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. Author manuscript; available in PMC: 2009 Oct 6.
Published in final edited form as: Eur J Clin Microbiol Infect Dis. 2008 Feb 19;27(7):519–529. doi: 10.1007/s10096-008-0466-x

Candida Infective Endocarditis

John W Baddley 1,2, Daniel K Benjamin Jr 3, Mukesh Patel 1,2, José Miró 4, Eugene Athan 5, Bruno Barsic 6, Emilio Bouza 7, Liliana Clara 8, Tom Elliott 9, Zeina Kanafani 10, John Klein 11, Stamatios Lerakis 12, Donald Levine 13, Denis Spelman 14, Ethan Rubinstein 15, Pilar Tornos 16, Arthur J Morris 17, Paul Pappas 18, Vance G Fowler Jr 3, Vivian H Chu 3, Christopher Cabell, for the International Collaboration on Endocarditis-Prospective Cohort Study Group3
PMCID: PMC2757733  NIHMSID: NIHMS129767  PMID: 18283504

Abstract

Purpose

Candida infective endocarditis (IE) is uncommon but often fatal. Most epidemiologic data are derived from small case series or case reports. This study was conducted to explore epidemiology, treatment patterns, and outcomes of patients with Candida IE.

Methods

We compared 33 Candida IE cases to 2716 patients with non-fungal IE in the International Collaboration on Endocarditis - Prospective Cohort Study. Patients were enrolled and data collected from June 2000 until August 2005.

Results

Patients with Candida IE were more likely to have prosthetic valves (p<0.001), short term indwelling catheters (p<0.0001), and have healthcare-associated infection (p<0.001). Reasons for surgery differed between the two groups: myocardial abscess (46.7% vs. 22.2% p=0.026) and persistent positive blood cultures (33.3% vs. 9.9%, p=0.003) were more common among those with Candida IE. Mortality at discharge was higher in patients with Candida IE (30.3%) when compared to non-fungal cases (17%, p=0.046). Among Candida patients, mortality was similar in patients who received combination surgical and antifungal therapy versus antifungal therapy alone (33.3% vs. 27.8%, p=0.26). New antifungal drugs, particularly echinocandins, were used frequently.

Conclusions

These multi-center data suggest distinct epidemiologic features of Candida IE when compared to non-fungal cases. Indications for surgical intervention are different and mortality is increased. Newer antifungal treatment options are increasingly used. Large, multi-center studies are needed to help better define Candida IE.

Introduction

Candida infective endocarditis (IE) is a rare and poorly understood complication of fungemia. Although Candida IE has been regarded traditionally as an uncommon infection, rates of fungemia have increased by as much as 128% in recent years, leaving a growing number of patients at risk for this complication[1]. Despite aggressive antifungal and surgical therapy, mortality approaches 80% in some series and a better understanding of this infection is needed[2–4].

Because of the rarity of candidal IE at any single institution, the epidemiology, prognosis, and optimal therapy of Candida IE are poorly defined, and treatment guidelines are derived mostly from single-site case series and case reports [3–6]. The recommended treatment of Candida IE is an amphotericin B-based regimen plus surgical intervention, often followed by long-term fluconazole for suppression[5]. However, because of the availability of safe, effective drugs for invasive candidiasis, emerging azole resistance, and high mortality, alternative drugs are now being increasingly used for Candida IE [7–14].

In the current investigation, we used a contemporary, prospective, international, multi-center cohort of patients with definite endocarditis to better evaluate the clinical characteristics, current antifungal treatment practices, and outcome of patients with Candida IE. Moreover, we compare and contrast Candida IE cases with non-fungal cases in order to highlight differences in epidemiology and outcomes.

Materials and Methods

Study Population

Patient data are derived from the International Collaboration of Endocarditis Prospective Cohort Study (ICE-PCS), a multi-national database of prospective cases of endocarditis. Details of the ICE-PCS have been described previously [15–17]. From June 2000 to August 2005, there were 2760 cases of definite IE contributed by sixty-one centers in 28 countries. Of the 2760 cases of definite IE, there were 33 cases due to Candida spp. All cases were classified as definite IE based on revised Duke criteria [18] and all cases were verified by the coordinating center (Duke University Medical Center). Fungal IE cases caused by organisms other than Candida (11 cases) were excluded from analysis. From each enrolled patient, data were collected from the index hospitalization and entered using an internet-based system. Data collected included demographics, symptoms associated with IE, underlying medical conditions, predisposing factors, clinical signs and symptoms, antifungal therapy, echocardiographic findings, associated complications and outcomes (stroke, embolic events, heart failure, intracardiac abscesses, persistently positive blood cultures, and death). Healthcare-associated IE was defined as either nosocomial infection or non-nosocomial healthcare-related infection. Nosocomial infection was defined as IE developing in a patient hospitalized for more than 48 hours before the onset of signs/symptoms consistent with IE. Death was determined at time of hospital discharge. Data on longer-term mortality was not collected.

Statistical Methods

Categorical variables were represented as frequencies and percentages of the specified group. The associations between clinical characteristics and Candida IE were measured using the Wilcoxon rank sum test for continuous variables and Chi square or Fisher’s exact methods for categorical variables. For all tests, statistical significance was determined at the 0.05 level. All statistical analyses were performed using SAS software (version 9.1, SAS Institute, Cary, NC).

Results

Patient characteristics

Of the 2,749 patients with definite IE, 33 (1.2%) were Candida IE cases. The mean age of patients with Candida IE was 54.9 years. Patient characteristics including diabetes, renal disease, malignancy, intravenous drug use, and congenital heart disease were similar between the two groups (Table 1). Patients with Candida IE were less likely to be male (51.5% vs. 67.9%, p=0.04), more frequently had previous endocarditis (21.2% vs. 7.8%, p=0.005), and were more likely to have short term indwelling catheters (21.2% vs. 4.4%, p<0.0001). Among patients who had an invasive procedure within 60 days prior to onset of symptoms, CABG was more common among Candida IE patients (22.2% vs. 3.7%, p=0.007). Prosthetic valve IE was more common in Candida patients (48.8% vs. 19.6%, p=0.005), and Candida IE patients were more likely to have the infection classified as being healthcare-related (51.5% vs. 25.8%, p=0.0009).

Table 1.

Characteristics of patients with Candida and non-fungal endocarditis from the International Collaboration of endocarditis (ICE) Database (n=2749)

Characteristic Level Candida
n =33(%)		 Non-fungal
n=2716 (%)		 P-valuea
Age Mean ± SD 54.9 ±18.95 56.7 ±17.84 0.58
Gender Male 17(51.5) 1844(67.9) 0.04
Female 16(48.5) 859 (31.6)
Missing 0(0.5) 14 (0.5)
Hemodialysis Yes 2 (6) 218(8) 0.68
No 31(94) 2259(83.2)
Missing 0 17(0.6)
Diabetes Yes 7(21.2) 440(16.2) 0.45
No 26(78.8) 2285(83.1)
Missing 0 17(0.6)
Current IVDA Yes 4(12.1) 262(9.7) 0.60
No 28(84.9) 2449(89)
Missing 1(3) 33(1.2)
HIV Yes 3(9) 54(2) 0.005
No 30(90.9) 2639(96.8)
Missing 0 32(1.2)
Malignancy Yes 2(6) 227(8.4) 0.63
No 31(94) 2480(91)
Missing 0 9(0.3)
Chronic Immunosuppressives Yes 5(15.2) 156(5.7) 0.023
No 28(84.9) 2530(93)
Missing 0 30(1.1)
Congenital Heart Disease Yes 4(12.1) 300(11) 0.82
No 27(81.8) 2294(84.5)
Missing 2(6) 122(4.5)
Type of IE Native 15(45.5) 1875(69) 0.0005
Prosthetic 16(48.8) 533(19.6)
Other 2(6) 169(6.2)
Missing 0 139(5.1)
Recent Dental Procedures Yes 1(3) 216(8) 0.27
No 27(81.8) 2011(741)
Missing 5(15.2) 489(18)
CABGb Yes 2(22.2) 18(3.7) 0.007
No 7(77.8) 447(92.4)
Missing 0 19(3.9)
Chronic Indwelling Catheter Yes 3(9.1) 132(4.9) 0.26
No 30(90.9) 2566(94.5)
Missing 0(0) 18(0.7)
Short term Indwelling Catheter Yes 7(21.2) 119(4.4) <0.0001
No 26(78.8) 2567(94.5)
Missing 0(0) 24(0.88)
Endocavitary Devicec Yes 6(18.2) 305(11.2) 0.65
No 27(81.8) 2411(88.8)
Missing 0 19(3.9)
Previous IE Yes 7(21.2) 213(7.8) 0.005
No 26(78.8) 2502(92.1)
Missing 0 1(0.04)
Healthcare Associated Yes 17(51.5) 702(25.8) 0.0009
No 16(48.5) 2014(74.1)
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a

P-values were obtained by Chi Square or Fischer’s exact methods.

b

Among patients who had an invasive procedure within 60 days prior to onset of symptoms

c

Refers to pacemakers, intracardiac defibrillators, or other.

SD=standard deviation; IVDA=intravenous drug abuse; IE=infective endocarditis; CABG=coronary artery bypass grafting

Clinical findings

Of patients with any IE etiology, most (75%; 2068/2749) experienced the first clinical manifestation less than one month before presentation, and timing of IE manifestations was similar between the two groups. The most common clinical manifestations among all patients were fever (79.5%; 2170/2728), new murmur (47.9%; 1053/2198), hematuria (22.1%; 607/2737), pulmonary edema (22.3%; 556/2491), and evidence of a vascular embolic event (15.9%; 435/2728). Overall, there was little difference of symptoms and signs at presentation between the Candida and non-fungal IE groups (Table 2). Thirteen-hundred sixteen (47.9%) of 2749 patients had surgery for endocarditis, and this was not different for the two groups.

Table 2.

Clinical Findings of Patients with Candida and Non-Fungal Endocarditis

Clinical Finding Level Candida
n =33(%)		 Non-fungal
n=2716(%)		 P Valuea
Time since clinical manifestation <1 month 22(66.7) 2046 (75.3) 0.41
>1 month 9(27.3) 602(22.2)
Missing 2(6) 689(2.5)
Evidence of IE on Exam Yes 25(75.6) 2272(83.6) 0.15
No 7(21.2) 344(12.7)
Missing 1(3) 100(3.7)
Fever > 38.0° Cb Yes 23(92) 2147(94.4) 0.42
No 2(8) 104(5.8)
Missing 0 21(0.9)
Osler’s Nodesb Yes 2(8) 73(3.21) 0.19
No 23(92) 2178(95.9)
Missing 0 21(0.9)
Janeway Lesionsb Yes 2(8) 116(5.1) 0.52
No 23(92) 2135(94)
Missing 0 21(0.9)
Roth spotsb Yes 2(8) 46(2) 0.04
No 23(92) 2205(97)
Missing 0 21(0.9)
Vascular Embolic Eventb Yes 6(24) 429(18.9) 0.53
No 19(76) 1822(80.2)
Missing 0 21(0.92)
Splenomegalyb Yes 3(12) 265(11.7) 0.97
No 22(88) 1986(87.4)
Missing 0 21(0.92)
New Murmur Yes 10(30) 1043(38) 0.15
No 19(57.6) 1134(41.8)
Missing 4(12) 539(19.9)
Intracranial Hemorrhage Yes 2(6) 111(4) 0.56
No 30(90.9) 2535(93.3)
Missing 1(3) 70(2.6)
Intracranial Hemorrhage Yes 5(15.2) 248(9.1) 0.22
No 27(8.18) 2408(88.7)
Missing 1(3) 12(0.59)
TTE Evidence of IEc Yes 17(68) 1448(64.5) 0.96
No 8(32) 667(29.7)
Missing 2(6) 75(2.76)
TEE Evidence of IEc Yes 24(96) 1757(90.7) 0.76
No 1(4) 100(5.1)
Missing 2(6) 94(3.7)
Surgery this episode Yes 15(45.5) 1301(47.9) 0.76
No 18(54.5) 1403(51.2)
Missing 0 12(0.44)
Indications for Cardiac Surgery
 CHF Yes 2(13.3) 554(42.6) 0.02
No 13(86.7) 735(56.5)
Missing 0 12(0.9)
 Embolization Yes 6(40) 257(19.8) 0.05
No 9(60) 1032(79.3)
Missing 0 12(0.9)
 Persistent positive blood cx. Yes 5(33.3) 129(9.9) 0.003
No 10(67) 1160(89.2)
Missing 0 12(0.9)
 Myocardial abscess Yes 7(46.7) 289(22.2) 0.026
No 8(53.3) 1000(76.9)
Missing 0 12(0.9)
 Valvular regurgitation Yes 6(40) 885(68) 0.018
No 9(60) 404(31)
Missing 0 12(0.9)
 Vegetation Yes 6(40) 639(49.1) 0.46
No 9(60) 651(50)
Missing 0 11(0.9)
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a

P-values were obtained by Chi Square or Fisher’s exact methods.

b

Includes patients who had evidence of IE on history or physical exam (n=25 for Candida group and N=2272 for non-fungal group)

c

Not all patients had echocardiography.

TTE=transthoracic echocardiography; TEE=tranesophageal echocardiography; CHF=congestive heart failure; IE=infective endocarditis; Cx=culture.

Candida IE patients were more likely to have surgery indicated because of embolization (40% vs. 19.8%, p=0.054), persistent fungemia (33% vs. 9.9%, p=0.003), and myocardial abscess (46.7% vs. 22.2% p=0.026). By contrast, surgery for the indications of congestive heart failure (42.6% vs 13.3%, p=0.02) and valvular regurgitation (68% vs 40%, p=0.018) were more common in patients with non-fungal IE.

Complications

Congestive heart failure, systemic embolization after presentation, and stroke were common but similar in occurrence in the two groups. Candida IE was associated with persistently positive blood cultures (39.4% vs. 8.8%, p<0.001) (Table 3). Mortality at time of discharge was higher among Candida IE patients than non-fungal IE patients (30.3% vs 17%, p=0.046). This mortality difference was more pronounced among those patients who had surgery for this episode of IE (33.3% vs. 13.8%, p=0.03). Among 15 Candida IE patients who underwent surgical intervention for this episode of endocarditis, mortality at discharge was similar to Candida IE patients who did not have surgery (33.3% vs. 27.8%, p=0.26). Those patients who underwent surgical intervention were more likely to have previous IE (40% vs. 5.7%; p=0.016), previous surgery for IE (33.3% vs. 5.6%; p=0.009), paravalvular complications on ECHO (46.7% vs. 11.1%; p=0.015), and systemic embolization (46.7% vs. 16.7%; p=0.04) when compared with patients with Candida IE who were not treated with surgical intervention.

Table 3.

Complications and Outcomes of Patients with Candida and Non-fungal endocarditis

Characteristic Level Candida
n=33 (%)		 Non-fungal
n =2716 (%)		 P Valuea
Stroke Yes 4(12.1) 450(16.6) 0.51
No 28(84.8) 2213(81.5)
Missing 1(3) 53(2)
Embolization Yes 10(30.3) 592(21.8) 0.23
No 22(66.7) 2053(75.6)
Missing 1(3) 71(2.6)
CHF Yes 8(24.2) 856(31.5) 0.44
No 23(69.7) 1794(66)
Missing 2(6) 66(2.4)
Persistent Positive Blood Cx Yes 13(39.4) 238(8.8) <0.001
No 19(57.6) 2397(88.3)
Missing 1(3) 81(3)
Mortality at Discharge Yes 10(30.3) 464(17) 0.046
No 23(69.7) 2243(82.6)
Missing 0 9(0.33)
Mortality (with surgery)b Yes 5(33.3) 179(13.8) 0.030
No 10(66.7) 1120(86.1)
Missing 0 2(0.2)
Mortality (without surgery)b Yes 5(27.8) 285(20.3) 0.83
No 13(72.2) 1117(79.6)
Missing 0 1(0.1)
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a

P-values were obtained by Chi Square and Fisher’s exact methods

b

Refers to cardiothoracic surgery. Mortality determined at time of discharge.

CHF=congestive heart failure. Cx=culture.

Organisms and Antifungal Treatment

Among the 33 patients with Candida IE, 16 (48%) were caused by C. albicans, 7 (21%) C. parapsilosis, 5 (15%) C. glabrata, and 3 (9%) C. tropicalis. Two (6%) isolates were not fully speciated. Treatment data were available for 27(82%) of 33 patients (Table 4). The most common antifungal agent used was amphotericin B (AmB), either conventional AMB (13/27; 48.1%) or a lipid formulation (3/27; 11.1%). Fluconazole was used in 12 (44.4%) of 27 patients. Primary therapy with fluconazole was used in 6 (54.5%) of 11 patients with complete fluconazole treatment data available. Ten patients (37%) received treatment with the newer antifungal agents caspofungin or voriconazole. Among patients who received single drug therapy, death occurred in 6(40%) of 15 patients; death occurred in 2(25%) of 8 who received sequential therapy. In only two cases combination therapy was used and both patients were alive at discharge. Two (20%) of 10 people who received newer therapies (caspofungin or voriconazole) died.

Table 4.

Treatment for 27 patients with Candida IE

Patient1 Organism Therapy Surgery Outcome2
1 C. parapsilosis AmB Yes Alive
2 C. albicans FLU then CASPO No Dead
3 C. albicans CASPO then FLU Yes Alive
4 C. parapsilosis FLU/CASPO3 No Alive
5 C. glabrata FLU then CASPO No Alive
6 C. albicans FLU No Alive
7 C. glabrata AmB No Alive
8 C. tropicalis AmB Yes Dead
9 C. albicans AmB then FLU No Dead
10 C. glabrata CASPO + Lipid AmB
followed by CASPO4 		No Alive
11 C. parapsilosis AmB/CASPO3 Yes Alive
12 C. glabrata CASPO No Alive
13 C. parapsilosis AmB Yes Alive
14 C. albicans Lipid AmB then FLU Yes Alive
15 C. albicans FLU No Dead
16 C. albicans FLU No Alive
17 C. parapsilosis CASPO Yes Dead
18 C. glabrata AmB No Alive
19 C. albicans AmB No Dead
20 C. albicans AmB Yes Alive
21 C. parapsilosis AMB then FLU No Alive
22 C. albicans FLU + 5-FC Yes Alive
23 C. tropicalis AmB No Alive
24 C. parapsilosis CASPO then FLU No Alive
25 C. tropicalis Lipid AmB Yes Dead
26 C. albicans AmB then VORI Yes Alive
27 C. albicans AmB No Dead
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1

Only 27 patients had treatment data available

2

Outcome at time of hospital discharge

3

Treatment data other than drugs received were unavailable

4

Patient received 1 month of VORI for suppressive therapy after an initial 11 weeks of treatment with CASPO and lipid AmB. Because of toxicity with VORI, CASPO was administered for an additional 8 weeks.

AmB= amphotericin B; Lipid AmB= liposomal AmB; CASPO=caspofungin; FLU=fluconazole; 5-FC=flucytosine; VORI=voriconazole

Discussion

Candida IE is an uncommon but frequently fatal infection [3, 4, 6]. A better understanding of the epidemiology, associated risk factors, and treatment methods is needed but difficult to obtain because of the rarity of cases and lack of large prospective cohorts. We compared contemporary clinically well-characterized cases of candidal IE to non-fungal IE cases registered as part of a large, multi-center, prospective dataset to better understand Candida IE. This analysis revealed several important observations regarding predisposing conditions, clinical findings, and treatment modalities.

Important risk factors or predisposing conditions for fungal endocarditis have been reported in recent, extensive reviews, and the most frequently reported are previous surgery, vascular lines, antibiotic use, underlying heart disease, prosthetic valves, and immunocompromising conditions [2–4, 6]. We found similar predisposing conditions and noted several distinct differences among Candida and non-fungal IE cases. First, coronary artery bypass grafting (CABG) and prosthetic valve IE were significantly more common in Candida patients. An increase in previous CABG among Candida IE patients could be explained by CABG being performed in association with prosthetic valve surgery. Second, healthcare-associated IE was more common among patients with Candida IE. The increase in hospital-acquired Candida IE in general is consistent with recent data describing Candida as an emerging nosocomial bloodstream pathogen over the past decade[19].

The clinical findings and presentation of patients with Candida and non-fungal IE are very similar, as has been previously described [6]. The most important exceptions discovered in our review are related to indications for cardiac surgery. Of patients who had surgery during this episode of IE, those with Candida IE were more likely to have surgery based on the finding of myocardial abscess, or persistently positive blood cultures. Non-fungal cases more commonly had heart failure or valvular insufficiency as a reason for surgery.

There were few differences in complications and outcomes in the two groups except mortality. Candida IE mortality has been reported to be up to 80% in previous reviews[2–4, 6], but variability in data collection and description of individual cases makes it difficult to determine an appropriate risk of death. Ellis and colleagues in a recent review demonstrated that the crude survival of patients with fungal endocarditis had increased over the past twenty years, from 14% before 1970 to 41% in the period of 1991–1995 [3]. Possible reasons for this improved survival were attributed to better echocardiographic techniques, earlier diagnosis of endocarditis, or better supportive care of ill patients [3]. Nearly one-third of patients in our series died during hospitalization, with mortality significantly greater than non-fungal cases. The mortality among patients with Candida IE in our series is surprisingly less than reported in previous reviews, but may be due to a multitude of factors. Diagnostic and treatment modalities have improved in the past decade, but likely cannot account for such a difference in survival. The inclusion of Candida cases only, which often have better survival compared to other fungal causes[3, 4]; and the survival end-point defined at hospital discharge (compared to literature reviews where follow-up data were available for up to several years) may reflect the lower mortality in this series [3]. Finally, the use of newer antifungal therapies such as the echinocandins and lipid preparations of amphotericin B, not included in previous reviews because of lack of availability, may have an impact on outcomes and warrant further evaluation.

The traditional antifungal treatment of Candida IE is amphotericin B (6–8 weeks), often followed by fluconazole as suppression because of frequent relapse [5, 6]. In addition, surgical intervention with valve replacement is generally recommended in most cases. The combination of antifungal and surgical therapy is purported to be more beneficial than antifungal therapy alone, although controlled studies have not been performed for confirmation [3, 4, 20]. In this cohort, surgical therapy was not associated with increased survival compared to antifungal therapy alone. It is encouraging that patients who did not receive surgical therapy fared relatively well; however, we speculate that the lack of a significant difference in the groups may reflect a combination of factors including increased morbidity and complications at presentation among patients who underwent surgery. Patients who underwent surgical intervention were more likely to have previous IE, previous surgery for IE, paravalvular complications on ECHO and systemic embolization. Although these may be important differences that influenced risk of death, with the limited number of patients evaluated it is difficult to draw conclusions with respect to the appropriate management.

In this cohort, an amphotericin B preparation was the most frequent drug used. Fluconazole was second most common, and was used either for primary or sequential therapy. Sequential therapy was frequently employed, and mortality in this group was lower than in patients who received a single agent. This probably results from selecting a subset of patients that lived long enough to “step down” to azole therapy. Length of therapy and dosages were not captured, so appropriate comparisons cannot be made. An important obstacle in successful antifungal therapy of Candida IE has been adverse events associated with prolonged amphotericin B administration. With the approval of new antifungal agents in the past several years, specifically echinocandins and newer azoles, questions have arisen about the role of these agents for the treatment of Candida IE. The echinocandins and voriconazole have shown efficacy and safety for the treatment of invasive candidiasis and candidemia [21, 22]; however, data on use in endocarditis is limited to case reports[7–14]. Although some clinical success has been documented, selection bias may be present, and determinations of efficacy cannot be made. Our series reflects a shift in the treatment of Candida IE. Greater than one-third of patients received newer antifungal agents, particularly the echinocandin, caspofungin, and mortality among these patients (20%) was similar to other groups. Adverse events from drug use and isolate susceptibilities were not captured in the database, so the reasons for the use of these drugs are unclear.

Although an important aspect of this dataset is its overall size, and this represents the largest reported number of definite Candida IE cases compared to non-fungal cases, there are important limitations. The data were collected prospectively, but analysis was conducted retrospectively. The number of Candida cases is not large enough to draw conclusions regarding treatment, and long-term mortality data were not collected.

These data represent a multi-center collaborative effort describing a large cohort of definite endocarditis cases. There appear to be distinct epidemiologic features of Candida IE when compared to non-fungal cases. Indications for surgical intervention are different, mortality is increased, and alternative antifungal treatment options are increasingly used for this devastating disease. Large datasets or series, despite limitations, are needed to help better define Candida IE.

Aknowledgements

Manuscript support.

This study was sponsored in part by a grant from Merck and Co., Inc. The sponsor had no role in the design and the conduct of the study; or in the collection, analysis, and interpretation of the data.

Research support from NICHD K23HD-0044799(DKB)

Appendix

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, Netherlands );Carol Kauffman MD, Suzanne Bradley MD, William Armstrong MD (Ann Arbor VA Medical Center, Ann Arbor, USA );Efthymia Giannitsioti MD, Helen Giamarellou MD,PhD (Attikon University General Hospital, Athens, Greece );Stamatios Lerakis MD FAHA, FACC, FASE, FCCP (Emory University, Atlanta, USA );Ana del Rio MD, Asuncion Moreno MD, Carlos A. Mestres MD, PhD, FETCS, Carlos Paré MD, Cristina Garcia de la Maria MD, Elisa De Lazzario BSc, Francesc Marco MD, Jose M Gatell MD, José M. Miró MD, PhD, Manel Almela MD, Manuel Azqueta MD, Maria Jesús Jiménez-Expósito 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 Falcó MD Xavier Claramonte MD, Yolanda Armero MD (Hospital Universitari Vall d'Hebron, 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 Besançon, Besançon, France );Anna Casey, Peter Lambert BSc,PhD,DSc, Richard Watkin MRCP, Tom Elliott B.M., B.S., B.Med.Sci., PhD., D.Sc., FRCPath (Queen Elizabeth Hospital, Birmingham, UK);Mukesh Patel MD, William Dismukes MD (University of Alabama at Birmingham, Birmingham, USA);Angelo Pan MD, Giampiero Caros MD (Spedali Civili - Università 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, José Horacio Casabé MD (Instituto de Cardiología y Cirugía 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, USA);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, USA);Manisha Shah MD, Roger Bedimo MD, MS (Dallas VA Medical Center, Dallas, USA);Arjun Reddy, Donald Levine MD, Gaurav Dhar MD (Wayne State University, Detroit, USA);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, Jeff Federspiel, John J Engemann MD, L. Barth Reller MD, Laura Drew RN, BSN, L.B. Caram MD,Martin Stryjewski MD,MHS, Susan Morpeth MBChB, Tahaniyat Lalani MD, Vance Fowler, Jr MD,MHS, Vivian Chu MD (Duke University Medical Center, Durham, USA);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 Universitetssjukhuset/Östra, Goteborg, 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, UK );Emilio Bouza MD,PhD, Mar Moreno MD,PhD, Marta Rodríguez-Créixems MD,PhD, Mercedes Marín MD, Miguel Fernández MD, Patricia Muñoz MD,PhD, Rocío Fernández, Victor Ramallo MD (Hospital General Universitario Gregorio Marañón, Madrid, Spain);Didier Raoult MD,PhD, Franck Thuny MD, Gilbert Habib MD, FACC, FESC, Jean-Paul Casalta MD, Pierre-Edouard Fournier MD (Faculté de Médecine 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, Hélène Coyard, Thanh Doco-Lecompte MD (CHU Nancy-Brabois, Nancy, France);Diana Iarussi MD, Emanuele Durante-Mangoni MD, PhD, Marie Françoise Tripodi MD, Riccardo Utili MD (II Università 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, USA );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, USA);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 (Hospitál 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. Clínico Pont. Universidad Católica de Chile, Santiago, Chile);Auristela Isabel de Oliveira Ramos MD (Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil);Marcelo Goulart Paiva MD, Regina Aparecida de Medeiros Tranchesi MD (Hospital 9 de Julho, São 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. Vincent's, Sydney, Australia);Ethan Rubinstein MD, LL.B, 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, Canada );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 );

Footnotes

Potential Conflicts of Interest

JWB: Research support from Astellas and Merck, Inc. Speaker’s bureau for Merck and Enzon. Consulting services for Pfizer and Enzon.

DKB: Research support from Astellas, Pfizer, Inc., Biosynexus, Cape Cod Associates, Inc, Johnson and Johnson, and Astra Zeneca. Fellowship support from Johnson & Johnson, and MedImmune. All monies go to Duke University. Dr. Benjamin does not own any stock or hold financial interest in any organization listed above.

MP: None

JM: None

EA: None

BB: Grant support from Croation Ministry of Science, No. 108-1080002-0102. Consulting services for Pliva Pharmaceuticals. Speaker’s bureau for Pliva Pharmaceuticals, Pharmasuiss Zagreb. Unrestricted research grant from Roche d.o.o Zagreb.

EB: None

LC: None

TE: None

ZK: None

JK: None

SL: None

DL: None

DS: None

ER: Research support from Theravance, Daiichi, Replidyne. Consulting services for Pfizer, Bayer, Wyeth, Teva, Replidyne, Schering Plough, Atox, and BiondVax.

PT: None

AJM: None

PP: None

VGF: Research funding from Theravance, Merck, Nabi, Inhibitex, Cubist and the National Institutes of Health. Consulting for Astellas, Biosynexus, Cubist, Inhibitex, Merck, Johnson & Johnson; and is on the speakers’ bureaus for Cubist and Pfizer.

VHC: None

CC: None

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