Infective Endocarditis Notes

Infective Endocarditis

Learning Objectives

  1. Determine a patient’s risk factors for developing infective endocarditis (IE).
  2. Describe the mechanism of antimicrobial synergy with aminoglycosides in the treatment of endocarditis.
  3. Identify patients who would benefit from aminoglycoside synergy in the treatment of endocarditis.
  4. Select appropriate antibiotic regimens to treat IE based on identified pathogens: MSSA, MRSA, Enterococcus spp., and Streptococcus spp.
  5. Recognize differences in the treatment of native valve and prosthetic valve endocarditis.
  6. Identify patients who would benefit from antimicrobial prophylaxis against IE before dental procedures (case).

Outline

  • Pathophysiology, microbiology, diagnosis
  • Treatment
    • Streptococcus spp.
    • Staphylococcus spp.
    • Enterococcus spp.
    • HACEK

Pathophysiology, Microbiology, Diagnosis

  • Infective Endocarditis results from:
    • Bacteria in the Bloodstream + Damaged Endothelium or Prosthetic Material

Risk Factors

  • Prosthetic valves
  • Intracardiac devices
  • Congenital heart diseases
  • History of infective endocarditis
  • Degenerative valvular lesions
  • Intravenous (IV) drug use
  • Hemodialysis
  • Diabetes

Microbiology

  • Staphylococcus spp.
  • Streptococcus spp.
  • Enterococcus spp.
  • Gram-negative bacilli
  • HACEK organisms
  • Fungi
  • Account for 80% of infections
  • 10% of infections are culture negative

Diagnosis: Signs and Symptoms

  • Variable and nonspecific
  • Commonly seen:
    • Fever
    • Cardiac murmur
  • May be present:
    • Peripheral manifestations “stigmata”: Osler’s nodes, Janeway lesions

Diagnosis

  • Microbiologic
    • Blood cultures
      • Three sets of blood cultures from different sites with first and last cultures collected at least one hour apart
    • Serologic testing
      • Bartonella spp., Coxiella burnetii, Brucella spp., Legionella spp.
    • Valve tissue specimens
      • Surgical intervention

Diagnosis: Echocardiogram

  • Transthoracic echocardiogram
    • Less invasive
      • Ultrasound performed over the chest
    • Less sensitive
      • Obese patients, COPD
  • Transesophageal echocardiogram
    • More invasive
      • No oral intake for 6 hours
      • Hold anticoagulation
    • More sensitive
      • Mobile mass or vegetation, paravalvular abscess, prosthetic valve dehiscence, new valvular regurgitation

Diagnosis: Modified Duke Criteria

  • Definite IE
    • Pathological criteria
    • Clinical criteria: 2 major criteria, 1 major criterion and 3 minor criteria, or 5 minor criteria
  • Possible IE
    • Clinical criteria: 1 major criterion and 1 minor criterion, or 3 minor criteria
  • Rejected

Duke Criteria - Major

  • Blood culture positive for IE
    • Typical microorganisms consistent with IE from 2 separate blood cultures:
      • Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus, or 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 h apart or all 3 or a majority of ≥4 separate cultures of blood (with first and last sample drawn at least 1 h apart)
    • Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer ≥1:800
  • Evidence of endocardial involvement
    • Echocardiogram positive for IE (TEE recommended for patients with prosthetic valves, rated at least possible IE by clinical criteria, or complicated IE [paravalvular abscess]; TTE as first test in other patients) defined as follows: 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; or new partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing or pre-existing murmur not sufficient)

Duke Criteria - Minor

  • Predisposition, predisposing heart condition, or IDU
  • Fever, temperature >38°C
  • Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions
  • Immunological phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor
  • Microbiological evidence: positive blood culture but does not meet a major criterion as noted above (excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis) or serological evidence of active infection with organism consistent with IE
  • Echocardiographic minor criteria eliminated

Antimicrobial Therapy Considerations

  • Standard is high dose bactericidal parenteral agents for extended durations of treatment
  • Inoculum effect
  • Source Control
  • Penetration
  • Bactericidal activity

Streptococcus spp.

  • Viridans groups streptococcus (VGS)
    • S. gallolyticus (formerly bovis)
    • S. sanguis, S. oralis (mitis), S. salivarius, S. mutans
    • Gemella morbillorum
    • S. anginosus (milleri) group
      • S. intermedius, S. anginosus, S. constellatus
      • Prone to abscess formation
      • Causes hematogenous spread (septic arthritis, vertebral osteomyelitis)
    • Nutritionally variant streptococci
      • Abiotrophia defectiva, Granulicatella spp.

Streptococcus spp. Antimicrobial Treatment

  • Penicillin MIC
  • Presence of extracardiac infection
  • Antimicrobial allergies and ability to tolerate aminoglycosides
  • Treatment Duration
    • Streptococcus species
      • A. defectiva, Granulicatella spp. are difficult to microbiologically cure
    • Native vs prosthetic valve
    • Presence of extracardiac infection

Streptococcus spp. Treatment Regimens

  • VGS, S. gallolyticus (PCN MIC≤0.12)
    • NVIE (Native Valve Infective Endocarditis):
      • PenG sodium 12-18mU/24h (divided in 4-6 doses) OR CTX 2g Q24h
      • DOT: 4 weeks
        • If no extracardiac dz, CrCl>20, no Abiotrophia/Granulicatella/Gemella: PenG sodium 12-18mU/24h (divided in 4-6 doses) OR CTX 2g Q24h + Gentamicin 3mg/kg Q24h
        • DOT: 2 weeks
      • PCN allergy: Vancomycin
        • DOT: 4 weeks
    • PVIE (Prosthetic Valve Infective Endocarditis):
      • PenG sodium 12-18mU/24h (divided in 4-6 doses) OR CTX 2g Q24h +/- Gentamicin 3mg/kg Q24h
      • DOT: 6 weeks for PenG/CTX, 2 weeks for Gentamicin
      • PCN allergy: Vancomycin
        • DOT: 6 weeks
  • VGS, S. gallolyticus (PCN MIC 0.12-0.5)
    • NVIE:
      • PenG sodium 24mU/24h (divided in 4-6 doses) OR CTX 2g Q24h + Gentamicin 3mg/kg Q24h
      • DOT: 4 weeks for PenG/CTX, 2 weeks for Gentamicin
      • PCN allergy: Vancomycin
        • DOT: 4 weeks
    • PVIE:
      • PenG sodium 12-18mU/24h (divided in 4-6 doses) OR CTX 2g Q24h + Gentamicin 3mg/kg Q24h
      • DOT: 6 weeks for PenG/CTX, 2 weeks for Gentamicin
      • PCN allergy: Vancomycin
        • DOT: 6 weeks
  • VGS, S. gallolyticus (PCN MIC≥0.5), A. defectiva, Granulicatella spp.
    • NVIE:
      • PenG sodium 18-30mU/24h (divided in 4-6 doses) OR CTX 2g Q24h + Gentamicin 1mg/kg Q8h
      • DOT: ID consult
      • PCN allergy: Vancomycin
        • DOT: ID consult
    • PVIE:
      • PenG sodium 18-30mU/24h (divided in 4-6 doses) OR CTX 2g Q24h + Gentamicin 1mg/kg Q8h
      • DOT: 6 weeks
      • PCN allergy: Vancomycin
        • DOT: 6 weeks
  • S. pyogenes, Group B, C, F, G β-hemolytic Streptococcus spp.
    • S. pyogenes:
      • PenG sodium 12-18mU/24h (divided in 4-6 doses)
      • DOT: 4-6 weeks
    • Group B, C, F, G strep:
      • PenG sodium 12-18mU/24h (divided in 4-6 doses) + Gentamicin 1mg/kg Q8h
      • DOT: 4-6 weeks for PenG, 2 weeks for Gentamicin
      • PCN allergy: Vancomycin
        • DOT: ? ID Consult

Aminoglycoside Synergy

  • Combination of penicillin or ceftriaxone + gentamicin results in synergistic killing in animal models Streptococcal IE
    • More rapid killing than beta-lactam alone
    • Faster eradication of susceptible streptococci from vegetations
  • Combination therapy has only been studied with streptomycin and gentamicin

Aminoglycoside Synergy: Dosing

  • Once daily dosing (ODD) vs traditional dosing for aminoglycosides (AG)
    • In vivo animal models show penicillin + ODD gentamicin vs. penicillin + traditional dosing gentamicin results in similar reduction in bacterial counts from vegetations
  • No studies of ODD gentamicin in penicillin-resistant streptococci so traditional dosing should be used

Streptococcal IE: Treatment Pearls

  • For highly susceptible VGS/S. gallolyticus, ODD AG can be added to PCN to shorten course to 2 weeks
  • ODD AG can NOT be used in VGS/S. gallolyticus that is highly-PCN resistant (use traditional dosing)
  • If vancomycin is used, gentamicin is NOT needed

Staphylococcus spp.

  • Rates as a result of increasing healthcare utilization
    • IV catheters
    • Hemodialysis
    • Indwelling prosthetic devices
  • Resistance
    • Methicillin
    • Vancomycin (?)

Staphylococcal NVE (Native Valve Endocarditis) Regimen

RegimenDoseDuration
Methicillin-susceptible
Nafcillin/oxacillin2 g IV Q 4 hours6 weeks
Cefazolin2 g IV Q 8 hours6 weeks
Methicillin-resistant
Vancomycin30 mg/kg/day IV6 weeks
Daptomycin≥ 8 mg/kg/dose IV6 weeks
  • Additional Considerations:
    • Vancomycin should be dosed based on pharmacokinetics to achieve an AUC goal of 400-600
    • Optimal daptomycin dosing is to be determined
    • Addition of an aminoglycoside is no longer recommended

Staphylococcal PVE (Prosthetic Valve Endocarditis) Regimen

RegimenDoseDuration
Methicillin-susceptible
Nafcillin/oxacillin +2 g IV Q 4 hours≥6 weeks
Rifampin +300 mg IV/PO Q 8 hours≥6 weeks
Gentamicin3 mg/kg/day IV2 weeks
Methicillin-resistant
Vancomycin +30 mg/kg/day IV≥6 weeks
Rifampin +300 mg IV/PO Q 8 hours≥6 week
Gentamicin3 mg/kg/day IV2 weeks
  • Additional Considerations:
    • Vancomycin should be dosed based on pharmacokinetics to achieve a vancomycin AUC goal of 400-600
    • Gentamicin should be administered in divided doses every 8 hours
    • Consider delaying rifampin therapy

Enterococcus spp.

  • Two main species
    • Enterococcus faecalis
    • Enterococcus faecium
  • Increasing rates of resistance
    • Beta-lactams
    • Glycopeptides
    • Aminoglycosides

Enterococcal IE: Susceptible to PCN and Gent

RegimenDoseDuration
Ampicillin or2 g IV Q 4 hours4-6 weeks
Penicillin +18-30 million U IV/day4-6 weeks
Gentamicin3 mg/kg/day IV4-6 weeks
OR
Ampicillin +2 g IV Q 4 hours6 weeks
Ceftriaxone2 g IV Q 12 hours6 weeks
  • Additional Considerations:
    • Gentamicin dose should be administered in equally divided doses every 8 hours
    • Ceftriaxone should be dosed at 2 g IV every 12 hours since it was studied with this regimen

Aminoglycoside Synergy Mechanism

  • Aminoglycoside Monotherapy
    • Gentamicin (NFL Running back)
      • 30S
      • Peptidoglycan (Defensive Line)
      • Bacterial Cell Survives
  • Synergistic Drug Combination
    • Gentamicin (NFL Running back)
      • Cell Wall Synthesis Inhibitor (NFL Offensive Front Line)
        • β-lactam or vancomycin induced gaps in growing cell wall
      • 30S
        • - gaps in cell wall
        • - protein synthesis inhibited irreversibly
      • End zone
      • Peptidoglycan
      • Bacterial Death

Dual Beta-lactam Therapy

  • Observational, nonrandomized, comparative multicenter cohort study
  • Patients with E. faecalis IE
  • Ampicillin + ceftriaxone (AC) vs. ampicillin + gentamicin (AG)
  • Results:
    • AC at baseline had a higher incidence of chronic renal failure, cancer, transplantation, and healthcare associated infection
    • No difference in mortality while on treatment (22% AC vs. 21% AG; p=0.81) or at 3-month follow up (8% AC vs. 7% AG; p=0.72)
    • More frequent discontinuation of antimicrobials due to toxicity in the AG group (25% vs. 1%; p<0.001)

Enterococcal IE: With Resistance to Beta-lactams

RegimenDoseDuration
Vancomycin +30 mg/kg/day IV6 weeks
Gentamicin3 mg/kg/day IV6 weeks
  • Additional Considerations:
    • Gentamicin dose should be administered in equally divided doses every 8 hours

Vancomycin Resistant Enterococcal IE

  • Daptomycin
  • Linezolid

HACEK Organisms

  • Fastidious gram-negative bacilli
  • Grow slowly in standard blood culture media, may require prolonged incubation
    • Only a fraction of blood cultures with HACEK organism demonstrate growth
  • Presence of these organisms is highly suggestive of IE, even without typical physical findings

HACEK Organisms: Species

  • Haemophilus spp.
  • Aggregatibacter spp.
  • Cardiobacterium hominis
  • Eikenella corrodens
  • Kingella spp.
  • Increasing frequency of β-lactamase positive strains
    • Treat as ampicillin/PCN resistant
    • Universally susceptible to 3rd/4th generation cephalosporins or fluoroquinolones

HACEK Organisms: Treatment

OrganismNVIEPVIE
HACEK OrganismsCeftriaxone 2g IV Q24hSame regimens as NVIE
Cefepime 2g IV Q8hDOT: 6 weeks
Alternatives:ID Consult
Ciprofloxacin, levofloxacin, moxifloxacin
Ampicillin/sulbactam
DOT: 4 weeks
Gentamicin is NOT recommended

Culture-Negative IE

  • 5-20% of patients with confirmed IE have negative blood cultures
    • Inadequate microbiological technique
    • Infection with fastidious bacteria
    • Previous administration of antimicrobials
  • Choice of antimicrobials depends on reason for negative cultures and most likely pathogens

Culture-Negative IE: True Culture-Negative

  • Caused by uncommon/rare pathogens that do not grow on blood culture
    • Bartonella spp.
    • Chlamydia spp.
    • Coxiella burnetii
    • Brucella spp.
    • Legionella spp.
    • Tropheryma whipplei
    • Fungi
  • Typically identifiable via serologic testing or PCR
  • ID Consult

Duration of Therapy: all IE

  • When to start counting for DOT?
    • No valve surgery: first day of negative blood cultures
      • Obtain blood cultures every 24-48h until clearance
    • If patient undergoes valve surgery:
      • If resected valve tissue cultures are positive or perivalvular abscess found: start date should be day of surgery
      • If resected tissue culture is negative: first day can be day of negative blood cultures
  • Positive gram stain + negative culture may represent dead organisms and should not define length of therapy