Expert Review of Anti-infective Therapy

ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20

Infective Endocarditis in Children in Italy from

2000 to 2015

Susanna Esposito, Alessandra Mayer, Andrzej Krzysztofiak, Silvia Garazzino,

Rita Lipreri, Luisa Galli, Patrizia Osimani, Emilio Fossali, Maria Di Gangi,
Laura Lancella, Marco Denina, Giulia Pattarino, Carlotta Montagnani, Filippo
Salvini, Alberto Villani & Nicola Principi

To cite this article: Susanna Esposito, Alessandra Mayer, Andrzej Krzysztofiak, Silvia Garazzino,
Rita Lipreri, Luisa Galli, Patrizia Osimani, Emilio Fossali, Maria Di Gangi, Laura Lancella, Marco
Denina, Giulia Pattarino, Carlotta Montagnani, Filippo Salvini, Alberto Villani & Nicola Principi
(2015): Infective Endocarditis in Children in Italy from 2000 to 2015, Expert Review of Anti-
infective Therapy, DOI: 10.1586/14787210.2016.1136787

To link to this article: http://dx.doi.org/10.1586/14787210.2016.1136787

Accepted author version posted online: 26

Dec 2015.

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 Publisher: Taylor & Francis
Journal: Expert Review of Anti-infective Therapy
DOI: 10.1586/14787210.2016.1136787
Original research

INFECTIVE ENDOCARDITIS IN CHILDREN IN ITALY FROM 2000 TO 2015

Susanna Esposito1, Alessandra Mayer1, Andrzej Krzysztofiak2, Silvia Garazzino3, Rita

Lipreri4, Luisa Galli5, Patrizia Osimani6, Emilio Fossali7, Maria Di Gangi8, Laura Lancella2,

Marco Denina3, Giulia Pattarino4, Carlotta Montagnani5, Filippo Salvini9, Alberto Villani2,
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Nicola Principi1 for the Italian Pediatric Infective Endocarditis Registry

1
Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation,

Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore

Policlinico, Milan, Italy; 2Unit of General Pediatrics and Pediatric Infectious Diseases,

IRCCS Bambino Gesù Hospital, Rome, Italy; 3Pediatric Infectious Diseases Unit, Regina

Margherita Children’s Hospital, University of Turin, Turin, Italy; 4Pediatric Unit, Niguarda

Hospital, Milan, Italy; 5Paediatric Infectious Disease Unit, Department of Health Sciences,

University of Florence, Anna Meyer Children's University Hospital, Florence,

Italy; 6Pediatric Infectious Diseases Unit, Salesi Hospital, Ancona, Italy; 7Emergency Room

Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan,

Italy; 8Pediatric Infectious Diseases Unit, Di Cristina Hospital, Palermo; 9

Pediatric Clinic,

San Paolo Hospital, University of Milan, Milan, Italy

Running title: Infective endocarditis in children.

Correspondence and requests for reprints should be addressed to:

Susanna Esposito

Pediatric Highly Intensive Care Unit,

Department of Pathophysiology and Transplantation,

Università degli Studi di Milano,

1
 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,

Via Commenda 9, 20122 Milano, Italy

Tel.: +39-02-55032498; Fax: +39-02-50320206,

E-mail: susanna.esposito@unimi.it

ABSTRACT

Objective: The Italian Society for Pediatric Infectious Diseases created a registry on
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children with infective endocarditis (IE) hospitalized in Italy.

Methods: A cross-sectional survey was conducted on patients hospitalized due to IE in

Italian paediatric wards between January 1, 2000, and June 30, 2015.

Results: Over the 15-year study period, 47 IE episodes were observed (19 males; age

range, 2-17 years). Viridans Streptococci were the most common pathogens among

patients with predisposing cardiac conditions and Staphylococcus aureus among those

without (37.9% vs. 5.5%, p=0.018, and 6.9% vs. 27.8%, p=0.089, respectively). Six of the

7 (85.7%) S. aureus strains were methicillin-resistant. The majority of patients with and

without predisposing cardiac conditions recovered without any complications.

Conclusion: In Italy, paediatric IE develops without any previous predisposing factors in a

number of children, methicillin-resistant S. aureus has emerged as a common causative

agent and the therapeutic approach is extremely variable.

Key words: antibiotics; anti-infective therapy; congenital heart disease; infective

endocarditis; Staphylococcus aureus; viridans Streptococci.

2
 INTRODUCTION

Infective endocarditis (IE) is a relatively rare disease in the paediatric population and

historically carries a high risk for morbidity and mortality [1, 2]. In recent years, particularly

in industrialized countries, the epidemiology and microbiology of paediatric IE have

changed significantly. The reduction in the incidence of rheumatic heart disease (RHD)

[3,4*], advances in cardiovascular surgery with improved intensive care management [5],
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and the increased use of long-term central venous catheters (CVCs) in subjects without

congenital heart disease (CHD) [6,7*] have modified both the characteristics of the

patients with IE and the microbiology of the disease. Moreover, an increased number of IE

cases in children without any known risk factors for IE have been reported [9,10**].

The variability in IE’s presentation causes great problems for clinicians. Diagnosis is

frequently delayed due to the non-specific signs and symptoms which can lead to poor

outcome [11,12]. Moreover, because Staphylococci have replaced penicillin-sensitive

Streptococci as the most common cause of IE, particularly in children with prosthetic valve

or CVC, and because many of these strains are poorly sensitive to traditionally prescribed

antibiotics, the best antimicrobial therapy must be adapted to different clinical scenarios

[13,14].

The knowledge of characteristics, approach, and outcome of paediatric IEs in each country

seems critical for a rational approach to children with this disease. However, to the best of

our knowledge, no data regarding paediatric IE have been reported in Italy. Therefore, the

Italian Society for Paediatric Infectious Diseases (SITIP) created a paediatric IE registry to

describe all the characteristics of IE occurring in Italian children in the period from January

1, 2000, to June 30, 2015. This manuscript summarizes the collected data.

MATERIAL AND METHODS

3
 Study design and population

This cross-sectional survey of paediatricians who participated in the SITIP paediatric IE

registry was carried out between July 1, 2015, and July 30, 2015. Paediatricians included

in the SITIP registry were e-mailed during the study period, and asked to participate to a

retrospective study regarding IE in paediatric age groups in Italy. Paediatric infectious

disease specialists working in eight Italian Paediatric Departments participated: 3 centers

in Milan, and 1 each in Rome, Turin, Florence, Ancona, and Palermo. Paediatricians were
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asked about IE patients <18 years old who had been admitted to their hospital between

January 1, 2000, and June 30, 2015. Surveys could be returned by mail or completed

online using the web link provided in the e-mail within September 30, 2015. Reminder e-

mails were sent one month later, during August 2015.

This study was approved by the Ethics Committee of the Fondazione IRCCS Ca’ Granda

Ospedale Maggiore Policlinico, Milan, Italy, and written informed consent was obtained

from the parents of all participants.

Questionnaire and study population

The questionnaire, which was prepared by two senior paediatric specialists (S.E. and

N.P.), was pilot-tested on a convenience sample of paediatric infectious disease

specialists to ensure clarity and ease of administration. It had four sections assessing (1)

the general characteristics of the paediatric patients with a diagnosis of IE; (2) their clinical

manifestations; (3) the results of diagnostic tests to confirm clinical suspicion; and (4) the

type of prescribed treatment (including the specific antibiotic, route of administration,

dosage, and duration of therapy) and its clinical outcome.

Inclusion criteria included a diagnosis of IE based on the modified Duke criteria validated

for use in patients <18 years old, age <18 years old at admission, admission between

January 1, 2000, and June 30, 2015, and availability of the medical charts.

4
 A predisposing cardiac condition was present in 29 (61.7%) of IE episodes. There was a

wide spectrum of cardiac lesions, and ventricular septal defect (5 cases), aortic stenosis (4

cases), tetralogy of Fallot (3 cases), and transposition of the great arteries (3 cases) were

the most common underlying diseases. In all cases, the diagnosis of CHD was established

before the diagnosis of IE. RHD was reported only in one child, who also suffered from

congenital aortic stenosis.

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Statistical analysis

The continuous variables were given as mean values ± standard deviation (SD), and were

analysed using a two-sided Student’s test if they were normally distributed (based on the

Shapiro–Wilk statistic) or a two-sided Wilcoxon rank-sum test if they were not. The

categorical variables were given as numbers and percentages and were analysed using

contingency table analysis and the chi-squared or Fisher’s exact test, as appropriate. All of

the analyses were two tailed, and p-values <0.05 were considered significant.

RESULTS

Over the 15-year study period, 47 IE episodes were identified in as many children. No

patient experienced two or more IE episodes. The mean age ± SD at IE diagnosis was 9.5

± 6.5 years (age range, 2 to 17 years; median age, 9 years). A rising frequency of IE

diagnosis was evidenced annually over the study period, although it was not possible to

calculate precisely the number of cases per 1,000 admissions per year. There were 13

(27.7%) IE episodes between 2000 and 2007 and 34 (72.3%) IE episodes between 2008

and 2015 with a similar number of admissions in the participating centres.

Table 1 summarizes the comparison of demographic data, underlying conditions, risk

factors, and clinical findings between children with and without predisposing cardiac

conditions. Of the 47 cases, 38 (80.9%) could be considered associated with a chronic

5
 underlying disease or a risk factor that increase IE occurrence; the remaining 9 (19.1%)

cases had no underlying disease or risk factors for IE. Among risk factors, previous heart

surgery (in all the cases within the last month) and the presence of prosthetic valve

material were significantly more frequent among patients with predisposing cardiac

conditions than among those without (51.7% vs. 11.1%, p<0.001, and 41.4% vs. 0.0%,

p=0.001, respectively).

Regarding clinical presentation, fever was the most common presenting symptom in both
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the groups, followed by asthenia. At physical examination, heart murmurs were

significantly more frequent among patients with predisposing cardiac conditions than

among those without (93.1% vs. 44.4%, p<0.001).

Table 2 shows the comparison of diagnostic findings, recommended treatment, and clinical

outcome between children with and without predisposing cardiac conditions. The majority

of patients in both groups had positive blood culture, with viridans Streptococci as the most

common pathogens among patients with predisposing cardiac conditions and S. aureus

among those without predisposing cardiac conditions (37.9% vs. 5.5%, p=0.018, and 6.9%

vs. 27.8%, p=0.089, respectively). Viridans Streptococci were represented by 5 cases of

S. mitis, 4 of S. sanguis, and 2 of S. mutans among patients with predisposing cardiac

conditions and one case of S. sanguis among those without predisposing cardiac

conditions. Six of the 7 (85.7%) detected S. aureus strains were methicillin-resistant.

Recommended antimicrobial treatment was largely variable, with no statistically significant

differences between the two groups. The most common therapeutic schedules included

glycopeptide + aminoglycoside (3 cases, 6.4%), penicillin + aminoglycoside + third-

generation cephalosporin (3 cases, 6.4%), rifampin + aminoglycoside + glycopeptide (3

cases, 6.4%), and penicillin + glycopeptide + aminoglycoside + third-generation

cephalosporin + carbapenem (3 cases, 6.4%). In addition to antibiotics, 2 (6.9%) patients

among those with predisposing cardiac conditions and 4 (22.2%) among those without

6
 received an antimycotic treatment. Antimycotic treatment was selected empirically in all

the patients. The mean duration of therapy was slightly longer in patients with

predisposing cardiac conditions than among those without (28 vs. 24 days), although the

difference was not statistically significant. Interestingly, 23 (79.3%) patients with

predisposing cardiac conditions and 12 (66.7%) of those without received antimicrobial

therapy that did not fulfil any of the recommended anti-infective regimens. The prevalence

of patients requiring surgery (i.e., valve replacement, vegetation removal or removal of

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infected grafts) was quite low among patients with or without predisposing cardiac

conditions (24.1% vs. 38.9%, p=0.455).

The majority of patients with and without predisposing cardiac conditions recovered

without any complications (68.9% vs. 66.7%, p=0.874). One (3.4%) child with predisposing

cardiac conditions showed IE relapse three weeks after discharge. Among children with

predisposing cardiac conditions, two (6.9%) patients developed complications: after valve

replacement, one child with CHD developed his first ventricular fibrillation and then a

complete atrioventricular block leading to the insertion of a pacemaker; another child had

to undergo a supplemental surgical intervention due to prosthetic valve malfunction.

Among children without predisposing cardiac conditions, one (5.5%) patient with normal

cardiac anatomy experienced septic embolization to the brain. The mortality rate was 0.0%

for patients with congenital heart disease and 16.7% for patients without predisposing

cardiac conditions (p=0.023). Among the three children who died, one had chronic renal

disease and a CVC in place, one had a CVC in place without any underlying chronic

disease, and the last had no predisposing factors for IE.

DISCUSSION

This study highlights that in Italy, the frequency of paediatric IE diagnosis seems to be

increasing, and RHD is no longer a common predisposing factor for IE development.

7
 Despite the fact that CHD remains a substantial cause of IE in a number of children, IE

often develops without any predisposing factors. Methicillin-resistant S. aureus has

emerged as a common causative agent, particularly in children without CHD, and the

therapeutic approach to IE is extremely variable.

An increase in the frequency of IE seems to be related to the growing numbers of children

who survive with complex CHD, indwelling lines and devices, and immunosuppressive

therapy [16,17,18*]. Moreover, the changes in antibiotic prophylaxis for IE prevention

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recently suggested by some scientific societies may have played a role in this regard

[13,19]. The evaluation of IE epidemiology in the UK in the 5 years following the revised

guidelines showed a substantial increase in IE incidence in both individuals at high risk

and those at lower risk of IE [20**].

Some years ago, children with RHD represented a significant proportion of paediatric

patients with IE [3]. In our study population, RHD was reported only in one child (2.1%).

Presently, RHD remains an important risk factor for IE only in low-income countries where

a diagnosis of streptococcal infections is often missed and prophylaxis with benzathine

penicillin G after diagnosis of RHD is often neglected [21,22].

In this study, a high frequency of IE in children without any risk factors was shown. This

finding is in agreement with previous studies that made a diagnosis of IE in approximately

20% of their cases without risk factors potentially associated with this severe infectious

disease [9,23,24]. In the absence of predisposing cardiac disease, IE involved mainly

mitral valce, whereas pulmonary valve was involved frequently in the presence of CHD.

Moreover, in the absence of predisposing cardiac disease IE may have a very severe

course and may manifest with congestive heart failure and embolic phenomena, mainly to

the central nervous system. Moreover, in some children, it can lead to death. In the Marom

et al. series, 7 out of 9 cases required urgent cardiac intervention and one patient died

[23]. In this study, one child died rapidly despite aggressive antibiotic therapy and surgical

8
 intervention and two other cases developed severe thromboembolic complications

involving the central nervous system. Signs and symptoms reported in our study

population are similar to those recently published by the American Heart Association and

appeared associated with a better outcome than that reported in adults [25**]. However,

given the high risk of a negative course, the high awareness of paediatricians to IE is

crucial in order to make a prompt correct diagnosis in children with no predisposing

cardiac factors.
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Although viridans Streptococci remain the most common infectious agents associated with

IE in children with CHD, Staphylococcus species, mainly methicillin-resistant S. aureus,

have been found with increasing frequency in children with IE, especially in the absence of

predisposing cardiac disease. Increasing use of long-term intravenous lines and invasive

procedures has led to an upsurge in rates of staphylococcal bacteraemia, a precursor of IE

[6,7*,23]. Interestingly, the large proportion of methicillin-resistant S. aureus strains

demonstrates that differently from what happens in mild to moderate infectious diseases

these aggressive pathogens are a more frequent cause of IE than susceptible S. aureus

strains, highlighting the need to use antibiotics active against methicillin-resistant S.

aureus in first-line antinfective regimen for IE.

Surprisingly, most of the treatment options recommended in our study population did not

follow precise therapeutic schemes, with no difference between patients with and without

predisposing cardiac disease. Recently, updated guidelines for the prevention, diagnosis,

and treatment of IE were published [26**]. Although they were not intended to be

paediatric guidelines, they contain references to paediatric antibiotic dosages. According

to these guidelines, less than 30% of the patients in our study received appropriate

antibiotic treatment, and in more than 70% of the cases an antibiotic regimen that did not

follow current recommendations was prescribed. Due to IE frequency and severity, an

9
 evidence-based clinical practice guidance for IE in children supported by national and

international Scientific Societies is required.

The main limitations of this study are its retrospective nature, the study design and the fact

that only 8 centres participated in the research. This research is based on a cross-

sectional survey performed 15 years after the beginning of the study period and the

increased incidence over years in IE cases may be related to recall biases. However, to

the best of our knowledge, this is the only study available on children in Italy, and results
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are in line with the most recent findings collected in other countries. Moreover, the 8

centres included the largest Italian children’s hospitals, and the SITIP president wrote to all

of the cardio-surgery and paediatric intensive care units to collect data on children with IE

that were not followed by a paediatric infectious disease specialist. Consequently, we

believe that the data provide a valid description of this quite rare but severe paediatric

infectious disease.

In conclusion, this is the first study performed in Italy on paediatric IE. The high number of

IE cases in children without CHD and the great number of children with IE without any

known risk factors highlight the modifications in the epidemiology of IE in children. These

findings, together with the evidence of the increasing causative role of methicillin-resistant

S. aureus and the potential negative evolution of a number of cases, highlight the

importance of the disease in children and the need for a prompt and accurate approach to

this condition. Considering the large variability in antibiotic prescriptions and the rate of

mortality in the absence of predisposing cardiac disease, specific therapeutic management

protocols for IE in paediatric patients are urgently needed.

KEY ISSUES

• In Italy, rheumatic heart disease (RHD) is no longer a common predisposing factor

for infective endocarditis (IE) development.

10
 • Despite the fact that congenital heart disease (CHD) remains a substantial cause of

IE in a number of children, IE often develops without any predisposing factors.

• Viridans Streptococci are the main aetiological agents in children with predisposing

cardiac disease, whereas methicillin-resistant S. aureus has emerged as a common

causative agent in children without predisposing cardiac disease.

• Treatment options recommended for paediatric IE did not follow precise therapeutic

schemes, and therapeutic approaches are extremely variable.

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• Considering the rate of mortality in the absence of predisposing cardiac disease,

specific therapeutic management protocols for IE in paediatric patients are urgently

needed.

Financial & competing interests disclosure

This study was supported in part by grants from the Italian Ministry of Health (Ricerca

Corrente 2015 850/01, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,

Milan, Italy). The authors have no other relevant affiliations or financial involvement with any

organization or entity with a financial interest in or financial conflict with the subject matter or

materials discussed in the manuscript apart from those disclosed.

11
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15
 Table 1. Comparison of demographic data, underlying conditions, risk factors, and
clinical findings between children with and without predisposing cardiac
conditions.

Characteristic Presence of Absence of

predisposing predisposing
cardiac disease cardiac disease
n= 29 n= 18 P value
Demographic data
Males 13 (44.8) 6 (33.3) 0.634
Mean age ± SD, yrs 11.1 ± 7.3 8.3 ± 6.4 0.102
Caucasian race 27 (93.1) 17 (94.4) 1.00
Chronic underlying disease
Central venous catheter 3 (10.3) 4 (22.2) 0.402
Primary immunodeficiency 4 (13.8) 1 (5.5) 0.635
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Chronic kidney failure 0 (0.0) 2 (11.1) 0.141

Parenteral nutrition 1 (3.4) 0 (0.0) 1.00
Other 6 (20.7) 2 (11.1) 0.691
Risk factors
Heart surgery 15 (51.7) 0 (0.0) <0.001
Prosthetic valve 12 (41.4) 0 (0.0) 0.001
Prolonged hospitalization in intensive care 8 (27.6) 3 (16.7) 0.492
unit
Involved valve
Mitral 4 (13.8) 8 (44.4) 0.036
Aortic 7 (24.1) 1 (5.5) 0.130
Tricuspid 4 (13.8) 4 (22.2) 0.691
Pulmonary 7 (24.1) 0 (0.0) 0.033
Symptoms
Fever 28 (96.6) 15 (83.3) 0.149
Malaise/asthenia 20 (68.9) 12 (66.7) 0.874
Anorexia/weight loss 12 (41.4) 4 (22.2) 0.302
Dyspnoea/polypnea 8 (27.6) 5 (27.8) 1.00
Chills 7 (24.1) 4 (22.2) 1.00
Abdominal pain 6 (20.7) 5 (27.8) 0.725
Myalgia 8 (27.6) 1 (5.5) 0.124
Vomiting/diarrhoea 3 (10.3) 5 (27.8) 0.229
Chest pain 5 (17.2) 2 (11.1) 0.691
Headache 2 (6.9) 3 (16.7) 0.356
Arthralgia 4 (13.8) 0 (0.0) 0.282
Sweating 3 (10.3)) 0 (0.0) 0.275
Irritability/drowsiness 0 (0.0) 3 (16.7) 0.050
Haemoptysis 1 (3.4) 0 (0.0) 1.00
Irritability/drowsiness 0 (0.0) 3 (16.7) 0.050
Other 5 (17.2) 3 (16.7) 1.00
Clinical signs
Heart murmur 27 (93.1) 8 (44.4) <0.001
Septic status 9 (31.0) 10 (55.6) 0.173
Splenomegaly 7 (24.1) 2 (11.1) 0.448
Janeway lesions 5 (17.2) 3 (16.7) 1.00
Neurological manifestations 1 (3.4) 4 (22.2) 0.063
Acute kidney failure 1 (3.4) 3 (16.7) 0.149
Osler's nodes 1 (3.4) 0 (0.0) 1.00
Roth's spots 1 (3.4) 0 (0.0) 1.00
SD: standard deviation. Numbers with percentages in parentheses.
Significant differences between patients with predisposing cardiac disease and those without are reported in bold.

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 Table 2. Comparison of diagnostic findings, recommended treatment, and clinical
outcome between children with and without predisposing cardiac conditions.
Presence of Absence of
predisposing predisposing
cardiac disease disease
n= 29 n= 18 p
Diagnostic exams
Laboratory data
Mean white blood cell count ± SD, cells/µL 9,886 ± 5,176 9,539 ± 5,071 0.826
Mean C reactive protein ± SD, mg/dL 7.4 ± 6,1 9.3 ± 8.8 0.566
Mean erythrocyte sedimentation rate ± SD, mm/1 h 55 ± 29 53 ± 44 0.897
Positive blood culture 23 (79.3) 12 (66.6) 0.463
Viridans Streptococci (S. mitis, S. sanguis, S. mutans) 11 (37.9) 1 (5.5) 0.018
Staphylococcus aureus 2 (6.9) 5 (27.8) 0.089
Coagulase negative Streptococci (S. epidermidis, S. 5 (17.2) 3 (16.7) 0.985
hominis)
Other pathogens 5 (17.2) 3 (16.7) 0.985
Downloaded by [University of California, San Diego] at 02:29 02 January 2016

Negative blood culture 6 (20.7) 6 (33.3) 0.492

Echocardiogram
Vegetation 22 (75.9) 11 (61.1) 0.455
Abnormal electrocardiography 10 (34.5) 4 (22.2) 0.571
Abnormal chest X-ray 10 (34.5) 9 (50.0) 0.454
Anti-infective treatment
Antibiotic treatment
Glycopeptide + aminoglycoside 1 (3.4) 2 (11.1) 0.549
Penicillin + aminoglycoside + 3rd-generation 1 (3.4) 2 (11.1) 0.549
cephalosporin
Rifampin + aminoglycoside + glycopeptide 2 (6.9) 1 (5.5) 1.00
Molecules not included in any guideline 23 (79.3) 12 (66.7) 0.492
Antimycotic treatment 2 (6.9) 4 (22.2) 0.229
Mean duration ± SD, days 28 ± 7 24 ± 8 0.716
Surgical treatment 7 (24.1) 7 (38.9) 0.455
Outcome
Mean duration of hospitalization ± SD, days 42 ± 14 64 ± 33 0.188
Healed without complications and relapse 20 (68.9) 12 (66.7) 0.874
Healed without complications and with relapse 1 (3.4) 0 (0.0) 1.00
Healed with complications and without relapse 2 (6.9) 1 (5.5) 1.00
Death 0 (0.0) 3 (16.7) 0.023
SD: standard deviation. Numbers with percentages in parentheses.
Significant differences between patients with predisposing cardiac disease and those without are reported in bold.

17