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Ashley EA, Niebauer J. Cardiology Explained. London: Remedica; 2004.

Cardiology Explained.

Contents

Chapter 10Infective endocarditis

Background

Endocarditis was first described by William Osler in 1885. It is an inflammatory process that affects the endocardium and may have an infective or noninfective (eg, systemic lupus erythematosus) origin. It is uncommon in the western world (22 cases per million), but more prevalent in developing countries.

Diagnosis

Symptoms

Endocarditis is rarely an obvious diagnosis for a generalist. It may present with a wide variety of clinical signs, some subtle; the diagnosis may be difficult or the signs misleading, and there is a wide differential diagnosis to consider. However, there is a wealth of clinical signs to look for.

Constitutional symptoms

Endocarditis should be considered in patients with vague or generalized constitutional symptoms such as fever, rigors, night sweats, anorexia, weight loss, or arthralgia.

Cardiac signs

The presence of a new murmur is very significant, as is a change in the nature of an existing murmur (a regurgitant murmur may disappear on worsening). Myocardial involvement or valvular dysfunction may both contribute to left ventricular failure.

Skin lesions

Endocarditis is indicated by:

Osler's nodes – tender lesions found on finger pulps and thenar/hypothenar eminences (see Figure 1)
Janeway lesions – transient, nontender macular papules on palms or soles
splinter hemorrhages
petechiae (embolic or vasculitic)
clubbing – in long-standing disease

Figure 1

Osler's nodes on a finger and foot.

Eyes

Roth spots (boat-shaped hemorrhages with pale centers, in retina) and conjunctival splinter hemorrhages may be found.

Splenomegaly

Splenic infarction may occur as a result of emboli. In this case, splenic palpation may be painful and tender, and a rub may be heard.

Neurological

An acute confusional state is common in patients with infective endocarditis (IE). Cerebral emboli, which usually affect the middle cerebral artery, result in hemiplegia and sensory dysfunction. Mycotic aneurysms also affect the middle cerebral artery, where rupture may cause a subarachnoid hematoma. Mycotic aneurysms can occur several years after endocarditis has been treated.

Renal

Infarction causes loin pain and hematuria. Immune complex deposition may result in glomerulonephritis.

Osler's Nodes

William Osler, 1909, on the eponymous Osler's nodes: "One of the most interesting features of [endocarditis] and one to which very little attention has been paid is the occurrence of ephemeral spots of a painful nodular erythema, chiefly in the skin of the hands and feet, the nodosités cutanées éphémerès of the French… The commonest situation is near the tip of the finger, which may be slightly swollen."

If any of these signs occur together with a fever, the patient should be urgently referred to a cardiologist for blood cultures and echocardiography – the level of risk will determine whether this is transesophageal echo (TEE) or transthoracic echo. Blind treatment with antibiotics should not be undertaken since it will delay diagnosis and identification of the causal organism. Antibiotics should not be initiated before three sets of blood cultures have been taken.

Formal diagnosis

The Duke diagnostic classification for IE divides signs and symptoms into major and minor criteria (see Table 1). IE is diagnosed if patients have:

Table 1

Definitions of terms used in the Duke criteria for the diagnosis of infective endocarditis (IE).

two major criteria; or
one major and three minor criteria; or
five minor criteria

These criteria are associated with a 99% specificity for diagnosis in follow-up studies. It has been proposed that the minor criteria be extended to include erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), splenomegaly, microscopic hematuria, and newly diagnosed clubbing. This adjustment increases diagnostic sensitivity by 10%.

Intravenous drug abuse

Right-sided endocarditis is common in intravenous drug abusers (IVDAs) because of nonsterile injection into the venous system. The presentation tends to differ from that of classic IE, in that these patients are more likely to develop pneumonia or septic pulmonary emboli than the characteristic signs mentioned above (which result from left-sided embolization). In addition, predominant right-sided failure is more common (look for significantly raised jugular venous pressure and gross peripheral edema). The tricuspid valve is most commonly affected (50%), whereas involvement of the mitral and aortic valves is less common (20% each). The involvement of multiple valves is common. Pulmonary valve endocarditis is rare.

Etiology

IE has a large number of causative organisms.

Streptococci

These account for 50%–80% of IE cases. Streptococcus viridans (eg, S. anguis, S. milleri, S. mutans, S. mitior) make up the normal bacterial flora of the pharynx and upper respiratory tract. Tonsillectomy, dental extraction, and dental cleaning can result in bacteremia and lead to infection.

William Osler, 1919

"Observe, record, tabulate, communicate. Use your five senses."

Sir William Osler (1849–1919) is one of the most admired and honored physicians in the history of medicine. He exerted a truly global influence through professorships (McGill, Johns Hopkins, and Oxford), his textbook The Principles and Practice of Medicine, and other clinical and philosophical writings. This influence is apparent not least in the sheer number of conditions that bear his name: Osler–Weber–Rendu syndrome (hereditary hemorrhagic telangiectasia), Osler's nodes, Osler–Libman disease (subacute bacterial endocarditis), and Osler–Libman–Sacks syndrome (systemic lupus erythematosus with endocarditis) are simply a few. But it was perhaps his overwhelming humanism and his dedication to patient-centered learning that marked him out as truly great (he once ran after an alcoholic beggar to whom he'd just given coins and added his own overcoat to the donation, saying: "You may drink yourself to death, and undoubtedly will, but I cannot let you freeze to death"). The combination of profound caring, a prolific output of creative writing and ideas, and a lifelong penchant for elaborate practical jokes has made him one of the most memorable physicians of the 20th century.

Staphylococci

Staphylococcus aureus and Staphylococcus epidermidis account for 20%–30% of subacute cases of IE and 50% of the acute forms. The presence of central venous catheters (feeding lines or temporary pacing lines) increases susceptibility. Acute S. aureus infection of previously normal valves has a mortality rate of 3%. This is the most common situation in IVDAs. Coagulase-negative staphylococci cause 30%–50% of prosthetic valve endocarditis.

Enterococci

Enterococci account for 5%–15% of IE cases. Enterococcal organisms, which include Streptococcus faecalis, have low infectivity.

HACEK organisms

The HACEK group of organisms – Haemophilus parainfluenza, Haemophilus aphrophilus, Actinobacillus (Haemophilus) actinomycetemcomitans, Cardiobacterium hominis, the Eikenella species, and the Kingella species – also commonly cause IE and can be difficult to diagnose. Their identification may require samples to be taken in special media.

IE is also caused by other, less common organisms. Candida, Aspergillus, Histoplasma, and Brucella infections are rare, but are found, in particular, in IVDAs, alcoholics, and patients with prosthetic heart valves. Coxiella burnetii (the causative agent of Q fever) can also cause a subacute infection.

Pathogenesis

Endocarditis infection occurs along the edges of the heart valves. The lesions, called vegetations, are masses composed of fibrin, platelets, and infecting organisms, held together by agglutinating antibodies produced by the bacteria. As inflammation continues, ulceration may result in erosion or perforation of the valve cusps, leading to valvular incompetence, damage to the conduction pathway (if in the septal area), or rupture of a sinus of Valsalva (if in the aortic area).

Although endocarditis can affect native and prosthetic valves, infection seldom affects a previously normal heart – the majority (60%) of IE patients have a predisposing cardiac condition. Vegetations usually affect the left side of the heart, with the most common underlying lesions being mitral valve prolapse and degenerative mitral and aortic regurgitation (see Figure 2).

Figure 2

Mitral valve vegetation.

Rheumatic disease is a risk factor for the development of endocarditis. Other predisposing cardiac lesions include hypertrophic cardiomyopathy with associated mitral reflux, subaortic stenosis, and ventricular aneurysm. There are also congenital lesions that predispose adults to endocarditis: these include ventricular septal defect (VSD), bicuspid aortic valve, and coarctation of the aorta.

Vegetations occur when a high-pressure jet enters a low-pressure cavity through a narrow orifice. This explains why endocarditis complicates a small VSD, but is not associated with a large VSD, mitral stenosis, or an atrial septal defect. In the presence of a VSD, vegetations can be found on the right ventricular side of the VSD, on the tricuspid valve, or where the jet impinges on the right ventricular wall. Vegetations found in coarctation usually occur distal to the obstruction.

Finally, in children, cyanotic heart disease is still the most common cause of endocarditis, and the risk does not diminish after surgical repair as prostheses carry their own risk.

Prosthetic valve endocarditis

A special subset of endocarditis is that affecting prosthetic valves. This is traditionally divided into early onset (within 60 days of surgery) or late onset. Early onset usually results from perioperative valve contamination with staphylococci, whereas the etiology of late prosthetic valve endocarditis resembles native valve infection, usually due to streptococci.

Refer with confidence

As mentioned above, IE can be a difficult diagnosis to make, and the key for the generalist is to always be aware of it as a differential. Fever and arthralgia are very common complaints, but if there is any suggestion that they are not due to a simple viral illness (eg, by the presence of a particularly high temperature or other clinical signs [see above]) then the patient should be referred for blood cultures and an echo. If fever and a changing murmur coexist then urgent referral is warranted, although, even here, it can be useful to take blood cultures and a bottle for serology (for the diagnosis of culture-negative endocarditis) yourself.

Specialist management

Investigations

Blood cultures

Blood cultures are the primary investigation in the diagnosis of IE and yield the causative micro-organism in up to 95% of cases. A failure to do so can be due to prior antibiotic treatment, the presence of fastidious organisms (eg, belonging to the HACEK group), or unusual organisms such as Candida, Chlamydia, or Brucella. Most importantly, blood has to be drawn before antibiotic treatment is initiated, at three different time points over a minimum of 1 hour. At each time point, blood should be taken from a different site of the patient's body – but not from central lines – and each sample is placed into a pair of blood culture bottles that cultivate aerobic and anaerobic bacteria separately.

If immediate antibiotic treatment is warranted, this can be initiated right after completion of blood culturing, once microbiology tests have identified a specific organism and the antibiotic therapy has been modified accordingly. Antibiotic therapy can have an enormous impact on the patient's prognosis; therefore, all efforts have to be made to collect and culture specimens as carefully as possible. This ensures the correct identification of the causative micro-organisms, and ultimately the correct use of antibiotics.

Echocardiography

This is the key investigation as it can assess underlying cardiac function as well as demonstrate vegetations. Chamber size, pre-existing rheumatic disease, and valve apparatus can be examined and the degree of valve incompetence assessed. Transthoracic two-dimensional echo can detect vegetations above 2 mm in diameter, whereas TEE has greater precision in detection of lesions (1–1.5 mm), with a sensitivity and specificity of over 90% (see Figure 3). Detection of prosthetic endocarditis is more sensitive with TEE.

Figure 3

Transesophageal echo for 1 mm lesions.

Other investigations

Other investigations include the following:

blood count – normochromic normocytic anemia is usual, while neutrophil leucocytosis is common
ESR – this may be raised
renal and liver function test – levels of creatinine may be raised; levels of liver enzymes may be raised in a hepatocellular (nonobstructive) pattern
CRP – increases acutely in bacterial infection
urine microscopy – microscopic hematuria is common in early disease
culture – culture any skin lesion, drip site, or other focus of infection
electrocardiography (ECG) – ECG regularly (daily if aortic or septal root abscess is suspected)

Treatment

Antibiotics

If, following blood cultures, the diagnosis is secure, high-dose IV antibiotics should be started immediately. It is becoming increasingly common to insert a tunneled central line to facilitate several weeks of IV treatment without the need for repeated cannulation – with the pain and attendant risk of secondary infection that this incurs.

Native valve endocarditis with a subacute onset is most likely to be caused by S. viridans or an enterococcal species. Treatment involves IV penicillin (2.4 g, 4 hourly) for up to 4 weeks, with gentamicin (1 mg/kg, 12 hourly) for 2 weeks. If the onset is acute, staphylococci need to be covered and treatment should include IV cloxacillin (flucloxacillin) (3 g, 6 hourly, in place of penicillin) with oral fusidic acid.

If the patient is allergic to penicillin, other possibilities are vancomycin (1 g twice daily) or teicoplanin (400 mg twice daily for 3 days, then 400 mg daily). Plasma levels of gentamicin and vancomycin need to be monitored every 48–72 hours.

Empirical treatment of endocarditis affecting prosthetic valves should cover streptococci, enterococci, staphylococci (including methicillin-resistant S. aureus), and Gram-negative organisms. Vancomycin or teicoplanin with gentamicin have good synergistic cover. In drug abusers, treatment for endocarditis should include cover for S. aureus and Gram-negative bacilli (eg, cloxacillin and pipercillin).

In the treatment of rarer causes of endocarditis, Coxiella may require doxycycline with cotrimoxazole or rifampicin. Candida and Aspergillus may respond to medical therapy (5-fluorouracil and amphotericin B, respectively), but, generally, all three of these infections respond poorly to medical therapy alone and require surgical intervention.

In the treatment of IE, from any source, fever may still be present 2 weeks after starting the appropriate treatment, even with drug-sensitive organisms. This could be due to the presence of an underlying large vegetation or abscess. If fever persists, the sensitivity of the infecting organism should be checked and drug levels monitored. Repeat echo should be performed to exclude increasing vegetation size or abscess formation. If, despite these measures, the fever remains, the possibility of antibiotic resistance should be considered and a further synergistic antimicrobial treatment may be required. A second site for fever should always be excluded.

Surgical intervention

Surgical intervention may be required in patients with persistent fever that is resistant to medical therapy. Surgery is also indicated in the following conditions:

valve obstruction
prosthetic-valve endocarditis caused by S. aureus or resistant organisms
aortic or mitral regurgitation not responding to medical therapy
paravalvular abscess
development of an aneurysm of a sinus of Valsalva
fungal endocarditis
multiple embolic episodes
progressive heart failure secondary to severe valve destruction
oscillating vegetation of >1 cm

Surgery may involve not only valve replacement, but also aortic root replacement for aortic root abscesses. After the relevant surgical procedure, a full course of antibiotic eradication therapy should be administered.

Prognosis

With effective treatment, patients with IE have a 70% survival rate. The prognosis is worse if there is no identifiable organism or if there is a resistant organism. Fungal infections are associated with increased mortality, as is prosthetic valve endocarditis. Overall death rates are 20% for native valve endocarditis, 30% for staphylococcal infections, and 20%–30% for late prosthetic valve infection, despite full medical and surgical treatment. The most common cause of death is intractable heart failure.

Prophylaxis

All patients at risk for IE should receive antibiotic cover for invasive procedures (see Tables 2 and 3, overleaf). Spontaneous bacteremia is also common as a result of poor dental hygiene, and susceptible patients need to be made aware of this.

Table 2

Prophylactic regimens for dental, oral, respiratory tract, or esophageal procedures.

Table 3

Prophylactic regimens for genitourinary/gastrointestinal (excluding esophageal) procedures.

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