Infective Endocarditis

Weiyi Mai M.D. & Ph.D.Department of Cardiology,

The First Affiliated Hospital,Sun Yat-sen University

Introduction• Infective endocarditis (IE) is a disease that

produces vegetations on the endocardium. A heart valve or endothelium of adjacent large

artery is usually involved.• Two major predisposing causes are: a

susceptible cardiovascular substrate and a source of bacteremia. Majority of cases caused by streptococcus, staphylococcus, enterococcus, or fastidious gram negative cocco-bacillary forms.

Microbiology sx’s<60 d post op

Classification

• Progression:

– Acute: days-6 wks, Staphylococcus aureus

– Subacute: 6wks-1yr, Viridans streptococci

• Valve:

– NativeNative: 75% Viridans streptococci, 6%Enterococci…

– ProstheticProsthetic: 50% S. epidermidis & aureus, G-& fungi

– Iv drug abusersIv drug abusers: 50% S. aureus, 20% streptococci & enterococci, 6% G- & 6% fungi

Epidemiology

• Exact incidence difficult to measure.– Estimated at 0.16 - 5.4 cases/1000 admissions.– Is increasing as the at-risk population grows.

• Age distribution is changing.– mean age of patient is up to 55 years.

• Male:Female = 2-9:1

• Uncommon in pregnancy

Epidemiology( cont.)

• Severe kidney disease

• Diabetes

• IVs or skin disease– (skin flora)

• Flossing (borderline)– (dental flora)

Terminology: SBE, IE, ABE, NVE, NBTE, or PVE?

• “Infectious endocarditis” now preferred…– subacute vs. acute is arbitrary and antiquated.– etiology may be fungal, bacterial, possibly viral– “Infectious” differentiates from marantic,

verrucous, rheumatic, etc.

HACEK organisms• Hemophilus, Actinobacillus, Cardiobacterium,

Eikenella, Kingella• Gram negative inhabitants of the upper

airways.• Large vegetations, high likelihood of

embolization.• Slow growing: hold cultures for 3 weeks.• Traditionally sensitive to beta lactams, now

some produce beta lactamase.

Pathogenesis

Path

egenesis

Modes of endothelial injury

– Lesions seen at coaptation points of valves• Atrial surface: mitral/tricuspid• Ventricular surface: aortic/pulmonic

Mechanism• High velocity jet• Flow from high pressure to low pressure chamber• Flow across narrow orifice of high velocity

– Bacteria deposited on edges of low pressure sink or site of jet impaction

Venturi Effect

Venturi Effect

PathologyNVE infection is largely confined to leafletsPVE infection commonly extends beyond valve

ring into annulus/periannular tissue Ring abscesses

• Septal abscesses• Fistulae• Prosthetic dehiscence

Invasive infection more common in aortic position and if onset is early

Microscopy

Predisposing Factors

• Aged

– Degenerative valvular dz.

– Increased exposure to nosocomial bacteremia

– Prosthetic valves

• Gender (M>F)

• Associated medical conditions :

– Long term HD

– DM

– Poor dental hygiene

– HIV (independent)

– Congenital defects

• MVP (100/100,000 p’t-yr, in advanced countries)

– MR

– Thickened leaflets

• ASD, VSD

– Injection-drug use (TV)

– Long-term indwelling intravenous catheters

– Rheumatic heart dz. (primarily the young in developing countries)

Pathophysiology

• Clinical manifestations– Direct

• Constitutional symptoms of infection (cytokine)

– Indirect • Local destructive effects of infection• Embolization – septic or bland• Hematogenous seeding of infection

• N.B. may present as local infection or persistent fever, metastatic abscesses may be small, miliary

• Immune response• Immune complex or complement-mediated

Pathophysiology (cont.)

• Local destructive effects• Valvular distortion/destruction

• Chordal rupture

• Perforation/fistula formation

• Paravalvular abscess

• Conduction abnormalities

• Purulent pericarditis

• Functional valve obstruction

Pathophysiology(cont.2)

• Embolization• Clinically evident 11 – 43% of patients

• Pathologically present 45 – 65%

• High risk for embolization• Large > 10 mm vegetation

• Hypermobile vegetation

• Mitral vegetations (esp. anterior leaflet)

• Pulmonary (septic) – 65 – 75% of i.v. drug abusers with tricuspid IE

Clinical FeaturesSymptoms % Signs %

Fever 80-85 Fever 80-90

Chills 42-75 Murmur 80-85

Sweats 25 Changing/new murmur 10-40

Anorexia 25-55 Neurological abnormalities 30-40

Weight loss 25-35 Embolic events 20-40

malaise 25-40 Splenomegaly 15-50

dyspnia 20-40 Clubbing 10-20

Cough 25 Peripheral manifestation

Stroke 13-20 Osler's nodes 7-10

Headache 15-40 Splinter hemorrhage 5-15

Nausea / vomiting 15-20 Petechiae 10-40

Myalgia / arthralgia 15-30 Janeway lesion 6-10

Chest pain 8-35 Retinal lesion/ Roth spot 4-10

Abdominal pain 5-15

Back pain 7-10

Confusion 10-20

Causative high virulence pyogenic bacteria:Staphylococcus aureus (50-80%)

low virulence pyogenic bacteria:α-hemolytic streptococcus viridans (50-90%)

PreexistingCardiac

abnormal

usually no,Normal valves orprosthetic heart valves

rheumatic valvular disease (50-60%),congenital heart disease (20%),ventricular septa defect (15%),normal valves 15%.

Vegetation big, soft, friable pus-like ,yellow-gray masses;white thrombus containing largeamount of polymorphous neutrophils

relatively firm, friable, irregular or polyp-likemasses;white thrombus containing less amount ofpolymorphous neutrophils

Valveschange

severe acute purulent valvulitis:the valves undergo erosion,perforation or rupture; granulationtissue is absent or scarce.

mild chronic purulent valvulitis:fibrous thickening, perforation (less common),with granulation tissue in the base of thevegetation

Chordaechange

break off very common fibrous thickened, shortened, break off lesscommon

Embolism Embolic abscesses Septicemia （ hepatomegaly, splenomegaly,hemorrhage of skin, mucosa, positive blood cultures）

Ischemic infarct (spleen, kidneys and brain)

AIE SIE

ABE and SBE• Acute

– Toxic presentation

– Progressive valve destruction & metastatic infection developing in days to weeks

– Most commonly caused by S. aureus

• Subacute– Mild toxicity

– Presentation over weeks to months

– Rarely leads to metastatic infection

– Most commonly S. viridans or enterococcus

Peripheral Manifestations

• Janeway Lesions:– erythematous, macular,

non tender.– septic emboli?

• Osler’s Nodes:– Tender, subcutaneous

nodules.– 4 P’s:

• Pink

• Painful

• Pea-sized

• Pulp of the fingers/toes.

– Immunologic origin?

Osler’s Node

Bleeding

• Subungual (splinter) hemorrhage

• Conjunctival hemorrhage

• Retinal hemorrhage: Roth Spot

Conjunctival Petechiae

Splinter Hemorrhage

Roth Spot

Clubbing

Lab Investigations• Anemia of Chronic Disease in 50-80%• ESR “almost always” elevated.

– May be normal in those with CHF.• Urinalysis

– gross or microscopic hematuria– casts in glomerulonephritis– bacteriuria and pyuria

• Elevated BUN and Creatinine• Rheumatoid factor present in 50%

Diagnosis

• Published criteria for diagnostic purposes in obscure cases

• High index of suspicion in patients with predisposing anatomy or behavior

• Blood cultures

• Echocardiography– TTE – 60% sensitivity– TEE – 80 – 95% sensitivity

Diagnosis-Duke Criteria

Major:

• Persistently positive blood cultures– Typical organisms for IE– Persistent bacteremia

• Evidence of endocardial involvement– Positive ECHO– New valvular regurgitation

Diagnosis-Duke Criteria (cont.)

Minor:

• Predisposing heart condition

• Fever

• Vascular phenomena

• Immunologic phenomena

• Positive BC (not meeting major)

• Positive ECHO (not meeting major)

Diagnosis-Duke Criteria (cont.2)

“Definite”:

• pathologic diagnosis– Micro-organisms or– Pathologic lesion (confirmed by histology)

• clinical diagnosis– 2 major criteria or– 1 major criterion plus 3 minor criteria or– 5 minor criteria

Diagnosis-Duke Criteria (cont.3)

“Probable”:– Findings consistent with endocarditis but fall

short of definite and– not rejected

“Rejected”– Firm alternate diagnosis for manifestations or– resolution of manifestations ≤ 4 days of using

antibiotics or– No pathologic evidence of IE at surgery or

autopsy after 4 days therapy

“Echo should be done in all cases of suspected endocarditis.”

(This is not all patients with fever or positive blood cultures).

Circulation 1997; 95: 1686-1784

Differential Diagnosis

• AIE:

Septicemia (S. pneumonia, Staph. Aureus, G (-) bacilli, etc.)

• SIE:

Rheumatic fever, Tb, SLE, myxoma, Lymphoma, glomerulonephritis, etc.

Treatment

Goal of Therapy

Eradicate infection

Definitively treat sequelae of destructive intra-cardiac and extra-cardiac lesions

Antibiotic Therapy

• Treatment tailored to etiologic agent Important to note MIC/MBC

relationship for each causative organism and the antibiotic used– High serum concentration necessary to

penetrate a vascular vegetation

• Combination therapy (synergic effect, eg. PG + aminoglycosides )

Antibiotic Therapy(2)

• Treatment before blood cultures turn positive

• Suspected ABE

• Hemodynamic instability

– Neither appropriate nor necessary in patient with suspected SBE who is hemodynamically stable

Antibiotic Therapy(3)

• Effective antimicrobial treatment should lead to defervescence within 7 – 10 days

Persistent fever in:• IE due to staph, pseudomonas, culture negative• IE with microvascular complications/major

emboli• Intracardiac/extracardiac septic complications• Drug reaction

• Adequate therapy (4-6 w)

Surgical Treatment of Intra-Cardiac Complications

• NYHA Class III/IV CHF due to valve dysfunction– Surgical mortality – 20-40%– Medical mortality – 50-90%

• Unstable prosthetic valve– Surgical mortality – 15-55%– Medical mortality – near 100% at 6 months

• Uncontrolled infection

Surgical Treatment of Intra-Cardiac Complications(2)

• Unavailable effective antimicrobial therapy– Fungal endocarditis– Brucella

• S. aureus PVE with any intra-cardiac complication

• Relapse of PVE after optimal therapy

Surgical Treatment of Intra-Cardiac Complications(3)

• Relative indications– Perivalvular extension of infection– Poorly responsive S. aureus NVE– Relapse of NVE– Culture negative NVE/PVE with persistent fever

(> 10 days)– Large (> 10mm) or hypermobile vegetation– Endocarditis due to highly resistant enterococcus

Prevention

• Prophylactic regimen targeted against likely organism– Strep. viridans – oral, respiratory, eosphogeal – Enterococcus – genitourinary, gastrointestinal– S. aureus – infected skin, mucosal surfaces

Prevention – the procedure

• Dental procedures known to produce bleeding

• Tonsillectomy

• Surgery involving GI, respiratory mucosa

• Esophageal dilation

• ERCP for obstruction

• Gallbladder surgery

• Cystoscopy, urethral dilation

• Urethral catheter if infection present

• Urinary tract surgery, including prostate

• Incision & drainage of infected tissue

Prevention – the underlying lesion

• High risk lesions– Prosthetic valves

– Prior IE

– Cyanotic congenital heart disease

– PDA

– AR, AS, MR,MS with MR

– VSD

– Coarctation

– Surgical systemic-pulmonary shunts

• Intermediate risk– MVP with murmur

– Pure MS

– Tricuspid disease

– Pulmonary stenosis

– ASH

– Bicuspid Ao valve with no hemodynamic significance

Lesions at highest risk

Prevention – the underlying lesion(2)

• Low/no risk (Prophylaxis Not Recommended)– MVP without murmur

– Trivial valvular regurg.

– Isolated ASD

– Implanted device (pacer, ICD)

– CAD

– CABG

ChemoprophylaxisAdult Prophylaxis: Dental, Oral, Respiratory, Esophageal

Standard Regimen

Amoxicillin 2g PO 1h before procedure or Ampicillin 2g IM/IV 30m before procedure

Penicillin Allergic Clindamycin

600 mg PO 1h before procedure or 600 mg IV 30m before

Cephalexin OR Cefadroxil 2g PO 1 hour before Cefazolin 1.0g IM/IV 30 min before procedure Azithromycin or Clarithromycin 500mg PO 1h before

Adult Genitourinary or Gastrointestinal Procedures High Risk Patients Standard Regimen

Before procedure (30 minutes): Ampicillin 2g IV/IM AND Gentamicin 1.5 mg/kg (MAX 120 mg) IM/IV

After procedure (6 hours later) Ampicillin 1g IM/IV OR Amoxicillin 1g PO

Penicillin Allergic Complete infusion 30 minutes before procedure

Vancomycin 1g IV over 1-2h AND Gentamicin 1.5 mg/kg IV/IM (MAX 120 mg)

Moderate Risk Patients Standard Regimen

Amoxicillin 2g PO 1h before OR Ampicillin 2g IM/IV 30m before

Penicillin Allergic Vancomycin 1g IV over 1-2h, complete 30m before

Bring Home Message

1) How is the pathogenesis of IE?2) What’s the composition of a vegetation?3) What are the characteristics of HACEK?4) How is the chemotherapeutic rule for IE?5) How is the indication of surgical treatment

for IE?6) What are predisposing factors? How is the

rule of chemoprophylaxis for IE?

Predisposing Conditions

MVP21%

CHD22%

Acquired19%

RHD10%

PVE14%

None14%

Strom BL, Abrutyn E, Berlin JA, Kinman JL, Feldman RS, Stolley PD, et al. Ann Intern Med. 1998;129:761-9.

IV drug users and nosocomial cases excluded.

Nonbacterial Thrombotic Endocarditis

• Sterile platelet-fibrin deposits

• Occur at sites of eddy currents or jet streams created by pre-existing cardiac disease

• Create the “soil” for bacterial deposition.

• Characteristically, non-inflammatory

Infection

Growth of vegetation by platelet-fibrin depositionyields a sanctuary for bacteria.

Streptococci in IE

Viridans Streptococci

• 30-65% of native valve endocarditis

• Normal oral commensals

• A group, composed of several species:– S. mitior, S. sanguis, S. mutans,etc.– Alpha-hemolytic, non-typable

• Typical agents of classic “SBE”

Other Streptococci

• S. bovis– Lancefield group D– Gut flora: associated with GI pathology

• S. pneumonia– 1-3% of cases of IE with predilection for AV– Usually, in those with immune suppression

• DM and Ethanolism

• Group B Streptococci– Elderly with chronic disease

Enterococcus

• Normal inhabitant of GI tract.

• Frequently encountered in UTIs.

• Up to 40% of cases without identified underlying predisposition to IE.

• Difficult to treat due to drug resistance.

Staphylococci

• Coagulase Positive (Staph. aureus)– a major causative agent in all populations of

IE– typically produces “acute” IE

• fulminant, rapidly progressive with few immunologic signs.

• CNS complications in 30-50%

• Coagulase Negative (Staph. epi, et al)– Major cause of PVE. 3-8% of NVE.

Fungi• Commonly encountered agents:

– Candida, Torulopsis, Aspergillus• Predispositions

– Prosthetic valves– IVDA– Immunosupression– Hyperalimentation– Prolonged abx treatment

• Large vegetations and frequent embolic events.

Other Organisms

• Pseudomonas

• Brucella

• Diphtheroids

• Listeria

• Bartonella

• Coxsiella

• Chlamydia

Diagnosis

• Frequently difficult to diagnose with certainty.– Highly variable and often non-specific

presentation.

• Overdiagnosis and Underdiagnosis are common.

Diagnosis

• Classic Clinical Approach: – Von Reyn (Beth Israel) Criteria

• Limitations:– No Use of Echo.

– IVDA not identified as a predisposition

– Lacks sensitivity for “acute” cases.

• Incorporation of Echo:– Durack (Duke) Criteria

• Increases proportion of definite diagnoses.

Use of Echo in Diagnosis of IE

• Native Valves-ACC Guidelines:– Detection/characterization of valvular lesions– Detection of vegetations and characterization of

lesions in patients with CHD– Detection of associated abnormalities– Reevaluation studies in complex IE– Evaluation of patients with high suspicion of

culture-negative IE

Use of Echo in Diagnosis of IE

• Prosthetic Valves-ACC Guidelines:– Detection/characterization of valvular lesions– Detection of associated abnormalities– Reevaluation in complex IE– Evaluation of suspected IE and negative

cultures– Evaluation of persistent fever without known

source

Use of Echo in Diagnosis of IE

• TEE:– Prosthetic valves– Poor visualization on TTE and high suspicion– Detection of associated complications– Preoperative– Reevaluation in complex IE

Medical Management

• Tailor therapy to results of susceptibility testing.

• Use parenteral drugs.• Plan for prolonged courses of abx.

– Be vigilant for adverse drug effects.

• Use bactericidal agents.• Synergistic combinations are useful.• Monitor levels of aminoglycosides.

Culture Negative Endocarditis

• Most common cause is recent use of abx.

• Fastidious organisms

• Fungal

• Intracellular agents: Bartonella, chlamdia, viruses.

• Non-infectious (marantic)

Anticoagulation

“If anticoagulation is indicated foranother reason it should be continued. Anticoagulation does not preventembolization due to IE.”

ACC guidelines on Diagnosis and Managementof Infective Endocarditis.

Class I Indications for Surgery• Acute AR or MR with heart failure.• Acute AR with tachycardia and early closure of

the MV.• Fungal endocarditis.• Annular or aortic abscess.• Sinus or aortic aneurysm.• Persistent bacteremia and valve dysfunction

– After 7-10 days of appropriate antibiotics.

Circulation. 98(18):1949-1984, 1998

Other Indications for Surgery

• Class IIa– Recurrent emboli after

appropriate abx.

– Agent with known poor response to abx (GNR) with valve dysfunction.

• Class IIb– Mobile vegetations

>10 mm.

• Class III– Early infections of MV

that can likely be repaired.

– Persistent pyrexia and leucocytosis with negative blood cultures.

Circulation. 98(18):1949-1984, 1998

Bayer AS, et al. Circ 98:25, 2936-48. 22/29 Dec 98

Features of High Risk for Complications

• Prosthetic cardiac valves

• Left-sided IE

• Staphylococcus aureus

• Fungal IE

• Prior IE

Features of High Risk for Complications

• Prolonged symptoms (>9 months)

• Cyanotic CHD

• Pulmonary-to-systemic shunts

• Poor response to antimicrobial therapy

Complications Occur in Over Half of All Cases

• Embolic: CNS and Peripheral– Ischemic– Hemorrhagic– Septic:

• mycotic aneurysm• metastatic abscess

• Local invasive– Conduction abnormalities– Valvular dysfunction– CHF

• Glomerulonephritis

CHF• High associated mortality

– Accounts for 80-90% of IE deaths

• Leading indication for surgery• More common with AV involvement• More common with Staph aureus?• Surgery is strongly indicated in most cases.

– In-house death reduced from 51% to 9%.– Once CHF develops, surgery should be performed

promptly.

Embolic Events• Occurs in 22-50% of cases.

• 65% of events occur in CNS

– 90% of these in MCA distribution

– Associated with high mortality

• Highest incidence with S. aureus, Candida sp., and HACEK organisms.

Embolic Events• Risk for embolism drops dramatically within

two weeks of antibiotic therapy institution.

– 13 to <1.2 events/1000 patient-days

– MV disease > AV disease, AML disease the highest.

• Size of vegetation and embolic potential remain incompletely explained.

Embolic Events: an Aggressive Approach Clinical Embolic Event (CNS or peripheral)

CT/MR of Brain

Small, ischemic infarcts &Mild neurologic impairment

Vegetations present by echo

Prompt Surgery

Large or hemorrhagic infarct

ObserveBlaustein ASCard Clin 14:3,1996

Mycotic Aneurysm

• 2-5% of all cerebral aneurysms

• More common in debilitated patients

• Suspect when encountered in…– Persistent fever– Pulsatile mass/erythema in peripheral regions– Headache, meningitis, neuro deficit for cerebral

• Surgery recommended whenever possible.

Periannular Extension of Infection

• 10-40% of all NVE

– AV>TV

• 56-100% of all PVE

– annulus is usually the primary site of infection

• May develop into fistulous tracts or shunts.

• New AV block has a PPV of 88%.

• Best diagnosed by TEE.

• Best surgical option is frequently the homograft.

– Improved penetration of antibiotics.

Circulation. 96(1):358-366, 1997 July 1.

Prophylaxis

High Risk: Prophylaxis Recommended

• Prosthetic cardiac valves, including bioprosthetic and homograft valves

• Previous bacterial endocarditis

• Complex cyanotic congenital heart disease (eg, single ventricle states, transposition of the great arteries, tetralogy of Fallot)

• Surgically constructed systemic pulmonary shunts or conduits

Moderate Risk: Prophylaxis Recommended

• Most other congenital cardiac malformations (other than above and below)

• Acquired valvular dysfunction (eg, rheumatic heart disease)

• Hypertrophic cardiomyopathy

• Mitral valve prolapse with valvular regurgitation and/or thickened leaflets

Low Risk: Prophylaxis Not Recommended

• Isolated secundum atrial septal defect

• Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus

– (without residua beyond 6 mo)

• Previous coronary artery bypass graft surgery• Mitral valve prolapse without valvular

regurgitation *

Low Risk: Prophylaxis Not Recommended

• Physiologic, functional, or innocent heart murmurs

• Previous Kawasaki disease without valvular dysfunction

• Previous rheumatic fever without valvular dysfunction

• Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators

Prophylaxis Recommended• Respiratory Tract

– Tonsillectomy– Violation of respiratory mucosa.– Rigid bronchoscopy.

• Gastrointestinal Tract– Esophageal sclerotherapy or stricture dilation– ERCP– Billiary surgery– Violation of intestinal mucosa

• GU Tract– Prostate surgery– Cystoscopy– Urethral dilatation

Prophylaxis Not Recommended

• Respiratory Tract– endotracheal intubation

– Flexible bronchoscopy

– PE tubes

• GI Tract

– TEE

– EGD

Prophylaxis Not Recommended• GU Tract

– Vaginal hysterectomy– Vaginal delivery– C - section– In uninfected tissue:

• D and C/Ab• Urethral cath• Sterilization• IUDs

– Circumcision

Antibiotic Prophylaxis

Antibiotic Prophylaxis

Infective Endocarditis

Questions?

“The practice of medicine is an art, not a trade; a calling, not a business; a calling in which your heart will be exercised equally with your head. Often the best part of your work will have nothing to do with potions and powders, but with the exercise of an influence of the strong upon the weak, of the righteous upon the wicked, of the wise upon the foolish.”

William Osler

Use of Echo in Diagnosis of IE

Bayer AS, et al. Circ 98:25, 2936-48. 22/29 Dec 98

Management of IE

The Sanford Guide to Antimicrobial Therapy

Gilbert DN, Moellering RC, Sande MA, eds. 28th ed. 1998.

Antimicrobial Therapy for IE

Sanford, et al.

Sanford, et al.

Sanford, et al.

+ gent x 14 d

Surgery for PVE

IE Prophylaxis in MVP

Antibiotic Prophylaxis

Antibiotic Prophylaxis

IE: More than a nostalgic disease.

• “One of the most serious of all infections.”*– Is uniformly fatal if untreated.– Continues to have a high case fatality rate even

in antibiotic era.• 4th leading cause of life-threatening ID.

• Incidence is increasing.

* Pathologic Basis of Disease. Cotran, Kumar, Robbins. 4th Ed.

IV Drug Users

• Accounts for 25% of cases of IE in US.

• 5:1 male:female• Pre-existing valvular

diseases uncommon.• Variable

microbiology.• Mortality<10%.

AV6%

MV24%

TV70%

Prosthetic Valve IE

• Affects 3% of prosthesis patients.– Highest risk in first 6 months post op.

• Accounts for 10-20% of all IE cases.

• Increased risk in…– Males– Blacks– Prolonged pump time– Multiple valve replacement

Prosthetic Valve IE

• “Early” (<2 months)-Staph epi

• “late” (after 2 months)- mimics NVE