Endocarditis and Bacteremia

Portal of entry determines organism

• Oral cavity/dental: Viridans group streptococci (S. sanguinis, S. mutans) produce dextran from sucrose, which mediates adherence to damaged valve endothelium — the classic subacute picture after dental work or in poor dentition
• Skin and vascular access: Staphylococcus aureus — now the most common cause of IE in the US overall — from injection drug use, hemodialysis catheters, central lines, and cellulitis; expresses fibronectin-binding proteins that let it seed structurally normal valves, producing acute, destructive disease
• Prosthetic material: coagulase-negative staphylococci (S. epidermidis) elaborate biofilm on sewing rings, driver leads, and grafts; dominate early prosthetic valve and cardiac device infection
• Gastrointestinal/genitourinary: Enterococcus faecalis after GU instrumentation or in elderly men with prostatic disease; Streptococcus gallolyticus (formerly S. bovis) translocating across neoplastic colonic mucosa
• Culture-negative/fastidious: HACEK organisms, Coxiella burnetii (Q fever, livestock exposure), Bartonella (body lice, homelessness, cat exposure), Tropheryma whipplei — diagnosed serologically or by PCR, not routine culture
• Fungal: Candida and Aspergillus in prolonged central venous access, TPN, or immunosuppression; bulky vegetations, large emboli, high mortality
• Non-infectious mimics: marantic (nonbacterial thrombotic) endocarditis with mucin-secreting adenocarcinoma, and Libman–Sacks endocarditis in SLE/antiphospholipid syndrome

Non-modifiable risk factors

• Prior infective endocarditis (the single strongest predictor), prosthetic valve or prosthetic repair material, unrepaired cyanotic congenital heart disease or repairs with residual shunt, cardiac transplant valvulopathy — the AHA 2021 update on prevention of viridans streptococcal IE limits antibiotic prophylaxis to exactly these highest-risk groups
• Rheumatic valve disease, bicuspid aortic valve, degenerative calcific aortic stenosis, mitral valve prolapse with regurgitation, hypertrophic cardiomyopathy, advancing age

Modifiable risk factors

• Injection drug use, poor oral hygiene and untreated caries, indwelling catheters and hemodialysis access, cardiac implantable electronic devices, uncontrolled diabetes, chronic immunosuppression
• Mitral valve prolapse without regurgitation and isolated ASD are not prophylaxis indications — a favorite distractor

• Initial bacteremia and seeding: Bacteria gain access to the bloodstream through dental procedures, poor oral hygiene, skin infections, or IV drug use; transient bacteremia allows organisms to lodge on abnormal endocardium (damaged native valves, prosthetic material, or septal defects create turbulent flow)

• Valve colonization and biofilm formation: Bacteria adhere to endocardium via adhesins and express pathogenic virulence factors; fibrin and platelets aggregate around bacterial colonies forming a vegetation (composed of fibrin, bacteria, platelets, and inflammatory cells), which is poorly penetrated by antibiotics and immune cells

• Valvular destruction and inflammation: Progressive vegetation enlargement causes mechanical valve dysfunction through regurgitation; bacterial toxins and inflammatory mediators damage underlying valve tissue leading to perforation, leaflet rupture, or chordae tendineae rupture; tissue factor expression triggers thrombosis within vegetations

• Septic embolization and immune phenomena: Septic emboli from friable vegetations lodge in organs (brain, lungs, kidneys, spleen) causing infarction and abscess formation; circulating immune complexes and antibody deposition cause vasculitis, glomerulonephritis, and manifestations like splinter hemorrhages and Osler nodes

• Prosthetic valve complications: Early-onset prosthetic valve IE (within 60 days post-implantation) typically involves skin flora (Staph. epidermidis, Staph. aureus) and leads to valve dehiscence; late-onset IE resembles native valve disease but with higher rates of mechanical failure and surgical necessity

• Classic constitutional symptoms: Fever, malaise, night sweats, and fatigue with insidious onset over weeks (subacute) or rapid progression over days (acute); patients often describe "feeling unwell" without localizing symptoms

• Cardiac findings: New or changing heart murmur (most important sign—present in >90% at diagnosis); aortic regurgitation murmur (early diastolic, best at left sternal border with patient leaning forward) most common; mitral regurgitation murmur; may hear "Carey Coombs murmur" (mid-diastolic, from immune complex glomerulonephritis)

• Vascular phenomena (Duke criteria stigmata):
• Splinter hemorrhages: Linear hemorrhages under nails (painful, non-blanching, NOT pathognomonic—seen in other conditions)
• Janeway lesions: Painless erythematous macules on palms/soles with pale centers (rare, highly specific)
• Osler nodes: Painful nodules on fingertips/toe pads (rare, highly specific)
• Petechiae on conjunctivae or skin (non-blanching, common)

• Embolic phenomena: Stroke from septic emboli to cerebral vessels (up to 20% of patients); septic pulmonary emboli causing pleurisy, hemoptysis, or pulmonary infiltrates in IV drug users with right-sided endocarditis; flank pain and hematuria from splenic or renal infarction

• Important variant—right-sided (tricuspid) endocarditis: Occurs almost exclusively in IV drug users; presents with fever and dyspnea; septic pulmonary emboli causing cough and hemoptysis; tricuspid regurgitation with prominent v waves on JVP; lower mortality if treated medically (but higher if surgical intervention needed)

• Prosthetic valve IE pearls: May present with mechanical valve dysfunction (new murmur, heart failure); early prosthetic IE more likely to require urgent surgery; late prosthetic IE clinically indistinguishable from native valve disease

• Blood cultures: ESSENTIAL and must be obtained before antibiotics; draw 2-3 sets from different sites using sterile technique; positive cultures in >90% of untreated IE; organisms isolated identify causative pathogen and direct antibiotic therapy; culture-negative endocarditis (5-10% of cases) seen with prior antibiotics, fastidious organisms (HACEK group, Coxiella burnetii, fungi), or bartonella

• Modified Duke criteria (2000): Diagnosis requires 2 major OR 1 major + 3 minor OR 5 minor criteria
• Major criteria: Positive blood cultures (typical organism from 2 cultures OR persistent positive cultures) AND endocardial involvement (new regurgitation on echo, vegetation, abscess, or dehiscence on echo)
• Minor criteria: Predisposition (valvular disease, IV drug use), fever >38.5°C, vascular phenomena (emboli, septic infarcts, mycotic aneurysm, conjunctival hemorrhages, splinter hemorrhages), immunological phenomena (Osler nodes, Roth spots, rheumatoid factor, glomerulonephritis), microbiological evidence not meeting major criteria

• Echocardiography:
• Transthoracic echo (TTE): First-line imaging, sensitivity ~60% for vegetations; adequate for initial screening
• Transesophageal echo (TEE): Sensitivity >90%, superior for prosthetic valves, small vegetations, abscesses, and valve perforations; MUST be done if high clinical suspicion with negative TTE; can identify complications requiring surgery
• Vegetation appearance: irregular, echogenic mass on valve leaflet or endocardium; size correlates poorly with prognosis but >10 mm associated with higher embolic risk

• ECG: May show new conduction abnormalities or heart block if abscess extends to conduction pathways; PR prolongation or complete heart block concerning for pervalvular spread

• Laboratory findings: Elevated ESR and CRP (nonspecific); mild anemia common; elevated WBC; hematuria and/or proteinuria (immune complex glomerulonephritis) in 50% of patients; mild elevation in liver enzymes; cryoglobulinemia may be present

• Diagnostic strategy: Obtain blood cultures immediately, initiate empiric antibiotics only after cultures obtained (can delay several hours to optimize culture yield), obtain TTE within 7 days, proceed to TEE if high suspicion despite negative TTE or for risk stratification

• Empiric antibiotic therapy (before culture results, in acute presentation):
• Native valve, IV drug users suspected source: Vancomycin 15-20 mg/kg IV Q8-12H (AUC-guided dosing, AUC/MIC 400-600 per the 2020 IDSA/ASHP consensus; trough-only targets are no longer recommended) PLUS gentamicin 3 mg/kg IV Q8H (goal peak 3-4 mcg/mL, trough <1 mcg/mL for synergy) to cover Staph. aureus including MRSA
• Prosthetic valve: Vancomycin PLUS gentamicin PLUS rifampin 300-600 mg IV/PO Q6-8H to cover Staphylococcus epidermidis and other biofilm-forming organisms
• Community-acquired, no IV drug use history: Ceftriaxone 2g IV Q12H PLUS vancomycin to cover streptococci and Staph. aureus

• Organism-directed therapy (after culture and sensitivities):
• Viridans group streptococci (penicillin-susceptible): Ceftriaxone 2g IV Q12H × 4 weeks ALONE OR penicillin G 4 million units IV Q4H × 4 weeks; gentamicin 3 mg/kg IV Q8H can be added for first 2 weeks to shorten therapy to 2 weeks
• Staphylococcus aureus (MSSA): Nafcillin or oxacillin 2g IV Q4H ×

Cardiac — the leading cause of death

• Acute valvular regurgitation with heart failure: leaflet perforation or chordal rupture dumps volume into a non-dilated, non-compliant ventricle; flash pulmonary edema, soft/short early diastolic murmur, tachycardia. Emergency — the ACC/AHA 2020 valvular guideline makes IE-associated heart failure a Class 1 indication for early surgery during the initial hospitalization, before completing antibiotics
• Perivalvular/aortic root abscess: infection burrows through the annulus into adjacent conduction tissue. Signal is a new PR prolongation or AV block on serial ECG, or persistent fever despite appropriate antibiotics. Urgent TEE and surgical referral
• Fistula, pseudoaneurysm, prosthetic dehiscence: new to-and-fro murmur or rocking prosthesis on echo

Embolic and metastatic

• Stroke and mycotic aneurysm: septic emboli occlude cerebral vessels or seed the vasa vasorum, weakening the arterial wall; rupture causes subarachnoid or intraparenchymal hemorrhage — an emergency warranting CTA/MRA. Embolic risk falls sharply within the first two weeks of effective therapy
• Splenic and renal infarcts/abscess: left-sided pleuritic flank pain, persistent bacteremia; splenic abscess requires drainage or splenectomy
• Septic pulmonary emboli: right-sided IE; nodular cavitating infiltrates, hemoptysis
• Vertebral osteomyelitis, epidural abscess, septic arthritis: back pain plus S. aureus bacteremia is spinal infection until imaged

Treatment-related

• Vancomycin: AUC-guided dosing per the 2020 IDSA/ASHP consensus limits acute kidney injury, which rises further when combined with piperacillin-tazobactam; infusion-rate–dependent histamine release causes vancomycin flushing syndrome
• Aminoglycosides: additive nephrotoxicity and irreversible vestibular ototoxicity
• Rifampin: potent CYP450 induction (warfarin, antiretrovirals), hepatotoxicity, orange body fluids
• Antistaphylococcal penicillins: acute interstitial nephritis; ceftriaxone: biliary sludging; any prolonged IV course risks C. difficile colitis and catheter-related bloodstream infection

• ***Streptococcus gallolyticus* (bovis) bacteremia or endocarditis mandates colonoscopy** — the association with colorectal neoplasia is the single most tested link in this topic. Enterococcus points instead to the GU tract

• Negative TTE does not exclude IE: with persistent bacteremia, a prosthetic valve, or high clinical suspicion, the single best next step is transesophageal echocardiography, not repeating the TTE or starting empiric therapy blindly

• New AV block in a febrile patient with a murmur = perivalvular abscess until TEE proves otherwise; it is a surgical indication under the ACC/AHA 2020 valvular guideline, not a pacemaker indication

• Do not treat MSSA with vancomycin: nafcillin, oxacillin, or cefazolin clear MSSA bacteremia faster and with lower mortality. De-escalating from vancomycin once susceptibilities return is the correct answer

• Right-sided IE in injection drug use: tricuspid valve, S. aureus, septic pulmonary emboli with cavitary nodules; the murmur may be absent or only a soft holosystolic murmur that increases with inspiration (Carvallo sign). Absence of a murmur does not exclude the diagnosis

• Prophylaxis is narrow: per the AHA 2021 statement, only prosthetic valves/prosthetic repair material, prior IE, specified congenital heart disease, and transplant valvulopathy — and only for dental procedures manipulating gingiva or perforating oral mucosa. Amoxicillin 2 g PO one hour before is the standard adult regimen. GI/GU procedures alone no longer warrant prophylaxis, and mitral valve prolapse is not an indication

• Culture-negative IE: think Coxiella burnetii (Q fever, livestock), Bartonella (homelessness, body lice), and HACEK — send serologies and valve PCR; prior outpatient antibiotics are the most common cause overall

• Distinguish the non-infectious mimics: marantic vegetations (sterile, friable, mucin-producing adenocarcinoma) and Libman–Sacks verrucae on both leaflet surfaces in SLE — febrile presentation and positive cultures argue against both