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Embolic events to the central nervous system are a major cause of morbidity and mortality in patients with infective endocarditis (IE). The appropriate role of valvular surgery in reducing such embolic events is unclear. The purpose of this study was to determine the relationship between the initiation of antimicrobial therapy and the temporal incidence of stroke in patients with IE and to determine if this time course differs from that shown for embolic events in previous studies. Prospective incidence cohort study involving 61 tertiary referral centers in 28 countries. Case report forms were analyzed from 1437 consecutive patients with left-sided endocarditis admitted directly to participating centers. The crude incidence of stroke in patients receiving appropriate antimicrobial therapy was 4.82/1000 patient days in the first week of therapy and fell to 1.71/1000 patient days in the second week. This rate continued to decline with further therapy. Stroke rates fell similarly regardless of the valve or organism involved. After 1 week of antimicrobial therapy, only 3.1% of the cohort experienced a stroke. The risk of stroke in IE falls dramatically after the initiation of effective antimicrobial therapy. The falling risk of stroke in patients with IE as a whole precludes stroke prevention as the sole indication for valvular surgery after 1 week of therapy.

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 (34%) 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 (60% vs. 31%; P < .001), or to have a central nervous system event (20% 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, 1.1–5.6), 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.

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.

Although cardiac devices have been found to reduce symptoms and mortality rates in appropriate patient populations, the implications of certain important risks, such as infection, are incompletely understood. The purpose of this study was to use a large population-based database to define the population that is at risk for cardiac device infections, determine the prevalence of device infections, and study changes in the rates of cardiac device implantation and infection in the past decade. Patients with cardiac device implantations and infections were identified with claims files from the Health Care Finance Administration for Medicare beneficiaries from January 1, 1990, through December 31, 1999. Rates of implantation of cardiac devices were determined. Time trend analyses were performed to determine the significance of the observed change in rates. Cardiac device implantation rates increased from 3.26 implantations per 1000 beneficiaries in 1990 to 4.64 implantations per 1000 beneficiaries in 1999, which represents an increase of 42% in 10 years ( P for trend <.001). Cardiac device infections showed a larger increase, from 0.94 device infections per 1000 beneficiaries in 1990 to 2.11 device infections per 1000 beneficiaries in 1999, which represents an increase of 124% during the study period ( P for trend <.001). During the previous decade, there was a significant increase in both cardiac device implantations and infections in elderly patients, although the increase in the rates of device infections was substantially higher. Additional studies are needed to better understand the relationship and timing between cardiac device implantation and infection.

Background. The causes of persistent bacteremia (PB) due to methicillin-resistant Staphylococcus aureus (MRSA) are poorly understood. This investigation examined potential associations between PB with key clinical features and several in vitro bacterial genotypic and phenotypic characteristics, in isolates from 1 institution. Methods. Pulsed-field gel electrophoresis (PFGE) relatedness, thrombin-induced platelet microbicidal protein (tPMP)-susceptibility phenotype, accessory gene regulator (agr) genotype and functionality (via δ-lysin production), and autolysis phenotypes were assessed in MRSA isolates from the bloodstream of 21 prospectively identified patients with PB (blood cultures positive after ⩾7 days of therapy) and of 18 patients with resolving bacteremia (RB) (sterile blood cultures within the first 2–4 days of therapy) due to MRSA. Results. The 2 groups had comparable baseline characteristics but differed in their clinical courses (e.g., endocarditis was more frequent in patients with PB than in those with RB [43% vs. 0%, respectively; P = .0016]); isolates from patients with PB exhibited higher rates of (1) survival in vitro after exposure to tPMP (22.4 ± 14.8% vs. 11.6 ± 6.5%, respectively; P = .005); (2) defective δ-lysin production (71.4% vs. 38.9%, respectively; P = .057); (3) non-agr genotype II profile (100% vs. 77.8%, respectively; P = .037); and (4) overrepresentation of a specific PFGE genotype (85.7% vs. 44.4%, respectively; P = .015). Conclusions. Isolates from patients with PB differed from those in patients with RB, in several in vitro characteristics. Further studies will be necessary to define how these factors might affect clinical outcome.

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).

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post-dose and mean terminal elimination half-life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half-life values ranged from 17.5–18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

The Cardiac Safety Research Consortium (CSRC), a transparent, public-private partnership established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University, is entering its second decade. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. Operationally, CSRC brings together a broad base of stakeholders from academia, industry, and government agencies in a collaborative forum focused on identifying barriers and then creating novel solutions through shared data, expertise, and collaborative research. This white paper provides a brief overview of the Consortium’s activities in its first decade and a context for some of our current activities and future directions. The growth and success of the CSRC have been primarily driven by members’ active participation and the development of goodwill and trust throughout our membership, which have facilitated novel collaborations across traditionally competitive or contentious stakeholder boundaries. The continued expansion of our base of participating academicians, industry experts, and regulators will define the Consortium’s success in our second decade. It is our hope that sharing our endeavors to date will stimulate additional participation in the CSRC and also provide a model for other groups starting to develop similar collaborative forums.

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.

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.