# Comparative effectiveness of empirical antibiotic treatments in methicillin-susceptible Staphylococcus aureus infective endocarditis: a post hoc analysis of a prospective French cohort study

Raphaël Lecomte, Colin Deschanvres, Alexis Bourreau, L Ruffier D'epenoux, Paul Le Turnier, Benjamin Gaborit, Marie Chauveau, Magali Michel, Thierry Le Tourneau, Pascale Bémer, et al.

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Raphaël Lecomte, Colin Deschanvres, Alexis Bourreau, L Ruffier D'epenoux, Paul Le Turnier, et al. Comparative effectiveness of empirical antibiotic treatments in methicillin-susceptible Staphylococcus aureus infective endocarditis: a post hoc analysis of a prospective French cohort study. International Journal of Infectious Diseases, 2024, pp.106989. 10.1016/j.ijid.2024.106989. inserm-04487879

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# Comparative effectiveness of empirical antibiotic treatments in methicillin-susceptible *Staphylococcus aureus* infective endocarditis: A post hoc analysis of a prospective French cohort study

<figure><img src="image_2.png" /></figure>

Raphaël Lecomte<sup>a,b,*</sup>, Colin Deschanvres<sup>a,b</sup>, Alexis Bourreau<sup>a,b</sup>, Louise Ruffier d'Epenoux<sup>c,d</sup>, Paul Le Turnier<sup>a,b</sup>, Benjamin Gaborit<sup>a,b</sup>, Marie Chauveau<sup>a,b</sup>, Magali Michel<sup>e</sup>, Thierry Le Tourneau<sup>e</sup>, Pascale Bémer<sup>c</sup>, Stéphane Corvec<sup>c,e</sup>, David Boutoille<sup>a,b</sup>

## ARTICLE INFO

**Article history:**

Received 5 December 2023

Revised 21 February 2024

Accepted 26 February 2024

**Keywords:**

Infective endocarditis

*Staphylococcus aureus*

Empiric treatment

Bacteraemia

## ABSTRACT

**Objectives:** The empirical treatment of infective endocarditis is still debated. The aim of this study was to compare the impact of empirical treatment with antistaphylococcal penicillin (ASP) or cefazolin vs. other treatments in methicillin-susceptible *Staphylococcus aureus* (MSSA) endocarditis.

**Methods:** A post hoc analysis of a prospective cohort study of patients hospitalized in a French reference centre with MSSA endocarditis was conducted between 2013 and 2022. The primary outcome was the duration of bacteraemia under treatment.

**Results:** Of the 208 patients included, 101 patients (48.6%) were classified in the reference group (ASP or cefazolin) and 107 (52.4%) in the non-reference group. Empirical treatment with ASP/cefazolin was associated with a shorter duration of bacteraemia compared to other treatments (3.6 d vs. 4.6 d, *P* = 0.01). This difference was not corrected by the addition of an aminoglycoside (3.6 d vs. 4.7 d, *P* < 0.01). In multivariate analysis, empirical treatment with ASP/cefazolin was associated with a duration of bacteraemia ≤72 h (*P* = 0.02), whereas endocarditis on native valves (*P* = 0.01), and intracardiac abscess were associated with longer duration of bacteraemia (*P* = 0.01).

**Conclusions:** Empirical treatment of endocarditis with ASP or Cefazolin is more effective than other treatments in MSSA endocarditis, even when the other treatments are combined with aminoglycosides.

© 2024 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

## Introduction

In most cases, treatment of infective endocarditis (IE) is empirical until the causative pathogens are identified, with two major important points. First, empirical antimicrobial therapy (EAT) is the cornerstone of sepsis therapy and any delay in time to appropriate antimicrobial therapy increases sepsis mortality, particularly in cases of septic shock [1]. Second, since *Staphylococcus aureus* is the leading cause of IE and is associated with higher mortality [2,3], it is crucial that EAT for infective endocarditis includes drugs that have optimal anti-staphylococcal activity [4,5].

Anti-staphylococcal penicillins (ASP) remain the reference treatment in Europe, when the IE is due to methicillin-susceptible *S. aureus* (MSSA), which is the most frequent situation in Europe [5,6]. Cefazolin is recommended as an alternative, and several retrospective studies have shown similar efficacy and better tolerance, both in bacteraemia and endocarditis [7,8]. However, the efficacy of other βlactams is debated, with contradictory results reported from studies in MSSA bacteraemia [9–20]. Paul et al. found that cefazolin and ASPs were superior to other βlactams, including third generation cephalosporin [10], but several other studies did not show significant differences between cefazolin or ASP and other βlactams [9,11–14,16,17,19]. However, these studies did not focus on patients with infective endocarditis nor assessed the impact of a combination with an aminoglycoside (Table S1, Supplementary appendix).

<footnote><sup>a</sup> Department of Infectious Diseases, CHU Hôtel-Dieu, Nantes, France</footnote>

<footnote><sup>b</sup> Centre d'Investigation Clinique, Unité d'Investigation Clinique, Nantes, France</footnote>

<footnote><sup>c</sup> Department of Bacteriology, Nantes, France</footnote>

<footnote><sup>d</sup> Université de Nantes, Nantes, France</footnote>

<footnote><sup>e</sup> Department of Cardiology, Institut du Thorax, University Hospital, Nantes, France</footnote>

<footnote>* Corresponding author: Raphaël Lecomte, Infectious Disease department, 1 Place Alexis Ricordeau, 44093, Nantes, France.</footnote>

<footnote>E-mail address: raphaël.lecomte@chu-nantes.fr (R. Lecomte).</footnote>
Hence, the EAT of community-acquired native valve endocarditis (NVE) or late prosthetic valve endocarditis (PVE) before pathogen identification is still debated: (i) the combination of ampicillin + (flu-cloxacillin) + gentamicin was recommended by the 2015 European society of cardiology (ESC) guidelines for acute severely ill patients, (ii) the 2023 ESC guidelines propose a combination of ampicillin with either ceftriaxone or cloxacillin, in addition to gentamicin [21] (iii) the 2015 American Heart Association (AHA) guidelines recommended the association of vancomycin and ampicillin-sulbactam without precisely stating the role of aminoglycosides [6].

The aim of this study was to compare the impact of EAT with antistaphylococcal penicillin (ASP) or cefazolin vs. other treatments in MSSA endocarditis, and the impact of the combination with aminoglycosides.

## Patients and methods

### Study design, setting and population

This study is a sub study of the prospective IE cohort of Nantes University hospital [7,22,23]. All consecutive patients admitted with a diagnosis of IE according to the modified Duke University criteria [24] and confirmed by the local endocarditis team from July 2013 to July 2022 are included in this cohort.

For this study, all patients with MSSA endocarditis were included. Patients were excluded if: (i) their initial blood culture results (within the first 5 d) were positive for more than one pathogen, (ii) they had an infection of cardiac implantable electronic devices (CIEDs) without valvular lesion, (iii) they died before having a sterile blood culture (primary endpoint not available). To analyse the impact (including mortality) of EAT for IE, patients who had not received the recommended definitive treatments (ASP or cefazolin) were also excluded.

### Exposure

EAT was defined as the first antibiotic treatment with antistaphylococcal activity administered after the collection of the first positive blood culture. Patients were divided in two groups according to the empirical treatment. The "reference group" included patients who received ASP or cefazolin. The "non-reference group" included patients who received a first-line treatment other than ASP/cefazolin but active on the strain of S. aureus isolated from blood cultures based on susceptibility testing. For the reference group, in accordance with international guidelines [21], local guidelines recommended a continuous administration of the antibiotics as follows: 6-8 g per day for cefazolin after a bolus of 2 g, and 150-200 mg/kg per day of ASP after a bolus of 2 g.

### Microbiological studies

All blood cultures were incubated using an automated BACTEC system (Becton-Dickinson, Sparks, United-States of America). All positive blood cultures were subcultured on blood agar plates (bioMérieux, Marcy l'Etoile, France). S. aureus identification was performed by using the VITEK MS system (bioMérieux) from blood agar plates of positive blood cultures incubated for 4 h, called early cultures. Antimicrobial susceptibility testing was performed by using a VITEKXL automated system (bioMérieux) with an AST-P668 bioMérieux card. Results were interpreted following the CA-SFM/EUCAST guidelines available on https://www.sfm-microbiologie.org/boutique/comite-de-lantibiogramme-de-la-sfm-casfm/.

### Endpoints

The primary outcome was the duration of bacteraemia once EAT was started. The secondary endpoints were (i) the probability of sterilization of blood culture per day of treatment, (ii) mortality from any cause within 30 d after the first positive blood culture was sampled, (iii) One year mortality with comparison of the survival curves (iv) the necessity of valvular surgery for IE (valve replacement within 90 d that was not planned before the episode of IE), (v) the occurrence of embolic events after the initiation of treatment, (vi) and relapse of IE.

### Data collection and definition

Data were prospectively collected from patients' electronic medical records and entered into a standardized case report form. Follow-up data were extracted from the patient's electronic medical record. If the 30-day mortality was not available, the information was systematically sought from the death records of the birthplace municipality of the patient in accordance with French legislation.

Duration of bacteraemia was defined as the number of days with a positive blood culture under antibiotic treatment. The probability of sterilization of blood cultures on a given day was defined as the probability that blood cultures collected the following day would be negative (see statistical section). Valvular surgery was defined as valve replacement resulting from IE within 90 days after the first positive blood culture that was not planned before the episode of endocarditis. Embolism under treatment was defined as acute onset of new clinical symptoms with the occurrence of new lesions on computed tomographic or magnetic resonance imaging. Relapse was defined as an additional episode of IE caused by the same microorganism with the same antibiotic susceptibility test during a 6-month follow-up. Modified intensive care unit (ICU) admission was defined as an admission for management of organ failure (patients admitted for preoperative check-up or postoperative monitoring are not included in this definition).

### Ethics and registration

This project has been declared to the CNIL (French Data Protection Authority), declaration number 1 719 346. Patients were informed of the study but did not have to provide individual consent, in accordance with French legal standards.

### Statistical analysis

A descriptive analysis was performed for baseline characteristics, primary and secondary outcomes. Quantitative variables were summarized by mean and standard deviation and/or median and interquartile range (IQR) and were compared by the Student t test (data normally distributed). Qualitative variables were summarized by frequency and percentages and compared by the chi-square or Fisher exact test as appropriate.

The probability of daily sterilization of blood cultures was defined as the mean probability for each day of treatment that the following day's blood cultures would be negative.

To study factors associated to persistent bacteraemia > 72 h [25], a univariate and multivariate logistic regression model was built estimating odds ratios (ORs) and 95% confidence intervals (CIs). In the multivariate model, we have included all explicative variables which are clinically relevant, or which have already been identified as being associated with longer duration of bacteraemia: PVE, presence of vegetation, intra-cardiac abscess, metastatic site of infection. No data were missing in the multivariate model.
Kaplan-Meier curves were constructed to compare time to 1-y mortality between two groups using log-rank test.

A two-sided *P* value of less than 5% was considered to indicate statistical significance for all analyses. Statistical analyses were performed by R 3.6.1 software (https://www.r-project.org/).

## Results

Among the 915 consecutive patients screened in the Nantes endocarditis cohort between January 2013 and July 2022, 240 patients were hospitalized for MSSA endocarditis. Thirty-two patients were excluded (cf. Fig. 1): 7 patients had polymicrobial IE, 7 patients had missing data, 6 patients had their diagnosis ruled out by the endocarditis team, 5 patients did not receive definitive treatment with ASP or cefazolin, 4 patients had isolated CIED infection without valvular IE and 3 patients had sterile blood cultures. Therefore, a total of 208 patients were analysed for the primary endpoint: 101 patients (48.6%) in the reference group and 107 patients (51.4%) in the non-reference group. The general characteristics of patients and type of EAT for the two groups are presented in Table 1. The median age was 65 y (SD ± 16.5) and 163 patients (78.3%) were male. At discharge, the IE was classified as definite in 197 patients (94.7%). There was no difference between both groups except for the Charlson comorbidity index, which was significantly higher in the non-reference group (*P* = 0.04). Each component of the Charlson comorbidity index is detailed in the Table S2 (Supplementary data). Antibiotic treatment was started within 24 h after the first positive blood culture was sampled in 177 of 208 cases (85.1%). An aminoglycoside was administered in 73.3% (74/101) of patients in the reference group and in 72% (77/107) in the non-reference group (*P* = 0.90) with a median duration of 3 d (IQR [1–6]). Surgery was performed in respectively 28.7% (29/101) and 33.6% (36/107) of patients (*P* = 0.54).

EAT were ASP for 51.5% (52/101) and cefazolin for 48.5% (49/101) of the patients in the reference group; a combination of βlactams/βlactamase inhibitors (BL/BLICs) for 28.0% (30/107), a third-generation cephalosporin for 34.6% (37/107), and other treatments with anti-staphylococcal activity for 37.4% (40/107) for the patients included in the non-reference group (See flowchart for details, Fig. 1). De-escalation to the reference treatment (ASP or cefazolin) was systematic in the non-reference group and performed in 2.6 d (SD 2.3 d).

### Primary outcome: duration of bacteraemia

Among the entire study population, the mean duration of bacteraemia under treatment was 3.55 ± 0.24 d among patients who received a reference treatment vs. 4.53 ± 0.28 d for those who received a non-reference treatment (Table 2). The absolute difference in the duration of bacteraemia was 0.9 d (95% confidence interval [CI], 0.2–1.7; *P* < 0.01). The addition of an aminoglycoside in the empirical treatment was not associated with shorter duration of bacteraemia for both reference (*P* = 0.67) and non-reference group (*P* = 0.81) (Table 2). Even when they received aminoglycosides, the duration of bacteraemia remained significantly longer for the patients in the non-reference group than in the reference group (4.6 d vs. 3.6 d, difference 1.1 d CI 95% 0.3–1.8, *P* < 0.01).

In univariate analysis (Table 3), EAT with a reference treatment was significantly associated with a duration of bacteraemia ≤72 h (OR 0.31; IC 95% (0.1–0.84, *P* = 0.03), whereas intracardiac abscesses were significantly associated with a duration of bacteraemia >72 h (OR 2.95; IC 95% (1.15–9.12, *P* = 0.04). After adjustment for potential confounding factors (vegetation, intracardiac abscess, metastatic site of infection, type of valve, and type of treatment), empirical treatment with ASP/cefazolin was significantly associated with a duration of bacteraemia ≤72 h compared with the

other treatments (OR 0.48; IC 95% (0.26–0.89, *P* = 0.02), whereas endocarditis on native valve (OR 2.8; IC 95% (1.2–6.5, *P* = 0.01), and intracardiac abscess were significantly associated with longer duration of bacteraemia (OR 4.9; IC 95% (1.6–19.4, *P* = 0.01).

### Probability of sterilization of blood cultures

The probability of sterilizing blood cultures per day of treatment was significantly higher in the reference group (28.1%) than in the non-reference group (12.7%), (*P* < 0.001), (Fig. 2A). Treatment with third generation cephalosporins had a lower probability of sterilizing blood cultures (4.7%) compared with the reference treatment group (28.1%), (*P* < 0.001) but also with the BL/BLICs combinations (18.0%), (*P* = 0.02), (see Fig. 2B). In contrast, there was no difference in probability of sterilizing blood cultures per day of treatment between cefazolin (29.9%) and antistaphylococcal penicillins (26.8%) when started as EAT (*P* = 0.63) (see Fig. 2D). The addition of aminoglycosides did not significantly modify the probability of sterilizing blood cultures, either combined with a reference (*P* = 0.35) or non-reference treatment (*P* = 0.92) (see Fig. 2C). Lastly, there was no significant difference in the probability of sterilization of blood cultures per day of treatment whether the reference treatment (ASP or cefazolin) was introduced as EAT (30.9%), or after a first phase of another treatment (28.1%), (*P* = 0.46), (See Fig. 2D). Because the probability of sterilizing blood cultures per day of treatment was significantly higher after 5 d under treatment (Fig. S1A, Supplementary data), we performed a sub-analysis considering only the probability of the first 5 d of treatment. The results were similar to those previously shown (Fig. S1B–D, Supplementary data).

### Other secondary outcomes (Table 2)

There was no statistically significant difference between the reference and non-reference groups regarding: 30-d mortality rate (10/101 (9.9%) vs. 16/107 (15.0%) respectively, *P* = 0.25, valvular surgery (29/101 (28.7%) vs. 36/107 (33.6%) respectively, *P* = 0.44), risk of embolic event (13/101 (12.9%) vs. 11/107 (10.3%) respectively, *P* = 0.56) or relapse (2/101 (1.9%) vs. 3/107 (3.8%) respectively, *P* = 1.00). Regarding long-term outcomes (Fig. S2, Supplementary data), there was no difference in 1-y mortality based on the survival analysis (See Kaplan Meier curves, *P* = 0.29).

## Discussion

By comparing the efficacy of EAT in MSSA endocarditis, an homogeneous population of patients with a high inoculum infection, we highlighted 3 main results of direct interest in daily practice: (i) treatment with ASP or cefazolin was significantly more effective in reducing days of bacteraemia than all other treatments studied, (ii) the addition of aminoglycosides in the EAT was not associated with shorter duration of bacteraemia whatever the therapeutic group, (iii) and addition of aminoglycosides did not allow non-reference treatments to regain any activity up to the level of reference treatments.

Several cohort studies have compared cefazolin with antistaphylococcal penicillins in MSSA bacteraemia and endocarditis and have shown similar efficacy. Similarly, there is evidence of superiority of antistaphylococcal βlactams over vancomycin in MSSA bacteraemia [26,27]. However, data comparing other treatments with antistaphylococcal activity are scarce (Table 1, Supplementary appendix). Paul et al. found that empirical treatment with βlactams other than cloxacillin or cefazolin in bacteraemia was associated with higher 30-d mortality [10]: the adjusted OR of 30-d mortality for empirical treatment with ceftriaxone or cefotaxime was 2.24 (95% CI 1.23–4.08) and for BL/BLICs
<caption>**Table 1**</caption>

Characteristics of 208 patients with methicillin-susceptible *Staphylococcus aureus* IE who received either the reference treatment (Cefazolin/ASP) or another treatment as empirical treatment.

<table><thead><tr><th>Characteristic</th><th>Reference (n = 101)</th><th>Non-reference (n = 107)</th><th>P Value</th></tr></thead><tbody><tr><td>Demographics</td><td></td><td></td><td></td></tr><tr><td>Age (y), mean (SD)</td><td>64.8 (16.4)</td><td>65.80 (16.5)</td><td>0.66</td></tr><tr><td>Male gender</td><td>82 (81.2%)</td><td>81 (75.7%)</td><td>0.43</td></tr><tr><td>Comorbidity</td><td></td><td></td><td></td></tr><tr><td>Charlson comorbidity index, mean (SD)</td><td>2.1 (2.2)</td><td>2.7 (2.2)</td><td>0.04</td></tr><tr><td>Intravenous drug use</td><td>11 (10.9%)</td><td>5 (4.7%)</td><td>0.16</td></tr><tr><td>Previous IE</td><td>2 (2.0%)</td><td>4 (3.7%)</td><td>0.59</td></tr><tr><td>Predisposing heart condition</td><td>40 (39.6%)</td><td>43 (40.2%)</td><td>1.00</td></tr><tr><td>Valve type</td><td></td><td></td><td></td></tr><tr><td>Prosthetic valve</td><td>19 (18.8%)</td><td>31 (29.0%)</td><td>0.12</td></tr><tr><td>CIED<sup>a</sup></td><td>30 (29.7%)</td><td>37 (34.6%)</td><td>0.58</td></tr><tr><td>Duke classification</td><td></td><td></td><td></td></tr><tr><td>Definite</td><td>93 (92.1%)</td><td>104 (97.2%)</td><td>0.10</td></tr><tr><td>Possible</td><td>8 (7.9%)</td><td>3 (2.8%)</td><td>0.10</td></tr><tr><td>Site of endocarditis</td><td></td><td></td><td></td></tr><tr><td>Aortic</td><td>39 (38.6%)</td><td>44 (41.1%)</td><td>0.82</td></tr><tr><td>Mitral</td><td>37 (36.6%)</td><td>34 (31.8%)</td><td>0.55</td></tr><tr><td>Tricuspid</td><td>18 (17.8%)</td><td>15 (14.0%)</td><td>0.58</td></tr><tr><td>Multivalve involvement</td><td>11 (10.9%)</td><td>15 (14.0%)</td><td>0.50</td></tr><tr><td>Intracardiac leads<sup>b</sup></td><td>10 (9.9%)</td><td>12 (11.2%)</td><td>0.93</td></tr><tr><td>Echocardiography</td><td></td><td></td><td></td></tr><tr><td>Vegetation</td><td>72 (71.3%)</td><td>72 (67.3%)</td><td>0.64</td></tr><tr><td>Vegetation length, mean (SD)</td><td>14.9 (8.9)</td><td>15.5 (9.6)</td><td>0.74</td></tr><tr><td>Perforation</td><td>7 (6.9%)</td><td>8 (7.4%)</td><td></td></tr><tr><td>Abscess</td><td>12 (11.9%)</td><td>16 (15.0%)</td><td>0.66</td></tr><tr><td>IE-related lesion</td><td></td><td></td><td></td></tr><tr><td>Neurological<sup>c</sup></td><td>38 (37.6%)</td><td>36 (38.3%)</td><td>0.84</td></tr><tr><td>Other location<sup>d</sup></td><td>65 (64.4%)</td><td>64 (59.8%)</td><td>0.92</td></tr><tr><td>Modified ICU admission<sup>e</sup></td><td>62 (61.4%)</td><td>64 (59.8%)</td><td>0.92</td></tr><tr><td>Empirical antibiotic treatment<sup>f</sup></td><td></td><td></td><td></td></tr><tr><td>(Cl)oxacillin</td><td>52 (51.5%)</td><td>-</td><td></td></tr><tr><td>Cefazolin</td><td>49 (48.5%)</td><td>-</td><td></td></tr><tr><td>βlactam/βlactamase inhibitor combinations<sup>g</sup></td><td>-</td><td>30 (28.0%)</td><td></td></tr><tr><td>Ceftriaxone/cefotaxime</td><td>-</td><td>37 (34.6%)</td><td></td></tr><tr><td>Other</td><td>-</td><td>40 (37.4%)</td><td></td></tr><tr><td>Aminoglycoside</td><td>74 (73.3%)</td><td>77 (72.0%)</td><td>0.90</td></tr><tr><td>Surgical treatment</td><td>29 (28.7%)</td><td>36 (33.6%)</td><td>0.54</td></tr><tr><td>Timing of surgery, days, mean (SD)<sup>h</sup></td><td>17.7 (14.9)</td><td>17.4 (12.4)</td><td>0.94</td></tr><tr><td>Positive valve culture</td><td>6/26 (23.1%)</td><td>9/33 (27.3%)</td><td>0.95</td></tr></tbody></table>

Data are presented as n (%) unless otherwise indicated.

Abbreviations: ASP, antistaphylococcal penicillin; CIED, cardiovascular implantable electronic device; ICU, intensive care unit; IE, infective endocarditis.

a Patients with CIED infection without associated valve damage were excluded (see exclusion criteria).

b For cardiovascular implantable electronic device.

c Including cerebral embolisms, abscesses or aneurysms.

d Including non-cerebral embolisms, metastatic foci (spondylodiscitis, abscesses) and mycotic aneurysms.

e Not including patients admitted to ICU for postsurgical period for recovery; or patients admitted to cardiac ICU for preoperative check-ups.

f Corresponds to the first antibiotic treatment given to the patient after collection of blood culture.

g Amoxicillin/clavulanic acid and piperacillin/tazobactam combinations.

h Timing between the introduction of treatment and the surgery.

<caption>**Table 2**</caption>

Comparison of treatment outcomes of reference group versus non reference group with methicillin-susceptible *Staphylococcus aureus* endocarditis.

<table><thead><tr><th>Outcome</th><th>Overall (n = 208)</th><th>Reference (n = 101)</th><th>Non reference (n = 107)</th><th>P Value</th></tr></thead><tbody><tr><td>Duration of bacteraemia (Mean ± SEM)</td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>4.06 ± 0.18</td><td>3.55 ± 0.24</td><td>4.53 ± 0.28</td><td><strong>0.009</strong></td></tr><tr><td>With aminoglycosides</td><td>4.18 ± 0.22</td><td>3.72 ± 0.29</td><td>4.64 ± 0.31</td><td><strong>0.03</strong></td></tr><tr><td>Secondary outcomes</td><td></td><td></td><td></td><td></td></tr><tr><td>Probability of sterilization (Mean ± SEM)<sup>a</sup></td><td>22.15 ± 1.71</td><td>28.13 ± 2.38</td><td>12.72 ± 2.21</td><td><strong>&lt;0.001</strong></td></tr><tr><td>90-d valvular surgery<sup>b</sup></td><td>65 (31.2)</td><td>29 (28.7)</td><td>36 (33.6)</td><td>0.44</td></tr><tr><td>Under treatment embolism<sup>c</sup></td><td>24 (11.5)</td><td>13 (12.9)</td><td>11 (10.3)</td><td>0.56</td></tr><tr><td>Relapse</td><td>5 (2.4)</td><td>2 (1.9)</td><td>3 (2.8)</td><td>1.00</td></tr><tr><td>30-d all-cause mortality</td><td>26 (12.5)</td><td>10 (9.9)</td><td>16 (15.0)</td><td>0.25</td></tr></tbody></table>

Data are presented as no. (%) unless otherwise indicated.

Abbreviations: SEM: standard errors of mean.

a The probability of sterilization of blood cultures per treatment day was defined by the probability that the patient had no more positive blood cultures from the day after the treatment day studied.

b Not included: patients who underwent CIED (device and/or probes) removal without valve surgery.

c Embolism occurring during treatment was defined as new clinical symptoms with acute onset and the occurrence of new lesions confirmed by computed tomographic or magnetic resonance imaging.
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Study flowchart. ASP, antistaphylococcal penicillin; IE, infective endocarditis; MRSA, methicillin-resistant *Staphylococcus aureus*. ¹Four patients received definitive treatment with daptomycin and one with ceftaroline. ²Patient with an isolate infection of cardiac implantable electronic devices. ³With or without aminoglycosides. ⁴Pristinamycin (n = 2); Levofloxacin (n = 1); ciprofloxacin (n = 1); ceftarolin (n = 1); Josacin (n = 1). ⁵List of dual therapy (except with aminoglycosides): Ceftriaxone vancomycine (n = 2), piperacillin tazobactam linezolid (n = 2), piperacillin tazobactam daptomycin (n = 1); meropenem daptomycin; ceftriaxone daptomycin (n = 1) Amoxicillin-clavulanate linezolid (n = 1); amoxicilline-clavulanate and ceftarolin (n = 1).</figcaption></figure>

2.68 (95% CI 1.23–5.85). However, two recent studies found no significant difference in mortality between BL/BLICs and reference treatment; the first study compared amoxicillin/clavulanic acid or piperacillin/tazobactam to cloxacillin/cefazolin (adjusted OR 0.53, 95% CI 0.18–1.51) [13] and the second compared piperacillin/tazobactam to cefuroxime (matched HR 0.82, 95% CI 0.47–1.46) [17]; while a third study found that the reference treatment was superior to piperacillin tazobactam (HR 0.10, 95% CI 0.01–0.78)[18].

In our study which involves patients with infective endocarditis, third generation cephalosporins were the least effective treatment compared with the reference treatment but also with BL/BLICs. Five recent studies including patients with MSSA bacteraemia compared ceftriaxone with one of the reference treatments (ASP or cefazolin) [12,14–16,19]. The results are conflicting, with only one study finding a significant difference [15]. Although the conflicting results may be explained by different designs and criteria of analysis, all these studies highlight the difficulty of evaluating a het-
<table><caption>**Table 3**
Crude and adjusted ORs to determine factor associated with duration of bacteraemia under treatment.</caption><thead><tr><th rowspan="2">n (%)</th><th rowspan="2">&lt;72 h (n = 75)</th><th rowspan="2">≥72 h (n = 132)</th><th colspan="2">Univariate</th><th colspan="2">Multivariate</th></tr><tr><th>OR (CI95%)</th><th>P</th><th>aOR (CI95%)</th><th>P</th></tr></thead><tbody><tr><td>Age (y, mean [SD])</td><td>66 (16.3)</td><td>65 (16.6)</td><td>1 (0.98-1.01)</td><td>0.76</td><td></td><td></td></tr><tr><td>Charlson index (mean [SD])</td><td>2.40 (2.30)</td><td>2.41 (2.22)</td><td>1 (0.88-1.14)</td><td>0.98</td><td></td><td></td></tr><tr><td>Native valve</td><td>51 (68.9)</td><td>105 (80.2)</td><td>1.82 (0.94-3.45)</td><td>0.07</td><td><strong>2.77 (1.24-6.46)</strong></td><td><strong>0.01</strong></td></tr><tr><td>CIED<sup>a</sup></td><td>28 (38.4)</td><td>39 (29.8)</td><td>0.68 (0.37-1.25)</td><td>0.21</td><td></td><td></td></tr><tr><td>Intracardiac leads<sup>b</sup></td><td>11 (14.7)</td><td>11 (8.3)</td><td>0.53 (0.22-1.3)</td><td>0.16</td><td></td><td></td></tr><tr><td>Vegetation</td><td>47 (62.7)</td><td>97 (73.5)</td><td>1.65 (0.9-3.03)</td><td>0.11</td><td>1.38 (0.69-2.72)</td><td>0.36</td></tr><tr><td>Intra-cardiac abscess</td><td>5 (6.7)</td><td>23 (17.4)</td><td>2.95 (1.15-9.12)</td><td>0.04</td><td><strong>4.95 (1.59-19.42)</strong></td><td><strong>0.01</strong></td></tr><tr><td>Neurological IE-related lesion</td><td>20 (31.7)</td><td>54 (43.9)</td><td>1.68 (0.9-3.23)</td><td>0.11</td><td></td><td></td></tr><tr><td>Metastatic site of infection</td><td>42 (57.5)</td><td>87 (69.6)</td><td>1.69 (0.93-3.09)</td><td>0.09</td><td>1.57 (0.83-2.97)</td><td>0.16</td></tr><tr><td>Reference treatment</td><td>45 (60.0)</td><td>56 (42.4)</td><td>0.31 (0.1-0.84)</td><td>0.03</td><td><strong>0.48 (0.26-0.89)</strong></td><td><strong>0.02</strong></td></tr></tbody></table>

Values presented as n (%) unless otherwise indicated; *P* < 0.05 was considered statistically significant. The multivariate model had no missing data. Primary outcome was assessed by multivariate logistic regression estimating odd ratios (OR) and 95% confidence intervals (CI). CIED, cardiovascular implantable electronic device; OR, odd ratio; aOR, adjusted OR.

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Probability of sterilization of blood cultures per treatment day according to the type of treatment in the 208 patients with methicillin-susceptible *Staphylococcus aureus* infective endocarditis included. The probability of sterilization of blood cultures per treatment day was defined by the probability that the patient had no more positive blood cultures from the day after the treatment day studied. (A) Comparison of the reference group (REF) with the non-reference group. (B) Comparison of the reference group (REF) with the subgroups betalactamine/betalactamase inhibitor, Ceftriaxone/Cefotaxime (TCG) and other treatments. (C) Comparison of the reference group (REF) with the non-reference group (NREF) according to the addition of aminoglycosides. (D) Comparison of the probability of sterilization of blood cultures per day of reference treatment (antistaphylococcal penicillin or cefazolin) according to whether this treatment was introduced as an empirical treatment (reference group, hatched columns) or after a "non-reference" treatment (non-reference group, second line). Abbreviations: REF: reference group; NREF: non reference group; ASP: antistaphylococcal penicillin; CZ: Cefazolin. Error bars represent upper limits of 95% confidence intervals. *** *P* < 0.001, ** *P* < 0.01, * *P* < 0.05.</figcaption></figure>

<footnote><sup>a</sup> Patients with CIED infection without associated valve damage were excluded (see exclusion criteria).</footnote>

<footnote><sup>b</sup> For cardiovascular implantable electronic device.</footnote>
erogeneous population in terms of primary site of infection, size of inoculum and severity (Table S.1, Supplementary appendix). Indeed, the impact of the choice of antibiotic therapy on the prognosis in infections of low severity and low inoculum is probably weak and showing a difference is very difficult. The choice of ceftriaxone as the antistaphylococcal treatment in the EAT of endocarditis in the ESC 2023 [21] recommendations is therefore an issue. This recommendation is based on a study of Buis et al. [14], where only 21% of patients (55/268) had IE and the median duration of bacteraemia, which was the primary outcome, was 1 d (vs. 4 d in IE). In addition, some studies focused only on the definitive treatment [12,15,16], once the inoculum was under control. In our study, we analysed only the EAT in a very homogeneous population of patients with MSSA endocarditis, a serious infection with a high inoculum, allowing a more precise evaluation of the specific activity of the different antibiotics studied.

Furthermore, the cited studies did not evaluate the impact of the addition of an aminoglycoside (Table S.1, Supplementary appendix). Indeed, combination therapy is often used for difficult-to-treat infections because it is supposed to accelerate clearance of *S. aureus*, although clinical evidence to support this notion is limited. In native valve endocarditis, the systematic addition of an aminoglycoside to the reference treatment is no longer recommended in guidelines, based on small retrospective studies [5,28,29] and two randomized studies [30,31] showing the lack of efficacy and the risk of nephrotoxicity. Our results support these earlier studies. More interestingly, in our study, the addition of an aminoglycoside to an alternative treatment does not allow to recover an activity similar to the reference treatment, thus demonstrating the crucial importance of integrating ASP/cefazolin in the EAT in case of endocarditis suspicion.

An unexpected result of our work is that PVE were significantly associated with a shorter duration of bacteraemia. One hypothesis is that the inoculum in PVE is probably lower at the initiation of treatment than in NVE, for two reasons: (i) Patients with PVE, categorized as high-risk according to European guidelines, have an earlier diagnosis [32]: in our study, the delay between the first positive blood culture and the introduction of EAT was 0.2 d in the PVE group vs. 0.96 d in the NVE group (Difference 0.76 d, 95%CI [-1.55;0.04], P = 0.06); (ii) Only 2% of patients (1/51) with PVE had osteoarticular localizations compared with 17.9% of patients (28/157) with NVE, which supports the argument of an earlier diagnosis in these patients but may also explain difficulties in sterilizing these complex localizations.

There was no difference between both groups except for the Charlson comorbidity index, which was significantly higher in the non-reference group (P = 0.04). Patients with comorbidities potentially had a less typical clinical presentation of their endocarditis than patients without comorbidities with several possible confounding aetiologies of sepsis. For this reason, they may be more likely to receive broad-spectrum antibiotics such as ceftriaxone or piperacillin tazobactam. However, this difference is statistically significant but of limited clinical significance (median Charlson comorbidity index: 2.1 in the reference group and 2.7 in the non-reference group).

We acknowledge several limitations in our study. First, we used a surrogate end point as the primary outcome. However, duration of bacteraemia is a commonly used clinical criterion to guide therapy, which is associated with mortality in IE [25]. It would have been necessary to include a large number of patients to show a significant difference in mortality in MSSA endocarditis, an uncommon pathology. In our study, the difference in 30-d mortality was not significant (9.9% (10/101) in the reference group vs 15.0% (16/107) in the non-reference group). Second, because this was a retrospective study, some patients did not have blood cultures collected daily and the duration of bacteraemia was there-

fore possibly underestimated since in our study, it was defined between the first and last positive blood culture. However, these are local recommendations and the mean time between the last positive blood culture and the first sterile blood culture was 1.9 ± 2.6 d and most importantly did not differ between the reference and non-reference groups (2.1 +/− 3.1 d vs. 1.8 +/− 2.1 d, P = 0.51) (Details of the delay between the last positive blood culture and the first negative blood culture are given in Table S4, Supplementary data). A randomized controlled trial is the optimal study design to compare different EAT. However, the preference of most clinicians for antibiotic therapy targeting MSSA makes it challenging to conduct such a clinical trial. Moreover, most of the recent progress in endocarditis and their management has been derived from cohort studies due to the scarcity of randomized trials in the field of IE [33]. Third, the study was not matched, which increases the risk of confounding by indication. This type of bias is common in non-randomized studies comparing two treatments. However, unlike previous studies, we only considered patients with IE and not all bacteraemia, and we attempted to adjust for these differences using multivariable regression analysis. Lastly, caution should be exercised when interpreting the efficacy of aminoglycosides, since in our work, as in previous publications, patients who receive aminoglycosides more frequently have prosthetic endocarditis and/or severity criteria (two indications for aminoglycosides still recommended; see Supplementary data Table S3).

In summary, we have presented herein the first study specifically focusing on EAT of IE, comparing the reference treatment of ASP/cefazolin with other antistaphylococcal treatments, whether or not associated with aminoglycosides. Treatment with ASP/cefazolin was significantly more effective in reducing the duration of bacteraemia than other treatments even combined with aminoglycosides. Our results are in conflict with the latest ESC 2023 guidelines [21], which propose ceftriaxone plus ampicillin and gentamicin as empirical treatment of community-acquired NVE or late PVE. Our results strongly suggest that ASP or cefazolin should always be included in the EAT of a suspected IE, whereas the addition of an aminoglycoside does not appear to be essential. However, many questions remain regarding the treatment of the initial phase of MSSA endocarditis, such as the benefit of adding to ASP/cefazolin antibiotics other than aminoglycosides, the place of surgery in the early phase, and the duration of treatment. Further prospective studies are needed to explore these questions.

## Declarations

**Funding:** No financial support.

**Competing interest:** The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgements

Study group: AL HABASH Ousama, ASQUIER-KHATI Antoine, BEMER Pascale, BIRON Charlotte, BIZOUARN Philippe, BOUTOILLE David, CHAUVEAU Marie, CORVEC Stéphane, DESCHANVRES Colin, GREGOIRE Matthieu, GABORIT Benjamin, LE GOFF Maëlle, LE GLOAN Laurianne, LE TOURNEAU Thierry, LECOMTE Raphaël, LEFEBVRE Maeva, MAREST Delphine, MICHEL Magali, PATTIER Sabine, PIRIOU Nicolas, RAFFI François, ROUSSEL Jean-Christian, SENAGE Thomas, SERFATY Jean-Michel.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ijid.2024.106989.
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