Epidemiology
- Incidence: 10-15k new cases of infective endocarditis are diagnosed each year in the US
- Incidence of Prosthetic Valve Infective Endocarditis: account for 10-20% of infective endocarditis cases
- Overall Incidence: 0.1% to 2.3% per patient-year
Risk Factors for Infective Endocarditis
- Age >60 y/o
- Valvular Heart Disease is Increasingly Prevalent in the Older Patients
- Older Patients are Undergoing More Invasive Procedures
- Chronic Hemodialysis (see Hemodialysis, [[Hemodialysis]])
- History of Infective Endocarditis
- Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
- Intravascular Device
- Automatic Implantable Cardioverter-Defibrillator (AICD) (see Automatic Implantable Cardioverter-Defibrillator, [[Automatic Implantable Cardioverter-Defibrillator]])
- Central Venous Catheter (CVC) (see Central Venous Catheter, [[Central Venous Catheter]])
- Invasive Intravascular Procedure
- Cardiac Pacemaker (see Cardiac Pacemaker, [[Cardiac Pacemaker]])
- Peritoneovenous Shunt (LeVeen Shunt) (see Peritoneovenous Shunt, [[Peritoneovenous Shunt]]): used for ascites
- Ventriculoatrial Shunt: used for hydrocephalus
- Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, [[Intravenous Drug Abuse]])
- Overall Incidence: 1-5% per year
- Tricuspid Valve is Infected in >70% of Cases
- Most Cases Have No Pre-Existing Heart Disease
- Male Sex
- Poor Dentition/Dental Infection
- Prosthetic Heart Valve
- Structural Heart Disease
- Congenital Heart Disease
- Valvular Heart Disease
Etiology
Non-Infective Endocarditis
- Behcet’s Disease (see Behcet’s Disease, [[Behcets Disease]])
- Systemic Lupus Erythematosus (see Systemic Lupus Erythematosus, [[Systemic Lupus Erythematosus]])
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Infective Endocarditis
Most Commonly Associated Organisms
- General Comments: Staphylococcus and Streptococcus account for the majority of infective endocarditis cases
- Staphylococcus (see Staphylococcus, [[Staphylococcus]])
- Staphylococcus Aureus (see Staphylococcus Aureus, [[Staphylococcus Aureus]]): accounts for 31% of infective endocarditis cases
- Staphylococcus Epidermidis (see Staphylococcus Epidermidis, [[Staphylococcus Epidermidis]]): accounts for 11% of infective endocarditis cases
- Staphylococcus Lugdunensis (see Staphylococcus Lugdunensis, [[Staphylococcus Lugdunensis]])
- Streptococcus (see Streptococcus, [[Streptococcus]])
- Viridans Group Streptococci (see Viridans Group Streptococci, [[Viridans Group Streptococci]]): account for 17% of infective endocarditis cases
- Streptococcus Anginosus Group (see Streptococcus Anginosus Group, [[Streptococcus Anginosus Group]])
- Streptococcus Bovis Group (see Streptococcus Bovis Group, [[Streptococcus Bovis Group]]): Streptococcus Bovis occurs with increased frequency in patients with ulcerative lesions of the colon (due to colon cancer or inflammatory bowel disease)
- Streptococcus Mitis Group (see Streptococcus Mitis Group, [[Streptococcus Mitis Group]])
- Streptococcus Mutans Group (see Streptococcus Mutans Group, [[Streptococcus Mutans Group]])
- Streptococcus Salivarius Group (see Streptococcus Salivarius Group, [[Streptococcus Salivarius Group]])
- Other Streptococci: accounts for 5% of infective endocarditis cases
- Viridans Group Streptococci (see Viridans Group Streptococci, [[Viridans Group Streptococci]]): account for 17% of infective endocarditis cases
- Enterococcus (see Enterococcus, [[Enterococcus]]): accounts for 11% of infective endocarditis cases
Other Organisms
- Abiotrophia (see Abiotrophia, [[Abiotrophia]])
- Abiotrophia Defectiva
- Bartonella (see Bartonella, [[Bartonella]])
- Bartonella Henselae (Cat Scratch Disease) (see Bartonella Henselae, [[Bartonella Henselae]])
- Bartonella Quintana (Formerly Known as Rochalimaea Quintana, Rickettsia Quintana, Rickettsia Weigli, Rickettsia Volhynia, and Rickettsia Pediculi) (see Bartonella Quintana, [[Bartonella Quintana]]): associated with body lice in homeless patients
- Brucella (see Brucella, [[Brucella]]): infective endocarditis due to Brucella occurs predominantly in regions where it is endemic
- Gram-Negative Rods: account for 2% of infective endocarditis cases
- Escherichia Coli (see Escherichia Coli, [[Escherichia Coli]])
- Physiology: adheres less readily to heart valves than Gram-positive organisms
- Klebsiella Pneumoniae (see Klebsiella Pneumoniae, [[Klebsiella Pneumoniae]])
- Physiology: adheres less readily to heart valves than Gram-positive organisms
- Pseudomonas Aeruginosa (see xxxx, [[xxxx]])
- Epidemiology: increased risk with intravenous drug abuse and HIV infection
- Salmonella (see Salmonella, [[Salmonella]])
- Epidemiology: increased risk with intravenous drug abuse and HIV infection
- Escherichia Coli (see Escherichia Coli, [[Escherichia Coli]])
- Granulicatella (see Granulicatella, [[Granulicatella]])
- Granulicatella Adiacens
- Granulicatella Elegans
- Fungi: account for 2% of infective endocarditis cases
- Aspergillus (see Aspergillus, [[Aspergillus]])
- Candida (see Candida, [[Candida]])
- HACEK Organisms: account for 2% of infective endocarditis cases
- Haemophilus Parainfluenzae (see Haemophilus Parainfluenzae, [[Haemophilus Parainfluenzae]])
- Aggregatibacter (see Aggregatibacter, [[Aggregatibacter]])
- Aggregatibacter Actinomycetemcomitans (Formerly Actinobacillus Actinomycetemcomitans) (see Actinobacillus Actinomycetemcomitans, [[Actinobacillus Actinomycetemcomitans]])
- Aggregatibacter Aphrophilus (Formerly Haemophilus Aphrophilus) (see Aggregatibacter Aphrophilus, [[Aggregatibacter Aphrophilus]])
- Aggregatibacter Paraphrophilus (Formerly Haemophilus Paraphrophilus) (see Aggregatibacter Paraphrophilus, [[Aggregatibacter Paraphrophilus]])
- Aggregatibacter Segnis (see Aggregatibacter Segnis, [[Aggregatibacter Segnis]])
- Cardiobacterium (see Cardiobacterium, [[Cardiobacterium]])
- Cardiobacterium Hominis (see Cardiobacterium Hominis, [[Cardiobacterium Hominis]])
- Cardiobacterium Valvarum (see Cardiobacterium Valvarum, [[Cardiobacterium Valvarum]])
- Eikenella Corrodens (see Eikenella Corrodens, [[Eikenella Corrodens]])
- Kingella (see Kingella, [[Kingella]])
- Kingella Denitrificans (see Kingella Denitrificans, [[Kingella Denitrificans]])
- Kingella Kingae (see Kingella Kingae, [[Kingella Kingae]])
- Listeria (see Listeria, [[Listeria]])
- Epidemiology: increased risk with HIV infection
Physiology
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Diagnosis
Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])
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Blood Culture (see Blood Culture, [[Blood Culture]])
- May Be Positive
Transthoracic Echocardiogram (TTE) (see Echocardiogram, [[Echocardiogram]])
- May Be Diagnostic
Transesophageal Echocardiogram (TEE) (see Echocardiogram, [[Echocardiogram]])
- More Invasive Than TTE
- More Sensitive Than TTE for Detecting Vegetations, Periannular Extension, and Abscess
-
Specificity:
- May be less specific than TTE: may detect Lambl’s excrescences (normal valvular strands that may be confused with findings of endocarditis)
- May distinguish between patients with uncomplicated Staph aureus bacteremia and endocarditis: 25% of patients with Staph aureus bacteremia were found to have unsuspected endocarditis by TEE (Fowler, 1997. J Am Coll Cardiol; 30: 1072-1078)
- TEE may help determine whether 2 or 4 wks of therapy is needed in cases of uncomplicated Staph aureus bacteremia with prompt resolution of fever and resolution of bacteremia with catheter removal (Rosen, 1999, Ann Intern Med; 130: 810: 820)
- TEE is more cost-effective than TTE or empiric therapy in patients with probability of endocarditis of 4-60%, with unexplained Staph aureus or Strep bacteremia (Heidenreich, 1999, Am J Med; 107: 198-208)
Duke Diagnostic Criteria
- Definite endocarditis: either 2 major , 1 major + 3 minor, OR 5 minor criteria
- Possible endocarditis: either 1 major + 1 minor OR 3 minor criteria
Major Criteria
- Typical organism (Staph aureus) grown from 2 blood c/s
- Any organism grown persistently from blood c/s
- Positive serology or single positive blood c/s for Coxiella burnetti (Q fever agent)
- Evidence of endocardial involvement on Echo (oscillating intracardiac mass, abscess, or new partial dehiscence of prosthetic valve)
- Physical exam with new valular regurg murmur (change in murmur is not sufficient)
Minor Criteria
- Predisposing heart condition or IVDA
- Fever >38 °C
- Embolic phenomena (major arterial emboli, septic pulmonary infarct, mycotic aneurysm, IC bleed, conjunctival hemorrhages, Janeway lesions)
- Petechiae or splinter hemorrhages are not sufficient
- Immunologic phenomena (GLN, Osler’s nodes, Roth spots, positive RF)
- Serologic evidence of infection or positive blood c/s not meeting the major criteria
- Single positive blood c/s for Staph epi is not sufficient
Clinical Manifestations
Cardiovascular Manifestations
Atrioventricular Heart Blocks
- General Comments: in cases with valve ring abscess
- Periannular Extension Occurs in 10-40% of Infective Endocarditis Cases
- Periannular Extension Occurs in 56-100% of Prosthetic Valve Infective Endocarditis Cases: it accounts for high mortality in this group
- Periannular Extension is Most Common in Aortic Valve Endocarditis: abscess expands near the membranous septum and atrioventricular node (which may result in heart block)
- Periannular Extension Occurs in 10-40% of Infective Endocarditis Cases
- First Degree Atrioventricular Block (First Degree Heart Block) (see First Degree Atrioventricular Block, [[First Degree Atrioventricular Block]])
- Second Degree Atrioventricular Block-Mobitz Type I (Wenckebach) (see Second Degree Atrioventricular Block-Mobitz Type I, [[Second Degree Atrioventricular Block-Mobitz Type I]])
- Second Degree Atrioventricular Block-Mobitz Type II (see Second Degree Atrioventricular Block-Mobitz Type II, [[Second Degree Atrioventricular Block-Mobitz Type II]])
- Third Degree Atrioventricular Block (Third Degree Heart Block, Complete Heart Block) (see Third Degree Atrioventricular Block, [[Third Degree Atrioventricular Block]])
Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
- Epidemiology
- Congestive heart failure complicating infective endocarditis has the greatest impact on prognosis of all complications
- Congestive heart failure complicating infective endocarditis is usually due to valvular regurgitation
- Physiology
- Congestive Heart Failure Due to Intracardiac Shunt Associated with a Fistulous Tract (see Intracardiac and Extracardiac Shunt, [[Intracardiac and Extracardiac Shunt]])
- Congestive Heart Failure Due to Prosthetic Valve Dehiscence or Obstruction
- Congestive Heart Failure Due to Severe Mitral/Aortic Regurgitation: presentation may be acute with perforation of native/bioprosthetic valve leaflet or rupture of infected mitral chordae
- Echocardiogram: elevated left ventricular end-diastolic pressure (LV-EDP) or significant pulmonary hypertension
- Congestive Heart Failure Due to Valve Obstruction by Vegetations: less common
Heart Murmur (see Heart Murmurs, [[Heart Murmurs]])
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Sinus of Valsalva Aneurysm with/without Rupture (see Sinus of Valsalva Aneurysm, [[Sinus of Valsalva Aneurysm]])
- Physiology: with involvement of aortic valve
Tamponade (see Tamponade, [[Tamponade]])
- Physiology: may occur with fistulous tract formation into the pericardial space
Dermatologic Manifestations
- Janeway Lesions (see xxxx, [[xxxx]]): painless dark spots on palms or soles
- Osler’s Nodes (see xxxx, [[xxxx]]): painful nodules on pads of the digits
- Vesicular-Bullous Skin Lesions (see Vesicular-Bullous Skin Lesions, [[Vesicular-Bullous Skin Lesions]])
Neurologic Manifestations
General Comments
- Incidence of Neurologic Events: occur in 20-40% of infective endocarditis cases
- Most Events are Due to Embolization of Vegetations
- Most Commonly Associated with Infective Endocarditis Due to Staphylococcus Aureus
- Neurologic Events May Be Silent
Neurologic Presentations
- Brain Abscess (see Brain Abscess, [[Brain Abscess]])
- Encephalopathy (see Obtundation-Coma, [[Obtundation-Coma]])
- Intracerebral Hemorrhage (Hemorrhagic Cerebrovascular Accident) (see Intracerebral Hemorrhage, [[Intracerebral Hemorrhage]])
- Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
- Meningitis (see Meningitis, [[Meningitis]])
- Mycotic Aneurysm (see Mycotic Aneurysm, [[Mycotic Aneurysm]])
- Seizure (see Seizures, [[Seizures]])
- Transient Ischemic Attack (TIA) (see Transient Ischemic Attack, [[Transient Ischemic Attack]])
Systemic Embolic Manifestations
- Epidemiology
- Incidence of Systemic Embolization: 22-50% of cases of infective endocarditis
- Timing of Systemic Embolization: most events occur before the diagnosis is made or within the first 2 wks
- Risk Falls Dramatically During/After the First 2-3 wks of Successful Antibiotic Therapy
- Highest Rate of Embolic Complications is Associated with Left-Sided Infective Endocarditis
- Risk of Systemic Embolization is Highest with Large (10-15 mm) Mobile Vegetations
- Organisms with the Highest Risk for Systemic Embolization in Infective Endocarditis
- Abiotrophia (see Abiotrophia, [[Abiotrophia]])
- Candida (see Candida, [[Candida]])
- HACEK Organisms: see above
- Staphylococcus Aureus (see Staphylococcus Aureus, [[Staphylococcus Aureus]])
- Physiology
- Vegetations may persist on the valve, even after cure
- Clinical: may be clinically silent in 25% of cases (detected only by imaging studies)
- Bowel Embolism
- Acute Mesenteric Ischemia (see Acute Mesenteric Ischemia, [[Acute Mesenteric Ischemia]])
- Coronary Artery Emboli
- Hepatic Embolism
- Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]]): central nervous system accounts for 65% of all emboli in infective endocarditis (90% of which are to the middle cerebral artery)
- Peripheral Vascular Embolism
- Septic Pulmonary Embolism (see Septic Embolism, [[Septic Embolism]])
- Splenic Embolism
- Bowel Embolism
Ophthalmologic Manifestations
- Roth Spots (see Roth Spots, [[Roth Spots]]): pale areas surrounded by hemorrhage on funduscopic exam
Other Manifestations
Sepsis (see Sepsis, [[Sepsis]])
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Treatment
Antibiotic Therapy
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Native valve:
1) PCN-susceptible Strep viridans/Strep bovis/other Strep:
a) PCN or ceftriaxone x 4 wks
b) PCN or cetriaxone + low-dose gent x 2 wks
c) Vanco x 4 wks
2) Relatively PCN-resistant Strep viridans/Strep bovis/other Strep:
a) PCN or ceftriaxone x 4 wks + low-dose gent x 2 wks
b) Vanco x 4 wks
3) Susceptible enterococcus/resistant Strep:
a) PCN or amp or vanco + low-dose gent x 4 wks (x 6 wks, if symptoms present for >3 mo)
4) Methicillin-sensitive Staph:
a) Naf or ox or cefazolin or vanco x 4-6 wks + low-dose gent x 3-5 days
5) Methicillin-resistant Staph:
a) Vanco x 4-6 wks + low-dose gent x 3-5 days
6) HACEK:
a) Ceftriaxone x 4 wks or amp + low-dose gent x 4 wks
7) Culture-negative:
a) Vanco +low-dose gent x 4 wks +/- ceftriaxone
Prosthetic valve: early prosthetic valve endocarditis (within 2 mo of surgery) usually requires replacement, while late endocarditis may be treated medically
1) PCN-susceptible Strep viridans/Strep bovis/other Strep:
a) PCN x 6 wks + low-dose gent x 2 wks
2) Relatively PCN-resistant Strep viridans/Strep bovis/other Strep:
a) PCN x 6 wks + low-dose gent x 2-4 wks
3) Susceptible enterococcus/resistant Strep:
a) PCN or amp or vanco + low-dose gent x 6 wks
4) Methicillin-sensitive Staph:
a) Naf or ox or cefazolin or vanco + PO rifampin (add after a few days to prevent selecting for resistance) x 6 wks + low-dose gent x 2 wks
5) Methicillin-resistant Staph:
a) Vanco x 6 wks + PO rifampin (add after few days) + low-dose gent x 2 wks
6) HACEK:
a) Ceftriaxone x 6 wks or amp + low-dose gent x 6 wks
7) Culture-negative:
a) Vanco +low-dose gent x 6 wks +/- ceftriaxone
Surgery
Clinical Factors in Considering Surgery
- Approximately 50% of All Patients with Endocarditis Will Ultimately Require Surgery
- Negative Blood Cultures are Not Required for Surgery
Indications for Surgery in Infective Endocarditis [MEDLINE]
- Cerebrovascular Complications
- Silent Neurological Complication
- Transient Ischemic Attack (TIA) (see Transient Ischemic Attack, [[Transient Ischemic Attack]])
- Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]]): provided that cerebral hemorrhage has been excluded and neurological complications are not severe (such as presence of coma)
- Surgery is contraindicated for at least one month after intracranial hemorrhage (unless neurosurgical or endovascular intervention can be performed to reduce the hemorrhagic risk)
- Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
- General Comments
- Surgery should be performed immediately, irrespective to antibiotic therapy, in patients with persistent pulmonary edema and/or cardiogenic shock
- Surgery can be delayed for days-weeks in cases where heart failure can be medically managed
- In infective endocarditis complicated by heart failure, surgery significantly decreases the mortality rate: best results are obtained when surgery is performed within 1 wk of presentation
- Congestive Heart Failure Due to Intracardiac Shunt Associated with a Fistulous Tract (see Intracardiac and Extracardiac Shunt, [[Intracardiac and Extracardiac Shunt]])
- Congestive Heart Failure Due to Prosthetic Valve Dehiscence or Obstruction
- Congestive Heart Failure Due to Severe Mitral/Aortic Regurgitation: with echocardiographic signs of elevated left ventricular end-diastolic pressure (LV-EDP) or significant pulmonary hypertension
- Congestive Heart Failure Due to Valve Obstruction by Vegetations: less common
- Congestive Heart Failure/Tamponade Due to Fistulous Tract Formation Into Pericardial Space (see Tamponade, [[Tamponade]])
- General Comments
- Difficult Organisms
- Aspergillus (see Aspergillus, [[Aspergillus]])
- Brucella (see Brucella, [[Brucella]]): aggressive organisms
- Candida (see Candida, [[Candida]])
- Gram-Negative Rods
- Methicillin-Resistant Staphylococcus Aureus (MRSA) (see Staphylococcus Aureus, [[Staphylococcus Aureus]]): resistant organism
- Pseudomonas Aeruginosa (see Pseudomonas Aeruginosa, [[Pseudomonas Aeruginosa]])
- Q Fever (Coxiella Burnetii) (see Q Fever, [[Q Fever]])
- Staphylococcus Aureus on Left-Sided Native Valve (Most Cases) (see Staphylococcus Aureus, [[Staphylococcus Aureus]])
- Staphylococcus Aureus on Prosthetic Valve (see Staphylococcus Aureus, [[Staphylococcus Aureus]])
- Staphylococcus Lugdunensis (see Staphylococcus Lugdunensis, [[Staphylococcus Lugdunensis]]): aggressive coagulase-negative organism
- Vancomycin-Resistant Enterococcus (VRE) (see Enterococcus, [[Enterococcus]]): resistant organism
- Periannular Extension
- Fistulous Tract
- Myocardial Abscess
- Persistent Sepsis (see Sepsis, [[Sepsis]])
- Fever/Positive Blood Cultures Persisting for 5-7 Days Despite Appropriate Antibiotics: assuming that vegetations and other surgically-amenable lesions persist and that extracardiac sources of sepsis are excluded
- Relapsing Endocarditis: especially when caused by organisms other than sensitive Streptococci or in patients with prosthetic valves
- Prosthetic Valve Endocarditis
- Virtually All Cases of Early Prosthetic Valve Endocarditis
- Virtually All Cases of Prosthetic Valve Endocarditis Caused by Staphylococcus Aureus
- Late Prosthetic Valve Endocarditis with Congestive Heart Failure Du eto Prosthetic Dehiscence or Obstruction
- Systemic Embolization: in these cases, surgery must be performed early, since risk of embolization is highest during the first days of therapy
- Large Vegetations (>10 mm) After One or More Clinical or Silent Embolic Events After Initiation of Antibiotic Therapy
- Large Vegetations and Other Predictors of a Complicated Course
- Recurrent Emboli Despite Appropriate Antibiotic Therapy
- Very Large Vegetations (>15 mm) Without Embolic Complications, Especially if Valve-Sparing Surgery is Likely: controversial indication
Clinical Efficacy
- Outcomes After Surgical Treatment of Native and Prosthetic Valve Endocarditis (Ann Thorac Surg, 2012) [MEDLINE]
- Surgical Treatment is Associated with a 90% Hospital Survival Rate
- 30-Day Outcomes Were Better for Native Valve Endocarditis Than for Prosthetic Valve Endocarditis
- Long-Term Outcomes are Similar for Both Native Valve and Prosthetic Valve Endocarditis
- Staphylococcus Aureus Was Associated with Significantly Higher Mortality Compared to Other Pathogens
- Comparison of Early Surgery vs Conventional Treatment in Endocarditis (NEJM, 2012) [MEDLINE]
- Early Surgery Decreases Embolic Events and All-Cause Mortality
Special Considerations
- Right-Sided Endocarditis: a more conservative approach is recommended, with surgery being indicated only if fever persiste despite 3 weeks of treatment (in the absence of lung abscess) [MEDLINE]
Infective Endocarditis Prophylaxis
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Prophylaxis: controversial, as risk of endocarditis related to dental procedures (other than tooth extraction) is low (Strom, 1998)
1) Dental/oral/resp/esoph procedure: amox 2 g PO 1 hr pre (or clinda 600 mg PO or cephalexin 2 g PO or azithro/clarithro 500 mg PO) or amp 2 g IV 30 min pre (or clinda 600 mg IV or cefazolin 1 g IV)
2) GU/other GI procedure:
a) High-risk: amp 2 IV + gent 1.5 mg/kg IV (<120 mg) 30 min pre and amp 1 g IV (or amox 1 PO) 6 hrs post
-Alt: vanco 1 g IV over 1-2 hrs + gent 1.5 mg/kg IV to finish 30 min pre
b) Mod-risk: amox 2 g PO 1 hr pre (or amp 2 g IV 30 min pre)
-Alt: vanco 1 g IV over 1-2 hrs to finish 30 min pre
Prognosis
- Strep endocarditis: 10% mortality
- Staph endocarditis: 35% mortality
- Prosthetic valve endocarditis: 25-50% mortality
- 33% of MV endocarditis and 66% of AV endocarditis require valve replacement within 5 yrs even if cured of first episode of endocarditis
References
- Surgical treatment of endocarditis. Prog Cardiovasc Dis. 1997;40:239–264 [MEDLINE]
- Surgery for infective endocarditis: who and when? Circulation 2010; 121:1141-1152 [MEDLINE]
- Outcomes after surgical treatment of native and prosthetic valve infective endocarditis. Ann Thorac Surg 2012; 93:489-493 [MEDLINE]
- Early surgery versus conventional treatment for infective endocarditis. N Engl J Med 2012; 366:2466-2473 [MEDLINE]
- HACEK endocarditis: state-of-the-art. Expert Rev Anti Infect Ther. 2016 Mar 8 [MEDLINE]