Vivian H. Chu

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.

Use of Vancomycin or First-Generation Cephalosporins for the Treatment of Hemodialysis-Dependent Patients with Methicillin-Susceptible Staphylococcus aureus Bacteremia

BACKGROUND Because of its ease of dosing, vancomycin is commonly used to treat methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in patients undergoing long-term hemodialysis. Clinical outcomes resulting from such a therapeutic strategy have not been well defined. METHODS We prospectively identified patients undergoing long-term hemodialysis who received a diagnosis of MSSA bacteremia. Clinical outcomes were grouped according to the predominant antibiotic received during their therapy (vancomycin or a first-generation cephalosporin [cefazolin]). Treatment failure (defined as death or recurrent infection) was determined at 12 weeks after the initial positive blood culture results. A multivariable analysis was used to adjust for confounders. RESULTS During an 84-month period, 123 hemodialysis-dependent patients with MSSA bacteremia were identified. Patients receiving vancomycin (n=77) tended to be younger (51 vs. 57 years; P=.06) and had a lower rates of metastatic complications at presentation (11.7% vs. 36.7%; P=.001) than did those receiving cefazolin (n=46). The 2 groups were similar with regard to Acute Physiology and Chronic Health Evaluation II scores, comorbidities, source of infection, type of hemodialysis access, and access removal rates. Treatment failure was more common among patients receiving vancomycin (31.2% vs. 13%; P=.02). In the multivariable analysis, factors independently associated with treatment failure included vancomycin use (odds ratio, 3.53; 95% confidence interval, 1.15-13.45) and retention of the hemodialysis access (odds ratio, 4.99; 95% confidence interval, 1.89-13.76). CONCLUSIONS Hemodialysis-dependent patients with MSSA bacteremia treated with vancomycin are at a higher risk of experiencing treatment failure than are those receiving cefazolin. In the absence of patient specific circumstances (e.g., allergy to beta-lactams), vancomycin should not be continued beyond empirical therapy for hemodialysis-dependent patients with MSSA bacteremia.

Early Predictors of In-Hospital Death in Infective Endocarditis

Background—Data on early determinants of outcome in infective endocarditis (IE) are limited. We evaluated the prognostic significance of early clinical characteristics in a large, prospective cohort of patients with IE. Methods and Results—Two hundred sixty-seven consecutive patients with definite or possible IE by modified Duke criteria and echocardiography performed within 7 days of presentation were evaluated. Acute physiology was assessed by the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score at the time of presentation, and early heart failure was diagnosed by Framingham criteria. In-hospital mortality rate in the cohort was 19% and similar for patients with definite or possible IE (20% versus 16%, respectively; P =0.464). Independent predictors of death determined by logistic regression modeling were diabetes mellitus (OR 2.48; 95% CI, 1.24 to 4.96), Staphylococcus aureus as causative organism (OR, 2.06; 95% CI, 1.01 to 4.20), APACHE II score (OR, 1.07; 95% CI, 1.01 to 1.12), and embolic event (OR, 2.79; 95% CI, 1.15 to 6.80). Early echocardiographic findings of the Duke criteria were not predictive of death. Conclusions—Early in the course of IE, readily available clinical characteristics that reflect the host-pathogen interaction are predictive of in-hospital death. These factors may identify those patients with IE for more aggressive treatment.

Analysis of the Impact of Early Surgery on In-Hospital Mortality of Native Valve Endocarditis Use of Propensity Score and Instrumental Variable Methods to Adjust for Treatment-Selection Bias

Background— The impact of early surgery on mortality in patients with native valve endocarditis (NVE) is unresolved. This study sought to evaluate valve surgery compared with medical therapy for NVE and to identify characteristics of patients who are most likely to benefit from early surgery. Methods and Results— Using a prospective, multinational cohort of patients with definite NVE, the effect of early surgery on in-hospital mortality was assessed by propensity-based matching adjustment for survivor bias and by instrumental variable analysis. Patients were stratified by propensity quintile, paravalvular complications, valve perforation, systemic embolization, stroke, Staphylococcus aureus infection, and congestive heart failure. Of the 1552 patients with NVE, 720 (46%) underwent early surgery and 832 (54%) were treated with medical therapy. Compared with medical therapy, early surgery was associated with a significant reduction in mortality in the overall cohort (12.1% [87/720] versus 20.7% [172/832]) and after propensity-based matching and adjustment for survivor bias (absolute risk reduction [ARR] −5.9%, P<0.001). With a combined instrument, the instrumental-variable–adjusted ARR in mortality associated with early surgery was −11.2% (P<0.001). In subgroup analysis, surgery was found to confer a survival benefit compared with medical therapy among patients with a higher propensity for surgery (ARR −10.9% for quintiles 4 and 5, P=0.002) and those with paravalvular complications (ARR −17.3%, P<0.001), systemic embolization (ARR −12.9%, P=0.002), S aureus NVE (ARR −20.1%, P<0.001), and stroke (ARR −13%, P=0.02) but not those with valve perforation or congestive heart failure. Conclusions— Early surgery for NVE is associated with an in-hospital mortality benefit compared with medical therapy alone.

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.

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.

Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: before and after study

Objective To quantify the change in prescribing of antibiotic prophylaxis before invasive dental procedures for patients at risk of infective endocarditis, and any concurrent change in the incidence of infective endocarditis, following introduction of a clinical guideline from the National Institute for Health and Clinical Excellence (NICE) in March 2008 recommending the cessation of antibiotic prophylaxis in the United Kingdom. Design Before and after study. Setting England. Population All patients admitted to hospital in England with a primary or secondary discharge diagnosis of acute or subacute infective endocarditis. Main outcome measures Monthly number of prescriptions for antibiotic prophylaxis consisting of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin, and monthly number of cases of infective endocarditis, infective endocarditis related deaths in hospital, or cases of infective endocarditis with a possible oral origin for streptococci. Results After the introduction of the NICE guideline there was a highly significant 78.6% reduction (P<0.001) in prescribing of antibiotic prophylaxis, from a mean 10 277 (SD 1068) prescriptions per month to 2292 (SD 176). Evidence that the general upward trend in cases of infective endocarditis before the guideline was significantly altered after the guideline was lacking (P=0.61). Using a non-inferiority test, an increase in the number of cases of 9.3% or more could be excluded after the introduction of the guideline. Similarly an increase in infective endocarditis related deaths in hospital of 12.3% or more could also be excluded. Conclusion Despite a 78.6% reduction in prescribing of antibiotic prophylaxis after the introduction of the NICE guideline, this study excluded any large increase in the incidence of cases of or deaths from infective endocarditis in the two years after the guideline. Although this lends support to the guideline, ongoing data monitoring is needed to confirm this, and further clinical trials should determine if antibiotic prophylaxis still has a role in protecting some patients at particularly high risk.

Clinical Characteristics and Outcome of Infective Endocarditis Involving Implantable Cardiac Devices

CONTEXT Infection of implantable cardiac devices is an emerging disease with significant morbidity, mortality, and health care costs. OBJECTIVES To describe the clinical characteristics and outcome of cardiac device infective endocarditis (CDIE) with attention to its health care association and to evaluate the association between device removal during index hospitalization and outcome. DESIGN, SETTING, AND PATIENTS Prospective cohort study using data from the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), conducted June 2000 through August 2006 in 61 centers in 28 countries. Patients were hospitalized adults with definite endocarditis as defined by modified Duke endocarditis criteria. MAIN OUTCOME MEASURES In-hospital and 1-year mortality. RESULTS CDIE was diagnosed in 177 (6.4% [95% CI, 5.5%-7.4%]) of a total cohort of 2760 patients with definite infective endocarditis. The clinical profile of CDIE included advanced patient age (median, 71.2 years [interquartile range, 59.8-77.6]); causation by staphylococci (62 [35.0% {95% CI, 28.0%-42.5%}] Staphylococcus aureus and 56 [31.6% {95% CI, 24.9%-39.0%}] coagulase-negative staphylococci); and a high prevalence of health care-associated infection (81 [45.8% {95% CI, 38.3%-53.4%}]). There was coexisting valve involvement in 66 (37.3% [95% CI, 30.2%-44.9%]) patients, predominantly tricuspid valve infection (43/177 [24.3%]), with associated higher mortality. In-hospital and 1-year mortality rates were 14.7% (26/177 [95% CI, 9.8%-20.8%]) and 23.2% (41/177 [95% CI, 17.2%-30.1%]), respectively. Proportional hazards regression analysis showed a survival benefit at 1 year for device removal during the initial hospitalization (28/141 patients [19.9%] who underwent device removal during the index hospitalization had died at 1 year, vs 13/34 [38.2%] who did not undergo device removal; hazard ratio, 0.42 [95% CI, 0.22-0.82]). CONCLUSIONS Among patients with CDIE, the rate of concomitant valve infection is high, as is mortality, particularly if there is valve involvement. Early device removal is associated with improved survival at 1 year.

Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study

ABSTRACT Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA.

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.