Infective endocarditis

Background

• Infection of endocardium, generally involving the heart valves, either prosthetic or native

Microbiology

• Bacteria
  • Staphylococcus aureus (most common)
  • Viridans group streptococci
  • Coagulase-negative staphylococci
  • Other streptococci
  • Enterococci
  • Gram-negative bacteria (5%)
    • HACEK group
    • Non-HACEK: particularly Pseudomonas aeruginosa and Escherichia coli
• Fungi
  • Candida
• Culture-negative endocarditis
  • Coxiella burnetii
  • Bartonella
  • Brucella
  • Legionella
  • Mycoplasma
  • Tropheryma whipplei
  • Abiotrophia
  • Cutibacterium acnes

Risk Factors

• Cardiac
  • Prior endocarditis
  • Prosthetic heart valve or implanted device
  • Congenital heart disease, especially unrepaired cyanotic congenital heart disease
  • Valve abnormalities, including acquired valvular dysfunction (e.g. from rheumatic heart disease), hypertrophic cardiomyopathy, bicuspid aortic valve, and mitral valve prolapse (especially with valvular regurgitation or thickened leaflets)
• Non-cardiac
  • Intravenous drug use
  • Indwelling intravenous lines
  • Immunosuppression
  • Recent dental work or surgical procedure associated with bacteremia

Clinical Manifestations

• In general, symptoms are fever, chills, and malaise in a patient at risk for endocarditis
• Tends to progress rapidly
• May have a new murmur, stroke syndrome, pulmonary embolism, arthralgias
• Specific organisms may be associated with specific risk factors
  • Injection drug use: Viridans group streptococci and Pseudomonas aeruginosa
  • Colon cancer: Streptococcus gallolyticus subspecies gallolyticus and Clostridium septicum

Subacute Bacterial Endocarditis

• Insidious onset with more pronounced constitutional symptoms progressing over weeks to months

Differential Diagnosis

• Non-infectious causes of endocarditis
  • Acute rheumatic fever
  • Libman-Sacks endocarditis
  • Rheumatoid arthritis
  • Marantic endocarditis
  • Löeffler endocarditis
• Any cause of fever or consitutional symptoms

Diagnosis

• Based on a combination of clinical exam, laboratory investigations, and ultrasound
  • Refer to Modified Duke criteria or ESC 2015 modified criteria for the diagnosis of infective endocarditis
  • C-reactive protein is fairly sensitive, while rheumatoid factor is fairly specific and decreases with treatment
• FDG-PET cardiac imaging is a new imaging modality
  • Can be useful when TEE and CTA are inconclusive, and may be able to diagnose IE earlier than those other modalities
    • May be most helpful in cases of prosthetic valves or other cardiac hardware
  • However, it is non-specific, and cannot differentiate between infection and inflammation
    • In these cases, a tagged WBC scan with SPECT can be helpful
  • False positives with inadequate preparation, or other inflammatory disorders
    • Most commonly is patients getting glucose (including in IV therapies) during the fasting period
  • False negatives can be from very small lesion, or several weeks of antibiotics (needs to be off fo r2 to 4 weeks)
  • To request, should have TEE done beforehand, then fax special access request to Ottawa
    • Response within 24-48 hours, with imaging to be done at local PET (St. Joseph's)

Management

• Varies by causative organism and prosthetic vs. native valve
• In patients who are in acute heart failure, may need to consider the sodium content of the antibiotics used

Antimicrobial Selection

Valve	Antibiotic	Dose	Duration	Notes
MSSA and other oxacillin-susceptible Staphylococcus
NVE	oxacillin	2 g IV q4h	6 weeks	can treat for 2 weeks in uncomplicated right-sided NVE
NVE	cefazolin	2 g IV q8h	6 weeks	in patients with non-anaphylactoid penicillin allergy
PVE	oxacillin	2 g IV q4h	≥6 weeks	use cefazolin or vancomycin if allergy
	+ rifampin	300 mg IV/PO q8h
	+ gentamicin	1 mg/kg IV/IM q8h	2 weeks
MRSA and other oxacillin-resistant Staphylococcus
NVE	vancomycin	15 mg/kg IV q12h	6 weeks	target trough 10-20 μg/mL
NVE	daptomycin	≥8 mg/kg/dose	6 weeks
PVE	vancomycin	15 mg/kg IV q12h	≥6 weeks	target vancomycin trough of 10-20 μg/mL
	+ rifampin	300 mg IV/PO q8h
	+ gentamicin	1 mg/kg IV/IM q8h	2 weeks
Enterococcus susceptible to penicillin and gentamicin
NVE/PVE	ampicillin	2 g IV q4h	4-6 weeks	4 weeks if symptoms <3 months; 6 weeks if symptoms >3 months or if PVE
	+ gentamicin	1 mg/kg IV q8h
NVE/PVE	ampicillin	2 g IV q4h	6 weeks	alternative regimen if CrCl <50
	+ ceftriaxone	2 g IV q12h
Enterococcus susceptible to penicillin and resistant to aminoglycosides
NVE/PVE	ampicillin	2 g IV q4h	6 weeks
	+ ceftriaxone	2 g IV q12h
Enterococcus resistant to penicillin and susceptible to vancomycin and aminoglycosides
NVE/PVE	vancomycin	15 mg/kg IV q12h	6 weeks
	+ gentamicin	1 mg/kg IV/IM q8h
Enterococcus resistant to penicillin, aminoglycosides, and vancomycin
NVE/PVE	linezolid	600 mg IV/PO q12h	>6 weeks
NVE/PVE	daptomycin	10-12 mg/kg IV q24h	>6 weeks
Viridans Streptococcus or Streptococcus gallolyticus highly susceptible to penicillin (MIC ≤0.12 μg/mL)
NVE	penicillin G	3-4 MU IV q4h	4 weeks
NVE	ceftriaxone	2 g IV/IM q24h	4 weeks
NVE	penicillin or ceftriaxone	as above	2 weeks
	+ gentamicin	3 mg/kg IV/IM q24h
NVE	vancomycin	15 mg/kg IV q12h	4 weeks	use if allergy, target 10-15 μg/mL
PVE	penicillin G	6 MU IV q4h	6 weeks
	± gentamicin	3 mg/kg IV/IM q24h	2 weeks
PVE	ceftriaxone	2 g IV/IM q24h	6 weeks
	± gentamicin	3 mg/kg IV/IM q24h	2 weeks
PVE	vancomycin	15 mg/kg IV q12h	6 weeks	use if allergy
Viridans Streptococcus or Streptococcus gallolyticus relatively resistant to penicillin (MIC >0.12 μg/mL)
NVE	penicillin G	6 MU IV q4h	4 weeks
	+ gentamicin	3 mg/kg IV/IM q24h	2 weeks
NVE	vancomycin	15 mg/kg IV q12h	4 weeks	use if allergy, target 10-15 μ/mL
PVE	penicillin G	6 MU IV q4h	6 weeks
	+ gentamicin	3 mg/kg IV/IM q24h
PVE	ceftriaxone	2 g IV/IM q24h	6 weeks
	+ gentamicin	3 mg/kg IV/IM q24h
PVE	vancomycin	15 mg/kg IV q12h	6 weeks	use if allergy
Streptococcus pneumoniae
NVE	penicillin	3-4 MU IV q4h	4 weeks	can use high dose if penicillin-resistant but without meningitis
NVE	cefazolin	2 g IV q8h	4 weeks
NVE	ceftriaxone	2 g IV/IM q24h	4 weeks
PVE	penicillin	3-4 MU IV q4h	6 weeks	can use high dose if penicillin-resistant but without meningitis
PVE	cefazolin	2 g IV q8h	6 weeks
PVE	ceftriaxone	2 g IV/IM q24h	6 weeks
Streptococcus pyogenes
NVE	penicillin G	3-4 MU IV q4h	4 weeks	can use high dose if penicillin-resistant but without meningitis
NVE	ceftriaxone	2 g IV/IM q24h	4 weeks
PVE	penicillin G	3-4 MU IV q4h	6 weeks	can use high dose if penicillin-resistant but without meningitis
PVE	ceftriaxone	2 g IV/IM q24h	6 weeks
Group B, C, or G Streptococcus
NVE	penicillin G	3-4 MU IV q4h	4 weeks	can use high dose if penicillin-resistant but without meningitis
	± gentamicin	3 mg/kg IV/IM q24h	2 weeks
NVE	ceftriaxone	2 g IV/IM q24h	4 weeks
	± gentamicin	3 mg/kg IV/IM q24h	2 weeks
PVE	penicillin G	3-4 MU IV q4h	6 weeks	can use high dose if penicillin-resistant but without meningitis
	± gentamicin	3 mg/kg IV/IM q24h	2 weeks
PVE	ceftriaxone	2 g IV/IM q24h	6 weeks
	± gentamicin	3 mg/kg IV/IM q24h	2 weeks
HACEK bacterium
NVE	ceftriaxone	2 g IV/IM q24h	4 weeks
PVE	ceftriaxone	2 g IV/IM q24h	6 weeks
NVE/PVE	ciprofloxacin	500 mg PO q12h	6 weeks
Non-HACEK Gram-negative bacillus
NVE/PVE	β-lactam		6 weeks	poor data guiding management
	± aminoglycoside or fluoroquinolone

Indications for Early Surgery

• Early valve surgery (that is, before discharge and completion of antibiotics) is recommended in some scenarios
• Left-sided endocarditis
  • Acute heart failure
  • Fungal endocarditis
  • Highly-resistant organisms
  • Heart block, annular or aortic abscess, or perforating valve lesion
  • Bacteremia or fever lasting more than 5-7 days despite appropriate antimicrobials
  • Severe valvular regurgitation and mobile vegetations >1 cm
  • Prosthetic valve endocarditis with recurrent emboli despite appropriate antimicrobials
  • Relapsed prosthetic valve endocarditis
• Right-sided endocarditis
  • Severe tricuspid valve regurgitation with right heart failure despite medical therapy
  • Persistent infection with difficult-to-treat organisms
  • Tricuspid valve vegetation >2 cm
  • Recurrent pulmonary emboli despite appropriate antimicrobials

Early Oral Therapy

• The POET study showed non-inferiority of early oral antibiotics (after 7 to 10 days of IV antibiotics) compared to traditional IV antibiotics for the treatment of left-sided endocarditis1
  • No patient had MRSA
  • All oral therapies included two antibiotics to which the isolate was susceptible
• The regimens in the study were:
  • Penicillin-susceptible staphylococci: (amoxicillin or linezolid) plus (rifampin or fusidic acid)
  • Methicillin-susceptible staphylococci: (dicloxacillin or linezolid) plus (rifampin or fusidic acid)
  • Methicillin-resistant coagulase-negative staphylococci: linezolid plus (rifampin or fusidic acid)
  • Enterococcus faecalis: amoxicillin plus rifampin, or linezolid plus (rifampin or moxifloxacin)
  • Penicillin-susceptible streptococci (MIC <1): amoxicillin plus rifampin, or linezolid plus (rifampin or moxifloxacin)
  • Penicillin-resistant streptococci (MIC ≥1): linezolid plus rifampin, or moxifloxacin plus (rifampin or clindamycin)
• Doses were:
  • Amoxicillin 1 g p.o. four times daily
  • Clindamycin 600 mg p.o. three times daily
  • Dicloxacillin 1 g p.o. q6h
  • Fusidic acid 750 mg p.o. twice daily
  • Linezolid 600 mg p.o. twice daily
  • Moxifloxacin 400 mg p.o. daily
  • Rifampin 600 mg p.o. twice daily
• A retrospective cohort study of people who inject drugs confirmed that these findings are likely generalizable to PWID2
  • Details of the regimens are not available, but included primarily doxycycline, TMP-SMX, and linezolid, as well as some beta-lactams, either as monotherapy or as combination therapy
• Another cohort study has shown that it can be effectively operationalized3
  • Indications for step-down to oral therapy, which could take from a few days to a few weeks:
    • Clinically stable with no indication for cardiac surgery
    • Bacteremia is cleared
    • No concern regarding GI absorption
    • No psychosocial concerns where IV would be preferable
    • An appropriate oral antibiotic was available, based on in vitro susceptibility testing and published clinical data
  • Recommended oral antibiotics:
    • Amoxicillin 1 g p.o. every 6 hours
    • Co-trimoxazole 960 mg/4800 mg p.o. total daily dose, divided
    • Dicloxacillin 1 g p.o. q6h
    • Levofloxacin 750 mg p.o. daily
    • Linezolid 600 mg p.o. twice daily
    • Moxifloxacin 400 mg p.o. daily
    • Rifampin 600 mg p.o. daily; preferred as second agent in prosthetic valve endocarditis

Organism	Oral Regimens
Penicillin-susceptible streptococci (MIC <= 0.12)	amoxicillin alone (native valve only)
	amoxicillin + rifampin
	linezolid +/- rifampin
	moxifloxacin + (rifampin or linezolid)
Penicillin-intermediate streptococci (MIC 0.25-1) or enterococci	amoxicillin + (rifampin or linezolid)
	linezolid +/- rifampin
	moxifloxacin + rifampin
MSSA	levofloxacin + (rifampin or linezolid)
	linezolid +/- rifampin
	co-trimoxazole
	dicloxacillin + rifampin
MRSA and CoNS	levofloxacin + (rifampin or linezolid)
	linezolid +/- rifampin
	co-trimoxazole

Prevention

• Prophylaxis is recommended for high-risk patients who are undergoing higher-risk procedures
  • High-risk patients include:
    • Prosthetic heart valve
    • Previous infective endocarditis
    • Unrepaired cyanotic congenital heart disease, or repaired within the past six months with prosthetic material in situ, or repaired with residual defect and with material in situ
    • Cardiac transplantation with valvulopathy
  • High-risk procedures include:
    • Dental procedures with manipulation of the gingiva or periapical region of teeth, perforation of mucosa
      • This includes professional cleaning procedures
    • Procedures involving incision of respiratory mucosa, including tonsillectomy and bronchoscopic biopsy
    • Procedures on infected tissue (skin, bone, joint, etc)
• Antibiotic options are:
  • Amoxicillin 2 g PO once, 30-60 minutes prior to procedure
  • If allergy: clindamycin 600 mg PO once, 30-60 minutes prior to procedure

Further Reading

• Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications. Circulation. 2015 Oct 13;132(15):1435-86. doi: 10.1161/CIR.0000000000000296
• 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). European Heart J. 2015;36(44):3075-3128. doi: 10.1093/eurheartj/ehv319