Infectious Disease Compendium

Endocarditis

Diagnosis

2013 NEJM Review

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:

Pathologic criteria

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).

MINOR CRITERIA

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 antibodie 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.

Epidemiologic Risks

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).

There is a marked association between mitral vavle prolapse and viridans group streptococci (PubMed)

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 osteo.

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).

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).

Transcatheter aortic valve replacement has a high risk of endocarditis (1.1% per year) and death (36%)(Pubmed)

Microbiology

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.

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 bactermia 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) 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 bioprosthesic valves (PubMed).

Health care associated endocarditis is usually due to S. aureus and coagulase negative staphylococci and they usually have a central line as a source.

Candida endocarditis often heroin users or a complication of central lines.  At least 4.2% of candademias will have endocarditis (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 in how you make the diagnosis (PubMed) (Pubmed)) and fungi of all types.

And vegetations do not mean infectious endocarditis: there is Libman­Sacks in SLE (PubMed) and marantic in patients (PubMed) with adenocarcinomas.

Gram negative endocarditis that is not HACEK is more often E. coli than Pseudomonas and is nosocomial (PubMed).

Empiric Therapy

Get lots of blood cultures, at least 12 hours apart, if you can BEFORE antibiotics.

- IVDA: an anti-staphylococcal penicillin PLUS gentamicin. If penicillin allergic or high suspicion of MRSA, vancomycin.

- Native valves: penicillin PLUS anti-staphylococcal penicillin PLUS gentamicin, if penicillin allergic or high suspicion of MRSA, vancomycin.

- Prosthetic valve: vancomycin PLUS gentamicin PLUS rifampin.

- 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).

Specific Treatments

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).

- Staphylococcus aureus, Left sided, native valve: 6 weeks of iv nafcillin or oxacillin> vancomycin. Aminoglycosides need only be used for first 3 to 5 days where 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).

Here is the tricky part: If it is MSSA and the MIC is elevated >= 1.5 to vancomycin, nafcillin will have a higher failure rate (PubMed).

If resistant or intolerant of standard therapy, linezolid may be just as bad (71% success rate) (PubMed).

Rifampin probably only adds toxicity (PubMed).

- 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.

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).

- Staphylococcus aureus, prosthetic valve. Remove it. If you want to try and probably fail at medical therapy: 6-8 weeks anti-staphylococcal penicillin > vancomycin iv PLUS gentamicin PLUS rifampin.

- Coagulase negative staphylococci, prosthetic valve: 6 - 8 weeks vancomycin PLUS gentamicin (2 weeks) PLUS rifampin.  As the MIC to vancomycin goes up, so does the mortality (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 pcn alone. If PCN allergic, vancomycin. MIC > 2.0 (PubMed): 4-6 weeks of penicillin AND gentamicin. If PCN allergic, vancomycin.

Keeping the penicillin dosed at q 4 gives better outcomes (PubMed).

If you need to use daptomycin, beware that the S. mitis group (mitis, anginosus, mutans and salivarious) and can rapidly develop resistance (PubMed).

- 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 actually works (PubMed) and is probably the treatment of choice (PubMed). Daptomycin should probably not be used for enterococcus (PubMed).

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. Beware of high level gentamicin resistance (MIC > 500).

There was a case of high level gentamicin resistant endocarditis treated with daptomycin plus ceftaroline (PubMed).

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 right to valve replacement.

- HACEK (test MIC): 4 weeks of ampicillin AND gentamicin OR qd ceftriaxone.

- how to treat culture negative endocarditis depends on what organisms you suspect, but cure rates are better if they get an aminoglycoside (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 vavle removal, I have cured two cases in patients who were deemed not surgical candidates and this has been supported in the literature (PubMed).

- other bugs? Anything can cause endocarditis, and often you need an ID consult.

Pearls

- a CT/PET may be the best way to look for complications/metastatic infection and diagnose prosthetic vavle infection, except they cost too much (PubMed)(PubMed).

- 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).

But. Even with S. aureus prosthetic valve endocarditis there is no survival benefit with early valve replacement (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.

- 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 perioperatively (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).

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.

- 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)."

Rants

By the way, the correct order is blood cultures, THEN antibiotics. Not the other way, as is often the apparent standard.