Academic Day Seminar – Feb 10 (Endocarditis)

Great job by Merisa and May! This was an excellent and well-organized presentation on different infectious diseases. 🙂

It was also great to have Dr. Lau provide us with clinical pearls, as well as, remind us to think about:

  • How to explain the infection and diagnostics in a patient-friendly manner
  • How to “make sense” of the clinical findings and recommended treatment (rather than trying to memorize)

✔ Endocarditis

Condition: Infective endocarditis is inflammation and infection of the inner lining of the heart (endocardium), which can affect the valves.
→ Surface of heart valve is damaged leading to formation of a clot on the valve (valves have tiny blood vessels nourishing them)
→ When bacteria is introduced to the blood, it clonizes and sticks to clot
(Strep + Staph produces dextran to help them stick to valves, G- don’t produce dextran and are less likely to stick)
→ Formation of “vegetation” of fibrin, platelets and bacteria protects the bacteria from the host

Complications:

  • Local valvular damage → HF, valvular insufficiency
  • Septic emboli → stroke, hemorrhage, pulmonary emboli, mycotic aneurysms, spleen infarction/abscess, kidney infarction, glumerulonephritis, petechiae, Janeway lesions, Osler nodes
  • 4-50% risk of mortality depends on organisms involved

Signs and symptoms: usually non-specific symptoms when presenting acutely – if see physical findings on skin, sign that it is long-term endocarditis and prognosis is not good

CNS Fever (most common), chills, weakness, malaise, sweats, stroke, delirium/coma, cerebral emboli, headache
HEENT Roth spots (2-10%), retinal hemorrhages (not specific to IE), soft palate petechiae, conjunctival petechiae
RESP Dyspnea, cough, hemoptysis, pulmonary emboli è Associated more with R sided endocarditis
CVS New or changing heart murmur (85%), chest pain, CHF
GI Splenomegaly, anorexia/weight loss, N/V, abdominal pain
GU Renal failure (↑sCr), proteinuria, hematuria
è Associated more with L sided endocarditis as blood flow is going to periphery
Heme ↑ WBC/neutrophils, ↓Hgb, ↓PLT, ↑ESR, ↑ CRP, bacteremia (90-95%)
Skin
/MSK
Petechaie (small red/purple spot due to bleeding into skin on skin extremities or on mucous membranes), Splinter hemorrhage, Janeway lesions, Osler nodes, clubbing, myalgia/arthralgia, back pain

Diagnostics: clinical, laboratory + echocardiographic findings

  • Modified Duke Criteria: developed for evaluation of L sided native valve
    → sensitivity (ability to r/o dx) is diminished in prosthetic valve IE, R sided IE and cardiac device infection
  • TTE, TEE
    → similar specificity, but TEE is more sensitive in detecing abscess and vegetation
    → TTE also lacks sensitivity in assessing valves
  • Snout → Sensitivity → negative = rule out
  • Spin → Specificity → positive = rule in
  • Negative result does not exclude infection as vegetation may be small or have embolized
  • Consider how to explain diagnostics to patients
    For example:
    (1) TTE has a sensitivity of  58-63% → meaning that if patient does have endocarditis, we could detect it 58-63% of the time (so not good for diagnosis, but good for screening since relatively high specificity)
    → if high sensitivity, if the test is negative – we can rule out diagnosis
    → if low sensitivity = increased rate of false –
    (2) TEE/TEE has a specificity of ~90% → meaning that if patient does not have endocarditis, ~10% of the time it will be a false +
    → if high specificity, if the test is positive → we can rule in diagnosis
    → if low specificity, increased rate of false +

    • Would do TTE first and if negative but still suspect endocarditis, would do a TEE

Epidemiology:

  • More common in > 50 yo (younger in IVDU)
  • More common in males (Male:Female ratio 2:1)

Risk Factors: → Essentially conditions that affect blood flow

  • Host → Heart disease
    • Valvular: Prosthetic valve(s), Degenerative valve disease, Rheumatic heart disease (may be precipitated by Strep Throat) → damage of heart valves, Mitral valve disease, Aortic valve disease
    • Congenital: Patent ductus arteriosus, Ventricular septal defect, Tetralogy of Fallot, Coarctation of aorta
    • Structural – Hypertrophic cardiomyopathy
  • Poor Immune System
  • Previous IE
  • Ask yourself: Where is the bug coming from? 
    → Cardiac implantable devices
    → Poor dental hygiene
    → Hx of IV drug abuse (IVDU usually affects tricuspid valve)
    → Prolonged indwelling line access
    → Long term HD

Pathogens:

  • Staph + Strep: 80% of cases
  • Enterococcus sp.
  • HACEK group organisms
  • Culture negative (usually due to prior antibiotics)

Treatment:

  • High doses of parenteral bactericidal antibiotics for an extended duration
  • Duration counts from 1st day of negative BCx in cases where initial BCx was +

STAPHYLOCOCCUS AUREUS
→ high virulence + common in IVDU and patients with intravascular catheters
→ associated with higher rates of embolism and mortality (25-47%) compared to other organisms (exception: R sided S. aureus IE in IVDU) 

I. MSSA in Native Valve

  • L sided:
    Cloxacillin 2g IV Q4H x 6 weeks + Gent 1mg/kg IV/IM Q8H x 3-5 ds
  • R sided, complicated (metastatic infection, renal failure, abscess formation, HIV, vegetation >1-2 cm):
    Cloxacillin 2g IV Q4H x 6 weeks + Gent 1mg/kg IV/IM Q8H x 3-5 ds
  • R sided, uncomplicated:
    Cloxacillin 2g IV Q4H + Gentamicin 1mg/kg IV/IM Q8H x 2 weeks
    → but in practice, commonly more aggressive and tx x 6 weeks
  • IDSA guidelines recommend against gentamicin for MSSA
    • Addition of AG may more rapidly clear bacteria from blood by ~ 1 day but no difference in survival
    • Risks (increased nephrotoxicity, monitoring) vs. Benefits
    • In practice, tend not to add AG unless bacteremia is persistent >7ds
  • If non-anaphylaxis B-lactam allergy: replace clox with cefazolin 2g IV Q8H
  • If anaphylaxis B-lactam allergy: replace clox with vancomycin (vancomycin kills more slowly than cloxacillin)
    • Other option is high dose daptomycin 8-12mg/kg (by expert opinion) – concentration-dependent antibiotic

Why shorter duration for R sided vegetations?:
Good prognosis + Clinical and microbiologic cure > 85%
IDSA 2015: Right-sided vegetations tend to have lower bacterial densities, which may result from host defense mechanisms, including polymorphonuclear activity or platelet derived antibacterial cationic peptides

II. MRSA in Native Valves

  • L sided or R-sided:
    Vancomycin 15mg/kg IV Q12H x 6 weeks + Gent 1mg/kg IV/IM Q8H x 3-5ds
  • IDSA recommends use of gentamicin for tx of NVE caused by MRSA

*PROSTHETIC VALVE = 3 AGENTS d/t high mortality rate with S. aureus PVE

  • Rifampin is added for biofilm penetration (some studies show that may develop resistance if add while still bacteremic)…but in practice, some would start rifampin with other therapy
  • May need valve replacement

III. Prosthetic Valve MSSA

  • Cloxacillin 2g IV Q4H + Rifampin 300mg PO/IV TID > 6 weeks
    + Gentamicin 1mg/kg IV/IM Q8H x 2 weeks

    • Rifampin IV is special access, but PO has good oral bioavailability

IV. Prosthetic Valve + MRSA

  • Vancomycin 15mg/kg IV Q12H + Rifampin 300mg PO/IV TID > 6 weeks
    + Gentamicin 1mg/kg IV/IM Q8H x 2 weeks

STAPHYLOCOCCUS EPIDERMIS (CoNS) → health care associated

  • Loves to stick to prosthetic valves
  • Entry: valve surgery, infected IV catheter (health care-associated)
  • Most common in early (
  • Typically methicillin-RESISTANT
  • Will likely require valve replacement

Treatment:

I. Native Valve: empirically as per MRSA regimen for NVE

  • Vancomycin 15mg/kg IV Q12H x 6 weeks + Gent 1mg/kg IV/IM Q8H x 3-5ds

II. Prosthetic Valve: empirically as per MRSA regimen for PVE

  • Vancomycing 15mg/kg IV Q12H + Rifampin 300mg PO/IV TID x > 6 weeks
    + Gentamicin 1mg/kg IV/IM Q8H x 2 weeks

STREPTOCOCCUS 

  • Most are Viridans Streptococci (source: human mouths)
  • Tx is also the same for Streptococcus bovis (source: gut) – not a viridans strep
  • Mortality rate (4-16%) is lower than S. aureus
  • Low virulence, typically easier to treatment
  • *REQUIRE MIC of PENCILLIN*

I. Highly Penicillin-susceptible Streptococcus (MIC < 0.12)
a. NVE (uncomplicated, normal renal function)

  • Pen G 12-18MU/d IV continuously or in 4-6 divided doses or CTX 2g IV/IM Q24H
    + Gent 1mg/kg IV/IM Q8H or 3mg/kg IV/IM daily x 2 wks

b. NVE (complicated – >65 yo, impaired eight cranial nerve function, abscess, poor renal fx)

  • Pen G 12-18 mU/day IV or CTX x 4 weeks
    • easier to treat so 12-18 instead of 24 (SPH has PPO guiding to 12-18 dosing, but VGH will do 24mU/day IV)

c. PVE

  • Pen G 24mU/day IV or CTX x 6 weeks
    + Gentamicin.x 2 weeks (tend not to add gentamicin but can add if concerned)

II. Relatively Penicillin-Resistant Streptococcus (MIC > 0.12mg/L to < 0.5mg/L)
→ IDSA recommends ID consult

a. NVE

  •  Pen G 24 mU/day IV or CTX  (or Vanco if B-lactam allergy) x 4 weeks
    + Gent 1mg/kg IV/IM Q8H or 3mg/kg IV/IM OD x 2 weeks

b. PVE

  • Pen G 24 mU/day IV or CTX (or Vanco if B-lactam allergy) x 6 weeks
    + Gent 1mg/kg IV/IM Q8H or 3mg/kg IV/IM OD x 6 weeks

III. Highly Penicillin-Resistant Strep (MIC > 0.5mg/L) → IDSA recommends ID consult

  • Generally go with vancomycin and not depend on penicillins
  • Typically treat as enterococcal IE
  • If pen-resistant, usually also amp-resistant as quite similar for Strep coverage

a. NVE

  • Pen G 18-30 MU/day IV or Amp 2g IV Q4H or Vanco IV + Gent 1mg/kg IV/IM Q8H
    →Duration as per ID

b. PVE

  • Pen G 24 mU/day IV or CTX or Vanco + Gent 1mg/kg IV/IM Q8H or 3mg/kg IV/IM OD
    → Duration as per ID

For Abiotrophia defectiva and Granulicatella species (nutritionally variant strep) are typically difficult to grow and treat → Would always recommend PEN + AG (but practice may differ)

ENTEROCOCCUS

  • Source: Gi tract (occasionally anterior urethra)
  • Low virulence but can be pathogenic in predisposed pts following GU procedures
  • More commonly E. faecalis (90% of isolates) and can also be E. faecium
  • More difficult to treat than staphylococci and streptococci because…High MIC to penicillin, Intrinsic resistance to all cephs and relative resistance occurs to AMG (low level of AMG resistance), increasing resistance and need combination of cell wall active agent AND AMG for killing

Susceptibilities:

  • (S) Pen, Amp, Gent, Strep
    → Pen G 18-30 MUéday IV or Amp 2g IV Q4H + Gent 1mg/kg IV/IM Q8H x 4-6 weeks
    (NVE: 4 weeks if symptoms of illness ❤ mos, 6 weeks if symptoms >3 mos)
    (PVE: 6 weeks)
    OR
    → Amp 2g IV Q4H + CTX 2g IV Q12H x 6 weeks

    • Why is CTX an option? Amp binds to PBP which impairs cell wall synthesis…but it doesn’t bind to all types of PBP so the cell wall can still repair itself. CTX will bind to the other types so that it cannot rebuild itself
  • (S) Pen, Amp, Strep BUT…(R) Gent
    → Pen G 18-30 MU/day IV or Amp 2g IV Q4H x 4-6 weeks
    + Streptomycin 7.5mg/kg IV/IM Q12H (→ usually 500mg IV Q12H, drop to 250mg IV Q12H if reduced renal function) x 4-6 weeks
    (NVE: 4 weeks if symptoms of illness ❤ mos, 6 weeks if symptoms >3 mos)
    (PVE: 6 weeks)
  • (S) Pen, Amp BUT…(R) Strep, Gent
    → Amp 2g IV Q4H + CTX 2g IV Q12H x 6 weeks
  • (S) Gent, Strep BUT…(R) Pen, Amp
    → Vanco IV + Gent 1mg/kg IV/IM Q8H x 6 weeks
  • (R) Pen, Amp, Gent, Strep
    → Vanco IV x 6 weeks
  • (R) Pen, Amp, Gent, Strep, Vancomycin
    → Linezolid 600mg IV or PO Q12H x > 6 weeks
    OR
    → Daptomycin 10-12mg/kg/day x > 6 weeks
    Based on limited case studies → involve ID, cardiology, CV surgery and clinical pharmacist

HACEK
Haemophilus, Aggregatibacter, Cardiobacterium hominis, Eikenella corrodens, Kingella sp

  • Accounts for ~5-10% of community acquired NVE in non-IVDUs
  • Grows slowly in blood cx media. Failutre of growth in in-vitro susceptibility testing is common
  • Previously susceptible to ampicillin, but growing resistance due to B-lactamase producing strain

NVE and PE

  • PREFERRED CHOICE:
    CTX 2g IV/IM Q24H or cefotaxime 2g IV Q8H x 4 weeks for NVE or 6 weeks for PVE
    OR
  • Amp 2g IV Q4H x 4 weeks (ONLY if C+S shows sensitivity as growing resistance)
    OR
  • Cipro 500mg PO Q12H or  400mg IV Q12H
    • only bsaed on a few cases reports…may be considered if patient cannot tolerate CTX

Culture-negative endocarditis:

  • Consider: previous ab use before blood cx, inadequate microbiological techniques, infection with highly fastidious bacteria or fungi, noncultivatable agents
  • Fungi → valve surgery for most cases
  • Brucella → usually requires valve replacement
  • Bartonella (RF: alcoholism, homelessness, contact with cats ㅇㅅㅇ)
    → Doxycyline + AMG
    → Will likely need valvular surgery
  • Q fever (bacteria spread by aerosol transmission by animals)
    → Hydroxychloroquine + Doxycyline x 18-24 months
    → 
    Will likely require surgical valve replacement

Non-pharmacological therapy

  • Surgical indications:
    • determined by cardiologist, ID, surgeon
    • Fungi IE
    • complication of HF, heart block, destructive penetrating lesions
    • failure of abs: persistent bacteremia or fever lasting >5-7 ds after the start of appropriate abs, or recurrent emboli or enlarging vegetation despite appropriate abs
    • severe valve regurgitation and mobile vegetations >10mm

Monitoring:

  • BCx → usually see bacteremia x 3 -7ds (not a sign of tx failure, but an expected course for endocarditis)…if BCx clears 1-2 days after, unlikely to be endocarditis!
    • After obtaining a negative BCx, wouldn’t repeat unless clinically deteriorating
    • repeat 2 sets of BCx Q24-48H until blood stream infection has cleared
  • Gentamicin levels: 1 hr after a 30 min infusion: 3mg/L, trough <1mg/L
    • baseline audiometry – test for high and low frequency, and e-test for vestibular toxicity then q weekly
  • Vancomycin trough levels: 15-20mg/L
  • CNS: resolving fever within ~ 5ds
  • CVS: repeat TTE at abx completion → not generally done in practice to assess valvular damage

Other clinical pearls:

  • ESR is elevated as erythrocytes are binding to inflammatory proteins and sedimenting at a faster rate
  • Renal adjustment for penicillins: B-lactam is time-dependent → would adjust dose (instead of interval); therefore, for Pen G 4mU IV Q4H should ideally be adjusted to 3mU IV Q4H for aggressive infection
  • Renal adjustment for aminoglycosides or fluoroquinolones → would adjust interval
    E.g. cipro 400mg IV Q12H → 400mg IV Q24H

Resources:

Other types of endocarditis:

  • Non-bacterial thrombotic IE: also known as  marantic endocarditis
    • Non-infectious endocarditis, characterized by deposition of sterile platelet thrombi on heart valves (mostly aortic and mitral)
    • Causes:
      • Most commonly associated with advanced malignancy
      • Other etiologies: SLE, inflammatory conditions (e.g. antiphospholipid syndrome, rheumatic heart disease, rheumatoid arthritis, sepsis, burns)
      • Thought that hypercoagulable state is critical in development
    • Manifestations:
      • often asymptomatic..clinical manifestations result from systemic emboli (e.g. to spleen, kidney, skin and exremities)
    • Treatment:
      • Anticoagulation and therapy directed at treating the underlying malignancy or associated condition
      • Hematology consult…typically indefinite anticoagulation
      • Uptodate: therapeutic LMWH or IV UFH

 

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