Contemporary Clinical Profile and Outcome of Prosthetic Valve Endocarditis

Andrew Wang; Eugene Athan; Paul A. Pappas; et al.

Online article and related content current as of November 13, 2009. JAMA. 2007;297(12):1354-1361 (doi:10.1001/jama.297.12.1354) http://jama.ama-assn.org/cgi/content/full/297/12/1354

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Bacterial Infections; Infectious Diseases, Other; Prognosis/ Outcomes; Cardiovascular Disease/ Myocardial Infarction; Infectious Diseases
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Heart Valve Infections

Janet M. Torpy et al. JAMA. 2007;297(12):1396.

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ORIGINAL CONTRIBUTION

CLINICIANS CORNER

Contemporary Clinical Profile and Outcome of Prosthetic Valve Endocarditis

Andrew Wang, MD Eugene Athan, MD Paul A. Pappas, MS Vance G. Fowler, Jr, MD, MHS Lars Olaison, MD Carlos Pare, MD Benito Almirante, MD Patricia Muoz, MD Marco Rizzi, MD Christoph Naber, MD Mateja Logar, MD Pierre Tattevin, MD Diana L. Iarussi, MD Christine Selton-Suty, MD Sandra Braun Jones, MD Jose Casabe, PhD Arthur Morris, MD G. Ralph Corey, MD Christopher H. Cabell, MD, MHS for the International Collaboration on Endocarditis-Prospective Cohort Study Investigators surgery is performed in more than 150 000 patients per year in the United States and Europe,1,2 and the number of prosthetic valve implantations continues to increase.3 Infection of a heart valve prosthesis, or prosthetic valve endocarditis (PVE), is an uncommon but potentially lethal complication of heart valve replacement surgery. Despite adSee also Patient Page. CME available online at www.jama.com Context Prosthetic valve endocarditis (PVE) is associated with significant mortality and morbidity. The contemporary clinical profile and outcome of PVE are not well defined. Objectives To describe the prevalence, clinical characteristics, and outcome of PVE, with attention to health careassociated infection, and to determine prognostic factors associated with in-hospital mortality. Design, Setting, and Participants Prospective, observational cohort study conducted at 61 medical centers in 28 countries, including 556 patients with definite PVE as defined by Duke University diagnostic criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to August 2005. Main Outcome Measure In-hospital mortality. Results Definite PVE was present in 556 (20.1%) of 2670 patients with infective endocarditis. Staphylococcus aureus was the most common causative organism (128 patients [23.0%]), followed by coagulase-negative staphylococci (94 patients [16.9%]). Health careassociated PVE was present in 203 (36.5%) of the overall cohort. Seventy-one percent of health careassociated PVE occurred within the first year of valve implantation, and the majority of cases were diagnosed after the early (60-day) period. Surgery was performed in 272 (48.9%) patients during the index hospitalization. In-hospital death occurred in 127 (22.8%) patients and was predicted by older age, health care associated infection (62/203 [30.5%]; adjusted odds ratio [OR], 1.62; 95% confidence interval [CI], 1.08-2.44; P=.02), S aureus infection (44/128 [34.4%]; adjusted OR, 1.73; 95% CI, 1.01-2.95; P=.05), and complications of PVE, including heart failure (60/183 [32.8%]; adjusted OR, 2.33; 95% CI, 1.62-3.34; P .001), stroke (34/101 [33.7%]; adjusted OR, 2.25; 95% CI, 1.25-4.03; P=.007), intracardiac abscess (47/144 [32.6%]; adjusted OR, 1.86; 95% CI, 1.10-3.15; P=.02), and persistent bacteremia (27/49 [55.1%]; adjusted OR, 4.29; 95% CI, 1.99-9.22; P .001). Conclusions Prosthetic valve endocarditis accounts for a high percentage of all cases of infective endocarditis in many regions of the world. Staphylococcus aureus is now the leading cause of PVE. Health careassociated infection significantly influences the clinical characteristics and outcome of PVE. Complications of PVE strongly predict inhospital mortality, which remains high despite prompt diagnosis and the frequent use of surgical intervention.
JAMA. 2007;297:1354-1361 Author Affiliations: Department of Medicine, Duke University Medical Center, Durham, NC (Drs Wang, Fowler, Corey, and Cabell); Department of Infectious Disease, The Geelong Hospital at the University of Melbourne, Melbourne, Australia (Dr Athan); Outcomes Research and Assessment Group, Duke Clinical Research Institute, Durham, NC (Mr Pappas); Department of Infectious Disease, Sahlgrenska Universitetssjukhuset/ Ostra, Gteborg, Sweden (Dr Olaison); Department of Cardiology, University of Barcelona, Barcelona, Spain (Dr Pare); Infectious Diseases Department, Hospital Uni versitari Vall dHebron, Barcelona, Spain (Dr Almirante); Department of Infectious Disease, Hospital General Universitario Gregorio Maranon, Barcelona, Spain (Dr Muoz); Department of Infectious Disease, Ospedali Riuniti, Bergamo, Italy (Dr Rizzi); Cardiology Clinic, University Essen, Essen, Germany (Dr Naber); Department of Infectious Disease, Medical Center Ljublijana, www.jama.com Ljublijana, Slovenia (Dr Logar); Department of Infectious Disease, Pontchaillou University, Rennes, France (Dr Tattevin); Department of Cardiology, II Universita di Napoli, Naples, Italy (Dr Iarussi); Cardiology Service, CHU Nancy-Brabois, Nancy, France (Dr SeltonSuty); Laboratorio de Tecnicas No Invasivas, Hospital Clinico Pont Universidad Catolica de Chile, Santiago, Chile (Dr Jones); Department of Cardiology, Instituto de Cardiologia y Cirugia Cardiovascular, Fundacion Favaloro, Buenos Aires, Argentina (Dr Casabe); Diagnos tic Medlab, Auckland City Hospital, Auckland, New Zealand (Dr Morris). A List of the ICE Investigators appears at the end of this article. Corresponding Author: Andrew Wang, MD, Department of Medicine, Duke University Medical Center, DUMC 3428, Room 7624 A, Durham, NC 27710 (a.wang@duke.edu).

EART VALVE REPLACEMENT

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CONTEMPORARY CLINICAL PROFILE AND OUTCOME OF PROSTHETIC VALVE ENDOCARDITIS

vances in its diagnosis and treatment, PVE is associated with substantial morbidity and mortality.4-8 Prosthetic valve endocarditis has been estimated to occur at a rate of 0.3% to 1% per patientyear and to account for 1% to 5% of all cases of infective endocarditis (IE).9-12 Recent studies of predominantly native valve infective endocarditis (NVIE) have found an increased rate of Staphylococcus aureus infection, with an association between health care contact and this causative organism.13-15 However, the contemporary clinical profile and outcome of PVE have not been evaluated in large, prospective studies. Much of the current understanding of PVE has been based on studies limited by small sample size, retrospective design, or single-center experiences, and many of these investigations antedated the routine use of echocardiography in the diagnosis of IE and the contemporary and validated Duke diagnostic criteria for IE.16,17 We hypothesized that the contemporary profile of PVE may be significantly influenced by health care associated infection. The objectives of this study were (1) to prospectively describe the prevalence, clinical characteristics, and outcome of PVE, with attention to health careassociated infection; and (2) to determine prognostic factors associated with inhospital mortality. To accomplish these goals, we analyzed data from the International Collaboration on EndocarditisProspective Cohort Study (ICE-PCS), a large, prospective, contemporary, multinational registry of endocarditis. METHODS
International Collaboration on Endocarditis-Prospective Cohort Study

database is maintained at the Duke Clinical Research Institute, which is the coordinating center for ICE studies. Informed consent (oral or written) was obtained from all patients according to local institutional review boards or ethics committee guidelines at all sites. Geographic regions participating in ICE-PCS that enrolled patients with definite PVE included the following: United States (10 sites), South America (7 sites), Northern/Central Europe (14 sites), Southern Europe/Middle East/ South Africa (11 sites), and Australia/ New Zealand/Asia (11 sites).
Patient Selection and Data Collection

Patients were identified prospectively using site-specific procedures to ensure consecutive enrollment.15,18 Patients were enrolled in ICE-PCS if they met criteria for possible or definite IE based on modified Duke criteria.16 Only patients with definite IE were included in the current study. To preserve the assumption of independence of observations, only the first episode of IE recorded for an individual patient was used in the analysis. The method of data collection for ICE-PCS has been previously reported.14 Briefly, a standard case report form was used at all sites to collect data. This case report form included 275 variables and was developed by ICE according to standard definitions.18 Data were collected during the index hospitalization and were then entered at the coordinating center or by site investigators using an Internet-based data entry system.
Definitions

ent at the onset of IE symptoms. Persistent bacteremia was defined as previously reported.16,17 An intracardiac abscess was defined as a thickened area or mass with a heterogeneous echogenic or echolucent appearance by echocardiography, or the presence of pus by direct visualization at the time of surgery.19 Early PVE was defined as the diagnosis of PVE within 60 days of prosthetic valve implantation.20-22 Health careassociated infection in PVE was categorized as either nosocomial or nonnosocomial health careassociated infection.23 Nosocomial infection was defined as PVE developing in a patient hospitalized for more than 48 hours before the onset of signs or symptoms consistent with IE. Non-nosocomial health careassociated 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 PVE; (2) attended a hospital or hemodialysis clinic or received intravenous chemotherapy within the 30 days before the onset of PVE; (3) was hospitalized in an acute care hospital for 2 or more days in the 90 days before the onset of PVE; or (4) resided in a nursing home or long-term care facility.23
Statistical Analysis

Data from the International Collaboration on Endocarditis (ICE) were used for this study. The background and inclusion criteria of this prospective, multicenter, international registry of IE have been reported previously.14,15,18 Between June 2000 and August 2005, 3250 patients from 61 centers in 28 countries were enrolled. The ICE-PCS

Definitions of the variables included in the ICE-PCS case report form have been previously reported.14 Intravascular access devices were defined as an arterialvenous fistula or an indwelling vascular catheter. A long-term indwelling central venous 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 pres-

Continuous variables were presented as medians with 25th and 75th percentiles. Categorical variables were presented as frequencies and percentages of the specified group. Univariable comparisons of clinical characteristics were made with the Wilcoxon rank-sum test or the 2 test as appropriate. Within the PVE group, analyses were performed to evaluate the nature of early PVE compared with late PVE and, more broadly, health careassociated PVE in comparison to community-acquired PVE. Regional differences in PVE were assessed by dividing the participating sites in ICE-PCS based on their geographic region while integrating regions with
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CONTEMPORARY CLINICAL PROFILE AND OUTCOME OF PROSTHETIC VALVE ENDOCARDITIS

few PVE cases (eg, Africa) with other proximal regions (Southern Europe and Middle East). An exploratory multivariable generalized estimating equation model was created to determine variables independently associated with in-hospital mortality in PVE. Final parameter estimates were converted to odds ratios with corresponding 95% confidence intervals. To avoid overfitting the data, 15 clinically relevant variables were considered for the final generalized estimating equation model using backward selection. Multicollinearity was assessed by examination of the estimated parameter correlation matrix and no significant collinearity was found. Clinically relevant interactions were investigated and none were found to be significant. Missing values were imputed to the most frequent category for categorical variables and to the median for continuous variables. Plots of each

variable considered for the final regression model against the outcome of interest were created to identify excessively influential observations and none were found. The fit of the final regression model to the data was evaluated by the Hosmer-Lemeshow test,24 which partitions the observations into 10 equal-sized groups according to their predicted probabilities and compares the observed and expected mortality across the partitions. Mortality rates for S aureus and health careassociated PVE were evaluated by plotting the survival distribution derived from Kaplan-Meier estimates, and differences in survival were assessed by the log-rank test. Event (or censoring) times for all patients were measured from the day of initial admission for PVE (time 0). 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). RESULTS Prosthetic valve endocarditis was diagnosed in 556 (20.1%) of 2670 patients with definite IE. Among patients with PVE, a prosthetic aortic valve was present in 384 patients (69.1%), prosthetic mitral valve or ring in 280 patients (50.4%), prosthetic tricuspid valve or ring in 52 patients (9.4%), and prosthetic pulmonic valve in 31 patients (5.6%). Of the overall PVE cohort, 127 (22.8%) patients died during hospital admission for PVE. TABLE 1 shows the clinical characteristics of individuals with PVE in comparison to NVIE. Patients with PVE were significantly older, less likely to use injection drugs, and more likely to have health careassociated infection and intracardiac abscess. In-hospital mortality was significantly higher among PVE cases despite similar rates of complications and surgical intervention. Although patients with PVE had a higher rate of coagulase-negative staphylococcal infection (16.9%) and a lower rate of S aureus infection (23.0%) than patients with NVIE (8.3% and 32.9%, respectively; P .001 for both), S aureus was the most common cause of PVE (TABLE 2). For 384 patients for whom time from valve implantation was available, the microbiology of early and late PVE are also shown. During the index hospitalization, surgical therapy was used in 272 (48.9%) patients with PVE and 879 (46.4%) patients with NVIE (P=.30). A comparison of PVE across geographic regions is shown in TABLE 3. Direct correlations were found between the percentages of PVE due to staphylococcal species (either S aureus or coagulase-negative staphylococcus as causative microorganism) and percentages of PVE cases (r = 0.713, P .001) as well as health care associated PVE (r=0.623, P .001). Patients in the United States were significantly more likely to have nonnosocomial health careassociated PVE, an intravascular device source of infec-

Table 1. Comparison of Patients With Prosthetic Valve Endocarditis (PVE) and Native Valve Infective Endocarditis (NVIE) in the International Collaboration on Endocarditis-Prospective Cohort Study*
Characteristic Age, mean (range), y Male Hemodialysis dependent Diabetes mellitus Current injection drug use Chronic immunosuppressive therapy Cancer Other chronic illness Previous endocarditis Health careassociated infection Transesophageal echocardiography performed Time from admission to transesophageal echocardiography, mean (range), d Echocardiographic findings Vegetation New regurgitation Abscess Complications and outcome Heart failure Stroke Other systemic embolization Surgery during admission Persistent bacteremia Duration of hospitalization, mean (range), d In-hospital death PVE (n = 556) 65.0 (49.9-74.3) 363 (65.3) 25 (4.5) 100 (18.0) 10 (1.8) 24 (4.3) 32 (5.8) 246 (44.2) 112 (20.1) 203 (36.5) 467 (84.0) 2.0 (0-6.0) NVIE (n = 1895) 56.3 (41.1-69.9) 1299 (68.6) 173 (9.1) 292 (15.4) 235 (12.4) 127 (6.7) 169 (8.9) 916 (48.3) 91 (4.8) 587 (31.0) 1290 (68.1) 3.0 (0-7.0) P Value .001 .17 .001 .13 .001 .05 .02 .12 .001 .01 .001 .13

406 (73.0) 257 (46.2) 165 (29.7) 183 (32.9) 101 (18.2) 83 (14.9) 272 (48.9) 49 (8.8) 33 (19-49) 127 (22.8)

1703 (89.9) 1346 (71.0) 222 (11.7) 616 (32.5) 322 (17.0) 468 (24.7) 879 (46.4) 166 (8.8) 29 (16-44) 310 (16.4)

.001 .001 .001 .90 .55 .001 .30 .92 .001 .001

*Data are presented as number and percentage unless otherwise indicated.

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tion, hemodialysis treatment, S aureus infection, and higher rates of complicated PVE (P .005 for all comparisons). In-hospital mortality rates were not statistically different across the various regions. Health careassociated PVE was reported in 36.5% (203/556) of the overall cohort. Of these patients with health careassociated PVE, 141 (69.5%) were classified as having nosocomial infection and 62 (30.5%) were classified as having nonnosocomial health careassociated infection. An intravascular device source of infection was presumed in 42.9% of health careassociated infections. Health careassociated PVE was characterized by high rates of S aureus (34.0%, including methicillin-resistant S aureus in 13.3%) and coagulasenegative staphylococci infection (25.6%) and low rates of enterococcal (9.4%) and viridans streptococcal (4.9%) infections. The in-hospital mortality rate of health care associated PVE was 30.5% (62/203), including 31.9% (45/141) of patients with nosocomial PVE who died and 27.4% (17/62) of patients with nonnosocomial, health careassociated infection who died (P=.52). Prosthetic valve endocarditis associated with health care contact occurred at a median of 83.5 days (interquartile range, 39.5-543.0 days) from

valve implantation, with 71% diagnosed within 1 year of prosthetic valve implantation. Health careassociated

PVE occurred beyond the early period in 62.1% (87/140) of patients. In comparison to early PVE, health care

Table 2. Causative Organisms for Total Cohort, Early, and Late Prosthetic Valve Endocarditis (PVE)
Causative Organism Staphylococccus aureus Methicillin-sensitive S aureus Methicillin-resistant S aureus Coagulase-negative staphylococci Enterococcus spp Viridans streptococci Culture negative Streptococcus bovis Fungal Polymicrobial HACEK spp* Escherichia coli Streptococcus agalactiae Propionibacterium acnes Streptococcus group G Propionibacterium NOS Pseudomonas aeruginosa Streptococcus anginosus Streptococcus NOS Streptococcus pneumoniae Listeria monocytogenes Micromonas micros Mycobacteria spp Serratia marcescens Streptococcus gallolyticus Streptococcus group B Streptococcus group C Total, No. (%) (n = 556) 128 (23.0) 82 (14.7) 36 (6.5) 94 (16.9) 71 (12.8) 67 (12.1) 62 (11.2) 29 (5.2) 23 (4.1) 10 (1.8) 8 (1.4) 7 (1.3) 5 (0.9) 4 (0.7) 4 (0.7) 3 (0.5) 3 (0.5) 3 (0.5) 3 (0.5) 3 (0.5) 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) Early PVE, No. (%) (n = 53) 19 (35.9) 8 (15.1) 10 (18.9) 9 (17.0) 4 (7.5) 1 (1.9) 9 (17.0) 1 (1.9) 5 (9.4) 0 0 1 (1.9) 0 0 0 0 1 (1.9) 0 0 0 0 0 0 1 (1.9) 0 0 0 Late PVE, No. (%) (n = 331) 61 (18.4) 43 (13.0) 11 (3.3) 66 (19.9) 42 (12.7) 34 (10.3) 41 (12.4) 22 (6.7) 11 (3.3) 6 (1.8) 7 (2.1) 3 (0.9) 3 (0.9) 3 (0.9) 3 (0.9) 2 (0.6) 1 (0.3) 2 (0.6) 2 (0.6) 3 (0.9) 2 (0.6) 2 (0.6) 1 (0.3) 0 0 0 1 (0.3)

Abbreviation: NOS, not otherwise speciated. *The HACEK group includes Haemophilus spp, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae bacteria.

Table 3. Regional Comparison of Clinical Characteristics of Prosthetic Valve Endocarditis (PVE)*

United States 10 116 20.9 21.1 52 (44.8) 25 (21.6) 32 (27.6) 15 (12.9) 38 (32.8) 20 (17.2) 22 (19.0) 53 (45.7) 21 (18.1) South America 7 66 11.9 10.3 22 (33.3) 5 (7.6) 5 (7.6) 2 (3.0) 7 (10.6) 7 (10.6) 3 (4.6) 27 (40.9) 16 (24.2)
2

Overall No. of sites No. of PVE cases PVE per total infective endocarditis cases reported, % Early PVE, % Health careassociated infection Non-nosocomial health careassociated infection Presumed intravascular device source Hemodialysis Staphylococcus aureus Coagulase-negative staphylococci Persistent bacteremia Congestive heart failure In-hospital mortality 53 556 20.1 13.8 203 (36.5) 62 (11.2) 87 (15.7) 25 (4.5) 128 (23.0) 94 (16.9) 49 (8.8) 183 (32.9) 127 (22.8)

Australia/ Southern Europe/ New Zealand/ North/Central Middle East/ P Asia Europe South Africa Value 11 120 21.6 11.7 38 (31.7) 12 (10.0) 11 (9.2) 2 (1.7) 28 (23.3) 14 (11.7) 7 (5.8) 23 (19.2) 21 (17.5) 14 109 19.6 12.7 45 (41.3) 11 (10.1) 17 (15.6) 3 (2.8) 30 (27.5) 17 (15.6) 7 (6.4) 30 (27.5) 27 (24.8) 11 145 26.1 13.0 46 (31.7) 9 (6.2) 22 (15.2) 3 (2.1) 25 (17.3) 36 (24.8) 10 (6.9) 50 (34.5) 42 (29.0)

.38 .11 .002 .001 .001 .003 .03 .001 .001 .13

*Data are presented as number and percentage unless otherwise indicated. P values are results of

analysis of each variable across all regions.

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Table 4. Relationship Between Prosthetic Valve Endocarditis Characteristics and In-Hospital Mortality
In-Hospital Mortality, No. (%) 42 (15.2) 38 (25.2) 47 (36.7) 76 (20.9) 28 (28.0) 21 (18.8) 10 (40.0) 30 (34.5) 62 (30.5) 44 (34.4) 24 (25.5) 64 (22.9) Odds Ratio (95% CI) Unadjusted 1 [Reference] 1.71 (1.01-2.90) 3.10 (1.80-5.32) 0.73 (0.47-1.12) 1.40 (0.92-2.13) 0.74 (0.49-1.12) 2.31 (1.12-4.77) 1.86 (1.03-3.38) 1.83 (1.22-2.74) 2.12 (1.25-3.60) 1.13 (0.81-1.58) 0.98 (0.70-1.38) 1.00 (0.99-1.01) 49 183 144 101 27 (55.1) 60 (32.8) 47 (32.6) 34 (33.7) 1.67 (1.07-2.27) 2.29 (1.59-3.32) 2.10 (1.22-3.60) 2.10 (1.25-3.53) 4.29 (1.99-9.22) 2.33 (1.62-3.34) 1.86 (1.10-3.15) 2.25 (1.25-4.03) 1.62 (1.08-2.44) 1.73 (1.01-2.95) Adjusted 1 [Reference] 1.82 (1.09-3.03) 3.73 (2.10-6.61)

Variable Age, y 65 65-75 75 Male Diabetes mellitus Prior infective endocarditis Hemodialysis Presumed intravascular device source Health careassociated infection Staphylococcus aureus Coagulase-negative staphylococci Mitral valve prosthesis Time since valve implantation in 30-d intervals Persistent bacteremia Congestive heart failure Intracardiac abscess Stroke
Abbreviation: CI, confidence interval.

No. 277 151 128 363 100 112 25 87 203 128 94 280

associated PVE beyond the early period was found to have a higher rate of coagulase-negative staphylococcal infection (early [17.0%] vs late, health careassociated PVE [39.1%]; P=.006); similar, high rates of presumed intravascular device source (32.1% vs 39.1%; P=.40) and S aureus infection (35.9% vs 29.9%; P = .46); and lower rates of persistent bacteremia (20.8% vs 5.8%; P = .007) and in-hospital mortality (47.2% vs 23.0%; P = .003). TABLE 4 depicts the unadjusted and adjusted analyses of PVE characteristics related to in-hospital mortality. Goodness of fit of the multivariable model was found by the HosmerLemeshow test ( = 8.72, P = .27). When the composite variable, health careassociated infection, was removed from the model and the individual criteria of nosocomial infection, presumed intravascular device source, and hemodialysis included, none was found to be independently associated with mortality. Mortality results for patients with S aureus PVE and health careassociated infection are shown in the FIGURE.

COMMENT Surgical treatment of valvular heart disease is an increasingly common cardiac intervention and as a result, the number of patients at risk of developing PVE is growing. 3 In addition, changes in health care delivery may influence the epidemiology of PVE. The current study, representing the largest study of PVE to date, offers several important insights regarding this disease in the current era. Prosthetic valve endocarditis accounted for over 20% of all IE cases in this prospective, multicenter, international registry, reflecting a considerably higher proportion of IE compared with earlier reports,9,10 but similar to the findings of a recent 1-year survey of IE in France.13 An increased sensitivity of diagnostic modalities, including use of the Duke criteria16,25 for all cases and transesophageal echocardiography in 84% of cases, likely enhanced the detection of PVE. Also, in contrast to previous estimates,26 we found that S aureus, rather than coagulase-negative staphylococcal infection, was the most common

causative microorganism for PVE. In studies of predominantly NVIE, S aureus has been similarly found to be the most common cause of NVIE,14 and a strong association between an increase in S aureus IE and health care contact has been noted.14,27,28 However, few data regarding health care associated PVE, aside from analyses of early PVE, have been reported and have generally been limited to small sample sizes and retrospective, single-center experiences.29,30 In 1993, an association between nosocomial bacteremia and new PVE in 18 patients was described.31 Although one third of new endocarditis cases were attributable to intravascular devices,31 the study was performed before routine diagnostic use of transesophageal echocardiography for evaluating staphylococcal bacteremia. More recently, among 50 cases of late-onset PVE at a single Spanish center, increases in staphylococcal infection and late, hospital-acquired PVE increased were observed.30 A causal relationship between health care contact and PVE has been inferred and well described for PVE occurring within 60 days of valve implantation.20-22 Initial reports estimated that early PVE accounted for approximately 35% to 50% of all cases of PVE22,32,33 and noted its association with gram-positive microorganisms (particularly coagulase-negative staphylococci and S aureus) presumed to be nosocomial in origin. Early PVE accounted for only 14% of all PVE cases in the ICE-PCS cohort but continued to be associated with an extremely high mortality rate. This lower rate of early PVE was similar to other recent reports30,34 and may be related to a number of factors, including improvements in surgical techniques, hygiene, and infection control.35 The current study demonstrates that health careassociated PVE beyond the early period, representing the majority of health careassociated infection, significantly influences the epidemiology of PVE. In a previous investigation, Calderwood et al reported that the cumulative hazard of developing PVE was

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CONTEMPORARY CLINICAL PROFILE AND OUTCOME OF PROSTHETIC VALVE ENDOCARDITIS

highest within the initial 12 months after valve replacement surgery, influenced by an increased incidence of coagulase-negative staphylococcal infection from 2 to 12 months after valve implantation.12 Our results confirm that the first year after implantation is a vulnerable period for prosthetic valve infection with both S aureus and coagulase-negative staphylococci. Possible explanations for the time course of health care associated PVE include greater exposure to health care contact and lack of complete endothelialization of the prosthetic valve early after implantation. Although PVE was diagnosed promptly and treated commonly with surgical intervention, the morbidity and in-hospital mortality rates were very high. Staphylococcus aureus and health careassociated infection were found to be independently predictive of inhospital mortality. These results confirm earlier studies that reported a significant association between S aureus infection and mortality in both native and prosthetic valve IE4,36,37 and adds prognostic significance to its high prevalence in this study. Prosthetic valve endocarditis occurring in association with health care contact may represent a composite of prognostic factors, such as virulence of causative organism and host factors (eg, end-stage renal disease or other conditions requiring intravascular catheter access) and emphasizes the need for preventive strategies, particularly those related to intravascular catheter access,38,39 to reduce this potential causative factor. The strongest predictors of mortality were well-recognized complications of PVE: persistent bacteremia, heart failure, intracardiac abscess, and stroke. Persistent bacteremia, as well as health careassociated infection, has been found to be independently associated with S aureus IE.14 These serious complications may be evident early in the course of the disease and are common indications for surgical intervention. Heart failure, one of the strongest predictors of in-hospital mortality in the current study, has been found to predict 6-month mor-

tality in NVIE40 and may identify a subgroup of patients for whom cardiac surgery is associated with a significant survival benefit.41 Our previous study demonstrated that hospital survival rates were similar between complicated PVE treated with surgery and uncomplicated PVE after adjustment for those characteristics associated with surgical intervention,4 but additional studies are needed to define more clearly the role, timing, and effect of surgery in PVE. Although the ICE-PCS study design was a large, prospective, multinational registry of definite IE cases, this investigation has certain limitations. This is an observational study involving centers with voluntary participation and thus, population sampling was not obtained, limiting any epidemiological inferences. Specifically, be-

cause this cohort only included patients with definite IE and not patients with normal prosthetic valves, we were unable to evaluate risk factors for developing PVE. The definition of nonnosocomial health careassociated infection, although previously validated as similar to nosocomial bloodstream infections with regard to source of infection, microbiology, antibiotic susceptibility, and prognosis,23 may be imprecise, particularly regarding recent hospitalization as the presumed source of infection. Because each geographic region was represented by a few centers, regional characterization was based only on those participating centers. Finally, the primary end point of mortality was assessed at hospital discharge, and thus, does not reflect PVE outcome at a specific time interval from diagnosis.

Figure. In-hospital Mortality as a Function of Causative Organism and Health Care Association
PVE Caused by Staphylococcus aureus or Other Organisms
0.6

Mortality, Proportion

0.5 0.4 0.3 0.2 0.1 0 0 10

Staphylococcus aureus Other Organisms

HR; 1.77 (95% CI, 1.21-2.57) Log-Rank P = .003 20 30 40 50 60 70 80 90

Days Since Initial Hospitalization

No. at Risk Staphylococcus aureus Other Organisms 128 417 120 388 98 316 73 238 53 175 39 110 29 78 20 56 9 41 8 30

Health CareAssociated or Community-Acquired PVE

0.6

Mortality, Proportion

0.5 0.4 0.3 0.2 0.1 0 0 10

Health CareAssociated Infection Community-Acquired Infection

HR; 1.54 (95% CI, 1.07-2.21) Log-Rank P = .02 20 30 40 50 60 70 80 90

Days Since Initial Hospitalization

No. at Risk Health CareAssociated Infection 199 Community-Acquired Infection 346 183 325 147 267 114 197 87 141 67 82 49 58 34 42 22 28 14 24

HR indicates hazard ratio; CI, confidence interval; PVE, prosthetic valve endocarditis. (Reprinted) JAMA, March 28, 2007Vol 297, No. 12 1359

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CONTEMPORARY CLINICAL PROFILE AND OUTCOME OF PROSTHETIC VALVE ENDOCARDITIS

In conclusion, PVE accounts for a high percentage of all cases of IE in many regions of the world. Staphylococcus aureus is now the leading cause of PVE. Health careassociated infection significantly influences the clinical characteristics and outcome of PVE. Despite prompt diagnosis and the common use of surgical treatment in PVE, morbidity and mortality remain high, emphasizing the need for further studies of preventive and therapeutic strategies for this serious disease.
Author Contributions: Dr Wang 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: Wang, Athan, Pappas, Fowler, Corey, Cabell. Acquisition of data: Athan, Fowler, Olaison, Pare, Almirante, Munoz, Rizzi, Naber, Logar, Tattevin, Iarussi, Selton-Suty, Jones, Morris. Analysis and interpretation of data: Wang, Athan, Pappas, Fowler, Tattevin, Casabe, Morris, Corey, Cabell. Drafting of the manuscript: Athan, Pappas, Fowler, Pare, Iarussi, Casabe, Morris, Corey, Cabell. Critical revision of the manuscript for important intellectual content: Wang, Athan, Pappas, Fowler, Olaison, Almirante, Mun oz, Rizzi, Naber, Logar, Tattevin, Selton-Suty, Jones, Morris, Corey, Cabell. Statistical analysis: Wang, Pappas, Cabell. Obtained funding: Wang, Corey, Cabell. Administrative, technical, or material support: Fowler, Naber, Selton-Suty, Corey. Study supervision: Wang, Athan, Fowler, Corey. Financial Disclosures: None reported. International Collaboration on Endocarditis (ICE) Registry Investigators 2007: David Gordon, MBBS, FRACP, FRCPA, PhD, Uma Devi, MD (Flinders Medical Centre, Adelaide, Australia); Denis Spelman, MD (Alfred Hospital, Amiens, France); Jan T.M. van der Meer, MD, PhD (University of Amsterdam, Amsterdam, The Netherlands); Carol Kauffman, MD, Suzanne Bradley, MD, William Armstrong, MD (Ann Arbor VA Medical Center, Ann Arbor, Mich); Efthymia Giannitsioti, MD, Helen Giamarellou, MD, PhD (Attikon University General Hospital, Athens, Greece); Stamatios Lerakis, MD, FAHA, FACC, FASE, FCCP (Emory University, Atlanta, Ga); Ana del Rio, MD, Asuncion Moreno, MD, Carlos A. Mestres, MD, PhD, FETCS, Carlos Pare, MD, Cristina Garcia de la Maria, MD, Elisa De Lazzario, BSc, Francesc Marco, MD, Jose M. Gatell, MD, Jose M. Miro, MD, PhD, Manel Almela, MD, Manuel Azqueta, MD, Maria Jesu s Jime nez Exposito, MD, Natividad de Benito, MD, Noel Perez, MD (Hosp. Clinic-IDIBAPS: University of Barcelona, Barcelona, Spain); Benito Almirante, MD, Nuria Fernandez-Hidalgo, MD, Pablo Rodriguez de Vera, MD, Pilar Tornos, MD, Vicente Falco, MD, Xavier Clar amonte, MD, Yolanda Armero, MD (Hospital Universitari Vall dHebron, Barcelona, Spain); Nisreen Sidani, RN, MSN, Souha Kanj-Sharara, MD, FACP, Zeina Kanafani, MD, MS (American University of Beirut Medical Center, Beirut, Lebanon); Annibale Raglio, MD, DTM&H, Antonio Goglio, MD, Fabrizio Gnecchi, MD, Fredy Suter, MD, Grazia Valsecchi, MD, Marco Rizzi, MD, Veronica Ravasio, MD (Ospedali Riuniti di Bergamo, Bergamo, Italy); Bruno Hoen, MD, PhD, Catherine Chirouze, MD, Efthymia Giannitsioti, MD, Joel Leroy, MD, Patrick Plesiat, MD, Yvette Bernard, MD, (University Medical Center of Besancon, Besancon,

France); Anna Casey, Peter Lambert, BSc, PhD, DSc, Richard Watkin, MRCP, Tom Elliott, BM, BS, BMedSci, PhD, DSc, FRCPath (Queen Elizabeth Hospital, Birmingham, England); Mukesh Patel, MD, William Dismukes, MD (University of Alabama at Birmingham); Angelo Pan, MD, Giampiero Caros, MD (Spedali CiviliUniversit di Brescia, Brescia, Italy); Amel Brahim Mathiron, Christophe Tribouilloy, MD, PhD, MD, Thomas Goissen, MD (South Hospital Amiens, Bron Cedex, France); Armelle Delahaye, Francois Delahaye, MD, MPH, FESC, Francois Vandenesch, MD, PhD (Hopital Louis Pradel, Bron Cedex, France); Carla Vizzotti, MD, Francisco M. Nacinovich, MD, Marcelo Marin, MD, Marcelo Trivi, MD, Martin Lombardero, MD (Instituto Cardiovascular, Buenos Aires, Argentina); Claudia Cortes, MD, Jose Horacio Casabe, MD (Instituto de Cardiologa y Ciruga Cardiovascular, Buenos Aires, Argentina); Javier Altclas, MD, Silvia Kogan, MD (Sanatorio Mitre, Buenos Aires, Argentina); Liliana Clara, MD, Marisa Sanchez, MD (Hospital Italiano, Buenos Aires, Argentina); Anita Commerford, MD, Cass Hansa, MD, Eduan Deetlefs, MD, Mpiko Ntsekhe, MD, Patrick Commerford, MD (Groote Schuur Hospital, Cape Town, South Africa); Dannah Wray, MD, MHS, Lisa L. Steed, PhD, Preston Church, MD, Robert Cantey, MD (Medical University of South Carolina, Charleston); Arthur Morris, MD, FRCPA, David Holland, MD, David Murdoch, MD, DTM&H, FRACP, FRCPA, FACTM, Katherine Graham, MD, Kerry Read, MD, Nigel Raymond, MD, Paul Bridgman, MD, Richard Troughton, MD, Selwyn Lang, MD, Stephen Chambers, MD (Canterbury Health Laboratories, Christchurch, New Zealand); Despina Kotsanas, BSc (Hons), Tony M. Korman, MD (Southern Health, Clayton, Australia); Gail Peterson, MD, Jon Purcell, BS, Paul M. Southern, Jr, MD (UT-Southwestern Medical Center, Dallas, Tex); Manisha Shah, MD, Roger Bedimo, MD, MS (Dallas VA Medical Center, Dallas, Tex); Arjun Reddy, Donald Levine, MD, Gaurav Dhar, MD (Wayne State University, Detroit, Mich); Alanna Hanlon-Feeney, Margaret Hannan, MD, BCh BAO, MSc, MRCPath, FRCPI, Sinead Kelly, MD (Mater Hospitals, Dublin, Ireland); Andrew Wang, MD, Christopher H. Cabell, MD, MHS, Christopher W. Woods, MD, MPH, Daniel J. Sexton, MD, Danny Benjamin, Jr, MD, MPH, PhD, G. Ralph Corey, MD, Jay R. McDonald, MD, John J. Engemann, MD, L. Barth Reller, MD, Laura Drew, RN, BSN, Martin Stryjewski, MD, MHS, Susan Morpeth, MBChB, Tahaniyat Lalani, MD, Vance Fowler, Jr, MD, MHS, Vivian Chu, MD (Duke University Medical Center, Durham, NC); Bahram Mazaheri, PhD, Carl Neuerburg, Christoph Naber, MD (University Essen, Essen, Germany); Eugene Athan, MD, Margaret Henry, BSc (Hons), PhD, Owen Harris, MD (Barwon Health, Geelong, Australia); Eric Alestig, MD, Lars Olaison, MD, PhD, Lotta Wikstrom, Ulrika Snygg-Martin, MD (Sahlgrenska Univer sitetssjukhuset/Ostra, Gteborg, Sweden); Johnson Francis, MD, DM, K. Venugopal, MD, DM, Lathi Nair MD, DM, Vinod Thomas, MD, DM (Medical College Calicut, Kerla, India); Jaruwan Chaiworramukkun, MD, Orathai Pachirat, MD, Ploenchan Chetchotisakd, MD, Tewan Suwanich, MD (Khon Kaen University, Khon Kaen, Thailand); Adeeba Kamarulzaman, MBBS, FRACP, Syahidah Syed Tamin, MD (University of Malaya Medical Center, Kuala Lumpur, Malaysia); Manica Mueller Premru, MD, PhD, Mateja Logar, MD, PhD, Tatjana Lejko-Zupanc, MD, PhD (Medical Center Ljublijana, Ljublijana, Slovenia); Christina Orezzi, John Klein, MD (St Thomas Hospital, London, England); Emilio Bouza, MD, PhD, Mar Moreno, MD, PhD, Marta Rodrguez-Creixems, MD, PhD, Mercedes Marn, MD, Miguel Fernandez, MD, Patricia Munoz, MD, PhD, Ro co Fernandez, Victor Ramallo, MD (Hospital Gen eral Universitario Gregorio Maranon, Madrid, Spain); Didier Raoult, MD, PhD, Franck Thuny, MD, Gilbert Habib, MD, FACC, FESC, Jean-Paul Casalta, MD, Pierre-Edouard Fournier, MD (Faculte de Medecine de

Marseille, Marseille, France); Natalia Chipigina, PhD, Ozerecky Kirill, MD, Tatiana Vinogradova, MD, PhD, Vadim P. Kulichenko, PhD (Russian Medical State University, Moscow, Russia); O.M. Butkevich, PhD (Learning Medical Centre of Russian Presidential Affairs Government, Moscow, Russia); Christine Lion, MD, Christine Selton-Suty, MD, Francois Alla, MD, PhD, Helne Coyard, Thanh Doco-Lecompte, MD (CHU Nancy-Brabois, Nancy, France); Diana Iarussi, MD, Emanuele Durante-Mangoni, MD, PhD, Marie Francoise Tripodi, MD, Riccardo Utili, MD (II Universit di Napoli, Naples, Italy); A. Sampath Kumar, MD, Gautam Sharma, MD (All India Institute of Medical Sciences, New Delhi, India); Stuart A. Dickerman, MD (New York University Medical Center, New York, NY); Alan Street, Damon Peter Eisen, MBBS, MD, FRACP, Emma Sue McBryde, MBBS, FRACP, PhD, Leeanne Grigg (Royal Melbourne Hospital, Parkville, Australia); Elias Abrutyn, MD (Drexel University College of Medicine, Philadelphia, Pa); Christian Michelet, MD, PhD, Pierre Tattevin, MD, Pierre Yves Donnio, PhD (Pontchaillou University, Rennes, France); Claudio Querido Fortes, MD (Hospital Universitario Clementino Fraga Filho/UFRJ, Rio de Janeiro, Brazil); Jameela Edathodu, MRCP, Mashael Al-Hegelan, MD (King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia); Bernat Font, MD, Ignasi Anguera, MD, PhD, Joan Raimon Guma, MD (Hospital de Sabadell, Sabedell, Spain); M. Cereceda, MD, Miguel J. Oyonarte, MD, Rodrigo Montagna Mella, MD (Hospital Clinico Universidad de Chile, Santiago, Chile); Patricia Garcia, MD, Sandra Braun Jones, MD (Hosp. Clnico Pont. Universidad Catolica de Chile, San tiago, Chile); Auristela Isabel de Oliveira Ramos, MD, (Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil); Marcelo Goulart Paiva, MD, Regina Aparecida de Medeiros Tranchesi, MD (Hospital 9 de Julho, Sao Paulo, Brazil); Lok Ley Woon, BSN, Luh-Nah Lum, BSN, Ru-San Tan, MBBS, MRCP (National Heart Centre, Singapore, Singapore); David Rees, MD, Pam Kornecny, MD, Richard Lawrence, MD, Robyn Dever, MD (St. George Hospital, Sydney, Australia); Jeffrey Post, MD, Phillip Jones, MD, Suzanne Ryan, MHSc, GCDM (The University of New South Wales, Sydney, Australia); John Harkness, MD, Michael Feneley, MD (St. Vincents, Sydney, Australia); Ethan Rubinstein MD, LLB, Jacob Strahilewitz, MD (Tel Aviv University School of Medicine, Tel Aviv, Israel); Adina Ionac, MD, PhD, Cristian Mornos, MD, Stefan Dragulescu, MD, PhD (Victor Babes University of Medicine and Pharmacy, Timisoar, Romania); Davide Forno, MD, Enrico Cecchi, MD, Francesco De Rosa, MD, Massimo Imazio, MD, FESC, Rita Trinchero, MD (Maria Vittoria Hospital, Torino, Italy); Franz Wiesbauer, MD, Rainer Gattringer, MD (Vienna General Hospital, Vienna, Austria); Ethan Rubinstein, MD, LLB, Greg Deans, MD (University of Manitoba, Winnipeg, Manitoba); Arjana Tambic Andrasevic, MD, PhD, Bruno Barsic, MD, PhD, Igor Klinar, MD, Josip Vincelj, MD, PhD, FESC, Suzana Bukovski, MD, Vladimir Krajinovic, MD (Univ. Hospital for Infectious Diseases, Zagreb, Croatia). None of the ICE Investigators received compensation for their work in the study. ICE Coordinating Center (Durham, NC): Christopher Cabell, MD, MHS, Judy Stafford, MS, Khaula Baloch, BA, Paul Pappas, MS, Thomas Redick, MPH, Tina Harding, RN, BSN. ICE Steering Committee: A.W. Karchmer, MD, Arnie Bayer, MD, Bruno Hoen, MD, PhD, Christopher H. Cabell, MD, MHS, Daniel J. Sexton, MD, David T. Durack, MD, DPhil, FACP, FRCP, FRACP, Elias Abrutyn, MD, Ethan Rubinstein, MD, LLB, G. Ralph Corey, MD, Jose M. Miro, MD, PhD, Phillipe Moreillon, Susan nah Eykyn, Vance Fowler, Jr, MD, MHS, Lars Olaison, MD, PhD. ICE Publications Committee: Arnie Bayer, MD, Bruno Hoen, MD,PhD, Christopher H. Cabell, MD, MHS, Elias Abrutyn, MD, Eugene Athan, MD, Jose M. Miro, MD,

1360 JAMA, March 28, 2007Vol 297, No. 12 (Reprinted)

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CONTEMPORARY CLINICAL PROFILE AND OUTCOME OF PROSTHETIC VALVE ENDOCARDITIS

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