Biomedical subjects

Christopher H Cabell

Publications and source records attributed to Christopher H Cabell.

At least 19 recordsLinked to original sources

PubMed2007

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.

Adult↗

PubMed2006

Periannular complications in infective endocarditis involving prosthetic aortic valves.

The periannular extension of infection in prosthetic valve endocarditis (PVE) is a serious complication of infective endocarditis associated with high mortality. Periannular lesions in PVE occasionally rupture into adjacent cardiac chambers, leading to aortocavitary fistulae and intracardiac shunting. It is unknown whether the prognosis of patients with aortocavitary fistulae is worse than that of those with nonruptured abscesses. The aims of this study were to determine the distinctive clinical characteristics of patients with PVE and either aortocavitary fistulization or nonruptured abscesses. In a retrospective multicenter study of >872 PVE episodes, 150 patients (17%) with periannular complications in PVE in the aortic position were identified (29 with aortocavitary fistulization and 121 with nonruptured abscesses). Early-onset PVE was present in 73 patients (49%). Rates of heart failure (p = 0.09), ventricular septal defect (p <0.01), and third-degree atrioventricular block (p = 0.07) were higher in patients with fistulization. Surgical treatment was undertaken in 128 patients (83%). In-hospital mortality in the overall population was 39%. Multivariate analysis identified heart failure (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.6 to 6.8), renal failure (OR 2.5, 95% CI 1.2 to 5.2), and co-morbidity (OR 2.4, 95% CI 1.1 to 5.1) as independent risk factors for death. Fistulous tract formation was not associated with increased in-hospital mortality (OR 1.6, 95% CI 0.7 to 3.7). The actuarial 5-year survival rate in surgical survivors was 100% in patients with fistulae and 78% in patients with nonruptured abscesses (log-rank p = 0.14). In conclusion, aortocavitary fistulous tract formation in PVE complicated with periannular complications is associated with higher rates of heart failure, ventricular septal defect, and atrioventricular block than nonruptured abscesses. Despite the frequent complications, fistulous tract formation in the current era of infective endocarditis is not an independent risk factor for mortality.

Abscess↗

PubMed2006

Periannular complications in infective endocarditis involving native aortic valves.

The extension of infection in native valve infective endocarditis (IE) from valvular structures to the periannular tissue is incompletely understood. It is unknown, for example, whether the prognosis of patients with aortocavitary fistulae is worse than that of those with nonruptured abscesses. The aims of this study were to determine the distinct clinical characteristics of patients with aortocavitary fistulae and nonruptured abscesses in native valve IE and to evaluate the impact of fistulization on the outcomes of patients with native aortic valve IE complicated with periannular lesions. In a retrospective multicenter study of 2,055 native valve IE episodes, 201 patients (9.8%) with periannular complications in aortic valve IE were identified (46 with aortocavitary fistulization and 155 with nonruptured abscesses). Rates of heart failure (p = 0.07), ventricular septal defect (p <0.001), and third-degree atrioventricular block (p = 0.07) were higher in patients with fistulization. Surgical treatment was undertaken in 172 patients (86%), and in-hospital mortality in the overall population was 29%. Multivariate analysis identified age >60 years (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.3 to 5.2), renal failure (OR 3.0, 95% CI 1.5 to 6.0), and moderate or severe heart failure (OR 2.5, 95% CI 1.2 to 5.2) as independent risk factors for death. There was a trend toward increased in-hospital mortality in patients with aortocavitary fistulae (OR 1.5, 95% CI 0.7 to 3.0). The actuarial 5-year survival rate in surgical survivors was 80% in patients with fistulae and 92% in patients with nonruptured abscesses (log-rank p = 0.6). In conclusion, aortocavitary fistulous tract formation in the setting of native valve IE is associated with higher rates of heart failure, ventricular septal defect, and atrioventricular block than nonruptured abscess. Despite these higher rates of complications, fistulous tract formation in the current era of IE is not an independent risk factor for mortality.

Abscess↗

PubMed2006

Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.

BACKGROUND: Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed. METHODS: We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy. RESULTS: Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, -10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, and methicillin-resistant S. aureus. Daptomycin therapy was associated with a higher rate of microbiologic failure than was standard therapy (19 vs. 11 patients, P=0.17). In 6 of the 19 patients with microbiologic failure in the daptomycin group, isolates with reduced susceptibility to daptomycin emerged; similarly, a reduced susceptibility to vancomycin was noted in isolates from patients treated with vancomycin. As compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P=0.06). Clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P=0.004). CONCLUSIONS: Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis. (ClinicalTrials.gov number, NCT00093067 [ClinicalTrials.gov].).

Adult↗

PubMed2006

Influence of diabetes mellitus on the clinical manifestations and prognosis of infective endocarditis: a report from the International Collaboration on Endocarditis-Merged Database.

The purpose of this investigation was to study the influence of diabetes mellitus (DM) on outcomes of infective endocarditis (IE). Outcomes were compared between 150 diabetic and 905 non-diabetic patients with IE from the International Collaboration on Endocarditis Merged Database. Compared to non-diabetic patients, diabetic patients were older (median age 63 vs 57 y, p<0.001), were more often female (42.0% vs 31.9%, p=0.01), more often had comorbidities (41.5% vs 26.7%, p<0.001), and were more likely to be dialysis dependent (12.7% vs 4.0%, p<0.001). S. aureus was isolated more often (30.7% vs 21.7%, p=0.02), and microorganisms from the viridans Streptococcus group less often (16.7% vs 28.2%, p = 0.001) in the diabetic group. There was no difference with respect to the presence of congestive heart failure, embolism, intra-cardiac abscess, new valvular regurgitation, or valvular vegetation. Diabetic patients underwent surgical intervention less frequently (32.0% vs 44.9%, p = 0.003), and had higher overall in-hospital mortality (30.3% vs 18.6%, p = 0.001). On multivariable analysis, DM was an independent predictor of mortality (odds ratio (OR) = 1.71, 95% confidence interval (CI) 1.08-2.70), especially in male patients, as diabetic males had higher mortality than non-diabetic males (OR 2.18, CI 1.08-4.35). DM is an independent predictor of in-hospital mortality among patients hospitalized with IE.

Aged↗

PubMed2005

Clinical characteristics and outcome of aortic endocarditis with periannular abscess in the International Collaboration on Endocarditis Merged Database.

The aims of this study were to determine the clinical characteristics and outcome of patients who had definite infective endocarditis (IE) complicated by aortic ring abscess formation that was detected with transesophageal echocardiography (TEE) and to determine the prognostic significance of abscess formation in aortic valve IE. Patients who had aortic valve IE were selected from the International Collaboration on Endocarditis Merged Database (ICE-MD) if they underwent TEE. Among 311 patients who had definite aortic valve IE, 67 (22%) had periannular abscesses. They were more likely to have infection in the setting of a prosthetic valve (40% vs 19%, p <0.001) and coagulase-negative staphylococcal IE (18% vs 6%, p < 0.01) and less likely to have streptococcal IE than were patients who did not develop abscess (28% vs 46%, p = 0.01). Systemic embolization, central nervous system events, and heart failure did not differ between those who developed abscess and those who did not, but power was limited. Patients who had abscess were more likely to undergo surgery (84% vs 36%, p <0.001), and their in-hospital mortality rate was higher (19% vs 11%, p = 0.09). Multivariate analysis of prognostic factors of mortality in aortic IE identified age (odds ratio [OR] 1.6, 95% confidence interval [CI]1.2 to 2.1), Staphylococcus aureus (S. aureus) infection (OR 2.4, 95% CI 1.1 to 5.2), and heart failure (OR 2.9, 95% CI 1.4 to 6.1) as variables that were independently associated with increased risk of death. Periannular abscess formation showed a nonsignificant trend toward an increased risk of death (OR 1.9, 95% CI 0.9 to 3.8). Multivariate analysis of prognostic factors of mortality in complicated aortic IE with abscess formation identified S. aureus infection (OR 6.9, 95% CI 1.6 to 29.4) as independently associated with increased risk of death. In conclusion, in the current era of TEE and high use of surgical treatment, periannular abscess formation in aortic valve IE is not an independent risk factor for mortality. S. aureus infection is an independent prognostic factor for mortality in patients who have abscess formation.

Abscess↗

PubMed2005

Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database.

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

Databases as Topic↗

PubMed2005

Staphylococcus aureus endocarditis: a consequence of medical progress.

CONTEXT: The global significance of infective endocarditis (IE) caused by Staphylococcus aureus is unknown. OBJECTIVES: To document the international emergence of health care-associated S aureus IE and methicillin-resistant S aureus (MRSA) IE and to evaluate regional variation in patients with S aureus IE. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational cohort study set in 39 medical centers in 16 countries. Participants were a population of 1779 patients with definite IE as defined by Duke criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to December 2003. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: S aureus was the most common pathogen among the 1779 cases of definite IE in the International Collaboration on Endocarditis Prospective-Cohort Study (558 patients, 31.4%). Health care-associated infection was the most common form of S aureus IE (218 patients, 39.1%), accounting for 25.9% (Australia/New Zealand) to 54.2% (Brazil) of cases. Most patients with health care-associated S aureus IE (131 patients, 60.1%) acquired the infection outside of the hospital. MRSA IE was more common in the United States (37.2%) and Brazil (37.5%) than in Europe/Middle East (23.7%) and Australia/New Zealand (15.5%, P<.001). Persistent bacteremia was independently associated with MRSA IE (odds ratio, 6.2; 95% confidence interval, 2.9-13.2). Patients in the United States were most likely to be hemodialysis dependent, to have diabetes, to have a presumed intravascular device source, to receive vancomycin, to be infected with MRSA, and to have persistent bacteremia (P<.001 for all comparisons). CONCLUSIONS: S aureus is the leading cause of IE in many regions of the world. Characteristics of patients with S aureus IE vary significantly by region. Further studies are required to determine the causes of regional variation.

Cross Infection↗

PubMed2005

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).

Endocarditis, Bacterial↗

PubMed2005

Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to gram-positive bacteria.

BACKGROUND: Telavancin, a novel lipoglycopeptide, exerts concentration-dependent, rapid bactericidal activity on account of its multiple mechanisms of action. Telavancin is highly active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate, and vancomycin-resistant strains. METHODS: We conducted a randomized, double-blind, controlled, phase-2 clinical trial. Patients > or = 18 years of age with a diagnosis of complicated skin and soft-tissue infection caused by suspected or confirmed gram-positive organisms were randomized to receive either intravenously administered telavancin once daily or standard therapy (antistaphylococcal penicillin 4 times daily or vancomycin twice daily). RESULTS: For the study, 167 patients were randomized and received at least 1 dose of study medication. Success rates were similar in all analysis populations at the test-of-cure evaluation. Of patients with S. aureus infection at baseline (n = 102), 80% of the telavancin group were cured and 77% of the standard therapy group were cured. For patients with MRSA infection at baseline (n = 48), cure rates were 82% for the telavancin group and 69% for the standard therapy group. Microbiologic eradication in patients with MRSA infection was 84% for the telavancin group versus 74% for the standard therapy group. MIC90 values were lower for telavancin in all tested strains of S. aureus (< or = 0.25 ug/mL) compared with the MIC90 values for vancomycin and oxacillin. Similar proportions of patients discontinued therapy for adverse events in both treatment groups (approximately 5%). Fewer serious adverse events were reported in the telavancin group (4 events) than were for the standard therapy group (9). CONCLUSION: Clinical and microbiological results of this study support the further development of telavancin, especially for treatment of infection due to MRSA.

Adult↗

PubMed2005

Aortic coarctation endarteritis in an adult: case report with cardiovascular magnetic resonance imaging findings and review of the literature.

We describe a case of coarctation endarteritis in an adult and review the literature pertaining to this condition. Adult coarctation endarteritis is a rare entity but often represents the initial presentation of coarctation. Diagnosis is critically important given the risk of rupture. Cardiovascular magnetic resonance imaging can be helpful in management.

Adolescent↗

PubMed2005

The use and effect of surgical therapy for prosthetic valve infective endocarditis: a propensity analysis of a multicenter, international cohort.

BACKGROUND: Although surgical intervention is often used in the treatment of prosthetic valve infective endocarditis (PVIE), an understanding of its effect on survival has been limited by the biases of observational studies and lack of controlled trials. METHODS: The International Collaboration on Endocarditis Merged Database is a large, multicenter, international registry of patients with definite endocarditis by Duke criteria, including 367 patients with PVIE. Clinical, microbiologic, and echocardiographic variables were analyzed to determine those factors associated with the use of surgery for PVIE. Logistic regression analysis was performed to create a propensity model of predictors of surgery use. Patients who underwent surgery during initial hospitalization were matched by propensity score with patients treated with medical therapy alone. Logistic regression analysis was performed to determine variables independently associated with inhospital mortality in this matched subset. RESULTS: Surgical therapy for PVIE was performed in 148 (42%) of 367 patients. Inhospital mortality was similar for patients treated with surgery compared with those treated with medical therapy alone (25.0% vs 23.4%, P = .729). Surgical therapy was independently associated with patient age, microorganism, intracardiac abscess, and congestive heart failure. After adjustment for these determinants, inhospital mortality was predicted by brain embolization (OR 11.12, 95% CI 4.16-29.73) and Staphylococcus aureus infection (OR 3.67, 95% CI 1.29-9.74), with a trend toward benefit for surgery (OR 0.56, 95% CI 0.23-1.36). CONCLUSIONS: Despite the frequent use of surgery for the treatment of PVIE, this condition continues to be associated with a high inhospital mortality rate in the contemporary era. After adjustment for factors related to surgical intervention, brain embolism and S aureus infection were independently associated with inhospital mortality and a trend toward a survival benefit of surgery was evident.

Aged↗

PubMed2005

Use of surgery in patients with native valve infective endocarditis: results from the International Collaboration on Endocarditis Merged Database.

BACKGROUND: Early surgery has been shown to be beneficial for patients with infective endocarditis (IE), yet surgery is not used in most patients. Evidence of the uncertainty around the use of surgery can be found in the wide variations in the use of cardiac surgery in IE with few precise indications for cardiac surgery yet defined. The aim of the study was to characterize patients with native valve IE relative to surgery and to determine if patients who benefit from an early surgical intervention can be identified. METHODS: The International Collaboration on Endocarditis Merged Database was used to quantify the differences between patients with IE receiving medical and surgical intervention in 1516 patients with definite native valve IE. Propensity models were built to identify a group of patients that benefit from early surgery. RESULTS: Patients in the early surgical group were more likely to be male, younger, and with less comorbidities compared with the early medical group (P < .001 for all) and were less likely to have infection with Staphylococcus aureus or viridans group streptococci (P < .05 for all). Intracardiac abscess and heart failure were much more common in the surgical group (P < .001 for all). In an unadjusted comparison, there was no statistically significant survival advantage in the surgical group. However, in the propensity analysis, in the subgroup of patients with the most indications for surgery, there was a significant decrease in mortality associated with early surgery (11.2% vs 38.0%, P < .001). CONCLUSIONS: The benefits of surgery are not seen uniformly in all patients with native valve IE, but are most realized in a targeted population. This observation requires confirmation in other populations of patients with definite IE.

Endocarditis, Bacterial↗

PubMed2005

Risk of endocarditis among patients with prosthetic valves and Staphylococcus aureus bacteremia.

PURPOSE: Staphylococcus aureus is a common cause of bacteremia and of native valve infective endocarditis. However, the risk of endocarditis in patients with a prosthetic valve who develop S. aureus bacteremia is unclear. The aim of this study was to define the risk of prosthetic valve endocarditis in patients with S. aureus bacteremia. SUBJECTS AND METHODS: All patients with a prosthetic valve or ring who developed S. aureus bacteremia during the 94-month study period were prospectively evaluated. The modified Duke criteria were used for the diagnosis of endocarditis. Patients were followed up for 12 weeks after the initial diagnosis of S. aureus bacteremia. RESULTS: The overall rate of definite prosthetic valve endocarditis among the study patients was 26/51 (51%). The risk of endocarditis was similar in patients with late (>or=12 months after valve implantation) vs. early S. aureus bacteremia (<12 months after prosthetic valve implantation) (50% vs. 52%, P=1.0), mitral vs. aortic prostheses (62% vs. 48%, P=0.24), and mechanical vs. bioprosthetic valves (62% vs. 44%, P=0.29). The 12-week mortality was higher among patients with definite vs. possible endocarditis (62% vs. 28%, P=0.019). CONCLUSION: In this investigation, approximately half of all patients with prosthetic valves who developed S. aureus bacteremia had definite endocarditis. The risk of endocarditis was independent of the type, location, or age of the prosthetic valve. The mortality of prosthetic valve endocarditis is high. All patients with a prosthetic valve who develop S. aureus bacteremia should be aggressively screened and followed for endocarditis.

Bacteremia↗

PubMed2005

Staphylococcus aureus bacteremia in patients with prosthetic devices: costs and outcomes.

PURPOSE: Although Staphylococcus aureus is a leading cause of nosocomial infection, little is known about the impact of S. aureus bacteremia on patients with prosthetic devices. This investigation sought to define the clinical outcome, health care resource use, and infection-associated costs of S. aureus bacteremia in patients with prostheses. SUBJECTS AND METHODS: All hospitalized patients with a prosthetic device and S. aureus bacteremia during the 96-month study period were identified prospectively. Clinical data were collected at the time of hospitalization. Data regarding infection-related resource utilization and infection-related costs within 12 weeks of the initial bacteremia were also recorded. RESULTS: 298 patients with > or =1 prosthesis and S. aureus bacteremia were identified (cardiovascular device--122 patients, orthopedic device--73 patients, long-term catheter--71 patients, and other devices-32 patients). Overall, 58% of patients underwent surgery as a consequence of the infection. Infection-related complications occurred in 41% and the overall 12-week mortality was 27%. The mean infection-related cost was 67439 dollars for patients with hospital-acquired S. aureus bacteremia and 37868 dollars for community-acquired S. aureus bacteremia (cost difference 29571 dollars; 95% confidence interval, 14370 dollars-49826 dollars). Rates of device infection, complications, 12-week mortality, and mean cost varied by prosthesis type. CONCLUSION: S. aureus bacteremia in patients with prosthetic devices is associated with frequent complications, substantial cost, and significant health care resource utilization.

Adult↗

PubMed2005

Clinical utility of the Food and Drug Administration Electrocardiogram Warehouse: a paradigm for the critical pathway initiative.

Although there are rising public expectations about the prospects for new therapies based on advances in biomedical discoveries, the rate of new product submissions to the Food and Drug Administration (FDA) has not been increasing. Alarmingly, over the past 6 years, there has been a 30% decline in submissions. The reasons for this are multifactorial and include new science not at its full potential, mergers/business arrangements have decreased candidates, chronic disease is harder to study, the failure rate has not improved, and rapidly escalating costs and complexity. Notably, societal investment in research and development to improve the drug approval process has been lacking in contrast to the large investments, both private and public, in basic research and specific product advances. The Critical Path Initiative has been developed by the FDA to combat many of these issues. This initiative is designed to be collaborative between government, academic, industry, and patient groups. The partnership is designed to expand product opportunities by sharing existing knowledge and data, allowing the development of enabling standards, to improve drug development and approval. A central tenant of Critical Path is a focus on the evaluative science of the drug approval process, including both efficacy and safety measures. The FDA Electrocardiogram Warehouse is 1 example where a government resource could be used by a confluence of groups to improve the science surrounding important components of the drug approval process such as cardiac safety evaluation.

Critical Pathways↗

PubMed2004

A meta-analysis of medical versus surgical therapy for Candida endocarditis.

OBJECTIVES: The optimal management of Candida infective endocarditis (IE) is unknown. METHODS: We reviewed all 879 cases of Candida IE reported from 1966-2002 in the peer-reviewed literature to better understand the role of medical and surgical therapies. This review included 163 patients from 105 reports that met our inclusion criteria: 31 cases treated with antifungal monotherapy, 25 cases treated with medical antifungal combination therapy, and 107 cases treated with adjunctive surgical plus medical antifungal therapy. We also used meta-analytic techniques to evaluate 22 observational case-series (72 patients) of the 105 reports with two or more patients with definite Candida IE. RESULTS: We found that in patients who underwent adjunctive surgery there was a lower reported proportion of deaths [prevalence odds ratio (POR)=0.56; 95% confidence interval (CI)=0.16, 1.99)]. Higher mortality was noted in patients treated prior to 1980 (POR=2.03; 95% CI=0.55, 7.61), treated with antifungal monotherapy (POR=1.49; 95% CI=0.39, 5.81), infected with Candida parapsilosis (POR=1.51; 95% CI=0.41, 5.52), or with left-sided endocarditis (POR=2.36; 95% CI=0.55, 10.07). CONCLUSIONS: Medical antifungal therapy of Candida IE is poorly characterized, and recent antifungal developments lend promise for those patients who cannot undergo surgery.

Adolescent↗

PubMed2004

Aorto-cavitary fistulous tract formation in infective endocarditis: clinical and echocardiographic features of 76 cases and risk factors for mortality.

AIMS: To investigate the clinical features, echocardiographic characteristics, management, and prognostic factors of mortality of aorto-cavitary fistulization (ACF) in infective endocarditis (IE). Extension of infection in aortic valve IE beyond valvular structures may result in peri-annular complications with resulting necrosis and rupture, and subsequent development of ACF. Aorto-cavitary communications create intra-cardiac shunts, which may result in further clinical deterioration and haemodynamic instability. METHODS AND RESULTS: In a retrospective multi-centre study over 4681 episodes of IE, a total of 76 patients with ACF [1.6%, confidence interval (CI) 95%: 1.2-2.0%] diagnosed by echocardiography or during surgery were identified. Fistulae were found in 1.8% of cases of native valve IE and in 3.5% of cases of prosthetic valve IE from the general population and in 0.4% of drug abusers. PVE was present in 31 (41%) cases of ACF. Transthoracic and transoesophageal echocardiography detected the fistulous tracts in 53 and 97% of cases, respectively. Peri-annular abscesses were detected in 78% of cases, fistulae originated in similar rates from the three sinuses of Valsalva, and the four cardiac chambers were equally involved in the fistulous tracts. Heart failure (HF) developed in 62% of cases and surgery was performed in 66 (87% CI 95% 77-93%) patients with a mortality of 41% (95% CI 30-53%) in the overall population. Multivariate analysis identified HF (OR 3.4, CI 95% 1.0-11.5), prosthetic IE (OR 4.6, CI 95% 1.4-15.4) and urgent or emergency surgical treatment (OR 4.3, CI 95% 1.3-16.6) as variables significantly associated with an increased risk of death. Major complications during follow-up (death, re-operation, or re-admission for HF) among the five operative survivors with residual fistulae occurred in 20 and 100% of patients at 1 and 2 years, respectively. CONCLUSION: Aorto-cavitary fistulous tract formation is an uncommon but extremely serious complication of IE. In-hospital mortality was exceptionally high despite aggressive management with surgical intervention in the majority of patients. Prosthetic IE, urgent surgery, and the development of HF identify the subgroup of patients with IE and ACF that have significantly increased risk of in-hospital death.

Adolescent↗