Infective Endocarditis

Definition

Infective Endocarditis is the microbial infection of the heart valve (native or prosthetic), the lining of a cardiac chamber or blood vessel, or a congenital anomaly (e.g., ventricular septal defect).

Causative Organisms

• Usually bacteria
• Rickettsia (e.g., Coxiella burnetii endocarditis)
• Chlamydia
• Fungi

General Characteristics

• Left-sided endocarditis is more common than right-sided (Left > Right).
• The mitral valve is affected more often than the aortic valve (Mitral > Aortic).
• Regurgitant valves are affected more frequently than stenotic valves (Regurgitant > Stenotic).

Prosthetic Valve Endocarditis

• Early: Occurs within 60 days post-surgery. Most commonly caused by Staphylococcus.
• Late: Occurs after 60 days post-surgery. Most commonly caused by Streptococcus.

Infective Endocarditis (IE): An infection of the heart’s endocardial surface.

Main Classification

• Native Valve IE
• Prosthetic Valve IE

Other classifications

• Intravenous Drug Abuse (IVDA) IE
• Nosocomial IE

Types of Infective Endocarditis

1. Acute Infective Endocarditis

• Toxic presentation
• Progressive valve destruction and metastatic infection developing within days to weeks
• Most commonly caused by Staphylococcus aureus

2. Subacute Infective Endocarditis

• Mild toxicity
• Presentation occurs over weeks to months
• Rarely leads to metastatic infection
• Most commonly caused by Streptococcus viridans or Enterococcus

• Preexisting endocardial damage
  • Virulent organisms (e.g., staphylococci) cause endocarditis in normal heart valves.
  • Tricuspid valve endocarditis is common in intravenous drug users (IVDU).
• Vulnerable cardiac lesions
  • A wide variety of acquired and congenital cardiac lesions are susceptible to endocarditis.
  • Lesions associated with high-pressure jets of blood, such as those in VSD, MR, AR, and stenotic lesions, are more prone to endocarditis.
  • Low-pressure lesions, like large ASD, are less likely to cause endocarditis.
• Breaks in skin
  • Endocarditis can occur at sites of endocardial damage.
  • Areas of damage attract platelets and fibrin, which provide a platform for bloodborne organisms to colonize.
• Infection progression
  • Once an infection is established, vegetation consisting of organisms, fibrin, and platelets grows and becomes large.
  • Vegetations may erode into the underlying myocardium, producing abscesses (ring abscess).
  • Perforation or disruption of chordae may occur.
• Embolization
  • Vegetation can break away and embolize to distant organs, causing further damage.
• Extra-cardiac manifestations
  • Examples include vasculitis, skin lesions, and emboli or immune complex deposits.
  • At postmortem:
    • Infarction of kidney and spleen.
    • Immune complex glomerulonephritis (GN).

• The majority of cases of infective endocarditis (IE) are caused by gram-positive bacteria.
• Staphylococcus aureus (SA) is now more common (31-54%) than oral Streptococci.
• Methicillin-sensitive SA is more frequent in community-acquired IE, infects mainly native valves, and is associated with bacteraemia of unknown origin.
• MRSA (Methicillin-resistant Staphylococcus aureus) is more related to nosocomial infections, wound infections, permanent IV catheters, or surgery in the previous 6 months.
• Strep viridans is now less common (12-26%) but difficult to isolate and confers partial resistance to antibiotics.
• Coagulase-negative Staphylococci were the main cause of prosthetic valve endocarditis in the past, especially within the first 6-12 months after valve surgery. MRSA is now more common.
• Enterococci
• HACEK group:
  • Haemophilus group
  • Actinobacillus group
  • Cardiobacterium hominis
  • Eikenella corrodens
  • Kingella kingae
  • All are commensals in the oral cavity.

Other Causes

• Candida and Aspergillus species cause the majority of fungal IE (1-3% of all IE cases).
• Risk factors: Patients with IV drug use, prosthetic valves, or long-term central venous catheters are more likely to develop fungal IE.
• Fungal IE should be considered in the presence of bulky vegetations, metastatic infection, perivalvular invasion, or embolization to large blood vessels despite negative blood cultures (BC).
• In 10-15% of all cases of endocarditis, no organism can be isolated from blood culture (referred to as "culture-negative" endocarditis).
• When BC-negative IE is suspected, other organisms to consider include:
  • Coxiella burnetti
  • Legionella spp
  • Brucella spp
  • Bartonella spp
  • Chlamydiae spp.

Symptoms & Signs

• Febrile illness
• Nonspecific symptoms such as:
  • Cough
  • Dyspnea
  • Arthralgia or arthritis
  • Diarrhea
  • Abdominal pain
• Cerebral emboli
• Subconjunctival hemorrhage
• Roth’s spot in fundi
• Petechial hemorrhage in mucous membranes & fundi
• Varying murmurs
• Conduction disorders
• Cardiac failure
• Splenomegaly
• Hematuria
• Osler’s nodes
• Digital clubbing
• Splinter hemorrhages
• Janeway lesions
• Systemic emboli
• Petechial rash

Splinter Hemorrhages

• Nonspecific
• Nonblanching
• Linear reddish-brown lesions found under the nail bed
• Usually do NOT extend the entire length of the nail

Subconjunctival Hemorrhages

• Often associated with embolic phenomena

Janeway Lesions

• More specific
• Erythematous, blanching macules
• Nonpainful
• Located on palms and soles

Osler Nodes

• More specific
• Painful and erythematous nodules
• Located on the pulp of fingers and toes
• More common in subacute IE

Roth Spots

• Retinal findings, indicative of embolic events

Essentials of Diagnosis

• Preexisting organic heart lesion
• Fever
• New or changing heart murmur
• Evidence of systemic emboli
• Positive blood culture
• Evidence of vegetation on echocardiography

The Modified Duke Criteria

The Modified Duke Criteria is based on clinical, microbiological, and echocardiographic findings, providing high sensitivity and specificity (~80%) for the diagnosis of infective endocarditis (IE) when applied to patients with native valve IE and positive blood cultures.

Major Diagnostic Criteria

1. Blood culture positive for IE
   • Typical microorganisms consistent with IE from 2 separate blood cultures:
     • Viridans streptococci
     • Streptococcus bovis
     • HACEK group
     • Staphylococcus aureus
     • Community-acquired enterococci in the absence of a primary focus
     • Or microorganisms consistent with IE from persistently positive blood cultures defined as follows:
       • At least 2 positive cultures of blood samples drawn >12 hours apart
       • Or all 3 or a majority of ≥4 separate blood cultures (with first and last sample drawn at least 1 hour apart)
   • Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer ≥1:800
2. Evidence of endocardial involvement by echocardiography
   • Echocardiogram positive for IE
     • TEE (Transesophageal Echocardiography) is recommended for patients with prosthetic valves, rated at least possible IE by clinical criteria, or complicated IE (e.g., paravalvular abscess).
     • TTE (Transthoracic Echocardiography) is the first test for other patients.
     • Defined as:
       • Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation.
       • Abscess
       • New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing pre-existing murmur not sufficient)

Minor Diagnostic Criteria

1. Predisposing heart condition or intravenous drug use
2. Temperature >38°C (100.4°F)
3. Vascular phenomena:
   • Arterial emboli
   • Pulmonary infarcts
   • Mycotic aneurysms
   • Intracranial bleed
   • Conjunctival hemorrhages
   • Janeway lesions
4. Immunologic phenomena:
   • Glomerulonephritis
   • Osler nodes
   • Roth spots
   • Rheumatoid factor
5. Microbiological evidence:
   • Positive blood culture but does not meet a major criterion as noted above, or serological evidence of active infection with an organism consistent with endocarditis (excluding coagulase-negative staphylococci and other common contaminants)

• Blood culture
  • Drawn from three different sites at 1-hour intervals.
  • 50% of fungal endocarditis cases may result in negative blood cultures.
  • PCR has been proposed in these cases.
  • PCR of excised valve tissue or embolic material should be performed in culture-negative IE (in cases of valve surgery or embolectomy).
• ESR (Erythrocyte Sedimentation Rate)
• CRP (C-Reactive Protein)
• CXR (Chest X-ray) - PA View
• ECG (Electrocardiogram)
• Echocardiography
  • Transthoracic Echocardiography (TTE): Sensitivity for detecting vegetation is 65% (with >3–5mm of vegetation).
  • Transesophageal Echocardiography (TEE): Sensitivity for detecting vegetation is 90% (with >1–1.5mm of vegetation).

Echocardiography Findings

• Vegetation: Hallmark lesion of IE
• Periannular abscess
• New dehiscence of valvular prosthesis
• Aortic/mitral regurgitation: Secondary to valvular necrosis, perforation, or prolapse
• Approximately 50-60% of patients with IE develop heart failure secondary to valvular destruction and require early surgery (mortality without surgery ~80%)

• Damage to valves and heart
• Embolic episodes
• Regurgitations
• Extension of infection to myocardium
• Abscess
• Conduction disorders
• Pulmonary abscesses

Prophylaxis

1. Prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts.
2. Prosthetic material used for cardiac valve repair, such as annuloplasty rings and chords.
3. Previous IE.
4. Unrepaired cyanotic congenital heart disease or repaired congenital heart disease, with residual shunts or valvular regurgitation at the site of or adjacent to the site of a prosthetic patch or prosthetic device.
5. Cardiac transplant with valve regurgitation due to a previous condition.

Regimen

Single dose 30 to 60 minutes before procedure

Situation	Agent	Adults	Children
Unable to take oral medication	Ampicillin	2 g IM or IV	50 mg/kg IM or IV
Oral	Amoxicillin	2 g	50 mg/kg
Unable to take oral medication	Cefazolin or Ceftriaxone	1 g IM or IV	50 mg/kg IM or IV
Allergic to penicillins or ampicillin (oral)	Cephalexin	2 g	50 mg/kg
Allergic to penicillins or ampicillin (oral)	Clindamycin	600 mg	20 mg/kg
Allergic to penicillins or ampicillin (oral)	Azithromycin or Clarithromycin	500 mg	15 mg/kg
Allergic to penicillins or ampicillin & unable to take oral medication	Cefazolin or Ceftriaxone	1 g IM or IV	50 mg/kg IM or IV
Allergic to penicillins or ampicillin & unable to take oral medication	Clindamycin	600 mg IV or IM	20 mg/kg IV or IM

• Relies on the combination of prolonged bactericidal antimicrobial therapy and, in about half of patients, surgical eradication of infected tissues.
• Drug treatment of prosthetic valve endocarditis (PVE) should last longer (at least 6 weeks) compared to native valve endocarditis (NVE), which lasts 2-6 weeks.
• The first day of treatment should begin with effective antibiotic therapy, not on the day of surgery.

Empirical Treatment of IE in Acute Severely Ill Patients (Before Pathogen Identification)

Condition	Class Level	Antibiotic	Dosage
Community Acquired NVE or Late PVE	IIa C	Ampicillin	12 gm per day IV in 4-6 divided doses
		Flucloxacillin/Cloxacillin	12 gm per day IV in 4-6 divided doses
		Gentamicin	3 mg/kg/day IV or IM in 1 dose
	IIb C	Vancomycin	30 mg/kg/day IV in 2-3 divided doses
		Gentamicin	3 mg/kg/day IV or IM in 1 dose
Early PVE or Nosocomial and Non-Nosocomial Healthcare Associated Endocarditis	IIb C	Vancomycin	30 mg/kg/day IV in 2-3 divided doses
		Gentamicin	3 mg/kg/day IV or IM in 1 dose
		Rifampicin	900-1200 mg IV or orally in 2-3 divided doses

Antibiotics

• Empirical treatment typically involves flucloxacillin & gentamicin as the first line.
• Treatment is adjusted according to microbiological culture and sensitivity (MCS).
• Vancomycin is used in patients with intracardiac prosthetic material or suspected MRSA.
• Benzylpenicillin is the first choice for Streptococcus or Enterococcus penicillin-susceptible strains.
• For vancomycin-resistant MRSA, teicoplanin, lipopeptide daptomycin, or oxazolidones (linezolid) are recommended.

Fungal IE

• Fungal endocarditis usually requires surgery.
• Amphotericin B does not penetrate well into vegetations but is used successfully against Candida endocarditis.
• Fluconazole is fungistatic and only active against Candida spp.
• Caspofungin is typically fungicidal for Candida spp., but its penetration into vegetations is unknown.

Treatment Course

• IV antibiotics are normally continued for 4-6 weeks, with the goal of sterilizing the vegetations.
• Infectious Disease (ID) specialists should be involved in blood culture-negative (BC-ve) IE cases.

Treatment Organism Specific

• Specific treatment should be adjusted based on the identified organism.

Surgery

• Antimicrobial therapy can offer curative treatment in ~50% of cases.
• The other 50% of patients require surgery.
• The surgical goal is valve repair, but most patients require valve replacement.
• Patients with IE, large vegetations, intracardiac abscesses (9-14%), or persisting infection (9-11%) almost always require surgery.