(Cl)oxacilline versus céfazoline pour le traitement des endocardites infectieuses à Staphylococcus aureus sensibles à la méthicilline : une étude quasi-expérimentale

Abstract

Introduction
Le fait que la céfazoline soit supérieure, ou non-inférieur, aux pénicillines du groupe M, pour le traitement des endocardites infectieuses (EI) à Staphylococcus aureus sensibles à la méthicilline (SASM), fait débat en l’absence d’essai randomisé. Dans des méta-analyses récentes, basées sur des études observationnelles, la céfazoline, pour le traitement des bactériémies à SASM, apparaît comme non inférieure, mais avec une meilleure tolérance que les pénicillines du groupe M. Malheureusement la validité de ces résultats est altérée par un biais d’indication. Dans cette étude quasi-expérimentale, nous avons comparé l’efficacité et la tolérance de ces deux traitements dans l’EI-SASM, en profitant de la période de pénurie en pénicilline du groupe M de 2016.

Matériels et méthodes
Avec cette étude monocentrique, nous avons comparé les patients, ayant un EI-SASM certaine (critères de DUKE-LI), traités par (cl)oxacilline de janvier 2015 à mars 2016, à ceux traités par céfazoline d’Avril 2016 à Octobre 2018. Le critère de jugement principal, évaluant l’efficacité, était la mortalité à 60 jours toutes causes confondues. Les critères de jugements secondaires, évaluant la tolérance, comprenaient la diminution significative du débit de filtration glomérulaire (DFG) et l’élévation significative des enzymes hépatiques durant le traitement. Le test du Logrank a été utilisé pour comparer le taux de survie et les tests du Chi² ou de Fischer pour comparer l’incidence des événements rénaux ou hépatiques.

Résultats
Parmi les 73 patients avec une EI-SASM certaine, 35 étaient traités par (cl)oxacilline et 38 par céfazoline. Les caractéristiques initiales des deux groupes étaient similaires (âge sexe, EI sur valves natives ou prothétiques, présentation clinique, complications cardiaques et septiques …). La mortalité à 60 jours toutes causes confondues était de 20 % (n = 7) dans le groupe (cl)oxacilline pour 23,7 % (n = 9) dans le groupe céfazoline (Logrank p = 0,56). Il n’y avait pas de différence significative entre les groupes concernant le nombre d’événements rénaux ou hépatiques avec respectivement dans les groupes (cl)oxacilline et céfazoline : diminution DFG 34,3 % (n = 12/35) vs 26,3 % (n = 10/38) p = 0,46 ; élévation ALAT 3,8 % (n = 1/26, donnée manquante pour neuf patients) vs 10,3 % (n = 3/29, donnée manquante pour neuf patients) p = 0,61, élévation bilirubine 44 % (n = 11/25, donnée manquante pour dix patients) vs 66,7 % (n = 18/27, donnée manquante pour onze patients) p = 0,10.

Conclusion
Dans cette étude quasi-expérimental, en l’absence de biais d’indication, la céfazoline n’apparait pas plus efficace ou mieux toléré que les pénicillines de groupes M pour le traitement des EI-SASM.

Full text

Vol.:(0123456789)
1 3
European Journal of Clinical Microbiology & Infectious Diseases
https://doi.org/10.1007/s10096-021-04313-3
ORIGINAL ARTICLE
Antistaphylococcal penicillins vs. cefazolin inthetreatment
ofmethicillin‑susceptible Staphylococcus aureus infective endocarditis:
aquasi‑experimental monocentre study
B.Lefèvre1,2,3 · B.Hoen1· F.Goehringer1· W.NgueyonSime4· N.Aissa5· C.Alauzet5,6· E.Jeanmaire1· S.Hénard1·
L.Filippetti7· C.Selton‑Suty7· N.Agrinier2,4· for AEPEI study group (Association pour l’Etude et la Prévention de
l’Endocardite Infectieuse)
Received: 3 March 2021 / Accepted: 9 July 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021
Abstract
Whether cefazolin is as effective and safer than antistaphylococcal penicillins (ASPs) for the treatment of methicillin-sus-
ceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) is still debated in the absence of a randomized controlled
trial. In this quasi-experimental study, we aimed to assess the effectiveness and safety of these two treatments in MSSA-IE,
using the ASPs nationwide shortage in April 2016 as a unique opportunity to overcome the indication bias associated with
observational studies. In this single-centre study, we compared patients with Duke-Li definite MSSA-IE treated with ASPs
from January 2015 to March 2016 versus those treated with cefazolin from April 2016 to December 2018, when ASPs
were not available. Effectiveness outcome was 90-day all-cause mortality. Safety outcomes included significant decrease
in GFR and significant increase in serum liver enzymes. Logrank test was used to compare survival rates. Of 73 patients
with MSSA-IE, 35 and 38 were treated with ASPs and cefazolin, respectively. Baseline patients’ characteristics (demogra-
phy, native or prosthetic valve IE, clinical characteristics, cardiac and septic complications) were similar between groups.
Ninety-day all-cause mortality was 28.6% and 21.1%, in patients treated with ASPs and cefazolin, respectively (logrank
p = 0.5727). There was no difference between groups for incident renal or liver toxicity events: acute kidney injury 45.7%
vs. 44.7% (p = 0.933), increased ALT 5.7% vs. 13.2% (p = 0.432), bilirubin increase 5.7% vs. 10.5% (p = 0.676), in ASPs vs.
cefazolin groups, respectively. In this quasi-experimental, effectiveness and safety did not statistically differ between ASPs
and cefazolin for MSSA-IE treatment.
Keywords Methicillin-susceptible Staphylococcus aureus· Infective endocarditis· Antistaphylococcal penicillins·
Cloxacillin· Oxacillin· Cefazolin
Introduction
Infective endocarditis (IE) is a rare but serious disease [1,
2]. Methicillin-susceptible Staphylococcus aureus (MSSA)
is the most frequent IE-causing agent in developed countries
[1–4]. MSSA-IE is associated with higher lethality (20–30%
in-hospital mortality) and morbidity (12 to 35% sympto-
matic embolism, 25 to 50% septic shock and need of valvular
surgery in 15 to 45% of cases) than streptococcal IE [5–9].
Antistaphylococcal penicillins (ASPs), which comprise
nafcillin, oxacillin, cloxacillin and flucloxacillin, are rec-
ommended as first-line treatment for MSSA-IE [10, 11]. In
2016, a shortage of ASPs occurred in France, which lasted
for months during which cefazolin was substituted for ASPs
in the treatment of MSSA infections [12]. Cefazolin is a
* B. Lefèvre
b.lefevre@chru-nancy.fr
1 Infectious andTropical Diseases, CHRU-Nancy, Université
de Lorraine, 54000Nancy, France
2 APEMAC, Université de Lorraine, 54000Nancy, France
3 Service Maladies Infectieuses Et Tropicales, Bâtiment
Des Spécialités Médicales, Hôpitaux de Brabois, Centre
Hospitalier Régional Universitaire de Nancy, Route de
Morvan, 54511Vandœuvre-Lès-NancyCedex, France
4 INSERM, CIC-EC, Epidémiologie clinique, CHRU-Nancy,
54000Nancy, France
5 Service de Microbiologie, CHRU-Nancy, 54000Nancy,
France
6 SIMPA, Université de Lorraine, 54000Nancy, France
7 Cardiology, CHRU-Nancy, 54000Nancy, France

European Journal of Clinical Microbiology & Infectious Diseases
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first-generation cephalosporin with a MSSA activity [13,
14]. In prior studies, which showed its higher susceptibility
to inoculum effect, cefazolin appeared to be less effective
than ASPs for the treatment of MSSA infections [15–23]. As
a result, cefazolin was used in case of allergy to penicillin or
recommended as a second-line treatment for MSSA-IE [10,
11]. More recently, several observational studies comparing
ASPs vs. cefazolin in bloodstream infections (BSI) showed
similar effectiveness outcomes and trends towards better tol-
erability of cefazolin [24–30]. To our knowledge, only one
observational study addressed this question in 210 MSSA-IE
and showed similar effectiveness outcome but more prema-
ture antibiotherapy discontinuation due to adverse event in
ASPs treatment group [31].
We aimed to assess the effectiveness and safety of ASPs
and cefazolin in the treatment of MSSA-IE, using the nation-
wide shortage of ASPs that started in 2016 as a unique
opportunity to overcome the indication bias usually associ-
ated with comparative observational studies.
Materials andmethods
Design andsetting
We used data from The French National Observatory on
Infective Endocarditis (ObservatoireEI, NCT03272724).
The objectives of this open cohort of IE patients are (i) to
describe patients’ characteristics, (ii) to describe prognostic
features and (iii) to assess the effectiveness of various thera-
peutic strategies in IE patients. Patients included in Observa-
toireEI had definite or possible IE according to Duke-Li cri-
teria [10], were 18years of age or older and were registered
in the French national health insurance system. Patients were
recruited from 11 participating centres, and were followed
up from hospital admission to discharge.
According to the guidelines in use [10, 11], the usual
treatment for MSSA-IE was based on ASPs. As a nationwide
shortage in ASPs occurred in April 2016 in France, cefazo-
lin was used as a substitute for ASPs. We thus conducted
a quasi-experimental before-and-after cohort study within
ObservatoireEI. Because information on antimicrobial treat-
ment were limited in ObservatoireEI database, we retrieved
additional information from patients’ medical records in
only the biggest participating centre of the ObservatoireEI.
Population andsampling
We selected patients admitted to Nancy University Hospital
between January 1, 2015, and December 31, 2018, with a defi-
nite MSSA-IE according to the Duke-Li criteria. Patients with
IE due to several pathogens; patients treated with both ASPs
and cefazolin during their hospital stay; and patients treated
with neither ASPs nor Cefazolin were excluded. Accordingly,
two groups of patients were considered: (i) the ASPs group
of MSSA-IE patients recruited between January 1, 2015, and
March 31, 2016, and treated with ASPs only; and (ii) the cefa-
zolin group of MSSA-IE patients recruited between April 1,
2016, and December 31, 2018, and treated with cefazolin only.
Data collection
Reuse ofdata fromObservatoireEI
Baseline characteristics were part of routine data collec-
tion in the ObservatoireEI and were used for these analyses.
These characteristics consisted of demographic characteris-
tics, i.e. age (years) and male sex; medical history, i.e. dia-
betes, hypertension, smoker, alcohol abuse, coronary heart
disease, heart failure, valvular disease, peripheral arterial
disease, chronic respiratory disease, gastric ulcer, chronic
kidney disease, neurological disorders, malignant disease,
haematological disease, liver diseases, immune deficiency,
autoimmune disease, prosthetic valve, intracardiac device
(pacemaker or implantable cardioverter-defibrillator), extra-
cardiac prosthetic device and Charlson index; medications,
i.e. anticoagulant, antiplatelet agents, statins and NSAIDs;
mode of acquisition, i.e. community, healthcare-related and
intravenous drug use; clinical characteristics, i.e. body mass
index (BMI, kg/m2), fever, initial Glasgow score, spleno-
megaly, Janeway lesions, purpura, Osler nodes, glomerulo-
nephritis, haematuria, cardiac murmur, severe regurgitation,
heart failure, NYHA III/IV, cardiac conduction abnormali-
ties, septic shock, spondylitis, arthritis, extracardiac pros-
thetic infection and haemodialysis for acute renal failure;
location of IE, i.e. aortic, mitral, tricuspid, pulmonary,
intracardiac device, other location and unknown; echo-
cardiographic characteristics, i.e. vegetation, perforation,
prosthetic valve complication, cardiac abscess and cardiac
fistula; vascular phenomena, i.e. arterial aneurysm, cerebral
complications and extracerebral embolic events; surgical
act, i.e. cardiac surgery indication, cardiac and extracardiac
surgery; and evolution, i.e. relapse, neurological sequelae,
valvular/prosthetic dysfunction and chronic heart failure.
The main outcome was mortality within 90days after
admission to hospital. Vital status and, when applicable, date
of death were collected. For survivors, data were censored
at 90days after hospital admission or at hospital discharge,
whichever came first.
Collection ofadditional data
Data on antibiotic treatment that were specifically collected
for this study consisted of international non-proprietary
names, dose and dates of treatment initiation and discon-
tinuation. As recommended in the guidelines [11], standard

European Journal of Clinical Microbiology & Infectious Diseases
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antibiotic dosages were used and adapted by drug monitor-
ing to target optimal blood concentrations.
We also collected serum creatinine and serum liver
enzyme (AST, ALT and total bilirubin) before antibiotic
initiation (basal) and during antibiotic treatment (retaining
the highest value observed). Inspired from adverse events
definitions of the Kidney Disease Improving Global Out-
comes and U.S. National Institute of Health [32, 33], sec-
ondary outcomes were occurrence of (i) acute kidney injury
(AKI), defined as an increase in creatinine ≥ 1.5 times the
baseline value or as an increase of 0.3mg/dL in compari-
son with baseline creatinine; (ii) hepatic cytolysis, defined
as an increase in aminotransferase (AST or ALT) ≥ 3 upper
limit normal (ULN) if baseline is normal or ≥ 1.5 ULN if
baseline is abnormal; and (iii) bilirubin increase, defined as
an increase in total bilirubin level ≥ 1.5 ULN if baseline is
normal or ≥ 1.0 ULN if baseline is abnormal.
Ethics
This study complies with the principles outlined in the Dec-
laration of Helsinki. Patients were informed of the study and
individual consent was waived, in accordance with French
legal standards. ObservatoireEI was authorized by the Com-
mission Nationale de l’Informatique et des Libertés (CNIL).
Statistical analyses
We first described baseline sociodemographic characteris-
tics, medical history, clinical and echocardiographic charac-
teristics and antibiotic treatment, stratified on antibiotic type,
using frequencies and percentages for categorical variables
and median with standard deviation for quantitative vari-
ables, except for doses and length of antibiotic treatment for
which range was also considered. These characteristics were
then compared between the two groups using Chi-squared
or Fisher test for categorical variables and Student t test or
Wilcoxon rank tests for quantitative variables, according to
the condition of use.
Likewise, we described antibiotic treatment prescribed
during the hospital stay and safety outcomes, stratified on
antibiotic type and on antibiotic treatment duration. We
then compared safety outcomes between groups in the
whole study sample and in those who had been treated for
Fig. 1 Flow chart of selection
of patients with methicillin-sus-
ceptible Staphylococcus aureus
(MSSA) infective endocarditis
(IE) derived from Observatoi-
reEI
Patients with definite
MSSA-IE treated with
ASPs or cefazolin
n=73
Patients with definite
MSSA-IE treated with
cefazolin
n = 38
Patients with definite
MSSA-IE treated with
ASPs
n = 35
Patients with no definite IE: n = 508
Patients recruited before Jan 2015 or
after Dec 2018: n = 1873
Patient from other centers n = 432
Patients treated in
Nancy university
hospital between
January 2015 and
December 2018 n = 385
Patients with definite
MSSA-IE n = 108
Patients included in
ObservatoireEI n = 3198
Patients with non-MSSA IE: n=216
Patients with polymicrobial IE: n = 42
Patients with culture negative IE: n = 13
Patients with multiple IE during the period: n = 6
Patients treated with ASPs after Apr 2016 or
cefazolin before Apr 2016: n=7
Patients treated with both ASPs and
cefazolin: n = 25
Patients treated with neither ASPs nor
cefazolin: n = 3

European Journal of Clinical Microbiology & Infectious Diseases
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Table 1 Baseline characteristics
and medical history of patients
with MSSA-IE in ASPs (Anti
Staphylococcal Penicillin) and
cefazolin groups
ASPs group (N = 35) Cefazolin group
(N = 38)
p value
N%N%
Demographics
Mean age in years (SD) 59.5 (19.1) 54.4 (18.2) 0.247
Men 27 77.1 27 71.1 0.554
Medical history
Diabetes 8 22.9 12 31.6 0.404
Hypertension 12 34.3 22 57.9 0.043
Smoker 11 35.5 15 46.9 0.359
Alcohol abuse 6 20.7 12 36.4 0.175
Coronary heart disease 10 28.6 8 21.1 0.457
Heart failure 5 14.3 11 28.9 0.130
Valvular disease 9 26.5 12 32.4 0.582
Arteritis 6 17.1 6 15.8 0.876
Chronic respiratory failure 5 14.3 5 13.2 0.889
Gastric ulcer 0 0.0 2 5.3 0.169
Chronic kidney disease 6 17.1 5 13.2 0.748
Neurological disorders 4 11.4 4 10.5 1.000
Malignant disease 6 17.1 5 13.2 0.635
Haematological disease 4 11.4 0 0.0 0.048
Liver disease 8 22.9 4 10.8 0.170
Immune deficiency 2 5.7 4 10.5 0.676
Autoimmune disease 1 2.9 2 5.3 1.000
Prosthetic valve 6 17.1 7 18.4 0.926
Extracardiac prosthetic device 10 28.6 12 31.6 0.780
Median Charlson index (IQR) 2.0 (4.0) 1.5 (3.0) 0.439
Medications
Anticoagulant 11 31.4 12 31.6 0.989
Antiplatelet agents 16 45.7 13 34.2 0.316
Statins 9 25.7 12 31.6 0.580
NSAIDs 0 0 1 2.6 1.000
Mode of acquisition
Community 13 37.1 17 44.7 0.510
Healthcare-related 11 31.4 12 31.6 0.989
Intravenous drug use 11 31.4 9 23.7 0.459
Clinical characteristics
Mean BMI kg/m2 (SD) 24.4 (5.8) 25.6 (6.1) 0.370
Fever 28 80.0 35 92.1 0.179
Media initial Glasgow score (IQR) 15 (0.0) 15 (0.0) 0.818
Splenomegaly 7 20.0 3 8,1 0.184
Janeway lesions 1 2.9 2 5.3 1.000
Purpura 5 14.3 4 10.5 0.729
Osler Nodes 4 11.4 2 5.3 0.418
Glomerulonephritis 13 38.2 7 25.0 0.267
Haematuria 15 46.9 7 26.9 0.119
Cardiac murmur 17 48.6 23 60.5 0.305
Severe regurgitation 6 17.6 12 31.6 0.173
Heart failure 12 34.3 14 36.8 0.820
NYHA III or IV 7 20.6 2 5.9 0.150
Cardiac conduction abnormalities 2 5.9 1 2.7 0.604
Septic shock 9 25.7 13 34.2 0.429

European Journal of Clinical Microbiology & Infectious Diseases
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more than 7days to count for a minimal time to antibiotic
exposure.
Ninety-day mortality was described in the two groups
using Kaplan–Meier estimates, and compared with logrank
test. The statistical significance level was set at 0.05.
All statistical analyses were performed using SAS 9.4
(SAS Institute, Inc., Cary, NC) software.
Results
A total of 35 patients formed the ASPs group and 38 the cefa-
zolin group (Fig.1).
Baseline characteristics (Table1) were similar between
groups, except for hypertension (12 [34.3%] in the ASPs
group vs. 22 [57.9%] in the cefazolin group, p = 0.043) and
haematological diseases (4 [11.4%] in the ASPs group and
none in the cefazolin group, p = 0.048).
ASPs, cefazolin, rifampicin, gentamicin, other antibiotics
doses and durations are described in Table2. Two patients
(5.7%) from the ASPs group received oxacillin, and one
patient (2.9%) received successively oxacillin and cloxacil-
lin. Due to early death, three (8.6%) patients received less
than 7days of antibiotic treatment in the ASPs group vs. four
(10.5%) patients in the cefazolin group. Without any signifi-
cant statistical difference, there were more relapses and cardiac
sequelae in cefazolin group vs. more neurological sequela in
ASPs group (Table1).
Frequencies of patients who received rifampicin and/
or gentamicin and treatment duration in combination with
β-lactam did not differ between groups (Table2). Rifampicin
doses were significantly higher in ASPs group (median 1.2g
Table 1 (continued) ASPs group (N = 35) Cefazolin group
(N = 38)
p value
N%N%
Spondylitis 6 17.1 2 5.3 0.142
Arthritis 4 11.4 7 18.4 0.519
Extracardiac prosthetic infections 6 17.1 8 21.1 0.672
Haemodialysis for AKI 5 14.3 11 28.9 0,130
Location of IE
Aortic 11 31.4 12 31.6 0.989
Mitral 10 28.6 16 42.1 0.228
Tricuspid 8 22.9 11 28.9 0.554
Intracardiac device 7 20.0 8 21.1 0.911
Others 1 2.9 3 7.9 0.616
Echocardiographic characteristics
Vegetation 27 77.1 31 81.6 0.639
Perforation 6 17.1 11 28.9 0.233
Prosthetic valve complication 2 33.3 0 0.0 0.192
Cardiac abscess 4 11.4 10 26.3 0.141
Cardiac fistula 1 2.9 3 7.9 0.616
Vascular phenomena
Arterial Aneurysm 3 8.6 2 5.3 0.666
Cerebral complication 9 25.7 7 18.4 0.452
Extracerebral embolic event 24 68.6 26 68.4 0.989
Surgery
Cardiac surgery indication 23 65.7 30 78.9 0.205
Cardiac surgery 12 34.3 19 50.0 0.175
Extracardiac surgery 5 14.3 7 18.4 0.634
Evolution
Relapse 0 0.0 2 5.3 0.494
Neurological sequelae 3 8.6 0 0.0 0.105
Valvular/Prosthetic dysfunction 0 0.0 3 10.3 0.237
Chronic heart failure 0 0.0 3 10.3 0.237

European Journal of Clinical Microbiology & Infectious Diseases
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Table 2 Additional antibiotic prescriptions during ASPs (anti staphylococcal penicillin) or cefazolin treatment period
Notes: *p value for comparison between total ASPs and cefazolin groups
** p value for comparison between ASPs and cefazolin subgroups of patients who received antibiotics during 7days or more
ASPs group (n = 35) Cefazolin group (n = 38) Statistical analysis
Total < 7days (n = 3) > = 7days (n = 32) Total < 7days (n = 4) > = 7days (n = 34) Total > = 7days
N (%) Median
(Min–Max)
N (%) Median
(Min–Max)
N (%) Median
(Min–Max)
N (%) Median
(Min–Max)
N (%) Median
(Min–Max)
N (%) Median
(Min–Max)
p*p**
ASPs or
cefazolin
35(100%) 38 (100%)
Average
daily dose
(gram)
12.0 (15.0–
18.8)
8.0 (8.0–12.0) 12.0
(3.2–18.0)
6.0 (1.9–8.6) 6.0 (6.0–6.0) 6.0 (1.9–8.6)
Duration
(days)
29.5
(1.0–85.0)
2.5 (1.0–4.0) 32.5
(7.0–85.0)
26.5
(2.0–86.0)
3.5 (2.0–5.0) 30.5
(8.0–86.0)
Rifampicin 24 (68.6) 1 (4.2) 21 (87.5) 19 (50.0) 1 (5.3) 18 (94.7) 0.170 0.426
Average
daily dose
(gram)
1.2 (1.0–1.8) 1.2 (1.2–1.2) 1.2 (1.0–1.8) 1.2 (0.6–1.2) 1.2 (1.2–1.2) 1.2 (0.6–1.2) 0.027 0.025
Duration
(days)
25.0
(1.0–56.0)
3.5 (1.0–6.0) 26.0
(1.0–56.0)
17.0
(3.0–60.0)
4.0 (4.0–4.0) 18.0
(3.0–60.0)
0.673 0.957
Gentamicin 29 (82.9) 3 (10.3) 26 (89.7) 29 (76.3) 3 (10.3) 26 (89.7) 0.688 0.862
Duration
(days)
3.0 (1.0–
14.0)
3.5 (2.0–5.0) 3.0 (1.0–14.0) 3.0 (1.0–18.0) 2.0 (2.0–3.0) 3.0 (1.0–18.0) 0.345 0.311
Others anti-
biotics
24 (68.6) 13 (54.2) 11 (45.8) 31 (81.6) 18 (58.1) 13 (41.9) 0.013 0.944

European Journal of Clinical Microbiology & Infectious Diseases
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Min–Max [1.0–1.8] vs. 1.2g Min–Max [0.6–1.2], p = 0.027;
Table2). Other antibiotics were prescribed for empiric anti-
biotic therapy purpose (before IE diagnosis), associated
infection or synergistic effect purpose. Patients in the ASPs
group received less frequently other antibiotics than patients
in the cefazolin group (24 [68.6%] vs. 31 [81.6%], p = 0.013;
Table2). These other antibiotics consisted of at least one dose
of amikacin (n = 2 in the ASPs group vs. n = 7 in the cefazolin
group), amoxicillin (n = 4 vs. n = 13), clavulanic acid (n = 1 vs.
n = 2), third-generation cephalosporin (n = 15 vs. n = 19), fluo-
roquinolones (n = 15 vs. n = 17), macrolides (n = 15 vs. n = 9),
piperacillin-tazobactam (n = 4 vs. n = 7), carbapenem (n = 1
vs. n = 2), vancomycin (n = 11 vs. n = 21), daptomycin (n = 2
vs. n = 5), linezolid (n = 4 vs. n = 2) and fosfomycin (n = 1 vs.
n = 1). Restricting analyses to patients receiving ASPs or cefa-
zolin during ≥ 7days did not modify these results.
A total of 18 patients died during the follow-up, 10 (28.6%)
in the ASPs group and 8 (21.1%) in the cefazolin group.
Ninety-day survival did not differ significantly between groups
(Fig.2). The median follow-up was 90.0days IQL [58.0–90.0]
vs. 90.0days IQL [90.0–90.0], respectively, in ASPs and cefa-
zolin groups. There were 3 patients lost to follow-up in ASPs
Fig. 2 Kaplan–Meier 90-day
survival estimates in patients
with MSSA-IE receiving ASPs
(Anti Staphylococcal Penicillin)
or cefazolin
Table 3 Safety events in patients with MSSA-IE receiving ASPs (antistaphylococcal penicillins) or cefazolin
Notes: *p value for comparison between total ASPs and cefazolin groups
** p value for comparison between ASPs and cefazolin subgroups of patients who received antibiotics during 7days or more
ASPs Cefazolin Statistical
analyses
Total* < 7days > = 7days** Total* < 7days > = 7days**
(n = 35) (n = 3) (n = 32) (n = 38) (n = 4) (n = 34) p*p**
N%N%N%N%N%N%
Acute kidney injury 16 45.7 2 66.7 14 43.8 17 44.7 2 50.0 15 44.1 0.933 0.976
AST hepatic cytolysis 2 5.7 1 33.3 1 3.1 7 18.4 2 50.0 4 11.8 0.155 0.357
ALT hepatic cytolysis 2 5.7 0 0.0 2 3.3 5 13.2 1 25.0 4 11.8 0.432 0.673
Bilirubin Increase 2 5.7 1 33.3 1 3.1 4 10.5 1 25.0 3 8.8 0.676 0.614

European Journal of Clinical Microbiology & Infectious Diseases
1 3
Table 4 Literature review of effectiveness and safety events associated with MSSA-BSI
ASPs group Cefazolin group Statistical analysis
N Mortality (%)* Acute kidney
injury (%)**
Hepatic cytoly-
sis (%)***
N Mortality (%)* Acute kidney
injury (%)**
Hepatic cytoly-
sis (%)***
p*p** p***
Observational studies
[24] Bai 2015 249 75 (30.1) 105 21 (20.0) 0.068
[25] Lee 2011 41 4 (9.8) 41 4 (9.8) 1.000
[28] Paul 2011 281 91 (32.4) 72 29 (40.3) 0.262
[29] Rao 2015 58 3 (5.2) 0 (0.0) 1 (1.7) 103 1 (1.0) 1 (1.0) 0 (0.0) 0.134 1.000 0.360
[30] Monogue 2018 71 3 (4.2) 12 (16.9) 71 0 (0.0) 2 (2.8) 0.245 0.009
[31] Lecomte 2020 157 45 (28.7) 53 13 (24.5) 0.561
[41] Pollet 2016 30 5 (16.7) 70 5 (7.1) 0.161
[42] Davis 2018 6520 731 (11.2) 792 83 (10.5) 1.000
[44] Li 2014 34 1 (2.9) 1 (2.9) 6 (17.7) 59 0 (0.0) 0 (0.0) 0 (0.0) 0.366 0.366 0.002
[43] Renaud 2011 13 2 (15.4) 14 1 (7.1) 0.596
[47] Flynt 2017 82 4 (4.9) 26 (31.7) 8 (9.8) 68 4 (5.9) 9 (13.2) 1 (1.5) 1.000 0.0136 0.041
[45] Youngster 2014 366 4 (10.9) 42 (11.5) 30 (8.2) 119 1 (0.8) 4 (3.4) 2 (1.7) 1.000 0.007 0.010
[46] Burrelli 2018 116 4 (12.1) 32 (29.1) 6 (5.8) 41 0 (0.0) 4 (15.4) 0 (0.0) 0.573 0.217 0.338
[48] Miller 2020 40 4 (10.0) 20(50.0) 9 (0.2) 50 3 (6.0) 1 (2.0) 0 (0.0) 0.695 < 0.001 < 0.001
[49] Chan 2020 119 NA 22 (18.5) 1 (0.8) 205 NA 4 (2.0) 2 (1.0) NA < 0.001 1.000
[38] Lee 2018 163 24 (14.7) 79 2 (2.5) 0.003
[39] McDanel 2018 2004 502 (25.1) 1163 231 (19.9) 0.001
[40] Twilla 2020 126 19 (15.1) 14 (11.1) 6 (4.8) 151 9 (6.0) 6 (4.0) 3 (2.0) 0.012 0.022 0.308
Meta-analysis
[34] Weiss 2019 2802 703 (25.1) 82 (11.9) 1589 289 (18.2) 17 (3.4) < 0.001 < 0.001
[35] Bidell 2018 2802 703 (25.1) 1589 289 (18.2) < 0.001
[36] Rindone 2018 2954 712 (24.1) 1774 295 (16.6) < 0.001
[37] Shi 2018 2997 711 (23.7) 1782 375 (21.0) 0.036
Subgroup of endocarditis in each study
[24] Bai 2015 30 2
[25] Lee 2011 13 1 (7.7) 1 1 (100.0) 0,257
[28] Paul 2011 3 3
[29] Rao 2015 12 2 (16.7) 17 4 (23.5) 1.000
[30] Monogue 2018 6 3
[31] Lecomte 2020 157 45 (28.7) 53 13 (24.5) 0.561
[41] Pollet 2016 5 10
[42] Davis 2018 442 82 (18.6) 47 5 (10.6) 0,251
[44] Li 2014 3 1 (33.3) 17 0 (0.0) 0,158
[43] Renaud 2011 1 0

European Journal of Clinical Microbiology & Infectious Diseases
1 3
group vs. none in cefazolin group. There was no difference for
safety events (Table3).
Discussion
In this study, effectiveness and safety profiles were not sig-
nificantly different between ASPs and cefazolin groups. To
our knowledge, it is the first study analysing MSSA-IE with
a specific design to try to overcome the indication bias.
Only one observational study compared ASPs to cefazo-
lin specifically in MSSA-IE, and showed no difference in
survival rates [31] (Table4). Results from four meta-analy-
ses comparing ASPs to cefazolin in BSI favoured cefazolin,
but were flawed by between-studies heterogeneity [34–37],
and failed to show any survival difference when focusing on
IE patients [34].
Among 17 observational studies that compared ASPs to
cefazolin in BSI, only three showed a better survival in the
cefazolin group [38–40] (Table4). However, ASPs were
more often prescribed than cefazolin in patients with IE,
higher SOFA score or more frequently admitted to ICU
[38–40]. Accordingly, worse patients’ baseline clinical sta-
tus, e.g. complicated MSSA-BSI (septic shock, meningitis,
endocarditis, etc.) or a high-inoculum infection (endocar-
ditis, abscesses, etc.), could explain the higher mortality
observed in patients receiving ASPs in these studies. This
highlights how indication bias alters initial groups’ compara-
bility in observational studies. Relying on the national short-
age of ASPs to tackle indication bias, we found no statistical
difference in mortality between patients treated with ASPs
and those treated with cefazolin in our study. Though statis-
tically insignificant, the magnitude of the observed mortal-
ity difference between groups might result from a lack of
power to detect a difference favouring cefazolin. However,
to detect such a difference of mortality between groups (i.e.
21% in patients treated with cefazolin vs. 28% in patients
treated with ASPs) with a power of 80% and a first order
set at 5%, a sample size of 1,180 patients with SAIE would
have been required. Only a multicentre RCT assessing the
effectiveness of ASPs vs. cefazolin could address indication
bias while ensuring sufficient power to detect any differ-
ence in effectiveness. Though relying on a non-inferiority
hypothesis, a large size randomized clinical trial comparing
ASPs vs. cefazolin in BSI is currently underway (CloCeBa,
NCT03248063), and will address both indication bias and
lack of power.
Concerning the safety profile, we found no difference
between groups in our study (Table3). In the literature, nine
studies and two of the four meta-analyses did not specifi-
cally address AKI or liver adverse events (Table4) [24, 25,
28, 31, 34, 37–39, 41–43]. Nevertheless, five studies and
two meta-analyses assessed the discontinuation rates due
Notes: *p value for mortality comparison between total ASPs and cefazolin groups
** p value for acute kidney injury comparison between ASPs and cefazolin groups
*** p value for hepatic cytolysis comparison between ASPs and cefazolin groups
Table 4 (continued)
ASPs group Cefazolin group Statistical analysis
N Mortality (%)* Acute kidney
injury (%)**
Hepatic cytoly-
sis (%)***
N Mortality (%)* Acute kidney
injury (%)**
Hepatic cytoly-
sis (%)***
p*p** p***
[47] Flynt 2017 22 11 (50.0) 11 3 (27.3) 0,278
[45] Youngster 2014 28 7
[46] Burrelli 2018 14 4
[48] Miller 2020 8 8
[49] Chan 2020 12 11
[34] Weiss 2019 588 101 (17.2) 64 7 (10.9) 0.202
[35] Bidell 2018 210 86
[36] Rindone 2018 106 84
[37] Shi 2018 254 125
[38] Lee 2018 11 1
[39] McDanel 2018 145 52
[40] Twilla 2020 20 13

European Journal of Clinical Microbiology & Infectious Diseases
1 3
to antibiotic adverse events, although without breakdown
of the adverse event types, showing better safety outcomes
witch cefazolin [25, 31, 35, 36, 38, 44, 45]. Three stud-
ies showed no difference in terms of AKI or liver adverse
events between ASPs and cefazolin (Table4) [29, 44, 46].
However, their retrospective design may have led to under-
estimate their frequency [29, 44, 46]. Seven studies and
two meta-analysis reported less AKI and/or hepatic safety
events in the cefazolin group (Table4) [30, 34, 37, 40, 44,
45, 47–49]. But, the heterogeneity between studies regard-
ing populations and events definition, within-studies lack
of baseline between-groups comparability and retrospective
data collection makes it difficult to draw any conclusions
in terms of causality. In our study, we assessed bilirubin
increase as a tolerability marker and found no significant
difference. However, we found no study that compared ASPs
vs. cefazolin for bilirubin increase. Sixteen studies reported
other adverse events that were not collected in our study
and failed to prove any significant difference: relapse/recur-
rence rates [24, 25, 28, 30, 34, 36–40, 44, 47], persistence of
bacteraemia [25, 28, 30, 38, 40, 44], ICU admission [24, 30,
39, 41, 42, 44], neurotoxicity [29], haematological toxicity
[30, 37, 40, 44, 45], rash and allergic events [29, 40, 44, 45,
47], diarrhoea [40, 44, 45, 47]. Only one study found more
allergic reaction in the ASPs treatment group [48].
Our work has some limitations. First, this before/after
quasi-experimental study does not provide the same level
of evidence and the same bias protection as a well-powered
randomized clinical trial and such data are still lacking.
Second, the duration of ASPs shortage was limited, which
explains the quite low number of patients with MSSA-IE
included, limiting the power of the study. Likewise, the
single-centre design limited the sample size and the scope
of our results. However, the selection of patients in a single
centre of ObservatoireEI led to a greater homogeneity of the
sample, which is always preferred in experimental studies.
To our knowledge, this quasi-experimental is the first to
assess the effectiveness and safety of ASPs vs. cefazolin in
the treatment of MSSA-IE. Despite our limited sample size,
our findings concur to others’ and suggest that cefazolin is a
reasonable alternative to ASPs in the treatment of MSSA-IE.
Acknowledgements We would like to acknowledge the entire Obser-
vatoireEI team.
Author contribution Personal contribution for the conception and
design of the study (BL, BH, FG, NAg), acquisition of data (BL, BH,
FG, NA, CA, EJ, SH, LF, CSS), analysis and interpretation of data
(BL, BH, WNS, NAg), drafting the article or revising it critically for
important intellectual content (BL, BH, WNS, NAg) and final approval
of the version to be submitted (BL, BH, FG, NA, WNS, NA, CA, EJ,
SH, LF, CSS, NAg).
Data and materials availability The datasets generated during and/or
analysed during the current study are not publicly available due to
restrictions by the French law, but are available from the last author on
reasonable request at the following email address: n.agrinier@chru-
nancy.fr.
Code availability Not applicable.
Declarations
Ethics approval This study complies with the principles outlined in the
Declaration of Helsinki. ObservatoireEI (NCT03272724) was author-
ized by the Commission Nationale de l’Informatique et des Libertés
(CNIL).
Consent to participate Patients were informed of the study and indi-
vidual consent was waived, in accordance with French legal standards.
Consent for publication Not applicable.
Conflict of interest The authors declare no competing interests.
References
1. Habib G, Erba PA, Iung B, Donal E, Cosyns B, Laroche C etal
(2019) Clinical presentation, aetiology and outcome of infective
endocarditis. Results of the ESC-EORP EURO-ENDO (European
infective endocarditis) registry: a prospective cohort study. Eur
Heart J 40:3222–3232. https:// doi. org/ 10. 1093/ eurhe artj/ ehz620
2. Selton-Suty C, Célard M, Le Moing V, Doco-Lecompte T, Chi-
rouze C, Iung B etal (2012) Preeminence of Staphylococcus
aureus in infective endocarditis: a 1-year population-based sur-
vey. Clin Infect Dis 1(54):1230–1239. https:// doi. org/ 10. 1093/ cid/
cis199
3. Olmos C, Vilacosta I, Fernández-Pérez C, Bernal JL, Ferrera C,
García-Arribas D etal (2017) The evolving nature of infective
endocarditis in Spain. J Am Coll Cardiol 70:2795–2804. https://
doi. org/ 10. 1016/j. jacc. 2017. 10. 005
4. Cahill TJ, Prendergast BD (2016) Infective endocarditis. Lancet
387:882–893. https:// doi. org/ 10. 1016/ S0140- 6736(15) 00067-7
5. Chu VH, Cabell CH, Benjamin DK, Kuniholm EF, Fowler VG,
Engemann J etal (2004) Early predictors of in-hospital death in
infective endocarditis. Circulation 13(109):1745–1749. https://
doi. org/ 10. 1161/ 01. CIR. 00001 24719. 61827. 7F
6. Hill EE, Herijgers P, Claus P, Vanderschueren S, Peetermans WE,
Herregods M-C (2008) Clinical and echocardiographic risk fac-
tors for embolism and mortality in infective endocarditis. Eur J
Clin Microbiol Infect Dis 27:1159–1164. https:// doi. org/ 10. 1007/
s10096- 008- 0572-9
7. Asgeirsson H, Thalme A, Weiland O (2018) Staphylococcus
aureus bacteraemia and endocarditis – epidemiology and out-
come: a review. Infect Dis 4(50):175–192. https:// doi. org / 10. 1080/
23744 235. 2017. 13920 39
8. Le Moing V, Alla F, Doco-Lecompte T, Delahaye F, Piroth L,
Chirouze C etal (2015) Staphylococcus aureus bloodstream infec-
tion and endocarditis - a prospective cohort study. PLoS ONE
28(10):e0127385. https:// doi. org/ 10. 1371/ journ al. pone. 01273 85
9. Hoen B, Duval X (2013) Infective endocarditis. N Engl J Med
11(368):1425–1433. https:// doi. org/ 10. 1056/ NEJMc p1206 782
10. Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta J-P,
Del Zotti F etal (2015) 2015 ESC Guidelines for the management
of infective endocarditis: The Task Force for the Management
of Infective Endocarditis of the European Society of Cardiology
(ESC) Endorsed by: European Association for Cardio-Thoracic

European Journal of Clinical Microbiology & Infectious Diseases
1 3
Surgery (EACTS), the European Association of Nuclear Medicine
(EANM). Eur Heart J 21(36):3075–3128. https:// doi. org/ 10. 1093/
eurhe artj/ ehv319
11. Baddour LM, Wilson WR, Bayer AS, Fowler VG, Tleyjeh IM,
Rybak MJ etal (2015) Infective endocarditis in adults: diagno-
sis, antimicrobial therapy, and management of complications:
A Scientific Statement for Healthcare Professionals From the
American Heart Association. Circulation 13(132):1435–1486.
https:// doi. org/ 10. 1161/ CIR. 00000 00000 000296
12. SPILF & GPIP (2016) Propositions d’alternatives à l’oxacilline
ou la cloxacilline par voie IV chez l’adulte et l’enfant en con-
texte de rupture de stock [Internet]. 22.https:// ansm. sante. fr/
var/ ansm_ site/ stora ge/ origi nal/ appli cation/ 5974b 225f7 73ec8
cdcae 133f2 86012 bc. pdf. Accessed April 2020
13. Quintiliani R (1978) Drugs five years later: cefazolin. Ann Intern
Med 1(89):650. https:// doi. org/ 10. 7326/ 0003- 4819- 89-5- 650
14. Madhavan T, Quinn EL, Freimer E, Fisher EJ, Cox F, Burch K
etal (1973) Clinical studies of cefazolin and comparison with
other cephalosporins. Antimicrob Agents Chemother 1(4):525–
531. https:// doi. org/ 10. 1128/ AAC.4. 5. 525
15. Nannini EC, Singh KV, Arias CA, Murray BE (2013) In Vivo
effects of cefazolin, daptomycin, and nafcillin in experimen-
tal endocarditis with a methicillin-susceptible Staphylococcus
aureus strain showing an inoculum effect against cefazolin.
Antimicrob Agents Chemother 57:4276–4281. https:// doi. org/
10. 1128/ AAC. 00856- 13
16. Sande MA, Johnson ML (1975) Antimicrobial therapy of exper-
imental endocarditis caused by Staphylococcus aureus. J Infect
Dis 1(131):367–375. https:// doi. org/ 10. 1093/ infdis/ 131.4. 367
17. Fernandez-Guerrero ML, de Gorgolas M (2005) Cefazolin
therapy for Staphylococcus aureus bacteremia. Clin Infect Dis
1(41):127–127. https:// doi. org/ 10. 1086/ 430833
18. Quinn EL, Pohlod D, Madhavan T, Burch K, Fisher E, Cox F
(1973) Clinical experiences with cefazolin and other cepha-
losporins in bacterial endocarditis. J Infect Dis 1(128):S386–
S391. https:// doi. org/ 10. 1093/ infdis/ 128. Suppl ement_2. S386
19. Goldman PL, Petersdorf RG (1980) Importance of -lactamase
inactivation in treatment of experimental endocarditis caused
by Staphylococcus aureus. J Infect Dis 1(141):331–337. https://
doi. org/ 10. 1093/ infdis/ 141.3. 331
20. Nannini EC, Stryjewski ME, Singh KV, Bourgogne A, Rude
TH, Corey GR etal (2009) Inoculum effect with cefazolin
among clinical isolates of methicillin-susceptible Staphylococ-
cus aureus: frequency and possible cause of cefazolin treat-
ment failure. Antimicrob Agents Chemother 1(53):3437–3441.
https:// doi. org/ 10. 1128/ AAC. 00317- 09
21. Steckelberg JM, Rouse MS, Tallan BM, Osmon DR, Henry
NK, Wilson WR (1993) Relative efficacies of broad-spectrum
cephalosporins for treatment of methicillin-susceptible Staphy-
lococcus aureus experimental infective endocarditis. Antimi-
crob Agents Chemother 1(37):554–558. https:// doi. org/ 10. 1128/
AAC. 37.3. 554
22. Carrizosa J, Santoro J, Kaye D (1978) Treatment of experimen-
tal Staphylococcus aureus endocarditis: comparison of cepha-
lothin, cefazolin, and methicillin. Antimicrob Agents Chemother
1(13):74–77. https:// doi. org/ 10. 1128/ AAC. 13.1. 74
23. Bryant RE, Alford RH (1977) Unsuccessful treatment of staphy-
lococcal endocarditis with cefazolin. JAMA 7(237):569–570
24. Bai AD, Showler A, Burry L, Steinberg M, Ricciuto DR, Fer-
nandes T etal (2015) Comparative effectiveness of cefazolin ver-
sus cloxacillin as definitive antibiotic therapy for MSSA bacterae-
mia: results from a large multicentre cohort study. J Antimicrob
Chemother 70:1539–1546. https:// doi. org/ 10. 1093/ jac/ dku560
25. Lee S, Choe PG, Song K-H, Park S-W, Kim HB, Kim NJ etal
(2011) Is cefazolin inferior to nafcillin for treatment of methicil-
lin-susceptible Staphylococcus aureus bacteremia? Antimicrob
Agents Chemother 55:5122–5126. https:// doi. org/ 10. 1128/ AAC.
00485- 11
26. Li J, Echevarria KL, Traugott KA (2017) β-Lactam Therapy for
methicillin-susceptible Staphylococcus aureus bacteremia: a com-
parative review of cefazolin versus antistaphylococcal penicillins.
Pharmacother J Hum Pharmacol Drug Ther 37:346–360. https://
doi. org/ 10. 1002/ phar. 1892
27. Loubet P, Burdet C, Vindrios W, Grall N, Wolff M, Yazdanpanah
Y etal (2018) Cefazolin versus anti-staphylococcal penicillins for
treatment of methicillin-susceptible Staphylococcus aureus bac-
teraemia: a narrative review. Clin Microbiol Infect 24:125–132.
https:// doi. org/ 10. 1016/j. cmi. 2017. 07. 003
28. Paul M, Zemer-Wassercug N, Talker O, Lishtzinsky Y, Lev B,
Samra Z etal (2011) Are all beta-lactams similarly effective in
the treatment of methicillin-sensitive Staphylococcus aureus bac-
teraemia? Clin Microbiol Infect 17:1581–1586. https:// doi. org/ 10.
1111/j. 1469- 0691. 2010. 03425.x
29. Rao SN, Rhodes NJ, Lee BJ, Scheetz MH, Hanson AP, Segreti J
etal (2015) Treatment outcomes with cefazolin versus oxacillin
for deep-seated methicillin-susceptible Staphylococcus aureus
bloodstream infections. Antimicrob Agents Chemother 59:5232–
5238. https:// doi. org/ 10. 1128/ AAC. 04677- 14
30. Monogue ML, Ortwine JK, Wei W, Eljaaly K, Bhavan KP (2018)
Nafcillin versus cefazolin for the treatment of methicillin-suscep-
tible Staphylococcus aureus bacteremia. J Infect Public Health
11:727–731. https:// doi. org/ 10. 1016/j. jiph. 2018. 02. 004
31. Lecomte R, Bourreau A, Deschanvres C, Issa N, Le Turnier P,
Gaborit B, etal (2020) Comparative outcomes of cefazolin versus
anti-staphylococcal penicillins in methicillin-susceptible Staphy-
lococcus aureus infective endocarditis: a post-hoc analysis of a
prospective multicentre French cohort study. Clin Microbiol Infect
S1198743X20305644. https:// doi. org/ 10. 1016/j. cmi. 2020. 08. 044
32. U.S. National Institutes of Health (NIH) Department of Health
And Human Services (2017) Common Terminology Criteria for
Adverse Events (CTCAE) Version 5.0 [Internet]. 27 [cited 2021
24].https:// ctep. cancer. gov/ proto colde velop ment/ elect ronic_ appli
catio ns/ ctc. htm# ctc_ 50. Accessed April 2020
33. KDIGO AKI Work Group (2012) KDIGO clinical practice guide-
lines for acute kidney injury. Kidney Int Suppl 2:2. https:// doi. org/
10. 1038/ kisup. 2012.2
34. Weis S, Kesselmeier M, Davis JS, Morris AM, Lee S, Scherag A
etal (2019) Cefazolin versus anti-staphylococcal penicillins for
the treatment of patients with Staphylococcus aureus bacteraemia.
Clin Microbiol Infect 25:818–827. https:// doi. org/ 10. 1016/j. cmi.
2019. 03. 010
35. Bidell MR, Patel N, O’Donnell JN (2018) Optimal treatment
of MSSA bacteraemias: a meta-analysis of cefazolin ver-
sus antistaphylococcal penicillins. J Antimicrob Chemother
1(73):2643–2651. https:// doi. org/ 10. 1093/ jac/ dky259
36. Rindone JP, Mellen CK (2018) Meta-analysis of trials compar-
ing cefazolin to antistaphylococcal penicillins in the treatment of
methicillin-sensitive Staphylococcus aureus bacteraemia: meta-
analysis: cefazolin vs. antistaphylococcal penicillin. Br J Clin
Pharmacol 84:1258–1266. https:// doi. org/ 10. 1111/ bcp. 13554
37. Shi C, Xiao Y, Zhang Q, Li Q, Wang F, Wu J, etal (2018) Effi-
cacy and safety of cefazolin versus antistaphylococcal penicil-
lins for the treatment of methicillin-susceptible Staphylococcus
aureus bacteremia: a systematic review and meta-analysis. BMC
Infect Dis [Internet] [cited 2019 15] 18. https:// doi. org/ 10. 1186/
s12879- 018- 3418-9
38. Lee S, Song K-H, Jung S-I, Park WB, Lee SH, Kim Y-S etal
(2018) Comparative outcomes of cefazolin versus nafcillin for
methicillin-susceptible Staphylococcus aureus bacteraemia: a pro-
spective multicentre cohort study in Korea. Clin Microbiol Infect
24:152–158. https:// doi. org/ 10. 1016/j. cmi. 2017. 07. 001

European Journal of Clinical Microbiology & Infectious Diseases
1 3
39. McDanel JS, Roghmann M-C, Perencevich EN, Ohl ME, Goto M,
Livorsi DJ etal (2017) Comparative effectiveness of cefazolin ver-
sus nafcillin or oxacillin for treatment of methicillin-susceptible
Staphylococcus aureus infections complicated by bacteremia: a
nationwide cohort study. Clin Infect Dis 1(65):100–106. https://
doi. org/ 10. 1093/ cid/ cix287
40. Twilla JD, Algrim A, Adams EH, Samarin M, Cummings C, Finch
CK (2020) Comparison of nafcillin and cefazolin for the treatment
of methicillin-susceptible Staphylococcus aureus bacteremia. Am
J Med Sci 360:35–41. https:// doi. org/ 10. 1016/j. amjms. 2020. 04.
006
41. Pollett S, Baxi SM, Rutherford GW, Doernberg SB, Bacchetti P,
Chambers HF (2016) Cefazolin versus nafcillin for methicillin-
sensitive Staphylococcus aureus bloodstream infection in a Cali-
fornia Tertiary Medical Center. Antimicrob Agents Chemother
60:4684–4689. https:// doi. org/ 10. 1128/ AAC. 00243- 16
42. Davis J, Turnidge J, Tong S (2018) A large retrospective cohort
study of cefazolin compared with flucloxacillin for methicillin-
susceptible Staphylococcus aureus bacteraemia. Int J Antimicrob
Agents 52:297–300. https:// doi. org/ 10. 1016/j. ijant imicag. 2018.
02. 013
43. Renaud CJ, Lin X, Subramanian S, Fisher DA (2011) High-dose
cefazolin on consecutive hemodialysis in anuric patients with
Staphylococcal bacteremia: High-dose cefazolin on consecutive
HD in anuric patients. Hemodial Int 15:63–68. https:// doi. org/ 10.
1111/j. 1542- 4758. 2010. 00507.x
44. Li J, Echevarria KL, Hughes DW, Cadena JA, Bowling JE, Lewis
JS (2014) Comparison of cefazolin versus oxacillin for treatment
of complicated bacteremia caused by methicillin-susceptible
Staphylococcus aureus. Antimicrob Agents Chemother 58:5117–
5124. https:// doi. org/ 10. 1128/ AAC. 02800- 14
45. Youngster I, Shenoy ES, Hooper DC, Nelson SB (2014) Com-
parative evaluation of the tolerability of cefazolin and nafcillin
for treatment of methicillin-susceptible Staphylococcus aureus
infections in the outpatient setting. Clin Infect Dis 1(59):369–375.
https:// doi. org/ 10. 1093/ cid/ ciu301
46. Burrelli CC, Broadbent EK, Margulis A, Snyder GM, Gold HS,
McCoy C etal (2018) Does the beta-lactam matter? Nafcillin
versus cefazolin for methicillin-susceptible Staphylococcus aureus
bloodstream infections. Chemotherapy 63:345–351. https:// doi.
org/ 10. 1159/ 00049 9033
47. Flynt LK, Kenney RM, Zervos MJ, Davis SL (2017) The safety
and economic impact of cefazolin versus nafcillin for the treat-
ment of methicillin-susceptible Staphylococcus aureus blood-
stream infections. Infect Dis Ther 6:225–231. https:// doi. org/ 10.
1007/ s40121- 017- 0148-z
48. Miller MA, Fish DN, Barber GR, Barron MA, Goolsby TA, Moine
P etal (2020) A comparison of safety and outcomes with cefazolin
versus nafcillin for methicillin-susceptible Staphylococcus aureus
bloodstream infections. J Microbiol Immunol Infect 53:321–327.
https:// doi. org/ 10. 1016/j. jmii. 2018. 07. 006
49. Chan L, Chan-Tompkins NH, Como J, Guarascio AJ (2020) Retro-
spective analysis of adverse drug events between nafcillin versus
cefazolin for treatment of methicillin-susceptible Staphylococcus
aureus infections. Ann Pharmacother 54:662–668. https:// doi. org/
10. 1177/ 10600 28019 897267
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