Current aspects of infective endocarditis

ISHAK A. MANSI, MD Clinical Associate Professor of Medicine, Louisiana State University Health Sciences Center School of Medicine, Shreveport.

DONNA CARDEN, MD Professor of Internal and Emergency Medicine, Louisiana State University Health Sciences Center School of Medicine, Shreveport.

Over the past several decades, infective endocarditis—usually involving the valvular surfaces of the heart but potentially also the interventricular septum or mural endocardium—has evolved in classification, age of affected patients, and pathogens. Here is a handy review.

In the past, infective endocarditis (IE) was classified as chronic, subacute, and acute, but the chronic type vanished as a result of advances in antibiotic therapy and cardiovascular surgery. Acute IE refers to disease with marked toxicity that progresses, over days to several weeks, to valvular destruction and metastatic infection. In contrast, subacute IE evolves over weeks or months with only modest toxicity and less propensity to metastatic infection. IE is also classified as native valve endocarditis (NVE) or prosthetic valve endocarditis (PVE), depending on the presence of cardiac valve replacement.

 

Drugs mentioned in this article

Amoxicillin Ampicillin Ceftriaxone Gentamycin Methicillin (Staphcillin) Nafcillin (Unipen) Penicillin G Rifampin (Rifadin, Rimactane) Vancomycin (Vancocin)

The mean age of patients with NVE increased from 35 years in the preantibiotic era to a current mean age of 54 years because of the decreased prevalence of rheumatic heart disease, increased population longevity, and the consequent greater number of cases of degenerative valve disease and the increased use of procedures (such as GU procedures) that predispose to bacteremia in older patients. However, a new group of younger patients with IE secondary to IV drug abuse has emerged.

The pathogens of IE have changed because of surges in cases due to

• Staphylococcus aureus secondary to IV drug abuse and various IV-access procedures

• Staphylococcus epidermidis secondary to an increase in prosthetic valve surgeries and IV-access procedures

• Fungus, gram-negative bacilli, and Pseudomonas aeruginosa secondary to IV drug abuse

• Enterococci secondary to an increase in GU procedures (see Table 1, and "Pathogenesis and microbiology of IE").

 

TABLE 1 IE in various adult populations
	General population	IV drug abusers	Prosthetic valve IE	Nosocomial IE
Predisposing heart disease	Present	Not necessary	History of valve prosthesis; risk is highest in the first 6 mo after surgery
Age	Median: 47-69	27-37	Variable	Older patients
Predominant pathogens	Viridans streptococci 30%-65%)	Staphylococcus aureus (>50%) Gram-negative bacilli, Pseudomonas aeruginosa, fungi. Polymicrobial	Coagulase-negative staphylococci (mainly Staphylococcus epidermidis) in the first 12 mo after surgery	S aureus, S epidermidis, enterococci in decreasing order of frequency)
Preexisting structural heart disease	Usually present (most common lesions are MVP, bicuspid aortic valve, PDA, VSD)	Frequently absent		Both in its presence and absence
Commonest valve affected	Left-sided valves or at the impact of the abnormal, high-pressure jet	Commonly, right-sided valves	Site of valve prosthesis	According to procedure type, and presence of previous valvular disease
Common sites of embolization	Systemic emboli brain, kidney, extremities)	Pulmonary emboli (recurrent pneumonia, lung abscess)	Usually systemic, as most of the prostheses are left-sided	According to the valve affected
Presence of murmurs in the first 3 wk	Frequently present	Frequently absent	Frequently obscured in early postoperative period by coexisting conditions and sounds	Frequently absent
Key: IE, infective endocarditis; MVP, mitral valve prolapse; PDA, patent ductus arteriosus; VSD, ventricular septal defect.

 

Pathogenesis and microbiology of IE Two major mechanisms appear to be pivotal to the development of infective endocarditis (IE). Organisms must gain access to the endocardium, usually through bacteremia. Microorganisms may invade the bloodstream if local anatomic barriers (skin, mucous membranes, subcutaneous tissues) are breached or if direct inoculation into capillaries and venules occurs (in dental or GU procedures or in IV drug abuse through infected needles and materials, for example). Organisms must be able to seed and persist on the endocardium, since intact endothelium is resistant to infection. Although some virulent organisms (such as Staphylococcus aureus and Pseudomonas aeruginosa) may be able to infect the endothelium, endothelial damage is generally required for the infection to occur. This damage results from hemodynamic turbulence in the face of a structural abnormality. Examples of these abnormalities are listed in the table.   Risk of IE in common heart diseases Significant risk Prosthetic heart valve Cyanotic congenital heart disease Aortic stenosis or regurgitation Mitral regurgitation (to a lesser extent, mitral stenosis) MVP with regurgitation VSD PDA Negligible risk Trivial valvular regurgitation on echocardiography without structural abnormality MVP without regurgitation Atrium secundum septal defect Key: IE, infective endocarditis; MVP, mitral valve prolapse; PDA, patent ductus arteriosus; VSD, ventricular septal defect.   Endothelial damage results in exposure of collagen, to which platelets and fibrin adhere to form a sterile platelet/fibrin complex. Bacterial adherence to the platelet/fibrin complex depends on many factors that affect the interaction between the bacterial surface and tissue receptors. For example, staphylococci and streptococci are much more adherent than the virulent P aeruginosa. Consequently, IE that is due to the less virulent viridans streptococci is more common than pseudomonal IE. Major pathogens Although almost any bacterium can cause IE, streptococci, enterococci, and staphylococci are responsible in the vast majority of cases. Viridans streptococci are the most common cause of native valve endocarditis (NVE). Affected patients usually have underlying cardiac disease. Viridans streptococci are part of normal oral flora and gain access to the bloodstream through breaches in the oral mucosa (in dental surgical procedures, for example). S aureus is the only coagulase-positive staphylococcus; other species that colonize humans are coagulase-negative, among which Staphylococcus epidermidis emerged as an important pathogen in the setting of implanted devices and in hospitalized patients. The course is often acute and there is high mortality, especially in mitral and aortic valve disease. Complications are more common in S aureus IE than in endocarditis caused by other bacteria and include conduction defects, myocardial abscess, valve ring abscess, purulent pericarditis, and peripheral emboli. Metastatic complications such as lung abscess (from tricuspid involvement), CNS abscess, and splenic abscess are seen in up to 40% of patients. Enterococci are increasingly recognized as a cause of IE. Older men undergoing GU procedures, women undergoing gynecologic procedures, and IV drug abusers are at particular risk. Forty percent of patients have no underlying heart disease. Gram-negative bacteria Gram-negative bacteria cause 5% to 10% of all cases of IE. IV drug abusers and patients with prosthetic valves are at greatest risk. The acronym HACEK designates a special group of fastidious aerobic gram-negative bacteria that cause a characteristic clinical variety of NVE: Haemopihilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. Clinical features include prior valvular disease, a subacute course, frequent embolic complications, large vegetations, and frequent need for valve replacement. Microbiology of PVE The pathogenesis of prosthetic valve endocarditis (PVE) involves microbial colonization of the prosthesis at the time of surgery. About one third of patients become ill within the first 2 months after surgery (early PVE), and two thirds after this time (late PVE). After 1 year, the rate of PVE drops, yet it still remains higher than that of NVE, and the microbiology becomes similar to that of NVE. S epidermidis, S aureus, enterococci, and gram-negative bacteria, in descending order of frequency, are the most common pathogens in PVE. Gram-negative bacilli and fungi are more likely to cause PVE than NVE. The mortality in PVE, 25% to 30%, is higher in patients with PVE caused by gram-negative organisms. IE in IV drug abusers Most cases of IE associated with drug abuse occur in patients with no previously recognized valvular abnormality. Staphylococci are the most common pathogens and usually infect the tricuspid valve (50% of cases) but can also infect the aortic valve (25%) and the mitral valve (25%). Women with mitral valve prolapse appear to be at particularly high risk of mitral valve IE. Culture-negative IE In 5% to 10% of patients with presumed IE, no etiologic microorganism is isolated from the blood. The most common factors behind this inability to identify the etiologic microorganism are prior antimicrobial therapy, intracellular organisms (such as Rickettsiae), fastidious organisms (such as the HACEK group of bacteria), fungi, and right-sided endocarditis until pulmonary infection occurs.

Clinical picture

A high index of suspicion is needed to diagnose IE. Certain features raise suspicion of IE in febrile patients, such as

• A history of underlying heart disease

• A history suggestive of a preceding bacteremic event such as dental work or instrumentation of the GI or GU tract

• A history of IV drug use

• Symptoms suggestive of multisystem involvement (for example, heart, lungs, and kidneys).

Fever is the most common constitutional symptom of IE, though it may be absent in the elderly or in severely debilitated patients. A new murmur or one with a changing character is an important sign of IE. Most patients with left-sided valvular disease have heart murmurs at some point in their illness. However, murmurs may be absent in the following conditions: tricuspid valve IE; occasionally during the first 2 weeks in left-sided IE; in early acute IE due to S aureus; and, in postoperative PVE, a murmur may be obscured by additional sounds, such as rubs.¹

Signs of IE are noted less frequently today and are absent in IE restricted to the tricuspid valve.² Nonspecific vascular signs of IE are skin petechiae and splinter hemorrhages (subungual linear, dark red streaks) Other classic signs of IE are Roth's spots (round or oval retinal hemorrhages with a clear, pale center), Osler's nodes (small, tender nodules, usually on the pads of the fingers or toes), and Janeway lesions (small, nontender hemorrhages with a slightly nodular character) on the palms or soles.

In patients with IE, pieces of vegetation may break off and cause embolism in the heart, brain, kidney, spleen, liver, lung, and extremities. Infarcts and, occasionally, abscesses may result. Septic embolization to the vasa vasorum or direct bacterial invasion of the arterial wall may lead to the formation of mycotic aneurysms, which may rupture. Mycotic aneurysms most often develop in the cerebral arteries and may manifest as subarachnoid or intracerebral hemorrhage.³

Patients with endocarditis usually have high titers of antibody to the infecting microorganism. This contributes to the formation of circulating immune complexes that may result in glomerulonephritis, arthritis, or various mucocutaneous manifestations of vasculitis, such as Osler's nodes and Roth's spots. Conjunctival hemorrhages and Janeway lesions also may have an embolic and/or immunologic etiology.

Right-sided IE

Right-sided IE is most common in IV drug users. In patients with tricuspid involvement, presenting symptoms are fever, chest pain, and cough (secondary to embolization to the lungs). At presentation, a murmur is usually absent, but eventually one-third of patients develop evidence of tricuspid insufficiency. The initial chest film may show nodular opacities, abscesses, or patchy areas of pneumonia. Always consider right-sided IE in the differential of a recurrent pneumonia-like illness.

Cardiac complications

Valvular damage resulting in hemodynamically significant valvular dysfunction is the most important cardiac complication of IE. Valvular insufficiency is most common, but when there are large vegetations, such as those seen in fungal endocarditis, obstruction may occur. The rapidity of development of the valve insufficiency, as well as the specific valve involved, determines the hemodynamic consequences. The mechanism of valvular insufficiency in NVE is destruction of the valve itself or of valve-supporting structures such as the annulus, chordae tendineae, or papillary muscles.³ In addition, a paravalvular abscess in the aortic valve may lead to heart block, and an aortic valve ring abscess may cause persistent fever.³

Heart failure, the most common cause of death in patients with IE, may result from valvular failure or obstruction, embolic MI, myocarditis, or dysrhythmias. Emboli to the coronary arteries also may result in MI. Pericarditis is found at autopsy in 15% to 20% of patients with IE.⁴

Making the diagnosis

For the Duke clinical criteria for the diagnosis of IE, see Table 2. Documentation of 2 major criteria, 1 major criterion and 3 minor criteria, or 5 minor criteria allows a clinical diagnosis of definite IE.

 

TABLE 2 Duke clinical criteria for the diagnosis of IE

Major criteria

Positive blood culture results for IE Typical microorganism from 2 separate blood cultures (eg, viridans streptococci, Streptococcus bovis, Staphylococcus aureus or enterococci, HACEK group of bacteria) Persistently positive blood culture results for a  microorganism consistent with IE: Blood cultures drawn more than 12 h apart or all of 3 or a majority of 4 or more separate blood cultures, with first and last drawn at least 1 h apart Evidence of endocardial involvement Positive echocardiogram results for endocarditis with Oscillating intracardiac mass Abscess New partial dehiscence of a prosthetic valve New valvular regurgitation

Minor criteria

Predisposing heart disease or IV drug use Fever >100.4°F (38°C) Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth’s spots, rheumatoid factor Microbiologic evidence not meeting major criterion Consistent echocardiogram results not meeting major criterion

Key: IE, infective endocarditis. Note: IE is classified as definite if pathologic criteria are met or if 2 major, 1 major criterion and 3 minor criteria, or 5 minor clinical criteria are met. Adapted with permission from Durack DT, Lukes AS, Bright KD, the Duke Endocarditis Service. New criteria for the diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-209. Copyright 1994, with permission from Excerpta Medica.

Transthoracic echocardiography reveals vegetations in about 50% to 60% of cases of IE that are diagnosed clinically. Transesophageal echocardiography is more accurate, with a sensitivity approaching 85% (see Figure 1). Echocardiography is also useful for identifying valvular abnormalities, perivalvular extension of infection, and heart failure.

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IE should be included in the differential diagnosis of

• Persistent fever of unknown etiology

• Diseases with multisystem involvement (for example, heart, kidney, brain, skin), including atrial myxoma, acute rheumatic fever, systemic lupus erythematosus, vasculitis, antiphospholipid syndrome, carcinoid syndrome, and thrombotic thrombocytopenic purpura.

Treatment of IE

Standard therapy includes bactericidal drugs given parenterally for prolonged periods (4-6 weeks). A shorter course of antibiotics (2 weeks) may be considered in methicillin-sensitive staphylococcal tricuspid IE. Initiation of antibiotic therapy should be delayed until blood cultures are collected and the diagnosis is confirmed. However, empiric antistaphylococcal agents may be considered in patients with PVE or those with a rapidly progressive illness consistent with acute IE. The choice of antibiotics depends on the type of organism that is suspected and the results of the blood cultures. Table 3 shows common antibiotic regimens that are used for specific circumstances.

 

TABLE 3 Common treatment regimens for IE
Pathogen	Antibiotic regimen
Penicillin-sensitive Streptococcus bovis or viridans streptococci	Penicillin G, 4 million units IV q6h for 4 wk Alternative regimens Penicillin G, 4 million units q6h plus gentamycin, 1mg/kg q8h for 2 wk Ceftriaxone, 2 g IV or IM once daily for 4 wk
Relatively penicillin-resistant S bovis or viridans streptococci	Penicillin G, 4 million units q4h for 4 wk plus gentamycin, 1 mg/kg q8h for 2 wk Alternative regimen Vancomycin, 15 mg/kg IV q12h for 4 wk
Methicillin-sensitive staphylococci in the absence of prosthetic material	Nafcillin, 2 g IV q4h plus gentamycin, 1 mg/kg q8h for 3-5 d Alternative regimen First-generation cephalosporin in equivalent dosages
Methicillin-resistant staphylococci in the absence of prosthetic material	Vancomycin, 15 mg/kg IV q12h for 4-6 wk
Methicillin-sensitive staphylococci in uncomplicated tricuspid endocarditis	Nafcillin, 2 g IV q4h plus gentamycin, 1 mg/kg q12h for 2 wk
Methicillin-resistant staphylococci in the presence of prosthetic material	Vancomycin, 15 mg/kg IV q12h plus gentamycin, 1 mg/kg IV or IM q8h plus rifampin, 300 mg po q8h for 6 wk
Key: IE, infective endocarditis. Source: Sande MA, Kartalija M, Anderson J. Infective endocarditis. In Fuster V, Alexander RW, O'Rourke RA, eds. Hurst’s the Heart. 10th ed. New York, NY: McGraw-Hill Co; 2087-2125.

IE prophylaxis

Antibiotic chemoprophylaxis is recommended before surgical and other invasive procedures in patients with preexisting cardiac disorders. These procedures include

• Dental extraction; dental procedures known to induce gingival or mucosal bleeding; and prophylactic dental cleaning when bleeding is anticipated

• Endoscopic retrograde cholangiography with biliary obstruction

• Surgery involving the GI tract, upper respiratory mucosa, urethra, and prostate

• Rigid bronchoscopy

• GI endoscopies (in patients at highest risk of IE, such as those with prosthetic valves).

Regimens for chemoprophylaxis for IE are as follows:

• For dental, respiratory tract, or esophageal procedures, give amoxicillin, 2 g po, 1 hour before the procedure

• For GU and GI (excluding esophageal) procedures, give ampicillin, 2 g IV or IM, plus gentamycin, 1.5 mg/kg IM or IV within 30 minutes of starting the procedure; 6 hours later, give ampicillin, 1 g IV or IM.

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IMAGES: TOP LEFT, © LOGICAL IMAGES/CMSP; TOP AND BOTTOM RIGHT, © 2002 UCSD SCHOOL OF MEDICINE/JOSH FIERER, MD.

PRODUCED BY PETER D'EPIRO

Dr Mansi and Dr Carden disclose that they have no financial involvement with any companies doing business in this field.

REFERENCES

1. Werner GS, Schulz R, Fuchs JB, et al. Infective endocarditis in the elderly in the era of transesophageal echocardiography: clinical features and prognosis compared with younger patients. Am J Med. 1996;100:90-97.

2. Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 1980-1990: a review of 210 episodes. Medicine. 1993;72:90-102.

3. Sexton DJ. Current best practices and guidelines: assessment and management of complications in infective endocarditis. Cardiol Clin. 2003;21:273-282.

4. Karchmer AW. Infective endocarditis. In Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A Textbook of Cardiovascular Medicine. Vol 1. 6th ed. Philadelphia, Pa; WB Saunders Co: 2001:1723.

SUGGESTED READING

Cabell CH, Jollis JG, Peterson GE, et al. Changing patient characteristics and the effect on mortality in endocarditis. Arch Intern Med. 2002;162:90-94.

Devlin RK, Andrews MM, von Reyn CF. Recent trends in infective endocarditis: influence of case definitions. Curr Opin Cardiol. 2004;19:134-139.

Dhawan VK. Infective endocarditis in elderly patients. Clin Infect Dis. 2002;34:806-812.

Hoen B. Special issues in the management of infective endocarditis caused by gram-positive cocci. Infect Dis Clin North Am. 2002;16:437-452, xi.

Horstkotte D, Follath F, Gutschik E, et al. Guidelines on prevention, diagnosis, and treatment of infective endocarditis executive summary; the Task Force on Infective Endocarditis of the European Society of Cardiology. Eur Heart J. 2004;25:267-276.

Woods CW, Cheng AC, Fowler VG, Jr, et al. Endocarditis caused by Staphylococcus aureus with reduced susceptibility to vancomycin. Clin Infect Dis. 2004;38:1188-1191.

 

Current aspects of infective endocarditis. Patient Care June 2004;38:38-44.