Individualized Diagnosis of Endocarditis and Its Therapy With a Focus on Infected Prosthetic materiAL

Study Overview
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Brief Summary
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Infective endocarditis (IE) is a frequent and serious complication of implanted intracardiac prosthetic material, with a high morbidity and mortality. Therefore, this study aims to improve outcome of IE, with a focus on patients with intracardiac prosthetic material. In this study the investigators deal with research questions about both the diagnosis (microbiological, imaging, and expert opinion) and treatment of IE (with antimicrobial agents and surgical), in order to improve these clinical components and ultimately aim to improve outcome.

Detailed Description
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Rationale Infective endocarditis (IE) is a frequent and serious complication of implanted intracardiac prosthetic material, with a high morbidity and mortality. The number of procedures where prosthetic material is implanted in the heart increases, as do the age and comorbidity of treated subjects. In current clinical practice diagnosis of infected intracardiac prosthetic material is often difficult because of the lack of sensitivity of the available diagnostic armamentarium for IE. As a general rule, first line treatment of intracardiac prosthetic material related endocarditis consists of surgical prosthesis removal, combined with appropriate antimicrobial therapy. The exception encompasses uncomplicated prosthetic valve endocarditis (PVE). PVE actually has a fair chance of successful medical treatment alone (>50%), depending on the causative micro-organism. Although there is evidence and consensus with regard to the first line treatment, surgical removal is not always possible because of its associated high risk, technical limitations, or unwillingness of patients to undergo an invasive surgical procedure. Second and third line treatments do not include surgery, and consist of antimicrobial therapy with biofilm-penetrating agents during a predetermined timespan (second line) or as life-long suppressive antimicrobial therapy (third line). These treatments are the alternative in situations wherein first line treatment is not feasible or is unwanted. Although not extensively investigated, these treatments are considered suboptimal. Therefore further research is necessary. More research is needed to diagnose IE more accurate and prompt, as current diagnostic criteria (the modified Duke criteria) for IE are insufficient and as it is unclear how to best allocate non-invasive imaging techniques, especially for intracardiac prosthetic material. More research is also needed to verify the indications for and optimize the use of second and third line treatments in patients with intracardiac prosthetic material. Objectives Primary To define the diagnostic value of the combination of 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose positron emission tomography (18F-FDG PET) and electrocardiogram-gated multidetector computed tomography angiography (ECG-gated MD-CTA) in patients suspected of IE, in particular those with intracardiac prosthetic material, when added to the standard diagnostic work-up for IE. Secondary To define the predictive value of MD-CTA and 18F-FDG PET with regard to relapse rate and mortality of IE; To identify sources of false positive and false negative results in MD-CTA and 18F-FDG PET (e.g. the effect of the use of antimicrobial therapy on imaging findings); To identify the best MD-CTA and 18F-FDG PET scanning protocol; To define the role of 18F-FDG PET for finding other infectious lesions in the body; To assess and compare current clinical practices in patients with intracardiac prosthetic material related infection when the foreign material cannot be removed; to determine the outcomes of second and third line treatment as compared with first line treatment, and to determine predictors of outcome; To investigate the potential of therapeutic drug monitoring (TDM) to improve the antimicrobial therapy in patients suspected of IE, in particular those with intracardiac prosthetic material: for which peak and through blood concentrations should be aimed at in IE for flucloxacillin, rifampicin, cefazolin, cefuroxime, ceftriaxone, amoxicillin, penicillin; fluconazole, flucytosine, amphotericin-B? for which peak blood concentrations should be aimed at for gentamicin in IE? for which peak and through blood concentrations should be aimed at for vancomycin in intracardiac prosthetic material related IE? for which through blood concentrations should be aimed at in IE for voriconazole? To investigate antimicrobial concentrations in resected cardiac tissue (e.g. heart valve or vegetation which has been removed based on medical indication) in patients with IE who have been treated medically with antimicrobials and who subsequently are operated upon. Study design Prospective multicentre observation study, with the University Medical Center Groningen (UMCG) in Groningen as the leading centre. Study population Patients (≥18 years) in which IE is suspected according to the britisch society for antimicrobial chemotherapy (BSAC) criteria 2012. Main study parameters/endpoints Number of clinically identified (prosthetic material related) endocarditis episodes, according to (multiple) constellation(s) of diagnostic criteria versus number of true (prosthetic material related) endocarditis episodes, according to our gold standard expert opinion after 12 months (+/- 2 weeks) follow-up (based on clinical reasoning, the modified Duke criteria, and findings during surgery and from pathology).

Official Title
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Individualized Diagnosis of Endocarditis and Its Therapy With a Focus on Infected Prosthetic materiAL

Conditions
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Endocarditis, Prosthetic Material Related Infection

Intervention / Treatment
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* Other: diagnostic workup


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients presenting to participating hospitals age ≥18 years BSAC-criteria 2012: suspicion of infective endocarditis, retained in the differential diagnosis after clinical reasoning, without alternative diagnosis Exclusion Criteria: not fulfilling inclusion criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Suspicion NVE<br>Patients with suspicion of native valve endocarditis, infective endocarditis and no intracardiac prosthetic material in situ | Other: diagnostic workup<br>* Our primary objective is to test whether the proportion of patients diagnosed correctly with the use of 18F-FDG-PET/CT, MD-CTA, and 18F-FDG-PET/MD-CTA added to the gold standard in current clinical practice, the modified Duke criteria by Li et al. 2000, is significantly higher as compared with the modified Duke criteria on itself. The gold standard is clinical judgement after clinical follow-up by a multidisciplinary team with medical specialists.<br>|
| Suspicion (PVE)<br>Patients with a suspicion of prosthetic valve endocarditis (PVE), infective endocarditis and one or more prosthetic valves in situ | Other: diagnostic workup<br>* Our primary objective is to test whether the proportion of patients diagnosed correctly with the use of 18F-FDG-PET/CT, MD-CTA, and 18F-FDG-PET/MD-CTA added to the gold standard in current clinical practice, the modified Duke criteria by Li et al. 2000, is significantly higher as compared with the modified Duke criteria on itself. The gold standard is clinical judgement after clinical follow-up by a multidisciplinary team with medical specialists.<br>|
| Suspicion pacemaker/ICD related endocarditis<br>Patients with a suspicion of infective endocarditis and a pacemaker or implantable cardiac defibrillator (ICD) in situ | Other: diagnostic workup<br>* Our primary objective is to test whether the proportion of patients diagnosed correctly with the use of 18F-FDG-PET/CT, MD-CTA, and 18F-FDG-PET/MD-CTA added to the gold standard in current clinical practice, the modified Duke criteria by Li et al. 2000, is significantly higher as compared with the modified Duke criteria on itself. The gold standard is clinical judgement after clinical follow-up by a multidisciplinary team with medical specialists.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IE clinical diagnosis | Number of clinically identified (prosthetic material related) endocarditis episodes, according to (multiple) constellation(s) of diagnostic criteria (the current gold standard of the modified Duke criteria, and newly set-up and to be investigated constellations of diagnostic elements) | 2 months | 
| IE final diagnosis | Number of true prosthetic material related endocarditis episodes, according to expert opinion after follow-up (important components being findings during surgery and from pathology) | 1 year | 
| Relapse/recurrence | Number of relapses / recurrences | 1 year | 
| 1 year mortality | Mortality after 1-year follow-up | 1 year | 
| 30 day mortality | Mortality after 30-days follow-up | 30 days | 
| Duration of antimicrobial therapy | Duration of antimicrobial therapy (including appropriateness of drug, dosing and dosing regimen) | 30 days | 
| Cardiac surgery | Cardiac surgery performed | 1 year | 
| Complications | Number of complications: congestive heart failure (CHF) or other hemodynamic consequences, septic emboli, metastatic infection | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Number of adverse and serious adverse events | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Imaging, Computed Tomography, Magnetic Resonance Imaging, Positron Emission Tomography, Leukocyte Scintigraphy, Microbiological diagnostics, Sonication, Drug Monitoring, Cardiac Surgery