Time Recommended to complete: 1 day
Frederick S. Southwick, M.D.
GUIDING QUESTIONS
1. Which cardiac lesions predispose to bacterial endocarditis?
2. If antibiotic prophylaxis is to be administered, when should the antibiotic be given?
3. What are the most common symptoms in subacute bacterial endocarditis?
4. When bacterial endocarditis is suspected, what are the skin lesions that should be searched for, and how often are they seen?
5. How should blood samples for culture be drawn if the clinician suspects bacterial endocarditis?
6. Are bacteriostatic antibiotics effective in the treatment of bacterial endocarditis?
7. In the patient with Staphylococcus aureus line-related bacteremia, how long should antibiotics be administered?
8. Which key physical finding is most helpful for detecting cardiac tamponade?
CARDIOVASCULAR INFECTIONS
INFECTIVE ENDOCARDITIS
POTENTIAL SEVERITY
Acute endocarditis is life-threatening and often requires surgical intervention. Subacute endocarditis is an indolent disease that can continue for months.
Epidemiology
Infective endocarditis remains a serious but relatively uncommon problem. The incidence varies from series to series, being estimated to be as high as 11 per 100,000 population, and as low as 0.6 per 100,000 population. The exact incidence is difficult to ascertain, because the definitions for endocarditis differ in many surveys. A reasonable estimate is probably 2 per 100,000 population.
This means that a primary care physician will encounter only 1-2 cases over a working lifetime.
Endocarditis is more common in men than in women, and the disease is increasingly becoming a disease of elderly individuals. In recent series, more than half of the patients with endocarditis were over the age of 50 years. With available rapid treatment for group A streptococcal infections, the incidence of rheumatic heart disease has declined, eliminating this important risk factor for endocarditis in the young. With life expectancy increasing worldwide, the percentage of elderly people will continue to rise, and the number of elderly patients with infective endocarditis can be expected to increase in the future.
KEY POINTS
About the Epidemiology of Infective Endocarditis
1. A rare disease; a primary care physician is likely to see just 1-2 cases in an entire career.
2. More common in men.
3. Increasingly a disease of elderly individuals.
Pathogenesis and Predisposing Risk Factors
HOST FACTORS
Infective endocarditis is usually preceded by the formation of a predisposing cardiac lesion. Preexisting endocardial damage leads to the accumulation of platelets and fibrin, producing nonbacterial thrombotic endocarditis (NBTE). This sterile lesion serves as an ideal site to trap bacteria as they pass through the bloodstream. Cardiac lesions that result in endocardial damage and predispose to the formation of NBTE include rheumatic heart disease, congenital heart disease (bicuspid aortic valve, ventricular septal defect, coarctation of the aorta, and Tetralogy of Fallot), mitral valve prolapse, degenerative heart disease (calcific aortic valve disease), and prosthetic valve placement.
Risk factors of endocarditis reflect the pathogenesis of the disease. Patients with congenital heart disease and rheumatic heart disease, those with an audible murmur associated with mitral valve prolapse, and elderly patients with calcific aortic stenosis are all at increased risk. The higher the pressure gradient in aortic stenosis, the greater the risk of developing endocarditis. Intravenous drug abusers are at high risk of developing endocarditis as a consequence of injecting bacterially contaminated solutions intravenously.
Platelets and bacteria tend to accumulate in specific areas of the heart based on the Venturi effect. When a fluid or gas passes at high pressure through a narrow orifice, an area of low pressure is created directly downstream of the orifice. The Venturi effect is most easily appreciated by examining a rapidly flowing, rock-filled river. When the flow of water is confined to a narrower channel by large rocks, the velocity of water flow increases. As a consequence of the Venturi effect, twigs and other debris can be seen to accumulate on the downstream side of the obstructing rocks, in the area of lowest pressure.
Similarly, vegetations form on the downstream or low-pressure side of a valvular lesion. In aortic stenosis, vegetations tend to form in the aortic coronary cusps on the downstream side of the obstructing lesion. In mitral regurgitation, vegetations are most commonly seen in the atrium, the low-pressure side of regurgitant flow. Upon attaching to the endocardium, pathogenic bacteria induce platelet aggregation, and the resulting dense plateletfibrin complex provides a protective environment. Phagocytes are incapable of entering this site, eliminating an important host defense. Colony counts in vegetations usually reach 109—1011 bacteria per gram of tissue, and these bacteria within vegetations periodically lapse into a metabolically inactive, dormant phase.
KEY POINTS
About Host Factors in the Pathogenesis of Infective Endocarditis
1. Nonbacterial thrombotic endocarditis (NBTE) results from valve damage that is followed by platelet and fibrin deposition.
2. NBTE results from
a) rheumatic heart disease, now rare
b) congenital heart disease (bicuspid valve, ventricular septal defect),
c) mitral valve prolapse,
d) degenerative valve disease (calcific aortic valve disease), or
e) prosthetic valve.
3. Venturi effect results in vegetation formation on the low-pressure side of high-flow valvular lesions.
4. Disease of the mitral or aortic valve is most common; disease of tricuspid valve is rarer (usually seen in intravenous drug abusers).
The frequency with which the four valves become infected reflects the likelihood of endocardial damage. Shear stress would be expected to be highest in the valves exposed to high pressure, and most cases of bacterial endocarditis involve the valves of the left side of the heart. The mitral and aortic valves are subjected to the highest pressures and are the most commonly infected. Right-sided endocarditis is uncommon (except in the case of intravenous drug abusers), and when right-sided disease does occur, it most commonly involves the tricuspid valve. The closed pulmonic valve is subject to the lowest pressure, and infection of this valve is rare.
Patients with prosthetic valves must be particularly alert to the symptoms and signs of endocarditis, because the artificial material serves as an excellent site for bacterial adherence. Patients who have recovered from an episode of infective endocarditis are at increased risk of developing a second episode.
BACTERIAL FACTORS
The organisms responsible for infective endocarditis are sticky. They adhere more readily to inert surfaces and to the endocardium. Streptococci that express dextran on the cell wall surface adhere more tightly to dental enamel and to other inert surfaces. Streptococci that produce higher levels of dextran demonstrate an increased ability to cause dental caries and to cause bacterial endocarditis. Streptococcus viridans, named for their ability to cause green (“alpha”) hemolysis on blood agar plates, often have a high dextran content and are a leading cause of dental caries and bacterial endocarditis. S. mutans and S. sanguisare the species in this group that most commonly cause endocarditis.
KEY POINTS
About Bacterial Factors in the Pathogenesis of Infective Endocarditis
1. Bacteria with high dextran content stick to nonbacterial thrombotic endocarditis (NBTE) more readily; they also cause dental caries.
a) Streptococcus viridans is the leading cause of subacute bacterial endocarditis.
b) S. bovis also has high dextran content; associated with colonic carcinoma.
2. Candida albicans adheres well to NBTE; C. krusei adheres poorly.
One group D streptococcus, S. bovis, produces high levels of dextran and demonstrates an increased propensity to cause endocarditis. This bacterium often enters the bloodstream via the gastrointestinal tract as a consequence of a colonic carcinoma. S. viridans also express the surface adhesin FimA, and this protein is expressed in strains that cause endocarditis. Candida albicans readily adheres to NBTE in vitro and causes endocarditis, particularly in intravenous drug abusers and in patients with prosthetic valves. C. krusei is nonadherent and seldom causes infective endocarditis.
Adherence to specific constituents in the NBTE also may be important virulence characteristics. For example, pathogenic strains of S. sanguis are able to bind to platelet receptors, and endocarditis-causing strains of Staphylococcus aureus demonstrate increased binding to fibrinogen and fibronectin.
CAUSES OF BACTEREMIA LEADING TO ENDOCARDITIS
Before bacteria can adhere to NBTE, they must gain entry to the bloodstream. Whenever a mucosal surface heavily colonized with bacterial flora is traumatized, a small number of bacteria enter the bloodstream, where they are quickly cleared by the spleen and liver. As outlined in Table 7.1, there are many causes of transient bacteremia; however, intravascular catheters are the most common cause of bacteremia leading to endocarditis, and 25% of all cases of endocarditis are now hospital acquired. Dental manipulations frequently precipitate transient bacteremia. Patients undergoing dental extraction or periodontal surgery are at particularly high risk, but gum chewing and tooth brushing can also lead to bacteremia. Oral irrigation devices such as the Waterpik should be avoided in patients with known valvular heart disease or prosthetic valves, because these devices precipitate bacteremia more frequently than simple tooth brushing. Other manipulations that can cause significant transient bacteremia include tonsillectomy, urethral dilatation, transurethral prostatic resection, and cystoscopy. Pulmonary and gastrointestinal procedures cause bacteremia in a low percentage of patients.
Table 7.1. Causes of Bacteremia Potentially Leading to Endocarditis
Adapted from Everett ED, Hirschmann JV. Transient bacteremia and endocarditis prophylaxis. A review. Medicine (Baltimore). 1977;56:61–77.
KEY POINTS
About Causes of Bacteremia Potentially Leading to Infective Endocarditis
1. Causes of bacteremia that can lead to infective endocarditis.
a) Intravascular catheters are now most common.
b) Dental manipulations (extraction, periodontal surgery), oral irrigators (Waterpik)
c) Tonsillectomy
d) Urology procedures (urethral dilatation, cystoscopy, prostatectomy)
e) Pulmonary procedures (rigid bronchoscopy, intubation)
f) Gastrointestinal (GI) procedures (upper GI endoscopy, sigmoidoscopy, colonoscopy)
Causes of Infective Endocarditis
The organisms most frequently associated with infective endocarditis are able to colonize the mucosa, enter the bloodstream, and adhere to NBTE or native endocardium (see Table 7.2). In native valve endocarditis, in earlier series, Streptococcus species were the most common cause, representing more than half of all cases. S. viridans species were most frequent, followed by S. bovis. However, Staphylococcus species are now the most common cause of native valve endocarditis followed by Streptococcal species. Staphy-lococcus aureus predominates, with coagulase-negative staphylococci playing a modest role. Enterococci (S. faecalis and S. faecium) are now classified separately from the streptococci, and in most series, these organisms are the third most common cause of infective endocarditis. Other rarer organisms include gram-negative aerobic bacteria, and the HACEK (Haemophilus aphrophilus, Actinobacillus—actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) group. These slow-growing organisms are found in the mouth and require CO2 for optimal growth. They may not be detected on routine blood cultures that are discarded after 7 days. Anaerobes, Coxiella burnetii (“Q fever endocarditis”) and Chlamydia species are exceedingly rare causes. In about 3—5% of cases, cultures are repeatedly negative.
Table 7.2. Microorganisms That Cause Infective Endocarditis
Adapted from Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, etiology, and outcome of infective endocarditis in theAdapted from Murdoch DR, 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med. 2009;169:463–473 and from Schlant RC, Alexander RW, O’Rourke RA, Soonneblick EH, eds. Hurst’s The Heart. 8th ed. New York, NY: McGraw-Hill; 1994:1681–1709.
In intravenous drug abusers, S. aureus and gram-negative organisms predominate as the most common causes (Table 7.2). In certain areas of the country—for example, Detroit, Michigan—methicillin-resistant S. aureus (MRSA) is the predominant pathogen. Pseudomonas aeruginosa, found in tap water, is the most common gram-negative organism. Streptococci also are common, particularly Enterococcus and S. viridans species. Fungi, primarily C. albicans, is another important cause of endocarditis in this population. Polymicrobial disease is also more frequent.
KEY POINTS
About the Causes of Infective Endocarditis
1. Native valve endocarditis:
a) Most common cause is Staphylococcus aureus.
b) Streptococci are second: S. viridans being most frequent, then S. faecalis (Enterococcus) and S. bovis (associated with colonic cancer).
c) HACEK group is an uncommon cause, but considered in culture-negative cases (hold blood cultures for more than 7 days).
2. Intravenous drug abusers:
a) Most common cause is S. aureus.
b) Gram-negative aerobic bacilli are the second most common cause; Pseudomonas aeruginosa
c) Fungi
d) Multiple organisms
3. Prosthetic valve:
a) “Early” is the result of nosocomial pathogens: S. aureus, coagulase-negative staphylococci, gram-negative bacilli, fungi.
b) “Late” (more than 2 months post-op) is the result of mouth and skin flora: S. viridans, coagulase-negative staphylococci, S. aureus, gram-negative bacilli, fungi.
The causes of prosthetic valve endocarditis depend on the timing of the infection (Table 7.2). The development of endocarditis within the first 2 months after surgery (“early prosthetic valve endocarditis”) is primarily caused by nosocomial pathogens. Staphylococcal species (coagulase-positive and -negative strains alike), gram-negative aerobic bacilli, and fungi predominate. In disease that develops more than 2 months after surgery (“late prosthetic valve endocarditis”), organisms originating from the mouth and skin flora predominate: S. viridans species, S. aureus, and coagulase-negative staphylococci being most common. Gram-negative aerobic bacilli and fungi are less common, but still important pathogens.
Clinical Manifestations
CASE 7.1
A 78-year-old retired advertising executive was admitted to the hospital with a chief complaint of increasing shortness of breath and ankle swelling. About 15 weeks before admission, he had had some dental work done. About 2 weeks after that work was completed, he began to experience shortness of breath following any physical exertion. He also noted increasing fatigue, night sweats, and intermittent low-grade fever. At that time, a diastolic murmur, II/VI was noted along the left sternal border, maximal at the third intercostal space. He was treated as an outpatient with diuretics for left-sided congestive heart failure (CHF).
The day before admission, he began experiencing increasingly severe shortness of breath. He also began coughing frothy pink phlegm, and he arrived in the emergency room gasping for air.
Physical examination showed a temperature of 39°C, blood pressure of 106/66 mmHg, a pulse of 85 per minute regular, and a respiratory rate of 36 per minute. The patient appeared lethargic and had rapid shallow respirations. His teeth were in good repair. No hemorrhages or exudates were seen in the fundi. With the patients sitting at a 30-degree angle, the jugular veins were distended to the level of his jaw; diffuse wheezes and rales were heard in lower two-thirds of both lung fields. The heart demonstrated a loud S3 gallop, II/VI nearly holosystolic murmur heard loudest in the left third intercostal space radiating to the apex, and a II/VI diastolic murmur heard best along left sternal border. Liver and spleen were not palpable. Pitting edema of the ankles (2+) extending midway up the thighs was noted. Nail beds had no splinter hemorrhages. Pulses were 2+ bilaterally.
The laboratory workup found a white blood cell (WBC) count of 11,700 mm3, with 69% polymorphonuclear leukocytes, 4% band forms, 22% lymphocytes, and 3% mononuclear cells, and a hematocrit of 30%, normochromic, normocytic. Urinalysis showed 1+ protein with 10-20 red blood cells and 5-10 WBCs per high-power field. The patient’s erythrocyte sedimentation rate was 67 mm/h. An electrocardiogram showed normal sinus rhythm, with left bundle branch block. A chest radiograph revealed extensive diffuse perihilar infiltration bilaterally. Four of four blood cultures were positive for Streptococcus viridans.
HISTORY
When the event leading to bacteremia can be identified, the incubation period usually required before symptoms develop is less than 2 weeks. In case 7.1, the onset of symptoms occurred 15 days after dental work. Because symptoms of endocarditis are usually nonspecific, delays as long as 5 weeks can occur in patients with subacute endocarditis, between the onset of symptoms and diagnosis. In case 7.1, the delay was 3 months.
As observed in this patient, the most common symptom is a low-grade fever. Body temperature is usually only mildly elevated in the 38°C range. Fever is frequently accompanied by chills and less commonly by night sweats. Fatigue, anorexia, weakness, and malaise are common complaints, and the patient often experiences weight loss. Myalgias and arthralgias are commonly present. Patients with subacute endocarditis are often mistakenly suspected of having a malignancy, connective tissue disease, or other chronic infection such as tuberculosis.
Another prominent complaint in a smaller percentage of patients is low back pain. Debilitating back pain that limits movement can be the presenting complaint, and health care personnel should always consider infective endocarditis as one possible cause of low back pain and fever. Systemic emboli are most common in S. aureus and can result in sudden hemiparesis or sudden limb pain as a consequence of tissue ischemia. In all patients who suffer a sudden cerebrovascular accident consistent with an embolic stoke, infective endocarditis should be excluded.
KEY POINTS
About the History of Infective Endocarditis
1. Nonspecific symptoms usually begin 2 weeks after initial bacteremia.
2. On average, for subacute endocarditis, diagnosis takes 5 weeks from onset of symptoms.
3. Low-grade fever is most common, may be accompanied by night sweats.
4. Fatigue, malaise, generalized weakness, anorexia, and weight loss are common; mimics cancer.
5. Myalgias and arthralgias may suggest a connective tissue disease.
6. Low back pain can be the initial primary complaint. Consider endocarditis, epidural abscess, and osteomyelitis when back pain is accompanied by fever.
7. Infective endocarditis must be excluded in all cases of embolic cerebrovascular accident, particularly in younger patients.
8. In acute endocarditis, fever is high (40°C range), and the patient appears acutely ill. Recently has become the most common presentation.
Acute endocarditis is becoming the most common presentation of endocarditis reflecting the high incidence S. aureus endocarditis. These patients present with a rapid onset (hours to days) of symptoms and signs. In addition to S. aureus, acute endocarditis is associated with enterococci, and occasionally with S. pneumoniae. Fever is often high, 40°C, accompanied by rigors. These patients are usually brought to the emergency room acutely ill. The likelihood of serious cardiac and extravascular complications is higher in these patients, particularly those with acute S. aureus endocarditis. Rapid diagnosis and treatment are mandatory to reduce valvular destruction and embolic complications.
PHYSICAL FINDINGS
The classical physical findings of infective endocarditis should be carefully searched for. Fever is the rule and is detected in 95% of patients. A heart murmur is almost always seen. The absence of an audible murmur should call into question the diagnosis of endocarditis, except in cases of right-sided endocarditis or infection of a mural thrombus (rare). Although classically described as a changing murmur, the character of the murmur usually does not change significantly over time unless a valve leaflet is destroyed (occurs most commonly with S. aureus) or a chordae tendineae ruptures. Detection of a new aortic regurgitant murmur is a bad prognostic sign and is commonly associated with the development of congestive heart failure (CHF), as described in case 7.1. The most common cause of acute aortic regurgitation is infective endocarditis; therefore, if a high-pitched diastolic murmur radiating along the left sternal border is heard, the initial workup should always include blood cultures. In case 7.1, the diagnosis was delayed because this man’s outpatient physician did not exclude infective endocarditis as the cause of the new diastolic murmur.
Careful attention must be paid to the fundi, skin, nail beds, and peripheral pulses, because manifestations attributable to emboli strongly suggest infective endocarditis. Fundoscopic examination may reveal classic Roth spots, retinal hemorrhages with pale centers, or, more commonly, flame-shaped hemorrhages. One of the most common locations to detect petechial hemorrhages is the conjunctiva [Figure 7.1(A)]. This finding is not specific for endocarditis, being also seen in patients after cardiac surgery and in patients with thrombocytopenia.
Figure 7.1. Embolic phenomena in infective endocarditis. A. Conjunctival petechiae: Arrows point to two discrete linear hemorrhages. B. Nail-bed splinter hemorrhage: Multiple petechiae are seen on both fingers. Arrow points to a splinter hemorrhage underlying the nail bed. C. Osler nodes: Arrows point to subtle discolorations of the pads of the toes. These sites were raised and tender to palpation. D. Janeway lesions: Painless hemorrhagic lesions (left). Biopsy of a typical lesion shows thrombosis and intravascular gram-positive cocci (right). Culture was positive for Staphylococcus aureus. See color image on color plate 1 & 2
Clusters of petechiae can be seen on any part of the body. Other common locations are the buccal mucosa, palate, and extremities. Presence of petechiae alone should be considered a nonspecific finding. The splinter hemorrhages (linear red or brownish streaks) that develop under the nail beds of the hands and feet are caused by emboli lodging in distal capillaries [Figure 7.1 (B)]. These lesions can also be caused by trauma to the fingers or toes. Osler nodes are small pea-sized subcutaneous, painful erythematous nodules that arise in the pads of the fingers, and toes and in the thenar eminence [Figure 7.1 (C)]. They are usually present only for a brief period, disappearing within hours to days. Janeway lesions are most commonly seen in association with S. aureus infection [Figure 7.1 (D)]. These hemorrhagic plaques usually develop on the palms and soles. Bacteria can sometimes be visualized on a skin biopsy of the lesion [Figure 7.1 (D)]. It must be kept in mind that, as observed in case 7.1, the majority of patients with infective endocarditis will demonstrate no physical evidence of peripheral emboli. The absence of embolic phenomena therefore does not exclude the diagnosis.
KEY POINTS
About the Physical Findings of Infective Endocarditis
1. A cardiac murmur is heard in nearly all patients.
a) Absence of a murmur should call into question the diagnosis of infective endocarditis.
b) Classic changing murmur is rare, but it may occur with rupture of chordae tendineae.
c) New aortic regurgitation is the result of infective endocarditis until proven otherwise.
2. Embolic phenomena are found in the minority of cases.
a) Are most common in the conjunctiva; clusters can be found anywhere.
b) Splinter hemorrhages, linear streaks, are found under nails.
c) Osler nodes, painful raised lesion in the pads of the fingers or toes, are evanescent.
d) Janeway lesions, red macules, are more persistent and most common in acute endocarditis attributable to Staphylococcus aureus.
e) Roth spots are retinal hemorrhages with a clear center.
3. Splenomegaly can be found; left upper quadrant tenderness can occur with embolic infarction.
4. Check all pulses as a baseline because of the risk of obstructive emboli.
5. Perform a thorough neurologic examination; a sudden embolic stroke can develop.
Other findings can include clubbing of the fingers and toes. As a consequence of earlier diagnosis and treatment, this manifestation is less common than in the past, but it may be found in patients with prolonged symptoms. Another commonly reported finding is splenomegaly. Some patients experience left upper quadrant pain and tenderness as result of splenic infarction caused by septic emboli. Joint effusions are uncommon; however, diffuse arthralgias and joint stiffness are frequently encountered.
Finally, all pulses should be checked periodically. A sudden loss of a peripheral pulse, accompanied by limb pain, warrants immediate arteriography to identify and extract occluding emboli. A thorough neurologic examination must also be performed. Confusion, severe headache, or focal neurologic deficits should be further investigated by computed tomography (CT) or magnetic resonance imaging (MRI) scan with contrast of the head looking for embolic infarction, intracerebral hemorrhage, or brain abscess.
LABORATORY FINDINGS
Laboratory abnormalities are nonspecific in nature. Case 7.1 had many of the typical laboratory findings of infective endocarditis. Anemia of chronic disease is noted in 70-90% of subacute cases. A normocytic, normochromic red cell morphology, low serum iron, and low iron binding capacity characterize this form of anemia. Peripheral leukocyte count is usually normal. The finding of an elevated peripheral white blood cell (WBC) count should raise the possibility of a myocardial abscess or another extravascular focus of infection. Leukocytosis is also often found in patients with acute bacterial endocarditis. The erythrocyte sedimentation rate, a measure of chronic inflammation, is almost always elevated. With the exception of patients with hemoglobinopathies that falsely lower the rate of red blood cell sedimentation, the finding of a normal sedimentation rate virtually excludes the diagnosis of infective endocarditis. In nearly all cases, C-reactive protein, another inflammatory marker, is also elevated. A positive rheumatoid factor is detected in half of these patients, and elevated serum globulins are found in 20-30% of cases. Cryoglobulins, depressed complement levels, positive tests for immune complexes, and a false positive serology for syphilis are other nonspecific findings that may accompany infective endocarditis. Urinalysis is frequently abnormal, with proteinuria and hematuria being found in up to 50% of cases. These abnormalities are the consequence of embolic injury or deposition of immune complexes causing glomerulonephritis.
KEY POINTS
About the Laboratory Findings of Infective Endocarditis
1. Anemia of chronic disease is found in most patients.
2. The peripheral white blood cell count is normal, unless myocardial abscess or acute disease is present.
3. Manifestations of chronic antigenemia mimic a connective tissue disorder:
a) Elevated sedimentation rate and C-reactive protein
b) Positive rheumatoid factor
c) Elevated immunoglobulins, cryoglobulins, and immune complexes
d) Decreased complement
e) Hematuria and proteinuria
4. A chest radiograph may be abnormal:
a) Circular, cannonball-like lesions in embolic right-sided endocarditis
b) Pulmonary edema pattern secondary to left-sided congestive heart failure
5. Monitor the electrocardiogram closely; conduction defects can progress to complete heart block.
A chest X-ray should be performed in all patients with suspected endocarditis. In patients with right-sided disease, distinct round cannonball-like infiltrates may be detected; these represent pulmonary emboli. In cases of acute mitral regurgitation or decompensated left-sided failure because of aortic regurgitation, diffuse alveolar fluid may be detected, indicating pulmonary edema. Finally, the patient’s electrocardiogram should be closely monitored. The finding of a conduction defect raises concern that infection has spread to the conduction system; in some cases, this spread may progress to complete heart block. In case 7.1, the PR interval was prolonged, and this patient subsequently developed complete heart block. Findings consistent with myocardial infarct may be detected when emboli are released from vegetations in the coronary cusps into the coronary arteries.
Diagnosis
BLOOD CULTURES
Blood cultures are the critical test for making a diagnosis of infective endocarditis. As compared with most tissue infections—such as pneumonia and pyelonephritis—that result in the intermittent release of large numbers of bacteria into the blood, infective endocarditis is associated with a constant low-level bacteremia (Figure 7.2). The vegetation is like a time-release capsule, with bacteria being constantly released in small numbers into the bloodstream. It is this constant antigenic stimulus that accounts for the rheumatic complaints and multiple abnormal serum markers associated with infective endocarditis.
Figure 7.2. Concentration of bacteria in the bloodstream over time in infective endocarditis versus bacteremia caused by other infections.
To document the presence of a constant bacteremia, blood samples for culture should be drawn at least 15 minutes apart. In patients with suspected subacute infective endocarditis, three blood cultures are recommended over the first 24 hours. In these patients, antibiotics should be withheld until the blood cultures are confirmed to be positive because administration of even a single dose of antibiotics can lower the number of bacteria in the bloodstream to undetectable levels and prevent identification of the pathogen. However, if the patient is acutely ill, 2-3 samples for culture should be drawn over 45 minutes, with empiric therapy begun immediately thereafter.
Because the number of bacteria in the blood is usually low (approximately 100/mL), a minimum of 10 mL of blood should be inoculated into each blood culture flask. Lower volumes reduce the yield and may account for many culture-negative cases. Routinely, blood cultures are held in the microbiology laboratory for 7 days and are discarded if negative. However, if a member of the slow-growing HACEK group is suspected, the laboratory must be alerted to hold the blood cultures for 4 weeks and to subculture the samples on chocolate agar in 5% CO2. If nutritionally deficient streptococci are suspected, specific nutrients need to be added to the blood culture medium.
The sensitivity of blood cultures is excellent, yields being estimated to be 85-95% on the first blood culture and improving to 95-100% with a second blood culture. The third blood culture is drawn primarily to document the constancy of the bacteremia; it does not significantly improve overall sensitivity. The administration of antibiotics within 2 weeks of blood cultures lowers the sensitivity, and patients who have received antibiotics often require multiple blood cultures spaced over days to weeks to identify the cause of the disease.
ECHOCARDIOGRAPHY
Echocardiography is the other essential test that all patients with suspected infective endocarditis must receive. Transthoracic echocardiography (TTE) is relatively insensitive (44-63%) for detecting vegetations as compared with transesophageal echocardiography (TEE: 94-100% sensitivity), which can detect vegetations smaller than 3 mm. As compared with TTE, TEE more readily detects extravalvular extension of infection (87% vs. 28% sensitivity); and more accurately visualizes valve perforations (95% vs. 45% sensitivity). A TEE is also preferred for investigating prosthetic valve endocarditis. When accompanied by Doppler-color flow analysis, echocardiography can assess valve function, myocardial contractility, and chamber volume—vital information for deciding on surgical intervention.
KEY POINTS
About the Diagnosis of Infective Endocarditis
1. Blood cultures document constant bacteremia with an endocarditis-associated pathogen:
a) Blood cultures spaced at least 15 minutes apart, three over 24 hours for subacute bacterial endocarditis.
b) Large volumes of blood (at least 10 mL) need to be added to blood culture flasks.
c) Blood cultures are usually negative for at least 7 days after an antibiotic is given.
2. Documentation of endocardial involvement [transesophageal echocardiography (TEE) is more sensitive than transthoracic echocardiography]; TEE always preferred in prosthetic valve endocarditis.
3. Duke criteria are helpful in making the clinical diagnosis of infective endocarditis in the absence of pathologic tissue.
THE MODIFIED DUKE CRITERIA
A definitive diagnosis of infective endocarditis in the absence of valve tissue histopathology or culture is often difficult, and many investigations of this disease have been plagued by differences in the clinical definition of infective endocarditis. Clinical criteria have been established that allow cases to be classified as definite and possible (Table 7.3). Using the modified Duke criteria, a finding of 2 major criteria, or 1 major criterion and 3 minor criteria, or 5 minor criteria classifies a case as definite infective endocarditis. A finding of 1 major and 1 minor criterion, or 3 minor criteria, classifies a case as possible infective endocarditis.
Table 7.3. Modified Duke Criteria for the Diagnosis of Bacterial Endocarditis
From Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633–638.
Complications
In the modern antibiotic era, complications associated with infective endocarditis remain common, with approximately 60% of patients experiencing one complication; 25%, two; and 8%, three or more complications.
CARDIAC COMPLICATIONS
Complications involving the heart are most frequent, occurring in one half of patients. CHF is the most common complication that leads to surgical intervention. Destruction of the valve leaflets results in regurgitation. Less commonly, vegetations become large enough to obstruct the outflow tract and cause stenosis. Perivalvular extension of infection also requires surgical intervention. This complication is more common with aortic valve disease, and spread from the aortic valvular ring to the adjacent conduction system can lead to heart block. This complication should be suspected in the infective endocarditis patient with peripheral leukocytosis, persistent fever while on appropriate antibiotics, or an abnormal conduction time on electrocardiogram. Transesophageal echo detects most cases, and this test should be performed in all patients with aortic valve endocarditis. Less common complications include pericarditis and myocardial infarction.
SYSTEMIC EMBOLI
Pieces of the vegetation—consisting of a friable collection of platelets, fibrin, and bacteria—frequently break off and become lodged in arteries and arterioles throughout the body. Small emboli are likely released in all cases of endocarditis, but they are symptomatic in only one-sixth to one-third of patients. Patients with large vegetations (exceeding 10 mm) and vegetations on the anterior leaflet of the mitral valve are at higher risk for systemic emboli. Because the right brachiocephalic trunk (innominate artery) is the first vessel to branch from the ascending aortic arch, emboli have a higher likelihood of passing through that vessel and into the right internal carotid artery.
The second branch coming off the aortic arch is the left common carotid artery, and the likelihood of emboli entering this vessel is also higher. These anatomic considerations probably account for the observation that two-thirds of left-sided systemic emboli from the heart lodge in the central nervous system. In addition to sudden neurologic deficits, patients can experience ischemic limbs and splenic and renal infarction.
Patients with right-sided endocarditis frequently develop recurrent pulmonary emboli. Symptomatic emboli more commonly occur in patients with S. aureus. S. bovis and fungal endocarditis. Antibiotic therapy is associated with fibrotic changes in the vegetation, and after 2 weeks of therapy, the risk of emboli is markedly reduced.
MYCOTIC ANEURYSMS
Infectious emboli can become lodged at arterial bifurcations, where they occlude the vasa vasorum or the entire vessel lumen, damaging the muscular layer of the vessel. The systemic arterial pressure causes ballooning of the weakened vessel wall and formation of an aneurysm. Aneurysms are most commonly encountered in the middle cerebral artery, abdominal aorta, and mesenteric arteries. On occasion, these aneurysms can burst, resulting in intracerebral or intra-abdominal hemorrhage. Because of the increased risk of hemorrhage, anticoagulation should be avoided in patients with infective endocarditis. Mycotic aneurysms are most commonly encountered in S. aureusendocarditis.
NEUROLOGIC COMPLICATIONS
Complications arising in the central nervous system are second only to cardiac complications in frequency, being seen in 25-35% of patients. In addition to embolic strokes and intracerebral hemorrhage, patients can develop encephalopathy, meningitis, meningoen-cephalitis, and brain abscess. In the past, development of a neurologic deficit was considered a contraindication to cardiac surgery. More recent experience indicates that surgery within 1 week of the neurologic event is not accompanied by worsening neurologic deficits.
KEY POINTS
About Complications Associated with Infective Endocarditis
1. Cardiac complications occur in up to half of patients:
a) Congestive heart failure
b) Myocardial abscess (aortic disease associated with conduction defects)
c) Myocardial infarction (rare complication of aortic disease)
2. Two-thirds of systemic emboli go to the cerebral cortex.
3. Neurologic complications can arise from emboli:
a) Embolic stroke (most commonly with Staphylococcus aureus, S. bovis, and fungi)
b) Mycotic aneurysms (most common with S. aureus infection)
c) Encephalopathy, meningitis, and brain abscess
4. Renal complications are possible:
a) Membranoproliferative glomerulonephritis resulting from deposition of immune complex
b) Interstitial nephritis
c) Embolic damage
RENAL COMPLICATIONS
Significant renal failure (serum creatinine above 2 mg/dL) can develop in up to one-third of patients, with the likelihood of this complication being higher in elderly patients and in those with thrombocytopenia. Renal dysfunction can be caused by immune complex glomerulonephritis, renal emboli, and drug-induced interstitial nephritis. Glomerulonephritis results from deposition of immune complex in the basement membranes of the glomeruli, resulting in the microscopic changes of membranoproliferative disease. Urinalysis reveals hematuria and mild proteinuria. Red cell casts are observed in glomerulonephritis, but not in interstitial nephritis. Glomerulonephritis usually improves rapidly with antibiotic therapy.
Treatment
ANTIBIOTICS
Whenever possible, the antibiotic therapy of subacute infective endocarditis should be based on the antibiotic sensitivities of the offending organism or organisms (Table 7.4 lists doses). Because bacteria are protected from neutrophil ingestion by the dense coating of fibrin found in the vegetation, bactericidal antibiotics are required to cure this infection. To design the most effective regimen, minimal bactericidal levels should be determined for multiple antibiotics, and combinations of these antibiotics tested for synergy (see Chapter 1). The goal is to achieve serum cidal levels of 1:8-1:32, these levels of cidal activity being associated with cure.
Table 7.4. Antibiotic Therapy for Infective Endocarditis
A second important principle of antibiotic therapy is the requirement of prolonged treatment. The concentrations of bacteria in the vegetation are high, and a significant percentage of the bacteria slow their metabolism and stop actively dividing for significant periods. These conditions prevent immediate sterilization by cidal antibiotics that require active bacterial growth for their action (penicillins, cephalosporins, and glycopeptide antibiotics). To prevent relapse, most curative regimens are continued for 4-6 weeks. One exception is uncomplicated subacute bacterial endocarditis caused by S. viridansspecies. The combination of penicillin G and gentamicin is synergistic and is associated with more rapid killing of bacteria in vegetations. Combination therapy for 2 weeks results in cure rates similar to those with penicillin alone for 4 weeks. A 2-week course of ceftriaxone and gentamicin achieves comparable results. The gentamicin dose should be adjusted to maintain peak serum levels of 3 µ-g/mL, the concentration required to achieve synergy.
In acute bacterial endocarditis, intravenous empiric antibiotic therapy should be initiated immediately after two to three blood samples for culture have been drawn. The combination of vancomycin, ampicillin, and gentamicin is recommended to cover the most likely pathogens (S. aureus, including MRSA; S. pneumoniae, and enterococci), pending culture results. Empiric therapy for culture-negative subacute bacterial endocarditis should include ampicillin and gentamicin to cover for enterococci, the HACEK group, and nutritionally deficient streptococci.
Table 7.4 outlines the regimens for each specific bacterial cause of endocarditis. Whenever possible, a synergistic regimen consisting of a β-lactam antibiotic and an aminoglycoside is preferred. One exception to this rule is S. aureus. Combination therapy with nafcillin or oxacillin and gentamicin may shorten the duration of positive blood cultures, but has not been shown to improve mortality or overall cure rates, and therefore dual antibiotic therapy is not recommended. With the exception of ceftazidime, minimum inhibitory concentrations (MICs) for cephalosporins correlate well with therapeutic response, and these agents are often therapeutically equivalent to the semisynthetic penicillins. The β-lactam antibiotics are preferred over vancomycin because vancomycin is less rapidly cidal, and failure rates of up to 40% have been reported when S. aureus endocarditis is treated with vancomycin. Daptomycin has been shown to be noninferior to vancomycin in MRSA bacteremia and endocarditis. In the penicillin-allergic patient with methicillin-sensitive S. aureus endocarditis, β-lactam desensitization should be strongly considered. In patients with enterococcal endocarditis, cephalosporins are ineffective and should not be used. Maximal doses of intravenous penicillin or ampicillin combined with gentamicin are preferred, and this combination is recommended for the full course of therapy. However, one series noted comparable cure rates when gentamicin was administered for the first 2 weeks of therapy. Vancomycin combined with gentamicin is a suitable alternative in the penicillin-allergic patient. With the exception of uncomplicated infection with S. viridans species, antibiotic treatment should be continued for 4-6 weeks.
Antibiotic therapy for prosthetic valve endocarditis presents a particularly difficult challenge. The deposition of biofilm on the prosthetic material makes cure with antibiotics alone difficult, and the valve often has to be replaced. Some patients with late-onset prosthetic valve endocarditis caused by very antibiotic-sensitive organisms can be cured by antibiotic treatment alone. In patients with coagulase-negative staphylococci, a combination of intravenous vancomycin (1 g twice daily) and rifampin (300 mg three times daily) for more than 6 weeks, plus gentamicin (1 mg/kg three times daily) for 2 weeks, is the preferred treatment of methicillin-resistant strains. For methicillin-sensitive strains, nafcillin or oxacillin (2 g every four hours) should be substituted for vancomycin.
KEY POINTS
About Antibiotic Therapy of Infective Endocarditis
1. Cidal antibiotics must be used, and therapy must be prolonged.
a) Therapy for 4-6 weeks (except for uncomplicated Streptococcus viridans infection, in which penicillin or ceftriaxone combined with low-dose gentamicin for 2 weeks is effective).
b) Therapy must be guided by minimum inhibitory concentration and synergy testing.
c) Synergistic therapy not shown to be of benefit in Staphylococcus aureus infection.
2. Whenever possible, β-lactam antibiotics are preferred over vancomycin.
3. Antibiotics alone rarely sterilize prosthetic valves. Some success with coagulase-negative staphylococci using vancomycin, gentamicin, and rifampin.
4. In tricuspid endocarditis
a) nafcillin or oxacillin plus gentamicin for 2 weeks is effective, except in HIV-infected patients;
b) oral ciprofloxacin plus rifampin for 4 weeks also may be effective.
Intravenous drug abusers with uncomplicated tricuspid valve S. aureus endocarditis can be treated with 2 weeks of intravenous nafcillin or oxacillin (2 g every four hours) combined with tobramycin (1 mg/kg three times daily). This abbreviated regimen is not recommended in HIV-antibody-positive patients. An oral regimen of ciprofloxacin (750 mg twice daily) and rifampin (300 mg twice daily) for 4 weeks has also proved effective, provided that the S. aureus strain is sensitive to ciprofloxacin.
SURGERY
Medical therapy alone is often not curative, particularly in prosthetic valve endocarditis. In a significant percentage of patients, surgical removal of the infected valve or debridement of vegetations greatly increases the likelihood of survival. As a consequence, in recent years, the threshold for surgery has been lowered.
In almost all cases of infective endocarditis, the cardiologist and cardiac surgeon should be consulted early in the course of the illness. The decision to operate is often complex, and appropriate timing of surgery must balance the risk of progressive complications with the risk of intraoperative and postoperative morbidity and mortality. Indications for surgery include the following:
1. Moderate-to-severe CHF. CHF is the most frequent indication for surgery. A delay in surgery often results in a fatal outcome because of irreversible left ventricular dysfunction. In patients with CHF death can be very sudden.
2. More than one systemic embolus. The ability to predict the likelihood of recurrent emboli by echocardiography is questionable. In some studies, large vegetations (exceeding 10 mm in diameter) and vegetations on the anterior leaflet of the mitral valve were found to have a higher probability of embolizing.
3. Uncontrolled infection. S. aureus is one of the most common pathogens to cause persistently positive blood cultures. Extravascular foci of infection should always be excluded before surgical intervention is considered.
4. Resistant organisms or fungal infection. The mortality in fungal endocarditis approaches 90%, and with the exception of a rare case of C. albicans, cures have not been achieved by medical therapy alone.
KEY POINTS
About Surgery of Infective Endocarditis
1. The threshold for surgery should be low; it increases the likelihood of cure.
2. The cardiologist and cardiac surgeon should be consulted early.
3. Indications for surgery include
a) moderate-to-severe congestive heart failure. Early surgery lowers intraoperative and postoperative mortality;
b) more than 1 systemic embolus;
c) uncontrolled infection;
d) resistant bacteria or a fungal pathogen;
e) perivalvular leak or myocardial abscess.
4. Neurologic deficits are not an absolute contraindication to surgery.
5. Neither positive blood cultures at the time of surgery nor positive valve cultures have been associated with increased risk of relapse.
5. Perivalvular/myocardial abscess. With the exception of very small abscesses, these lesions usually enlarge on medical therapy and require surgical debridement and repair.
As discussed earlier in “Neurologic complications” section, a focal neurologic deficit is not an absolute contraindication to surgery. Whenever possible, surgery should be delayed until blood cultures are negative to reduce the risk of septic intraoperative complications. However, even in the setting of ongoing positive blood cultures, infection of the new valve is uncommon, particularly if the surgeon thoroughly debrides the infected site. Relapse following surgery is rare (0.8%) and has not been shown to be related to positive blood cultures at the time of surgery or to positive valve cultures. Identification by PCR of the bacterial cause of valve tissue infection is a promising experimental method that should make diagnosis and treatment of culture-negative bacterial endocarditis more accurate.
Prognosis
The overall 6-month mortality associated with native and prosthetic endocarditis is 22-27%. Cure rates depend on the organism involved and the valve infected. S. aureus remains a particularly virulent pathogen and continues to be associated with a 50% mortality in patients over the age of 50 years. Patients with an infected aortic valve accompanied by regurgitation also have a 50% mortality. Fungal infections and infections with gram-negative aerobic bacilli are associated with poor outcomes. Development of CHF or onset of neurologic deficits is associated with a worse prognosis. Patients with early prosthetic valve endocarditis often do poorly despite valve replacement, with cure rates ranging from 30% to 50%. Late prosthetic valve endocarditis has a better outcome. In patients with late prosthetic valve infection with S. viridans species, cure rates of 90% have been achieved when antibiotic therapy is accompanied by surgery and 80% with antibiotic treatment alone. Patients with S. epidermidis late prosthetic valve endocarditis have been cured 60% of the time medically, and they have a 70% cure rate when medical treatment is combined with valve replacement.
Prevention
The efficacy of prophylaxis for native valve endocarditis has never been proven. As documented in Table 7.1, individuals probably experience multiple episodes of transient bacteremia each day, and this cumulative exposure is hundreds of times greater than a single procedure. As a consequence of these concerns, the American Heart Association now recommends antibiotic prophylaxis only for high-risk patients. High-risk patients are defined as patients with prosthetic valves (including bioprosthetic and homograft valves), a history of endocarditis, complex cyanotic congenital heart disease, or surgically constructed systemic pulmonary shunts.
KEY POINTS
About Prophylaxis in Infective Endocarditis
1. The efficacy of prophylaxis has not been proved; however, it is considered the standard of care.
2. Give to high-risk (prosthetic valve, previous endocarditis, cyanotic heart disease, surgical shunt) patients only.
3. Give in time to achieve peak antibiotic levels at the time of the invasive procedure.
Invasive procedures that warrant prophylaxis include the following:
• Dental procedures (dental extractions and gingival surgery carry the highest risk)
• Tonsillectomy and adenoidectomy
• Surgical procedures that involve intestinal or respiratory mucosa
The timing of antibiotic prophylaxis is important. The antibiotic should be administered before the procedure and timed so that peak serum levels are achieved at the time of the procedure. Table 7.5 outlines the suggested agents and schedules.
Table 7.5. Doses and schedules of Prophylactic Antibiotics in Native-Valve Endocarditis
CENTRAL VENOUS CATHETER INFECTIONS
POTENTIAL SEVERITY
Can be life-threatening. Often prolong hospital stay, and can be complicated by metastatic lesions and bacterial endocarditis.
Epidemiology and Pathogenesis
Annually, over 250,000 catheter-related bloodstream infections are reported in the United States. These infections cost an average of $35,000 per episode and can be associated with mortality rates as high as 35%. Bacteria most commonly infect catheters by tracking subcutaneously along outside of the catheter into the fibrin sheath that surrounds the intravascular segment of the catheter. Bacteria can also be inadvertently introduced into the hub and lumen of the catheter from the skin by a caregiver or as a consequence of a contaminated infusate. Less commonly, catheters can be infected by hematogenous spread caused by a primary infection at another site.
Once bacteria invade the fibrin sheath surrounding the catheter, they generate a biofilm that protects them from attack by neutrophils. This condition makes sterilization by antibiotics alone difficult. The risk of infection is greater for some devices than others:
KEY POINTS
About the Epidemiology and Pathogenesis of CVL Infections
1. Bacteria infect catheters in three ways:
a) Skin flora migrates along the catheter track.
b) Bacteria are injected into the port.
c) Hematogenous spread occurs.
2. Catheter location and type affect the risk of infection.
3. Regular exchange of central venous catheters over guide wires does not reduce the incidence of infection; the technique is not recommended, because it can precipitate bacteremia.
4. Gram-positive cocci predominate:
a) Coagulase-negative staphylococci are the most common, adhere to catheters using a glycocalyx
b) S. aureus
c) Enterococci
d) Corynebacteria
5. Gram-negative organisms account for one third of infections:
a) Enterobacter species, Escherichia coli, Acineto-bacter species, Pseudomonas species, and Serratia species.
b) Klebsiella species, Citrobacter, or non-aerugi-nosa strains of Pseudomonas are associated with contaminated infusate.
6. Candida albicans also forms an adherent glycocalyx; associated with high glucose solutions.
1. Catheters
a) Femoral vein >internal jugular >subclavian
b) Nontunneled >tunneled
c) Centrally inserted central venous >peripherally inserted central
d) Conventional tips >silver-impregnated tips
e) Hemodialysis >others
2. Ports and other devices
a) Tunneled >totally implanted
b) Uncuffed >cuffed
c) Hyperalimentation >standard infusion
The organisms most commonly associated with intravascular device infection are skin flora. Grampositive cocci predominate, with coagulase-negative staphylococci being most common, followed by S. aureus. Coagulase-negative staphylococci produce a glycocalyx that enhances its adherence to synthetic materials such as catheter tips. Enterococci, corynebacteria, and bacillus species are other common gram-positive pathogens. Gram-negative bacilli account for up to one-third of infections, with Klebsiella pneumoniae, Enterobacter species, Escherichia coli, Pseudomonas species, Acinetobacter species, and Serratia species being most common. Positive blood cultures for Klebsiella, Citrobacter, and non-aeruginosa strains of Pseudomonas suggest a contaminated infusate.
Fungi now account for 20% of central venous catheter infections, Candida albicans predominating. Like coagulase-negative staphylococci, C. albicans is able to form a glycocalyx that enhances adherence to catheters. Patients receiving high glucose solutions for hyperalimentation are at particularly high risk for this infection.
Clinical Manifestations and Diagnosis
CASE 7.2
A 53-year-old white woman was admitted to the hospital with complaints of severe shaking during infusion of her hyperalimentation solution. She had been receiving intravenous hyperalimentation for 16 years for a severe dumping syndrome that prevented eating by mouth. She had had multiple complications from her intravenous lines, including venous occlusions and line-associated bacteremia, requiring 24 line replacements. She had last been admitted 6 months earlier with Enterobacter cloacae infection of her central venous line requiring line removal and intravenous cefepime. At that time, a tunneled catheter had been placed in her left subclavian vein, and she had been doing well until the evening before admission. As she was infusing her solution, she developed rigors, and her temperature rose to 39.2°C. She continued to experience chills and developed a headache.
On physical examination, her temperature was found to be 38°C and her blood pressure 136/50 mmHg. She was nontoxic appearing. A II/VI systolic ejection murmur was noted along the left sternal border (present for years). The site of the catheter was not erythematous or tender. Two blood cultures were positive for Escherichia coli. The sample from the catheter became culture-positive 6 hours after being drawn, and a simultaneous peripheral blood sample became culture-positive 5 hours later (11 hours after being drawn).
The clinical presentation of central venous line (CVL) infection is nonspecific, generally involving fever, chills, and malaise. The finding of purulence around the intravascular device is helpful, but this sign is not always present. The absence of an alternative source for bacteremia should always raise the possibility of a CVL infection. As observed in case 7.2, the abrupt onset of chills or hypotension during infusion of a solution through the CVL strongly suggests catheter-associated infection or contamination of the infusate. The rapid resolution of symptoms following removal of the device, plus positive blood cultures for coagulase-negative staphylococci, corynebacteria, or a fungus are other findings that suggest an infected CVL. However, the absence of these findings does not exclude the diagnosis.
Rapid diagnosis can be achieved by drawing 100 μL blood from the catheter while still in place, subjecting the sample to cytospin, and performing Gram and acridine orange staining. However, this method is less sensitive than culture of the removed catheter tip. Two methods for testing the catheter are recommended. The roll method (catheter is rolled across the culture plate) is semiquantitative (positive with 15 cfu or more); the vortex or sonication method (releases bacteria into liquid media) is quantitative (positive with 100 cfu or more). The roll method detects bacteria on the outer surface of the catheter; the vortex or sonication method also detects bacteria from the lumen. The sonication method is more sensitive, but more difficult to perform than the roll method is. The use of antibiotic- and silver-impregnated catheters may lead to false negative results with these methods. Cultures of removed catheter tips should be performed only when a catheter-related bloodstream infection is suspected. Routine surveillance culturing of removed catheter tips is not recommended.
When a CVL infection is suspected, at least two and preferably three blood samples for culture should be drawn: one set from the intravenous catheter and one to two sets from the peripheral veins. A negative blood culture from a sample drawn from the intravenous line is very helpful in excluding the diagnosis of catheter-related bloodstream infection. A positive culture requires clinical interpretation. As in case 7.2, when catheter removal is not desirable, quantitative blood culturing has been recommended. A finding of colony counts from the catheter sample that are 5-10 times more than those found from the peripheral samples suggests catheter-related infection.
KEY POINTS
About the Clinical Manifestations and Diagnosis of CVL Infections
1. Symptoms are nonspecific. These historical facts are suggestive:
a) Rigors or chills associated with infusion
b) Resolution of symptoms on removal of the intravenous catheter
c) Blood cultures positive for Staphylococcus epidermidis, corynebacteria, or Candida albicans
2. Purulence around the catheter site provides strong evidence, but this sign is absent in many cases.
3. Cytospin Gram or acridine orange staining of catheter sample provides rapid diagnosis.
4. Roll and sonication methods can be used for quantitating bacteria on the catheter tip. Surveillance cultures are not recommended.
5. Blood samples for culture should be drawn simultaneously from the catheter and the peripheral veins.
a) Bacterial growth from the catheter sample that is 5-10 times than that from the peripheral sample is quantitative for catheter infection.
b) Positive bacterial growth from a catheter >2 hours before positive growth in a peripheral sample indicates catheter infection.
A more practical approach (used in case 7.2) takes advantage of the automated colorimetric continuous monitoring of blood cultures now available in most clinical microbiology laboratories. The time required to detect bacteria in the catheter sample is compared with the time required in the peripheral sample. Detection of bacteria in the catheter sample >2 hours before the peripheral sample suggests a catheter-associated infection. In case 7.2, the history of rigors during intravenous infusion combined with the earlier detection of bacteria in the catheter culture than in the peripheral culture provided strong evidence that the infection originated in the CVL.
Treatment
Empiric antibiotic therapy should be initiated after appropriate cultures have been obtained. Vancomycin is usually recommended to cover for MRSA and for methicillin-resistant coagulase-negative staphylococci. In the severely ill or immunocompromised patient, additional coverage for gram-negative bacilli is recommended a fourth-generation (cefepime) cephalosporin or a semisynthetic broad-spectrum penicillin with a β lactamase inhibitor (piperacillin–tazobactam or ticarcillin–clavulanate). In the severely ill patient, the catheter should be removed immediately. The catheter should also be removed if fever persists and blood cultures continue to be positive beyond 48 hours, and if the patient is infected with virulent, and/or difficult-to-treat pathogens (S. aureus; bacillus, micrococcus species, gram-negative bacilli, particularly Pseudomonas aeruginosa; and fungi). Polymicrobial bacteremia suggests heavy contamination of the line and usually warrants catheter removal. Other indications for removal include neutropenia, tunnel or pocket infection, valvular heart disease or endocarditis, septic thrombophlebitis, or the presence of metastatic abscesses.
The duration of therapy has not been examined in carefully controlled trials. Therapy is usually continued for 10-14 weeks in uncomplicated infection. For patients with coagulase-negative staphylococci, treatment for 5-7 days is sufficient if the catheter is removed, but treatment should be continued for a minimum of 2 weeks if the catheter is left in place. In complicated infections in which bacteremia continues despite removal of the catheter, treatment must be continued for 4-6 weeks. Because of the high incidence of relapse, follow-up blood cultures are important if the infected line was kept in place.
The salvage rate for tunnel catheters can be improved by filling the catheter lumen with pharmacologic concentrations of antibiotic—termed “antibiotic lock therapy.” For gram-positive infections, vancomycin (25 mg in 5 mL of solution) is usually recommended, and for gram-negative bacilli, gentamicin (5 mg in 5 mL) is the agent of choice. This treatment exposes the bacteria to very high concentrations of antibiotic that are more likely to penetrate the biofilm. Antibiotic lock therapy is particularly helpful in tunnel catheters, because the associated infections usually develop within the catheter lumen. Cure rates from 60% to 80% have been achieved. More recently, 70% ethanol lock has been shown in preliminary studies to be highly efficacious, and additional trials of this simple and cost-effective regimen are warranted.
Because of the ability of S. aureus to attach to and destroy normal heart valves (70% of S. aureus endocarditis cases occur on previously normal heart valves), infection with this pathogen poses a unique challenge. The duration of therapy after prompt catheter removal is best guided by TEE. The presence of valvular vegetations on TEE warrants 4 weeks of therapy; the absence of vegetations by this test allows treatment to end after 2 weeks without significant risk of relapse. Short-course therapy should be considered only in patients who promptly defervesce on antibiotic therapy and who do not have valvular heart disease or an extravascular focus of infection.
KEY POINTS
About the Treatment of CVL Infections
1. The catheter should be removed if
a) the patient is severely ill;
b) fever and positive blood cultures persist for more than 48 hours;
c) a virulent organism is the infecting agent;
d) bacteremia is polymicrobial;
e) tunnel infection, neutropenia, endocarditis, metastatic infection, or septic thrombophlebitis is present.
2. Empiric therapy is vancomycin and an antipseudomonal third- or fourth-generation cephalosporin.
3. Duration of therapy has not been studied.
a) Average duration is 3 weeks.
b) For coagulase-negative staphylococci, continue treatment for 7-10 days if the line has been removed, and 2 weeks if line has been kept in place.
c) For complicated infections, continue treatment for 4-6 weeks.
4. Antibiotic lock therapy improves cure rate for tunneled catheters (vancomycin, gen-tamicin).
5. Infection with S. aureus has a high risk for endocarditis; transesophageal echocardiography helpful in determining the duration of therapy.
6. For Candida albicans infection, always remove the line, and treat for 2 weeks to prevent endophthalmitis.
a) Fluconazole for uncomplicated catheter-related infection.
b) Amphotericin B for severely ill, neutropenic, or resistant fungus-infected patients.
In patients infected with Candida species, the intravenous catheter must be removed. Because of the high risk of Candida endophthalmitis (10-15%), catheter removal must be accompanied by antifungal therapy. In uncomplicated C. albicans infection, an echinocandin is recommended (anidulafungin, caspofungin, or micafungin). Therapy with systemic liposomal amphotericin B may be warranted in patients with persistent fungemia and severe systemic complaints, or neutropenia.
Prevention
A specialized team dedicated to placing CVLs has been shown to reduce the incidence of CVL infection. Use of a checklist to assure that five specific conditions are fulfilled has proved effective in reducing CVL infection throughout the state of Michigan from 7.7 to 1.4 infections per 1000 days.
CVL checklist is as follows:
1. Hand washing
2. Full barrier precautions during insertion of CVCs
3. Chlorhexidine for skin disinfection
4. Avoidance of the femoral insertion site
5. Removal of catheters when no longer indicated
Regular exchange of central venous catheters over guide wires does not reduce the incidence of infection. In fact, reinsertion of a catheter through an infected soft-tissue site can precipitate bacteremia.
PERICARDITIS
POTENTIAL SEVERITY
Viral pericarditis usually has a self-limiting benign course. However, patients with purulent pericarditis have a high mortality and require emergent care.
Pathogenesis
Inflammation of the pericardium has multiple infectious and noninfectious causes. Of cases in which a cause can be determined, a virus is most common. The same viruses that invade the myocardium also attack the pericardium. Bacteria can also cause pericarditis, resulting in purulent disease. In the antibiotic era, pericarditis has become rare. S. aureus, S. pneumoniae, and other streptococci are the leading causative organisms, although virtually any bacterium can cause purulent pericarditis. The pericardium can become infected as a result of hematogenous spread (the most common route today) or by spread from a pulmonary, myocardial, or subdiaphragmatic focus. Purulent pericarditis can also be a delayed complication of a penetrating injury or cardiac surgery. Postoperative infections are most commonly caused by S. aureus, gram-negative aerobic rods, and Candida species.
Tuberculous pericarditis results from hematogenous spread during primary disease, from lymphatics draining the respiratory tract, or from direct spread originating in the lung or pleura. Initially, infection causes fibrin deposition and development of granulomas containing viable mycobacteria; gradual accumulation of pericardial fluid—initially containing polymorphonuclear leukocytes, and then eventually lymphocytes, monocytes, and plasma cells—follows. Finally, the effusion is absorbed, and the pericardium thickens, becomes fibrotic, and calcifies. Over time, the pericardial space shrinks, causing constrictive pericarditis.
Clinical Manifestations
Clinical manifestations of pericarditis vary depending on the cause. Viral and idiopathic pericarditis usually present with substernal chest pain, which is usually sharp and made worse by inspiration. Pain is also worsened by lying supine, the patient preferring to sit up and lean forward. In acute bacterial pericarditis, the patient suddenly develops fever and dyspnea, and only one-third of patients complain of chest pain. Because of the lack of specific symptoms, a diagnosis of purulent pericarditis is often not considered, and the diagnosis is made only at autopsy. Tuberculous pericarditis is more insidious in clinical onset. Vague, dull chest pain, weight loss, night sweats, cough, and dyspnea are most commonly reported.
KEY POINTS
About the Causes, Pathogenesis, and Clinical Manifestations of Pericarditis
1. Pericarditis has three forms:
a) Viral, with enteroviruses most common (Coxsackievirus and Echovirus)
b) Purulent, which is usually hematogenous (multiple organisms, including Staphylo-coccus aureus)
c) Tuberculous, which is usually seeded during primary disease, but can spread from a pulmonary focus
2. Main symptom is substernal chest pain, which is relieved by sitting forward. Pain is less common in purulent pericarditis and has a gradual onset in tuberculous disease.
3. Physical examination shows
a) three-component friction rub early; rub later disappears with increased pericardial fluid;
b) pulsus paradoxus (exceeding 10 mmHg is abnormal);
c) jugular venous distension with depressed Y descent.
The classic physical findings of pericarditis include a scratchy three-component friction rub (as result of the moving heart rubbing against the abnormal pericardium during atrial systole), early ventricular filling, and ventricular systole. When the pericardial effusion increases in volume, the friction rub usually disappears. The hemodynamic consequences of the pericardial effusion can be assessed by checking for pulsus paradoxus; a value exceeding 10 mmHg indicates significant tamponade. A second hemodynamic consequence of pericardial tamponade is a rise in right ventricular filling pressure. High right-sided pressure causes an increase in jugular venous distension and abnormal jugular venous pulsations with a loss of Y descent. The patient often has a rapid respiratory rate and complains of dyspnea. However, because of the equalization of right- and left-sided cardiac pressures, pulmonary edema does not develop, and the lung fields are clear on auscultation.
Diagnosis and Treatment
Electrocardiogram is abnormal in 90% of patients and may show diffuse ST segment elevation, depression of the PR segment, and (when the effusion is large) decreased QRS voltage and electrical alternans. The electrocardiography findings are usually not specific, and when pericarditis is being considered, echocardiography is the critical test that needs to be ordered. The echocardiogram readily detects pericardial thickening and pericardial fluid accumulation. In life-threatening tamponade, echocardiography can be used to guide pericardiocentesis. In the absence of hemodynamic compromise, pericardiocentesis is not recommended because of the low diagnostic yield and moderate risk of the procedure. However, in patients with significant pericardial tamponade, pericardial fluid yields a diagnosis in one quarter of cases, and pericardial biopsy in half of patients. Pericardial fluid and tissue biopsy can be performed surgically. In an emergency, echocardiography-guided catheter pericardiocentesis can be performed. In patients with a thickened pericardium, a percutaneous pericardial biopsy can safely be performed.
KEY POINTS
About the Diagnosis and Treatment of Pericarditis
1. Echocardiography should be performed immediately:
a) Allows for assessment of pericardial thickness, pericardial fluid, and tamponade.
b) Can be used to guide emergency pericardio-centesis.
2. Electrocardiogram shows diffuse ST and T changes, depressed PR interval, decreased QRS voltage, and electrical alternans.
3. Pericardiocentesis only for those with tamponade or suspected of having purulent pericarditis. Pericardial biopsy improves the diagnostic yield.
4. Viral or idiopathic pericarditis is self-limiting.
a) Use nonsteroidal agents only if no myocarditis.
b) Colchicine can be used.
5. Purulent pericarditis requires emergency surgical drainage and systemic antibiotics. Mortality is 30%.
6. Tuberculous pericarditis is treated with
a) a four-drug antituberculous regimen, and
b) prednisone to prevent constriction (20-50% incidence during treatment);
c) Calcific form requires pericardiectomy.
Viral and idiopathic pericarditis is usually benign self-limiting disorders that can be treated with bed rest. Nonsteroidal anti-inflammatory agents are helpful for reducing chest pain, but they should probably be avoided in patients with accompanying myocarditis. Colchicine (1 mg daily) may also be helpful for reducing symptoms in cases of idiopathic disease.
In patients with purulent pericarditis, surgical drainage of the pericardium should be performed emergently, accompanied by systemic antibiotic therapy. This disease continues to be accompanied by a 30% mortality.
Tuberculous pericarditis should receive four-drug anti-tuberculous therapy. However, during treatment, 20-50% of patients progress to constrictive pericarditis. This complication can be prevented by simultaneous administration of oral prednisone (60 mg for 4 weeks, 30 mg for 4 weeks, 15 mg for 2 weeks, and 5 mg for 1 week). Patients who have developed calcific tuberculous pericarditis at the time of diagnosis require pericardiectomy for relief of symptoms.
FURTHER READING
Bacterial Endocarditis
Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394-e434.
Durante-Mangoni E, Bradley S, Selton-Suty C, et al. Current features of infective endocarditis in elderly patients: results of the International Collaboration on Endocarditis Prospective Cohort Study. Arch Intern Med. 2008;168:2095-2103.
Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2012;67:269-289.
McDonald JR, Olaison L, Anderson DJ, et al. Enterococcal endocarditis: 107 cases from the international collaboration on endocarditis merged database. Am J Med. 2005;118:759-766.
Morris AJ, Drinkovic D, Pottumarthy S, MacCulloch D, Kerr AR, West T. Bacteriological outcome after valve surgery for active infective endocarditis: implications for duration of treatment after surgery. Clin Infect Dis. 2005;41:187-194.
Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med. 2009;169:463-473.
Piper C, Korfer R, Horstkotte D. Prosthetic valve endocarditis. Heart. 2001;85:590-593.
Ramsdale DR, Turner-Stokes L. Prophylaxis and treatment of infective endocarditis in adults: a concise guide. Clin Med. 2004;4: 545-550.
Selton-Suty C, Celard M, Le Moing V, et al. Preeminence of Staphylococcus aureus in infective endocarditis: a 1-year population-based survey. Clin Infect Dis. 2012;54(9):1230-1239.
Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee. Circulation. 2007;116:1736-1754.
Central Venous Line Infections
Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49:1-45.
O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52:e162-e193.
Parienti JJ, du Cheyron D, Timsit JF, et al. Meta-analysis of subclavian insertion and nontunneled central venous catheter-associated infection risk reduction in critically ill adults. Crit Care Med. 2012;40:1627-1634.
Raad I, Hanna HA, Alakech B, Chatzinikolaou I, Johnson MM, Tarrand J. Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections. Ann Intern Med. 2004;140:18-25.
Safdar N, Fine JP, Maki DG. Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection. Ann Intern Med. 2005;142:451-466.
Pericarditis
Aikat S, Ghaffari S. A review of pericardial diseases: clinical, ECG and hemodynamic features and management. Cleve Clin J Med. 2000;67:903-914.
Adler Y, Finkelstein Y, Guindo J, et al. Colchicine treatment for recurrent pericarditis. A decade of experience. Circulation. 1998;97: 2183-2185.
Levy PY, Corey R, Berger P, et al. Etiologic diagnosis of 204 pericardial effusions. Medicine (Baltimore). 2003;82:385-391.
Trautner BW, Darouiche RO. Tuberculous pericarditis: optimal diagnosis and management. Clin Infect Dis. 2001;33:954-961.