Imad M. Tleyjeh

Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association.

Background— Infective endocarditis is a potentially lethal disease that has undergone major changes in both host and pathogen. The epidemiology of infective endocarditis has become more complex with today‘s myriad healthcare‐associated factors that predispose to infection. Moreover, changes in pathogen prevalence, in particular a more common staphylococcal origin, have affected outcomes, which have not improved despite medical and surgical advances. Methods and Results— This statement updates the 2005 iteration, both of which were developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It includes an evidence‐based system for diagnostic and treatment recommendations used by the American College of Cardiology and the American Heart Association for treatment recommendations. Conclusions— Infective endocarditis is a complex disease, and patients with this disease generally require management by a team of physicians and allied health providers with a variety of areas of expertise. The recommendations provided in this document are intended to assist in the management of this uncommon but potentially deadly infection. The clinical variability and complexity in infective endocarditis, however, dictate that these recommendations be used to support and not supplant decisions in individual patient management.

Statins for the Prevention and Treatment of Infections A Systematic Review and Meta-analysis

BACKGROUND Emerging epidemiological evidence suggests that statin use may reduce the risk of infections and infection-related complications. Our objective was to examine the association between statin use and the risk of infections and related outcomes. METHODS We searched several electronic databases from inception through December 2007 for randomized trials and cohort studies that examined the association between statin use and the risk or outcome of infections. Data on study characteristics, measurement of statin use, outcomes (adjusted for potential confounders), and quality assessment were extracted. RESULTS Sixteen cohorts were eligible and differed in representativeness, outcome assessment, and comparability of exposed (statin) and unexposed (nonstatin) groups. Nine cohorts addressed the role of statins in treating infections: bacteremia (n = 3), pneumonia (n = 3), sepsis (n = 2), and bacterial infection (n = 1). The pooled adjusted effect estimate was 0.55 (95% confidence interval, 0.36-0.83; I(2) = 76.5%) in favor of statins. Seven cohorts addressed infection prevention in patients with vascular diseases (n = 3), chronic kidney disease (n = 1), diabetes (n = 1), intensive care unit-acquired infections (n = 1), and in general practice (n = 1). The pooled effect estimate was 0.57 (95% confidence interval, 0.43-0.75; I(2) = 82%) in favor of statin use; there was some evidence of publication bias for this analysis (Egger test; P = .07). Meta-regression did not identify potential effect modifiers that explain the between-study heterogeneity. CONCLUSIONS Results for our meta-analysis suggest that statin use may be associated with a beneficial effect in treating and preventing different infections. Given the presence of heterogeneity and publication bias, there is a need for randomized trials to confirm the benefit of statin use in this context.

Efficacy of Antioxidant Supplementation in Reducing Primary Cancer Incidence and Mortality : Systematic Review and Meta-analysis

OBJECTIVE To estimate the association between antioxidant use and primary cancer incidence and mortality and to evaluate these effects across specific antioxidant compounds, target organs, and participant subgroups. METHODS Multiple electronic databases (MEDLINE, Cochrane Controlled Clinical Trials Register, EMBASE, Science Citation Index) were searched from their dates of inception until August 2005 to identify eligible randomized clinical trials. Random effects meta-analyses estimated pooled relative risks (RRs) and 95% confidence intervals (CIs) that described the effect of antioxidants vs placebo on cancer incidence and cancer mortality. RESULTS Twelve eligible trials, 9 of high methodological quality, were identified (total subject population, 104,196). Antioxidant supplementation did not significantly reduce total cancer incidence (RR, 0.99; 95% CI, 0.94-1.04) or mortality (RR, 1.03; 95% CI, 0.92-1.15) or any site-specific cancer incidence. Beta carotene supplementation was associated with an increase in the incidence of cancer among smokers (RR, 1.10; 95% CI, 1.03-1.10) and with a trend toward increased cancer mortality (RR, 1.16; 95% CI, 0.98-1.37). Selenium supplementation was associated with reduced cancer incidence in men (RR, 0.77; 95% CI, 0.64-0.92) but not in women (RR, 1.00; 95% CI, 0.89-1.13, value for interaction, P< .001) and with reduced cancer mortality (RR, 0.78; 95% CI, 0.65-0.94). Vitamin E supplementation had no apparent effect on overall cancer incidence (RR, 0.99; 95% CI, 0.94-1.04) or cancer mortality (RR, 1.04; 95% CI, 0.97-1.12). CONCLUSION Beta carotene supplementation appeared to increase cancer incidence and cancer mortality among smokers, whereas vitamin E supplementation had no effect. Selenium supplementation might have anticarcinogenic effects in men and thus requires further research.

Granulocyte colony-stimulating factor therapy for cardiac repair after acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND Small clinical studies of granulocyte colony-stimulating factor (G-CSF) therapy for cardiac repair after acute myocardial infarction (MI) have yielded divergent results. The effect of G-CSF therapy on left ventricular (LV) function and structure in these patients remains unclear. METHODS We searched MEDLINE, EMBASE, Science Citation Index, CINAHL, and the Cochrane CENTRAL database of controlled clinical trials (July 2007) for randomized controlled trials of G-CSF therapy in patients with acute MI. We conducted a fixed-effects meta-analysis across 8 eligible studies (n = 385 patients). RESULTS Compared with controls, G-CSF therapy increased LV ejection fraction (EF) by 1.09%, increased LV scar size by 0.22%, decreased LV end-diastolic volume by 4.26 mL, and decreased LV end-systolic volume by 2.50 mL. None of these effects were statistically significant. The risk of death, recurrent MI, and in-stent restenosis was similar in G-CSF-treated patients and controls. Subgroup analysis revealed a modest but statistically significant increase in EF (4.73%, P < .0001) with G-CSF therapy in studies that enrolled patients with mean EF <50% at baseline. Subgroup analysis also showed a significant increase in EF (4.65%, P < .0001) when G-CSF was administered relatively early (< or =37 hours) after the acute event. CONCLUSIONS Granulocyte colony-stimulating factor therapy in unselected patients with acute MI appears safe but does not provide an overall benefit. Subgroup analyses suggest that G-CSF therapy may be salutary in acute MI patients with LV dysfunction and when started early. Larger randomized studies may be conducted to evaluate the potential benefits of early G-CSF therapy in acute MI patients with LV dysfunction.

Temporal Trends in Permanent Pacemaker Implantation: A Population-Based Study

BACKGROUND Limited data exist regarding temporal trends in permanent pacemaker (PPM) implantation. To describe trends in incidence and comorbidities of PPM recipients, we conducted a retrospective population-based cohort study over a 30-year period. METHODS All 1291 adult residents of Olmsted County, Minnesota, undergoing PPM implantation between 1975 and 2004 were included in the study. Trends in PPM implantation incidence, pacing mode and indication, and comorbidities (via Charlson Comorbidity Index [CCI]) were assessed through the Rochester Epidemiology Project. Permanent pacemaker recipients were compared with age- and sex-matched PPM-free controls from the population. RESULTS Adjusted implantation incidence rates increased from 36.6 per 100,000 person-years during 1975 to 1979 to 99 per 100,000 person-years during 2000 to 2004 (P < .0001). After adjusting for age (hazard ratio [HR] 1.06 per year), male sex (HR 1.28), and implant year (HR 0.98), the HR for death among PPM recipients by CCI quartiles was 1.0, 1.79, 2.29, and 3.91 for CCI of 0 to 1 (reference), 2 to 3, 4 to 6, and > or = 7, respectively (P < .0001). Overall, PPM recipients had higher CCI than the population-based controls (P = .04), with higher mean CCI noted since 1990. Mean age-adjusted CCI increased from 3.15 to 4.60 among the cases (P < .0001) and from 3.06 to 3.54 among the age- and sex-matched controls (P = .047). CONCLUSIONS There have been significant increases in incidence of PPM implantation over 30 years, and PPM recipients have had an age-independent increase in comorbidities relative to the underlying population, especially over the past 15 years.

The Impact of Valve Surgery on 6-Month Mortality in Left-Sided Infective Endocarditis

Background— The role of valve surgery in left-sided infective endocarditis has not been evaluated in randomized controlled trials. We examined the association between valve surgery and all-cause 6-month mortality among patients with left-sided infective endocarditis. Methods and Results— A total of 546 consecutive patients with left-sided infective endocarditis were included. To minimize selection bias, propensity score to undergo valve surgery was used to match patients in the surgical and nonsurgical groups. To adjust for survivor bias, we matched the follow-up time so that each patient in the nonsurgical group survived at least as long as the time to surgery in the respective surgically-treated patient. We also used valve surgery as a time-dependent covariate in different Cox models. A total of 129 (23.6%) patients underwent surgery within 30 days of diagnosis. Death occurred in 99 of the 417 patients (23.7%) in the nonsurgical group versus 35 deaths among the 129 patients (27.1%) in the surgical group. Eighteen of 35 (51%) patients in the surgical group died within 7 days of valve surgery. In the subset of 186 cases (93 pairs of surgical versus nonsurgical cases) matched on the logit of their propensity score, diagnosis decade, and follow-up time, no significant association existed between surgery and mortality (adjusted hazard ratio, 1.3; 95% confidence interval, 0.5 to 3.1). With a Cox model that incorporated surgery as a time-dependent covariate, valve surgery was associated with an increase in the 6-month mortality with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.1 to 3.2). Because the proportionality hazard assumption was violated in the time-dependent analysis, we performed a partitioning analysis. After adjustment for early (operative) mortality, surgery was not associated with a survival benefit (adjusted hazard ratio, 0.92; 95% confidence interval, 0.48 to 1.76). Conclusions— The results of our study suggest that valve surgery in left-sided infective endocarditis is not associated with a survival benefit and could be associated with increased 6-month mortality, even after adjustment for selection and survivor biases as well as confounders. Given the disparity between the results of our study and those of other observational studies, well-designed prospective studies are needed to further evaluate the role of valve surgery in endocarditis management.

Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

Introduction Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). Methods Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. Results We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. Conclusions In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship.

Epidemiological trends of infective endocarditis: a population-based study in Olmsted County, Minnesota.

OBJECTIVE To provide a contemporary profile of epidemiological trends of infective endocarditis (IE) in Olmsted County, Minnesota. PATIENTS AND METHODS This study consists of all definite or possible IE cases among adults in Olmsted County from January 1, 1970, through December 31, 2006. Cases were identified using resources of the Rochester Epidemiology Project. RESULTS We identified 150 cases of IE. The age- and sex-adjusted incidences of IE ranged from 5.0 to 7.9 cases per 100,000 person-years with an increasing trend over time differential with respect to sex (for interaction, P=.02); the age-adjusted incidence of IE increased significantly in women (P=.006) but not in men (P=.79). We observed an increasing temporal trend in the mean age at diagnosis (P=.04) and a decreasing trend in the proportion of cases with rheumatic heart disease as a predisposing condition (P=.02). There were no statistically significant temporal trends in the incidence of either Staphylococcus aureus or viridans group streptococcal IE. Data on infection site of acquisition were available for cases seen in 2001 and thereafter, with 50.0% designated as health care-associated, 42.5% community-acquired, and 7.5% nosocomial. CONCLUSION The incidence of IE among women increased from 1970 to 2006. Ongoing surveillance is warranted to determine whether the incidence change in women will be sustained. Subsequent analysis of infection site of acquisition and its impact on the epidemiology of IE are planned.

The Impact of Penicillin Resistance on Short-Term Mortality in Hospitalized Adults with Pneumococcal Pneumonia: A Systematic Review and Meta-Analysis

BACKGROUND The clinical impact of penicillin resistance on the outcome of pneumococcal pneumonia has remained controversial. We performed a meta-analysis of prospective cohort studies to examine the association between penicillin resistance and short-term all-cause mortality for pneumococcal pneumonia. METHODS We retrieved studies published in any language by a comprehensive search of the Medline, Current Contents, and Embase databases for all appropriate articles published up to January 2005. We also manually reviewed bibliographies of retrieved articles, recent national treatment guidelines, and review articles. We included prospective cohort studies that involved adult subjects, and we examined the association between penicillin resistance and short-term mortality for pneumococcal pneumonia. Two reviewers independently extracted data on crude and adjusted risk estimates of all-cause mortality for pneumococcal infections with different levels of penicillin resistance and assessed the methodological quality of selected studies. We also contacted authors to obtain additional information. We performed meta-analyses using a random-effect model. RESULTS Of 1152 articles identified in the search, 10 studies that involved 3430 patients (most of whom were hospitalized) were included. The mortality rate was 19.4% in the penicillin-nonsusceptible Streptococcus pneumoniae group and 15.7% in the penicillin-susceptible S. pneumoniae group. The combined relative risks of all-cause mortality for the penicillin-nonsusceptible, -intermediate, and -resistant S. pneumoniae groups, compared with the penicillin-susceptible S. pneumoniae group, were 1.31 (95% confidence interval [CI], 1.08-1.59), 1.34 (95% CI, 1.13-1.60), and 1.29 (95% CI, 1.01-1.66), respectively. The combined adjusted relative risks of mortality for penicillin-nonsusceptible versus penicillin-susceptible S. pneumoniae group was 1.29 (95% CI, 1.04-1.59) for the 6 studies that adjusted for age, comorbidities, and severity of illness. There was minimal between-study heterogeneity in these analyses. CONCLUSION Penicillin resistance is associated with a higher mortality rate than is penicillin susceptibility in hospitalized patients with pneumococcal pneumonia. Additional efforts are needed to understand the mechanisms of this association.

Incidence of Infective Endocarditis Caused by Viridans Group Streptococci Before and After Publication of the 2007 American Heart Association's Endocarditis Prevention Guidelines

Background— The American Heart Association published updated guidelines for infective endocarditis (IE) prevention in 2007 that markedly restricted the use of antibiotic prophylaxis in certain at-risk patients undergoing dental and other invasive procedures. The incidence of IE caused by viridans group streptococci (VGS) in the United States after publication of the 2007 American Heart Association guidelines has not been reported. Methods and Results— We performed a population-based review of all definite or possible cases of VGS-IE using the Rochester Epidemiology Project of Olmsted County, Minnesota. Patient demographics and microbiological data were collected for all VGS-IE cases diagnosed from January 1, 1999, through December 31, 2010. We also examined the Nationwide Inpatient Sample hospital discharge database to determine the number of VGS-IE cases included between 1999 and 2009. We identified 22 cases with VGS-IE in Olmsted County over the 12-year study period. Rates of incidence (per 100 000 person-years) during time intervals of 1999–2002, 2003–2006, and 2007–2010 were 3.19 (95% confidence interval, 1.20–5.17), 2.48 (95% confidence interval, 0.85–4.10), and 0.77 (95% confidence interval, 0.00–1.64), respectively (P=0.061 from Poisson regression). The number of hospital discharges with a VGS-IE diagnosis in the Nationwide Inpatient Sample database during 1999–2002, 2003–2006, and 2007–2009 ranged between 15 318 to 15 938, 16 214 to 17 433, and 14 728 to 15 479, respectively. Conclusions— On the basis of data complete through 2010, there has been no perceivable increase in the incidence of VGS-IE in Olmsted County, Minnesota, since the publication of the 2007 American Heart Association endocarditis prevention guidelines.