Infectious Endocarditis

• An infection of the endocardium which may involve the valves/valve apparatus, septal defects, mural endocardium (rare), ventricular assist devices, surgical shunts/septal defect occluders
• Relapsed IE is a repeat episode by the same organism within 6 months (ie treatment failure)
• Re-infection is new episode with a different organism (or same organism but >6/12 later)
• Primary types
  • • Native valve IE (75%)
    • Prosthetic valve IE (15%, early or late post-op)
    • Cardiac device related IE (10%, CIED IE)
• Often due to a perfect storm
  • • Predisposing risk factors (eg prosthetic valve, device, CHD, prior IE, valvular HD)
    • Pathogens entering bloodstream (eg IV drug use, dental work, dialysis)
    • Hosts immune response (immunosuppression)
• Most common portals of entry – GI, GU, skin, mouth, IV drugs use, iatrogenic
• Similar rates of infection in aortic valve and mitral valve. Right heart infection can be difficult to manage
• Often a long incubation phase followed by rapid deterioration
• 1-year mortality 35%
• Increasing in incidence, and mortality has not improved
• Risk of prosthetic valve IE is 5% after 10 years. Metal and tissue vales and TAVI – all have similar infection rates

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Clinical features

• Can present with a wide range of signs and symptoms
• Embolic phenomena occur in about 25%.
• Can present acutely (more likely caused by MSSA), or sub-acutely/chronic
• Fever (75%) – An important cause of PUO (and an essential rule out if pre-existing cardiac lesion)
• Non-specific symptoms if subacute
  • • SOB, fatigue, headache, muscloskeletal pain, weight loss in 30%
    • May have seen GP many times, and received previous antibiotics
    • Rashes (Osler’s nodes and Janeway lesions can come and go, and may not be there on presentation)
• Murmur (80%)
• Splinter haemorrhages – linear, longitudinal, distal nail bed. Especially relevant if lots.
• Petechiae – conjunctivae, palate, skin
• Osler’s nodes – tender, pea-sized nodules in finger pulps, red or purple, 2%. May disappear over hours/day.
• Janeway lesions – flat, irregular, non-tender red spots on palms and soles which blanch. Can bleed into the skin. Last days to weeks. 3%
• Roth’s spots in fundus – flame shaped retinal haemorrhages with cotton wool centre
• Neurological features from emboli in 40%
  • • Haemorrhage, mycotic aneurysms, CVA (7%), meningitis
    • If present, mortality higher
    • Can be dependent on characteristics of the vegetation and antibiotic duration (much less common after one week of treatment)
    • CVA may be asymptomatic
• Signs of anaemia
• Splenomegaly (20%)
• Heart failure (28%)
• Splenic or renal infarcts (incidentally found)
• Lower limb emboli with acute ischaemia
• Septic shock (6%)
• Discitis (4%)
• Valve dysfunction
• Metastatic abscesses – renal, splenic, cerebral, vertebral
• Fever and flow murmurs occur but are common in all patients and usually not IE, but have increased suspicion in the case of a regurgitant murmur
• The classic signs of IE are quite rare

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Risk factors

• Cardiac
  • • Prosthetic valves (especially in the first 3 months)
    • Congenital heart disease
      • • Including surgically corrected (excluding fully repaired ASD, repaired VSD or patent ductus)
        • Especially common in unrepaired VSD
    • HOCM
    • Previous IE
    • Any valvular heart disease
      • • Mitral valve prolapse is the commonest association
    • TAVI-IE
      • • Especially common in first 3 months
        • These patients may also have residual AR, low placed valve, vascular/bleeding complications during the procedure, valve-in-valve procedures.
        • Often acquired in the healthcare setting.
        • Presentation can be a bit atypical and fever and vegetations less common.
        • Often due to enterococcus, strep and coag neg staph

• Non-cardiac
  • • Patient on haemodialysis
    • PPM lead infection
    • Central lines / indwelling lines / devices – suspect IE if line infection diagnosed, line then removed, and blood cultures persistently positive
    • IVDU
    • Immunosuppression – can present atypically
    • Recent dentistry

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Microbiology

• Over 60% is streptococcus or staphylococcus
• Common
  • • Strep viridans (22%)
    • Staph Aureus (25%) – Common in IVDUs. Highest mortality
    • Enterococci (14%). 90% enterococcus faecalis. Of note Enterococcus faecium (which is different) is often associated with UTIs and catheters, and causes 5% of enterococcal IE
    • Coagulase negative staph (10%), less aggressive than staph aureus, and usually associated with prosthetic valve IE
    • Other streptococci
      • • Strep bovis, aka Streptococcus gallolyticus (common, comes from bowel and can be associated with cancer)
        • Strep mitis, sanguinis, salivaris, downei, mutans, oralis
• Uncommon
  • • Fungi – candida, aspergillus. These patients tend to have large vegetations, and often immunocompromised
    • HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella)
    • Pseudomonas
    • Q fever
    • Bartonella
    • Brucella
    • Strep pneumoniae (often associated with pneumonia or meningitis) and beta haemolytic strep (strep anginosus, constellatus, intermedius). Group B strep infection (agalactiae) has a high mortality
    • Legionella
    • T Whipplei
• Very rare – other gram negatives eg E. coli, chlamydia (<2% of IE), mycoplasma
• 10% culture negative

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Investigations

• ECG
  • • Look for ischaemia (emboli), pericardial involvement, conduction disease (look at PR interval)
    • Patients with aortic valve IE or staph aureus bacteraemia often get daily ECGs to monitor PR interval (consider aortic root abscess if lengthening)
• Standard bloods and consider PCT, lactate, LFTs, troponin, BNP
• Consider drug levels in treated patients – vancomycin levels (target serum pre-dose level between 15 and 20 mg/L) or gentamycin levels (aim pre-dose levels ≤1 mg/L and post-dose levels 3–5 mg/L).
• Note that IE can cause false positive syphilis test and Rheumatoid Factor positive. Worth sending RF as it’s a minor part of the diagnostic criteria
• Send urine for red calls and casts
• Blood cultures (ideally pre-antibiotics) – Do 3 sets / pairs
  • • Some advocate taking 6 hours apart if patient stable
    • ESC guidelines advises every 30 mins
    • If acute/septic, do 2 sets within the first hour
    • Don’t need the patient to be pyrexic – just take the culture whenever suits
    • The more blood the better! (improves sensitivity)
    • 3 sets significantly increases the yield (from 70% to >90%). If > 1 blood culture positive – this increases index of suspicion and useful for cardiology to know
    • Bacteraemia should be (almost) continuous, so a solitary positive culture should reduce your suspicion (if 3 sets taken before antibiotics, this virtually always identifies the most typical causes of IE)
    • Don’t culture through lines (only useful for catheter related infection)
    • If patient is stable and already on antibiotics, consider stopping them to get cultures
    • Can adapt antibiotics based on initial gram stain, and again once complete ID made (usually the following day)
    • Repeat blood cultures every 48 hours until bacteraemia has cleared
• Culture negative IE
  • • Always discuss with micro if cultures are negative after 48 hours and IE sill suspected
    • Can be due to certain fastidious organisms – Q fever, bartonella, aspergillus, legionella, brucella, mycoplasma, other fungi, mycobacteria
    • Or due to antibiotics given pre-culture – this is the most common cause of culture negative IE
    • Take large volume cultures if getting negative results
    • Ask about animal exposure, travel, occupation, consumption of unpasteurised dairy products
    • Consider checking serology and PCR
      • • Serological testing for Coxiella (Q fever), Bartonella, legionella, aspergillus, brucella, mycoplasma
        • PCR for tropheryma whipplei, bartonella and fungi
        • Fungal markers
    • Consider sending autoantibodies if cultures, serology and PCR negative (ANA, antiphospholipid, RF, anti-pork antibodies, anti-β₂-glycoprotein 1 antibodies (IgG and IgM))
    • Molecular microbiology can be useful in culture negative cases (usually from valve tissue)
      • • 16S – prokaryotes (bacteria)
        • 18S – eukaryotes (fungi, protozoa)
• Transthoracic echo
  • • For diagnosis of IE, but also for complications such as abscesses, pseudoaneurysm, perforation/flail, valvular regurgitation, fistulae, prosthetic valve dehiscence, HF
    • Can be normal or inconclusive in IE (especially in prosthetic valve IE, device-related IE, congenital HD)
    • Sensitivity only about 65%. 90% specific
    • Less specific in prosthetic valves
    • Echo all patients with Staph aureus, E faecalis, some strep species or candida in blood cultures
    • Look for vegetations, abscess, pseudoaneurysm, intracardiac fistula, valve perforation / aneurysm, new dehiscence of prosthetic valve, cardiac function (which can determine whether they get surgery)
    • Repeat if any new complication suspected
    • Repeat echo in 7 days if negative and suspicion persists (if culture negative and 2^nd echo normal – risk of IE is incredibly small)
    • Repeat echo in confirmed IE once antibiotics completed
    • Vegetations
      • • Size and mobility of vegetations correlates with risk of embolism (if >10mm or very mobile rather than fixed = worse prognosis). Embolism also more common in the 1^st week after starting antibiotics.
        • Typically form on atrial side of MV, prolapse into LA on systole and then move into LV in diastole.
        • Aortic valve vegetations typically lie on ventricular side and prolapse into the LVOT in diastole and extend into aortic root in systole
        • Differential of vegetations includes heavy calcification and RA masses
• Transoesophageal echo (TOE) for some
  • • Do TOE if normal or inconclusive TTE and high risk (especially if prosthetic valves, previous IE).
    • And consider TOE if positive transthoracic echo and perivalvular complications suspected but not diagnosed
    • Sensitivity of TOE is 95%
    • If ‘unfit for TOE’, then unfit for cardiac surgery
    • TOE is also advised when patient has been diagnosed, is stable and prior to switching from IV to oral antibiotics according to ESC guidelines, but rarely done in UK practice
• Cardiac CT
  • • Best to do in all patients if you have a reasonable suspicion of the diagnosis
    • Better than echo at diagnosing perivalvular complications, but echo is better at diagnosing small vegetations
    • Particularly useful if TTE non-diagnostic – can increase index of suspicion eg if infarcts
    • Can be done alongside TOE, or if TOE contraindicated
    • Can diagnose bystander pathology eg cancer in strep bovis IE
    • CT PET – only if diagnostic uncertainty (not better than TOE). Can be useful in prosthetic valves, and often advised here.
• Other investigations to look for source or sequelae
  • • CT CAP – Can show embolic phenomena, especially in brain, lungs, spleen, kidneys, spine.
    • CT head +/- CTA – CVA very common and can be asymptomatic/subclinical. MRI more sensitive but less available
    • MRI or PET – consider for suspected discitis or vertebral osteomyelitis (diagnostic accuracy over 90%, but ensure not done too early)
    • CT colon – if strep bovis (aka Streptococcus gallolyticus)
    • US KUB – if enterococcus faecium
    • Joint aspiration – tropheryma whipplei

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Diagnosis

• Use the updated modified Dukes criteria (2023) to assist making the diagnosis
• Results in definite IE, possible IE, or rejected IE
• Involves (but not a full breakdown of the criteria)
  • • Micro major criteria
      • • A typical organism in at least 2 blood cultures (or 3 cultures for atypical organisms)
        • ‘Typical’ organisms is not necessarily a frequent cause, but its identification is strongly associated with IE
        • Typical organisms include
          • • All strep (except strep pneumoniae and strep pyogenes)
            • Staph aureus and staph lugdunensis
            • Enterococcus faecalis
            • Strep-like bacteria – granulicatella, abiotrophia spp, gemelli
            • HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella)
            • And in suspected prosthetic valve IE only – coagulase negative staph, corynebacterium, Serratia, pseudomonas, cutibacterium acnes, NTMs
    • Imaging major criteria
      • • Includes echo/CT/PET findings, new regurgitation, new partial prosthetic valve dehiscence
    • Surgical criteria
    • Minor criteria – mostly risk factors, clinical signs or micro/radiology that doesn’t fit into the major criteria
    • Pathologic criteria
• ESC 2023 guidelines have a slightly different version – more of a radiology focus, and slightly less sensitive, but probably more specific
• If possible IE – consider repeating cultures, imaging, and using different imaging to make the diagnosis more secure

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Antibiotics

• Document if previous antibiotics in community
• Regimen depends on
  • • Severity of infection
    • Type of valve affected – native or prosthetic, latter needs longer. Also right sided valve infections often more treatable than left
    • Risk factors for unusual or resistant pathogens – some bugs more likely to form biofilms, consider previous antibiotic use
    • Culture results and MIC
      • • Enterococcus often quite resistant = check aminoglycoside MIC (and maybe avoid use if >128)
        • MIC useful to know in MRSA and vanc-resistant staph infections (if very high, consider a regime with daptomycin)
    • Any drug allergies / contraindications
• Often treat for 2-6 weeks
  • • Generally 4 weeks for native valve infection
    • Generally 6 weeks if prosthetic valves, enterococcus faecalis, abscess
    • First 2 weeks often IV treatment in hospital, then some can be stepped down to OPAT
• Some principles – follow local policy, but broadly speaking…
  • • Empiric treatment for native valve IE could be amoxicillin, flucloxacillin and gentamycin (or vancomycin and gentamycin if penicillin allergic). Could use ceftriaxone instead of flucloxacillin
    • Empiric treatment of prosthetic valve IE (<12 months since surgery) could be vancomycin, gentamycin and rifampicin
    • Empiric treatment of late prosthetic valve IE can be the same as for native valve IE
    • Ensure correct doses use – often higher than for other infections
• Some considerations once the bugs ID’d
  • • Flucloxacillin first line for Staph in native valves
    • Aminoglycosides not indicated in staph native valve IE, but often given in streptococcal IE (and generally only used for 2 weeks)
    • Amoxicillin useful for enterococci
    • Cephalosporin + gentamycin for HACEK
    • Vancomycin or daptomycin, gentamycin and rifampicin for prosthetic valves (empirically). Rifampicin can help penetrate biofilms, but often given after 3-5 days of the other antibiotics
    • Give vancomycin if history if IV drug use
    • Daptomycin (high dose) can be given for staph and enterococcus (with a betalactam)
    • Fosfomycin sometimes given in place of betalactam if allergic
    • MRSA can be treated with daptomycin, vancomycin, and less commonly prescribed antibiotics
    • HACEK gram negative infections may be susceptible to ceftriaxone and fluroquinolones (but often resistant to penicillins)
    • Antifungals – consider if immunocompromised and fungal IE suspected. Amphotericin B often used for candida, and voriconazole for aspergillus
    • For Q fever IE – hydroxychloroquine and doxycycline for 2 years. Get hydroxychloroquine levels, do regular eye checks, check G6PD screen
• Monitoring and side effects
  • • Daptomycin requires twice weekly CK levels. It can also cause eosinophilia
    • Check LFTs if giving high dose penicillins
    • Check lactate in linezolid treatment
    • Fosfomycin has a high sodium load (and can precipitate AKI or HF)
• Outpatient antibiotic therapy can be considered later – there is a move to earlier switch to orals
  • • Consider outpatient antibiotics (PO or IV) if left sided IE caused by strep, enterococcus, staphylococcal infection if had >10 days of IV antibiotics, clinically stable, no abscess formation or requirement for surgery
    • Outpatient treatment not advised if IE caused by difficult to treat organisms, history of liver cirrhosis, those with severe cerebral emboli, abscesses, valve complications, IVDU, uncontrolled infection, BMI >40

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Endocarditis MDT

• All patients should be discussed in an MDT in a tertiary centre.
• MDT will often include radiology, cardiology, cardiothoracics, ID/micro and others
• Best to manage any complicated patients in a hospital with cardiothoracics on site – the time to transfer a patient can be a critical one

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Surgery

• There has been a move towards early surgery, even in frail patients. Rapid identification of surgical candidates is important
• 50% need surgery, early is best to reduce metastatic abscesses and embolic events (which can cause ischaemic limbs, CVA, blindness, organ infarction – especially common if fungal).
• Clear indications include:
  • • Decompensated heart failure (strong evidence of benefit)
    • Uncontrolled infection / sepsis (resistant pathogen, virulent pathogen (eg staph aureus), persistent sepsis, or failure to clear bacteraemia, or persistent pyrexia)
    • Abscess formation
    • Prevention of embolism in larger vegetations
    • Recurrent embolic events (or high risk of embolism)
    • Severe valve regurgitation
• Mortality is very high if you have an indication for surgery but it is not performed
• Mortality also a lot higher if re-do surgery required
• Some patients are too sick for surgery
• Emergency surgery (within 24 hours) for cardiogenic shock and pulmonary oedema
• Urgent surgery (3-5 days) if haemodynamically unstable but not shocked, uncontrolled infection, local complications or large >10mm vegetations
• Surgery usually required in cases of prosthetic valve IE caused by staph aureus or non-HACEK gram negs
• Aspergillus IE nearly always require surgery

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Complications

• Stroke (15%)
  • • Especially common in left sided lesions eg if anterior mitral valve leaflet involved, or in staph infection
    • Thrombectomy can be considered in embolic stroke, but thrombolysis contraindicated
    • Haemorrhagic stroke can significantly delay required cardiac surgery (as bypass and anticoagulation can make the stroke worse)
    • Do CT and CTA (which will also pick up infected aneurysms) or MRA
• Heart failure (30%)
  • • The main indication for urgent/emergency surgery
    • Mainly caused by leaflet perforation or chordal rupture, causing severe acute regurgitation
• Thromboembolism (35%)
  • • Higher rate in larger, mobile vegetations, mitral valve IE and staph aureus/candida/strep gallolyticus infection.
    • Highest risk is day after starting antibiotics, reduced rate after 48 hours of antibiotics, and 15x lower risk at 2 weeks
    • Left sided IE can cause emboli to brain and spleen
    • Right sided IE can cause PE
    • Predicting the risk of embolism is important
• Sepsis and septic shock
  • • Persistent positive cultures after 72 hours confers a worse prognosis
    • Consider abscesses (including extracardiac ones) if infection uncontrolled, and consider if surgery appropriate
    • New AV block may indicate abscess formation
    • Some infections less likely to be controlled with drugs alone – for example fungi, MRSA, VRE, non-HACEK gram negs, Staph Aureus (usually sensitive but very aggressive)
• Other cardiac complications
  • • Local complications – abscess, false aneurysm, fistula, prosthetic dehiscence
    • Peri/myo-carditis
    • Cardiac ischaemia due to coronary emboli
    • AV block – especially in aortic valve IE/abscess. Can be a post-op complication too.
• Infected (mycotic) aneurysm
  • • Can occur in the brain with neurological symptoms/signs, and can be associated with haemorrhage. DSA scan useful here (more sensitive than CTA or MRA)
    • Surgery or IR treatment sometimes indicated
• Splenic infarction, abscess formation and rupture
  • • Infarcts very common (20%) and often asymptomatic
    • 5% of infarcts progress to an abscess – if suspected, image with CT or USS
• Osteoarticular infection (7%)
  • • In any patient with discitis, risk of IE is 10x higher (so always echo these patients)
    • Discitis usually causes back pain (but only 4% of IE patients with back pain have discitis)
    • Get an MRI. Sometimes discitis found incidentally on PET CT in IE patients (and doesn’t seem to worsen prognosis)
• Antibiotic side effects – some described above
• Renal failure. Caused by:
  • • Immune complex and vasculitic glomerulonephritis
    • Renal infarction from emboli
    • Pre-renal injury
    • Nephrotoxic antibiotics (especially aminoglycosides, vancomycin – ensure checking levels)
    • Contrast nephropathy
• Mortality 20-30%. Poor prognostic signs include
  • • Large, mobile vegetations
    • Large CVA
    • Heart failure (often due to severe valve regurgitation)
    • Staph Aureus or non-HACEK gram negs or fungi
    • Prosthetic valve IE has twice the inpatient mortality than native valve IE

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Antibiotic prophylaxis

• No longer routinely required before operations and dentistry, however many cardiologists would still advise giving them to patients at high risk of IE
• In most cases (aside from very high risk), prophylaxis has been shown to reduce risks of bacteraemia, but not IE. And prescribing obviously risks side effects and resistance
• Antibiotics recommended for high-risk patients having dental procedures and oral surgery
• Consider antibiotics if high risk and having invasive procedure to respiratory, teeth/gums, GI, GU, skin or musculoskeletal systems.
• Highest risk patients considered to be those with:
  • • Previous IE
    • Prosthetic valves (or those with surgical valve repair)
    • Congenital HD, especially untreated cyanotics
    • Ventricular assist device for end stage HF
    • Transcatheter implanted aortic or pulmonary prostheses
• Consider antibiotic prophylaxis in
  • • Heart transplant recipients
    • Transcatheter mitral and tricuspid valve repair
• Note that native valve disease is not deemed highest risk
• If giving prior to a procedure, could give amoxicillin 2g PO, or cefalexin 2g if penicllin allergic
• General prevention measures to help prevent IE in anyone venerable include
  • • Good dental care
    • Disinfected of wounds
    • Limitation of catheters/invasive procedures
    • Strict asepsis for any procedure
    • Discourage tattooing/piercing
    • Optimise treatment of chronic skin conditions

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Other measures

• Device-related IE
  • • Can be systemic or localised
    • BLISTER score – assesses risk of infection
    • Extraction and re-implantation later on (often different site or device)
• Ongoing recreational IV drug use significantly worsens prognosis. Methadone treatment programmes improve it.
• Anticoagulation – assuming no neurology / CVA, it can often continue (but best to substitute oral anticoagulation for LMWH)

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Pitfalls in management

• Delay in transferring to a surgical centre
• Delay in taking to theatre
• Not thinking of it – early diagnosis is vital, delays can be catastrophic
• Not recognising the high-risk patients – MSSA IE, prosthetic valves, congenital HD, previous IE, persistent infection despite antibiotics, decompensated HF, new AV block
• Not involving the IE MDT
• Not taking enough blood cultures