European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-024-04851-6

RESEARCH

Effectiveness and safety of cefazolin versus cloxacillin in endocarditis

due to methicillin-susceptible Staphylococcus spp.: a multicenter
propensity weighted cohort study
Anne-Laure Destrem1 · Alexis Maillard2 · Mathieu Simonet3 · Soline Simeon4 · Adrien Contejean5,6 ·
Clémentin Vignau7 · Lucas Pires8 · Margaux Isnard1 · Virginie Vitrat3 · Tristan Delory8 · Mylène Maillet3

Received: 21 March 2024 / Accepted: 9 May 2024

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024

Abstract
Purpose To compare the effectiveness and safety of cefazolin versus cloxacillin for the treatment of infective endocarditis
(IE) due to methicillin-sensitive Staphylococci (MSS).
Methods Data were retrospectively collected on patients treated for a definite MSS endocarditis who received cefazolin
or cloxacillin for at least 10 consecutive days in six French hospitals between January-1 2014 and December-31 2020. The
primary endpoint was treatment failure defined as a composite of death within 90 days of starting antibiotherapy, or embolic
event during antibiotherapy, or relapse of IE within 90 days of stopping antibiotherapy. We used Cox regression adjusted for
the inverse probability of treatment weighting of receiving cefazolin.
Results 192 patients were included (median age 67.8 years). IE was caused by S.aureus in 175 (91.1%) and by coagulase-
negative staphylococci in 17 (8.9%). Ninety-four patients (48.9%) received cefazolin, and 98 (51%) received cloxacillin.
34 patients (34.7%) with cefazolin and 26 (27.7%) with cloxacillin met the composite primary endpoint, with no significant
differences between groups (adjusted HR = 1.13, 95% CI 0.63 to 2.03). There were no significant differences in secondary
efficacy endpoints or biological safety events.
Conclusion The effectiveness of cefazolin did not significantly differ from cloxacillin for the treatment of MSS endocarditis.

Keywords Endocarditis · Methicillin-susceptible Staphylococcus · Cefazolin · Cloxacillin · Antistaphylococcal

Penicillin

Mylène Maillet
mmaillet@ch-annecygenevois.fr Abbreviations
ASP Antistaphylococcal Penicillin
1
Infectious Diseases Department, Centre Hospitalier MSSA Methicillin susceptible Staphylococcus
Métropole Savoie, Chambéry, France aureus
2
Infectious Diseases Department, Pitié-Salpêtrière University MSS Methicillin sensitive Staphylococcus
Hospital, Paris, France IPTW Inverse probability of treatment weighting
3
Infectious Diseases Department, Centre Hospitalier Annecy S.A Staphylococcus aureus
Genevois, Annecy, France CONS Coagulase Negative Staphylococcus
4
Infectious Diseases Department, Henri Mondor University PCR Polymerase Chain Reaction
Hospital, Paris, France MALDI-TOF Matrix Assisted Laser Desorption Ioniza-
5
Infectious Diseases Department, Cochin University Hospital, tion-Time of Flight
Paris, France MIC Minimum Inhibitory Concentration
6
Hematology Department, Centre Hospitalier Annecy CI Confidence interval
Genevois, Annecy, France
7
Infectious Diseases Department, Grenoble University
Hospital, Grenoble, France
8
Clinical Research Unit, Centre Hospitalier Annecy Genevois,
Annecy, France

13

Introduction
Infective endocarditis remains associated with high mor-
bidity and mortality [1] but its epidemiology has evolved
over the past few decades [2]. Staphylococcus aureus has
become the most common pathogen, and the main cause of
poor outcomes [3], while coagulase-negative staphylococci
have emerged as major pathogens in prosthetic valve-asso-
ciated endocarditis [4].
Cloxacillin, the preferred reference anti-staphylococcal
penicillins (ASPs) was temporarily out of stock in France in
2016, prompting physicians to use cefazolin as an alternative
therapy to treat IE due to methicillin-susceptible Staphylo-
coccus spp. [5]. Yet, there is limited data on the effective-
ness and safety of cefazolin in this indication. While data on
coagulase-negative staphylococci bloodstream infections
are limited to case reports [6, 7], previous observational
studies have suggested that cefazolin may be as effective
as ASPs for methicillin-susceptible Staphylococcus aureus
(MSSA) bloodstream infection treatment [8–12], may be
associated with a lower incidence of acute kidney injury
[11, 13, 14], and may even be associated with a reduction in
all-cause mortality [11].
However, in vitro studies have raised concerns about a
potential inoculum effect against cefazolin, which could
compromise its bactericidal activity and increase mortal-
ity [15–17], especially in deep infections with high bacte-
rial loads. Only a few retrospective studies evaluated the
effectiveness of cefazolin in patients with MSSA endocardi-
tis [18–20]. Although they found no significant differences
in outcomes, their limited sample sizes preclude definitive
conclusions about the effectiveness of cefazolin in these
settings.
The aim of this study was to compare the effectiveness
and biological safety of cefazolin versus cloxacillin in the
treatment of infective endocarditis caused by methicillin-
susceptible Staphylococci spp. (MSS).
Methods
Study design and settings
We retrospectively reviewed the electronic health records
of consecutive adult patients identified with an International
Classification of Diseases 10 (ICD 10) code related to an
infective endocarditis for main diagnosis, related diagno-
sis, or significant associated diagnosis in 6 French hospi-
tals, between January-1, 2014 and December-31, 2020. We
included patients presenting with a definite diagnosis of
infective endocarditis caused by methicillin-susceptible S.
aureus or coagulase-negative Staphylococci, on a native or
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European Journal of Clinical Microbiology & Infectious Diseases
a prosthetic valve, according to the modified Duke criteria
[5], and who were treated with cefazolin or cloxacillin for at
least 10 consecutive days. Patients were assigned to either
to the cefazolin or the cloxacillin group according to the
antibiotic they first received for at least 10 consecutive days.
We excluded patients under 18 years of age, those under
guardianship or curatorship. To get a significant duration of
treatment, we also excluded patients who had a switch of
antibiotic therapy or who died within the first 10 days of
antibiotic therapy. The Staphylococci strains were identified
either using standard culture, Polymerase Chain Reaction
(PCR) GenXpert, or Matrix Assisted Laser Desorption Ion-
ization - Time of Flight (MALDI-TOF), depending on the
center and according to the last CASFM-EUCAST guide-
lines [21].
Data collection
We collected data from patients’ electronic medical records.
Data included the (i) clinical history at the onset of endocar-
ditis: Charlson score index, immunodeficiency status (use
of long-term (> 3 months) or high-dose (> 0.3 mg/kg/day)
steroids for at least 15 days in the past 3 months, use of other
immunosuppressant drugs, solid organ transplantation, che-
motherapy in the last 3 months, hematologic malignancy,
HIV infection with CD4 < 200/mm3 or primary immune
deficiency, hematopoietic stem cell transplantation), pre-
existing valvulopathy or intra-cardiac device, the use of
injectable drugs, temperature, Quick Sofa score, embolic
events; (ii) biological parameters over time (at the onset
of endocarditis and 14 days after) for C-reactive protein
(CRP), creatinine level, liver enzymes level, prothrombin
time (PT); (iii) microbiological data at the onset of endocar-
ditis: strain involved, minimal inhibitory concentration; (iv)
and echocardiographic data: vegetations, leak, perforation,
abscess. We also collected (v) details of antimicrobial ther-
apy: drug, dose, frequency, duration; and (vi) incident clini-
cal outcomes within 90 days of initiation of antimicrobial
therapy: cardiac surgery, embolic event under antimicrobial
therapy, and death; as well as (vii) relapse of endocarditis
(according to modified Duke criteria) within 90 days of ces-
sation of antimicrobial therapy.
Endpoints
The primary composite endpoint was infective endocarditis
treatment failure defined as the occurrence of at least one of
the following three criteria: death within 90 days of the start
of antimicrobial therapy, embolic event during antimicro-
bial therapy, relapse of endocarditis due to the same bacteria
90 days after the end of the first-line antimicrobial therapy.
Secondary effectiveness endpoints were the components
European Journal of Clinical Microbiology & Infectious Diseases
of the primary composite endpoint. Secondary biological
safety endpoints were the incidence of the following adverse
events: acute kidney injury, coagulopathy, or liver cytolysis.
Statistical analysis
Data are expressed as the median [Interquartile range (IQR)
Q1-Q3]. Between-group comparisons were performed using
the Mann–Whitney U test for continuous variables and χ2 or
Fisher’s exact tests for categorical variables, as appropriate.
The level for significance was 5% bilateral. We performed
all analyses using the R software (v4.1.1).
Propensity score estimation
We computed a propensity score for the probability of
receiving cefazolin versus cloxacillin [22]. We selected
baseline variables to be included in the computation of the
propensity score using a causal directed acyclic graph that
we built on DAGitty (v3.0) [23]. The selection of variables
was based on the literature [5] and clinical experience, as
shown in Figure S1. Selected variables with ≥ 30% missing
data were discarded (Table S1). Missing data for other vari-
ables were imputed using multiple imputation by chained
equations (MICE package, 20 imputations per variable)
using all other variables included in the propensity score
calculation. The final propensity model included the fol-
lowing baseline variables at the start of antibiotic therapy:
Quick Sofa score value, existing confusion, presence of
cerebral emboli, large vegetation size (> 10 mm), valve leak,
prosthetic valve-associated endocarditis, presence of endo-
cavitary probe, history of chronic kidney disease, creatinine
Fig. 1 Flow chart
level > 100 µmol/L, immunocompromised patient, year of
enrolment after 2016, and causative bacteria (S.aureus ver-
sus coagulase negative Staphylococcus).
Survival modeling
We calculated Kaplan-Meier estimates for the primary and
secondary effectiveness endpoints. A Cox proportional
hazards model was used to compare endpoints by treat-
ment group (cefazolin vs. cloxacillin). To induce a balance
between the treatment groups at the start of antibiotic ther-
apy, we calculated adjusted hazard ratios (aHR) by weight-
ing the analysis of endpoints using the inverse probability
of treatment weighting (IPTW) [21]. Weights were derived
to obtain estimates representing the population’s average
treatment effects. Visual inspection of histograms of the
distributions of the estimated propensity scores confirmed
a high degree of overlap. We also assessed standardized
differences in baseline covariates, with a threshold of 0.1
indicating imbalance (Figure S2). To account for a potential
center effect, we stratified all survival analyses by center
(coxph function).
Results
Population characteristics
We included 192 patients with an infective endocarditis
(Fig. 1): 94 (48.9%) were treated with cloxacillin as defini-
tive antibiotic therapy, and 98 (51.1%) with cefazolin.
Patients characteristics are detailed in Table 1. The median
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 European Journal of Clinical Microbiology & Infectious Diseases

Table 1 Baseline characteristics of 192 patients according to group of antimicrobial therapy (cefazolin or cloxacillin)
Overall Cefazolin Cloxacillin p-value
n 192 98 94
Demographics
Age (years) 67.8 [51.6, 79.1] 67.9 [52.0, 79.2] 67.3 [51.5, 78.2] 0.680
Sex (male) 137 (71.4) 65 (66.3) 72 (76.6) 0.157
Weight (kg) 71.0 [64.0, 84.0] 72.0 [60.0, 83.2] 70.5 [65.0, 84.0] 0.477
Comorbidities
Myocardial infarction 26 (13.5) 12 (12.2) 14 (14.9) 0.745
Congestive heart failure 29 (17.1) 16 (20.8) 13 (14.0) 0.333
Chronic respiratory disease 21 (10.9) 12 (12.2) 9 (9.6) 0.718
Diabetes mellitus 46 (24.0) 21 (21.4) 25 (26.6) 0.503
Chronic liver disease 15 (7.9) 10 (10.3) 5 (5.3) 0.311
Chronic kidney disease 46 (24.0) 31 (31.6) 15 (16.0) 0.018
Solid tumor 14 (7.3) 11 (11.2) 3 (3.2) 0.063
Hematological malignancy 9 (4.7) 6 (6.1) 3 (3.2) 0.536
Charlson comorbidity index 2.0 [0.0, 4.0] 2.0 [0.0, 4.8] 1.0 [0.0, 2.8] 0.053
Risk factors for infectious endocarditis
Immunocompromised patient 20 (10.4) 12 (12.2) 8 (8.5) 0.542
IV substance abuse 23 (12.0) 11 (11.2) 12 (12.8) 0.915
Known valvular disease 87 (45.3) 43 (43.9) 44 (46.8) 0.793
Prosthetic valves 58 (31.0) 31 (31.6) 27 (30.3) 0.974
Endocavitar probes 35 (18.2) 14 (14.3) 21 (22.3) 0.208
Clinical manifestations
Time since symptoms onset (days) 4.0 [2.0, 9.0] 4.0 [2.0, 9.0] 3.0 [2.0, 8.0] 0.508
Time since admission to hospital (days) 2.0 [1.0, 3.0] 2.0 [1.0, 4.0] 1.0 [1.0, 3.0] 0.237
Temperature (°C) 38.6 [38.1, 39.4] 38.5 [37.8, 39.0] 39.0 [38.4, 39.5] 0.005
Respiratory rate > 22/min 28 (19.7) 13 (17.3) 15 (22.4) 0.586
Systolic blood pressure < 100 mmHg 127 (73.8) 67 (76.1) 60 (71.4) 0.597
Confusion 39 (22.7) 13 (14.8) 26 (31.0) 0.019
Quick Sofa score 1.0 [1.0, 1.0] 1.0 [1.0, 1.0] 1.0 [1.0, 2.0] 0.125
Cerebral emboli 41 (23.7) 14 (16.5) 27 (30.7) 0.044
Extra cerebral emboli 105 (56.5) 52 (55.9) 53 (57.0) 1.000
Source of infection 0.002
Community acquired infection 119 (62.6) 50 (51.5) 69 (74.2)
Healthcare-associated infection 43 (22.6) 31 (32.0) 12 (12.9)
Hospital acquired infection 24 (12.6) 12 (12.4) 12 (12.9)
Unknown 4 (2.1) 4 (4.1) 0 (0.0)
Biological tests
Creatinine (µmol/L) 100.0 [73.0, 154.5] 96.0 [62.5, 183.5] 102.0 [74.8, 138.5] 0.471
CRP (mg/L) 159.5 [80.5, 274.5] 166.0 [79.0, 276.0] 158.0 [84.5, 270.5] 0.842
PT (%) 72.0 [55.0, 80.0] 65.0 [51.0, 79.2] 73.0 [56.0, 83.5] 0.161
ALT (UI/L) 30.0 [16.0, 49.0] 25.0 [14.0, 44.0] 31.0 [20.0, 50.0] 0.037
Albumin (g/L) 27.0 [21.0, 30.0] 24.0 [21.0, 29.0] 27.5 [21.0, 32.8] 0.630
Blood cultures
Number of blood cultures collected (days) 8.0 [5.0, 14.0] 7.0 [5.0, 10.0] 9.5 [6.0, 19.0] < 0.001
Number of positive blood cultures (days) 4.0 [3.0, 7.0] 4.0 [2.5, 5.5] 5.0 [3.0, 8.0] 0.016
Total duration of bacteriemia (days) 3.0 [2.0, 6.0] 3.0 [1.0, 5.0] 4.0 [2.0, 7.5] 0.028
Germ: MSSA (vs. CNS) 175 (91.1) 86 (87.8) 89 (94.7) 0.151
Echocardiography
Aortic endocarditis 81 (42.4) 41 (41.8) 40 (43.0) 0.986
Mitral endocarditis 76 (39.6) 35 (35.7) 41 (43.6) 0.331
Tricuspid endocarditis 29 (15.3) 15 (15.3) 14 (15.2) 1.000
Pulmonary endocarditis 2 (1.0) 0 (0.0) 2 (2.2) 0.454
Endocavitar probe involvment 25 (13.1) 7 (7.1) 18 (19.4) 0.022
Vegetation 153 (80.1) 75 (76.5) 78 (83.9) 0.276
Vegetation size (mm) 11.5 [7.0, 17.0] 10.0 [7.0, 17.0] 12.0 [8.0, 16.0] 0.450

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European Journal of Clinical Microbiology & Infectious Diseases

Table 1 (continued)
Overall Cefazolin Cloxacillin p-value
n 192 98 94
Valvular leakage 98 (52.7) 47 (48.5) 51 (57.3) 0.289
Valvular perforation 24 (12.8) 8 (8.2) 16 (18.0) 0.074
Intracardiac abcess 35 (18.6) 16 (16.3) 19 (21.1) 0.513
Cefazolin/Cloxacillin duration (days) 31.0 [18.5, 43.0] 30.0 [18.0, 43.0] 32.0 [19.0, 43.8] 0.835
Results are presented as n (%) or median [IQR].

Table 2 Management of infectious endocarditis

Overall Cefazolin Cloxacillin p-value
n 192 98 94
Cefazolin/Cloxacillin
Continuous (vs. intermittent) administration 83 (44.9) 45 (46.9) 38 (42.7) 0.672
Switch from cefazolin/cloxacillin to cloxacillin/cefazolin 11 (5.7) 6 (6.1) 5 (5.3) 1.000
Cefazolin/Cloxacillin duration (days) 31.0 [18.5, 43.0] 30.0 [18.0, 43.0] 32.0 [19.0, 43.8] 0.835
Therapeutic drug monitoring 78 (44.3) 48 (50.0) 30 (37.5) 0.131
Other antimicrobial therapy
Initial use of Glyco/Lipopeptide 57 (29.8) 28 (28.6) 29 (31.2) 0.813
Aminoglycosides 84 (43.8) 31 (31.6) 53 (56.4) 0.001
Duration (days) 4.0 [2.0, 12.0] 8.0 [2.0, 14.0] 4.0 [2.0, 9.0] 0.087
Rifampicin 72 (37.5) 30 (30.6) 42 (44.7) 0.062
Duration (days) 30.0 [16.0, 41.0] 32.5 [18.5, 45.0] 24.5 [10.0, 38.5] 0.208
Fluoroquinolones 43 (22.4) 22 (22.4) 21 (22.3) 1.000
Duration (days) 16.5 [8.2, 36.0] 14.0 [7.5, 22.2] 32.0 [8.8, 43.8] 0.082
Oral antimicrobial therapy 40 (21.1) 13 (13.4) 27 (29.0) 0.014
Time of IV therapy before oral therapy 27.5 [16.0, 36.8] 22.0 [16.0, 34.0] 28.0 [20.0, 43.5] 0.370
Duration of oral therapy 23.0 [15.0, 35.0] 29.0 [18.0, 65.0] 20.5 [13.8, 32.0] 0.111
Total duration of antimicrobial therapy 42.0 [25.5, 49.0] 38.0 [25.0, 49.0] 43.0 [27.2, 49.0] 0.207
Surgical management 59 (31.1) 26 (26.5) 33 (35.9) 0.217
Valvular replacement 18 (31.0) 9 (36.0) 9 (27.3) 0.671
Time since the beginning of antimicrobial therapy 8.5 [4.0, 17.0] 8.0 [5.2, 15.8] 10.0 [3.0, 17.5] 0.994
Results are presented as n (%) or median [IQR].

age at the diagnosis of infective endocarditis was 67.8 years
[51.6–79.1], and most patients were male (137, 71.4%).
The median Charlson Comorbidity Index was 2 [0–4].
Twenty-three patients (11.9%) were injecting drug users,
and 20 (10.4%) were immunocompromised. Patients receiv-
ing cefazolin were more likely to have pre-existing severe
hepatopathy (9.3% vs. 0%, p-value = 0.007) and renal
impairment (31.6% vs. 16.0%, p-value = 0.018). Predis-
posing valvular disease was found in 87 (45.3%) patients,
and 35 (18.2%) patients had an implantable cardiac elec-
tronic device. Endocarditis was healthcare-associated in 67
patients (34.8%), with a lower rate of infection involving an
implantable device in those receiving cefazolin (7.1%) than
cloxacillin (19.4%, p = 0.022). S.aureus was the main patho-
gen involved in endocarditis (91.1%), mostly with aortic
(81, 42.4%) or mitral (76, 39.6%) valve localization. Valvu-
lar vegetation was found in 153 (80.1%) patients, and a val-
vular leaking in 98 (52.7%). Concurrent cerebral embolism
was found in 14 (16.5%) patients receiving cefazolin versus
27 (30.7%) patients receiving cloxacillin (p-value = 0.044).
Antibiotics received for the treatment of IE are detailed in
Table 2. 29.8% patients received glycopeptides or lipogly-
copeptides as initial antibiotic therapy. The median duration
of the antibiotic of interest (cefazolin/cloxacillin) was simi-
lar between groups: 30 days [18–43] for cefazolin versus 32
days [19–44] for cloxacillin. Therapeutic drug monitoring
was performed in 78 (44.3%) patients, with no differences
between groups. Fifty-nine patients (31.1%) underwent sur-
gery with a median delay of 8.5 days [4–17] after starting
antimicrobial therapy. More data about the surgery and its
delay according to the presence or absence of implantable
cardiac electronic device or prosthetic valves are available
in Table S2. Ten patients were lost to follow-up (Fig. 1).
The minimum inhibitory concentration value was available
for only 29 (15.1%) patients, with no differences between
groups.

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 European Journal of Clinical Microbiology & Infectious Diseases

Table 3 Results of primary and secondary effectiveness endpoints

Cloxacillin Cefazolin Raw survival analysis Adjusted survival analysis
cefazolin vs. cloxacillin cefazolin vs. cloxacillin
94 98 HR (95%CI) p-value HR (95%CI) p-value
Primary composite endpoint
Treatment failure 26 (27.7%) 34 (34.7%) 1.36 (0.81 to 2.28) 0.241 1.13 (0.63 to 2.03) 0.690
Secondary endpoint
Death within 90 days 21 (22.3%) 28 (28.6%) 1.35 (0.76 to 2.41) 0.308 1.13 (0.60 to 2.13) 0.716
Attributed to IE 17 (85.0%) 23 (85.2%)
Relapse withing 90 days after 4 (4.3%) 1 (1.0%) 1.46 (0.41 to 5.17) 0.559 1.9 (0.47 to 7.67) 0.396
the end of treatment
New embolic event during 4 (4.3%) 6 (6.1%) 0.24 (0.03 to 2.13) 0.200 0.3 (0.02 to 3.97) 0.431
antimicrobial therapy
Results are presented as n (%) or median [IQR].

Fig. 2 Kaplan Meier estimate of failure-free survival (primary end- (red) or cloxacillin (blue). (b) Kaplan-Meier estimates with 95% con-
point) and global survival. (a) Kaplan-Meier estimates with 95% con- fidence interval for global survival after treatment with cefazolin (red)
fidence interval for failure-free survival after treatment with cefazolin or cloxacillin (blue)

Effectiveness of cefazolin endocarditis was documented in 10 (5.2%) cases: 6 (6.1%)

Overall, 60 (32.6%) patients experienced treatment failure
according to the composite endocarditis criteria: 34 (34.7%)
in the cefazolin group, and 26 (27.7%) in the cloxacillin
group with no significant difference between groups in the
analysis of crude survival (HR = 1.36, 95%CI 0.81–2.28)
nor after the propensity score adjustment (aHR = 1.13,
95%CI 0.63–2.03), Table 3; Fig. 2. Ninety days after start-
ing antimicrobial therapy, 49 (25.5%) patients had died:
28 (28.6%) with cefazolin, and 21 (22.3%) with cloxacil-
lin. The median time to death was 22 days [15–40] without
difference between groups. Five patients had an incident
embolic event during antimicrobial therapy: 1 (1.0%)
with cefazolin, and 4 (4.3%) with cloxacillin. Relapse of
after receiving a treatment with cefazolin, and 4 (4.3%) with
cloxacillin (Figure S3).
Biological safety
After 14 days of antibiotic therapy, we found no statistical
difference in the evolution of biological safety parameters,
but for liver enzymes. Patients receiving cloxacillin had a
higher rate of moderate hepatic cytolysis (19.1%) than those
receiving cefazolin (8.2%, p-value = 0.044). Details of the
evolution of biological safety parameters are shown in Table
S3.

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European Journal of Clinical Microbiology & Infectious Diseases
Discussion
In this retrospective multicentric cohort study, we found no
differences in effectiveness between cefazolin and cloxacil-
lin for the treatment for infective endocarditis caused by
methicillin-susceptible Staphylococcus spp.
Our results support the conclusions of the previous ret-
rospective studies comparing cefazolin with ASPs for the
treatment of MSSA endocarditis [18–20]. Although these
studies did not show any significant difference in effective-
ness between treatment groups, their power was limited by
their small sample sizes, especially for cefazolin, with only
38 to 53 patients. It should also be noted that the condi-
tion of the patients at the time of diagnosis of endocarditis
was worse in the ASP group in one of these previous studies
[18], although the results were consistent in the multivari-
ate analysis. Similarly, although observational studies have
shown improved survival with cefazolin in MSSA blood-
stream infections [24–26], patients exposed to ASP were
more seriously ill at the start of antimicrobial therapy. In
the present study, we used propensity scores to adjust the
analysis of endpoints for patients’ baseline characteris-
tics. Significantly more aminoglycosides were used in the
cloxacillin group and this additional antibiotic therapy was
not included in the propensity score: it could have had an
impact on clinical outcomes by improving the effectiveness
of cloxacillin or increasing adverse events.
Regarding biological safety (Table S1), the use of clox-
acillin was associated with an increased risk of hepatic
cytolysis at D14 (19.1% vs. 8.1%). Unlike previous reports
[13, 27], the incidence of acute kidney injury remained low
and similar between groups. Cefazolin did not increase
prothrombin time after 14 days of treatment, but a risk of
coagulopathy has been described elsewhere [28]. This is in
contrast to previous reports which showed a better tolerabil-
ity profile with cefazolin [8, 12]. In MSSA endocarditis, sig-
nificantly fewer treatment interruptions have been reported
with cefazolin than with ASPs, possibly because of a lower
rate of clinically relevant adverse events [18].
Our study has several limitations. First, we acknowledge
the possibility of a selection bias, as the two groups were
not strictly comparable in terms of comorbidities and sever-
ity of endocarditis at diagnosis (Table 1). On the one hand,
patients were more severely ill in the cloxacillin group with
higher rate of endocarditis involving a cardiac device, and
cerebral embolism. On the other hand, cefazolin was given
preferentially to patients with comorbidities, including
those with chronic liver disease and chronic kidney injury.
To reduce this bias and increase the comparability between
groups at the time of antibiotic therapy initiation, we used a
propensity-based modelling [22]. Second, we only included
patients who received at least 10 days of antibiotic therapy,
which is likely to have excluded patients with early changes
in antibiotic therapy (possibly due to antibiotic-related
adverse events), embolic events or death. This made it pos-
sible to obtain a relevant and homogeneous sample, on the
basis of a significant period of treatment. Of note, in previ-
ous studies comparing cefazolin with ASPs, a single dose
of the targeted antibiotic was sufficient to be included in
the cohort, resulting in high heterogeneity between groups
[18, 19]. Third, cefazolin inoculum effect testing [29] was
not available and results were not stratified by presence of
cefazolin inoculum effect, which varies by can affect about
20–50% of Staphylococcus isolates, precluding conclu-
sion about a possible cefazolin inoculum effect previously
described for MSSA bloodstream infections [17] or endocar-
ditis [30]. Then, although we were not able to give details on
which drug was used for the majority of the antibiotic course
or which drug was the initial therapy, the median duration
of the antibiotic of interest was similar between groups. We
did not collect data on suppressive antibiotic therapy pre-
scription which could have been prescribed, especially for
non-operated patients despite a theorical indication. Like-
wise, we were not able to investigate the effect of therapeu-
tic drug monitoring on treatment failure or adverse events
[31]. Finally, our study was not designed to assess the effect
on microbiota, whereas cefazolin is known to have a greater
effect on Enterobacterales than cloxacillin [32].
However, this large multicentric cohort is the only one
providing a head-to-head comparison of cefazolin with a
single anti-staphylococcal penicillin, rather than a mix of
antibiotics. Our cohort was designed to match with the pro-
file of patients enrolled in the EURO-ENDO cohort [1]. We
only included patients with definite diagnosis of endocar-
ditis according to Duke criteria [5] to ensure homogeneity
within the population. We reinforced the comparativeness
of the groups by using a propensity-based modelling on the
choice of antibiotic. Considering bacteriological aspects, it
is the only study including both Staphylococcus aureus and
coagulase-negative staphylococci. This is important given
the increasing incidence in healthcare-associated endocar-
ditis due to CONS [4], and the equally poor prognosis of
these infections [33].
Conclusion
Cefazolin may be a possible alternative to cloxacillin for the
treatment of infective endocarditis caused by methicillin-
susceptible Staphylococcus spp. There is a strong need for
randomized non-inferiority trials in this indication.
Supplementary Information The online version contains
supplementary material available at https://doi.org/10.1007/s10096-
024-04851-6.
13

Acknowledgements We would like to thank the following colleagues :
La Pitié Salpêtrière University Hospital : Alexis Maillard, Henri Mon-
dor University Hospital : Soline Simeon, Cochin University Hospital :
Adrien Contejean, Grenoble University Hospital : Clementin Vignau,
Olivier Epaulard, Annecy Hospital : Mylène Maillet, Tristan Delory,
Lucas Pires, Virginie Vitrat, Mathieu Simonet, Chambery Hospital :
Margaux Isnard, Emmanuel Forestier.
Author contributions AL.D and M.M participated to design the study,
data collection and drafting the article. A.M and T.D participated to
design the study, statistical analyses and drafting the article. M.S, S.S,
CV, M.I, A.M and AC participated to data collection. LP made the
database.
Funding No external funding was received.
Data availability The datasets generated and analysed during the cur-
rent study may be available from the corresponding author on reason-
able request.
Declarations
Competing interests The authors declare no competing interests.
Date availability The datasets generated and analysed during the cur-
rent study may be available from the corresponding author on reason-
able request.
Ethical approval and consent to participate The institutional review
board n°IORG0009802 of the “Comité d’Ethique de Recherche en
Maladies Infectieuses et Tropicales” approved the study protocol on
2018-11-20. Data collection process was compliant with the European
General Data Protection Regulations. The research was conducted in
accordance with the Declaration of Helsinki and national and institu-
tional standards.
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