSA-IE or other antibioticresistant phenotypes were enrolled, rendering the results not fully generalizable.Among the several proposed schemes, the most commonly used during the trial were dicloxacillin or amoxicillin and rifampicin for S. aureus, linezolid and rifampicin or fusidic acid for CoNS, amoxicillin and linezolid or moxifloxacin for E. faecalis, and amoxicillin and rifampicin or moxifloxacin for streptococci [192].
The five-year follow-up of the same trial demonstrated that the composite primary outcome (defined as death from any cause, unplanned cardiac surgery, embolic events, and relapse of a blood culture result positive for the primary pathogen) occurred in 32.8% and 45.2% of step-down and continued intravenous treatment groups, respectively.Interestingly, this difference was mainly driven by a lower incidence of death from any cause in the first group, while no differences were observed for the other parameters of the composite outcome [193].
Taken together, these findings appear somehow reassuring concerning the potential role of oral step-down therapy for the treatment of selected and stable patients with left-side IE.
A recent published multicentre retrospective cohort confirmed this potential role, with no significant difference between the IV-only and oral groups in terms of clinical success at 90 days.Moreover, the oral group patients had significantly fewer adverse events.In this cohort, the most commonly used therapy was 600 mg of oral linezolid twice a day with or without rifampin [13].Focused on E. faecalis IE, a small case series proposed an interesting oral step-down combination therapy with amoxicillin/clavulanate and cefditoren [194].In a study published in 2009, the authors proposed an early switch from intravenous VAN to oral linezolid for the treatment of MRSA IE only after an aggressive surgical approach.This oral step-down showed a reduction in recurrences, hospitalization, and economic costs [195].
Possible oral strategies for the sequential step-down therapy are shown in Table 6.Additional results will be available after the completion of the RODEO trials, which will compare oral switch and intravenous antibiotic therapies in patients with staphylococcal and streptococcal/enterococcal left-sided IE (RODEO-1 and RODEO-2, respectively) [196].
Tedizolid phosphate (TDZ) is a second-generation form of oxazolidinone.Compared to linezolid, TDZ is administered once daily with less myelotoxicity and fewer drug-drug interactions.There is no clinical data on TDZ in human IE.Based on in vitro and in vivo activity, TDZ may be considered a possible agent for the treatment of IE only as a sequential therapy after IV treatment with other agents in patients not eligible for other regimens [197,198].Due to the lack of clinical evidence, no recommendation on its use for IE may be given and it remains a potential candidate without sufficient clinical evidence.Table 6.Possible oral strategies for sequential step-down therapy.The decision to use sequential step-down oral therapy must only be made if the patient is clinically stable, and the choice of drug regimen must always be based on the antimicrobial susceptibility of the bacteria isolated (adapted from [192]).

Bacteria
Oral

New Therapeutic Strategies: Considerations for Their Optimal Use in IE
IE is a major public health challenge associated with high morbidity and mortality [2].Recently released guidelines have introduced several updates regarding its prevention, diagnosis, and management [5].From a therapeutic point of view, by introducing the possibility of a step-down oral strategy in selected stable patients, the new recommendations divided the antibiotic treatment of IE into two phases: the first one (critical phase), which can last up to 2 weeks, includes in-hospital intravenous therapy using combinations of rapidly bactericidal antibiotics to destroy planktonic bacteria; after this period, selected clinically stable patients can end the antibiotic treatment at home with intravenous (OPAT) or oral antibiotic regimens for up to 6 weeks (continuation phase) [5].
Compared to the previous 2015 guidelines, the choice of antibiotics in the first phase has been expanded with the introduction of new molecules and combinations, including, among others, the combination DAP and FOS or CPT for MSSA and MRSA.As for the consolidation phase, weekly DAL schemes as an alternative to oral or OPAT strategies have been considered [5,6].
In the present manuscript, we reviewed the currently available in vitro, in vivo, and clinical evidence on the use of new beta-lactams (CPT, BPR), long-acting agents (DAL and ORI), and the repurposed drug FOS for their possible use in the treatment of IE.
As shown in Figure 1A, the evidence supporting the use of CPT and BPR (alone or in combination with DAP), FOS, and long-acting DAL and ORI for staphylococcal IE has accumulated over time [7,[9][10][11]14,39,65,68,182].Despite exhibiting pre-clinical evidence, the new beta-lactams and their associations with DAP have garnered less clinical evidence for MSSA IE, which has been limited to case series/case reports (shown as yellow or yellow/green colour, Figure 1A); this could be possibly explained by the strong efficacy of the currently recommended agents (i.e., cefazolin) [39,65].
In contrast, the combination of DAP and FOS has gained clinical evidence supporting its use thanks to the RCT by Pujol et al. (shown as green colour, Figure 1A).Likewise, for MRSA the combinations of DAP and FOS and DAP and CPT gained pre-clinical and clinical evidence supported by the RCTs by Pujol et al. and by Geriak et al., respectively, as well as by observational studies [8,10].Choosing one of these two regimens over the other should be based on several factors, including beta-lactam allergies, which favuor DAP and FOS, or the risk of exacerbating cardiac or renal failure with the sodium overload associated with FOS, a condition favouring DAP and CPT.
According to the promising results of the recent ERADICATE RCT, which included 20 patients with S. aureus IE, a green/yellow colour was attributed to BPR for S. aureus, similar to the evidence available for BPR and DAP (Figure 1A) [39].However, we believe that the use of BPR for the treatment of staphylococcal IE (alone or in combination with DAP) will increase over time.
As for the long-acting agents, so far, the majority of clinical evidence is available for DAL, especially with regard to MSSA and MRSA (shown as green colour, Figure 1A).Nevertheless, the most effective administration schedule is still not clear, since high variability is present in the literature concerning the number of dosages, their interval, and the duration of therapy [96].Consensus agreement in this setting is highly warranted.In contrast, ORI's clinical evidence for MSSA and MRSA is limited only to case reports/case series (shown as green/yellow colour, Figure 1A), probably due to its only recent introduction in the market [142].However, based on ORI in vitro activity towards these pathogens, it is likely that additional clinical evidence will accumulate in the coming years, positioning ORI as a potential additional therapeutic strategy in the treatment of IE.
Although supported by less clinical evidence than S. aureus, the same considerations mentioned above may be drawn for CoNS (Figure 1A).
Since strong and consolidated clinical evidence exists concerning the management of beta-lactam-susceptible E. faecalis and streptococcal IE, we only reviewed the available literature data on the potential use of new agents for IE.
As shown by Figure 1B, most of the evidence regarding CPT+/−DAP or the longacting drugs for streptococcal IE comes from evidence supported by in vitro activity, animal studies, and case reports/series (shown as yellow/green colour, Figure 1B), while, for BPR or beta-lactams and FOS, evidence is supported by in vitro activity and animal studies in the absence of clinical evidence for their effectiveness against streptococcal IE (shown as yellow colour, Figure 1B).As for E. faecalis IE, beta-lactams and FOS or CPT+/−DAP present poor in vitro data and no in vivo and clinical evidence and therefore are shown as yellow/red colour (Figure 1B).
Likewise, the combinations FOS or BPR and DAP for streptococcal IE present an absence of in vitro, animal, and clinical data (shown as red colour, Figure 1B).BPR in combination with ampicillin was investigated in a small series of E. faecalis IE cases, showing promising results [40] (shown as yellow/green colour, Figure 1B).
Much less knowledge has been gained concerning E. faecium or VAN-R enterococcal IE, where the currently available evidence only comes from in vitro and animal studies, while clinical evidence is still lacking (yellow/red or red colour, Figure 1B).In this regard, a recent study showed that the combination of high-dose daptomycin with FOS improved the survival rate of patients with VRE-BSI compared to daptomycin alone.However, only one case of IE was included, which was treated with DAP alone [152].Additional clinical evidence on the potential role of DAP and FOS in the setting of IE is therefore needed.
The only regimen whose evidence is supported also by clinical evidence is DAL for E. faecalis IE, which therefore may be considered as a possible strategy after the initial phase of in-hospital intravenous therapy when other options are not feasible and may be associated with cost-effectiveness and reductions in hospitalization lengths [9,110].Although active in vitro, ORI suffers from a lack or paucity (only case reports/case series) of clinical evidence concerning E. faecium and E. faecalis IE.However, similar to what we have hypothesised concerning staphylococcal IE, we believe that, as evidence accumulates, ORI will be an important therapeutic step-down regimen for enterococcal IE.Legend of color.Green: evidence supported by in vitro, animal, and preliminary clinical studies; Green-yellow lines: evidence supported by in vitro activity, animal studies, and case report series; Yellow: evidence supported by in vitro activity and animal studies but lacking clinical evidence; Legend of color.Green: evidence supported by in vitro, animal, and preliminary clinical studies; Green-yellow lines: evidence supported by in vitro activity, animal studies, and case report series; Yellow: evidence supported by in vitro activity and animal studies but lacking clinical evidence; Yellow-red lines: poor in vitro data, no in vivo data, no clinical data; Red: absence of in vitro, animal, and clinical data and/or no drug activity.

JFigure 1 .
Figure 1.(A).Summary of the available in vitro, in vivo, and clinical evidence for a possible place in therapy for new antimicrobial strategies for Staphylococcus spp.infective endocarditis.*: Other regimens recommended for the treatment of Staphylococcus spp.IE due to strong and consolidated clinical evidence are not shown in this figure but are discussed in the text; **: clinical evidence derives from randomised clinical trials [10].(B).Summary of available in vitro, in vivo, and clinical evidence for a possible place in therapy for new antimicrobial strategies for Streptococcus spp.and Enterococcus spp.infective endocarditis.*:Other regimens recommended for the treatment of Streptococcus and E. faecalis spp.IE due to strong and consolidated clinical evidence are not shown in this figure but are discussed in the text.** As for E. faecalis, the suggested green/yellow colour refers only to clinical evidence for BPR in combination with ampicillin.

Figure 1 .
Figure 1.(A).Summary of the available in vitro, in vivo, and clinical evidence for a possible place in therapy for new antimicrobial strategies for Staphylococcus spp.infective endocarditis.*: Other regimens recommended for the treatment of Staphylococcus spp.IE due to strong and consolidated clinical evidence are not shown in this figure but are discussed in the text; **: clinical evidence derives from randomised clinical trials [10].(B).Summary of available in vitro, in vivo, and clinical evidence for a possible place in therapy for new antimicrobial strategies for Streptococcus spp.and Enterococcus spp.infective endocarditis.*: Other regimens recommended for the treatment of Streptococcus and E. faecalis spp.IE due to strong and consolidated clinical evidence are not shown in this figure but are discussed in the text.** As for E. faecalis, the suggested green/yellow colour refers only to clinical evidence for BPR in combination with ampicillin.

Table 1 .
Clinical studies investigating the treatment of infective endocarditis with ceftobiprole.

Table 2 .
Clinical studies investigating the treatment of infective endocarditis with ceftaroline.

Table 3 .
Clinical studies investigating the treatment of infective endocarditis with dalbavancin.

Table 4 .
Clinical studies investigating the treatment of infective endocarditis with oritavancin.

Table 5 .
Clinical studies investigating the treatment of infective endocarditis with fosfomycin.