The classic clinical triad is emboli, new or changing murmur, and positive blood cultures.
However, life and medicine are rarely that clear cut. So we have the Duke criteria:
Definite infective endocarditis:
Microorganisms demonstrated by culture OR histology in a vegetation OR in a vegetation that has embolized OR in an intracardiac abscess OR Pathologic lesions: vegetation OR intracardiac abscess present, confirmed by histology showing active endocarditis OR, since we usually have to rely on clinical criteria, we have
Clinical criteria which consist of 2 major criteria OR 1 major and 3 minor criteria OR 5 minor criteria.
MAJOR CRITERIA POSITIVE BLOOD CULTURE FOR INFECTIVE ENDOCARDITIS
Typical microorganism for infective endocarditis from 2 separate blood cultures: Viridans Streptococci, Streptococcus bovis, HACEK group, OR Community-acquired Staphylococcus aureus OR Enterococcus, in the absence of a primary focus OR Persistently positive blood cultures for any microorganism (i.e., from blood cultures drawn more than 12 hours apart), OR all of 3 OR majority of 4 OR more separate blood cultures, with first and last specimens drawn at least 1 hour apart.
EVIDENCE OF ENDOCARDIAL INVOLVEMENT
Findings on echocardiogram positive for infective endocarditis: Oscillating intracardiac mass on valve OR supporting structures OR in the path of regurgitant jets OR on iatrogenic devices, in the absence of an alternative anatomic explanation OR Abscess OR new partial dehiscence of prosthetic valve OR new valvular regurgitation (increase OR change in preexisting murmur not sufficient).
Predisposition: predisposing heart condition OR intravenous drug use.
Fever: 38.0°C (100.4°F).
Vascular phenomena: arterial embolism, septic pulmonary infarcts, mycotic aneurysms (PubMed), intracranial hemorrhage, Janeway lesions. Patients on prior anti-platelet therapy have marked decrease (2/3's) chance of having emboli (PubMed).
Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor, false positive VDRL (one hopes) and positive ANCA (PubMed).
Antiphospholipid antibodies are significantly more often positive, and at higher levels, in patients with definite IE(PubMed).
Echocardiogram: findings consistent with infective endocarditis but not meeting major criterion above.
Microbiologic evidence: positive blood culture but not meeting major criterion above OR serologic evidence of active infection with organism consistent with infective endocarditis.
Congenital (bicuspid aortic valve or any of the congenital eponyms I cannot remember) or acquired (rheumatic fever, prior endocarditis, old valve) valvular disease, hypertrophic cardiomyopathy, prosthetic valve, use of needles (dialysis (who have a 50% mortality rate (PubMed)), diabetes, IVDA).
Health care associated endocarditis is an emerging issue (PubMed) and if often right sided disease and may account for up to 25% of endocarditis. Those who are at high risk for endocarditis from nosocomial bacteremia include those with sustained bacteremia (duh), hemodialysis, pacer systems and those who get vertebral osteomyelitis.
Bacteremia is part of life and if you have an abnormal valve you may get unlucky. While S. viridans is the most commonly isolated organism by cultures, if molecular techniques are used a dental extraction results in "13.4±1.7 bacterial families and 22.8±1.1 genera per sample" in the blood (PubMed).
Is dental work a risk? Probably not (PubMed).
The dentist always wants you to floss, but who gets endocarditis? Those who "use toothpicks, dental water jet, interdental brush, and/or dental floss... (but) were less likely to brush teeth after meals." (PubMed).
Invasive dental work does increase the risk for prosthetic valve endocarditis just a tich (PubMed).
For prosthetic valves, 1/20 get endocarditis over a 10 year span (!?!) and bioprosthesis had a bigger risk, I would bet due to the lack of anticoagulation (PubMed). Clot bad.
Transcatheter aortic valve replacement has a high risk of endocarditis (1.1% per year) and death (36%)(Pubmed).
Risk of outpatient proceedures:
Procedure Relative Risk: Gastroscopy 2.50 (1.59 - 3.94), Colonoscopy 2.89 (1.35 - 6.17), Dialysis 4.33 (2.10 - 8.95), Bone marrow puncture 4.33 (1.24 - 15.21), Coronary angiography 4.75 (1.61 - 13.96), Bronchoscopy 5.00 (1.10 - 22.82) and Transfusion 5.50 (1.22 - 24.80) (PubMed).
Damn near anything can cause endocarditis, but there are patterns (Pubmed).
The most common causes: S. aureus, Streptococci (especially the viridans group), enterococcus, The HACEK Group of gram negative coccobacilli: Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella.
Abiotrophia and Granulicatella are more prevalent than HACEK in one study and approximately one-tenth as prevalent as viridans streptococci; periannular complications like myocardial abscess were more frequent (PubMed).
One small study that did PCR on valves found it to be polymicrobial more often than not (PubMed) and due to unculturable organisms; I wonder it the vegetation is being repeatedly seeded by the bacteremia of life. But if the patient is not responding to antibiotics, perhaps it is due to unculturable organisms.
In prosthetic valve (and native valve (PubMed)0 endocarditis, coagulase negative staphylococci lead the list in the first year after valve replacement, then the microbiology is similar to native valve endocarditis. Mycobacterium chelonae and M. lentiflavum can occur in bioprosthetic valves (PubMed).
Culture negative endocarditis (PubMed): usually due to prior antibiotics; organisms to consider include Coxiella burnetii (the statistically most common cause), Bartonella, Legionella, Mycobacterium, Tropheryma whippeli, (also the most common cause, it depends on how you make the diagnosis (PubMed) (Pubmed)) and fungi of all types.
Can make the diagnosis in culture negative disease with cell free DNA tests (Abstract) even in those who have negative cultures due to antibiotics. As of 10/18 it cost 2 grand.
Get lots of blood cultures, at least 12 hours apart if you can, BEFORE antibiotics.
- a pearl: if the patient has MSSA and you start with Vancomycin and switch to Nafcillin, there is higher mortality, so maybe maybe patients should be on Nafcillin and Vancomycin up front. Maybe (PubMed).
All antibiotics should be given at maximum dose for age, size and CrCl.
Can oral antibiotics be used? In some circumstances but I have never than the courage. Here is the review (PubMed). In a 2018 study of let sided endocarditis in the NEJM, stable patients who were changed to oral antibiotics at about day 17 had the same outcomes as those had the complete course IV. I can see doing that for streptococci, there is an old literature of treating streptococcal endocarditis with only oral therapy, but I would be leery about doing it with S. aureus or Enterococcus (PubMed). And note all the patients who were excluded.
- Staphylococcus aureus, left sided, native valve: 6 weeks of iv nafcillin or oxacillin > vancomycin. Aminoglycosides? Now passe they decrease the number of febrile days but do not decrease mortality or need for valve replacement. Gentamicin toxicity causes CrCr to decrease at a rate of 0.5% per day but does not adversely alter outcome (PubMed). Another study demonstrated that low dose gentamicin tripled the nephrotoxicity rate without altering outcomes (PubMed).
Rifampin probably only adds toxicity (PubMed) for native valve.
- Staphylococcus aureus, right sided, native valve: 4 weeks of iv anti-staphylococcal penicillin > vancomycin OR two weeks iv of anti-staphylococcal penicillin PLUS tobramycin for uncomplicated disease. In right sided disease requiring ICU, adding an aminoglycoside was associated with increased survival (PubMed).
Daptomycin at 6 mg/kg/d for 28 d is non-inferior to vancomycin (PubMed). 8 or 10 mg/kg is almost certainly the better dosing for endocarditis (PubMed), although daptomycin should probably not be used for enterococcus (PubMed). While daptomycin should not be used for pneumonia, some data suggests it is ok for Staphylococcal septic pulmonary emboli from endocarditis (PubMed).
- Viridans Streptococci: MIC < 0.1 : 4 weeks iv penicillin OR 2 gm qd ceftriaxone. If PCN allergic, vancomycin. MIC 0.1-1.0: 2 weeks of penicillin AND gentamicin THEN two weeks of penicillinsalivarius alone. If PCN allergic, vancomycin. MIC > 2.0 (PubMed): 4-6 weeks of penicillin AND gentamicin. If PCN allergic, vancomycin.
- Enterococcus: For high level gentamicin resistance and gentamicin susceptible, ampicillin 12 grams a day PLUS ceftriaxone 2 gm q 12 for 6 to 8 weeks works (PubMed) and is the treatment of choice (PubMed). Daptomycin should probably not be used for enterococcus (PubMed) unless no other option.
The old school is 6 weeks of ampicillin (preferred; 12 grams a day) PLUS an aminoglycoside OR vancomycin PLUS an aminoglycoside no matter what it does to the ears or kidneys (although the risk for gent toxicity may be genetic). If patients have been ill less than three months, 4 week may be enough, at least one study suggests everyone should get 6 weeks (PubMed). Beware of high level gentamicin resistance (MIC > 500).
Maybe, for VRE, use daptomycin PLUS ampicillin for 8 to 10 weeks or quinupristin/dalfopristin for 6 weeks or linezolid or daptomycin (high dose) WITH tigecycline. Best bet is to go right to valve replacement.
Other combinations of antibiotics have been tried for endocarditis, reviewed in 2018 (PubMed).
- how to treat culture negative endocarditis depends on what organisms you suspect, but cure rates are better if they get an aminoglycoside (PubMed).
Gram negatives account for maybe 2% of endocarditis and often have cardiac implantable electronic device (CIED) endocarditis, a central venous catheter, diabetes mellitus or to be on immunosuppressive therapy (PubMed).
- Candida endocarditis, which can be a complication of both catheters and IVDA, is best treated with valve resection and a long course of ? amphotericin ? fluconazole (PubMed) ? other. While classically an absolute indication for valve removal, I have cured two cases in patients who were deemed not surgical candidates and this has been supported in the literature (PubMed) with a iv echinocandin or amphotericin followed by a year of po fluconazole. My endpoint was a negative 1-3 beta D glucan.
For prosthetic valve endocarditis, start with lipid amphotericin not an echinocandin (PubMed). Improves survival. And, oddly, surgery did not have better outcomes than medical therapy alone, although small numbers and retrospective.
- other bugs? Anything can cause endocarditis, and often you need an ID consult.
- Who should get a valve replacement? Refractory CHF, recurrent emboli, S. aureus prosthetic valve infection, gram negative or yeast as the causative organism, failure of therapy (usually manifests as fever and is often due to a ring abscess).
And perhaps you should get a CNS angio before anticoagulation; stroke and aneurysms, often silent, are not uncommon (PubMed).
"Multivariate risk factors for ischemic stroke included prior stroke, Staphylococcus infection, mitral vegetations and valvular abscess ). Risk factors for hemorrhagic stroke included fungal infection, male sex and rheumatic heart disease (PubMed)."
There is some annoying data to suggest that S. aureus endocarditis who get valve replacement have less long term mortality mostly in those who have CHF; valve replacement is always such a great intervention in the IVDA.
- Whether valve replacement should be a first line therapy due to increased survival or the increased survival seen with surgery (PubMed) is due to treating patients medically who have contraindications to surgery is not known.
- vegetation >= 10 mm are associated with increase in embolism and death (PubMed). So take it out? Oddly, vegetations are not amenable to IR interventions.
- But CNS emboli can be removed mechanically since anticoagulation is to be avoided (PubMed).
- there is one prospective trial to suggest benefit from early valve replacement (PubMed). It is important to see who was enrolled: "a diagnosis of definite infective endocarditis according to the modified Duke criteria and had severe mitral valve or aortic valve disease and vegetation with a diameter greater than 10 mm. To minimize the number of unnecessary surgeries and the risk of prosthesis- related morbidity, we only enrolled patients with infective endocarditis accompanied by severe valve disease."
- there is no survival benefit in delaying surgery in patient who present with stroke (PubMed) although before valve replacement perhaps you should check for silent CNS events: they can be just as deadly preoperatively (PubMed). But "observational data supports delaying surgery by 7-14 days if possible in IE complicated by ischemic stroke and >21 days in hemorrhagic stroke to lower perioperative mortality and neurological exacerbation (PubMed). "
- But, and there is always a but, one retrospective analysis suggests that surgery for left sided endocarditis and a large vegetation as the only indication had a worse outcome. Damned if you do, damned if you don't (PubMed).
- patients who have endocarditis who present with sepsis/septic shock have increased survival with surgery (PubMed)
Replace with a mechanical or bioprosthetic valve? The data, such as it is, points to better outcomes with mechanical valves (PubMed).
After the valve is replaced? If the cultures of the valve are negative, probably two weeks and post-op rifampin is not needed (Pubmed)
- ANY patient with CHF should probably get valve replacement; it decreases short term and long term survival (PubMed): "In-hospital mortality was 29.7% ...for the entire HF cohort, with lower mortality observed in patients undergoing valvular surgery compared with medical therapy alone (20.6% ... vs 44.8%..., respectively; P < .001). One-year mortality was 29.1%...in patients undergoing valvular surgery vs 58.4%... in those not undergoing surgery (P < .001)."
-ECHO, especially transthoracic, to "rule out" endocarditis is way stupid. Please note the criteria above. TEE is much better for finding a vegetation, so, if you really want to make the diagnosis of native valve IE, go right to TEE. All patients with prosthetic valve IE should get a TEE to look for a ring abscess. A vegetation > 1.0 to 1.5 cm has a high likelihood of emboli, which is a risk for death, so perhaps this should be a reason for valve replacement (PubMed).
- negative ECHO, even a TEE, does not mean they do not have a valve infection. Almost 20% of those with endocarditis will have a normal echo (PubMed). For example, Pneumococcus can destroy a valve and have nary a blip on the TEE (PubMed).
- TTE on IVDA in the outpatient setting will often have valve pathology and 5% will have vegetations without endocarditis (PubMed).
- prosthetic valve endocarditis can have difficult to evaluate TEE due to interference, a tagged WBC scan may be of help to confirm the diagnosis (PubMed) although I think the data suggests a PET is better.
- 'silent' CNS emboli occur in a quarter of patients (PubMed) and CNS emboli have a bad prognosis (PubMed). And many patients will have silent lesions on MRI; what to do about them and when too look is not known (Pubmed).
- multivalve disease is associated with more morbidity, but no mortality (PubMed).
- organisms that rarely cause IE: Group A strep, most anaerobes and most aerobic gram negative rods (at least in non IVDA).
- S. aureus is a particularly bad player: in almost every study it is an independent risk factor for death and 1/4 will die in the next year.
- H\half of Enterococcal endocarditis patients will have a colonic neoplasm so they require a colonoscopy (PubMed).
- IDDM patients do especially poorly, as with all infections
- CRP > 122 after a week is a poor prognostic sign. As if I care (PubMed); I call it a C ReActive Protein. CRAP.
- bacteremia is common with brushing teeth, one study found "98 different bacterial species recovered from 151 bacteremic subjects. Of interest, 48 of the isolates represented 19 novel species of Prevotella, Fusobacterium, Streptococci, Actinomyces, Capnocytophagia, Selenomonas, and Veillonella" (PubMed).
- elevated troponin is a bad prognostic sign (PubMed).
- large pericardial effusions with native valve endocarditis is associated with increased mortality and other complications (PubMed).
- prior antiplatelet therapy and institution of antiplatelet therapy may decrease mortality; do NOT, however, use warfarin (Reference).
- up to a year after left sided disease, patients have poor quality of life and 11% can have PTSD (PubMed).
- here is some weirdness: vancomycin and gentamicin can make you fat. "A major and significant weight gain can occur after a six-week intravenous treatment by vancomycin plus gentamicin for IE with a risk of obesity, especially in males older than 65 who have not undergone surgery. We speculate on the role of the gut colonization by Lactobacillus sp, a microorganism intrinsically resistant to vancomycin, used as a growth promoter in animals, and found at a high concentration in the feces of obese patients (Plos)."
By the way, the correct order is blood cultures, THEN antibiotics. Not the other way, as is often the apparent standard.
Relevant links to my Medscape blog
Last Update: 10/15/18.