Staphylococcus aureus Native Valve Infective Endocarditis: Report of 566 Episodes from the International Collaboration on Endocarditis Merged Database

Abstract

Staphylococcus aureus native valve infective endocarditis (SA-NVIE) is not completely understood. The objective of this investigation was to describe the characteristics of a large, international cohort of patients with SA-NVIE.
The International Collaboration on Endocarditis Merged Database (ICE-MD) is a combination of 7 existing electronic databases from 5 countries that contains data on 2212 cases of definite infective endocarditis (IE).
Of patients with native valve IE, 566 patients [corrected] had IE due to S. aureus, and 1074 patients had IE due to pathogens other than S. aureus (non-SA-NVIE). Patients with S. aureus IE were more likely to die (20% vs. 12%; P < .001), to experience an embolic event (61% [corrected] vs. 31%; P < .001), or to have a central nervous system event (21% [corrected] vs. 13%; P < .001) and were less likely to undergo surgery (26% vs. 39%; P < .001) than were patients with non-SA-NVIE. Multivariate analysis of prognostic factors of mortality identified age (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.7), periannular abscess (OR, 2.4; 95% CI, 1.0 [corrected] -5.6), heart failure (OR, 3.9; 95% CI, 2.3-6.7), and absence of surgical therapy (OR, 2.3; 95% CI, 1.3-4.2) as variables that were independently associated with mortality in patients with SA-NVIE. After adjusting for patient-, pathogen-, and treatment-specific characteristics by multivariate analysis, geographical region was also found to be associated with mortality in patients with SA-NVIE (P < .001).
S. aureus is an important and common cause of IE. The outcome of SA-NVIE is worse than that of non-SA-NVIE. Several clinical parameters are independently associated with mortality for patients with SA-NVIE. The clinical characteristics and outcome of SA-NVIE vary significantly by geographic region, although the reasons for such regional variations in outcomes of SA-NVIE are unknown and are probably multifactorial. A large, prospective, multinational cohort study of patients with IE is now under way to further investigate these observations.

Full text

S. aureus Native Valve Infective Endocarditis • CID 2005:41 (15 August) • 507
MAJOR ARTICLE
Staphylococcus aureus Native Valve Infective
Endocarditis: Report of 566 Episodes from
the International Collaboration on Endocarditis
Merged Database
Jose´ M. Miro,
1
Ignasi Anguera,
2
Christopher H. Cabell,
7
Anita Y. Chen,
7
Judith A. Stafford,
7
G. Ralph Corey,
7
Lars Olaison,
3
Susannah Eykyn,
4
Bruno Hoen,
5
Elias Abrutyn,
8
Didier Raoult,
6
Arnold Bayer,
9
Vance G. Fowler, Jr.,
7
and the International Collaboration on Endocarditis Merged Database Study Group
a
1
Hospital Clinic Institut d’Investigacions Biome`diques August Pi i Sunyer, University of Barcelona, and
2
Corporacio´ Sanita`ria Parc Taulı´–Hospital
de Sabadell, Barcelona, Spain;
3
Sahlgrenska University Hospital, Go¨teborg, Sweden;
4
St. Thomas’ Hospital, London, United Kingdom;
5
Hoˆpital
Saint-Jacques, Besanc¸on, and
6
Unite des Rickettsies, Marseille, France;
7
Duke University, Durham, North Carolina;
8
Drexel University College
of Medicine and School of Public Health, Philadelphia, Pennsylvania;
9
LA Biomedical Research Institute at Harbor–University of California
Los Angeles Medical Center, Torrance, California
Background. Staphylococcus aureus native valve infective endocarditis (SA-NVIE) is not completely understood.
The objective of this investigation was to describe the characteristics of a large, international cohort of patients
with SA-NVIE.
Methods. The International Collaboration on Endocarditis Merged Database (ICE-MD) is a combination of 7
existing electronic databases from 5 countries that contains data on 2212 cases of definite infective endocarditis (IE).
Results. Of patients with native valve IE, 566 patients (34%) had IE due to S. aureus, and 1074 patients had
IE due to pathogens other than S. aureus (non–SA-NVIE). Patients with S. aureus IE were more likely to die (20%
vs. 12%; ), to experience an embolic event (60% vs. 31%; ), or to have a central nervous systemP
! .001 P ! .001
event (20% vs. 13%; ) and were less likely to undergo surgery (26% vs. 39%; ) than were patientsP
! .001 P ! .001
with non–SA-NVIE. Multivariate analysis of prognostic factors of mortality identified age (odds ratio [OR], 1.4;
95% confidence interval [CI], 1.1–1.7), periannular abscess (OR, 2.4; 95% CI, 1.1–5.6), heart failure (OR, 3.9;
95% CI, 2.3–6.7), and absence of surgical therapy (OR, 2.3; 95% CI, 1.3–4.2) as variables that were independently
associated with mortality in patients with SA-NVIE. After adjusting for patient-, pathogen-, and treatment-specific
characteristics by multivariate analysis, geographical region was also found to be associated with mortality in
patients with SA-NVIE ( ).P
! .001
Conclusions. S. aureus is an important and common cause of IE. The outcome of SA-NVIE is worse than that
of non–SA-NVIE. Several clinical parameters are independently associated with mortality for patients with SA-NVIE.
The clinical characteristics and outcome of SA-NVIE vary significantly by geographic region, although the reasons
for such regional variations in outcomes of SA-NVIE are unknown and are probably multifactorial. A large, prospective,
multinational cohort study of patients with IE is now under way to further investigate these observations.
Staphylococcus aureus infective endocarditis (SAIE) is a
complication of S. aureus bacteremia in 4 clinically dis-
tinct groups: injection drug users, hospitalized patients
with nosocomial infections, prosthetic valve recipients,
Received 12 November 2004; accepted 23 March 2005; electronically published
6 July 2005.
Reprints or correspondence: Dr. Jose M. Miro, Infectious Diseases Service,
Hospital Clinic Universitari, Helios-Villarroel Bldg., Desk no. 26, Villarroel, 170,
08036, Barcelona, Spain (jmmiro@ub.edu or miro97@fundsoriano.es).
Clinical Infectious Diseases 2005;41:507–14
 2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4104-0014$15.00
and non–injection drug users with community-
acquired infective endocarditis. Although right-side SAIE
(usually associated with injection drug use) typically has
a favorable prognosis with medical treatment alone [1–
4], left-side SAIE remains a disease with high morbidity
and mortality [5–12]. Because SAIE is uncommon at any
single institution, prior investigations of infective en-
docarditis have been limited by small sample size,
Presented in part: 41st Interscience Conference on Antimicrobial Agents and
Chemotherapy, American Society for Microbiology, Chicago, Illinois, 2001 (abstract
L-2292).
a
Study group members are listed at the end of the text.
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508 • CID 2005:41 (15 August) • Miro et al.
Table 1. Main characteristics of the 7 endocarditis databases that have included data for cases of definite infective endocarditis (IE).
Characteristic
Site of database
Philadelphia,
PA [14]
Durham,
NC [15]
Besanc¸on,
France [16]
Marseille,
France [17]
London,
England [18]
Goteborg,
Sweden [19]
Barcelona,
Spain [20]
All sites
combined
Study period 1988–1990 1995–1999 1990–1999 1988–1999 1979–1999 1995–1999 1979–1999 1979–1999
Cases of IE
All 188 152 254 161 291 674 492 2212
Native valve 163 (86.7) 10 (70.4) 199 (78.3) 112 (69.6) 228 (78.4) 573 (85.0) 415 (84.3) 1797 (81.2)
Prosthetic valve 25 (13.3) 28 (18.4) 47 (18.5) 49 (30.4) 63 (21.6) 98 (14.5) 57 (11.6) 367 (16.6)
Other NA 17 (11.2) 8 (3.2) NA NA 3 (0.5) 20 (4.1) 48 (2.2)
Patient characteristic
Injection drug use 6 (3.2) 13 (8.6) 8 (3.2) 4 (2.5) 23 (7.9) 71 (10.5) 183 (37.2) 308 (13.9)
Heart failure 52 (27.7) 45 (29.6) 111 (43.7) 64 (39.8) 73 (25.1) 246 (36.5) 190 (38.6) 781 (35.3)
Surgery during index
hospitalization 47 (25.0) 48 (31.6) 119 (46.9) 81 (50.3) 159 (54.6) 208 (30.9) 164 (33.3) 826 (37.4)
Mortality among overall cohort
a
21 (11.2) 24 (15.8) 45 (17.7) 12 (7.5) 66 (22.7) 68 (10.1) 112 (22.8) 348 (15.7)
Staphylococcus aureus IE
b
40 (21.3) 62 (40.8) 53 (20.9) 22 (13.7) 88 (30.2) 194 (28.8) 193 (39.2) 652 (29.5)
MRSA IE
c
NA 25 (40.3) NA NA 12 (13.6) NA 13 (6.7) 50 (7.7)
S. aureus native valve IE
d
35 (87.5) 48 (77.4) 43 (81.1) 18 (81.8) 69 (78.4) 179 (92.3) 174 (90.2) 566 (86.8)
Mortality
a
for S. aureus
native valve IE 4 (11.4) 11 (22.9) 9 (20.9) 4 (22.2) 22 (31.9) 22 (12.3) 40 (23.0) 112 (19.8)
NOTE. Data are no. (%) of patients, unless otherwise indicated. MRSA, methicillin-resistant S. aureus; NA, not available.
a
In-hospital mortality.
b
As a proportion of total cases of IE.
c
As a proportion of total cases of S. aureus IE, including both native valve MRSA IE (43 patients) and prosthetic valve MRSA IE (7 patients).
d
As a proportion of total cases of S. aureus IE.
single-site enrollment, and/or inclusion of a wide spectrum of
clinical factors influencing patient outcome. As a result of these
limitations, fundamental features of S. aureus native valve in-
fective endocarditis (SA-NVIE) remain unclear.
The International Collaboration on Endocarditis Merged Da-
tabase (ICE-MD) was designed to provide a large, multicenter,
international resource for data on uniformly defined cases of
infective endocarditis. The objective of the ICE-MD project is
to evaluate regional and global aspects of infective endocarditis
and to improve understanding of the clinical characteristics
and outcome of a large, international cohort of patients with
well-characterized infective endocarditis [13]. In this report, we
defined risk factors, clinical characteristics, and prognostic fac-
tors for adverse outcomes among patients with definite SA-
NVIE.
PATIENTS, MATERIALS, AND METHODS
Patient data. The methods used to create the ICE-MD have
been described elsewhere [12–14]. In brief, the International
Collaboration on Endocarditis investigators were queried to
determine sites that maintained prospective databases in an
electronic format. The ICE-MD was designed to allow a mul-
tinational consortium of investigators to have the ability to
combine existing databases, with data collected during 1979–
1999 about prospectively identified patients with infective en-
docarditis. Seven sites from 5 countries (United States [15, 16],
France [17, 18], the United Kingdom [19], Sweden [20], and
Spain [21]) contributed data in a predesigned electronic format.
The database from each center was sent to the coordinating
center (Duke Clinical Research Institute, Durham, NC) for
characterization and merging. Key domains, which contained
core variables common to the individual databases, were de-
termined. Standard definitions for each core variable were de-
veloped, and the merger was accomplished with use of a hier-
archial variable structure that was described previously [13].
Definitions. Infective endocarditis was defined on the basis
of the Duke Criteria [22]. Data entered into the merged da-
tabases that involved patients identified from 1979 to 1994 (i.e.,
before publication of the Duke criteria) were redefined retro-
spectively with use of this diagnostic schema. The variable “total
embolism” included embolisms in any major arterial vessel,
including pulmonary embolisms. CNS events were defined as
CNS embolization, hemorrhage, or infection (e.g., meningitis
or brain abscess). Surgical rates and mortality rates refer to in-
hospital surgery and mortality rates, respectively. The remaining
clinical, echocardiographic, and outcome variables were defined
as reported elsewhere [21–24].
Statistical analysis. Descriptive statistics for continuous
variables were summarized as medians and interquartile ranges
(IQRs). All sites did not collect all variables. Thus, each cate-
gorical variable was reported as the number of patients affected
and as a percentage of patients for whom that variable was
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Table 2. Clinical characteristics, surgery findings, and outcomes for patients with native valve infective endocarditis
(NVIE).
Variable
Patients with
non–SA-NVIE
(n p 1074)
Patients with SA-NVIE
P
All
(n p 566)
United
States
(n p 83)
Europe
(n p 483)
SA-NVIE
vs.
non–SA-NVIE
United
States
vs. Europe
Demographic characteristic
Age, median years (IQR) 60.0 (44–71) 46.0 (29–66) 58.0 (44–70) 43.0 (27–65)
!.001 !.001
Male sex 749/1074 (69.7) 360/566 (63.6) 43/83 (51.8) 317/483 (65.6) .013 .019
Diabetes mellitus 73/632 (11.6) 39/344 (11.3) 23/83 (27.7) 16/261 (6.1) 1.000
!.001
Dialysis dependency 20/632 (3.2) 25/344 (7.3) 3/48 (6.3) 69/235 (29.4) .006
!.001
HIV infection 30/476 (6.3) 72/283 (25.4) 15/83 (18.1) 10/261 (3.8)
!.001 !.001
Other chronic disease 115/507 (22.7) 67/309 (21.7) 18/48 (37.5) 16/261 (6.1) .795
!.001
Long-term IVC 21/507 (4.1) 34/309 (11.0) 33/48 (68.8) 34/261 (13.0)
!.001 !.001
Acquisition in community 605/677 (89.4) 280/369 (75.9) 46/83 (55.4) 234/286 (81.8)
!.001 !.001
Injection drug use 59/1074 (5.5) 209/566 (36.9) 8/83 (9.6) 201/483 (41.6)
!.001 !.001
Congenital heart disease 123/757 (16.3) 22/387 (5.7) 6/83 (7.2) 16/304 (5.3)
!.001 .592
Echocardiography finding
!.001 .002
Transthoracic 305/949 (32.1) 224/531 (42.2) 15/48 (31.3) 209/483 (43.3)
Transesophageal 183/949 (19.3) 81/531 (15.3) 5/48 (10.4) 76/483 (15.7)
Both 393/949 (41.4) 185/531 (34.8) 28/48 (58.3) 157/483 (32.5)
Vegetation location
Aortic 335/1074 (31.2) 90/566 (15.9) 10/83 (12.1) 80/483 (16.6)
!.001 .334
Mitral 364/1074 (33.9) 145/566 (25.6) 19/83 (22.9) 126/483 (26.1)
!.001 .588
Tricuspic 54/1074 (5.0) 177/566 (31.3) 13/83 (15.7) 164/483 (34.0)
!.001 !.001
Pulmonic 12/581 (2.1) 6/335 (1.8) 0/60 (0.0) 6/275 (2.2) 1.000 1.000
Intracardiac abscess 94/1074 (8.8) 39/566 (6.9) 5/83 (6.0) 34/483 (7.0) .216 1.000
Outcome
Pulmonary embolism 37/929 (4.0) 138/426 (32.4) 9/70 (12.9) 129/356 (36.2)
!.001 !.001
CNS event 124/931 (13.3) 86/417 (20.6) 12/60 (20.0) 74/357 (20.7)
!.001 1.000
Total embolism 330/1074 (30.7) 343/566 (60.6) 35/83 (42.2) 308/483 (63.8)
!.001 !.001
Heart failure 401/1073 (37.4) 183/560 (32.7) 25/83 (30.1) 158/477 (33.1) .065 .615
Surgery at index episode 416/1074 (38.7) 148/566 (26.2) 16/83 (19.3) 132/483 (27.3)
!.001 .138
In-hospital death 130/1062 (12.2) 112/562 (19.9) 15/83 (18.1) 97/479 (20.3)
!.001 .766
NOTE. Data are no. of patients with finding /no. of patients with data (%), unless otherwise indicated. IVC, intravascular catheter; SA, Staph-
ylococcus aureus.
available. The Wilcoxon rank sum test and Fisher’s exact test
were used to evaluate group differences for continuous and
categorical variables, respectively. Descriptive univariate analy-
sis of mortality-related factors was performed. For univariate
analysis, sites for which data were not available for the variable
of interest were excluded. For the multivariable analysis, only
those variables that were available from all sites were entered
into the model. P values of
!.05 were considered to be statis-
tically significant. All analyses were performed using SAS soft-
ware, versions 6.12 and 8.2 (SAS Institute).
RESULTS
Data for a total of 2212 cases from the 20-year study period
were collected (table 1). Native valve infective endocarditis
(NVIE) was present in 81.2% of patients, and prosthetic valve
infective endocarditis was present in 16.6%. Definite infective
endocarditis due to S. aureus was present in 652 patients
(29.5%), and SA-NVIE was present in 566 patients (25.6%).
These 566 cases represent 353 cases in patients described in a
previous report [14], 209 cases associated with injection drug
use, and 4 cases in patients aged
!18 years.
Patients with SA-NVIE were younger and more likely to have
comorbid conditions or to have engaged in injection drug use
than were patients with non–SA-NVIE (table 2). Patients with
SA-NVIE were significantly less likely to have undergone val-
vular surgery (26.2% vs. 38.7%; ) and were more likely
P
! .001
to die during hospitalization (19.9% vs. 12.2%; ) than
P
! .001
were patients with non–SA-NVIE.
US patients with SA-NVIE were older, had a higher frequency
of comorbid conditions, and had a lower rate of injection drug
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Table 3. Clinical characteristics, surgery findings, and out-
comes for patients with methicillin-susceptible Staphylococcus
aureus (MSSA) native valve infective endocarditis (NVIE) and
those with methicillin-resistant S. aureus (MRSA) NVIE.
Variable
Patients with
MSSA NVIE
(n p 248)
Patients with
MRSA NVIE
(n p 43) P
Demographic characteristic
Age, median years (IQR) 33.0 (25–58) 60.0 (44–73)
!.001
Male sex 164/248 (66.1) 21/43 (48.8) .039
Year of diagnosis
!.001
Before 1990 101/248 (40.7) 4/43 (9.3)
1990 or after 147/248 (59.3) 39/43 (90.7)
Diabetes mellitus 18/248 (7.3) 12/43 (27.9)
!.001
HIV infection 70/187 (37.4) 2/35 (5.7)
!.001
Dialysis dependency 18/248 (7.3) 7/43 (16.3) .072
Long-term IVC 15/248 (6.1) 17/43 (39.5) !.001
Other chronic disease 37/248 (14.9) 20/43 (46.5)
!.001
Acquisition in community 208/248 (83.9) 8/43 (18.6)
!.001
Injection drug use 136/248 (54.8) 6/43 (14.0)
!.001
Congenital heart disease 13/248 (5.2) 2/43 (4.7) 1.000
Vegetation location
Aortic 43/248 (17.3) 3/43 (7.0) .112
Mitral 45/248 (18.2) 17/43 (39.5) .004
Tricuspid 106/248 (42.7) 10/43 (23.3) .018
Pulmonic 2/248 (0.8) 0/43 (0.0) 1.000
Periannular abscess 20/248 (8.1) 2/43 (4.7) .753
Outcome
Pulmonary embolism 117/239 (49.0) 7/43 (16.3)
!.001
CNS event 49/240 (20.4) 8/39 (20.5) 1.000
Total embolization 158/248 (63.7) 19/43 (44.2) .018
Heart failure 57/243 (23.5) 11/42 (26.2) .700
Surgery at index episode 61/248 (24.6) 11/43 (25.6) .851
In-hospital death 57/246 (23.2) 16/43 (37.2) .058
NOTE. Data are no. of patients with finding/ no. of patients with data (%),
unless otherwise indicated. Data were obtained from 3 sites (2 sites in Europe
and 1 site in the United States). IVC, intravascular catheter.
Table 4. Clinical characteristics, surgery findings, and out-
comes for right-side and left-side Staphylococcus aureus native
valve infective endocarditis (SA-NVIE) in patients with echocar-
diographically defined vegetations.
Variable
Patients with
left-side
SA-NVIE
(n p 219)
Patients with
right-side
SA-NVIE
(n p 170) P
Demographic characteristic
Age, median years (IQR) 61.0 (44–70) 29.5 (24–39)
!.001
Male sex 143/219 (65.3) 102/170 (60.0) .292
Year of diagnosis
!.001
Before 1990 23/219 (10.5) 50/170 (29.4)
1990 or after 196/219 (89.5) 120/170 (70.6)
Diabetes mellitus 24/110 (21.8) 5/110 (4.6)
!.001
Dialysis dependency 14/110 (12.7) 5/110 (4.6) .052
HIV infection 3/100 (3.0) 47/107 (43.9) !.001
Other chronic disease 36/107 (33.6) 12/110 (10.9)
!.001
Long-term IVC 18/107 (16.8) 9/110 (8.2) .065
Acquisition in community 77/123 (62.6) 104/120 (86.7)
!.001
Injection drug use 18/219 (8.2) 131/170 (77.1)
!.001
Congenital heart disease 10/135 (7.4) 2/122 (1.6) .037
Echocardiography finding
!.001
Transthoracic 59/216 (27.3) 106/170 (62.4)
Transesophageal 42/216 (19.4) 17/170 (10.0)
Both 107/216 (49.5) 40/170 (23.5)
Periannular abscess 26/219 (11.9) 2/170 (1.2)
!.001
Outcome
Pulmonary embolism 4/160 (2.5) 91/136 (66.9) !.001
CNS event 48/163 (29.5) 10/125 (8.0)
!.001
Total embolization 112/219 (51.1) 127/170 (74.7)
!.001
Heart failure 98/218 (45.0) 23/167 (13.8)
!.001
Surgery at index episode 87/219 (39.7) 21/170 (12.4)
!.001
In-hospital death 62/217 (28.6) 10/169 (5.9)
!.001
NOTE. Data are no. of patients with finding/ no. of patients with data (%),
unless otherwise indicated. IVC, intravascular catheter.
use than did European patients with SA-NVIE. Rates of per-
iannular abscess formation, heart failure, and surgical therapy
were similar between these 2 geographic regions.
Methicillin-resistant S. aureus (MRSA) endocarditis occurred
in 14.8% of patients from centers where antimicrobial suscep-
tibility testing was performed (table 3). Mitral valve involve-
ment predominated in patents with NVIE due to MRSA, and
tricuspid infection predominated in patients with NVIE due to
methicillin-susceptible S. aureus (MSSA). Rates of surgical ther-
apy were similar among patients with NVIE due to MSSA and
those with NVIE due to MRSA, although the mortality rate
was higher for patients with NVIE due to MRSA (23.2% vs.
37.2%; ).P p .058
Right-side NVIE occurred in younger patients and in injec-
tion drug users, and it occurred less frequently during the last
decade of the study (1990–1999) (table 4). Right-side NVIE
was associated with fewer comorbid conditions (e.g., diabetes
mellitus and chronic diseases) than was left-side NVIE. Surgical
treatment was required more frequently for patients with left-
side NVIE (39.7% vs. 12.4%; ), and the in-hospitalP
! .001
mortality rate was also higher for patients with left-side NVIE
(28.6% vs. 5.9%; ), compared with patients with right-P
! .001
side NVIE.
Univariate logistic regression analyses were used to quantify
the relationship between important clinical characteristics and
in-hospital mortality rates (table 5). Important predictors of
mortality in the study population included age (based on 10-
year increments), presence of aortic or mitral valve vegetation,
periannular abscess formation, heart failure, and CNS events.
Characteristics associated with mortality in patients with SA-
NVIE on multivariate analysis included increasing age (OR,
1.38; 95% CI, 1.15–1.66), presence of heart failure (OR, 3.90,
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Table 5. Factors associated with in-hospital mortality in patients with Staphylococcus
aureus native valve infective endocarditis.
Variable
Univariate analysis
Multivariate analysis
OR (95% CI) P OR (95% CI) P
Demographic characteristic
Year of infective endocarditis
diagnosis before 1990 1.12 (0.69–1.83) .643 …
Age at entry
a
1.37 (1.22–1.52) !.001 1.38 (1.15–1.66) !.001
Male sex 0.86 (0.56–1.32) .490 0.93 (0.56–1.54) .777
Geographic location
Philadelphia, PA 0.51 (0.20–1.28) .023 0.43 (0.15–1.21)
!.001
Marseille, France 1.32 (0.49–3.57) 1.05 (0.36–3.11)
Goteborg, Sweden 0.96 (0.67–1.78) 0.36 (0.24–0.86)
Durham, NC 1.17 (0.62–2.21) 0.97 (0.47–2.00)
Besanc¸on, France 1.04 (0.53–2.07) 0.89 (0.41–1.93)
Barcelona, Spain 1.20 (0.79–1.81) 2.23 (1.33–3.73)
London, UK 1.85 (1.11–3.09) 3.53 (1.90–6.55)
Comorbid condition
Hemodialysis dependency 1.31 (0.55–3.10) .539 …
Diabetes mellitus 1.96 (0.96–3.97) .064 …
HIV infection 0.46 (0.22–0.95) .037 …
Other chronic illness 2.26 (1.26–4.06) .006 …
Long-term IVC 1.49 (0.69–3.21) .314 …
Community-acquired infection 0.90 (0.48–1.67) .736 …
Predisposing conditions
Current injection drug use 0.33 (0.20–0.55)
!.001 0.96 (0.39–2.39) .927
Congenital heart disease 0.31 (0.07–1.35) .120 …
Intracardiac findings
Aortic valve vegetation 2.54 (1.54–4.17)
!.001 1.91 (1.00–3.66) .050
Mitral valve vegetation 1.87 (1.20–2.92) .006 1.62 (0.89–2.96) .114
Tricuspid valve vegetation 0.30 (0.17–0.53)
!.001 0.67 (0.32–1.42) .296
Periannular abscess 2.87 (1.45–5.71) .003 2.43 (1.05–5.64) .038
Outcome
Heart failure 3.58 (2.33–5.49)
!.001 3.90 (2.27–6.68) !.001
Overall systemic embolization 0.66 (0.44–1.01) .054 1.17 (0.71–1.94) .544
Peripheral embolization 0.83 (0.23–3.03) .772 …
Pulmonary embolization 0.24 (0.13–0.45)
!.001 …
CNS event, including embolization 2.39 (1.37–4.17) .002 …
Surgery at this episode 1.14 (0.72–1.80) .585 0.43 (0.24–0.79) .007
NOTE. Reference for geographic location is the average overall mortality among all sites. Reference
for community-acquired endocarditis is health care–associated endocarditis. IVC, intravascular catheter.
a
Per 10-year increase in age.
95% CI, 2.27–6.68) or periannular abscess (OR, 2.43; 95% CI,
1.05–5.64), presence of an aortic valve vegetation (OR, 1.91;
95% CI, 1.00–3.66), and the geographic location in which the
patient was identified. Surgical therapy was associated with re-
duced in-hospital mortality (OR, 0.43; 95% CI, 0.24–0.79) after
adjustment for characteristics of the patients.
DISCUSSION
Although S. aureus is an important cause of NVIE in the mod-
ern era, its relative infrequency at any single site has limited
the ability to evaluate large cohorts of patients with this con-
dition. In addition, the findings from such single-site reports
may not be generalizable to other practice settings. The current
investigation is a start in the attempt to overcome the limita-
tions of previous SA-NVIE studies, because it uses a multi-
national collection of data for well-characterized patients, and
it contributes to our understanding of this disease with several
key observations.
The current investigation is, to our knowledge, the first to
provide compelling evidence underscoring a regional variation
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512 • CID 2005:41 (15 August) • Miro et al.
in the outcomes for patients with infective endocarditis. This
regional variation persisted in a cohort of patients with the
same disease type (NVIE) caused by the same pathogen (S.
aureus), even after adjustment for a number of distinct patient-
specific characteristics. Although such regional variation has
been reported for other potentially lethal conditions, such as
acute myocardial infarction [25], it has not been previously
identified for patients with infective endocarditis. The reasons
for this finding may relate, in part, to regional variations in
treatment strategies (e.g., different health care access, practice
variations in antimicrobial therapy, and variations in referral
patterns), in patient demographic characteristics (e.g., host sus-
ceptibility to S. aureus infection), or in innate virulence attrib-
utes of the pathogen. Of note, the current prospective Inter-
national Collaboration on Endocarditis cohort study should
begin to address the underlying causes of such regional vari-
ations [13].
This investigation also emphasizes the increasing importance
of S. aureus as a cause of NVIE in the modern era. In our
cohort of
12000 patients with infective endocarditis, S. aureus
was the most common cause of NVIE. By contrast, the pro-
portion of cases of infective endocarditis due to viridans group
streptococci or enterococci was significantly lower than that in
studies that have encompassed cases from the last 2 decades
[26, 27]. Our observations on the increasing prevalence of SA-
NVIE reflect the probable convergence of 2 important trends:
there is an increasing number of patients (e.g., geriatric patients
and patients with transvenous pacemakers or indwelling cath-
eters) who are at risk for endocarditis in general, and there is
an increasing number of patients (e.g., patients with immu-
nosuppression, diabetic patients, and persons undergoing he-
modialysis) who are at risk for S. aureus bacteremia [8, 16, 28–
30]. Given that gram-positive organisms have now overtaken
gram-negative pathogens as the most common cause of sep-
ticemia in the United States [31], it is likely that rates of SA-
NVIE will continue to increase.
MRSA endocarditis occurred in 14.8% of patients from cen-
ters in which antimicrobial susceptibility testing was recorded,
and at least one-third of SAIE cases were due to MRSA at one
center since 1990. In agreement with prior observations [32,
33], patients with NVIE due to MRSA tended to have more
comorbid conditions than did patients with NVIE due to
MSSA. The mortality rate for MRSA-infected patients also
tended to be higher, although this observation did not achieve
statistical significance ( ). Although some investiga-
P p .054
tions have reported a similar association between MRSA in-
fection and worse clinical outcomes [34–36], others have failed
to demonstrate this association when adjustment for comorbid
conditions was made [30, 31, 37, 38]. It is still a matter of
debate whether the increase in mortality for MRSA-infected
patients is related to increased virulence of the strain, an in-
crease in the number of comorbid diseases, or the relative in-
effectiveness of vancomycin. Given the large increase in serious
community-acquired MRSA infections in the past few years
[39], it is highly likely that the proportion of cases of SA-NVIE
caused by MRSA will continue to increase.
The findings of the current investigation also confirm the
virulence of S. aureus compared with other causes of NVIE.
Patients with SA-NVIE in this and prior investigations [8, 10,
11, 28, 40, 41] had a higher mortality than patients with NVIE
due to other pathogens. However, this is the first investigation
to demonstrate this pathogen-specific virulence across different
countries and health care systems. These findings suggest that
S. aureus strains causing infective endocarditis possess a similar
capacity for virulence throughout diverse geographic regions
of the world.
The present study has several limitations. Different data col-
lection methods were used at each site, potentially reducing the
precision of certain core variables. Referral bias is also likely,
because the study institutions are predominantly tertiary care
referral centers. Finally, the apparent regional variation in out-
come of SA-NVIE may be related to factors not specifically
addressed in this investigation (e.g., varying rates of comorbid
conditions, higher rates of injection drug use among individual
sites, health care access, treatment practices, and potential vir-
ulence properties of bacteria). Thus, the findings of this in-
vestigation should be considered on for generation of hypoth-
eses until they are externally validated with a separate cohort.
Despite these limitations, we believe that the findings of this
study underscore the global significance of S. aureus and iden-
tify several patient and environmental factors associated with
mortality in SA-NVIE. A large, prospective, multinational co-
hort study of patients with infective endocarditis is now under
way to validate these observations and to further evaluate clin-
ical, pathogen-specific, and host-specific determinants of out-
come in this devastating infection.
SA-NVIE is a potentially life-threatening infection of global
significance. It is primarily associated with either injection drug
use or comorbid conditions. In this investigation, patients with
SA-NVIE from different geographic regions had different risks
of mortality. Future prospective, multinational investigations
are required to validate our observations and to further evaluate
clinical, pathogen-specific, and host-specific determinants of
apparent differences in outcome between SA-NVIE and non–
SA-NVIE.
MEMBERS OF THE ICE-MD STUDY GROUP
J. M. Miro´ , A. del Rı´o, M. A. Baraldes, M. J. Jime´nez-Expo´sito,
N. de Benito, X. Claramonte, M. E. Dı´az, O. Sued, C. Manzardo,
A. Moreno, J. M. Gatell, F. Marco, C. Garcı´a de la Marı´a, Y.
Armero, M. Almela, M. T. Jime´nez de Anta, J. C. Pare´, M. Az-
queta, C. A. Mestres, S. Ninot, R. Cartan˜a, J. L. Pomar, N. Pe´rez,
by guest on May 16, 2011cid.oxfordjournals.orgDownloaded from

S. aureus Native Valve Infective Endocarditis • CID 2005:41 (15 August) • 513
J. Ramı´rez, and T. Ribalta (Barcelona, Spain); P. Stolley (Balti-
more, MD); B. Hoen, C. Selton-Suty, T. Doco-Lecompte, F.
Ducheˆne, N. Khayat, Y. Bernard, and C. Chirouze (Besanc¸on
and/or Nancy, France); G. R. Corey, D. J. Sexton, V. G. Fowler,
Jr., C. W. Woods, A. Wang, G. E. Peterson, J. G. Jollis, D. J.
Anderson, R. Singh, C. H. Cabell, D. Glower, A. Chen, and J.
Stafford (Durham, NC); L. Olaison and the Swedish Society of
Infectious Diseases Quality Assurance Study Group for Endo-
carditis (Goteborg, Sweden); A. Thalme (Stockholm, Sweden);
S. Eykyn (London, UK); D. Raoult, G. Habib, J. P. Casalta, K.
Barrau, and P. E. Fournier (Marseille, France); and E. Abrutyn,
B. L. Strom, J. A. Berlin, J. L. Kinman, R. S. Feldman, M. E.
Levison, O. M. Korzeniowski, and D. Kaye (Philadelphia, PA).
Acknowledgments
Financial support. National Institutes of Health (AI 059111 [to V.G.F.]
and HL70861 [to C.H.C.]), the Red Espan˜ola de Investigacio´ n en Patologı´a
Infecciosa (V-2003-REDC14A-O), and the Fundacio´n Privada Ma´ximo So-
riano Jime´nez for the grant supporting the Hospital Clı´nic Endocarditis
Database (to J.M.M.). J.M.M. received a research grant from the Institut
d’Investigacions Biome`diques August Pi i Sunyer.
Potential conflicts of interest. V.G.F. has received research grants from
Cubist, Inhibitex, Nabi, National Institutes of Health, Theravance, Merck,
Ortho-McNeil, and Vicuron; has received speaking honoraria from Pfizer,
Cubist, and Aventis; and has consulted for Merck, Nabi, Inhibitex, Elusys,
Cubist, Vicuron, and GlaxoSmithKine. All other authors: no conflicts.
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ERRATUM • CID 2005:41 (1 October) • 1075
Clinical Infectious Diseases 2005;41:1075–7
 2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4107-0035$15.00
ERRATUM
In an article in the 15 August 2005 issue of the journal (Miro
JM, Anguera I, Cabell CH, et al. Staphylococcus aureus native
valve infective endocarditis: report of 566 episodes from the
International Collaboration on Endocarditis Merged Database.
Clin Infect Dis 2005; 41:507–14), errors appeared in the abstract
and in table 1.
In the Results section of the abstract, the percentage listed
after “566 patients” was incorrect and has been deleted. Also,
the percentages of patients with S. aureus infective endocarditis
who experienced embolic and central nervous system events
should be 61% and 21%, respectively (not 60% and 20%, re-
spectively). Finally, the 95% CI for periannular abscess should
be 1.0–5.6 (not 1.1–5.6). The corrected section of the abstract
appears below. The authors regret these errors.
Results. Of patients with native valve IE, 566 patients had
IE due to S. aureus, and 1074 patients had IE due to pathogens
other than S. aureus (non–SA-NVIE). Patients with S. aureus
IE were more likely to die (20% vs. 12%; ), to experienceP
! .001
an embolic event (61% vs. 31%; ), or to have a central
P
! .001
nervous system event (21% vs. 13%; ) and were less
P
! .001
likely to undergo surgery (26% vs. 39%; ) than wereP
! .001
patients with non–SA-NVIE. Multivariate analysis of prognostic
factors of mortality identified age (odds ratio [OR], 1.4; 95%
confidence interval [CI], 1.1–1.7), periannular abscess (OR, 2.4;
95% CI, 1.0–5.6), heart failure (OR, 3.9; 95% CI, 2.3–6.7), and
absence of surgical therapy (OR, 2.3; 95% CI, 1.3–4.2) as var-
iables that were independently associated with mortality in pa-
tients with SA-NVIE. After adjusting for patient-, pathogen-,
and treatment-specific characteristics by multivariate analysis,
geographical region was also found to be associated with mor-
tality in patients with SA-NVIE ( ).
P
! .001
For table 1, the references listed for the 7 databases are in-
correct. The correct references are as follows: Philadelphia, PA
[15] (not [14]); Durham, NC [16] (not [15]); Besanc¸on, France
[17] (not [16]); Marseille, France [18] (not [17]); London, En-
gland [19] (not [18]); Goteborg, Sweden [20] (not [19]); and
Barcelona, Spain [21] (not [20]). The journal and the authors
regret these errors. Furthermore, the number of patients with
native valve infective endocarditis for Durham, NC, should be
107 (not 10). The journal regrets this error. The corrected ver-
sion of table 1 appears on the next page (p. 1076).
In addition, the authors would like to emend table 2. For
the column labeled “Patients with non–SA-NVIE ( ),”
n p 1074
it should be noted that the data refer to cases that involve
known pathogens. The corrected version of table 2 appears
after table 1 (on p. 1077), with the added information shown
in footnote a.
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1076 • CID 2005:41 (1 October) • ERRATUM
Table 1. Main characteristics of the 7 endocarditis databases that have included data for cases of definite infective endocarditis (IE).
Characteristic
Site of database
Philadelphia,
PA [15]
Durham,
NC [16]
Besanc¸on,
France [17]
Marseille,
France [18]
London,
England [19]
Goteborg,
Sweden [20]
Barcelona,
Spain [21]
All sites
combined
Study period 1988–1990 1995–1999 1990–1999 1988–1999 1979–1999 1995–1999 1979–1999 1979–1999
Cases of IE
All 188 152 254 161 291 674 492 2212
Native valve 163 (86.7) 107 (70.4) 199 (78.3) 112 (69.6) 228 (78.4) 573 (85.0) 415 (84.3) 1797 (81.2)
Prosthetic valve 25 (13.3) 28 (18.4) 47 (18.5) 49 (30.4) 63 (21.6) 98 (14.5) 57 (11.6) 367 (16.6)
Other NA 17 (11.2) 8 (3.2) NA NA 3 (0.5) 20 (4.1) 48 (2.2)
Patient characteristic
Injection drug use 6 (3.2) 13 (8.6) 8 (3.2) 4 (2.5) 23 (7.9) 71 (10.5) 183 (37.2) 308 (13.9)
Heart failure 52 (27.7) 45 (29.6) 111 (43.7) 64 (39.8) 73 (25.1) 246 (36.5) 190 (38.6) 781 (35.3)
Surgery during index
hospitalization 47 (25.0) 48 (31.6) 119 (46.9) 81 (50.3) 159 (54.6) 208 (30.9) 164 (33.3) 826 (37.4)
Mortality among overall cohort
a
21 (11.2) 24 (15.8) 45 (17.7) 12 (7.5) 66 (22.7) 68 (10.1) 112 (22.8) 348 (15.7)
Staphylococcus aureus IE
b
40 (21.3) 62 (40.8) 53 (20.9) 22 (13.7) 88 (30.2) 194 (28.8) 193 (39.2) 652 (29.5)
MRSA IE
c
NA 25 (40.3) NA NA 12 (13.6) NA 13 (6.7) 50 (7.7)
S. aureus native valve IE
d
35 (87.5) 48 (77.4) 43 (81.1) 18 (81.8) 69 (78.4) 179 (92.3) 174 (90.2) 566 (86.8)
Mortality
a
for S. aureus
native valve IE 4 (11.4) 11 (22.9) 9 (20.9) 4 (22.2) 22 (31.9) 22 (12.3) 40 (23.0) 112 (19.8)
NOTE. Data are no. (%) of patients, unless otherwise indicated. MRSA, methicillin-resistant S. aureus; NA, not available.
a
In-hospital mortality.
b
As a proportion of total cases of IE.
c
As a proportion of total cases of S. aureus IE, including both native valve MRSA IE (43 patients) and prosthetic valve MRSA IE (7 patients).
d
As a proportion of total cases of S. aureus IE.
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ERRATUM • CID 2005:41 (1 October) • 1077
Table 2. Clinical characteristics, surgery findings, and outcomes for patients with native valve infective endocarditis (NVIE).
Variable
Patients with
non–SA-NVIE
a
(n p 1074)
Patients with SA-NVIE
P
All
(n p 566)
United
States
(n p 83)
Europe
(n p 483)
SA-NVIE
vs. non–SA-NVIE
United
States
vs. Europe
Demographic characteristic
Age, median years (IQR) 60.0 (44–71) 46.0 (29–66) 58.0 (44–70) 43.0 (27–65)
!.001 !.001
Male sex 749/1074 (69.7) 360/566 (63.6) 43/83 (51.8) 317/483 (65.6) .013 .019
Diabetes mellitus 73/632 (11.6) 39/344 (11.3) 23/83 (27.7) 16/261 (6.1) 1.000 !.001
Dialysis dependency 20/632 (3.2) 25/344 (7.3) 3/48 (6.3) 69/235 (29.4) .006
!.001
HIV infection 30/476 (6.3) 72/283 (25.4) 15/83 (18.1) 10/261 (3.8)
!.001 !.001
Other chronic disease 115/507 (22.7) 67/309 (21.7) 18/48 (37.5) 16/261 (6.1) .795
!.001
Long-term IVC 21/507 (4.1) 34/309 (11.0) 33/48 (68.8) 34/261 (13.0)
!.001 !.001
Acquisition in community 605/677 (89.4) 280/369 (75.9) 46/83 (55.4) 234/286 (81.8)
!.001 !.001
Injection drug use 59/1074 (5.5) 209/566 (36.9) 8/83 (9.6) 201/483 (41.6)
!.001 !.001
Congenital heart disease 123/757 (16.3) 22/387 (5.7) 6/83 (7.2) 16/304 (5.3)
!.001 .592
Echocardiography finding
!.001 .002
Transthoracic 305/949 (32.1) 224/531 (42.2) 15/48 (31.3) 209/483 (43.3)
Transesophageal 183/949 (19.3) 81/531 (15.3) 5/48 (10.4) 76/483 (15.7)
Both 393/949 (41.4) 185/531 (34.8) 28/48 (58.3) 157/483 (32.5)
Vegetation location
Aortic 335/1074 (31.2) 90/566 (15.9) 10/83 (12.1) 80/483 (16.6)
!.001 .334
Mitral 364/1074 (33.9) 145/566 (25.6) 19/83 (22.9) 126/483 (26.1)
!.001 .588
Tricuspic 54/1074 (5.0) 177/566 (31.3) 13/83 (15.7) 164/483 (34.0)
!.001 !.001
Pulmonic 12/581 (2.1) 6/335 (1.8) 0/60 (0.0) 6/275 (2.2) 1.000 1.000
Intracardiac abscess 94/1074 (8.8) 39/566 (6.9) 5/83 (6.0) 34/483 (7.0) .216 1.000
Outcome
Pulmonary embolism 37/929 (4.0) 138/426 (32.4) 9/70 (12.9) 129/356 (36.2)
!.001 !.001
CNS event 124/931 (13.3) 86/417 (20.6) 12/60 (20.0) 74/357 (20.7)
!.001 1.000
Total embolism 330/1074 (30.7) 343/566 (60.6) 35/83 (42.2) 308/483 (63.8)
!.001 !.001
Heart failure 401/1073 (37.4) 183/560 (32.7) 25/83 (30.1) 158/477 (33.1) .065 .615
Surgery at index episode 416/1074 (38.7) 148/566 (26.2) 16/83 (19.3) 132/483 (27.3) !.001 .138
In-hospital death 130/1062 (12.2) 112/562 (19.9) 15/83 (18.1) 97/479 (20.3)
!.001 .766
NOTE. Data are no. of patients with finding/ no. of patients with data (%), unless otherwise indicated. IVC, intravascular catheter; SA, Staphylococcus
aureus.
a
Data are for cases that involve known pathogens.
by guest on May 16, 2011cid.oxfordjournals.orgDownloaded from