Endocarditis overview

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Overview

Historical Perspective

Classification

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Differentiating Infective Endocarditis from other Diseases

Epidemiology and Demographics

Risk Factors

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Natural History, Complications & Prognosis

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History and Symptoms

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Laboratory Findings

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2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-in-Chief: Maliha Shakil, M.D. [2] Cafer Zorkun, M.D., Ph.D. [3] Kosar Doraghi, M.D.[4]

Overview

Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. While acute bacterial endocarditis is caused by an infection with a virulent organism such as Staphylococcus aureus, group A or other beta-hemolytic streptococci, subacute bacterial endocarditis is an indolent infection with less virulent organisms such as streptococcus viridans. Patients with unexplained fever for more than 48 hours and who are at high risk for infective endocarditis and patients among whom valve regurgitation is newly diagnosed should undergo a diagnostic workup to rule out endocarditis. The diagnosis of endocarditis depends on a thorough history and physical exam as well as on the results of the blood cultures and the findings on transthoracic echocardiogram or transesophageal echocardiogram. The modified Duke criteria is used to establish the diagnosis of endocarditis. Endocarditis is initially treated with empiric antibiotic therapy until the causative agent is identified.

Historical Perspective

Endocarditis was first described in 1554. The inflammatory process associated with endocarditis was discovered in 1799. Vegetations were first discovered to be associated with endocarditis in 1806.

Classification

Endocarditis may be classified based on the underlying pathophysiology of the process (infective vs. non-infective), the onset of the disease (acute vs. subacute or short incubation vs. long incubation), results of the cultures (culture-positive vs. culture-negative), the nature of the valve (native vs. prosthetic) and the valve affected (aortic, mitral, or tricuspid valve).

Pathophysiology

The pathogenesis of infective endocarditis includes valvular damage, altered and turbulent flow, bacteremia, and lack of blood supply to the valves. Damaged endothelium becomes a site for attachment of infectious agents in infectious endocarditis. Nonbacterial thrombotic endocarditis is related to hypercoagulable states such as pregnancy or systemic bacterial infection. The characteristic lesion of endocarditis is vegetation. Vegetations are composed of fibrin, inflammatory cells, platelets, and microorganisms.

Causes

The majority of cases of infective endocarditis are due to bacteria. Common causes of infective endocarditis include Streptococcus viridans, Staphylococci, and Enterococcus.

Differentiating Endocarditis From Other Diseases

Endocarditis must be differentiated from other causes of a fever of unknown origin (FUO) such as pulmonary embolism, deep vein thrombosis, lymphoma, drug fever, cotton fever, and disseminated granulomatosis.

Risk Factors

Common risk factors for endocarditis include prosthetic heart valves, valvular heart disease, congenital heart disease, intravenous drug use, age-related degenerative valvular lesions, immunosuppression, and colon cancer.

Epidemiology and Demographics

The incidence of native valve infective endocarditis is approximately 1.7-6.2 cases per 100,000 individuals per year in the United States and Europe. The prevalence of infective endocarditis among IV drug users ranges from 10 to 15%. The incidence of endocarditis increases with age; the median age of patients is 47 to 69 years. There is an increased incidence of infective endocarditis in persons 65 years of age and older. Males are more commonly affected with endocarditis than females. The male to female ratio is approximately 1.7:1.

Natural History, Complications, and Prognosis

If left untreated, patients with endocarditis may progress to develop congestive heart failure. Complications of endocarditis can occur as a result of the locally destructive effects of the infection. These complications include perforation of valve leaflets causing congestive heart failure, abscesses, and disruption of the heart's conduction system. Endocarditis may also cause embolization to the brain (causing a stroke), to the coronary artery (causing a heart attack), to the lung (causing pulmonary embolism), to the spleen (causing a splenic infarct), and to the kidney (causing a renal infarct). Prognosis of endocarditis is generally poor and the overall mortality rate for both native and prosthetic valve endocarditis ranges from 20-25%. The mortality rate for right-sided endocarditis in injection drug users is approximately 10%. The 5 year survival rate for native valve endocarditis is 70-80% and 50-80% for prosthetic valve endocarditis.

Diagnosis

Diagnostic Criteria

The Duke criteria can be used to establish the diagnosis of endocarditis. The Duke clinical criteria for infective endocarditis require either: Two major criteria, or one major and three minor criteria, or five minor criteria.

History and Symptoms

Common symptoms of endocarditis include fever, chills, new onset of murmur, anorexia, malaise, weight loss, and back pain.

Physical Examination

Common signs on physical examination of endocarditis include fever, rigors, osler's nodes, janeway lesions and evidence of embolization. Aortic insufficiency with a wide pulse pressure, mitral regurgitation or tricuspid regurgitation may be present depending upon the valve that is infected.

Laboratory Tests

Two blood cultures should be ordered when infective endocarditis is suspected. Laboratory findings consistent with the diagnosis of endocarditis include elevated white blood cell count, erythrocyte sedimentation rate, rheumatoid factor, and elevated BUN and creatinine if glomerulonephritis is present.

Chest x-ray

On chest x-ray, right sided endocarditis is characterized by pleural effusions, multiple round densities, and cavitary multilobar infiltrates.

Electrocardiography

On EKG, endocarditis may be characterized by conduction abnormalities, low QRS voltage, ST elevation, heart block, ventricular tachycardia, and supraventricular tachycardia. The EKG may show ST elevation in the presence of embolization of a vegetation or clot down the coronary artery.

Cardiac MRI

Findings on cardiac MRI suggestive of infective endocarditis include valvular vegetations, valvular and perivalvular damage, and vascular endothelial involvement.

CT Scan

CT scans may be helpful in the diagnosis of endocarditis. CT scan findings suggestive of endocarditis include vegetations, paravalvular abscesses, and pseudoaneurysms.

Echocardiography

Echocardiography may be diagnostic of endocarditis. Echocardiography allows detection of microbial vegetations and the degree of valvular dysfunction. Findings on transthoracic and transesophageal echocardiogram diagnostic of endocarditis include vegetations, valvular regurgitation, pseudoaneurysms, paravalvular abscess, and fistulas.

Treatment

Medical Therapy

Antimicrobial therapy is the mainstay of therapy for endocarditis. Empiric antimicrobial therapy depends on the nature of the valve (native vs. prosthetic) and the onset of endocarditis following valve implantation (less than 1 year vs. more than 1 year). In patients with endocarditis, antithrombotic therapy may be administered when needed. The prothrombin time must be carefully monitored as anticoagulants may cause or worsen hemorrhage in patients with endocarditis. Heparin administration should be avoided if possible.

2023 ESC Guidelines for the management of endocarditis ESC Clinical Practice Guidelines (DO NOT EDIT)

New recommendations (DO NOT EDIT)[1]

Recommendations for antibiotic prophylaxis in patients with cardiovascular diseases undergoing oro-dental procedures at increased risk of infective endocarditis (DO NOT EDIT)

Class I
"1. (General prevention measures are recommended in individuals at high and intermediate risk of IE) (Level of Evidence: C)"[2]
2. (Antibiotic prophylaxis is recommended in patients with ventricular assist devices) (Level of Evidence: C)"[3]
Class IIb
"1. (Antibiotic prophylaxis may be considered in recipients of heart transplant) (Level of Evidence: C)"

Recommendations for infective endocarditis prevention in high-risk patients (DO NOT EDIT)

Class IIb
"1. (Systemic antibiotic prophylaxis may be considered for

high-risk patients undergoing an invasive diagnostic or therapeutic procedure of the respiratory, gastrointestinal, genitourinary tract, skin, or musculoskeletal systems) (Level of Evidence: C)"

Recommendations for infective endocarditis prevention in cardiac procedures (DO NOT EDIT)

Class I
"1. (Optimal pre-procedural aseptic measures of the site of implantation is recommended to prevent CIED infections.) (Level of Evidence: B)"
2. (Surgical standard aseptic measures are recommended during the insertion and manipulation of catheters in the catheterization laboratory environment) (Level of Evidence: C)"
Class II
"1. (Antibiotic prophylaxis covering for common skin flora including Enterococcus spp. and S. aureus should be considered before TAVI and other transcatheter valvular procedures) (Level of Evidence: C)"

Recommendations for the role of echocardiography in infective endocarditis (DO NOT EDIT)

Class I
"1. (TOE is recommended when the patient is stable before switching from intravenous to oral antibiotic therapy) (Level of Evidence: B)"

Recommendations for the role of computed tomography, nuclear imaging, and magnetic resonance in infective endocarditis (DO NOT EDIT)

Class I
"1. (Cardiac CTA is recommended in patients with possible NVE to detect valvular lesions and confirm the diagnosis of IE) (Level of Evidence: B)"
2. ([18F]FDG-PET/CT(A) and cardiac CTA are recommended in possible PVE to detect valvular lesions and confirm the diagnosis of IE.) (Level of Evidence: B)"
Class IIb
"1. ([18F]FDG-PET/CT(A) may be considered in possible CIED-related IE to confirm the diagnosis of IE.) (Level of Evidence: B)"
Class I
"1. (Cardiac CTA is recommended in NVE and PVE to diagnose paravalvular or periprosthetic complications if echocardiography is inconclusive.) (Level of Evidence: B)"
2. (Brain and whole-body imaging (CT, [18F]FDG-PET/CT, and/or MRI) are recommended in symptomatic patients with NVE and PVE to detect peripheral lesions or add minor diagnostic criteria) (Level of Evidence: B)"
Class II
"1. (WBC SPECT/CT should be considered in patients with high clinical suspicion of PVE when echocardiography is negative or inconclusive and when PET/CT is unavailable) (Level of Evidence: C)"
Class IIb
"1. (Brain and whole-body imaging (CT, [18F]FDG-PET/ CT, and MRI) in NVE and PVE may be considered for screening of peripheral lesions in asymptomatic patients) (Level of Evidence: B)"

Recommendations for outpatient antibiotic treatment of infective endocarditis (DO NOT EDIT)

Class II
"1. (Outpatient parenteral antibiotic treatment should be considered in patients with left-sided IE caused by Streptococcus spp., E. faecalis, S. aureus, or CoNS who were receiving appropriate i.v. antibiotic treatment for at least 10 days (or at least 7 days after cardiac surgery), are clinically stable, and who do not show signs of abscess formation or valve abnormalities requiring surgery on TOE) (Level of Evidence: A)"
Class III
"1. (Outpatient parenteral antibiotic treatment is not recommended in patients with IE caused by highly difficult-to-treat microorganisms, liver cirrhosis (Child–Pugh B or C), severe cerebral nervous system emboli, untreated large extracardiac abscesses, heart valve complications, or other severe conditions requiring surgery, severe post-surgical complications, and in PWID-related IE.) (Level of Evidence: C)"

Recommendations for the treatment of neurological complications of infective endocarditis (DO NOT EDIT)

Class IIb
"1. (In embolic stroke, mechanical thrombectomy may be considered if the expertise is available in a timely manner) (Level of Evidence: C)"
Class III
"1. (Thrombolytic therapy is not recommended in embolic stroke due to IE) (Level of Evidence: C)"

Recommendations for pacemaker implantation in patients with complete atrioventricular block and infective endocarditis (DO NOT EDIT)

Class II
"1. (Immediate epicardial pacemaker implantation should be considered in patients undergoing surgery for valvular IE and complete AVB if one of the following predictors of persistent AVB is present: pre-operative conduction abnormality, S. aureus infection, aortic root abscess, tricuspid valve involvement, or previous valvular surgery) (Level of Evidence: C)"

Recommendations for patients with musculoskeletal manifestations of infective endocarditis (DO NOT EDIT)

Class I
"1. (MRI or PET/CT is recommended in patients with suspected spondylodiscitis and vertebral osteomyelitis complicating IE) (Level of Evidence: C)"
2. (TTE/TOE is recommended to rule out IE in patients with spondylodiscitis and/or septic arthritis with positive blood cultures for typical IE microorganisms) (Level of Evidence: C)"
Class II
"1. (More than 6-week antibiotic therapy should be considered in patients with osteoarticular IE-related lesions caused by difficult-to-treat microorganisms, such as S. aureus or Candida spp., and/or complicated with severe vertebral destruction or abscesses) (Level of Evidence: C)"

Recommendations for pre-operative coronary anatomy assessment in patients requiring surgery for infective endocarditis (DO NOT EDIT)

Class I
"1. (In haemodynamically stable patients with aortic valve vegetations who require cardiac surgery and are high risk of CAD, a high-resolution multislice coronary CTA is recommended) (Level of Evidence: B)"
2. (Invasive coronary angiography is recommended in patients requiring heart surgery who are high risk of CAD, in the absence of aortic valve vegetations.) (Level of Evidence: C)"
Class II
"1. (In emergency situations, valvular surgery without pre-operative coronary anatomy assessment regardless of CAD risk should be considered.) (Level of Evidence: C)"
Class IIb
"1. (Invasive coronary angiography may be considered despite the presence of aortic valve vegetations in selected patients with known CAD or at high risk of significant obstructive CAD.) (Level of Evidence: C)"

Indications and timing of cardiac surgery after neurological complications in active infective endocarditis (DO NOT EDIT)

Class II
"1. (In patients with intracranial haemorrhage and unstable clinical status due to HF, uncontrolled infection, or persistent high embolic risk, urgent or emergency surgery should be considered weighing the likelihood of a meaningful neurological outcome.) (Level of Evidence: C)"

Recommendations for post-discharge follow-up (DO NOT EDIT)

Class I
"1. (Patient education on the risk of recurrence and preventive measures, with emphasis on dental health, and based on the individual risk profile, is recommended during follow-up.) (Level of Evidence: C)"
2. (Addiction treatment for patients following PWID-related IE is recommended) (Level of Evidence: C)"
Class II
"1. (Cardiac rehabilitation including physical exercise training should be considered in clinically stable patients based on an individual assessment.) (Level of Evidence: C)"
Class IIb
"1. (Psychosocial support may be considered to be integrated in follow-up care, including screening for anxiety and depression, and referral to relevant psychological treatment.) (Level of Evidence: C)"

Recommendations for prosthetic valve endocarditis (DO NOT EDIT)

Class I
"1. (Surgery is recommended for early PVE (within 6 months of valve surgery) with new valve replacement and complete debridement) (Level of Evidence: C)"

Recommendations for cardiovascular implanted electronic device-related infective endocarditis (DO NOT EDIT)

Class I
"1. (Complete system extraction without delay is recommended in patients with definite CIED-related IE under initial empirical antibiotic therapy.) (Level of Evidence: B)"
Class II
"1. (Extension of antibiotic treatment of CIED-related endocarditis to (4–)6 weeks following device extraction should be considered in the presence of septic emboli or prosthetic valves.) (Level of Evidence: C)"
Class IIb
"1. (Use of an antibiotic envelope may be considered in select high-risk patients undergoing CIED reimplantation to reduce risk of infection) (Level of Evidence: B)"
"1. (In non-S. aureus CIED-related endocarditis without valve involvement or lead vegetations, and if follow-up blood cultures are negative without septic emboli, 2 weeks of antibiotic treatment may be considered following device extraction.) (Level of Evidence: C)"
Class III
"1. (Removal of CIED after a single positive blood culture, with no other clinical evidence of infection, is not recommended) (Level of Evidence: C)"

Recommendations for the surgical treatment of right-sided infective endocarditis (DO NOT EDIT)

Class II
"1. (Tricuspid valve repair should be considered instead of valve replacement, when possible.) (Level of Evidence: B)"
2. (Surgery should be considered in patients with right-sided IE who are receiving appropriate antibiotic therapy and present persistent bacteraemia/sepsis after at least 1 week of appropriate antibiotic therapy.) (Level of Evidence: C)"
3. (Prophylactic placement of an epicardial pacing lead should be considered at the time of tricuspid valve surgical procedures) (Level of Evidence: C)"
Class II
"1. (Debulking of right intra-atrial septic masses by aspiration may be considered in select patients who are high risk of surgery.) (Level of Evidence: C)"

2023 Recommendations for antibiotic prophylaxis in patients with cardiovascular diseases undergoing oro-dental procedures at increased risk for infective endocarditis (DO NOT EDIT)

Class I
"1. (General prevention measures are recommended in individuals at high and intermediate risk for IE.) (Level of Evidence: C)"
2. (Antibiotic prophylaxis is recommended in patients with previous IE.) (Level of Evidence: B)"
3. (Antibiotic prophylaxis is recommended in patients with surgically implanted prosthetic valves and with any material used for surgical cardiac valve repair.) (Level of Evidence: C)"
2. (Antibiotic prophylaxis is recommended in patients with transcatheter implanted aortic and pulmonary valvular prostheses.) (Level of Evidence: C)"
2. (Antibiotic prophylaxis is recommended in patients with untreated cyanotic CHD, and patients treated with surgery or transcatheter procedures with post-operative palliative shunts, conduits, or other prostheses. After surgical repair, in the absence of residual defects or valve prostheses, antibiotic prophylaxis is recommended only for the first 6 months after the procedure.) (Level of Evidence: C)"
2. (Antibiotic prophylaxis is recommended in patients with ventricular assist devices.) (Level of Evidence: C)"
Class Ila
"1. (Antibiotic prophylaxis should be considered in patients with transcatheter mitral and tricuspid valve repair.) (Level of Evidence: C)"
Class Ilb
"1. (Antibiotic prophylaxis may be considered in recipients of heart transplant.) (Level of Evidence: C)"
Class III
"1. (Antibiotic prophylaxis is not recommended in other patients at low risk for IE.) (Level of Evidence: C)"

2023 ESC Guidelines Recommendations for Prophylactic antibiotic regime for high-risk dental procedures

2023 ESC Guidelines Recommendations for Diagnostic Procedures of rare causes of blood culture-negative infective endocarditis

Recommendations for infective endocarditis prevention in high-risk patients (DO NOT EDIT)

Class I "1. (Antibiotic prophylaxis is recommended in dental extractions, oral surgery procedures, and procedures requiring manipulation of the gingival or periapical region of the teeth.) (Level of Evidence: B)"
Class IIb
"1. (Systemic antibiotic prophylaxis may be considered for high-riskc patients undergoing an invasive diagnostic or therapeutic procedure of the respiratory, gastrointestinal, genitourinary tract, skin, or musculoskeletal systems.) (Level of Evidence: C)"

Recommendations for infective endocarditis prevention in cardiac procedures (DO NOT EDIT)

Class I
"1. (Pre-operative screening for nasal carriage of S. aureus is recommended before elective cardiac surgery or transcatheter valve implantation to treat carriers.) (Level of Evidence: A)"
2. (Peri-operative antibiotic prophylaxis is recommended before placement of a CIED.) (Level of Evidence: A)"
3. (Optimal pre-procedural aseptic measures of the site of implantation is recommended to prevent CIED infections.) (Level of Evidence: B)"
3. (Periprocedural antibiotic prophylaxis is recommended in patients undergoing surgical or transcatheter implantation of a prosthetic valve, intravascular prosthetic, or other foreign material.) (Level of Evidence: B)"
3. (Surgical standard aseptic measures are recommended during the insertion and manipulation of catheters in the catheterization laboratory environment.) (Level of Evidence: C)"
Class IIa
2. (Elimination of potential sources of sepsis (including of dental origin) should be considered ≥2 weeks before implantation of a prosthetic valve or other intracardiac or intravascular foreign material, except in urgent procedures.) (Level of Evidence: C)"
2. (Antibiotic prophylaxis covering for common skin flora including Enterococcus spp. and S. aureus should be considered before TAVI and other transcatheter valvular procedures.) (Level of Evidence: C)"
Class III
"1. (Systematic skin or nasal decolonization without screening for S. aureus is not recommended.) (Level of Evidence: C)"

Recommendations for the Endocarditis Team Recommendations (DO NOT EDIT)

Class I
"1. (Diagnosis and management of patients with complicated IE are recommended to be performed at an early stage in a Heart Valve Centre, with immediate surgical facilities and an Endocarditis Team’ to improve the outcomes.) (Level of Evidence: B)"
2. (For patients with uncomplicated IE managed in a Referring Centre, early and regular communication between the local and the Heart Valve Centre endocarditis teams is recommended to improve the outcomes of the patients.) (Level of Evidence: B)"

Recommendations for the role of echocardiography in infective endocarditis (DO NOT EDIT)

Class I
"1. (TTE is recommended as the first-line imaging modality in suspected IE.) (Level of Evidence: B)"
2. (TOE is recommended in all patients with clinical suspicion of IE and a negative or non-diagnostic TTE.) (Level of Evidence: B)"
3. (TOE is recommended in patients with clinical suspicion of IE, when a prosthetic heart valve or an intracardiac device is present.) (Level of Evidence: B)"
3. (Repeating TTE and/or TOE within 5–7 days is recommended in cases of initially negative or inconclusive examination when clinical suspicion of IE remains high.) (Level of Evidence: C)"
3. (TOE is recommended in patients with suspected IE, even in cases with positive TTE, except in isolated right-sided native valve IE with good quality TTE examination and unequivocal echocardiographic findings.) (Level of Evidence: C)"
Class IIa
2. (Performing an echocardiography should be considered in S. aureus, E. faecalis, and some Streptococcus spp. bacteraemia.) (Level of Evidence: C)"
Class I
"1. (Repeating TTE and/or TOE is recommended as soon as a new complication of IE is suspected (new murmur, embolism, persisting fever and bacteraemia, HF, abscess, AVB) (Level of Evidence: B)"
2. (TOE is recommended when patient is stable before switching from intravenous to oral antibiotic therapy.) (Level of Evidence: B)"
Class IIa
2. (During follow-up of uncomplicated IE, repeat TTE and/ or TOE should be considered to detect new silent complications. The timing of repeat TTE and/or TOE depends on the initial findings, type of microorganism, and initial response to therapy.) (Level of Evidence: B)"
Class I
"1. (Intra-operative echocardiography is recommended in all cases of IE requiring surgery) (Level of Evidence: C)"
2. (TTE and/or TOE are recommended at completion of antibiotic therapy for evaluation of cardiac and valve morphology and function in patients with IE who did not undergo heart valve surgery.) (Level of Evidence: C)"

Recommendations for the role of computed tomography, nuclear imaging, and magnetic resonance in infective endocarditis (DO NOT EDIT)

Class I
"1. (Cardiac CTA is recommended in patients with possible NVE to detect valvular lesions and confirm the diagnosis of IE) (Level of Evidence: B)"
2. ( 18F FDG-PET/CT(A) and cardiac CTA are recommended in possible PVE to detect valvular lesions and confirm the diagnosis of IE) (Level of Evidence: B)"
3. (Cardiac CTA is recommended in NVE and PVE to diagnose paravalvular or periprosthetic complications if echocardiography is inconclusive.) (Level of Evidence: B)"
3. (Brain and whole-body imaging (CT, 18F FDG-PET/ CT, and/or MRI) are recommended in symptomaticc patients with NVE and PVE to detect peripheral lesions or add minor diagnostic criteria) (Level of Evidence: B)"
Class IIa
"1. (WBC SPECT/CT should be considered in patients with high clinical suspicion of PVE when echocardiography is negative or inconclusive and when PET/CT is unavailable.) (Level of Evidence: C)"
Class IIb
"1. (18F FDG-PET/CT(A) may be considered in possible CIED-related IE to confirm the diagnosis of IE) (Level of Evidence: B)"
2. (Brain and whole-body imaging (CT, [18F]FDG-PET/ CT, and MRI) in NVE and PVE may be considered for screening of peripheral lesions in asymptomatic patients) (Level of Evidence: B)"

Surgery

Surgical removal of the valve is necessary for patients who fail to clear micro-organisms from their blood in response to antibiotic therapy, or in patients who develop cardiac failure resulting from destruction of a valve by infection. A removed valve is usually replaced with an artificial valve which may either be mechanical (metallic) or obtained from an animal such as a pig; the latter are termed bioprosthetic valves. Surgical treatment of endocarditis involves excision of all infected valve tissue, drainage and debridement of abscess cavities, repair or replacement of damaged valves, and repair of any associated pathology such as fistulas or septal defects.

Prevention

Prevention of infective endocarditis can be achieved through the administration of antibiotic prophylaxis to high risk subjects who are undergoing high risk procedures. The choice of antibiotic prophylaxis depends on whether the subject can tolerate oral intake or not, as well as on whether patient has allergy to penicillin or not.

References

  1. Delgado V, Ajmone Marsan N, de Waha S, Bonaros N, Brida M, Burri H; et al. (2023). "2023 ESC Guidelines for the management of endocarditis". Eur Heart J. 44 (39): 3948–4042. doi:10.1093/eurheartj/ehad193. PMID 37622656 Check |pmid= value (help).
  2. Habib G, Erba PA, Iung B, Donal E, Cosyns B, Laroche C; et al. (2019). "Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EURO-ENDO (European infective endocarditis) registry: a prospective cohort study". Eur Heart J. 40 (39): 3222–3232. doi:10.1093/eurheartj/ehz620. PMID 31504413.
  3. Maeda K, Hirai Y, Nashi M, Yamamoto S, Taniike N, Takenobu T (2022). "Clinical features and antimicrobial susceptibility of oral bacteria isolated from the blood cultures of patients with infective endocarditis". J Dent Sci. 17 (2): 870–875. doi:10.1016/j.jds.2021.09.023. PMC 9201522 Check |pmc= value (help). PMID 35756779 Check |pmid= value (help).

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