Infective Endocarditis

Infective Endocarditis

A cardiology case (video): Infective endocarditis of a prosthetic mitral valve -Transesophageal echocardiography 
This is a case of a 32 years old female with a history of mitral valve replacement (with a bileaflet mechanical valve) 3 years before, presenting with fever and a cerebrovascular stroke.
( Echo images are courtesy of dr Abdallah Almaghraby )
To watch the video in full screen click on  the symbol [] at the lower right corner

Infective endocarditis (IE) is a microbial infection of the endocardium or implanted intracardiac materials (eg prosthetic valves, conduits), or pacing electrodes, and indwelling catheters. The most typical pathologic feature of IE is a mobile vegetation associated with valve leaflets. Vegetations are composed of fibrin, platelets, debris, and bacteria. Left-sided lesions are more common than right-sided lesions (the latter are common in intravenous drug
use and congenital abnormalities).
Infective endocarditis (IE) is a serious disease carrying potential for high morbidity and mortality, in part due to the difficulty in establishing an accurate diagnosis early in the course of the disease.
The incidence of IE in the general population is approximately 3-4 cases in 100.000 people per year. 
The most common microorganism involved is staphylococcus aureus , the next most common are streptococci of the oropharyngeal cavity (mostly streptococcus viridians), followed in order of frequency by enterococcus, coagulase-negative staphylococci, other streptococcal species, microorganisms of the HACEK group (Haemophilus, Actinobacillus, Cardiobacterium hominis, Eikenella corrodens, Kingella) group, non HACEK Gram-negative bacteria, and fungi.
Pathogenesis of IE 
In most cases, an injury to the endothelium is involved, being the result of turbulent blood flow at the site of a preexisting cardiac lesion. This results in the deposition of platelets and fibrin on the site and these early deposits are called nonbacterial thrombotic endocarditis. In case of a microorganism present in the blood, for  example due to a dental procedure, or an infection, the microorganism can enter these thrombotic deposits and grow, resulting in the development of vegetations, composed of fibrin, platelets, debris, and bacteria and also often in invasion and destruction of cardiac structures, such as valve tissue, or occasionally invasion of the adjacent myocardium (formation of an abscess).  
 Heart conditions predisposing to endocarditis 
Conditions that predispose to the development of IE by order of frequency include degenerative valve disease , presence of a prosthetic heart valve, intravenous narcotic drug use, rheumatic heart disease and congenital heart disease. 
Conditions predisposing to endocarditis (if significant bacteremia also occurs) are classified according to their relative risk for endocarditis and are the following:
Cardiac conditions with a relatively high or intermediate  risk for IE
Prosthetic valves, including surgically and transcatheter-implanted prostheses, or presence of prosthetic material used for cardiac valve repair (high risk -there is an indication of antibiotic prophylaxis for procedures that can cause bacteremia)
Previous infective endocarditis (obviously high risk)
Indwelling right heart catheters for hyperalimentation are associated with 
high risk for IE, but indwelling right heart catheters for other purposes pose an intermediate risk
 Unrepaired congenital heart disease:
 Coarctation of the aorta, patent ductus arteriosus and arteriovenous fistula are conditions with a high risk for IE. Tetralogy of Fallot has an intermediate risk
Marfan syndrome (relatively high risk)
Valvular heart disease:
 Aortic regurgitation is considered to be associated with a relatively high risk, but calcific aortic stenosis with an intermediate risk. Mitral regurgitation in general is considered to have a relatively high risk, but specifically mitral valve prolapse with regurgitation, as well as mitral stenosis are of intermediate risk for IE. Tricuspid valve disease is also an intermediate risk condition for IE. 
Hypertrophic obstructive cardiomyopathy (intermediate risk)
Nonvalvular intracardiac prosthesis (intermediate risk)
Cardiac conditions with a low risk for IE are:
Mitral valve prolapse without regurgitation
Congenital heart disease with low risk for IE: an uncorrected atrial septal defect and surgically corrected congenital lesions without a prosthesis >6 months after surgery
Cardiac pacemakers
Aortocoronary bypass surgery (negligible risk)

The most important non-cardiac predisposing factors to bacterial endocarditis (by causing bacteremia) are : IV drug use, dental procedures that cause bleeding, oral and upper respiratory tract surgery, genitourinary surgery. 
Antibiotic prophylaxis for IE
Current guidelines have restricted the indications for antibiotic prophylaxis compared to older common practice, because of changes in pathophysiological conceptions and risk-benefit analyses. Cardiac conditions which require prophylactic antibiotic therapy for the avoidance of IE, in case of a procedure predisposing to endocarditis (dental procedures inducing gingival or mucosal bleeding, including professional cleaning, tonsillectomy, adenoidectomy, surgical operations that involve intestinal or respiratory mucosa) are the following :
 Prosthetic heart valves, including bioprosthetic and homograft valves, or a prosthetic material (eg a prosthetic ring) placed for valve repair,
Previous bacterial endocarditis, even in the absence of heart disease  Most congenital cardiac malformations, if not repaired, especially cyanotic lesions (except isolated atrial septum defect which is a low risk condition for IE) or repaired congenital heart disease (CHD) with shunts or conduits, repaired CHD when a residual defect is present , and recent repair of CHD (<6 months) involving prosthetic device or material. 
A cardiac transplant with valve regurgitation due to a structurally abnormal valve
Antibiotic prophylaxis is also recommended before implantation of pacemakers, or implantable defibrillators (ICDs), to avoid infection of the device.
Procedures predisposing to endocarditis are divided into: Procedures with a clear indication for antibiotic prophylaxis (if one of the above cardiac conditions is present) such as dental procedures which induce gingival or mucosal bleeding, (professional cleaning is included), tonsillectomy and  adenoidectomy and
Procedures with a less clear indication for antibiotic prophylaxis, such as operations that involve intestinal or respiratory mucosa. 

Clinical manifestations of IE
The most typical presentation of IE is the presence of fever and a new murmur (in about 85%) of cases. However, fever may be absent in the elderly, uremic, or immunosuppressed. A murmur may be absent with right-sided or mural infection or with infection of an intracardiac device. Nonspecific symptoms such as malaise, fatigue and night sweats are common. Dyspnea is also common.
Congestive heart failure occurs in up to 55% of cases
Neurologic symptoms and findings, are usually indications of an embolic complication and may include clinically apparent cerebral emboli (20%), rupture of a mycotic aneurysm (< 5%), meningitis, or brain abscess (< 5%).
Additional possible manifestations of IE, are due to embolic or immune complex phenomena and  include mucosal petechiae (in about 20% -30% of cases),  Osler’s nodes (painful, tender red nodules on the pads of fingers or toes: 10% -20%), splinter hemorrhages (dark red linear streaks under the nails in about  10% -20%), an arterial embolism (the clinical picture depends on the site of embolism,see below),  Janeway lesions (these are more rare, they are red, macular, nontender lesions on the fingers, palms, or soles, observed in  < 5% of IE cases), splenomegaly (in about 30% of cases), and Roth’s spots (retinal hemorrhages: < 5%). These classic physical findings are not sensitive and (also not specific) for the diagnosis of IE.
Systemic embolization occurs in about 20% - 40% of cases of IE and may result in manifestations of  an acute stroke (cerebral emboli), or it can mimic peritonitis (embolization to the spleen, kidney, or bowel), a pulmonary embolism (from IE involving the right side of the heart), an acute coronary syndrome (coronary artery emboli), or it may result in a cold extremity with reduced or absent pulse (embolization of a peripheral artery).
In summary, the clinical picture of IE is highly variable, ranging from subtle and slowly progressive symptoms to acute severe congestive heart failure due to severe valvular regurgitation. IE can be divided into acute and subacute.
Acute infective endocarditis, the most common cause of which is staphylococcus aureus, is associated with rapid symptom onset, often with high fever and it is a more invasive infection which tends to produce large vegetations (2 mm to 2 cm), rapid valve destruction and, commonly, embolic complications. Invasion of myocardium with the formation of an abscess cavity, is also common.
With subacute infective endocarditis, streptococcus viridans (a microorganism of the oral cavity) is the most common causative agent. Clinical course is characterized by slow onset with vague or nospecific symptoms, such as low-grade fever, malaise, fatigue, weight loss, flulike symptoms, chills, night sweats, and musculoskeletal aches.  It  leads to valve lesions and valve dysfunction but with a more gradual course, in comparison to acute IE. It tends to produce smaller vegetations than those observed in acute IE. 
Diagnosis of IE
 The modified Duke criteria are widely used for the diagnosis of IE. A combination of 2 major criteria, or the combination of 1 major and 3 minor criteria, or five minor criteria will constitute a definite clinical diagnosis. 
The major diagnostic criteria can be summarized as 
 Positive blood cultures and 
An abnormal echocardiogram with typical findings for IE. 
A more detailed description of the major clinical diagnostic criteria is the following:
• A positive blood culture for infective endocarditis, as defined by the recovery of a typical microorganism from two separate blood cultures in the absence of a primary focus.
(Typical microorganisms include viridans streptococci, community-acquired staphylococcus aureus or enterococcus species, streptococcus bovis, HACEK group, abiotrophia species and granulicatella species), or
• A persistently positive blood culture, for a microorganism consistent with IE from either blood samples obtained more than 12 hours apart, or all three, or a majority of four or more separate blood samples, with the first and last obtained at least 1 hour apart, or
• A positive serological test for Q fever, with an immunofluorescence assay showing phase 1 IgG antibodies at a titre >1 : 800, or
• Echocardiographic evidence of endocardial involvement:
-An oscillating intracardiac mass on a cardiac valve or its supporting structures, in the path of regurgitant jets, or on implanted material in  the absence of an alternative anatomical explanation, or
-An abscess, or
-New partial dehiscence of a prosthetic valve, or
-New valvular regurgitation.

The minor criteria are: 
Predisposing cardiac lesion
IV drug use
Vascular phenomena (arterial embolic, septic pulmonary infarcts, Janeway lesions),
Immunologic phenomena (such as Osler nodes, Roth spots, glomerulonephritis, or a positive rheumatoid factor)
Microbiologic evidence (positive blood cultures not meeting major criteria or evidence of active infection with an organism consistent with infective endocarditis)

I recommend the following videos, because appart from a summary of the topic, they also provide images of some physical signs of IE, such as mucosal petechiae, Osler’s nodes, splinter hemorrhages, Janeway's lesions, Roth spots. LINKS :

Diagnostic tests
In IE, bacteremia is almost constant, therefore positive blood cultures remain the cornerstone of diagnosis and permit identification of the causative micro-organism and susceptibility testing. Samples for blood culture should be taken before antibiotic administration (At least three sets of blood cultures at 30-minute intervals, each containing 10 ml of blood, incubated in both aerobic and anaerobic culture media). The sample should be obtained from a peripheral vein rather than from a central venous catheter with a meticulous sterile technique. This almost always is sufficient to identify the usual causative microorganisms. 
Blood culture-negative IE refers to IE in which no causative microorganism can be grown and identified by the usual blood culture methods and it can occur in approximately 10- 20% of all cases of IE.  It often poses important diagnostic and therapeutic dilemmas. Blood culture-negative IE commonly arises as a consequence of previous antibiotic administration, or it is IE caused by fungi or fastidious bacteria (especially obligatory intracellular bacteria). Such microorganisms need culture on specialized media, in order to be isolated. Moreover, their growth is relatively slow.

Four echocardiographic findings are major criteria for the diagnosis of IE: a vegetation,  an abscess or pseudoaneurysm , a new dehiscence of a prosthetic valve and a new valvular regugitation. With current technology the sensitivity for the diagnosis of vegetations for  transthoracic echocardiography (TTE) in native and prosthetic valves is 70% and 50%, respectively,  and for transesophageal echocardiography (TEE)  95% and 92%, respectively (roughly let us say more than 90 %).  Specificity is approximately 90% for both TTE and TEE.
Some echocardiographic findings, that can be observed in infective enocarditis (IE):
A vegetation, on echocardiography, appears as an irregularly shaped, discrete echogenic mass which is adherent to, but distinct from, the endocardial surface or an intracardiac device. Oscillation of the mass is supportive for the diagnosis, but not mandatory.
An abscess, on echocardiography, is a thickened, nonhomogeneous area near a valve with echodense or echolucent appearance. Evidence of flow into the region is supportive for the diagnosis, but not mandatory.
Perforation of a valve leaflet is defined as interruption of tissue continuity of valve leaflet with demonstration of flow with color flow doppler, through the defect.
Dehiscence of a prosthetic valve is shown by demonstration of paravalvular regurgitation by transthoracic or transesophageal echocardiography, with or without a rocking motion of the prosthesis.
Pseudoaneurysm is a perivalvular cavity communicating with the cardiovascular lumen and in echocardiography it appears as a pulsatile perivalvular echo-free space (an echolucent cavity) with color-Doppler detected entering this space.
A valve aneurysm is a saccular outpouching or bulging of valvular tissue (meaning that  a portion of the valvular tissue protrudes outward).

Treatment of IE  
According to the latest guidelines, the best management of IE can be achieved  via an "endocarditis team", a multidisciplinary collaboration among cardiologists, cardiac surgeons, and infectious 
disease specialists (Although, this is not always quite possible).
In IE, prompt initiation of parenteral antibiotic therapy is important, because the rate of complications, such as embolization, decreases rapidly within several days, after initiation of proper antibiotic treatment. 
In severely ill patients with IE initial empirical antibiotic treatment (before pathogen identification) should start immediately after obtaining three separate blood cultures at 30 minute time intervals. When the pathogen is identified the antibiotic regimen can change according to the specific microorganism and its antibiotic subsceptibility. Generally in IE the duration of antibiotic treatment is usually about 4-6 weeks. Repeat sets of blood cultures
after the initiation of antibiotic treatment are obtained every  48 hours, until the resolution of bacteremia is confirmed.
Indications for surgery in IE include: 
Heart failure with pulmonary edema or cardiogenic shock, or signs and symptoms of heart failure, or valve dysfunction with echocardiographic signs of poor haemodynamic tolerance.
Findings suggesting that the infection cannot be controlled or is allready uncontrolled such as persisting positive blood cultures despite appropriate antibiotic therapy and adequate control of septic metastatic foci,  or
 local findings of uncontrolled infection such as abscess, false aneurysm, fistula, or an enlarging vegetation,
or IE by fungi or multiresistant organisms, or
 prosthetic valve endocarditis caused by staphylococci or non-HACEK gram-negative bacteria (this is a class IIa indication, meaning that surgery probably should be considered but not as an absolute indication).
Surgery is also indicated in infective endocarditis for prevention of embolic complications:
After an embolic episode in a patient with IE involving a native or prosthetic aortic or mitral valve with persistent vegetations >10 mm despite appropriate antibiotic therapy.
IE involving an aortic or mitral valve (native or prosthetic) with very large vegetations >30 mm (this is a relative-class IIa-indication for surgery).

The objective of surgery is the total removal of infected tissues and repair of cardiac damage, including repair of the affected valve, or replacement of the affected valve with a prosthetic one.
 Proposed antibiotic regimens for empirical treatment (before pathogen identification)  are the following: 
For community-acquired endocarditis of native valves, or late endocarditis of prosthetic valves (≥12 months post surgery) : Ampicillin 12 g/day i.v. in 4–6 doses+ (Flu)cloxacillin or oxacillin + Gentamycin (for drug dosages see below) or
 for patients allergic to penicillin, a very good regimen is Vancomycin + Gentamycin (for dosages see below)
For early prosthetic valve endocarditis (<12 months post surgery) or for healthcare associated endocarditis 
Vancomycin +Gentamycin +Rifampin (rifampin is recommended only for prosthetic valve IE and should be started 3–5 days later than the other two drugs). For drug dosages see below.

Therapy of I E caused by some common specific microorganisms
Treatment for Streptococus viridans: (and also in general for oral and digestive streptococci) : Penicillin G 12–18 million U/day i.v. either in 4–6 doses or continuously or 
Amoxicilline 100–200 mg/kg/day i.v. in 4–6 doses
or Ceftriaxone 2 g/day i.v. or i.m. in one dose.
Treatment duration is 4 weeks.
Alternative treatment for 2 weeks : one of the above anibiotics + 
an aminoglycoside ( Gentamycin 3 mg/kg/day i.v. or i.m. in one dose, or Netilmycin 4–5 mg/kg/day i.v. in one dose).
For patients allergic to beta-lactam antibiotics (penicillines, cephalosporines) : Use for 4 weeks Vancomycin 30 mg/kg/day i.v. in 2 doses.
For strains relatively resistant to penicillin (MIC 0.250–2mg/l) : Penicillin G 24 million U/day i.v. either in 4–6 doses or continuously or Amoxicilline 200 mg/kg/day i.v. in 4–6 doses, or Ceftriaxone for 4 weeks + 
Gentamycin for 2 weeks (the last two antibiotics with dosages as above).
or in allergic patients Vancomycin (4 weeks) + Gentamycin (2 weeks), dosages as above

Methicillin-sensitive staphylococcus (native valve infection) treatment duration is for 4-6 weeks : (Flu)cloxacillin or oxacillin 12 g/day i.v. in 4–6 doses
 If the patient is allergic to penicillin, or for methicillin-resistant staphylococci (native valves) treatment is for 4-6 weeks with: Vancomycin 30–60 mg/kg/day i.v. in 2–3 doses/ or Daptomycin 10 mg/kg/day i.v. once daily.
For staphylococcus (Methicillin-susceptible) endocarditis of  prosthetic valves  (Flu)cloxacillin or Oxacillin (for ≥ 6 weeks) + Rifampine (for ≥ 6 weeks) 900–1200 mg i.v. or orally in 2 - 3 divided doses   Gentamycin (for 2 weeks).
For staphylococcus (Methicillin-resistant) endocarditis of  prosthetic valves, or allergy to penicillin, instead of Flucloxacillin, or Oxacillin use Vancomycin, with the same other 2 drugs. Treatment duration is the same.

Enterococcus:   4-6 weeks treatment with Amoxicillin 200 mg/kg/day i.v. in 4–6 doses  +  Gentamycin for 2-6 weeks
Alternative treatment (in penicillin-allergic patient or resistant strain of enterococcus):Vancomycin + Gentamycin, both for 6 weeks (Dosages as usual, see above). 

(Pediatric doses of antibiotics in IE: Penicillin G 200,000 U/kg/day i.v. in 4–6 divided doses, Amoxicillin 300 mg/kg/day i.v. in 4–6 divided doses ,
Ceftriaxone 100 mg/kg/day i.v. or i.m. in one dose,
Gentamycin 3 mg/kg/day i.v. or i.m. in 1 dose or 3 equally divided doses,

 Vancomycin 40 mg/kg/day i.v. in 2 or 3 equally divided doses,
Rifampin 20 mg/kg/day i.v. or orally in 3 equally divided doses 

Treatment for HACEK group microorganisms. These are slow growing fastidious gram negative bacilli. They are susceptible to ceftriaxone, other third-generation cephalosporins and quinolones. Standard treatment is ceftriaxone 2 g/day ( treatment duration in native valve enodcardis is 4 weeks and in prosthetic valve endocarditis is 6 weeks.

For Gram-negative bacteria that do not belong to the HACEK group the recommended treatment is early surgery plus long-term (at least 6 weeks) therapy with bactericidal combinations of beta-lactams and aminoglycosides. A quinolone or cotrimoxazole may be added to the above treatment.

Cardiac device related endocarditis (CDRIE) is a special and difficult problem (microbial infection of the leads of a pacemaker, or implanted defibrillator). Cardiac device (pacemaker, or implanted defibrillator) infection is generally classified in two categories: pocket infection and endocarditis. Patients may present with regional or systemic manifestations, which can include : 
In cases of pocket infection : erythema (redness), pain, local warmth, purulent discharge, or erosion of the skin.
In cases of endocarditis: fever is the most common symptom, fatigue, malaise, loss of appetite are common, and local signs of pocket infection may be present. A septic pulmonary embolus may occur.
with PM/ICD infections may present with regional or
systemic symptoms. Erythema, pain, erosion, redness,
increased warmth, purulent drainage, and cellulitis are fre-
quent regional findings in pocket infections.In endocarditis,
fever and rash are present in addition to regional findings.
Positive surface and blood cultures suggest the presence of
a device infection.
Three or more sets of blood cultures are recommended before prompt initiation of antimicrobial therapy and a transesophageal echocardiogram (TEE) must be performed in patients with suspected CDRIE with positive or negative blood cultures, to assess for the presence of lead-related endocarditis and heart valve infection. TEE may show electrode or valvular vegetations.
 In the majority of patients, CDRIE must be treated by complete hardware (device and leads) removal and prolonged antibiotic therapy (i.e. before and after hardware removal). The same treatment is also recommended in presumably isolated pacemaker or defibrillator pocket infection (i.e infection at the site, where the battery of the device has been implanted).Before reimplantation of the device a re-evaluation of the indication for implantation is necessary, because in some cases, reimplantation is not necessary. The new device should be implanted on the contralateral side. Immediate reimplantation should be avoided, because there is a significant risk of new infection. Blood cultures should be negative for at least 72 hours before placement of a new device. The decision on the timing of reimplantation needs a consideration of several factors such as persistent bacteremia, persistent vegetation and how dependent is the patient from the pacemaker or the implantable cardioverter defibrillator. When there is evidence of remnant valvular infection, implantation should be delayed for at least 14 days. Temporary pacing should be avoided if possible, because it is a risk factor for subsequent cardiac device infection. In a pacing-dependent patient, temporary use of active fixation leads connected to an external device can be a "bridging strategy", until the placement of a new permanent device is considered safe.

Bibliography and Links :

I recommend this video (by 123sonography) showing echocardiography in native valve endocarditis  Link:
Echo in Endocarditis-Prof. Thomas Binder

2015 ESC Guidelines for the management of infective endocarditis

Hoen B, Duval X. Infective endocarditis. N Engl J Med 2013; 368:1425–1433

Baddour LM, Wilson WR, et al: Infective endocarditis: diagnosis, antimicrobial therapy and management of complications. Circulation 2005;111: e394–e434

Li JS, Sexton DJ, et al: Proposed modifications to the Duke criteria for the  diagnosis of infective endocarditis, Clin Infect Dis 2000;30:633–638