Complex pathogens in infective endocarditis

Endocarditis; Diagnosis; TreatmentEndocarditis; Diagnóstico; TratamientoEndocarditis; Diagnòstic; TractamentInfective endocarditis (IE) is a complex disease whose prognosis depends on the causative microorganism, among other factors. The latter can be difficult to identify and/or treat. In this narrative review, we identify knowledge gaps in the diagnosis and antimicrobial treatment of IE, and attempt to shed light on current questions. Specifically, we: (1) analyze the factors that may hinder the microbiological diagnosis of blood culture-negative IE, as well as the role of new imaging techniques, such as 18F-fluorodeoxyglucose ([18F]FDG PET/CT), in the diagnostic capacity of this disease, understanding their advantages and assuming their limitations; (2) discuss the therapeutic approach to various difficult-to-treat microorganisms. In particular, we focus on the treatment of staphylococcal IE since, at present, staphylococci are the most frequent cause of IE in developed countries and staphylococcal IE is one of those with the highest short- and long-term mortality. We critically evaluate the current evidence on combination therapy and address the occurrence of serious side effects, an aspect that is often overlooked owing to the severity of the infection; and (3) emphasize the need for home antimicrobial treatment of patients with IE, as these are fragile people who benefit from an early return to their environment. This poses undoubted logistical challenges and requires robust evidence to ensure the best short- and long-term outcomes.Laura Escolà-Vergé has a Juan Rodés contract in the call 2020 Strategic Action Health from the Instituto de Salud Carlos III of Spanish Health Ministry for the years 2021-2024. This research was supported by CIBER-Consorcio Centro de Investigación Biomédica en Red (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea - NextGenerationEU

Predicting the occurrence of embolic events: an analysis of 1456 episodes of infective endocarditis from the Italian Study on Endocarditis (SEI)

Background: Embolic events are a major cause of morbidity and mortality in patients with infective endocarditis. We analyzed the database of the prospective cohort study SEI in order to identify factors associated with the occurrence of embolic events and to develop a scoring system for the assessment of the risk of embolism. Methods: We retrospectively analyzed 1456 episodes of infective endocarditis from the multicenter study SEI. Predictors of embolism were identified. Risk factors identified at multivariate analysis as predictive of embolism in left-sided endocarditis, were used for the development of a risk score: 1 point was assigned to each risk factor (total risk score range: minimum 0 points; maximum 2 points). Three categories were defined by the score: low (0 points), intermediate (1 point), or high risk (2 points); the probability of embolic events per risk category was calculated for each day on treatment (day 0 through day 30).Results: There were 499 episodes of infective endocarditis (34%) that were complicated by 65 1 embolic event. Most embolic events occurred early in the clinical course (first week of therapy: 15.5 episodes per 1000 patient days; second week: 3.7 episodes per 1000 patient days). In the total cohort, the factors associated with the occurrence of embolism at multivariate analysis were prosthetic valve localization (odds ratio, 1.84), right-sided endocarditis (odds ratio, 3.93), Staphylococcus aureus etiology (odds ratio, 2.23) and vegetation size 65 13 mm (odds ratio, 1.86). In left-sided endocarditis, Staphylococcus aureus etiology (odds ratio, 2.1) and vegetation size 65 13 mm (odds ratio, 2.1) were independently associated with embolic events; the 30-day cumulative incidence of embolism varied with risk score category (low risk, 12%; intermediate risk, 25%; high risk, 38%; p < 0.001).Conclusions: Staphylococcus aureus etiology and vegetation size are associated with an increased risk of embolism. In left-sided endocarditis, a simple scoring system, which combines etiology and vegetation size with time on antimicrobials, might contribute to a better assessment of the risk of embolism, and to a more individualized analysis of indications and contraindications for early surgery

Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

IMPORTANCE Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. OBJECTIVE To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. EVIDENCE REVIEW This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. FINDINGS A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. CONCLUSIONS AND RELEVANCE In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed

Current Challenges in the Management of Infective Endocarditis

Infective endocarditis is a relatively rare, but deadly cause of sepsis, with an overall mortality ranging from 20 to 25% in most series. Although the classic clinical classification into syndromes of acute or subacute endocarditis have not completely lost their usefulness, current clinical forms have changed according to the profound epidemiological changes observed in developed countries. In this review, we aim to address the changing epidemiology of endocarditis, several recent advances in the understanding of the pathophysiology of endocarditis and endocarditis-triggered sepsis, new useful diagnostic tools as well as current concepts in the medical and surgical management of this disease. Given its complexity, the management of infective endocarditis requires the close collaboration of multidisciplinary endocarditis teams that must decide on the diagnostic approach; the appropriate initial treatment in the critical phase; the detection of patients needing surgery and the timing of this intervention; and finally the accurate selection of patients for out-of-hospital treatment, either at home hospitalization or with oral antibiotic treatment

Four weeks versus six weeks of ampicillin plus ceftriaxone in Enterococcus faecalis native valve endocarditis: A prospective cohort study

Enterococcus faecalis infective endocarditis (EFIE) is a severe disease of increasing incidence. The objective was to analyze whether the outcome of patients with native valve EFIE (NVEFIE) treated with a short course of ampicillin plus ceftriaxone (4wAC) was similar to patients treated according to international guidelines (6wAC). Between January 2008 and June 2018, 1,978 consecutive patients with definite native valve IE were prospectively included in a national registry. Outcomes of patients with NVEFIE treated with 4wAC were compared to those of patients who received 6wAC. Three hundred and twenty-two patients (16.3%) had NVEFIE. One hundred and eighty-three (56.8%) received AC. Thirty-nine patients (21.3%) were treated with 4wAC for four weeks and 70 patients (38.3%) with 6wAC. There were no differences in age or comorbidity. Patients treated 6wAC presented a longer duration of symptoms before diagnosis (21 days, IQR 7-60 days vs. 7 days, IQR 1-22 days; p = 0.002). Six patients presented perivalvular abscess and all of these received 6wAC. Surgery was performed on 14 patients (35.9%) 4wAC and 34 patients (48.6%) 6wAC (p = 0.201). In-hospital mortality, one-year mortality and relapses among 4wAC and 6wAC patients were 10.3% vs. 11.4% (p = 0.851); 17.9% vs. 21.4% (p = 0.682) and 5.1% vs. 4.3% (p = 0.833), respectively. In conclusion, a four-week course of AC may be considered as an alternative regimen in NVEFIE, notably in patients with shorter duration of symptoms and those without perivalvular abscess. These results support the performance of a randomized clinical trial to evaluate the efficacy of this short regimen.This work was supported in part by the “Fondo de Investigaciones Sanitarias” (FIS) grant 17/01251 from the “Instituto de Salud Carlos III”, Madrid, Spain awarded to JMM. JMM received a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–19. JMP was member of the Endocarditis Team of the Hospital Clinic of Barcelona, Spain when this project was approved by the GAMES Steering Committee.

Diagnostics and management of infective endocarditis post-transcatheter aortic valve implantation - A systematic review

Background: As transcatheter aortic valve implantation (TAVI) has expanded the treatment options to otherwise inoperable patients, it has become as prevalent as surgical aortic valve replacement. TAVI infective endocarditis (IE) has thereby become a feared complication. IE is heterogenous in its presentation, identifying characteristics and diagnostic criteria among these patients is crucial in diagnosing IE. Treatment entails a conventional approach with antibiotics or in combination with surgery. Treatment option for TAVI IE is highly debated in high-risk patients. The primary aim of this systematic review is to find knowledge on how TAVI IE patients are diagnosed and treated as stated in the literature. Method: Records were searched in MEDLINE and EMBACE. The search strategy is based on how TAVI IE is diagnosed, clinical presentation, treatment, and outcome. EndNote, Rayyan and EPPI-REVIEWER were used in the process of screening and selecting studies. All studies were first assessed by titles and abstracts, then selected articles in full text against the inclusion criteria. All disagreements between the (three) researchers were discussed until agreement. Results: Final selection process left us with 16 empirical retrospective/prospective studies and 51 case studies, between year 2005-2019. Conclusion: Diagnosing TAVI IE is based on the modified duke criteria’s (MDC), where pathological findings and clinical judgement are the cornerstone. This review indicates a rise of enterococci as the causative microorganism for TAVI IE, while the common first symptoms recognized are fever, heart failure and systolic murmur. Treatment choice for TAVI IE should be a case-by-case decision based on clinical judgment and managed individually. Studies included in this review indicate that surgical option as a treatment to TAVI IE should be reserved for complicated and life‐threatening cases. Unfortunately, there are not enough studies/data to determine whether surgery or antibiotics are appropriate and when

A narrative review of the interpretation of guidelines for the treatment of infective endocarditis

The recommendations of the current guidelines and the position papers of professional societies from the European Society of Cardiology/European Society of Cardiothoracic Surgeons (ESC), the American College of Cardiology/American Heart Association/Society of Thoracic Surgeon (ACC/AHA/STS) and American Association of Thoracic Surgeon (AATS) regarding management of patients with valvular heart endocarditis were updated over the past decade. However, some of the recommendations appear to contradict one another. Given the changing paradigms on how the disease manifests, our aim was to review the respective guidelines and highlight these differences whilst drawing attention to the subsequent studies from which they were derived. In particular, concerns regarding antibiotic prophylaxis and therapy, imaging modality for diagnosis and follow-up, cerebrovascular sequalae and timing of surgery are appraised in detail. We also identified the novel techniques used such as transcatheter therapies and advances in imaging modalities used for diagnosis and treatment of this condition. The lack of randomised control trials (RCTs) does raise several issues regarding applicability of findings in day-to-day practice. Therefore, the focus of upcoming studies should be on clearly defined multicenter RCTs to provide more robust evidence for the management and treatment of infective endocarditis as future guidelines will be based on the outcomes of these trials

The epidemiology of infective endocarditis in Portugal : Prevalence, incidence, risk factors, management and prognosis of infective endocarditis in a general population

Infective endocarditis (IE) is an infrequent clinical condition with a challenging diagnosis and management. An infection of the endocardium, prosthetic or intracardiac devices predominantly caused by bacteria occurs, with a multisystemic involvement and heterogeneous clinical presentation. A long hospitalization course is usually mandatory. Despite several advances in the fields of medical imaging, microbiology techniques, antibiotic and cardiac surgery, complications are common, with fatal outcome still being a frequent finding. Its incidence rate in developed countries from Europe and North America is estimated between 3 and 12 per 100000 people. A progressive shift in the epidemiology of affected patients has been observed. Older patients, with a higher burden of comorbidities and long-term survivors of repaired structural or congenital heart disease have been progressively replacing the former stereotype of younger patients with rheumatic valve disease described in medical conferences more than one century ago. Likewise, more aggressive infectious agents such as Staphylococcus or Enterococcus have been replacing the dominance of Streptococcus in the last decades. Early aggressive surgical management of such patients has become the new standard. Still, prognosis continues poor with an in-hospital mortality rate ranging between 15 and 25%. In industrialized countries, a generalized growing trend noted in the incidence rate of IE and a shift in its epidemiology have been a consequence of the evolution in Medicine itself. Ageing of the population, with an increasing exposure to more invasive medical interventions, that in the case of structural heart disease have led to an increase in the prevalence of intracardiac devices and prosthesis carriers, have been in the cornerstone of these findings. In Portugal, ageing of the population has been well noted, consequently leading to a higher prevalence of comorbidities and structural heart disease. Nevertheless, there is limited understanding on the epidemiology and outcome of patients hospitalized with IE. Its impact, mainly assessed by the publication of single centre retrospective cross-sectional cohorts, lacks a populational perspective. International populational based analyses although useful, reveal significant variability. Prudence is required on the application of their conclusions in the Portuguese clinical setting. The main objectives in this thesis were: i) to provide a population-based analysis on the epidemiological and prognosis of IE in Portugal; ii) to identify temporal trends and predictors of incidence and mortality due to IE in Portugal; iii) to identify indicators of cardiac surgery for IE in Portugal and outcome (mortality); iv) to characterize the use of IE prophylaxis among physicians caring for high-risk patients in Portugal. With the purpose of understanding the published evidence on the epidemiology of IE in Portuguese hospital centres, we undertook a thorough systematic review of all relevant scientific publications concerning cohort studies of hospitalized patients with IE in Portuguese hospitals in the last three decades. The search resulted in the analysis of eighteen retrospective cohort studies, three of them exclusively surgical. One thousand eight hundred seventy two patients were described. Older patients, predominantly men with a higher involvement of native left heart valves were identified. Staphylococcus and Streptococcus were the most frequent infectious agents involved. Nearly 30% of total cohort underwent surgical intervention. Short-term mortality rate averaged 21.9% in the overall cohort, ranging between 13.1 to 16% in the post-operative subgroup. Afterwards, we conducted a nationwide retrospective temporal trend study on the incidence of IE in Portugal, between 2010 and 2018. Additionally, we analysed clinical characteristics, involved infectious agents, heart valve surgical intervention and outcomes of patients hospitalized with IE in that period. We used an administrative medical database derived from the Central Administration of Health System of the Portuguese Ministry of Health. The database included information derived from medical discharge reports of hospitalization episodes, including demographic and clinical diagnoses (coded using International Classification of Disease versions 9 and 10). Seven thousand five hundred seventy four patients were hospitalized with IE in Portuguese public hospitals between 2010 and 2018. Anonymised clinical data was used. Statistical analysis included univariate analysis and multivariate logistic regression models to evaluate factors associated with surgical intervention and all cause in hospital mortality. Odds Ratio (OR) and 95% confidence intervals (CIs) were reported for categorical variables. The analysis was conducted at a 5% level of significance. Between 2010 and 2018, 7574 episodes of hospitalization with IE were analysed. The annual incidence of IE in Portugal that period was 8.3 per 100000 people, higher in men (9.9 versus 6.8 in women per 100000 people) and peaking in patients older than 79 years old (40.6 per 100000 people). 12.4% of patients underwent cardiac valve surgery during the index hospitalization and one fifth of the total cohort died. Men were predominant (56.9% versus 43.1%). Women were older (76 versus 69 years old) and were less likely to undergo cardiac surgery (OR 0.48 – 95%CI 0.40-0.57, p< 0.001), but with a higher odd of dying in the postoperative period (OR 1.84, 95%CI 1.19-2.84, p=0.006). The sub-analysis of patients submitted to cardiac surgery (n= 937 patients) revealed that patients younger than 60 years old, with previous valve or congenital heart disease, infection with Streptococcus spp or the presence of heart failure, systemic embolization or acute renal failure were associated with a higher rate of intervention. In addition, the initial admission of a patient with a diagnosis of IE in a tertiary hospital with cardiac surgery unit was also related with cardiac surgery during the hospitalization. Nearly 74% of patients underwent single valve surgical intervention, with aortic valve being the most frequently involved. In-hospital all-cause postoperative mortality rate was 15.6%. Also, factors linked with in-hospital mortality were older age, female gender, liver, kidney and coronary disease, cardiac valve prosthesis, Staphylococcus spp, acute renal failure and sepsis during hospitalization. Furthermore, we conducted a retrospective temporal trend analysis of all patients whose basic cause of death was IE, in Portugal, between 2002 and 2018. Data was gathered from national death certificates. Three thousand six hundred thirty four people died from IE throughout the 17-year study period with an annual specific mortality rate of 2.1 per 100 000 people. 89% were at least 60 years old, and most were women (55%). Mortality rate was higher in colder months. Finally, we performed a cross sectional study based on a self-completed online questionnaire distributed to physicians, members of the Portuguese Society of Cardiology, evaluating the current practice regarding IE prophylaxis. 253 valid questionnaires were replied. 83% follow the European scientific orientations. 61% find IE prophylaxis challenging. Discrepancy between scientific orientations and some high-risk cardiac conditions or procedures was noted among responders. These findings provide novel insight into the epidemiology and prognosis of IE in Portugal. Additionally, they raise concern regarding temporal incidence, surgical management, and mortality trends compared to other developed countries settings. Our results support the implementation of a national multicentric clinical registry for further evaluation

Aspects of infective endocarditis. Molecules, microbiology, management, and more.

AbstractEndocarditis, or heart valve infection, can be caused by a number of pathogens, many of which are Gram-positive bacteria. The diagnosis is based on imaging techniques such as echocardiography and on blood culture. The implementation of fast and accurate species identification methods, such as the matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS) in routine use for bacteria found in blood culture, has meant that bacteria previously thought to be rare have become increasingly recognised in the clinic. Some of these newly recognised bacteria are the aerococci, a genus of bacteria consisting of eight identified species, first identified in 1956. Other areas where MALDI-TOF MS and other new bacteriological methods have been helpful are the differentiation between the groups of NBHS (non-beta-haemolytic streptococci), also known as alpha streptococci, and in the identification of other Gram-positive cocci such as Abiotrophia, Gemella, and Granulicatella.This thesis consists of six different studies on endocarditis and endocarditis-causing Gram-positive bacteria. The first of these covers Aerococcus urinae. Using mass spectrometry, two distinct LPATG-anchored proteins named Asp 1 and Asp 2 were identified on the surface of the bacterium. The presence of these proteins was also confirmed using antibodies generated against recombinantly expressed Asp 1 and Asp 2. After sequencing 25 A. urinae genomes, six different variants of asp genes, named asp1-6, were found. All sequenced isolates contained one or two of these asp-genes located in the same region of the chromosome designated Locus Encoding Aerococcal Surface Protein (LASP).The possible synergy between benzylpenicillin and gentamicin against bacteria has long been an argument used in guidelines recommending combination therapy in infective endocarditis (IE). Two of the studies in this thesis look at this, one of which also describes the characteristics of IE caused by aerococci. Bactericidal synergy was shown against 14 of 24 streptococcal isolates and against 7 of 15 tested aerococcal isolates. The characterisation of aerococcal IE (based on data from the Swedish Endocarditis Registry) showed, amongst other things, that the mean age was significantly higher than in IE caused by NBHS or Staphylococcus aureus.By using a cohort of Swedish patients with NBHS-bacteraemia with or without IE, the HANDOC score was constructed: one point given for heart murmur or heart valve disease (H); one point given for an aetiology of Streptococcus bovis-group, Streptococcus sanguinis-group, or Streptococcus mutans-group, and one point subtracted for Streptococcus anginosus-group bacteraemia (A); one point added if the number of positive blood cultures was two or more (N); one point added for a duration of symptoms of seven days or more (D); one point if only one species was present in the blood culture (O); and one point added for a community-acquired infection (C). Using a cut-off of two points, the sensitivity was 100% for detecting IE and the specificity was 76%. The HANDOC score was then validated in a second cohort of Danish patients with NBHS in blood culture. The HANDOC score and the previously published DENOVA score (originally developed to distinguish IE from non-IE in enterococcal bacteraemia) were then applied in cases of bacteraemia with Aerococcus, Abiotrophia, Gemella, and Granulicatella. The sensitivities of HANDOC and DENOVA were 97% and 93%, respectively, with specificities of 85% and 90%. Thus, HANDOC can possibly be used to decide whether or not to perform IE diagnostics in cases of NBHS bacteremia, and both HANDOC and DENOVA can possibly be used for the decision to perform IE diagnostics in cases of bacteremia with Aerococcus, Abiotrophia, Gemella, or Granulicatella

Diagnosis, treatment and prevention of infective endocarditis: Turkish consensus report-2019 [İnfektif endokarditin tanısı, tedavisi ve önlenmesi: Ulusal uzlaşı raporu-2019]

Infective endocarditis (IE) is a rare but still important as an infectious disease due to high rate of morbidity and substantial mortality. Although IE is not a notifiable disease in Turkey, and an incidence study has not been performed, the incidence may be higher than that in the developed countries due to frequent predisposing cardiac conditions and higher rates of nosocomial bacteremia, which may lead to IE in risk groups. IE generally affects the elderly in developed countries but it is frequently encountered among young individuals in Turkey. In order to reduce mortality and morbidity, it is critical to diagnose IE, to determine the causative agent, and to start treatment rapidly. Most patients cannot be diagnosed at the first visit, about half can be diagnosed after 3 months, and the disease often goes unnoticed. In patients diagnosed with IE, the rate of the identification of a causative organism is significantly lower in Turkey than that in developed countries. Some important microbiological diagnostic tests are not performed in most centers and several antimicrobials that are recommended as the first option for the treatment particularly antistaphylococcal penicillins, are unavailable in Turkey. These problems necessitate reviewing the epidemiological, laboratory, and clinical characteristics of IE in our country, as well as the current information about its diagnosis, treatment, and prevention together with local data. The diagnosis and treatment processes of IE should be standardized at every stage so that the management can be conducted in a setting in which physicians of various specialties are involved and is consistent with the current recommendations. The Study Group for Infective Endocarditis and Other Cardiovascular Infections of the Turkish Society of Clinical Microbiology and Infectious Diseases called for the collaboration of the relevant specialist organizations to establish a consensus report on the diagnosis, treatment, and prevention of IE in the context of current information and local data in Turkey. © 2020 Turkish Society of Cardiology