Endocarditis

I. What Every Physician Needs to Know.

This chapter summarizes the American Heart Association (AHA) and Infectious Disease Society of America (IDSA) guidelines for infectious endocarditis (IE), with a focus on the key points for the front-line clinician.

Infective endocarditis (IE) is relatively uncommon, but this is difficult to determine because few diagnosed cases are “definite.” Manifestations of disease vary widely and so it can be seen in almost any medical subspecialty.

Pathogenesis requires both alterations in the valvular endothelial surface and other factors to produce pathology.

Management depends on the causative organism and whether the patient has native or prosthetic valve endocarditis. These factors affect drug choices, length of therapy, and the need for surgery.

Recent changes in the rates of resistant organisms have made some aspects of treatment more complicated than what is noted historically.

II. Diagnostic Confirmation: Are you sure your patient has Endocarditis?

The Duke Criteria for diagnosing endocarditis should be used when suspected. See Figure 1.

Suspected IE can fall under three categories:

Definite (2 major criteria, 1 major and 3 minor, or 5 minor criteria);

Possible (1 major and 1 minor criteria, or 3 minor criteria);

Rejected (firm alternative diagnosis, resolution of IE syndrome with antibiotic therapy for less than or equal to 4 days, no pathologic evidence of IE at surgery or autopsy, or does not meet the above criteria).

The Duke criteria should be used as a clinical guide, but the clinician should always use his/her best judgment since IE can present itself in such varied ways.

Diagnosis is made by blood cultures and echo findings. Note that Coxiella burnetii can be diagnosed by blood culture or anti-phase 1 IgG antibody titer.

Most common organisms in IE: Staphylococcus aureus (31%), Streptococcus viridans (17%), Enterococci (11%), Coagulase-negative staphylococcus(11%), Streptococcus bovis (7%), other Streptoccocus species including nutritionally variant species (5%), non-HACEK gram negatives (2%), Fungi (2%), HACEK (2%), culture negative (8%), polymicrobial (1%), other (3%).

See Figure 2 for Epidemiological features.

Epidemiological features that point towards the etiologic diagnosis of culture-negative IE.

A. History Part I: Pattern Recognition.

IE can have an acute, subacute, or chronic course.

Since Staph aureus is now the most common organism of IE in the developed world, increasingly more IE cases have acute courses rather than subacute or chronic.

IE should be higher on the differential diagnosis in patients with a history of valvular disease, IE, prosthetic valves, IVDA, indwelling IV catheters, pacemakers with intracardiac leads, ESRD on HD.

Patients who are febrile and have a new murmur should be considered.

Patients bacteremic with Staph aureus should be evaluated for IE.

Patients with IE can have a variety of symptoms, many of which are nonspecific. Historically, symptoms include fever (80%), chills (40%), weakness (40%), dyspnea (40%), sweats (25%), anorexia (25%), weight loss (25%), malaise (25%), cough (25%), skin lesions (20%), stroke (20%), nausea/vomiting (20%), headache (20%), myalgias/arthralgias (15%), edema (15%), chest pain (15%), abdominal pain (15%), delirium/coma (10-15%), hemoptysis (10%), back pain (10%).

B. History Part 2: Prevalence.

It is difficult to estimate the exact incidence of IE. Hospital admissions for endocarditis in one study looking at hospitals within the US from 1998-2009 noted that the rate rose from approximately 25,000 to approximately 39,000 in 2009.

Incidence: Men > Women (generally 1.7:1, but can range from 1:1 or 3:1) although in patients age <35, Women>Men.

IE has become more common in the elderly although the rise in incidence in the US is not explained by an aging population alone.

IE is more common in patients with a history of valvular disease, IE, prosthetic valves, intravenous drug abuse (IVDA), indwelling IV catheters, pacemakers with intracardiac leads, ESRD on HD, and congenital heart disease.

Most common organisms in IE include: Staphylococcus aureus (32%), Streptoccocus viridans (18%), Enterococci (11%), Coagulase-negative staphylococcus(11%), Streptoccocus bovis (7%), other Streptoccocus species including nutritionally variant species (5%), non-HACEK gram negatives (2%), Fungi (2%), HACEK (2%), culture negative (8%), polymicrobial (1%), other (3%).

C. History Part 3: Competing diagnoses that can mimic Endocarditis.

This list could be made much longer, but these are simply to mention just a few:

Bacteremia without IE.Viral Hepatitis.Lyme disease.Sepsis: Difficult to distinguish in the short-term as both are fulminant infections. An echo and the causative organism would help distinguish between these infections.Abdominal abscess.Osteomyelitis.Malignancy.Atrial myxoma.Autoimmune and Connective tissue diseases: Differentiating requires respective laboratory and biopsy results.Hereditary fever syndromes: Distinguishing between these and IE would depend on the specific entity suspected.Tuberculosis.

D. Physical Examination Findings.

A complete and thorough physical exam should look especially for any following:

Significant cardiac findings (new regurgitant murmur or signs of new onset heart failure).

Skin findings (petechiae, Janeway lesions, splinter hemorrhages, Osler nodes).

Fundascopic findings (Roth spots).

Focal neurologic findings (weakness, changes in sensorium, etc.).

Physical exam findings in IE can also be non-specific and given the shift in epidemiology (Staph is now more common than Strep as a causative organism likely leading to more acute rather than subacute onset of disease), some physical findings may not be as prevalent as previously noted (since there may not be enough time for immunologic phenomenon to occur).

Physical findings include fever (96%), heart murmur (85%), changing murmur (20%), new murmur (48%), petechiae (20-40%), vascular embolic event (17%), Osler nodes (3%), splinter hemorrhages (8%), Janeway lesion (5%), splenomegaly (11%), Roth’s spots (2%), hematuria (26%), conjunctival hemorrhage (5%), neurologic manifestations (20-40%), uremic symptoms (<10%)

IVDA patients will more likely show right-sided phenomenon although systemic embolic manifestations can still occur.

The most common skin manifestation is petechiae. See Figure 3for an example. Other physical findings are listed below.

Janeway lesions are generally flat and painless and are septic emboli that become embedded into the skin. Commonly occur in the palms and soles. See Figure 4.

Osler’s nodes are swollen, red, and painful from immune complexes. Seen more frequently in “subacute” IE. See Figure 5.

Splinter hemorrhages are nonspecific embolic phenomenon affecting the capillary beds of nails. See Figure 6.

Roth spots appear to be a hemorrhage in the retina with a white center. They can also be seen in leukemia, DM, and collagen vascular diseases. See Figure 7.

E. What diagnostic tests should be performed?

Blood cultures should be obtained before antibiotic therapy if possible. At least three sets of cultures should be taken from different venipuncture sites and at different times – the first and the last set should be drawn at least 1 hour apart from each other. More specimens may be necessary if the patient has had antibiotics within the last 2 weeks.

Echocardiograms should be performed expediently. See Figure 8 and Figure 9.

The risk for embolization of vegetations is highest >10 mm in diameter and on the anterior mitral leaflet. However, it is important to note that some researchers have found that Staph or fungal IE have a high rate of embolization regardless of vegetation size.

A TEE is the preferred image modality, but a TTE is reasonable if TEE is unable to be obtained in a timely fashion. Of note, a TTE could be more useful in detecting lesions in right-sided IE.

Repeat TEE 7-10 days after an initially negative result if there is still a high IE suspicion. Also reasonable in patients with worsening clinical problems or unchanging symptoms (patient is still febrile despite several days of appropriate antimicrobial therapy).

After completion of therapy, a TTE should be obtained to determine the new baseline for the patient.

EKG – look for signs of heart block which could be a sign of a perivalvular abscess.

CXR – look for signs of septic pulmonic emboli especially in an IVDA and signs of right sided IE. See Figure 10.

Consider targeted computed tomography (CT) and/or magnetic resonance imaging (MRI) imaging of various parts of the body if one is suspicious for embolisms. Given the high incidence of neurologic complications, cerebrovascular imaging may be considered in all patients with left-sided IE even if the patient has no neurologic signs or symptoms.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The yield of blood cultures is increased when an increased volume of blood is drawn.

The patient does not need to be febrile in order to take cultures because most patients have a fairly constant low-grade bacteremia.

Blood cultures should be held for at least 3-4 weeks because some organisms are slow-growing.

Some organisms require special media in which to grow (e.g., – nutritionally variant streptococci). Infectious disease (ID) consultation should be obtained in all patients who are to be started on therapy for suspected IE, and can help determine what special conditions/media are required given the patient and circumstances.

Patients with “subacute” IE may not have a significant leukocytosis, but those with more acute cases are more likely to have high WBC counts. Anemia is also common (70-90%), but nonspecific. Thrombocytopenia occurs in 5-15% (more common in neonatal IE).

A urinalysis (UA) is frequently abnormal with proteinuria (50-65% of cases), microscopic hematuria (30-60%), and RBC casts (12%). Other findings include: WBC casts, bacteriuria, pyuria, and gross hematuria.

Complete metabolic profile (CMP) to look at the patient’s renal function. Transaminitis could represent liver involvement or hepatic congestion from decompensated CHF.

If the patient has surgery, valve culture and valve histopathology should be obtained.

One can consider the following lab tests, but many are nonspecific and the diagnostic utility is limited:

An antiphase I IgG titer of >1:800 for Coxiella burnetii is one of the major criteria for diagnosing IE. However, this organism is a relatively uncommon cause of IE.

A rheumatoid factor can be checked as this is also part of the Duke minor criteria. More likely to be positive in subacute cases when the duration is >6 weeks.

ESR is elevated in 90-100% of cases, but this is a nonspecific finding. The same can be said for a CRP.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Please refer to Figure 9for the use of echocardiograms in IE.

A TEE is the preferred image modality, but a TTE is reasonable if TEE is unable to be obtained in a timely fashion.

Repeat TEE 7-10 days after an initially negative result if there is still a high IE suspicion. This would also reasonable in patients with worsening clinical problems or unchanging symptoms (patient is still febrile despite several days of appropriate antimicrobial therapy).

After completion of therapy, a TTE should be obtained to determine the new baseline for the patient.

EKG – look for signs of heart block which could be a sign of a perivalvular abscess.

CXR – look for signs of septic pulmonic emboli especially in an IVDA and signs of right sided IE. See Figure 10.

Consider targeted CT and/or MRI imaging of various parts of the body if one is suspicious for embolisms. Given the high incidence of neurologic complications, cerebrovascular imaging may be considered in all patients with left-sided IE even if the patient has no neurologic signs or symptoms.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

ESR is elevated in 90-100% of cases, but this is a nonspecific finding. The same can be said for a CRP.

Hyperglobulinemia, cryoglobulins, hypocomplementemia, circulating immune complexes, false positive tests for syphilis and Lyme disease, but these are fairly low yield and nonspecific.

III. Default Management.

Consider surgery in the following:

1. Blood cultures should be obtained before antibiotic therapy if possible. At least three sets of cultures should be taken from different venipuncture sites and at different times – the first and the last set should be drawn at least 1 hour apart from each other. More specimens may be necessary if the patient has had antibiotics within the last 2 weeks.

Obtain other “basic” tests including labs (CBC with differential, CMP, UA), EKG, CXR.

EKG: look for signs of heart block which could be a sign of a perivalvular abscess.

CXR: look for signs of septic pulmonic emboli especially in an IVDA and signs of right sided IE. See 1. Figure 10.

2. Initiate antimicrobial therapy immediately if acutely ill. The choice of empiric therapy will depend on the patient demographics, history of prosthetic valve, currently clinical condition, previously administered antibiotics, and previous microbiologic history (e.g., pt has a history of MRSA, would give vancomycin as part of treatment strategy). Consult ID for guidance on initial therapy.

3. Obtain echocardiogram. See 3. Figure 9.

The risk for embolization of vegetations is highest if >10 mm in diameter and on the anterior mitral leaflet.

A TEE is the preferred image modality, but a TTE is reasonable if TEE is unable to be obtained in a timely fashion.

Repeat TEE 7-10 days after an initially negative result if there is still a high IE suspicion. Also reasonable in patients with worsening clinical problems.

After completion of therapy, a TTE should be obtained to determine the new baseline for the patient.

4. Recommend ID consultation. Consider surgical consultation depending on the likelihood of surgical necessity. All patients with a history of CHF (regardless of mechanism) should have a surgical consultation.

5. Consider targeted CT and/or MRI imaging of various parts of the body if suspicious for embolic phenomenon.

6. Await results of blood culture findings. Tailor antibiotics to the organism and whether the patient has a prosthetic valve.

Please refer to AHA and IDSA guidelines for antibiotic selection for specific organisms.

Daptomycin is another option that is often used in patients with IE with resistant Gram positive organisms. It has been approved by the US Food and Drug Administration (FDA) for the treatment of Staphylococcus aureus bacteremia and right sided Staphylococcus aureus IE.

7. Determine whether the patient needs valve replacement surgery. ID as well as cardiothoracic surgery should be consulted if this is a possibility.

The threshold for operating in prosthetic valve IE is generally much lower than native valve IE.

General indications for surgery in native valve endocarditis include the following:

CHF (especially if it is mod-severe) directly related to valve dysfunction.

More than one serious systemic embolic episode despite appropriate antibiotic therapy during the first 2 weeks of therapy.

Uncontrolled infection (persistent bacteremia for >5-7 days provided other areas of infection and fever have been excluded) after starting appropriate antimicrobial therapy.

Physically significant valve dysfunction as shown by echo. Ineffective antimicrobial therapy is available (e.g., fungal IE).Resection of mycotic aneurysms.

Most cases of prosthetic valve IE caused by more antibiotic-resistant pathogens (e.g. – Vancomycin-resistant enterococcus, multidrug-resistant Gram-negative bacilli).

Local suppurative complications, including perivalvular or myocardial abscesses.

Consider surgery in the following:

Embolic events despite appropriate regimen or a large (>10 mm) vegetation.

Vegetations >10 mm in diameter even in absence of embolic events.

Persistent vegetation after systemic embolization.

Increase in vegetation size after 4 weeks despite appropriate therapy.

8. Repeat blood cultures 48-72 hours after antibiotic therapy to determine if bacteremia has “cleared.”. If still bacteremic, repeat blood cultures every 24-48 hours until bacteremia has resolved.

If prolonged bacteremia, a CT and/or MRI of the chest / abdomen / pelvis may be appropriate to see if there are signs of an abscess or other nidus of infection causing ongoing bacteremia.

If still bacteremic 7 days after starting appropriate antibiotic therapy, the patient likely needs valve replacement.

9. When bacteremia has cleared, the patient is clinically stable, and the patient is taking antibiotics he/she can tolerate, place PICC line and order outpatient antibiotics.

Weekly labs should be drawn to look for toxicities.

10. The patient should receive antibiotic prophylaxis in the future if a dental procedure, certain respiratory/GI/GU tract procedures, and certain skin and musculoskeletal tissue procedures. See antibiotic prophylaxis chapter 5053.

A. Immediate Management.

Obtain other “basic” tests including labs (CBC with differential, CMP, UA), EKG, CXR.

EKG: look for signs of heart block which could be a sign of a perivalvular abscess.

CXR: look for signs of septic pulmonic emboli especially in an IVDA and signs of right sided IE. See Figure 10.

2. Initiate antimicrobial therapy immediately if acutely ill. Note that immediate empiric therapy is not always necessary if the patient does not have acute symptoms. Consult ID for guidance on initial therapy.

3. Obtain echocardiogram. See Figure 9.

The risk for embolization of vegetations is highest if >10 mm in diameter and on the anterior mitral leaflet.

A TEE is the preferred image modality, but a TTE is reasonable if TEE is unable to be obtained in a timely fashion.

Repeat TEE 7-10 days after an initially negative result if there is still a high IE suspicion. Also reasonable in patients with worsening clinical problems.

After completion of therapy, a TTE should be obtained to determine the new baseline for the patient.

4. Recommend ID consultation. Consider surgical consultation depending on the patient’s likelihood of surgical necessity. All patients with a history of CHF (regardless of mechanism) should have a surgical consultation.

B. Physical Examination Tips to Guide Management.

Cardiac findings include new regurgitant murmur or signs of new onset heart failure.

Skin manifestations (Janeway lesions, splinter hemorrhages, Osler nodes, petechiae).

Fundoscopic findings (Roth spots).

Focal neurologic findings (septic emboli to the brain).

Musculoskeletal findings may include arthritic pain.

Any worsening in any of these findings may indicate the need for further evaluation.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

Await results of blood culture findings. Tailor antibiotics to the organism and whether the patient has a prosthetic valve.

Repeat blood cultures 48-72 hours after antibiotic therapy to determine if bacteremia has “cleared.” If still bacteremic, repeat blood cultures every 24-48 hours until bacteremia has resolved.

A BMP should be checked periodically to ensure that renal function remains stable. CBC should also be checked periodically since many antimicrobials can have effects on the hematologic system.

Other specific lab tests that need to be ordered will depend on what antibiotic is used (oxacillin – ALT/AST/Alk phos; daptomycin – creatine kinase; vancomycin – vancomycin trough, etc.).

D. Long-term Management.

When bacteremia has cleared, the patient is clinically stable, and the patient is taking antibiotics he/she can tolerate, place PICC line and order outpatient antibiotics.

Weekly labs should be drawn to look for toxicities.

After completion of therapy, a TTE should be obtained to determine what is the new baseline for the patient.

The patient should receive antibiotic prophylaxis in the future if a dental procedure, certain respiratory/GI/GU tract procedures, and certain skin and musculoskeletal tissue procedures. See antibiotic prophylaxis 5053.

E. Common Pitfalls and Side-Effects of Management.

The most common pitfall is giving of antibiotics before adequate blood culture specimens are obtained since this significantly reduces the diagnostic yield.

If valve replacement surgery is something that seems likely, early involvement of cardiothoracic surgery is important as oftentimes earlier surgical intervention lead to improved outcomes.

Penicillin side-effects (including unasyn, ampicillin):

Allergic reactions (rash, anaphylaxis, serum sickness, allergic vasculitis, Coomb’s hemolytic anemia).

Interference with platelets.

Interstitial nephritis.

Lowers seizure threshold.

GI disturbances.

Hepatitis (especially nafcillin/oxacillin).

Cephalosporin side-effects:

Allergic reactions (rash, anaphylaxis, serum sickness).

Cross-reactivity to cephalosporins in patients with penicillin allergies is <5%.

Diarrhea (look for C difficency especially in patients receiving 2nd or 3rd generation cephalosporins).

Nausea, vomiting.

Biliary sludge (ceftriaxone).

Eosinophilia, neutropenia, thrombocytopenia, impaired platelet aggregation, hemolytic anemia.

Interstitial nephritis.

Vancomycin side-effects:

Phlebitis (3-14%).

“Red-man” syndrome (fevers, chills, rash); if present, slow down the infusion rate and / or premedicate with diphenhydramine and Tylenol.

Ototoxicity (very rare, associated with early uses of the drug w/serum levels between 80-100 mcg/mL).

Nephrotoxicity (0-7%, rare if used as a single agent and no other nephrotoxins administered).

Neutropenia (relatively infrequent (1-2%), but increases in likelihood with prolonged use).

Aminoglycoside side-effects:

Nephrotoxicity (ranging 5-25% of cases; however, most of the doses used in the treatment of IE are lower than what is given when aminoglycosides are given as a single agent. The difference is synergistic dosing).

Cochlear toxicity (incidence 3-14%).

Vestibular toxicity.

Neuromuscular blockade (exceedingly rare).

Rifampin side-effects:

Multiple drug-drug interactions (too many to list here).

Abdominal pain, nausea, vomiting.

Transaminitis (incidence is low, but increased risk in patients with chronic liver disease).

Mild thrombocytopenia, leukopenia, granulocytopenia.

Uveitis.

Rash, hypersensistivity reactions.

Lupus-like syndrome.

Discoloration of sweat, tears, urine, and other bodily fluids.

Linezolid side-effects:

Reversible myelosuppression (occurs usually 2 weeks or more into therapy. Thrombocytopenia is most common, but anemia and neutropenia can also occur).

Serotonin syndrome (linezolid is a MAO-inhibitor).

Optic neuritis, blurred vision.

Nausea, vomiting, diarrhea, constipation.

Rash.

Dizziness.

Headache.

Daptomycin side-effects:

Muscle toxicity (associated with rhabdomyolitis).

Paresthesias, dysesthesias and peripheral neuropathies.

Can cause a falsely elevated INR level.

Quinupristin-dalfopristin side-effects:

Phlebitis (especially if given in a peripheral IV; Quinupristin-dalfopristin is preferably given through central access).

Arthralgias (9.1%) and myalgias (6.6%): these can be severe, but the CK will be normal: increased risk in patients with chronic liver disease, elevated bilirubin, liver transplant patients, and those taking mycophenolate and cyclosporine.

Significant P-450 3A4 inhibition (watch dosing of diazepam, statins, verapamil, and other drugs metabolized through this pathway).

Ciprofloxacin side-effects:

GI disturbances (nausea, vomiting, diarrhea [including C diff], abdominal pain).

Prolongation of the QT interval.

Rash, photosensitivity.

Arthralgia, tendon, or ligament damage (avoid in children <18 years old).

Headache, dizziness.

Imipenem side-effects:

Rash, urticaria, hypersensitivity reactions.

Cross-reactivity to imipenem and penicillins is <10%.

Imipenem (more so than other B-lactam antibiotics and other carbapenems) is associated with seizures. Meropenem has the same spectrum of activity but not associated with an increased seizure risk.

Nausea, diarrhea.

Doxycycline side-effects:

Nausea, vomiting.

Photosensitivity, morbilliform rashes.

Pseudotumor cerebri.

Gray-brown to yellow discoloration (avoid in children <8 years old).

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Dose adjustments are necessary depending on GFR and which antibiotic is used (for example, oxacillin/nafcillin require no adjustment for renal insufficiency).

B. Liver Insufficiency.

Closer monitoring is necessary in patients w/chronic liver problems if patient is being given rifampin.

C. Systolic and Diastolic Heart Failure.

Patients need close monitoring to for signs of worsening heart failure secondary to IE as they would need more urgent valve replacement.