Paul Pappas

Clinical Presentation, Etiology, and Outcome of Infective Endocarditis in the 21st Century: The International Collaboration on Endocarditis–Prospective Cohort Study

BACKGROUND We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. METHODS Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. RESULTS The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. CONCLUSIONS In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.

Current features of infective endocarditis in elderly patients: Results of the international collaboration on endocarditis prospective cohort study

BACKGROUND Elderly patients are emerging as a population at high risk for infective endocarditis (IE). However, adequately sized prospective studies on the features of IE in elderly patients are lacking. METHODS In this multinational, prospective, observational cohort study within the International Collaboration on Endocarditis, 2759 consecutive patients were enrolled from June 15, 2000, to December 1, 2005; 1056 patients with IE 65 years or older were compared with 1703 patients younger than 65 years. Risk factors, predisposing conditions, origin, clinical features, course, and outcome of IE were comprehensively analyzed. RESULTS Elderly patients reported more frequently a hospitalization or an invasive procedure before IE onset. Diabetes mellitus and genitourinary and gastrointestinal cancer were the major predisposing conditions. Blood culture yield was higher among elderly patients with IE. The leading causative organism was Staphylococcus aureus, with a higher rate of methicillin resistance. Streptococcus bovis and enterococci were also significantly more prevalent. The clinical presentation of elderly patients with IE was remarkable for lower rates of embolism, immune-mediated phenomena, or septic complications. At both echocardiography and surgery, fewer vegetations and more abscesses were found, and the gain in the diagnostic yield of transesophageal echocardiography was significantly larger. Significantly fewer elderly patients underwent cardiac surgery (38.9% vs 53.5%; P < .001). Elderly patients with IE showed a higher rate of in-hospital death (24.9% vs 12.8%; P < .001), and age older than 65 years was an independent predictor of mortality. CONCLUSIONS In this large prospective study, increasing age emerges as a major determinant of the clinical characteristics of IE. Lower rates of surgical treatment and high mortality are the most prominent features of elderly patients with IE. Efforts should be made to prevent health care-associated acquisition and improve outcomes in this major subgroup of patients with IE.

Early Surgery in Patients with Infective Endocarditis: A Propensity Score Analysis

BACKGROUND An accurate assessment of the predictors of long-term mortality in patients with infective endocarditis is not possible using retrospective data because of inherent treatment biases and predictable imbalances in the distribution of prognostic factors. Largely because of these limitations, the role of surgery in long-term survival has not been adequately studied. METHODS Data were collected prospectively from 426 patients with infective endocarditis. Variables associated with surgery in patients who did not have intracardiac devices who had left-side-associated valvular infections were determined using multivariable analysis. Propensity scores were then assigned to each patient based on the likelihood of undergoing surgery. Using individual propensity scores, 51 patients who received medical and surgical treatment were matched with 51 patients who received medical treatment only. RESULTS The following factors were statistically associated with surgical therapy: age, transfer from an outside hospital, evidence of infective endocarditis on physical examination, the presence of infection with staphylococci, congestive heart failure, intracardiac abscess, and undergoing hemodialysis without a chronic catheter. After adjusting for surgical selection bias by propensity score matching, regression analysis of the matched cohorts revealed that surgery was associated with decreased mortality (hazard ratio, 0.27; 95% confidence interval, 0.13-0.55). A history of diabetes mellitus (hazard ratio, 4.81; 95% confidence interval, 2.41-9.62), the presence of chronic intravenous catheters at the beginning of the episode (hazard ratio, 2.65; 95% confidence interval, 1.31-5.33), and paravalvular complications (hazard ratio, 2.16; 95% confidence interval, 1.06-4.44) were independently associated with increased mortality. CONCLUSIONS Differences between clinical characteristics of patients with infective endocarditis who receive medical therapy versus patients who receive surgical and medical therapy are paramount. After controlling for inherent treatment selection bias and imbalances in prognostic factors using propensity score methodology, risk factors associated with increased long-term mortality included diabetes mellitus, the presence of a chronic catheter at the onset of infection, and paravalvular complications. In contrast, surgical therapy was associated with a significant long-term survival benefit.

Candida infective endocarditis

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 the epidemiology, treatment patterns, and outcomes of patients with Candida IE. We compared 33 Candida IE cases to 2,716 patients with non-fungal IE in the International Collaboration on Endocarditis—Prospective Cohort Study (ICE-PCS). Patients were enrolled and the data collected from June 2000 until August 2005. We noted that 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 infections (p < 0.001). The 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. 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.

Emergence of Coagulase-Negative Staphylococci as a Cause of Native Valve Endocarditis

BACKGROUND Coagulase-negative staphylococci (CoNS) are an infrequent cause of native valve endocarditis (NVE), and our understanding of NVE caused by CoNS is incomplete. METHOD The International Collaboration on Endocarditis-Prospective Cohort Study includes patients with endocarditis from 61 centers in 28 countries. Patients with definite cases of NVE caused by CoNS who were enrolled during the period June 2000-August 2006 were compared with patients with definite cases of NVE caused by Staphylococcus aureus and patients with NVE caused by viridans group streptococci. Multivariable logistic regression was used to determine factors associated with death in patients with NVE caused by CoNS. RESULTS Of 1635 patients with definite NVE and no history of injection drug use, 128 (7.8%) had NVE due to CoNS. Health care-associated infection occurred in 63 patients (49%) with NVE caused by CoNS. Comorbidities, long-term intravascular catheter use, and history of recent invasive procedures were similar among patients with NVE caused by CoNS and among patients with NVE caused by S. aureus. Surgical treatment for endocarditis occurred more frequently in patients with NVE due to CoNS (76 patients [60%]) than in patients with NVE due to S. aureus (150 [33%]; P=.01) or in patients with NVE due to viridans group streptococci (149 [44%]; P=.01). Despite the high rate of surgical procedures among patients with NVE due to CoNS, the mortality rates among patients with NVE due to CoNS and among patients with NVE due to S. aureus were similar (32 patients [25%] and 124 patients [27%], respectively; P=.44); the mortality rate among patients with NVE due to CoNS was higher than that among patients with NVE due to viridans group streptococci (24 [7.0%]; P=.01). Persistent bacteremia (odds ratio, 2.65; 95% confidence interval, 1.08-6.51), congestive heart failure (odds ratio, 3.35; 95% confidence interval, 1.57-7.12), and chronic illness (odds ratio, 2.86; 95% confidence interval, 1.34-6.06) were independently associated with death in patients with NVE due to CoNS (c index, 0.73). CONCLUSIONS CoNS have emerged as an important cause of NVE in both community and health care settings. Despite high rates of surgical therapy, NVE caused by CoNS is associated with poor outcomes.

Native Valve Endocarditis Due to Coagulase-Negative Staphylococci: Report of 99 Episodes from the International Collaboration on Endocarditis Merged Database

Using a large cohort of patients from the International Collaboration on Endocarditis Merged Database, we compared coagulase-negative staphylococcal (CoNS) native-valve endocarditis (NVE) to NVE caused by more common pathogens. Rates of heart failure and mortality were similar between patients with CoNS NVE and patients with Staphylococcus aureus NVE, but rates for both groups were significantly higher than rates for patients with NVE due to viridans streptococci. These results emphasize the importance of CoNS as a cause of NVE and the potential for serious complications with this infection.

Non-HACEK Gram-Negative Bacillus Endocarditis

Context Infective endocarditis due to non-HACEK organisms has been considered to be associated with injection drug use. Contribution Analysis of 2761 cases of patients with infective endocarditis from an international collaborative of 61 hospitals found that non-HACEK organisms account for fewer than 2% of the cases, and that most patients with non-HACEK endocarditis had infections associated with health care. Of patients with non-HACEK infections, 59% had implanted endovascular devices or prosthetic valves, but only 4% had injection drug use. More than one half of patients with non-HACEK infections required cardiac surgery and 24% died. Implication Infective endocarditis due to non-HACEK organisms is a rare but frequently fatal condition. It is much more frequently associated with implanted endovascular devices than with injection drug use. The Editors Infective endocarditis caused by non-HACEK (species other than Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, or Kingella species) gram-negative bacilli is a rare and poorly characterized disease. The literature describing non-HACEK gram-negative bacillus endocarditis primarily consists of several small case series from the 1970s and 1980s of outbreaks in injection drug users in large urban areas, such as Detroit (1, 2), Cleveland (3), and San Francisco (4, 5). As a result, endocarditis due to non-HACEK gram-negative bacilli has been considered to be almost exclusively associated with injection drug use (6, 7). In contrast to this reporting bias, however, non-HACEK gram-negative bacillus endocarditis has been occasionally reported to be a nosocomial problem, particularly in patients with early endocarditis after cardiac surgery (811). The International Collaboration on Endocarditis Prospective Cohort Study (ICE-PCS) database was created in 1999. From 1 January 2000 to 31 August 2005, 2761 patients with definite endocarditis from 61 centers in 28 countries were prospectively enrolled. This resource offers a unique opportunity to evaluate the epidemiology, characteristics, and outcome of endocarditis due to non-HACEK gram-negative bacilli in a large, contemporary, and international cohort of well-characterized patients with endocarditis. Methods The International Collaboration on Endocarditis Prospective Cohort Study Hospitalized patients with endocarditis (12) were identified prospectively by using site-specific procedures to ensure consecutive enrollment. Informed consent (oral or written) was obtained from all patients according to local institutional review board or ethics committee instructions. A standard case report form containing 275 variables was completed for each patient on enrollment at the participating site. The ICE-PCS database is maintained at the Duke Clinical Research Institute, Durham, North Carolina, which serves as the coordinating center for the ICE studies, with approval from the institutional review board. We included all patients with endocarditis from sites that met performance criteria for participation. These site criteria included 1) minimum enrollment of 12 cases per year in a center with access to cardiac surgery, 2) the presence of patient identification procedures to ensure consecutive enrollment and to minimize ascertainment bias (as described elsewhere) (13, 14), 3) high-quality data with query resolution, and 4) institutional review board or ethics committee approval or waiver based on local standards. All patients from sites that did not meet these criteria (totaling 494 case-patients from 14 sites) were excluded. Sample We included patients who had both definite endocarditis according to the modified Duke criteria (12) and isolation of a pure culture of an aerobic gram-negative bacillus from the bloodstream or valve. To ensure that the diagnosis of gram-negative endocarditis was accurate, the following additional criteria were applied when interpreting the blood culture results: 1) the patients bacteremia had to meet the definition for persistently positive blood cultures when applying the modified Duke criteria; 2) a single blood culture positive for a gram-negative organism was not considered to constitute a minor microbiological criterion when applying the modified Duke criteria; and 3) patients with endocarditis due to anaerobes, Brucella species, HACEK organisms, or other fastidious gram-negative pathogens (for example, Pasteurella species) or polymicrobial infections were excluded. Definitions We used published definitions of health carerelated variables (15, 16). Nonnosocomial health careassociated infection was defined as a health careassociated infection that was not acquired as a hospital inpatient (for example, hemodialysis, outpatient cancer chemotherapy, or receipt of intravenous antibiotics at home) (16). A nosocomial infection was defined as a health careassociated infection that was acquired after at least 48 hours as a hospital inpatient. Prosthetic endocarditis was defined as endocarditis involving a prosthetic heart valve or implanted endovascular device, such as a permanent cardiac pacemaker, cardioverter defibrillator, or aortic stent. Statistical Analysis Patients with definite non-HACEK gram-negative bacillus endocarditis were compared with all other patients with definite endocarditis in the ICE-PCS database. Continuous variables are presented as medians and 25th and 75th percentiles. Categorical variables are presented as frequencies and percentages of the specified group. Univariable comparisons were made by using the Wilcoxon rank-sum test or the chi-square test as appropriate. For all tests, a P value of 0.05 or less was considered statistically significant. Missing data for each variable were excluded from the denominator as indicated in Table 1. All statistical analyses were performed by using SAS software (version 8.2, SAS Institute, Cary, North Carolina). Table 1. Frequency of Individual Duke Criteria among 49 Patients with Non-HACEK Gram-Negative Bacillus Endocarditis* Role of the Funding Source The study did not receive funding. Results Of the 2761 patients with definite endocarditis, 49 (1.8%) had endocarditis due to non-HACEK gram-negative bacilli. Twenty-six of these patients (53%) were enrolled from Europe; 11 (22%) from North America; and the remainder from South America, New Zealand, Australia, the Middle East, and Asia. Patient enrollment was constant throughout the study period. Characteristics of Non-HACEK Gram-Negative Bacillus Endocarditis Patients with non-HACEK gram-negative bacillus endocarditis were more likely to have had symptoms for more than 1 month than were patients infected with other pathogens (90% [95% CI, 82% to 98%] vs. 77% [CI, 75% to 79%], respectively; P= 0.035) (Table 2). Injection drug use was uncommon in patients with non-HACEK gram-negative bacillus endocarditis and in patients with endocarditis due to other organisms (4% [CI, 0% to 9%] vs. 10% [CI, 9% to 11%]; P= 0.20). In contrast, health care contact was a statistically significant risk factor for non-HACEK gram-negative bacillus endocarditis (57% [CI, 43% to 71%] vs. 30% [CI, 28% to 32%]; P< 0.001), largely because the proportion of nosocomial infections was higher in the non-HACEK gram-negative bacillus endocarditis group (39% [CI, 25% to 53%] vs. 14% [CI, 13% to 15%]; P< 0.001). The Figure shows the routes of acquisition of non-HACEK gram-negative bacillus endocarditis compared with Staphylococcus aureus endocarditis (15) and all other causes of endocarditis in the ICE-PCS database. Table 2. Characteristics of Patients with Non-HACEK Gram-Negative Bacillus Infective Endocarditis and Those with Other Causes of Endocarditis* Figure. Routes of acquisition among patients with definite endocarditis due to non-HACEK gram-negative bacilli, Staphylococcus aureus , and other pathogens. HACEK = Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, or Kingella species. Implanted endovascular devices were more common in patients with non-HACEK gram-negative bacillus endocarditis than in patients with other pathogens (29% [CI, 16% to 42%] vs. 11% [CI, 10% to 12%]; P< 0.001). Patients with non-HACEK gram-negative bacillus endocarditis were also statistically significantly more likely than patients with other causes of endocarditis to have a presumed source of infection involving the genitourinary or nonoral gastrointestinal tract (35% [CI, 22% to 48%] vs. 12% [CI, 11% to 13%]; P< 0.001). A nondental invasive procedure within 60 days before symptom onset was more likely in patients with non-HACEK gram-negative bacillus endocarditis than in patients with other causes of endocarditis (38% [CI, 24% to 52%] vs. 19% [CI, 18% to 20%]; P= 0.002). Intracardiac abscesses were statistically significantly more common in patients with non-HACEK gram-negative bacillus endocarditis than in patients with endocarditis due to other organisms (25% [CI, 13% to 37%] vs. 14% [CI, 13% to 15%]; P= 0.034). The in-hospital mortality rate was 24% (CI, 12% to 36%) for patients with non-HACEK gram-negative bacillus endocarditis and 17% (CI, 16% to 18%) for patients with other causes of endocarditis (P= 0.190). Of the 49 patients with non-HACEK gram-negative bacillus endocarditis, 20 (41%) had native-valve endocarditis and 29 (59%) had prosthetic endocarditis. All 49 cases were confirmed as definite endocarditis by the modified Duke criteria: 22 (45%) were histopathologically (16 patients [33%]) or macroscopically (at surgery in 6 patients [12%]) confirmed (Table 1). Of the 16 patients with pathologic confirmation, 8 had valve cultures, 2 had device cultures, and 1 had an aortic aneurysm culture. Microbiology of Non-HACEK Gram-Negative Bacillus Endocarditis The most common pathogens in patients with non-HACEK gram-negative bacillus endocarditis were Escherichia coli (14 patients [29%]) and Pseudomonas aeruginosa (11 patients [22%]). Othe

Repeat Infective Endocarditis: Differentiating Relapse from Reinfection

Repeat infective endocarditis due to the same species can represent relapse of the initial infection or a new infection. We used time-based clinical criteria and pulsed-field gel electrophoresis-based molecular criteria to classify 13 cases of repeat infective endocarditis as either relapse or reinfection. The agreement between clinical and molecular criteria was imperfect (agreement in 10 [77%] of 13 cases).

Influence of the Timing of Cardiac Surgery on the Outcome of Patients With Infective Endocarditis and Stroke

BACKGROUND The timing of cardiac surgery after stroke in infective endocarditis (IE) remains controversial. We examined the relationship between the timing of surgery after stroke and the incidence of in-hospital and 1-year mortalities. METHODS Data were obtained from the International Collaboration on Endocarditis-Prospective Cohort Study of 4794 patients with definite IE who were admitted to 64 centers from June 2000 through December 2006. Multivariate logistic regression and Cox regression analyses were performed to estimate the impact of early surgery on hospital and 1-year mortality after adjustments for other significant covariates. RESULTS Of the 857 patients with IE complicated by ischemic stroke syndromes, 198 who underwent valve replacement surgery poststroke were available for analysis. Overall, 58 (29.3%) patients underwent early surgical treatment vs 140 (70.7%) patients who underwent late surgical treatment. After adjustment for other risk factors, early surgery was not significantly associated with increased in-hospital mortality rates (odds ratio, 2.308; 95% confidence interval [CI], .942-5.652). Overall, probability of death after 1-year follow-up did not differ between 2 treatment groups (27.1% in early surgery and 19.2% in late surgery group, P = .328; adjusted hazard ratio, 1.138; 95% CI, .802-1.650). CONCLUSIONS There is no apparent survival benefit in delaying surgery when indicated in IE patients after ischemic stroke. Further observational analyses that include detailed pre- and postoperative clinical neurologic findings and advanced imaging data (eg, ischemic stroke size), may allow for more refined recommendations on the optimal timing of valvular surgery in patients with IE and recent stroke syndromes.

Enterococcal prosthetic valve infective endocarditis: report of 45 episodes from the International Collaboration on Endocarditis-merged database

Enterococcal prosthetic valve infective endocarditis (PVE) is an incompletely understood disease. In the present study, patients with enterococcal PVE were compared to patients with enterococcal native valve endocarditis (NVE) and other types of PVE to determine differences in basic clinical characteristics and outcomes using a large multicenter, international database of patients with definite endocarditis. Forty-five of 159 (29%) cases of definite enterococcal endocarditis were PVE. Patients with enterococcal PVE were demographically similar to patients with enterococcal NVE but had more intracardiac abscesses (20% vs. 6%; p=0.009), fewer valve vegetations (51% vs. 79%; p<0.001), and fewer cases of new valvular regurgitation (12% vs. 45%; p=0.01). Patients with either enterococcal PVE or NVE were elderly (median age, 73 vs. 69; p=0.06). Rates of in-hospital mortality, surgical intervention, heart failure, peripheral embolization, and stroke were similar in both groups. Patients with enterococcal PVE were also demographically similar to patients with other types of PVE, but mortality may be lower (14% vs. 26%; p=0.08). Notably, 93% of patients with enterococcal PVE came from European centers, as compared with only 79% of patients with enterococcal NVE (p=0.03). Thus, patients with enterococcal PVE have higher rates of myocardial abscess formation and lower rates of new regurgitation compared to patients with enterococcal NVE, but there are no differences between the groups with regard to surgical or mortality rates. In contrast, though patients with enterococcal PVE and patients with other types of PVE share similar characteristics, mortality is higher in the latter group. Importantly, the prevalence of enterococcal PVE was higher in the European centers in this study.