Beta Lactams Plus Daptomycin Combination Therapy for Infective Endocarditis: An Italian National Survey (BADAS)

Background: infective endocarditis (IE) remains a severe disease frequently encountered in clinical practice and often requiring interdisciplinary medical and surgical management. This national survey aims to describe the clinical prescribing habits of the use of daptomycin in the setting of IE and the possible role for combination therapy with beta-lactams. Methods: The study was a cross-sectional internet-based questionnaire survey on therapy with daptomycin. The questionnaire was designed with closed-ended questions and distributed using the SurveyMonkey® platform between October 2019 to December 2020. Results: 55 clinicians from twelve Italians regions joined the questionnaire. The survey reported use of daptomycin as first-line choice in 31.48% of cases and as the first-line anti-MRSA agent in 44.44%. The empiric use of daptomycin was stated in the high suspicion of MRSA rather than MSSA, enterococcal or streptococcal IE. The rationale of daptomycin for the empirical treatment of native and prosthetic valve IE was mostly the possibility of administering an aminoglycoside-sparing combination regimen, high bacterial killing rate and high clinical efficacy. Conclusions: In conclusion, in selected patients, daptomycin could be a feasible option for the treatment of infective endocarditis in line with data from the European registry of daptomycin.

Recently, the European Society of Cardiology (ESC) EURObservational Research Programme (EORP) implemented the European Endocarditis (EURO-ENDO) international registry, confirming the high prevalence of gram-positive microorganisms involved in both native and prosthetic valve endocarditis [6,7]: Staphylococcus spp., oral streptococci, Enterococcus spp., and Streptococcus gallolyticus are the most common pathogens in this registry [6,7]. Furthermore, the IE population has been transforming, with increasing incidence in elderly adults, highly comorbid patients and prosthetic heart valve cases [1][2][3]6,7]. IE populations often have multiple comorbidities, such as cardiovascular diseases, diabetes mellitus, cancer, and chronic liver and kidney diseases [1][2][3]6,7]. IE in this population requires effective and manageable therapies according to the frailty. Frail patients are characterized by high morbidity and mortality and puts the subjects at greater risk of developing adverse antibiotic effects [1][2][3]6,7].
Daptomycin, a lipopeptide antimicrobial with concentration-dependent bactericidal activity against gram-positive organisms, including antimicrobial-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), is approved for treating complicated skin and soft tissue infections [cSSSI], furthermore clinical experiences and preliminary data are increasing and are favourable to treating osteoarticular infections [8]. Daptomycin was originally found non-inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis at the daily dose of 6 mg/kg. [9]. Later on, Daptomycin was successfully used at median dose of 5.93 mg/kg for vancomycin-resistant Enterococcus spp. (VRE) bloodstream infections, and it has been recently used in the therapy of both left and rightsided IE [10][11][12]. Nevertheless, the use of standard dosing of 6 mg/kg once-daily has led to the emergence of resistant strains associated with clinical failures and, more recently, higher doses (8-12 mg/kg once daily) provided improved effectiveness in the treatment of Gram-positive endocarditis [10][11][12].
Considering daptomycin in IE treatment represents an option to encourage aminoglycoside and glycopeptide sparing strategy in order to avoid renal damage, especially in elderly comorbid population [12,13]. Moreover, daptomycin has been demonstrated safe and effective when vancomycin minimum inhibitory concentration (MIC) values rise above 1 mg/L obtaining faster clearance of bacteremia and lower rates of clinical failure [14] Observational and randomized controlled trials suggested the combination of daptomycin with a beta-lactam in patients with MRSA bacteremia [15][16][17][18] Nonetheless, a recent metanalysis including 1636 patients in this setting showing higher cure rates with the combination therapy failed to demonstrate a difference in mortality rates or renal damage because of the heterogeneity in the choice of the beta-lactam [19]. Finally, some uncertainty on the daptomycin combination therapy with beta-lactams remains in the contest of IE.
This national survey aims to describe the clinical prescribing habits of the use of daptomycin in the setting of IE and the possible role for combination therapy with betalactams.
A slightly higher use of daptomycin plus beta-lactams over monotherapy was recorded for enterococcal IE (18.52%; 10), and this combination was used, especially as a targeted therapy during hospitalization followed by oral de-escalation (35.85%; 19) and OPAT with the withdrawal of beta-lactams after discharge (26.42%; 14).

Discussion
Our survey aimed to explore the prescribing habits for the management of IE involving the use of daptomycin, with a particular interest in beta-lactam plus daptomycin combination therapy for IE, as prescribed by ID and internal medicine physicians in Italy between 2019 and 2020.
Respondents from different hospitals located in 13 regions covered homogeneous Italian territory (southern, central and northern Italy). Our results showed that respondents mainly worked within large (≥500 beds) university hospitals that frequently included an ICU and neuro/cardio-surgical unit, and they had access to ID consultants or antibiotic guidelines. The incidence of IE appeared to be low, and possibly, as a consequence, endocarditis teams were not widespread in our sample. Interestingly, cardiac-surgeons were largely available in hospitals from which we retrieved data, which may provide a window of opportunity to create endocarditis teams with a multidisciplinary and comprehensive approach, as suggested by current guidelines [1][2][3][4][5]. In fact, the benefit of an endocarditis team has been well established in reducing in-hospital and long-term mortality, improving antimicrobial therapy adherence and reducing deaths caused by embolic events and multiple organ failure. [1][2][3][4][5]20].
Empirical combination therapy was preferred over monotherapy as a starting regimen, regardless of native or prosthetic valve IE. Treatment duration was four to six weeks, with no difference regarding the surgical infection control culture-negative valve. This appears to be in line with IE guidelines [1,2]. Interestingly, almost all respondents considered vancomycin or an aminoglycoside unnecessary in the regimen, providing the opportunity for opening up the possibility of fewer nephrotoxic treatments that spare these molecules. Daptomycin was primarily preferred over other MRSA IE therapies (90%) and was the first line in the empiric approach in a third of cases.
Combination therapy, including high-dose daptomycin, was preferred over monotherapy, mainly adding beta-lactams or novel cephalosporins. This data might be explained by the in vitro synergistic effect of these compounds and the emerging data on higher rate of clinical failure associated with the emergence of non-susceptible strains in the contest of infection with high inoculum treated with daptomycin monotherapy, such as MRSA persistent bacteremias [21][22][23]. In vitro studies reported that combination of daptomycin and β-lactams could change the superficial charge of cell envelope finally enhancing daptomycin-mediate killing and boosting the cationic antimicrobial peptides-mediate killing even against VRE strains [24,25].
The combination of daptomycin plus beta-lactam in MRSA BSI, especially when including anti-MRSA novel cephalosporins, achieved a clinical success rate ranging from 60 to 100% [15,16,18,19,26]. In another recent study, aminoglycosides were rarely prescribed with daptomycin, and AG-sparing combination regimens were stated as one of the main reasons for choosing daptomycin plus beta-lactams in native IE likely with regard to the synergistic effect in enterococcal etiology. This is noteworthy given the higher mortality rate registered in patients with bacteraemia or IE and renal failure [26,27].
Lower dosage daptomycin was generally less common, both for combination and monotherapy. This can be explained by the fact that higher doses result in achieving better microbiological outcomes. Because of this, many clinicians have stated that the choice of daptomycin is driven by the possibility of achieving good bactericidal, high clinical efficacy and anti-biofilm activity in prosthetic endocarditis.
According to respondents, in one-third of cases, a daptomycin plus beta-lactam regimen after hospitalisation allowed oral de-escalation or attendance at an outpatient antimicrobial therapy clinic (OPAT) with the withdrawal of beta-lactam within one to two weeks for patients with stable disease or after surgical treatment.
In this survey, considered de-escalation options are heterogeneous, including oral [28,29] and long-acting injectable agents, such as dalbavancin, as successfully observed in recent studies [30,31]. Interestingly, for one out of five participants, de-escalation was not commonly performed, probably highlighting difficulties in the follow up of patients outside the hospital setting.
This survey has different limits: respondents have been selected on a voluntary basis from the group of the SITA and not directly from the hospital setting. A possible bias towards respondents who may have a fair knowledge on the subject matter and. By using closed-ended questions to assess the level of knowledge on daptomycin use and IE management, respondents may have selected the most favourable answer instead of using qualitative methods to revel misconceptions.

Survey Design
The study was a cross-sectional internet-based questionnaire survey on therapy with daptomycin. The questionnaire was designed with closed-ended questions and distributed using the SurveyMonkey ® platform (San Mateo, CA, United States). We requested information on the participant's specialty, hospital name, and size and type of hospital. Furthermore, we requested information regarding infectious diseases (ID) service in their hospital, antibiotic guidelines and stewardship programmes. Questions on incidence and management of IE caused by different Gram-positive bacteria were submitted to clinicians with focus on monotherapy or combination therapy for IE. Finally, the use of daptomycin, alone or in combination was investigated (the full questionnaire is available in the Supplementary Material Flie S1).
The questionnaire was developed by three primary investigators (TL, SC, CP, CT and FGDR) and pre-tested by all authors for clarity and technical functionality.
Our target population were ID and internal medicine physicians treating patients, giving advice on antibiotic treatment in Italy and members of the Italian Society of Antimicrobial Therapy "Società Italiana di Terapia Anti-infettiva" (SITA and SITA GIOVANI).
We asked respondents to reply by describing the most common actual practice at their hospital. Only one participant from each hospital was included.

Survey Administration
One investigator submitted the proposal to join the questionnaire through electronic mail. After a positive response, an invitation was sent by the survey coordinator.
Participants were able to access the questionnaire multiple times to allow possible changes and completion later. The survey was voluntary, with no incentives offered to participants (other than being listed as a collaborator).
Participants have had three months (from October 2019 to December 2020) to access the questionnaire.
The survey and the questions did not require a mandatory answer but could also be skipped.

Response Rates
Response rates were calculated as numbers of clinicians from which an answer was recorded. Information on hospital names was used to screen for duplicate entries, but all data were subsequently anonymized for the analyses.

Statistical Analysis
Both completed and partially completed questionnaires were analysed using the number of completed responses per item as the denominator.

Conclusions
In conclusion, daptomycin could be a feasible option for the treatment of high inoculum intravascular infections (i.e., bacteremia with metastatic complications, endocarditis), especially in selected patients who had a higher risk of MRSA invasive infections, carrying prosthetic valves which required a drug with high bactericidal effect on biofilm [32]. High doses and combination therapy with beta-lactams, including ceftaroline or ceftobiprole, are more likely to be chosen. Moreover, a prospective interventional study comparing daptomycin plus beta-lactams should be considered to evaluate outcomes.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.