Infective Endocarditis

Overview & definition

Infective endocarditis (IE) is an infection of the cardiac valves (or the endocardium) by microorganisms that adhere to the valve surface and form a vegetation (a mass of platelets, fibrin, and organisms). In the ICU, it presents acutely (often with Staphylococcus aureus — aggressive, causing septic shock, acute severe valve failure, and septic emboli). The modified Duke criteria provide the diagnostic framework.[1]

The modified Duke criteria

Definite IE: 2 major, OR 1 major + 3 minor, OR 5 minor.[1]

Major criteria:

1. Typical positive blood cultures from 2 separate cultures (viridans streptococci, S. aureus, HACEK, or enterococci).
2. Echocardiographic evidence — a vegetation, an abscess, or a new partial dehiscence of a prosthetic valve. [1]

Minor criteria:

1. Predisposition (a predisposing heart condition — a prosthetic valve, a previous IE, a congenital heart disease, or IV drug use).
2. Fever over 38 degrees Celsius.
3. Vascular phenomena — arterial emboli, septic pulmonary infarcts, mycotic aneurysms, intracranial haemorrhage, Janeway lesions, conjunctival haemorrhages.
4. Immunological phenomena — glomerulonephritis, Osler nodes, Roth spots, a positive rheumatoid factor.
5. Microbiological evidence not meeting the major criterion (a single positive culture or a serological evidence).[1]

The organisms

• Staphylococcus aureus — the commonest in the ICU and in IV drug users; aggressive, acute; often causes acute severe valve failure and septic emboli. High mortality.[1]
• Viridans streptococci (Streptococcus sanguis, S. mutans) — subacute, from the dental plaque; the classic organism of the native-valve subacute endocarditis.[1]
• Enterococci (E. faecalis, E. faecium) — often from the gastrointestinal or the genitourinary tract; resistant organisms are increasing.[1]
• HACEK (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella) — fastidious Gram-negatives; culture-negative if the lab does not hold the cultures long enough.
• Culture-negative — Coxiella burnetii (Q fever), Bartonella, Brucella, fungi (Candida, Aspergillus); consider if the standard cultures are negative.[1]

Clinical features

• Fever (over 90 per cent of cases) and constitutional symptoms (malaise, weight loss).
• A new or changed murmur (the vegetation alters the valve function — a regurgitant murmur).
• Embolic phenomena — a stroke, a splenic infarct or abscess, a mesenteric ischaemia, a renal infarct, a limb ischaemia (from embolisation of vegetation fragments).
• Immunological phenomena — Osler nodes (tender nodules on the finger pulps), Roth spots (retinal haemorrhages with a pale centre), a glomerulonephritis.
• Vascular phenomena — Janeway lesions (painless macules on the palms or soles from septic emboli), a conjunctival haemorrhage, a mycotic aneurysm.
• Splenomegaly.[1]

Echocardiography

• Transthoracic echo (TTE) — the first test; a sensitivity of about 60 per cent for the native valve (less for the prosthetic). A vegetation appears as an oscillating mass on the valve.
• Transoesophageal echo (TOE) — if the TTE is negative or for the prosthetic valve; a sensitivity over 90 per cent; also detects the complications (an abscess, a fistula, a perforation, a prosthetic dehiscence).[1]

Treatment

Empirical antibiotics (while awaiting the blood cultures):[1]

• For the native valve: ampicillin + gentamicin + flucloxacillin (covering the streptococci, the enterococci, and the staphylococci), OR vancomycin + gentamicin (if penicillin-allergic or if MRSA is suspected).
• For the prosthetic valve: vancomycin + gentamicin + rifampicin (covering the staphylococci including MRSA, the streptococci, and the enterococci).

Targeted therapy (once the organism and the sensitivities are known):[1]

• IV therapy for 4-6 weeks (longer for some organisms — fungi, resistant enterococci).
• Monitor the inflammatory markers (CRP), the renal function (nephrotoxicity from the gentamicin), and the repeat echo (the vegetation size, the valve function).

Surgical indications

Surgery (valve repair or replacement) is indicated for:[1]

• Heart failure from the acute severe valve dysfunction (the commonest indication — acute severe AR or MR with pulmonary oedema or cardiogenic shock).
• Uncontrolled infection — a persistent bacteraemia or fever after 5-7 days of appropriate antibiotics; fungal or resistant organisms that cannot be eradicated medically.
• Prevention of embolism — a large vegetation (over 10 mm) with one or more embolic events, or a very large vegetation (over 15 mm) even without an embolus.
• Perivalvular extension — an abscess, a fistula, a heart block (from the aortic-root abscess extending into the septum).
• Prosthetic valve endocarditis — early (within 1 year of the surgery) or complicated (dehiscence, obstruction).[1]

The ICU-specific problems

• Septic shock from S. aureus IE — resuscitate per the sepsis protocol; source control is the valve surgery.
• Acute severe valve failure (AR or MR with pulmonary oedema or cardiogenic shock) — urgent surgery; temporise with vasodilators, inotropes, or an IABP.
• Septic emboli — a stroke (may need neurosurgical input for a haemorrhagic transformation or a mycotic aneurysm); a mesenteric ischaemia; a splenic abscess (drain or splenectomy); a limb ischaemia (embolectomy).[1]

[1]

Red flags

Modified Duke criteria — interpretation and the 2023 update

The modified Duke criteria are the diagnostic standard, but the diagnostic categories (definite, possible, rejected) drive every clinical decision and are the most frequently examined nuance. The 2023 ESC update (incorporating the Duke-ISCVID 2023 criteria) added imaging findings (PET-CT uptake around a prosthetic valve, abnormal CT of a paravalvular lesion) as major criteria and re-weighted S. aureus bacteraemia.[1]

[1]

The 2023 Duke-ISCVID additions (now a major criterion): a single positive blood culture for Coxiella burnetii (or phase I IgG titre over 1:800); imaging evidence of IE (abnormal FDG uptake on PET-CT around a prosthetic valve, paravalvular lesions on cardiac CT, a new vegetation on repeat echo); and a single positive culture for a typical IE organism is now weighted more heavily. Staphylococcus aureus bacteraemia — even nosocomial — is now a major criterion when no alternative focus is identified.[1]

The organisms — epidemiology and clinical associations

The organism predicts the syndrome, the prognosis, and the empiric therapy. The ICE-PCS cohort (over 2,700 patients, the 21st-century reference) and the EURO-ENDO registry (over 3,100 patients) define the modern epidemiology.[9][13]

[1]

Streptococcal IE — the subacute archetype

Viridans streptococci are the classic organism of native-valve, subacute endocarditis. The patient has weeks of low-grade fever, weight loss, and malaise; the valves are usually pre-damaged (rheumatic, bicuspid, degenerative). The organism is penicillin-sensitive (MIC under 0.12 mg/L), and 4 weeks of IV penicillin G or ceftriaxone gives a cure rate above 95 per cent.[1] Streptococcus gallolyticus is special — its presence mandates colonoscopy because of the strong association with colonic neoplasia (the bacteraemia arises from a mucosal breach over a tumour).[13]

Staphylococcal IE — the ICU archetype

Staphylococcus aureus is the organism the intensivist fears. Unlike viridans streptococci, it can colonise and destroy a previously normal valve; it produces a fulminant, acute illness with high fever, septic shock, and rapid valvular destruction; and it has the highest embolic rate of any organism (over 50 per cent of patients embolise). The mortality of 25-40 per cent has not improved in two decades despite better antibiotics and surgery.[6] Coagulase-negative staphylococci cause prosthetic valve IE (the organism of early PVE from perioperative contamination) — with the critical exception of S. lugdunensis, which is virulent like S. aureus and causes aggressive native-valve IE requiring the same aggressive management.[8]

Enterococcal IE

Enterococci (mainly E. faecalis) cause IE in older men after genitourinary instrumentation or in patients with bowel pathology. They are intrinsically resistant to cephalosporins (the cell wall target is altered), so therapy is ampicillin (or vancomycin) PLUS an aminoglycoside (gentamicin or streptomycin) for synergy, or ampicillin plus ceftriaxone (the double-beta-lactam regimen) for 4-6 weeks. Vancomycin-resistant enterococci (VRE) require linezolid or daptomycin.[8]

HACEK and culture-negative IE

The HACEK group are fastidious Gram-negatives of the oropharynx that need prolonged incubation (modern automated blood-culture systems usually grow them within 5 days, but they were historically a cause of "culture-negative" IE). They produce large vegetations and embolise frequently; ceftriaxone for 4 weeks is curative.[8] Culture-negative IE has a defined differential: prior antibiotics (the commonest cause — repeat cultures after a washout period), Coxiella burnetii (Q fever — phase I IgG), Bartonella ( homelessness, alcoholism, body lice), Brucella (unpasteurised dairy), Tropheryma whipplei (Whipple disease), and fungi. The workup is serology and PCR, and a history of antibiotic exposure, animal contact, or travel directs the search.[1]

Fungal endocarditis

Fungal IE (Candida most often, then Aspergillus) is rare but devastating: the vegetations are large and friable (over 50 per cent embolise), blood cultures may be negative, and medical cure is rarely achieved. Surgical valve replacement is mandatory, combined with prolonged antifungal therapy (liposomal amphotericin B plus flucytosine, then long-term fluconazole suppression; echinocandins for Candida). Risk factors are IV drug use, prolonged antibiotics, total parenteral nutrition, immunosuppression, and indwelling central lines.[8]

Echocardiography — the TTE then TOE strategy

Echocardiography is the single most important diagnostic test in suspected IE. The strategy is TTE first, then TOE — but in the ICU, with a critically ill intubated patient, TOE is low-risk and high-yield, so the threshold to proceed to TOE is low.[1]

[1]

When TOE is mandatory (do it, regardless of the TTE result): any prosthetic valve; a suspected complication (abscess, fistula, new heart block, persistent bacteraemia); S. aureus bacteraemia; a negative TTE but a strong clinical suspicion; before surgery to define the anatomy; and after surgery to confirm eradication.[1][8] Even if the TTE shows a vegetation, a TOE is still performed to assess for abscess, perforation, fistula, and the extent of destruction — these change the surgical plan and are missed on TTE.

Beyond echo — multimodality imaging

For prosthetic valve IE, where echo is limited by shadowing, 18F-FDG PET-CT (abnormal uptake around the valve) and cardiac CT (paravalvular complications — abscess, pseudoaneurysm, dehiscence) are now major Duke criteria. PET-CT is most useful more than 3 months after surgery (early post-operative inflammation causes false positives).[1] Cerebral imaging (MRI) is performed in all patients with left-sided IE — silent cerebral emboli are found in over 50 per cent, and they alter the surgical timing.

Antimicrobial therapy — native vs prosthetic valve

IE requires prolonged, high-dose, bactericidal IV therapy. The principles: (1) culture before antibiotics (3 sets, different sites, 30 minutes apart); (2) use beta-lactams at high dose (concentration-independent time-dependent killing — the time above the MIC drives efficacy); (3) add gentamicin for synergy in staphylococcal and enterococcal IE (but limit to 2 weeks to limit nephrotoxicity); (4) add rifampicin for prosthetic-valve staphylococcal IE (biofilm penetration); (5) treat for 4-6 weeks IV.[1][8]

[1] [1]

Antibiotic pharmacology — synergy, biofilm, and toxicity

• Gentamicin synergy — added to beta-lactams/vancomycin for enterococcal and staphylococcal IE; once-daily dosing (3 mg/kg) reduces nephrotoxicity; limit to 2 weeks (the synergy benefit is early, the toxicity accrues with time); monitor trough (under 1 mg/L) and creatinine. Stop if renal function declines.[8]
• Rifampicin and the biofilm — prosthetic material (mechanical valves, rings) develops a bacterial biofilm that beta-lactams cannot penetrate. Rifampicin is highly lipophilic and uniquely penetrates biofilm, killing the embedded staphylococci. Start it AFTER 3-5 days of vancomycin/flucloxacillin (to reduce the bacterial load and delay the emergence of rifampicin resistance, which is rapid in a high-inoculum setting).[4][12]
• Vancomycin — for MRSA and penicillin-allergic staphylococcal IE; target a trough of 15-20 mg/L (or AUC-guided dosing); slower infusion, nephrotoxicity (worsened by concurrent gentamicin/piperacillin-tazobactam). If the vancomycin MIC is over 1.5 mg/L, switch to daptomycin.[8]
• Daptomycin — bactericidal lipopeptide; an alternative for MRSA IE (especially right-sided) and VRE; not for pneumonia (inactivated by surfactant); higher doses (8-12 mg/kg/day) for IE; creatine kinase monitoring (myopathy).
• Ceftriaxone once-daily — the workhorse for streptococcal and HACEK IE; enables hospital-in-the-home and partial-oral regimens.[3]

The POET trial — partial oral switch for selected patients

The POET trial (Iversen 2019) challenged the dogma that IE must be treated entirely IV. In 400 patients with left-sided, culture-positive, streptococcal/staphylococcal/enterococcal IE who had responded to IV therapy and had no prosthesis, abscess, or heart failure, a switch to oral antibiotics (after at least 10 days IV) was non-inferior to continued IV therapy for the composite of all-cause mortality, unplanned surgery, embolic events, and relapse.[3] Caveats: the regimen was carefully selected (oral bioavailability confirmed by serum bactericidal titre), it excluded the sickest patients, and the oral drugs were chosen by an infectious-diseases specialist. The take-home: carefully selected, clinically improving, non-complicated IE can be completed orally — but this is the exception, not the default, and requires close follow-up.

Surgery — indications, timing, and the cerebral-embolism problem

Around 40-50 per cent of patients with IE need surgery. The decision is multidisciplinary (the "Endocarditis Team" — cardiology, infectious diseases, cardiac surgery) and is driven by four indications, in order of urgency: heart failure, uncontrolled infection, embolic prevention, and prosthetic/perivalvular extension.[1][2]

[1]

Cerebral embolism and the timing of surgery

A cerebral embolic event is the most feared complication and the most common reason for delaying surgery. The problem: cardiopulmonary bypass requires full heparinisation, which risks haemorrhagic transformation of a recent cerebral infarct. The ESC guidance:[1]

• Ischaemic stroke, no coma, no haemorrhage — surgery can proceed, but a short delay (ideally 2 weeks) is preferred if heart failure allows. Intracranial haemorrhage must be excluded by CT/MRI first.
• Haemorrhagic stroke or coma — delay surgery for at least 3-4 weeks if at all possible.
• Heart failure is life-threatening — operate DESPITE the stroke. Heart failure, not the stroke, is the threat to life, and the mortality of unoperated heart failure exceeds the risk of bypass-related haemorrhagic transformation.
• Silent cerebral emboli on MRI — do not, by themselves, contraindicate or delay surgery. [1]

Complications — embolic stroke, mycotic aneurysm, heart block

The complications of IE are the causes of death: heart failure (covered above), septic embolisation (stroke, splenic, mesenteric, limb, renal, coronary), mycotic aneurysm (especially intracranial), perivalvular extension (abscess, fistula, heart block), renal involvement (glomerulonephritis, acute kidney injury), and the septic shock of uncontrolled infection.[5][8]

Embolic stroke

Systemic embolisation occurs in 20-40 per cent of patients with left-sided IE; the brain is the commonest site (over half of emboli). The risk is highest in the first week, before antibiotics work, and is driven by vegetation size (over 10 mm), mobility, mitral location, S. aureus, and increasing CRP.[11] Management: STOP any anticoagulation; CT brain (ischaemic vs haemorrhagic); exclude a mycotic aneurysm (CT/MR angiography) before surgery; if a large mobile vegetation remains, consider early surgery to prevent further emboli.[1]

Mycotic (intracranial infectious) aneurysm

A mycotic aneurysm is a destructive arteritis caused by septic embolisation of the vasa vasorum or the arterial lumen — most often distal middle cerebral artery branches in left-sided IE. It may rupture (subarachnoid or intracerebral haemorrhage — a catastrophe) or be found incidentally on screening angiography. Suspect it in any IE patient with a sudden severe headache, a new neurologic deficit, or a haemorrhagic stroke.[14]

[1]

Heart block and perivalvular extension

The aortic valve annulus is anatomically adjacent to the AV node and the bundle of His. An aortic-root or anterior mitral-annular abscess can extend into the septum, destroy the conduction tissue, and produce a new AV block (first degree progressing to complete heart block). A new conduction abnormality in aortic-valve IE is, until proven otherwise, a perivalvular abscess — confirm with TOE (the test of choice) and proceed to surgical debridement. A temporary pacing wire is placed; permanent pacing, if needed, is done at surgery (epicardial) because transvenous leads infect the new valve.[8]

Other embolic complications

• Splenic infarct or abscess — left upper quadrant pain; CT diagnosis; small infarcts need no treatment, an abscess may need drainage or splenectomy.
• Mesenteric ischaemia — abdominal pain out of proportion to examination; CT angiography; surgical resection of infarcted bowel.
• Renal infarct — flank pain, haematuria; usually managed medically; septic emboli to the kidney can also cause renal abscess.
• Limb ischaemia — a cold, painful limb; urgent embolectomy and assessment for compartment syndrome.
• Coronary embolus — embolisation to a coronary artery can cause myocardial infarction (often the right coronary, given its origin); manage per the MI protocol but the source is the vegetation. [1]

Acute kidney injury in IE

AKI in IE is multifactorial: septic acute tubular necrosis (the commonest), post-infectious glomerulonephritis (immune complex, low complement), embolic renal infarction, antibiotic nephrotoxicity (gentamicin, vancomycin), and the haemodynamics of acute valvular regurgitation. The glomerulonephritis may continue to worsen even as the infection is treated; in severe or rapidly progressive disease, consider plasma exchange and immunosuppression after the infection is controlled.[8]

Pitfalls and myths

Additional red flags

Key trials and evidence

[1] [1] [1] [1] [1] [1]

Exam practice

[1]

The high-yield summary

References

1. [1]Delgado V, Ajmone Marsan N, de Waha S, et al. 2023 ESC Guidelines for the management of endocarditis Eur Heart J, 2023.PMID 37622656
2. [2]Habib G, Lancellotti P, Antunes MJ, et al. 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). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM) Eur Heart J, 2015.PMID 26320109
3. [3]Iversen K, Ihlemann N, Gill SU, et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis N Engl J Med, 2019.PMID 30152252
4. [4]Kang DH, Kim YJ, Kim SH, et al. Early surgery for infective endocarditis N Engl J Med, 2012.PMID 23034033
5. [5]Hasbun R, Vikram HR, Barakat LA, Buenconsejo J, Quagliarello VJ. Complicated left-sided native valve endocarditis in adults: risk classification for mortality JAMA, 2003.PMID 12697795
6. [6]Fowler VG Jr, Miro JM, Hoen B, et al. Staphylococcus aureus endocarditis: a consequence of medical progress JAMA, 2005.PMID 15972563
7. [7]Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis Clin Infect Dis, 2000.PMID 10770721
8. [8]Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America Circulation, 2005.PMID 15956145
9. [9]Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study Arch Intern Med, 2009.PMID 19273776
10. [10]Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group Circulation, 2007.PMID 17446442
11. [11]Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis J Am Coll Cardiol, 2001.PMID 11263610
12. [12]Chirouze C, Alla F, Fowler VG Jr, et al. Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study Clin Infect Dis, 2015.PMID 25389255
13. [13]Habib G, Erba PA, Iung B, et al. Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EURO-ENDO (European infective endocarditis) registry: a prospective cohort study Eur Heart J, 2019.PMID 31504413
14. [14]Cahill TJ, Prendergast BD. Infective endocarditis Lancet, 2016.PMID 26341945