Infective Endocarditis (IE): Diagnosis and Treatment

Overview

Diagnosis: The 2023 Duke Criteria

Classification

Major Criteria

• Typical organisms (Viridans streptococci, S. bovis, HACEK group, S. aureus, community-acquired enterococci) isolated from 2+ separate blood culture sets
• Less typical organisms isolated from 3+ separate culture sets
• At least 2 positive cultures drawn >12 hours apart, OR all of 3 or majority of >4 cultures (first and last drawn ≥1 hour apart)
• Single positive blood culture for Coxiella burnetii OR antiphase IgG antibody titer >1:800

• Positive PCR/nucleic acid test from blood for Coxiella burnetii, Bartonella spp., or Tropheryma whipplei

• Echocardiography/cardiac CT: vegetation, valvular perforation/aneurysm, abscess, pseudoaneurysm, intracardiac fistula, significant new valvular regurgitation (compared to prior imaging), new partial prosthetic valve dehiscence
• 18F-FDG PET/CT: abnormal metabolic activity (at least 3 months after implantation) involving native/prosthetic valve, ascending aortic graft, intracardiac device leads, or other prosthetic material

• Evidence of IE observed by direct inspection during cardiac surgery (in absence of major microbiologic or imaging criteria)

Minor Criteria

Echocardiographic Workup

• TTE first in all patients; proceed to TEE when TTE is non-diagnostic or of poor quality
• TEE as first-line for prosthetic valve IE (sensitivity much higher than TTE)
• TEE immediately (Class I) when: TTE non-diagnostic with high suspicion, prosthetic valve involved, suspected complications (abscess, perforation, fistula), pre-operative planning, intraoperative guidance
• Repeat imaging is indicated with clinical deterioration, new murmur, persistent fever/bacteremia, or virulent organisms (e.g., S. aureus)
• High-risk echo features warranting closer follow-up: large/mobile vegetations, valvular insufficiency, perivalvular extension, secondary ventricular dysfunction

Treatment

Team-Based Approach

Empiric Antibiotic Therapy

Definitive Antibiotic Therapy (by Organism)

• Penicillin G or ceftriaxone (4 weeks) - outpatient once-daily ceftriaxone is acceptable after initial hospital observation

• MSSA: Nafcillin or oxacillin (6 weeks); cefazolin is an alternative in beta-lactam intolerant patients
• MRSA: Vancomycin (6 weeks); note vancomycin has inferior microbiologic outcomes compared to nafcillin for MSSA
• Daptomycin is an option (particularly for right-sided IE)

• Penicillin/ampicillin + gentamicin (4-6 weeks) - gentamicin is critical for synergy in enterococcal IE
• Ampicillin + high-dose ceftriaxone (2g IV q12h) is an alternative to avoid aminoglycoside toxicity in E. faecalis
• VRE: daptomycin, linezolid, or quinupristin-dalfopristin (high relapse rates; surgery often needed)

• Ceftriaxone or ampicillin-sulbactam (4 weeks)
• Often curable with antibiotics alone without surgery

• Doxycycline + hydroxychloroquine for ≥18 months (native valve); minimum until PCR becomes negative in blood

Surgical Indications

Native Valve IE

• Heart failure caused by valve dysfunction (severe regurgitation or obstruction)
• IE caused by fungi or highly resistant organisms
• Heart block, annular or aortic abscess, or destructive penetrating lesions

• Persistent bacteremia >5-7 days despite appropriate antibiotics
• Recurrent emboli and persistent/enlarging vegetations despite appropriate therapy
• Severe valve regurgitation + mobile vegetations >10 mm

• Mobile vegetations >10 mm (especially anterior mitral leaflet) with other relative indications

Prosthetic Valve IE (PVE)

• Symptomatic heart failure from valve dehiscence, intracardiac fistula, or severe prosthetic dysfunction
• Persistent bacteremia >5-7 days despite appropriate therapy
• Heart block, annular/aortic abscess, or destructive lesions
• Fungi or highly resistant organisms

• Recurrent emboli despite appropriate antibiotics
• Relapsing PVE

Right-Sided IE

• Surgery generally avoided if possible (especially in IV drug users)
• Indications include heart failure, recurrent emboli, resistant organisms, very large vegetations (≥20 mm), or persistent bacteremia
• Valve repair preferred over replacement when feasible

Timing of Surgery with Neurologic Complications

• No delay needed for: silent microembolism, TIA, cerebral abscess, ischemic stroke without hemorrhagic conversion and without severe neurological deficits
• Delay at least 4 weeks for: major ischemic stroke or intracranial hemorrhage

Antibiotic Prophylaxis (Prevention)

• Prosthetic cardiac valve or valve repair with prosthetic material
• Previous IE
• Left ventricular assist devices or implantable hearts
• Certain congenital heart diseases (unrepaired cyanotic CHD, repaired CHD with residual defects)
• Cardiac transplant with valvulopathy

• Textbook of Clinical Echocardiography (2023 Duke Criteria table)
• Fuster & Hurst's The Heart, 15th Ed. (modified Duke criteria, surgical indications)
• Goldman-Cecil Medicine (treatment algorithms, empiric/definitive regimens)
• Braunwald's Heart Disease (AHA 2021 prophylaxis update, echocardiographic approach)

Pyrexia of Unknown Origin (PUO / FUO)

Definition

1. Fever ≥38.3°C (101°F) on at least two occasions
2. Illness duration of at least 3 weeks
3. No known immunocompromised state (immunocompromised patients form a separate category requiring a more aggressive approach)
4. No diagnosis despite appropriate evaluation

The "FUO Paradox"

Classification of Causes

1. Infections (~15-66% by region)

• Abdominal/pelvic abscess, epidural abscess, intracranial abscess, muscle abscess, renal abscess
• Endocarditis (culture-negative), osteomyelitis, spondylodiscitis
• Sinusitis, cholangitis, cholecystitis, diverticulitis, prostatitis, pyelonephritis
• Septic arthritis, infected vascular/joint prosthesis, infected vascular catheter
• Mycotic aneurysm

• Mycobacterium tuberculosis (most common single infectious cause globally; responsible for up to 50% of infections in non-Western cohorts)
• Brucellosis, bartonellosis, leptospirosis, typhoid fever, listeriosis
• Q fever (Coxiella burnetii), rickettsiosis, ehrlichiosis
• Whipple disease (Tropheryma whipplei)
• Actinomycosis, nocardiosis, nontuberculous mycobacteria
• Lyme disease, relapsing fever (Borrelia spp.)
• Legionellosis, melioidosis, tularemia, psittacosis
• Syphilis, gonococcus, chronic meningococcemia

• Epstein-Barr virus (EBV), Cytomegalovirus (CMV)
• Acute HIV infection
• Hepatitis A, B, or E
• COVID-19 (post-acute sequelae)
• Dengue, West Nile virus, enteroviruses, hantavirus, Lassa fever

• Malaria, visceral leishmaniasis (kala-azar), toxoplasmosis
• Babesiosis, filariasis, trichinosis
• Aspergillosis, candidiasis, histoplasmosis, coccidioidomycosis, Pneumocystis

2. Non-Infectious Inflammatory Diseases (NIIDs) - ~15-25%

• Adult-onset Still disease (AOSD)
• Giant cell arteritis / temporal arteritis
• Polymyalgia rheumatica
• Systemic lupus erythematosus (SLE)
• Inflammatory bowel disease (Crohn's disease more than UC)
• Sarcoidosis

• Rheumatoid arthritis (with systemic features)
• Polyarteritis nodosa, granulomatosis with polyangiitis (GPA), Takayasu arteritis
• Antiphospholipid syndrome
• Sjögren's syndrome, mixed connective tissue disease
• Autoinflammatory syndromes: Familial Mediterranean fever (FMF), TRAPS, CAPS, PFAPA
• Hemophagocytic lymphohistiocytosis (HLH)
• Castleman disease
• Kikuchi-Fujimoto disease (necrotizing lymphadenitis)
• Behçet's disease
• Kawasaki disease

3. Malignancy (~7-14%)

• Hodgkin lymphoma
• Non-Hodgkin lymphoma
• Leukemia (especially AML, CLL)
• Multiple myeloma, myelodysplastic syndrome
• Intravascular lymphoma (often undetected until autopsy)

• Renal cell carcinoma (classic fever-flank pain-hematuria triad, but often presents with fever alone)
• Hepatocellular carcinoma
• Colon and gastric adenocarcinoma
• Melanoma, mesothelioma
• Atrial myxoma (cardiac tumour mimicking IE or embolic disease)

4. Miscellaneous (~5-8%)

• Drug fever - virtually any drug can cause fever, even after long-term use; common culprits: allopurinol, carbamazepine, phenytoin, sulfonamides, minocycline, vancomycin, beta-lactams, isoniazid, furosemide. Often accompanied by eosinophilia ± lymphadenopathy (DRESS/DIHS)
• Factitious fever - patient manipulates thermometer (fraudulent); dissociation between pulse rate and temperature is a clue; confirm by simultaneous multi-site temperature measurement
• Self-induced fever - injection of contaminated material; more common in those with healthcare access
• Hematoma (especially retroperitoneal)
• Pulmonary embolism / chronic thromboembolic disease
• Drug-induced hyperthermia (neuroleptic malignant syndrome, serotonin syndrome, malignant hyperthermia)
• Subacute thyroiditis
• Hyperthyroidism / hypoadrenalism (Addison disease) - endocrine causes
• Pheochromocytoma
• Periodic fever syndromes
• Central causes: hypothalamic dysfunction, CVA, encephalitis, brain tumor
• Peripheral dysregulation: anhidrotic ectodermal dysplasia, exercise-induced hyperthermia, heat stroke

5. No Diagnosis (~16-50%)

Relevant History Questions

Fever Characteristics

• Pattern: continuous/sustained (typhoid, brucellosis), intermittent (malaria - tertian/quartan pattern), relapsing (Borrelia, lymphoma, FMF), hectic/spiking (abscess, lymphoma, Still disease)
• Duration: how long has fever been present? Any episodes before?
• Height and timing: morning vs. evening predominance
• Associated symptoms: rigors (bacteremia, malaria), night sweats (TB, lymphoma, HIV)
• Response to antipyretics

Travel and Geographic Exposure

• Recent AND remote travel history (malaria, typhoid, brucellosis, visceral leishmaniasis, melioidosis, histoplasmosis, coccidioidomycosis vary by region)
• Country of origin (TB endemic areas, FMF in Mediterranean/Middle East populations)
• Rural vs. urban exposure
• Water sources (leptospirosis, tularemia)

Animal and Environmental Contacts

• Farm animals / cattle / goats (Q fever, brucellosis)
• Cats (bartonellosis/cat scratch, Q fever)
• Dogs (leptospirosis, brucellosis)
• Ticks (Lyme, rickettsiosis, ehrlichiosis, tick-borne relapsing fever, tularemia)
• Birds/poultry (psittacosis, histoplasmosis)
• Rodents (leptospirosis, hantavirus)
• Unpasteurized dairy (brucellosis, TB, listeriosis)
• Soil/construction/caves (histoplasmosis, coccidioidomycosis, melioidosis)

Past Medical and Surgical History

• Previous cardiac valve disease, prosthetic valves (endocarditis, infected prosthesis)
• Previous surgery (intra-abdominal abscess, spondylodiscitis)
• Previous TB or TB contacts
• Malignancy history (recurrence, post-treatment lymphoma)
• Autoimmune disease history
• Recurrent infections (immunodeficiency)

Drug History (Critical)

• All current and recently stopped medications (drug fever can occur after months of use)
• Over-the-counter drugs, herbal/traditional remedies, supplements
• Recent antibiotic or corticosteroid use (can mask diagnosis and render cultures sterile)
• Vaccinations (BCG infection)

Sexual and Social History

• HIV risk factors (unprotected sex, intravenous drug use, transfusions)
• Injection drug use (endocarditis, septic emboli, HIV, hepatitis)
• Occupation (healthcare workers - TB; veterinarians/abattoir workers - Q fever, brucellosis)
• Alcohol use (hepatic abscess, TB predisposition)

Family History

• Familial Mediterranean fever (FMF) or other periodic fever syndromes
• Hereditary malignancies
• Autoimmune diseases

Systemic Review - Key Symptoms to Ask

• Weight loss (TB, lymphoma, malignancy, HIV, inflammatory disease)
• Night sweats (TB, lymphoma, HIV, brucellosis)
• Lymphadenopathy (lymphoma, EBV, CMV, HIV, TB, toxoplasmosis, cat scratch, sarcoidosis, Still disease)
• Rash (Still disease - classic evanescent salmon-colored rash during fever spikes; SLE malar rash; drug rash; rickettsia; viral exanthem; vasculitis)
• Joint pains (Still disease, SLE, reactive arthritis, brucellosis, Lyme, IBD)
• Headache/neck stiffness (CNS infection, vasculitis)
• Visual symptoms (giant cell arteritis - jaw claudication, scalp tenderness, visual loss)
• Abdominal pain (abscess, IBD, FMF attacks)
• Urinary symptoms (occult UTI, pyelonephritis, renal abscess, renal cell carcinoma)
• Cardiac symptoms - new murmur, palpitations (endocarditis, atrial myxoma)
• Respiratory symptoms (TB, fungal, sarcoidosis, lymphoma mediastinal adenopathy)

Structured Diagnostic Approach

1. Identify all PDCs (potentially diagnostic clues) from history + exam + obligatory tests
2. If PDCs present → targeted, diagnosis-directed investigations
3. If PDCs absent → 18F-FDG-PET/CT (detects a cause in 30-60% of cases; identifies metabolically active foci for biopsy, and can itself be diagnostic for large-vessel vasculitis)
4. If still no diagnosis → tissue biopsy (lymph node, liver, bone marrow, temporal artery) guided by PET/CT
5. Undiagnosed + stable → watchful waiting, periodic re-evaluation, consider NSAIDs
6. Undiagnosed + deteriorating → empirical therapeutic trial (antibiotics if infection suspected, antituberculars if TB likely, NSAIDs/colchicine/IL-1 inhibitors if inflammatory disease probable)

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Chapter 22 - Fever of Unknown Origin
• Goldman-Cecil Medicine, Chapter 259 - Approach to Fever / FUO