Includes both nosocomial and nonnosocomial health care–associated
infections, community-acquired injection drug use–associated S aureus endocarditis, and community-acquired noninjection drug use–associated S aureus endocarditis by geographic region.
Fowler VG, Miro JM, Hoen B, Cabell CH, Abrutyn E, Rubinstein E, Corey GR, Spelman D, Bradley SF, Barsic B, Pappas PA, Anstrom KJ, Wray D, Fortes CQ, Anguera I, Athan E, Jones P, van der Meer JTM, Elliott TSJ, Levine DP, Bayer AS, ICE Investigators FT. Staphylococcus aureus EndocarditisA Consequence of Medical Progress. JAMA. 2005;293(24):3012-3021. doi:10.1001/jama.293.24.3012
Author Affiliations: Duke University Medical
Center, Durham, NC (Drs Fowler, Cabell, Corey, Anstrom, and Mr Pappas); Hospital
Clinic-IDIBAPS, University of Barcelona, Spain (Dr Miro); Hôpital Saint-Jacques,
Besançon, France (Dr Hoen); Drexel University College of Medicine,
Philadelphia, Pa (Dr Abrutyn); Tel Aviv University, School of Medicine, Tel
Aviv, Israel (Dr Rubinstein); Alfred Hospital, Melbourne, Australia (Dr Spelman);
University of Michigan, Ann Arbor (Dr Bradley); University Hospital for Infectious
Diseases, Zagreb, Croatia (Dr Barsic); Medical University of South Carolina,
Charleston (Dr Wray); Hospital Universitario Clementino Fraga Filho, Rio de
Janeiro, Brazil (Dr Fortes); Hospital de Sabadell, Sabadell, Spain (Dr Anguera);
Geelong Hospital, Geelong, Australia (Dr Athan); Prince of Wales Hospital,
Sydney, Australia (Dr Jones); Academic Medical Center, University of Amsterdam,
the Netherlands (Dr van der Meer); Queen Elizabeth Hospital, Birmingham, England
(Dr Elliott); Wayne State University, Detroit, Mich (Dr Levine); and Harbor-UCLA
Medical Center and the LA Biomedical Research Institute, Los Angeles (Dr Bayer).
Context The global significance of infective endocarditis (IE) caused by Staphylococcus aureus is unknown.
Objectives To document the international emergence of health care–associated S aureus IE and methicillin-resistant S aureus (MRSA) IE and to evaluate regional variation in patients with S aureus IE.
Design, Setting, and Participants Prospective observational cohort study set in 39 medical centers in
16 countries. Participants were a population of 1779 patients with definite
IE as defined by Duke criteria who were enrolled in the International Collaboration
on Endocarditis-Prospective Cohort Study from June 2000 to December 2003.
Main Outcome Measure In-hospital mortality.
Results S aureus was the most common pathogen among
the 1779 cases of definite IE in the International Collaboration on Endocarditis
Prospective-Cohort Study (558 patients, 31.4%). Health care−associated
infection was the most common form of S aureus IE
(218 patients, 39.1%), accounting for 25.9% (Australia/New Zealand) to 54.2%
(Brazil) of cases. Most patients with health care−associated S aureus IE (131 patients, 60.1%) acquired the infection outside of
the hospital. MRSA IE was more common in the United States (37.2%) and Brazil
(37.5%) than in Europe/Middle East (23.7%) and Australia/New Zealand (15.5%, P<.001). Persistent bacteremia was independently associated
with MRSA IE (odds ratio, 6.2; 95% confidence interval, 2.9-13.2). Patients
in the United States were most likely to be hemodialysis dependent, to have
diabetes, to have a presumed intravascular device source, to receive vancomycin,
to be infected with MRSA, and to have persistent bacteremia (P<.001 for all comparisons).
Conclusions S aureus is the leading cause of IE in many
regions of the world. Characteristics of patients with S aureus IE vary significantly by region. Further studies are required
to determine the causes of regional variation.
For decades, infective endocarditis (IE) caused by Staphylococcus aureus has been viewed primarily as a community-acquired
disease, especially associated with injection drug use.1- 7 In
contrast, patients with nosocomial or intravascular catheter–associated S aureus bacteremia were considered to be at low risk for
IE.5,6,8- 11S aureus IE is relatively infrequent at any individual
institution, and observations of its characteristics were based primarily
upon relatively small samples,1,3,6,9,12- 14 single-center
experiences,5,6,8,9,13- 16 or
retrospectively identified patients.2,7,8,15,16 Patient
characteristics, treatment practices, and outcomes in these single-center
studies often differed considerably. Moreover, because no large, prospectively
collected, and geographically diverse cohort of patients with IE existed before
now, the impact of regional variations on the characteristics, treatment,
and outcome of S aureus IE was unknown.
Recent substantive changes in health care delivery and in antimicrobial
resistance patterns have changed the epidemiology of S aureus infections. Rates of S aureus infection,
particularly bacteremia associated with health care contact, have increased
among hospitalized patients17,18 and
among those receiving outpatient medical therapy.19 Rates
of infections due to methicillin-resistant S aureus (MRSA)
in both hospital18 and community settings20 have also increased dramatically. Finally, the number
of patients with implanted medical devices (eg, prosthetic heart valves, grafts,
hemodialysis catheters, pacemakers), a population at high risk for S aureus bacteremia and endocarditis, has also risen in the past 2
decades.21- 23 However,
the extent to which these findings can be generalized is unknown.
The current investigation aimed (1) to document the characteristics
of IE caused by S aureus, including IE associated
with health care contact and IE due to MRSA, in different parts of the world;
and (2) to assess regional differences and the effect of these differences
on clinical outcomes among patients with S aureus IE.
Data from the International Collaboration on Endocarditis (ICE) were
used for this study. ICE began in June of 1999 after the fifth meeting of
the International Society of Cardiovascular Infectious Diseases in Amsterdam,
the Netherlands. ICE investigators initiated the ICE-Prospective Cohort Study
(ICE-PCS),24 which enrolled 1779 patients in
39 centers in 16 countries between June 15, 2000, and December 31, 2003.
Patients with definite IE were determined by Duke criteria. All patients
with IE from sites that met criteria for participation were included in this
study. These site criteria included (1) minimum enrollment of 12 cases per
year in a center with access to cardiac surgery, (2) patient identification
procedures in place to ensure consecutive enrollment and to minimize ascertainment
bias,24,25 (3) high-quality data
with query resolution, and (4) institutional review board (IRB)/ethics committee
approval or waiver based upon local standards. Sites not meeting these criteria
were excluded from this analysis (3 sites representing 23 patients). The ICE-PCS
database is maintained at the Duke Clinical Research Institute, which is the
coordinating center for ICE studies with IRB approval. Informed consent (oral
or written) was obtained from all patients according to local IRB/ethics committee
Patients were identified prospectively using site-specific procedures
to ensure consecutive enrollment.24,25 Physical
examination findings and clinical demographic data were recorded at the time
of patient enrollment. Patients were enrolled in ICE-PCS if they met criteria
for possible or definite IE, based upon the modified Duke criteria.26 Only patients with definite IE were admitted (n = 30
excluded) in the current investigation. To preserve the assumption of independence
of observations, only the first episode of S aureus IE
recorded for an individual patient was included in the analysis.
A standard case report form was used at all sites to collect data. The
case report form included 275 variables and was developed by ICE according
to standard definitions.24 Domains included
specific data on demographics, medical history, medications, clinical procedures,
presence of intravascular devices, predisposing factors, clinical examination,
microbiology, serology, nosocomial or community acquisition, antibiotic therapy,
echocardiography, surgery, complications, and outcome. Data were collected
during the index hospitalization and were then entered at the coordinating
center or by the site investigators using an Internet-based data entry system.
Queries were developed on all critical variables and were distributed to the
sites for reconciliation when necessary. Query responses were reviewed and
Chronic immunosuppressive therapy was defined as the administration
of recognized immunosuppressive agents (including oral corticosteroids or
other agents such as those used in solid organ transplantation or rheumatologic
disorders) for more than 30 days at the time of IE diagnosis.
A cardiac device was defined as a permanent pacemaker, cardioverter-defibrillator,
and/or prosthetic cardiac valve. Intravascular access devices were defined
as an arterial-venous fistula or an indwelling vascular catheter. A chronic
indwelling central catheter was defined as a tunneled, cuffed catheter, or
a subcutaneous port catheter. An intravascular access device was presumed
to be a possible source of IE if it was present at the onset of IE symptoms.
Vascular evidence of IE was defined as conjunctival hemorrhages, vascular
embolic events, or Janeway lesions.27 Immunologic
evidence of IE was defined as the presence of Osler nodes or Roth spots.27 Heart murmurs were defined as present or absent according
to the physical examination performed by the investigators at the time of
initial evaluation. A stroke was defined as an acute neurological deficit
of vascular etiology lasting more than 24 hours.28 Systemic
embolization was defined as an embolic event outside of the central nervous
system. Congestive heart failure was defined according to the New York Heart
Association classification system.29 Persistent
bacteremia was identified using Duke Endocarditis Service criteria.27
Health care–associated IE was defined as either nosocomial infection
or nonnosocomial health care–associated infection. Nosocomial infection
was defined as IE developing in a patient hospitalized for more than 48 hours
prior to the onset of signs/symptoms consistent with IE.
Nonnosocomial health care–associated infection was defined as
IE diagnosed within 48 hours of admission in an outpatient with extensive
health care contact as reflected by any of the following criteria: (1) received
intravenous therapy, wound care, or specialized nursing care at home within
the 30 days prior to the onset of S aureus–IE;
(2) attended a hospital or hemodialysis clinic or received intravenous chemotherapy
within the 30 days before the onset of S aureus IE;
(3) was hospitalized in an acute care hospital for 2 or more days in the 90
days before the onset of S aureus IE; or (4) resided
in a nursing home or long-term care facility.19
Community-acquired IE was defined as IE diagnosed at the time of admission
(or within 48 hours of admission) in a patient not fulfilling the criteria
for health care–associated infection. Infections were considered to
be injection drug use (IDU)–associated if the patient actively used
these substances at the time of IE diagnosis and was admitted from the community
without an alternate presumed source. Vancomycin therapy was defined as being
present if it was identified by the investigator as the predominant antibiotic
used in the treatment of the infection.
Geographic regions participating in ICE included the following: United
States (9 sites), South America (2 sites each from Brazil, Argentina, and
Chile), Australia/New Zealand (7 sites), and Europe/Middle East (17 sites).
For multivariate modeling, the European/Middle Eastern region was further
subdivided a priori into Northern/Central Europe (a total of 10 sites in France,
United Kingdom, Sweden, Germany, Croatia, and the Netherlands) and Southern
Europe/Middle East (a total of 7 sites in Italy, Spain, Israel, and Lebanon).
Because it contained the highest number of participating centers, Northern/Central
Europe was used as the referent category for all multivariate analyses in
which the geographic region of the infection was considered.
Continuous variables were represented as medians with 25th and 75th
percentiles. Categorical variables were represented as frequencies and percentages
of the specified group. Univariate comparisons were made with the Wilcoxon
rank-sum test or the χ2 test as appropriate. A generalized
estimating equation method was used to determine factors that predict S aureus IE among IE patients, in-hospital death among
native valve S aureus IE patients, and MRSA among
native valve S aureus IE patients.30 Variables
found to have a univariate association with the outcome of interest (P<.10) were considered for the final model in a stepwise
fashion. The variables included in the final adjusted regression models were
selected based on a combination of statistical significance (P<.05) and clinical judgment. The generalized estimating equation
method produces consistent parameter estimates that measure association between
in-hospital death and the baseline covariates while accounting for the correlation
in outcomes of patients from the same hospital. Final parameter estimates
were converted to odds ratios (ORs) with corresponding 95% Wald confidence
intervals (CIs). The fit of the multivariable models to the data was assessed
by the concordance index, which estimates the probability that a patient who
had the outcome of interest was assigned a greater probability of sustaining
the outcome of interest than was a patient who did not sustain the outcome
of interest. For all tests, statistical significance was determined at the
.05 level. All statistical analyses were performed using SAS software version
8.2 (SAS Institute, Cary, NC).
During the 48-month study period, 1779 patients with definite IE from
16 countries were enrolled into ICE-PCS. S aureus was
the most commonly identified pathogen and was present in 558 patients (31.4%)
(Table 1). By univariate analysis, patients
with IE due to S aureus were more likely than patients
with IE due to other pathogens to be female (P<.001),
hemodialysis dependent (P<.001), to have diabetes
mellitus (P = .009), or to have other chronic
illnesses (P<. 001) (Table 2). Patients with S aureus IE were
also significantly more likely to have health care–associated IE (P<.001) than were patients with non-S aureus IE. Cardiac surgery was significantly less frequent among
patients with S aureus IE than among patients with
non–S aureus IE (P<.001),
and it was more likely to be performed due to embolization (P<.001) or persistent bacteremia (P<.001).
Relative to patients with non–S aureus IE,
patients with S aureus IE also had higher rates of
stroke (P<.001), systemic embolization (P = .001), persistent bacteremia (P<.001), and death (P<.001).
Next, a multivariate model was fitted using the entire cohort and the
candidate variables listed in Table 2 to
identify clinical features independently associated with S aureus IE (concordance index, 0.78). Patient characteristics associated
with S aureus IE by multivariate modeling included
IDU (OR, 9.3; 95% CI, 6.3-13.7), first clinical presentation less than 1 month
after first symptoms (OR, 5.1; 95% CI, 3.2-8.2), health care–associated
infection (OR, 2.9; 95% CI, 2.1-3.8), persistent bacteremia (OR, 2.3; 95%
CI, 1.5-3.8), presence of a presumed intravascular device source (OR, 1.7;
95% CI, 1.2-2.6), stroke (OR, 1.6; 95% CI, 1.2-2.3), and diabetes mellitus
(OR, 1.3; 95% CI, 1.1-1.8).
S aureus IE occurred in 3 distinct clinical
settings in this investigation: health care–associated infection (218
patients, 39.1%), community-acquired infection in persons with no history
of IDU (209 patients, 37.5%), and community-acquired IDU-associated infection
(117 patients, 21.0%) (Table 2). The
presumed place of infection was missing in 14 patients (2.5%). Of the 218
patients with health care–associated IE, 131 (60.1%) had nosocomial
infection, and 87 (39.9%) had nonnosocomial health care–associated infection.
Patients with health care–associated IE were more likely to be from
the United States (46.3%) than were patients with community-acquired IDU-associated
IE (40.2%) or community-acquired non-IDU–associated IE (21.1%) (P<.001); they were also older (median age, 64.6 vs 36.2
vs 60.6 years, P<.001), more likely to be infected
with MRSA (49.1% vs 10.3% vs 13.4%, P<.001), and
more likely to have mitral valve involvement (55.8% vs 19.6% vs 49.2%, P<.001). However, they were less likely to have a new/worsening
cardiac murmur (33.5% vs 52.1% vs 41.2%, P = .004).
Patient outcomes differed according to the clinical setting. Patients
with health care–associated IE had higher rates of in-hospital mortality
(29.4%) than did patients with community-acquired IDU-associated IE (11.1%)
or community-acquired non-IDU–associated IE (21.1%) (P<.001). Patients with health care–associated IE had higher
rates of mortality within each of the 4 geographic regions represented in
this study (Figure). They also had higher
rates of persistent bacteremia (P<.001). Despite
these observations, patients with health care–associated IE were less
likely to undergo surgical therapy (33.0%) than were patients with community-acquired
IDU-associated IE (35.0%) or community-acquired non-IDU–associated IE
(44.5%, P = .04) (Table 3).
Cardiac devices were present in 130 (23.3%) of the patients in the overall
cohort with S aureus IE (permanent pacemakers in
36 patients, cardioverter-defibrillators in 5 patients, prosthetic cardiac
valves in 64 patients, and more than one device present in 25 patients). Patients
with cardiac devices had higher rates of cardiac surgery (46.9% vs 35.6%, P = .02) and in-hospital mortality (27.7% vs
20.0%, P = .07) than did patients without
A total of 153 patients (27.4%) with S aureus IE
were known to be infected with MRSA. We compared the characteristics and outcome
of these patients with those of patients with methicillin-susceptible S aureus (MSSA) IE. Patients with IDU were excluded from
these analyses because the predominance of MSSA and the low mortality in this
population would have confounded outcome comparisons. Of the 424 patients
with definite S aureus IE and no history of active
IDU, 141 (33.3%) were infected with MRSA (Table
4). Patients with MRSA IE had more chronic comorbid conditions and
were more likely to have health care–associated infection (75.9% vs
37.1%, P<.001). MRSA- and MSSA-infected patients
had similar rates of cardiac surgery. Complications differed between the 2
groups: MSSA-infected patients had higher rates of systemic embolization (26.2%
vs 17.7%, P = .06), whereas MRSA-infected
patients experienced higher rates of persistent bacteremia (42.6% vs 8.8%, P<.001). MRSA-infected patients tended to have higher
mortality rates than did MSSA-infected patients, although this difference
was not statistically significant (29.8% vs 23.3%, P = .14).
A multivariate model was then fit using the patient characteristics
and variables presented in Table 4 to
identify clinical features independently associated with MRSA IE. Patient
characteristics associated with MRSA IE included persistent bacteremia (OR,
6.2; 95% CI, 2.9-13.2), chronic immunosuppressive therapy (OR, 4.1; 95% CI,
2.0-8.6), health care–associated infection (OR, 3.4; 95% CI, 2.1-5.5),
a presumed intravascular device source (OR, 2.1; 95% CI, 1.2-3.7), and diabetes
mellitus (OR, 2.0; 95% CI, 1.1-3.7).
The characteristics of patients with S aureus IE
are presented by geographic region in Table 5. Compared with patients from other regions, patients from the United
States were more likely to be hemodialysis dependent, to be diabetic, to have
a hemodialysis fistula or a chronic indwelling central catheter as a presumed
source of infection, and to receive vancomycin therapy (P<.001 for all comparisons). US patients were also more likely to
have nonnosocomial health care–associated IE. Patients from the United
States (37.2%) and Brazil (37.5%) were more likely to have MRSA IE than were
patients from Europe/Middle East (23.7%) and Australia/New Zealand (15.5%)
(P<.001). Although in-hospital mortality rates
were similar among regions, United States patients were significantly more
likely to develop persistent bacteremia (25.6%, P<.001).
Determinants of outcome of patients with S aureus IE were next evaluated using a multivariate model (Table 6). Patients were included in the model if they had definite
native valve S aureus IE and no history of active
IDU. Characteristics independently associated with mortality among patients
with S aureus IE included stroke (OR, 3.67; 95% CI,
1.94-6.94), persistent bacteremia (OR, 3.06; 95% CI, 1.75-5.35), diagnosis
in Southern Europe/Middle East (OR, 3.21; 95% CI, 1.17-10.56), and age in
10-year intervals (OR, 1.49, 95% CI, 1.23-1.81).
Changes in health care delivery and in antimicrobial resistance patterns
have altered the epidemiology of S aureus infections.
This investigation documents several new and important aspects of S aureus IE in the current era.
S aureus was the most common cause of IE in
the overall ICE-PCS cohort, and IE due to S aureus exhibited
distinct characteristics as compared with IE due to other pathogens. The finding
of S aureus as the leading cause of IE differs from
previous reports12,15 and may
be due in part to increasing rates of staphylococcal bacteremia related to
health care contact in industrialized nations. For example, rates of sepsis
due to gram-positive organisms increased by an average of 26.3% annually from
1979 to 2000, making these bacteria the leading cause of sepsis in the United
States.17 In addition, S
aureus was the second most common pathogen isolated in 2 recent, large
studies of bloodstream infections in the United States18 and
Europe.31 Our findings emphasize that, in addition
to sepsis and bacteremia, S aureus is now also the
leading cause of IE in many regions of the globe.
The current investigation definitively establishes the global emergence
of health care contact as a critical risk factor for S aureus IE. In contrast to older, smaller, and often retrospective reports,
health care–associated infection was the single most common form of S aureus IE in this study. Indeed, health care-associated
infection accounted for one quarter to one half of S aureus IE cases reported in the represented geographic regions. In a significant
proportion of these patients, an intravascular device was the presumed source
of bacteremia, confirming previous single-center observations.13,14,16,32- 34 Prosthetic
cardiac devices (pacemakers, defibrillators, and prosthetic cardiac valves)
were present in almost one quarter of the patients in this investigation.
This finding is consistent with a recent report using Medicare claims data
to demonstrate increasing numbers of cardiac device infections over the previous
decade.21S aureus IE
was also associated with immunosuppression in this and prior reports.25 This association may be due to either the health
care for underlying diseases that are being treated with immunosuppressive
therapy or the immunosuppression itself. Taken together, these findings indicate
an important shift in the epidemiology of S aureus IE:
it is increasingly a consequence of medical progress.
Based upon the findings in this investigation, we suggest that health
care–associated IE is a distinct clinical subtype of S aureus IE, distinguished by a relative infrequency of classic clinical
stigmata of IE, a predominance of mitral valve involvement, and a high mortality
rate. The lower rates of surgery among patients with health care-associated S aureus IE may reflect a higher rate of comorbid conditions
or advanced age, a lower rate of clinical recognition of IE, or the higher
rate of stroke among patients with S aureus IE in
this study. These findings underscore the need to reduce the number of health
care–associated infections through improved compliance with infection
control procedures, as well as the need for new interventions and preventive
This investigation also conclusively establishes MRSA as a significant
cause of IE internationally, accounting for almost 40% of the IE caused by S aureus in certain regions. Not surprisingly, patients
with MRSA IE were significantly more likely to have preexisting chronic conditions
and health care–associated IE by both univariate and multivariate modeling.
One distinct characteristic of MRSA IE suggested in the current investigation
was persistent bacteremia. This finding is consistent with previous reports35,36 and may be due in part to the use
of vancomycin, an agent associated with delayed bactericidal activity against S aureus.35- 37 Despite
a higher rate of persistent bacteremia, the difference in mortality between
MRSA- and MSSA-infected subjects did not achieve statistical significance.
This observation may be due in part to the overall high mortality of S aureus IE (regardless of the antimicrobial resistance
profile of the infecting pathogen) or due simply to an insufficient sample
It is important to note that approximately 20% of patients with MRSA
IE developed their infection in the absence of identifiable health care contact.
Community-acquired MRSA cases differ demographically from health care–associated
MRSA cases; MRSA isolates from community-acquired infections commonly possess
distinct exotoxin gene profiles (eg, Panton-Valentine leukocidin genes) compared
with health care–associated isolates.20 The
findings of the current investigation, coupled with the increasing number
of reports of community-acquired MRSA infection, suggest that these strains
may be an emerging cause of IE in many regions of the world.
One clinical profile seen almost exclusively in US patients was the
development of IE among non-hospitalized subjects with extensive health care
contact, often in the context of long-term intravascular access. Almost one
third of US patients developed nonnosocomial health care–associated
IE, and in approximately 20%, the presumed source was a chronic indwelling
central catheter. This finding may reflect the recent increasing trend in
the United States toward outpatient medical therapy, such as long-term antibiotics,
parenteral nutrition, and hemodialysis. United States patients with S aureus IE were also significantly more likely to be infected
with MRSA and to develop persistent bacteremia. The higher rates of persistent
bacteremia in US patients may be due in part to the fact that they were more
likely to receive vancomycin.
While the ICE-PCS represents the largest and most geographically diverse
collection of prospectively identified patients with S aureus IE ever assembled, this investigation has limitations. This is an
observational study of patients with definite IE from centers that have self-selected
to participate in the ICE-PCS. Therefore, a population sample was not obtained
from any specific region, limiting any epidemiologic inferences. Similarly,
as only a select group of centers within each geographic region participated
in the current investigation, regional characterization is based solely on
data from these centers. In addition, these hospitals are typically referral
centers that have cardiac surgical programs. Therefore, the results of this
study may not generalize to other patient populations with S aureus IE or to patients receiving care at other types of medical
S aureus is now the most common cause of IE
in many areas of the developed world. Patients with IE due to S aureus exhibit distinct characteristics compared with patients with
IE due to other pathogens. Health care–associated IE is emerging as
the most common form of S aureus IE and has distinct
features compared with more familiar forms of S aureus IE,
such as community-acquired IDU-associated infection. MRSA is now encountered
internationally as a relatively common cause of IE and is associated with
persistent bacteremia. Future investigations are required to identify better
treatment and prevention strategies for this serious and common consequence
of medical progress.
Corresponding Author: Vance G. Fowler, Jr,
MD, MHS, Box 3281, Division of Infectious Diseases, Duke University Medical
Center, Durham, NC 27710 (firstname.lastname@example.org).
Author Contributions: Dr Fowler had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Fowler, Miro, Hoen,
Abrutyn, Rubinstein, Corey, Spelman, Pappas, Elliott.
Acquisition of data: Fowler, Miro, Hoen, Cabell,
Abrutyn, Rubinstein, Corey, Spelman, Bradley, Barsic, Wray, Fortes, Anguera,
Athan, Jones, van der Meer, Elliott, Levine.
Analysis and interpretation of data: Fowler,
Miro, Hoen, Cabell, Abrutyn, Corey, Spelman, Barsic, Pappas, Anstrom, Jones,
Drafting of the manuscript: Fowler, Miro, Cabell,
Corey, Spelman, Barsic, Anguera, Elliott, Bayer.
Critical revision of the manuscript for important
intellectual content: Fowler, Miro, Hoen, Cabell, Abrutyn, Rubinstein,
Corey, Spelman, Bradley, Barsic, Pappas, Anstrom, Wray, Fortes, Anguera, Athan,
Jones, van der Meer, Elliott, Levine, Bayer.
Statistical analysis: Abrutyn, Spelman, Pappas,
Obtained funding: Cabell, Corey, Fowler.
Administrative, technical, or material support:
Fowler, Hoen, Rubinstein, van der Meer, Elliott.
Study supervision: Fowler, Miro, Abrutyn, Rubinstein,
Corey, Anguera, Athan.
Financial Disclosures: Dr Fowler has received
research grants from Cubist, Inhibitex, Nabi, Theravance, Merck, Ortho-McNeil,
and Vicuron; speaking honoraria from Pfizer, Cubist, and Aventis; consulting
fees from Merck, Nabi, Inhibitex, Elusys, Cubist, Vicuron, and GlaxoSmithKline.
Funding/Support: This study was supported by
the following grants from the National Institutes of Health: AI-059111 (Dr
Fowler), HL-70861 (Dr Cabell), and AI-39108 (Dr Bayer); the Red Española
de Investigación en Patología Infecciosa (V-2003-REDC14A-O)
(Dr Miro); the Fundación Privada Máximo Soriano Jiménez
(Barcelona, Spain) (Dr Miro); the Institut d’Investigacions Biomèdiques
August Pi i Sunyer (IDIBAPS, Barcelona Spain) (Dr Miro); Fondo de Investigaciones
Sanitarias de la Seguridad Social (FIS 00-0475) (Dr Miro); and the Ministry
of Science, Republic of Croatia (0108309) (Dr Barsic).
Role of the Sponsor: The sponsors played no
role in the design and conduct of the study; collection, management, analysis,
and interpretation of the data; or preparation, review, or approval of the
ICE Steering Committee: E Abrutyn (Co-Chair),
B Hoen (Co-Chair), CH Cabell, AS Bayer, GR Corey, DT Durack, S Eykyn, VG Fowler,
AW Karchmer, JM Miro, P Moreillon, L Olaison, D Raoult, E Rubinstein, D Sexton.
ICE Publications Committee: E Abrutyn, AS Bayer,
GR Corey, B Hoen, JM Miro.
ICE Coordinating Center (Duke Clinical Research Institute,
Durham, NC): CH Cabell (Director), T Harding (Project Leader), K Anstrom,
K Baloch, L Clevenger, C Dixon, M Molina, P Pappas, T Reddick, J Stafford.
ICE Investigators: W Armstrong, S Bradley,
C Kauffman (Ann Arbor, Mich); L Adams, I Dale, W Dismukes, N Nanda, M Patel
(Birmingham, Ala); O Aksoy, P Brown, CH Cabell, GR Corey, VG Fowler, C Moore,
L Meyer, DS Sexton (Durham, USA); E Abrutyn, K de Almeida (Philadelphia, Pa);
G Peterson, P Southern; S Hasan, M Shah (Dallas, Tex); R Cantey, P Church,
D Wray (Charleston, USA); N Ali, R Gella, D Levine, C Tittle (Detroit, Mich);
C Kennedy, S Lerakis (Atlanta, Ga). United Kingdom: T
Elliott, N Khattak, S Lang, R Watkins (Birmingham); S Eykyn, C Orezzi (London). Sweden: E Alestig, L Olaison, K Schadewitz, U Snygg-Martin,
L Wikstrom (Göteborg). Spain: M Almela, M Azqueta,
X Claramonte, N de Benito, E de Lazzari, C Garcia de la Maria, JM Gatell,
MJ Jiménez-Expósito, F Marco, CA Mestres, A Moreno-Camacho,
JM Miro, JC Paré, JL Pomar, N Perez B Almirante, P Tornos (Barcelona);
I Anguera, B Font, J Guma (Sabadell); E Bouza, M Moreno, P Muňoz, M
Rodríguez-Créixems (Madrid). France: D
Iarussi, M Tripodi, R Utili (Napoli); Y Bernard, C Chirouze, B Hoen, J Leroy,
P Plesiat (Besançon); J-P Casalta, P-E Fournier, G Habib, D Raoult,
F Thuny (Marseille); T Doco-Lecompte, C Selton-Suty (Nancy). Israel: E Nadir, E Rubinstein, K Strahilewitz (Tel Aviv). Australia: P Bergin, D Spelman (Melbourne); P Jones, P Kornecny, R
Lawrence, D Rees, S Ryan (Sydney); E Athan, S Graves (Greelong); T Ferguson,
D Gordon, A Lee (Adelaide); T Korman (Clayton). Aregentina: L Clara, M Sanchez (Buenos Aires); J De Ierolamo, M Marvin, F Nacinovich,
M Trivi (Buenos Aires). Lebanon: Z Kanafani, S Kanj-Sharara
(Beirut). Brazil: C Fortes (Rio de Janeiro); A de
Oliveira Ramos (São Paulo). Chile: S Braun
Jones (Santiago); R Montagna Mella, M Oyonarte (Santiago). New Zealand: P Bridgman, S Chambers, D Holland, D Murdoch, S Lang,
A Morris, N Raymond, K Read (Auckland, Christchurch, Wellington); Croatia: B Barsic, A Boras, I Klinar (Zagreb); the
Netherlands: J van der Meer, D Verhagen (Amsterdam).