Infective Endocarditis
John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
Updated: Aug 23, 2009
Introduction
Background
Infective endocarditis (IE) is an infection of the endocardial surface of the heart. The intracardiac effects of this infection include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. IE also produces a wide variety of systemic signs and symptoms through several mechanisms, including both sterile and infected emboli and various immunological phenomena.
Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must not be misdiagnosed or overlooked. The history of IE can be divided into several eras. Lazaire Riviere first described gross autopsy findings of the disease in 1723. In 1885, William Osler presented the first comprehensive description of endocarditis in English. Lerner and Weinstein presented a thorough discussion of this disease in modern times in their landmark series of articles, "Infective Endocarditis in the Antibiotic Era," published in 1966 in the New England Journal of Medicine.1,2,3
IE currently can be described as infective endocarditis in the era of intravascular devices, as infection of intravascular lines has been determined to be the primary risk factor for Staphylococcus aureus bloodstream infections (BSIs). S aureus is the primary pathogen of endocarditis.4
Acute bacterial endocarditis caused by Staphy...
Acute bacterial endocarditis caused by Staphylococcus aureus with perforation of the aortic valve and aortic valve vegetations. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Administration Medical Center.
Acute bacterial endocarditis caused by Staphy...
Acute bacterial endocarditis caused by Staphylococcus aureus with aortic valve ring abscess extending into myocardium. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Administration Medical Center.
Since the 1960s, the clinical characteristics of IE have changed significantly. The dramatic "graying" of the disease and the increase in recreational drug use and proliferation of invasive vascular procedures underlie this phenomenon. Varieties of IE that were uncommon in the early antibiotic era have become prominent. Cases of nosocomial infective endocarditis (NIE), intravenous drug abuse (IVDA) IE, and prosthetic valve endocarditis (PVE) have markedly increased. Valvular infections have entered the era of IE caused by intravascular devices and procedures.
The underlying valvular pathology has also changed. Rheumatic heart disease currently accounts for less than 20% of cases, and 6% of patients with rheumatic heart disease eventually develop IE. Approximately 50% of elderly patients have calcific aortic stenosis as the underlying pathology. Congenital heart disease accounts for 15% of cases, with the bicuspid aortic valve being the most common example.
Other contributing congenital abnormalities include ventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot. Atrial septal defect (secundum variety) is rarely associated with IE. Mitral valve prolapse is the most common predisposing condition found in young adults and is the predisposing condition in 30% of cases of native valve endocarditis (NVE) in this age group.
IE complicates 5% of cases of asymmetrical septal hypertrophy, usually involving the mitral valve.
The most significant risk factor for IE is residual valvular damage caused by a previous attack of endocarditis.5,6
In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of these infections involve the tricuspid valve.7
PVE accounts for 10-20% of cases of IE. Eventually, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and, after 1 year, bioprosthetic valves are more likely to be infected. The valves in the mitral valve position are more susceptible than those in the aortic areas.8
Analogous to PVE are infections of implantable pacemakers and cardioverter-defibrillators. Usually, these devices are infected within a few months of implantation. Infection of pacemakers includes that of the generator pocket (the most common), infection of the proximal leads, and infection of the portions of the leads in direct contact with the endocardium. This last category represents true pacemaker IE, is the least common infectious complication of pacemakers (0.5% of implanted pacemakers), and is the most challenging to treat. Of pacemaker infections, 75% are produced by staphylococci, both coagulase-negative and coagulase-positive.
NIE is defined as an infection that manifests 48 hours after the patient is hospitalized or that is associated with a hospital, based on a procedure performed within 4 weeks of clinical disease onset. The term health care?associated infective endocarditis (HCIE) is preferable to NIE, since it is inclusive of all sites that deliver patient care, such as hemodialysis centers. The term NIE should be applied to cases of IE acquired in the hospital. An appropriate alternative term would be iatrogenic IE.
Two types of NIE have been described. The right-sided variety affects a valve that has been injured by placement of an intravascular line (eg, Swan-Ganz catheter). Subsequently, the valve is infected by a nosocomial bacteremia. The second type develops in a previously damaged valve and is more likely to occur on the left side. S aureus has been the predominant pathogen of NIE/HCIE since the recent prevalence of intravascular devices. Enterococci are second most commonly isolated pathogens. These usually arise from a genitourinary source.
The classic clinical presentation and clinical course of IE has been characterized as either acute or subacute. Acute IE frequently involves normal valves. It is a rapidly progressive illness in persons who are healthy or debilitated. Subacute IE typically affects only abnormal valves. Its course, even in untreated patients, may extend over many months. Indiscriminate antibiotic usage and an increase in immunosuppressed patients have blurred the distinction between these 2 major types of IE (see below). However, the classification still has clinical merit.9
Organism clinical features
* S aureus
o Overall, S aureus infection is the most common cause of IE, including PVE, acute IE, and IVDA IE.
o Approximately 35-60.5% of staphylococcal bacteremias are complicated by IE.
o More than half the cases are not associated with underlying valvular disease.
o The mortality rate of S aureus IE is 40-50%.
o S aureus infection is the second most common cause of nosocomial BSIs, second only to coagulase-negative staphylococci (CoNS) infection.
o The incidence of methicillin-resistant S aureus (MRSA) infections, both the hospital- and community-acquired varieties, has dramatically increased (50% of isolates). Sixty percent of individuals are intermittent carriers of MRSA or methicillin-sensitive S aureus.
o The primary risk factor for S aureus BSI is the presence of intravascular lines. Other risk factors include cancer, diabetes, corticosteroid use, IVDA, alcoholism, and renal failure.
o The realization that approximately 50% of hospital- and community-acquired staphylococcal bacteremias arise from infected vascular catheters has led to the reclassification of staphylococcal BSIs. BSIs are acquired not only in the hospital but also in any type of health care facility (eg, nursing home, dialysis center).
o Of S aureus bacteremia cases in the United States, 7.8% (200,000) per year are associated with intravascular catheters.
* Streptococcus viridans
o This organism accounts for approximately 50-60% of cases of subacute disease.
o Most clinical signs and symptoms are mediated immunologically.
* Streptococcus intermedius group
o These infections may be acute or subacute.
o S intermedius infection accounts for 15% of streptococcal IE cases.
o S intermedius is unique among the streptococci; it can actively invade tissue and can cause abscesses.
* Abiotrophia species (formerly known as nutritionally variant streptococci)
o Approximately 5% of subacute cases of IE are due to infection with Abiotrophia species.
o They require metabolically active forms of vitamin B-6 for growth.
o This type of IE is associated with large vegetations that lead to embolization and a high rate of posttreatment relapse.
* Group D streptococci
o Most cases are subacute.
o The source is the gastrointestinal or genitourinary tract.
o It is the third most common cause of IE.
o They pose major resistance problems for antibiotics.
* Nonenterococcal group D organisms
o The clinical course is subacute.
o Infection often reflects underlying abnormalities of the large bowel (eg, ulcerative colitis, polyps, cancer).
o The organisms are sensitive to penicillin.
* Group B streptococci
o Acute disease develops in pregnant patients and older patients with underlying diseases (eg, cancer, diabetes, alcoholism).
o The mortality rate is 40%.
o Complications include metastatic infection, arterial thrombi, and congestive heart failure.
o It often requires valve replacement for cure.
* Group A, C, and G streptococci
o Acute disease resembles that of S aureus IE (30-70% mortality rate), with suppurative complications.
o Group A organisms respond to penicillin alone.
o Group C and G organisms require a combination of synergistic antibiotics (as with enterococci).
* Coagulase-negative S aureus
o This causes subacute disease.
o It behaves similarly to S viridans infection.
o It accounts for approximately 30% of PVE cases and less than 5% of NVE cases.10
* Pseudomonas aeruginosa
o This is usually acute, except when it involves the right side of the heart in IVDA IE.
o Surgery is commonly required for cure.
* HACEK organisms (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)
o These organisms usually cause subacute disease.
o They account for approximately 5% of IE cases.
o They are the most common gram-negative organisms isolated from patients with IE.
o Complications may include massive arterial emboli and congestive heart failure.
o Cure requires ampicillin, gentamicin, and surgery.
* Fungi
o These usually cause subacute disease.
o The most common organism of both fungal NVE and fungal PVE is Candida albicans.
o Fungal IVDA IE is usually caused by Candida parapsilosis or Candida tropicalis.
o Aspergillus species are observed in fungal PVE and NIE.
* Bartonella species
o The most commonly involved species is Bartonella quintana.
o IE typically develops in homeless males who have extremely substandard hygiene. Bartonella must be considered in cases of culture-negative endocarditis among homeless individuals.
* Polymicrobial infective endocarditis
o Pseudomonas and enterococci are the most common combination of organisms.
o It is observed in cases of IVDA IE
o The cardiac surgery mortality rate is twice that associated with single-agent IE.11
Approximately 5% of cases of possible IE yield negative blood culture results (ie, culture-negative IE). These may have noninfectious causes (eg, vasculitis) or may be caused by fastidious organisms. Modern blood culture systems recover the vast majority of pathogens within 4-5 days, including members of the HACEK group and Abiotrophia species. Overall, the most common cause of culture-negative IE is the prior use of antibiotics. In certain populations, infections with Coxiella burnetii (in southern France and Israel) and Bartonella species (among homeless persons) have become more frequent causes of culture-negative IE. The blood culture results in fungal valvular infections are often sterile. In S aureus IE, the blood cultures results may be negative when the organism burrows deep within the thrombus, leaving the surface of the valvular thrombus sterile (surface sterilization).12
IE remains a diagnostic and therapeutic challenge. Its manifestations may be muted by the indiscriminate use of antimicrobial agents or by underlying conditions in frail and elderly individuals or immunosuppressed persons. Effective therapy has become progressively more difficult to achieve because of the proliferation of implanted biomechanical devices and the rise in the number of resistant organisms. Antibiotic prophylaxis has probably had little effect in decreasing the incidence of IE.
Pathophysiology
All cases of IE develop from a commonly shared process, as follows:
1. Bacteremia (nosocomial or spontaneous) that delivers the organisms to the surface of the valve
2. Adherence of the organisms
3. Eventual invasion of the valvular leaflets
The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis, a sterile fibrin-platelet vegetation. The development of subacute IE depends on a bacteria inoculum sufficient to allow invasion of the preexistent thrombus. This critical mass is the result of bacterial clumping produced by agglutinating antibodies.
In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma from intravenous catheters or pacing wires (ie, NIE). S aureus can invade the endothelial cells (endotheliosis) and increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. Nonbacterial thrombotic endocarditis may result from stress, renal failure, malnutrition, systemic lupus erythematosus, or neoplasia.
The Venturi effect also contributes to the development and location of nonbacterial thrombotic endocarditis. This principle explains why bacteria and the fibrin-platelet thrombus are deposited on the sides of the low-pressure sink that lies just beyond a narrowing or stenosis. In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial surface of the valve. In patients with aortic insufficiency, they are located on the ventricular side. In these examples, the atria and ventricles are the low-pressure sinks. In the case of a ventricular septal defect, the low-pressure sink is the right ventricle and the thrombus is found on the right side of the defect. Nonbacterial thrombotic endocarditis may also form on the endocardium of the right ventricle, opposite the orifice that has been damaged by the jet of blood flowing through the defect (ie, the MacCallum patch).
IE develops most commonly on the mitral valve, closely followed in descending order of frequency by the aortic valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve. Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection.
The microorganisms that most commonly produce endocarditis (ie, S aureus; S viridans; group A, C, and G streptococci; enterococci) resist the bactericidal action of complement and possess fibronectin receptors for the surface of the fibrin-platelet thrombus. Among the many other characteristics of IE-producing bacteria demonstrated in vitro and in vivo, some features include the following:
* Increased adherence to aortic valve leaflet disks by enterococci, S viridans, and S aureus
* Mucoid-producing strains of S aureus
* Dextran-producing strains of S viridans
* S viridans and enterococci that possess FimA surface adhesin
* Platelet aggregation by S aureus and S viridans and resistance of S aureus to platelet microbicidal proteins
The pathogenesis of pacemaker IE is similar. Shortly after implantation, the development of a fibrin-platelet thrombus (similar to the nonbacterial thrombotic endocarditis described above) involves the generator box and conducting leads. After 1 week, the connective tissue proliferates, partially embedding the leads in the wall of the vein and endocardium. This layer may offer partial protection against infection during a bacteremia.
Many possible risk factors for the development of pacemaker infection have been described, including diabetes mellitus, age, and use of anticoagulants and corticosteroids. The evidence for these is conflicting. The major risk factor is probably surgical intervention to any part of the pacemaker system, especially elective battery replacements. The rate of infection associated with battery replacements is approximately 5 times that of the initial implantation (6.5% vs 1.4%). Other significant risk factors include the development of a postoperative hematoma, the inexperience of the surgeon, and a preceding temporary transvenous pacing.
Bacteremia (either spontaneous or due to an invasive procedure) infects the sterile fibrin-platelet vegetation. BSIs develop from various extracardiac types of infection, such as pneumonias or pyelonephritis, but most commonly from gingival disease. Of those with high-grade gingivitis, 10% have recurrent transient bacteremias (usually streptococcal species). Most cases of subacute disease are secondary to the bacteremias that develop from the activities of daily living (eg, brushing teeth, bowel movements).
Bacteremia can result from various invasive procedures, ranging from oral surgery to sclerotherapy of esophageal varices to genitourinary surgeries to various abdominal operations. The potential for invasive procedures to produce a bacteremia varies greatly. Procedures, rates, and organisms are as follows:
* Endoscopy
o Rate of 0-20%
o CoNS, streptococci, diphtheroids
* Colonoscopy
o Rate of 0-20%
o Escherichia coli, Bacteroides species
* Barium enema
o Rate of 0-20%
o Enterococci, aerobic and anaerobic gram-negative rods
* Dental extractions
o Rate of 40-100%
o S viridans
* Transurethral resection of the prostate
o Rate of 20-40%
o Coliforms, enterococci, S aureus
* Transesophageal echocardiography
o Rate of 0-20%
o S viridans, anaerobic organisms, streptococci
The incidence of nosocomial bacteremias, mostly associated with intravascular lines, has more than doubled in the last few years. Up to 90% of BSIs caused by these devices are secondary to the placement of various types of central venous catheters. Hickman and Broviac catheters are associated with the lowest rates, presumably because of their Dacron cuffs. Peripherally placed central venous catheters are associated with similar rates.
Intravascular catheters are infected from 1 of 4 sources, including (1) infection of the insertion site, (2) infection of the catheter, (3) bacteremia arising from another site, and (4) contamination of the infused solution. Bacterial adherence to intravascular catheters depends on the response of the host to the presence of this foreign body, the properties of the organism itself, and the position of the catheter. Within a few days of insertion, a sleeve of fibrin and fibronectin is deposited on the catheter. S aureus adheres to the fibrin component.
S aureus also produces an infection of the endothelial cells (endotheliosis), which is important in producing the continuous bacteremia of S aureus BSIs. Endotheliosis may explain many cases of persistent methicillin-susceptible S aureus (MSSA) and MRSA catheter-related BSIs without an identifiable cause. S aureus catheter-related BSIs occur even after an infected catheter is removed, apparently attributable to specific virulence factors of certain strains of S aureus that invade the adjacent endothelial cells. At some point, the staphylococci re-enter the bloodstream, resulting in bacteremia.13
Four days after placement, the risk of infection markedly increases. Lines positioned in the internal jugular are more prone to infection than those placed in the subclavian vein. Colonization of the intracutaneous tract is the most likely source of short-term catheter-related BSIs. Among lines in place for more than 2 weeks, infection of the hub is the major source of bacteremia. In some cases, the infusion itself may be a reservoir of infection.
Colonization of heart valves by microorganisms is a complex process. Most transient bacteremias are short-lived, are without consequence, and are often not preventable. Bacteria rarely adhere to an endocardial nidus before the microorganisms are removed from the circulation by various host defenses.
Once microorganisms establish themselves on the surface of the vegetation, platelet aggregation and fibrin deposition accelerate at the site. As the bacteria multiply, they are covered by ever-thickening layers of platelets and thrombin, which protect them from neutrophils and other host defenses. Organisms deep in the vegetation hibernate because of the paucity of available nutrients and are therefore less susceptible to bactericidal antimicrobials that interfere with bacterial cell wall synthesis (see Treatment).
Complications of subacute endocarditis result from embolization, slowly progressive valvular destruction, and various immunological mechanisms. The pathological picture of subacute IE is marked by valvular vegetations in which bacteria colonies are present both on and below the surface.
The cellular reaction occurs primarily with mononuclear cells and lymphocytes, with few polymorphonuclear cells. The surface of the valve beneath the vegetation shows few organisms. Proliferation of capillaries and fibroblasts is marked. Areas of healing are scattered among areas of destruction. Over time, the healing process falls behind, and valvular insufficiency develops secondary to perforation of the cusps and damage to the chordae tendineae. Compared with acute disease, little extension of the infectious process usually occurs beyond the valvular leaflets.
Levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins are markedly increased in patients with subacute endocarditis. Many of the extracardiac manifestations of this form of the disease are due to circulating immune complexes. Among these include glomerulonephritis, peripheral manifestations (eg, Osler nodes, Roth spots, subungual hemorrhages), and, possibly, various musculoskeletal abnormalities. Janeway lesions usually arise from infected microemboli.
The complication of arterial embolization is second in frequency to congestive heart failure for both subacute and acute IE. The frequency of this complication has decreased, from 80% in the preantibiotic era to 15-35% today. The emboli are usually sterile because of the minimally invasive nature of the causative organisms (eg, S viridans). The persons most at risk are younger (20-40 y), have mitral or aortic valve (native or prosthetic) involvement, and are infected with certain organisms such as Candida or Aspergillus species, S aureus, Haemophilus parainfluenzae, group B streptococci, and nutritionally variant streptococci.
The prevalence of embolization appears to be the same for both types of disease. The most common areas of deposition include the coronary arteries, kidneys, brain, and spleen. Infarction at the site of embolization is common; abscess formation is not. Cerebral emboli occur in 33% of patients. The middle cerebral artery is involved most often.
Other neurological embolic damage includes cranial nerve palsies, cerebritis, and mycotic aneurysms caused by weakening of the vessel walls and produced by embolization to the vasa vasorum. Mycotic aneurysms may occur in the abdominal aorta and the splenic, coronary, and pulmonary arteries.
Congestive heart failure due to aortic valve insufficiency is the most common intracardiac complication of subacute endocarditis. It develops after months of untreated disease but may occur a full year following microbiological cure.
The microscopic appearance of acute bacterial endocarditis differs markedly from that of subacute disease. Vegetations that contain no fibroblasts develop rapidly, with no evidence of repair. Large amounts of both polymorphonuclear leukocytes and organisms are present in an ever-expanding area of necrosis. This process rapidly produces spontaneous rupture of the leaflets, of the papillary muscles, and of the chordae tendineae. The complications of acute bacterial endocarditis result from intracardiac disease and metastatic infection produced by suppurative emboli. Because of their shortened course, immunological phenomena are not a part of acute IE.
The frequency of aneurysms and other suppurative intracardiac complications is high. In addition to valvular insufficiency, other intracardiac complications of acute IE include (1) aortocardiac and other fistulas, (2) aneurysms of the sinus of Valsalva, (3) intraventricular abscesses, (4) ring abscesses, (5) myocardial abscesses, (6) mycotic aneurysms, (7) septic coronary arterial emboli, and (8) pericarditis.
In patients with acute disease, especially disease caused by S aureus infection, emboli almost inevitably lead to abscesses in the areas where they are deposited. Multiple abscesses can occur in almost every organ, including the kidneys, heart, and brain. Mycotic aneurysms may occur in almost any artery. Paradoxically, they are less common in patients with acute IE.14,15
Frequency
United States
The incidence of IE is approximately 2-4 cases per 100,000 persons per year. This rate has not changed in the past 50 years.16
International
The incidence of IE in other countries is similar to that in the United States.
Mortality/Morbidity
* If left untreated, IE is generally fatal. Anecdotal reports describe the resolution of right-sided valvular infection caused by S aureus infection in individuals who abuse intravenous drugs after just a few days of oral antibiotics.
* Early detection and appropriate treatment of this uncommon disease can be lifesaving.
Race
* IE has no racial predilection.
Sex
* IE is 3 times as common in males as in females.
Age
* IE may occur in a person of any age. Its frequency is increasing in elderly individuals, with 25-50% of cases occurring in those older than 60 years.
Clinical
History
The diagnosis of subacute infective endocarditis (IE) is suggested by a history of an indolent process characterized by fever, fatigue, anorexia, back pain, and weight loss. Less common developments include a cerebrovascular accident or congestive heart failure.
The patient should be questioned about invasive procedures and recreational drug use that may be causing the bacteremia. Most subacute disease caused by S viridans infection is related to dental disease. However, most cases are not caused by dental procedures but by transient bacteremias caused by gingivitis. In 85% of patients, symptoms of endocarditis appear within 2 weeks of dental or other procedures. The interval between the onset of disease and diagnosis averages approximately 6 weeks. The fact that less than 50% of patients have previously diagnosed underlying valvular disease significantly limits the effectiveness of antibiotic prophylaxis.
Acute IE is a much more aggressive disease. The patient notices an acute onset of high-grade fevers and chills and a rapid onset of congestive heart failure. Again, a history of antecedent procedures or illicit drug use must be investigated.
The distinction between these 2 polar types of IE has become less clear. Intermittent use of antibiotics aimed at treating misdiagnosed endocarditis can suppress bacterial growth within the valvular thrombus, giving rise to the state of muted IE. This is often the case in nosocomial infective endocarditis (NIE), which commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis fever, leukocytosis, and multiple organ failure). The source of the bacteremia may be an infection in another organ (eg, pneumonia, pyelonephritis) or in a central venous catheter. Most often, these patients are in the intensive care unit. Approximately 45% of cases of NIE occur in patients with prosthetic valves. Muted IE due to S aureus infection may resemble IE that results from S viridans infection.
* The symptoms of early subacute native valve endocarditis (NVE) are usually subtle and nonspecific. They include low-grade fever (absent in 3-15% of patients), anorexia, weight loss, influenzalike syndromes, polymyalgialike syndromes, pleuritic pain, syndromes similar to rheumatic fever (eg, fever, dulled sensorium as in typhoid, headaches), and abdominal symptoms (eg, right upper quadrant pain, vomiting, postprandial distress, appendicitislike symptoms).
o When appropriate therapy is delayed for weeks or months, additional clinical features, embolic or immunological in origin, develop.
o Signs and symptoms secondary to emboli include acute meningitis with sterile spinal fluid, hemiplegia in the distribution of the middle cerebral artery, regional infarcts that cause painless hematuria, infarction of the kidney or spleen, unilateral blindness caused by occlusion of a retinal artery, and myocardial infarction due to embolization of a coronary artery.
o The emboli of right-sided IE commonly produce pulmonary infarcts. The rate of embolization is related to the organism, the size of the vegetation and its rate of growth or resolution, and its location.
o The vegetations of S aureus, Haemophilus influenzae, H parainfluenzae, and the fungi are much more likely to embolize than those of S viridans. Those larger than 10 mm in diameter and mobile or prolapsing have a high rate of embolization. A vegetation that grows during therapy is associated with a significant increase in the risk of embolization but with the persistence of bacteremia.
o Clinically separating the importance of the absolute size and the rate of change in the size of the vegetation from the causative organism is difficult. The vegetations of the mitral valve are much more likely to embolize than those in any other location (see Echocardiographic predictors of embolization). The risk of embolization markedly decreases after 1 week of appropriate antibiotic therapy.
o The deposition of circulating immune complexes in the kidney may produce interstitial nephritis or proliferative glomerulonephritis, with renal failure progressing to the point of uremia at the time of the patient's presentation. Similarly, various musculoskeletal symptoms (44% of patients) arise from immunologically mediated synovitis.
o Osler nodes and Roth spots arise from immune-mediated vasculitis. Patients may experience palpitations, ie, the symptoms of an immune-mediated myocarditis.
o The origin of lumbosacral back pain in patients with subacute IE (15%) is unclear but probably results from the deposition of immune complexes in the disk space. However, antibiotic therapy rapidly abolishes these symptoms. In 50% of patients with cerebral emboli, this event is the first manifestation of IE and is associated with a 2- to 4-times higher mortality rate. Stroke in younger people should always raise the possibility of underlying IE.
* Rarely observed today, the bacteria-free state of IE is one in which patients have multiple negative blood culture results in the presence of severe congestive heart failure, renal failure, multiple sterile emboli, massive splenomegaly, severe anemia, brown facial pigmentation, bilateral thigh pain, and massive leg edema. These patients are usually afebrile. This process appears to indicate prolonged and unchecked stimulation of the immune system.
* The clinical symptoms of acute IE result from either embolic or intracardiac suppurative complications. The onset of illness is abrupt, with rapidly progressive destruction of the infected valve. The valvular leaflets are quickly destroyed by bacteria that multiply rapidly within the ever-growing friable vegetations. Complications develop within a week. These include the dyspnea and fatigue of severe congestive heart failure and a wide spectrum of neuropsychiatric complications resulting from CNS involvement.
* Patients with right-sided IVDA IE (53% of cases) frequently present with pleuropulmonary (pneumonia and/or empyema) manifestations.
o Symptoms due to metastatic infection develop early disease course caused by S aureus.
o Infection with P aeruginosa has a high rate of neurological involvement, with 2 distinctive features: (1) mycotic aneurysms with a higher-than-average rate of rupture and (2) panophthalmitis (10% of patients). The course of infection with P aeruginosa is much slower than that of S aureus.
o Right-sided disease is associated with a low rate of congestive heart failure and valvular perforation.
o The course of left-sided IVDA IE is similar to that of non-IVDA disease.
o Approximately 5-8% of febrile individuals who abuse intravenous drugs have underlying IE. Many users of illicit drugs may lose their fever within a few hours of hospitalization. This phenomenon, termed cotton wool fever, is probably caused by the presence of adulterants contained within the injected drugs.
* Early prosthetic valve endocarditis (PVE) is defined as infection occurring within 60 days of valve implantation. Late PVE occurs after this period. For valvular infection with CoNS, this division should be extended to 12 months.
o Clinical features of PVE closely resemble those of NVE.
o Congestive heart failure occurs earlier and is more severe in persons with PVE. The patient may present with symptoms of myocarditis or pericarditis. The rate of embolic stroke is high in the first 3 days of PVE.
* The clinical presentation in a person with a pacemaker infection and pacemaker IE depends on several factors, including the site of infection (eg, generator pocket vs intravascular leads or epicardial leads), the type of organism, and the origin of the infection (eg, pocket erosion, localized infection of the generator pocket, bacteremia from a remote site).
o Early infections, within a few months of implantation, manifest as acute or subacute infections of the pulse-generator pocket. Bacteremia may be present even in the absence of clinical signs and symptoms. Fever is the most common finding and may be the only finding in approximately 33% of patients.
o Late infections of the pocket may be due to erosion of the overlying skin without systemic involvement. Such erosions always indicate infection of the underlying device.
o The most significant late infections involve the transvenous or epicardial leads. With epicardial infection, signs and symptoms of pericarditis or mediastinitis may be present along with bacteremia. Infection of the transvenous electrode produces signs and symptoms of right-sided endocarditis. Those that occur early after implantation (33% of cases) show prominent systemic signs of infection, often with obvious localization to the pacemaker pocket.
o Late infections have much more subtle manifestations. They may occur up to several years after implantation or reimplantation.
o Fever is almost universal in persons with pacemaker IE. Signs of right-sided endocarditis (ie, pneumonia, septic emboli) are observed in up to 50% of patients.
* NIE commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis fever, leukocytosis, and multiple organ failure).
o The source of bacteremia may develop from an infection in another organ (eg, pneumonia, pyelonephritis) or from a central venous catheter.
o Most often, these patients are in the intensive care unit.
o Approximately 45% of cases of NIE/health care?associated infective endocarditis (HCIE) occur in patients with prosthetic valves.
Physical
Approximately 3-15% of patients with subacute IE (primarily elderly and chronically ill individuals) have normal or subnormal temperatures. The vast majority of patients have detectable heart murmurs. The presence of a murmur is so common (99% of cases) that its absence should cause clinicians to reconsider the diagnosis of IE. The major exception is right-sided IE, in which only one third of patients have a detectable murmur. Because many of these murmurs are hemodynamically insignificant and have been present for years, their role in the patient's illness may be underestimated. The saying "a changing murmur is extremely helpful in diagnosing subacute IE" is a myth. Only 15% do so early in the course of infection.
* The peripheral lesions of subacute IE are observed in only approximately 20% of patients, compared with 85% in the preantibiotic era. Currently, the most common of these is petechiae. They may occur on the palpebral conjunctivae, the dorsa of the hands and feet, the anterior chest and abdominal walls, the oral mucosa, and the soft palate.
* Subungual hemorrhages (ie, splinter hemorrhages) are linear and red. They are usually caused by workplace trauma to the hands and feet rather than by valvular infection. Hemorrhages that do not extend for the entire length of the nail are more likely the result of infection rather than trauma.
* Osler nodes are smallish tender nodules that range from red to purple and are located primarily in the pulp spaces of the terminal phalanges of the fingers and toes, soles of the feet, and the thenar and hypothenar eminences of the hands. Their appearance is often preceded by neuropathic pain. They last from hours to several days. They remain tender for a maximum of 2 days. The underlying mechanism is probably the circulating immunocomplexes of subacute IE. They have been described in various noninfectious vasculitides.
* Clubbing of fingers and toes was found almost universally, but it is now observed in less than 10% of patients. It primarily occurs in those patients who have an extended course of untreated IE.
* The arthritis associated with subacute IE is asymmetrical and is limited to 1-3 joints. Clinically, it resembles the joint changes found in patients with rheumatoid arthritis, Reiter syndrome, or Lyme disease. The fluid is usually sterile.
* Splenomegaly is observed more commonly in patients with long-standing subacute disease. It may persist long after successful therapy.
* Roth spots are retinal hemorrhages with pale centers. The Litten sign represents cotton-wool exudates.
* Murmurs are absent in approximately one third of patients with acute IE. The most common type is an aortic regurgitation murmur. Because of the suddenness of onset, the left ventricle does not have a chance to dilate. In this situation, the classic finding of increased pulse pressure in significant valvular insufficiency is absent.
* Fever is always present and is usually high.
* Janeway lesions are irregular erythematosus and painless macules (1-4 mm in diameter). They most often are located on the thenar and hypothenar eminences of the hands and feet. They usually represent an infectious vasculitis of acute IE resulting from S aureus infection.
* Acute septic monoarticular arthritis in patients with acute IE most often is caused by S aureus infection.
* Purulent meningitis may be observed in patients with acute IE, compared with the aseptic type observed in patients with subacute disease. Other neurological findings are similar to those observed in patients with subacute disease.17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32
Causes
The following is a summary of particular pathogens associated with subtypes of IE.
* S aureus is the most common bacteria found in patients with IVDA IE. Groups A, C, and G streptococci and enterococci are also recovered from patients with IVDA IE. Currently, gram-negative organisms are involved infrequently. P aeruginosa and the HACEK family are the most common examples.
* CoNS are the most frequent cause of PVE (30%). S aureus causes 17% of early PVE and 12% of late PVE. Corynebacterium, nonenterococcal streptococci, fungi (eg, C albicans, Candida stellatoidea, Aspergillus species), Legionella, and the HACEK organisms cause the remaining cases.
* The organisms that cause NIE obviously are related to the type of underlying bacteremia. The gram-positive cocci (ie, S aureus, CoNS, enterococci, nonenterococcal streptococci) are the most common pathogens.
Differential Diagnoses
Antiphospholipid Syndrome
Reactive Arthritis
Atrial Myxoma
Systemic Lupus Erythematosus
Cardiac Neoplasms, Primary
Lyme Disease
Polymyalgia Rheumatica
Other Problems to Be Considered
Thrombotic nonbacterial endocarditis
Vasculitis
Temporal arteritis
Marantic endocarditis
Workup
Laboratory Studies
* The criterion standard test for diagnosing infective endocarditis (IE) is the documentation of a continuous bacteremia (>30 min in duration) based on blood culture results.
o Exceptions are observed in patients with prosthetic valve endocarditis (PVE) and right-sided IE. Approximately 5-10% of patients with IE have false-negative blood culture results. Prior use of antibiotics is the most common cause of false-negative blood culture results (see Organism clinical features). Other causes include fastidious organisms and inadequate blood volume; a blood-to-broth ratio of 1:10 is needed. Currently, with modern automated blood culture systems, fastidious organisms such as nutritionally variant streptococci and members of the HACEK group rarely cause culture-negative IE.
o As many as 50% of positive blood culture results have been estimated to be falsely positive. This rate has probably decreased, but false-positive blood culture results remain a major diagnostic challenge. One such result can lead to 4 days of unnecessary patient hospitalization. The significance of positive blood culture results correlates with (1) the type of organism, (2) the clinical setting (CoNS are significant in patients with prosthetic valves but not in those with native valves.), (3) multiple blood cultures positive for the same organism, (4) shorter incubation time for recovery, and (5) the degree of severity of clinical illness.
o Never draw only one set of blood cultures; one is worse than none. For diagnosing subacute IE, draw 3-5 sets of blood cultures over 24 hours. This helps detect 92-98% of cases in patients who have not recently received antibiotics. In the case of acute IE, 3 sets may be drawn over 30 minutes (with separate venipunctures) to help document a continuous bacteremia.
o Using various types of blood culture bottles (with resins added to interfere with antibiotic action) probably has little advantage. Some of these may interfere with bacterial growth.
o When blood culture results fail to show an infectious agent after blood is drawn 48 hours after antibiotic therapy has been stopped, the second set of blood for cultures must be drawn approximately 7 days later. If these later culture results remain negative, the diagnosis of IE must be reconsidered. In general, blood for culture should not be drawn through intravenous lines unless this is part of an approach for diagnosing line infection.
* The diagnosis of catheter infection may be made in 1 of 2 ways, as follows:
o Culturing the device via the roll-plate semiquantitative method is the most common approach but requires a catheter removal. In the case of long-term catheters, blood may be drawn simultaneously through the line and the peripheral vein. If it is impossible to draw blood from a peripheral vein in the presence of a multilumen catheter, one sample may be obtained through each of 2 catheter lumens. In a catheter infection, the colony count of the sample obtained from the suspected port is 3-fold greater than that drawn from a peripheral vein or from another port of the catheter. Retrieval of organisms from blood drawn from a catheter hub at least two hours earlier before their growth is detected in the blood obtained from peripheral vein meets the differential time to positivity criteria of a catheter infection.
o A sterile culture of the insertion site has a highly negative predictive value for line infection.
* Patients with culture-negative IE occasionally present with signs and symptoms highly suggestive of IE, but the blood cultures remain negative.
o Valvular vegetations may be detected during cardiac ultrasonographic examinations, but the blood culture results are persistently negative. In this situation, 3 separate blood cultures spaced over a 24-hour period are usually sufficient to detect microorganisms in the blood. Additional blood cultures are not usually helpful.
o The most common cause of culture-negative IE is prior antimicrobial therapy that can suppress bacterial growth within the vegetation but is insufficient to eliminate the valvular infection.
o Many pathogens once considered to be fastidious are no longer classified as such (see above). Bartonella, Legionella, and C burnetii remain significant causes of culture-negative IE. These require special culture media or a prolonged incubation period for retrieval. C burnetii IE is usually diagnosed with serological testing. Buffered charcoal and yeast agar are required for the isolation of Legionella. Brucella species require up to 6 weeks.
* Serologic tests are often the most practical means for diagnosing valvular infection with fastidious organisms (eg, C burnetii and Chlamydia, Brucella, and Legionella species).
* Most types of fungal IE have a low rate of positive blood culture results. At best, only 50% of Candida species are associated with positive blood culture results. Histoplasma and Aspergillus are almost never retrieved from the bloodstream. Fungal endocarditis must always be considered in the clinical setting of culture-negative IE that fails to respond to appropriate antibiotic therapy.
* Establishing the diagnosis of pacemaker IE is difficult because of its subtle presentation, especially late-onset disease. The addition of pocket infection and the presence of pulmonary emboli to the Duke criteria have increased the rate of diagnosis from 16% to 87.5% of cases. Importantly, fever and/or a positive blood culture result without evidence of a primary source in patients with a pacemaker or implantable cardioverter-defibrillator represents device-associated IE until proven otherwise.33,34,35,36,37,38,39
Imaging Studies
* Although blood cultures remain key in making the diagnosis of IE, the need for indirect diagnostic techniques that are both specific and sensitive is increasing. This is because the nature of valvular infections has changed over the years. The numbers of fastidious organisms have increased, and the rate of the classic peripheral stigmata of IE is much lower. Patients who are elderly, chronically ill, or immunosuppressed are often afebrile and unable to mount a significant fever or exhibit the classic stigmata of valvular infection.
* Echocardiography has become the indirect diagnostic method of choice, especially in patients who present with a clinical picture of IE but who have nondiagnostic blood culture results. Echocardiography is useful for predicting the potential complications of IE, especially those that are embolic in nature (see Complications). The diagnosis of IE can never be excluded based on negative echocardiogram findings, either transthoracic or transesophageal.
o Transthoracic echocardiography (TTE) can detect vegetations in approximately 60% of patients with native valve endocarditis (NVE) but in only 20% of patients with PVE.
o Transesophageal echocardiography (TEE) was developed to overcome the problems in visualizing prosthetic valve thrombi and right-sided events. TEE eliminates the need for the operator to find a clear field for the beam. The use of higher-frequency waveforms is permitted because of the decreased distance between the heart and the probe. The sensitivity of TEE in detecting the vegetations of NVE is 90-100%. In patients with PVE, the sensitivity of TEE under optimal circumstances is greater than 90%. TEE is far more sensitive than TTE for detecting myocardial abscesses (95% vs 28%).
o TEE successfully visualizes vegetations of the leads or of the tricuspid valve in more than 90% of cases of pacemaker IE, compared with less than the 50% achieved by TTE.
o Neither TEE nor TTE should be used for screening purposes (ie, patients with fever of unknown origin or those with positive blood culture results and no other signs or symptoms of IE) because nearly 60% of vegetations revealed are sterile. Approximately 15% of positive study results are false-positive results because the images are, in reality, not those of vegetations but of thickened valves, nodules, or valvular calcifications.
o Echocardiographic predictors of systemic embolization in patients with IE are (1) large valvular vegetations (>10 mm in diameter), (2) multiple vegetations, (3) mobile but pedunculated vegetations, (4) noncalcified vegetations, (5) vegetations that are increasing in size, and (6) prolapsing vegetations.
o In summary, the indications for performing echocardiography with Doppler in patients with IE are (1) to provide a baseline in proven or highly suggestive cases of IE and (2) to provide a means of documenting complications during therapy.
+ In most cases, TTE is sufficient.
+ TEE is indicated (1) when mechanical prosthetic valves are present, (2) to detect right-sided lesions, and (3) to visualize myocardial abscesses. Because of the endoscopic portion of the test, TEE carries the risk factor of inducing bacteremias.
+ Approximately 15% of cases of IE do not demonstrate any detectable vegetations at the time of the echocardiographic study.
* Two-dimensional cardiac ultrasound Doppler testing has been a significant advance for diagnosing and evaluating IE. It provides information about the presence and size of vegetations, which helps in diagnosis and, to some extent, in predicting embolization.
o The Doppler method can detect distorted blood flow and certain types of cardiac pathology not otherwise visualized by standard echocardiography.
o It is good for visualizing jet lesions and differentiating cusp perforation from valvular insufficiency.
o The combination of TEE and color Doppler is excellent for detecting intracardiac fistulas.
o The resolution of either TEE or TTE in real life is approximately 2 mm.
o Conditions that are positively related to the detection of valvular thrombi are (1) the location, ie, right-sided structures are poorly visualized, especially by TTE; (2) disease lasting longer than 2 weeks; (3) abscesses of the valves or myocardium; and (4) aneurysms of the sinus of Valsalva.
* Various radionuclide scans using, for example, gallium Ga 67?tagged white cells and indium In 111?tagged white cells, have proven to be of little use in diagnosing IE. Radionuclide scans of the spleen are useful to help rule out a splenic abscess, which is a cause of bacteremia that is refractory to antibiotic therapy.
* A CT scan of the head should be obtained in patients who exhibit CNS symptoms or findings consistent with a mass effect (eg, macroabscess of the brain).40,41,42
Other Tests
* Electrocardiography may help detect the 10% of patients who develop a conduction delay during IE by documenting an increased P-R interval.
* Rheumatoid factor (ie, "poor man's" circulating immune complex) becomes positive in 50% of patients with subacute disease. It becomes negative after successful treatment.
* Durack and colleagues developed diagnostic criteria that combine the clinical, microbiological, pathological, and echocardiographic characteristics of a specific case.43
o Major blood culture criteria
+ Two blood cultures positive for organisms typically found in patients with IE (ie, S viridans, Streptococcus bovis, a HACEK group organism, community-acquired S aureus, or enterococci in the absence of a primary focus)
+ Blood cultures persistently positive for one of the above organisms from cultures drawn more than 12 hours apart
+ Three or more separate blood cultures drawn at least 1 hour apart
o Major echocardiographic criteria
+ Echocardiogram positive for IE, documented by an oscillating intracardiac mass on a valve or on supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomical explanation
+ Myocardial abscess
+ Development of partial dehiscence of a prosthetic valve
+ New-onset valvular regurgitation
o Minor criteria
+ Predisposing heart condition or intravenous drug use
+ Fever of 38?C (100.4?F) or higher
+ Vascular phenomenon, including major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, or Janeway lesions
+ Immunological phenomenon such as glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor
+ Positive blood culture results not meeting major criteria or serologic evidence of active infection with an organism consistent with IE (eg, Brucella, C burnetii [ie, Q fever], Legionella)
+ Echocardiogram results consistent with IE but not meeting major echocardiographic criteria
o Definitive pathological diagnosis is established by demonstrating microorganisms, by culture or histology, in vegetations removed by surgery, embolectomy, or drainage of an intracardiac abscess. Alternatively, a definitive clinical diagnosis is made based on the presence of 2 major criteria, 1 major criterion and 3 minor criteria, or by 5 minor criteria.
o A diagnosis of possible IE is made when findings consistent with IE fall short of the criteria for definite IE but do not meet the criteria for rejection.
o Rejection criteria for the diagnosis of IE are as follows:
+ The presence of a firm alternative diagnosis of the manifestations of endocarditis
+ Resolution of manifestations of endocarditis after 4 or fewer days of antimicrobial therapy
+ No pathologic evidence of IE at surgery or autopsy after 4 or fewer days of antimicrobial therapy
o These criteria may, at times, overdiagnose IE and may not be as applicable in patients with subacute disease.
* A major clinical challenge is that at least 25% of S aureus BSIs represent IE or metastatic infections. The question is whether a continuous bacteremia in the presence of an intravascular line is representative of IE.
o Blood cultures should only be drawn through intravascular lines for the purpose of diagnosing catheter-related BSIs and have limited value for answering this clinical challenge.
o Because of the ability of S aureus to produce an endotheliosis, the presence of a continuous bacteremia does not necessarily imply an infected valvular vegetation.
o An important clue to continuous bacteremia/IE is the presence of S aureus bacteruria associated with hematuria. Hematuria in the setting of IE is due to embolic renal infarction or immunologically mediated glomerulonephritis. Echocardiography has developed into a useful tool for meeting this clinical challenge.
o Twenty-five percent of patients with staphylococcal bacteremia and 23% of those with catheters as the primary focus have evidence of IE based on TEE findings, in the absence of clinical and TTE findings.43
Procedures
* Catheterization of the heart is rarely required for the diagnosis of IE or any of its complications. The findings from echocardiography correlate well with the findings from cardiac catheterization.
Histologic Findings
The characteristic findings of IE are intravascular endocardial vegetations that contain microorganisms surrounded by fibrin and platelets (see Pathophysiology).
Treatment
Medical Care
The major goals of therapy for infective endocarditis (IE) are to eradicate the infectious agent from the thrombus and to address the complications of valvular infection. The latter includes both the intracardiac and extracardiac consequences of IE. Much of the discussion of dealing with the effects of IE is in Surgical Care.
* Mild congestive heart failure resulting from valvular insufficiency or myocarditis may be managed with standard medical therapy. Often, this is progressive, and, despite achieving a microbiological cure, it requires valvular surgery.
* Although thrombosis is a key element of IE, anticoagulation with heparin (Coumadin) is controversial. Indeed, evidence indicates patients who are anticoagulated have worse outcomes than those who are not anticoagulated. Patients who are treated with anticoagulation appear to have a higher rate of intracerebral bleeding. If an established reason for anticoagulation (eg, deep venous thrombosis, presence of a mechanical prosthetic valve) exists, a standard regimen of anticoagulation should be followed.
* Antibiotics remain the mainstay of treatment for IE.
o In the setting of acute IE, institute antibiotic therapy as soon as possible to minimize valvular damage. Three to 5 sets of blood cultures are obtained within 60-90 minutes, followed by the infusion of the appropriate antibiotic regimen. By necessity, the initial antibiotic choice is empiric in nature, determined by clinical history and physical examination findings.
o In the case of subacute IE, treatment may be safely delayed until culture and sensitivity results are available. Waiting does not increase the risk of complications in this form of the disease.
o Eradicating bacteria from the fibrin-platelet thrombus is extremely difficult because (1) the high concentration of organisms present within the vegetation (ie, 10-100 billion bacteria per gram of tissue), (2) their position deep within the thrombus, (3) their location in both a reduced metabolic and reproductive state, and (4) the interference of fibrin and white cells with antibiotic action. For all of these reasons, bactericidal antibiotics are considered necessary for cure of valvular infection.
o Intravenous administration is preferred because more reliable therapeutic levels are achieved with this route.
o Treat all patients in a hospital or skilled nursing facility to allow adequate monitoring of the development of complications and the response to antibiotic therapy.
* Management of S aureus bacteremia in the presence of an intravascular catheter includes (1) promptly removing the catheter, (2) initiating appropriate antibiotic therapy, (3) monitoring of blood culture results in 24-48 hours, and (4) performing a TEE.
o If the follow-up blood culture and TEE findings are negative and no evidence of metastatic infection is found, then 2 weeks of antistaphylococcal therapy is appropriate.
o If the follow-up blood culture findings are positive and the TEE results indicate the presence of IE, then the patient is treated for 4-6 weeks with antistaphylococcal antibiotics.
o If the follow-up blood culture results are positive and the TEE findings show no evidence of IE, then metastatic infection, such as a splenic abscess or osteomyelitis, must be considered while appropriate antibiotic therapy is continued and while the extracardiac source of infection is sought.
* It is important to recognize that, in up to one third of cases, a cause of persistent BSI is not identified. A good deal of these may be explained by endotheliosis. For the time being, the duration of antibiotic therapy for each case of S aureus catheter-related BSI must be individualized. The author and others would treat cases that meet the criteria of continuous bacteremia for a total of 4 weeks despite a negative TEE result.44,45,46
Surgical Care
Approximately 15-25% of patients with IE eventually require surgery.
* Indications for surgical intervention in patients with native valve endocarditis (NVE) are as follows:
o Congestive heart failure refractory to standard medical therapy
o Fungal IE (except that caused by Histoplasma capsulatum)
o Persistent sepsis after 72 hours of appropriate antibiotic treatment
o Recurrent septic emboli, especially after 2 weeks of antibiotic treatment
o Rupture of an aneurysm of the sinus of Valsalva
o Conduction disturbances caused by a septal abscess
o Kissing infection of the anterior mitral leaflet in patients with IE of the aortic valve
* Congestive heart failure in a patient with NVE is the primary indication for surgery. A second relapse, during or after completion of treatment, requires replacement of the valve.
* Paravalvular abscess and intracardiac fistula almost always require surgical intervention. Patients with culture-negative NVE who remained febrile for more than 10 days should be considered surgical candidates. Persistent hypermobile vegetations, especially those with a history of embolization beyond 7 days of antibiotic therapy, should be treated with surgery. Cardiac surgery should be considered in patients with multiresistant organisms (eg, enterococci).
* The indications for surgery in patients with prosthetic valve endocarditis (PVE) are the same as those for patients with NVE, with the addition of the conditions of valvular dehiscence and early PVE.
* Surgery is often required for treatment of metastatic infections (eg, cerebral and other types of aneurysms and macroabscesses of the brain and spleen). Many cerebral abscesses may not be accessible. If this is the case, they can be monitored because 30% may heal when treated medically.
* Occasionally, local debridement and the administration of appropriate antibiotics may be sufficient to cure an uncomplicated pacemaker pocket infection. However, most studies indicate that complete removal of the system is necessary for cure in most cases. Many patients in whom this is not possible eventually die of complications from relapsing infection. This aggressive approach is especially necessary when dealing with pacemaker IE.
o After removal of the infected device, placing a temporary transvenous pacer is best. Immediate insertion of a permanent pacemaker at a new site can be safely accomplished.
o In the past, removal of the intracardiac leads that had been in place for several months often necessitated open heart surgery. The use of laser technology to dissolve the pacemaker lead adhesions has proven successful, with a 94% success rate. The risk of dislodging vegetations during removal of infected leads is negligible.
o Patients whose leads cannot be removed are started on permanent antibiotic suppression.47,48
Consultations
* Personnel in the clinical microbiology laboratory must have the skill to isolate the organism, properly identify it, and perform susceptibility testing appropriate for the growth characteristics and requirements of the organism (with determination of the minimum inhibitory concentration [MIC] of clinically relevant antimicrobial agents). To obtain the best possible information, the attending physician should work closely with the microbiology laboratory personnel.
* In general, both a cardiologist and an infectious diseases specialist should be involved in the care of patients with IE.
* Consulting a cardiothoracic surgeon may be necessary. See Surgical Care.
Diet
No special diets are recommended for patients with endocarditis; however, if the patient has congestive heart failure, administer a sodium-restricted diet.
Activity
Activity limitations are determined by the severity of the illness, complications (eg, stroke), and the presence of significant congestive heart failure.
Medication
Goals to maximize treatment success are (1) early diagnosis, (2) accurate microorganism identification, (3) reliable susceptibility testing, (4) prolonged intravenous administration of bactericidal antimicrobial agents, (5) proper monitoring of potentially toxic antimicrobial regimens, and (6) aggressive surgical management of correctable mechanical complications.
The American Heart Association has developed guidelines for treating infective endocarditis (IE) caused by the most frequently encountered microorganisms. Updated guidelines (October 2007) are detailed here. Antibiotic doses are predicated on normal renal function.
Adult native valve endocarditis (NVE) caused by penicillin-susceptible S viridans, S bovis, and other streptococci (MIC of penicillin of ? 0.1 mcg/mL) should be treated with one of the following regimens:
* Administer penicillin G at 12-18 million U/d intravenously (IV) by continuous pump or in 6 equally divided doses for 4 weeks.
* Administer ceftriaxone at 2 g/d IV for 4 weeks. It may be given intramuscularly (IM) for short periods if venous access problems develop. Ceftriaxone allows once-a-day outpatient intravenous therapy for clinically stable patients.
* Administer penicillin G and gentamicin at 1 mg/kg (based on ideal body weight) every 8 hours for 2 weeks. Short-course therapy with ceftriaxone and gentamicin for 2 weeks is a cost-effective regimen and is effective in selected patients. Short-course therapy is recommended for those with uncomplicated NVE caused by sensitive S viridans and of less than 3 months' duration.
* In patients who are allergic to penicillin, use vancomycin at 30 mg/kg/d IV in 2 equally divided doses for 4 weeks. The vancomycin dose should not exceed 2 g/d unless serum levels are monitored and can be adjusted to attain a peak vancomycin level of 30-45 mcg/mL 1 hour after completion of the intravenous infusion of vancomycin.
For NVE caused by relatively resistant streptococci (MICs of penicillin of 0.1-0.5 mcg/mL), the following regimens are recommended:
* Administer penicillin G at 18 million U/d IV, either by continuous pump or in 6 equally divided doses, for 4 weeks.
* Administer cefazolin at 6 g/d IV in 3 equally divided doses for 4 weeks.
* Both of these alternatives are combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for the first 2 weeks of therapy.
* For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d IV in 2 equally divided doses (usually, do not exceed 2 g/d unless serum levels are monitored) for 4 weeks. Peak vancomycin levels of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
IE caused by nonresistant enterococci, resistant S viridans (MICs of penicillin G of >0.5 mcg/mL), or nutritionally variant S viridans and prosthetic valve endocarditis (PVE) caused by penicillin-G?susceptible S viridans or S bovis should be treated as follows:
* Administer penicillin G at 18-30 million U/d IV, either by continuous pump or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
* Alternatively, administer ampicillin at 12 g/d by continuous infusion or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
* In patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d in 2 equally divided doses (usually, do not exceed 2 g/24 h unless serum levels are monitored). This may be combined with gentamicin for 4-6 weeks of treatment. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
Enterococcal PVE generally responds as well as disease involving native valves. Six weeks of treatment is recommended for patients with symptoms of enterococcal IE of more than 3 months' duration, with relapsed infection, or with PVE.
A combination of an inhibitor of cell wall synthesis (ie, penicillin, vancomycin) with an aminoglycoside (ie, gentamicin, streptomycin) is necessary to achieve bactericidal activity against the enterococci. Tobramycin or amikacin does not act synergistically with antibiotics active against the bacterial cell wall.
Increasing numbers of enterococci have aminoglycoside-inactivating enzymes that make them relatively resistant to the usual synergistic combinations. These aminoglycoside-resistant strains have an MIC of 2000 mcg/mL or more for streptomycin and 500 mcg/mL or more for gentamicin. Of gentamicin-resistant enterococcal strains, 25% are susceptible to streptomycin. Continuously infused ampicillin (serum level of 16 mcg/mL) is probably the best therapy for aminoglycoside-resistant enterococci. Alternative choices are imipenem, ciprofloxacin, or ampicillin with sulbactam. Vancomycin does not appear to be as useful as the aforementioned antibiotics.
Enterococcus faecalis may become resistant to the penicillins because of their production of beta-lactamases. These strains can be treated with ampicillin combined with sulbactam or with vancomycin combined with gentamicin.
High peak levels of gentamicin are not necessary to establish synergistic bactericidal activity against enterococci. Peak gentamicin levels of 3-5 mcg/mL, with a trough of less than 2 mcg/mL, frequently can be obtained with a dose of gentamicin of 1 mg/kg IV every 8 hours. Once-a-day gentamicin dosing should not be used because a prolonged postantibiotic effect against gram-positive organisms does not occur, and synergistic killing requires the simultaneous presence of an agent active in the cell wall and an aminoglycoside.
A recent study indicates that gentamicin usage, even for synergy, is associated with decreasing renal function. However, overall mortality does not appear to be increased. Certainly, gentamicin therapy should be continued to achieve synergy against enterococci, but the practice of administering gentamicin for 5 days in the treatment of S aureus IVDA IE should be questioned.
Vancomycin-resistant isolates of Enterococcus faecium and Enterococcus faecalis (ie, vancomycin-resistant enterococci [VRE]) produce some of the most challenging nosocomial infections. Presently, no therapy has been proven highly effective for IE caused by strains of VRE. Quinupristin/dalfopristin (ie, Synercid) may suppress E faecium bacteremia but frequently is not bactericidal. Other options for therapy include linezolid, a combination of ampicillin and imipenem, and chloramphenicol. In one small series, the combination of ampicillin and ceftriaxone was found to be useful against VRE. Often, the valve must be replaced to achieve a cure.
NVE caused by methicillin-sensitive S aureus should be treated as follows:
* Administer nafcillin or oxacillin at 2 g IV every 4 hours for 4-6 weeks.
* Administer cefazolin at 2 g IV every 8 hours for 4-6 weeks.
* For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg (usually, do not to exceed 2 g/24 h unless serum levels are monitored) for 4-6 weeks. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
Vancomycin therapy is associated with a significant failure rate (up to 35%) in the treatment of MSSA and MRSA BSI/IE. It appears that vancomycin should not be used to treat infections with staphylococci with an MIC of greater than 1.5-2 mcg/mL. In these cases, alternative agents such as linezolid or daptomycin should be used.
PVE caused by MRSA should be treated with vancomycin at 30 mg/kg/d in 2 equally divided doses (usually, do not exceed 2 g unless serum levels are monitored) for 4-6 weeks. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
PVE caused by methicillin-sensitive S aureus should be treated as follows:
* Administer nafcillin or oxacillin at 2 g IV every 4 hours for 6 weeks or longer.
* Alternatively, administer cefazolin at 2 g IV every 8 hours for 6 weeks or longer.
* Each of these options should be combined with rifampin at 300 mg orally every 8 hours for 6 weeks or longer and with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for the first 2 weeks.
PVE caused by MRSA should be treated with vancomycin at 30 mg/kg (not to exceed 2 g/d unless serum levels are monitored) for 6 weeks or longer combined with rifampin and gentamicin as outlined above. A significant concern is that MRSA may become resistant to vancomycin.
Treatment with linezolid appears to result in outcomes superior to those with vancomycin against many types of infections caused by MRSA and methicillin-sensitive S aureus. The use of linezolid should be strongly considered instead of vancomycin in patients who are seriously ill. Another advantage of linezolid is that its dose does not need to be adjusted in patients with renal failure. White blood cell counts, red blood cell counts, and platelet counts need to be monitored frequently while the patient is on this drug. The risk of developing serotonin syndrome is low. After the fourth week of therapy, the risk of hematological and neuropathic complications rapidly increases.
Daptomycin (6 mg/kg/24 h) has recently been approved for the treatment of S aureus BSI and right-sided IE. Higher doses of daptomycin (12 mg/kg/24 h) are more effective, with little increase in adverse effects. Patients who have received vancomycin have a higher rate of resistance to daptomycin.
HACEK microorganisms should be treated as follows:
* Administer ceftriaxone at 2 g/d IV for 4 weeks.
* Alternatively, administer ampicillin at 12 g/d by continuous pump or in 6 equally divided doses daily. This may be combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4 weeks.
Culture-negative NVE is usually treated with vancomycin and gentamicin. In patients who have previously received antibiotics, initial therapy should consist of either ampicillin-sulbactam plus gentamicin (3 mg/kg/d) or vancomycin plus gentamicin and ciprofloxacin. Because of the increased risk of renal failure with gentamicin, the latter regimen is preferred.
Patients with culture-negative PVE are usually given vancomycin and gentamicin, targeting possible enterococcal or coagulase-negative staphylococcal infections. In patients with suspected PVE who have previously received antibiotics, enteric therapy should consist of vancomycin, gentamicin, cefepime, and rifampin. Because of the risk of developing resistance to rifampin, many clinicians would start this antibiotic only after the blood cultures results become negative.
Treatment of other microorganisms is as follows:
* For P aeruginosa, administer ceftazidime, cefepime, or imipenem, combined with high-dose tobramycin at 8 mg/kg/d in 3 divided doses, to attain peak blood levels of 15-20 mcg/mL, for 6 weeks.
* For enteric gram-negative rods (eg, E coli, Proteus mirabilis), administer ampicillin, ticarcillin-clavulanic acid (Timentin), piperacillin, piperacillin-tazobactam, ceftriaxone, or cefepime combined with gentamicin or amikacin for 4-6 weeks.
* For Streptococcus pneumoniae, administer ceftriaxone at 2 g/d IV or vancomycin (if penicillin allergy or high-level penicillin G resistance [MIC of 2 mcg/mL or more]) for 4 weeks.
* For diphtheroids, administer penicillin G at 18-24 million U/d in 6 divided doses or vancomycin combined with gentamicin for 4 weeks.
* For Q fever (C burnetii infection), administer doxycycline combined with rifampin, sulfamethoxazole-trimethoprim, or a fluoroquinolone for 3-4 years.
PVE is especially difficult to treat because the microorganisms adhere to the foreign body and may make them impervious to the bactericidal action of agents active in the cell wall. All patients with PVE require at least 6 weeks of antimicrobial therapy. Rifampin is the key drug in the treatment of PVE, as it is one of the only antimicrobial agents that penetrate the biofilm laid down by S aureus and CoNS. Because of the risk of these organisms developing resistance to rifampin, many clinicians withhold the addition of rifampin until blood cultures have cleared.
Penicillin-sensitive S viridans PVE should be treated with 2 weeks of penicillin G or ceftriaxone combined with gentamicin, followed by 4 weeks of penicillin G or ceftriaxone.
If the S viridans PVE is caused by an organism with a penicillin MIC of 0.2 mcg/mL or more, penicillin G or ceftriaxone combined with gentamicin combination therapy should be administered for 4-6 weeks. If the combination therapy is administered for only 4 weeks, penicillin G or ceftriaxone should be continued for an additional 2 weeks. Vancomycin is substituted for penicillin or ceftriaxone if the patient has a history of severe, immediate penicillin hypersensitivity, such as urticaria, anaphylaxis, or angioedema.
Enterococcal PVE therapy is complicated by the multiple types of enterococcal antimicrobial resistance, including beta-lactamase production (rare), different types of aminoglycoside-inactivating enzymes (more common), and VRE (increasingly common). If the enterococci are highly resistant to both gentamicin and streptomycin, ampicillin should be administered for 8-12 weeks by continuous infusion.
No effective therapy is known for VRE PVE.
Patients with PVE must be monitored carefully for signs of valve dysfunction, congestive heart failure, and heart block. They should also be monitored for clinical response to therapy, conversion of positive blood culture results, renal function status, and serum blood levels of vancomycin and aminoglycosides. Valve replacement surgery should be performed promptly if any of the following occurs: (1) moderate-to-severe congestive heart failure, (2) valve dysfunction, (3) perivalvular or myocardial abscess formation, (4) the presence of an unstable valve that is becoming detached from the valve ring, (5) more than one embolic episode with persistent vegetations observed on transtracheal echocardiogram, or (6) the presence of vegetations larger than 1 cm in diameter.
If PVE does not respond to antimicrobial therapy and blood cultures results remain positive or if a relapse of bacteremia occurs after infection, the prosthetic valve should be replaced. In the presence of microorganisms that have no microbicidal agent (eg, VRE, fungi) or in the presence of other recalcitrant organisms (eg, P aeruginosa, S aureus, enteric gram-negative rods, Brucella species, C burnetii), past clinical experience shows that early replacement of the prosthetic valve improves the chances for cure.
Fungal endocarditis is rare and primarily occurs after prosthetic valve surgery and in individuals who abuse intravenous drugs. Candida species and Aspergillus species are the organisms most frequently encountered. Currently available antifungal agents have not been successful in eliminating fungal IE. The only cures for proven fungal IE have resulted when surgical excision of the infected valves was combined with amphotericin B therapy.
Empiric therapy of IVDA IE should be aimed at S aureus. Whether to use vancomycin or oxacillin/nafcillin depends on the incidence of MRSA in the community. Generally, gram-negative organisms occur infrequently, and delay in covering them initially is acceptable.
Some clinicians obtain peak and trough blood samples during the course of antimicrobial therapy of IE in order to run serum bactericidal tests. These tests are performed by incubating serial 2-fold dilutions of serum that contains antimicrobials with an inoculum of 100,000 colony-forming units per milliliter of the target microorganism that has been previously isolated from the patient's blood for 24-48 hours.
Peak antimicrobial concentrations that inhibit and kill the bacteria at a 1:32 or greater dilution in serum are a consistent predictor of a favorable clinical response. Antimicrobial dosages are adjusted to try to attain this goal. However, many clinicians feel that the serum bactericidal test does not have a reproducible result, and these clinicians rely on standardized tests of antimicrobial susceptibility (ie, MICs) and serum antimicrobial assays of peak and trough levels to determine whether sufficient amounts of antimicrobial agents are being administered.49,50,51,52,53,54
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Penicillin G (Pfizerpen)
For IE caused by S viridans or S bovis with penicillin G MIC of 0.1 mcg/mL or less.
Dosing
Adult
MIC <0.1 mcg/mL: 12-18 million U/d IV by pump or divided into 6 equal doses for 4 wk (duration 2 wk if combined with gentamicin)
MIC 0.1-0.5 mcg/mL: 18 million U/d IV by continuous pump or divided into 6 equal doses for 4 wk
MIC >0.5 mcg/mL or enterococci: 18-30 million U/d IV by continuous pump or in 6 equally divided doses, with gentamicin for 4-6 wk
Pediatric
<20 kg: 12.5 mg/kg IV q6h
>20 kg: Administer as in adults
Interactions
Probenecid can increase effects; coadministration of tetracyclines can decrease effects
Contraindications
Documented hypersensitivity; do not mix with gentamicin (mutual interaction will occur)
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired renal function; phlebitis may develop with potassium penicillin G
Ceftriaxone (Rocephin)
Once-daily treatment of S viridans or HACEK IE. Third-generation cephalosporin with broad-spectrum gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Dosing
Adult
2 g IV qd for 4 wk; may be given IM for short periods if central access is lost
Pediatric
37.5 mg/kg IV q12h
Interactions
Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity; do not mix in the same bag as gentamicin because of mutual inactivation
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal impairment; caution in breastfeeding and allergy to penicillin; may form biliary sludge and cause biliary colic; monitor for Clostridium difficile colitis
Vancomycin (Vancocin, Lyphocin, Vancoled)
DOC for patients who are allergic to penicillin who have streptococcal or enterococcal endocarditis, those with MRSA IE, and those with other beta-lactam?resistant gram-positive IE infections.
Duration of treatment is 4 wk in penicillin-susceptible streptococcal IE and 4-6 wk for staphylococcal infections, prosthetic valve infections, or enterococcal IE.
Dosing
Adult
30 mg/kg IV qd divided bid; not to exceed 2 g/d unless serum levels are monitored and dose is adjusted to attain peak level of 30-45 mcg/mL 1 h after completion of infusion
Pediatric
Infants (aged 1 mo) and children: 20 mg/kg IV q12h
Interactions
Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal failure and neutropenia; red man syndrome is caused by an IV infusion that is too rapid (dose given over a few min) but rarely happens when dose given as 2-h administration, PO, or with intraperitoneal administration; red man syndrome is not an allergic reaction; monitor blood levels, with a goal of 30-40 mcg/mL 1 h after completion of IV dose
Administer slowly; rapid administration is associated with hypotension and histamine release, ie, red man syndrome
Gentamicin (Garamycin, Gentacidin)
Combination therapy used to attain bactericidal activity against enterococci and resistant streptococcal species, to shorten treatment of penicillin-susceptible streptococcal IE, and for prosthetic staphylococcal IE
Duration for penicillin-susceptible streptococcal IE is 2 wk. For penicillin-resistant streptococci and enterococci, 4-6 wk.
Dosing
Adult
1 mg/kg (calculated based on ideal body weight) IV q8h
Pediatric
Infants and children: 2.5 mg/kg IV q8h
Interactions
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus, prolonged respiratory depression may occur
Coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Contraindications
Documented hypersensitivity; non ? dialysis-dependent renal insufficiency
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment
Monitor blood levels to reduce toxicity; a peak level of 3-4 mcg/mL is sought tid in order to sustain synergistic killing of gram-positive organisms; maximum allowable peak level is 10 mcg/mL; maximum trough level is 2 mcg/mL; once-a-day administration not recommended because a sustained level is required for synergistic killing of gram-positive bacteria; change dose in renal failure; calculate doses based on ideal body weight rather than actual weight in patients who are obese
Ampicillin (Marcillin, Omnipen, Polycillin, Principen)
For treatment of enterococcal IE, IE caused by HACEK organisms, or as penicillin G substitute for penicillin-susceptible organisms.
For enterococcal endocarditis, duration is 4-6 wk in combination with gentamicin.
Dosing
Adult
12 g IV qd by continuous pump or in 6 equally divided doses
Pediatric
<20 kg: 50 mg/kg, IV q6h
>20 kg: Administer as in adults
Interactions
Probenecid and disulfiram elevate levels; allopurinol decreases effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction
Cefazolin (Ancef, Kefzol, Zolicef)
Used for staphylococcal endocarditis susceptible to methicillin/oxacillin. Substitute for penicillin G or ampicillin for penicillin-susceptible streptococcal endocarditis.
Used if develop mild rash to penicillins but no anaphylaxis or severe immediate hypersensitivity reactions.
Dosing
Adult
2 g IV q8h for 4-6 wk
Pediatric
Infants and children: 25 mg/kg IV q6h
Interactions
Probenecid prolongs effects; coadministration with aminoglycosides may increase renal toxicity; may yield false-positive urine-dip test results for glucose
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal impairment; superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy
Nafcillin (Nafcil, Unipen, Nallpen)
Used for staphylococcal IE caused by organisms susceptible to methicillin/oxacillin.
Dosing
Adult
2 g IV q4h for 4-6 wk
Pediatric
Older infants and children: 20 mg/kg IV q4h
Interactions
Associated with warfarin resistance when administered concurrently; effects may decrease with bacteristatic action of tetracycline derivatives
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
To optimize therapy, determine causative organisms and susceptibility; treatment of 10 d or longer needed to eliminate infection and prevent sequelae (eg, endocarditis, rheumatic fever); take cultures after treatment to confirm infection is eradicated
Linezolid (Zyvox)
Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteristatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of VRE.
Dosing
Adult
600 mg PO/IV q12h for 14-28 d
Pediatric
Not established
Interactions
May cause hypertension when used concomitantly with adrenergic agents, including pseudoepinephrine, sympathomimetic agents, or vasopressor or dopaminergic agents (reduce dose of dopamine or epinephrine if concurrent use required); serotonin syndrome may occur if used concomitantly with serotonergic agents, including TCAs, meperidine, dextromethorphan, trazodone, venlafaxine, and selective serotonin reuptake inhibitors
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Has mild MAOI properties and potential to have same interactions as other MAOIs; caution in uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism and in patients who are at increased risk for bleeding, have preexisting thrombocytopenia, receive concomitant medications that may decrease platelet count or function, or who may require > 2 wk of therapy (monitor platelet counts); unnecessary use may lead to development of resistance
Follow-up
Further Inpatient Care
* Patients should have blood cultures taken after 3-4 days of treatment to document eradication of the bacteremia.
o Blood cultures during treatment are essential if persistent fever or other signs develop that suggest failing treatment.
o Failure to sterilize the bloodstream, despite adequate serum levels of appropriate antibiotics, should prompt a search for metastatic infection (eg, abscesses, especially splenic, or mycotic aneurysm).
o Fever lasting longer than 10 days into therapy with an indicated antibiotic regimen should be of concern and should prompt a search for suppurative complications. Approximately 30% of patients have a return of fever after the initial response. This is usually caused by an intracardiac abscess or metastatic infection. Causes of unresponsive fever include myocardial or septal abscesses, large vegetations that resist sterilization, and metastatic infection. Occasionally, fever in patients with uncomplicated infective endocarditis (IE) may take as long as 3 weeks to abate.
* Relapse of IE usually occurs within 2 months of finishing clinically effective therapy.
o Infection with S aureus, enterococci, and gram-negative organisms (especially P aeruginosa) is associated with a high rate of relapse.
o Those with pretreatment symptoms of IE of more than 3 months' duration are at greater risk for relapse.
o Enterococcal infection of the mitral valve has the greatest potential for relapse.
o Recurrent IE occurs most often in individuals who abuse intravenous drugs. Valvular infections in these patients recur at a rate of 40%.
o Other significant risk factors for recurrence include a previous episode of IE, the presence of a prosthetic valve, and congenital heart disease.
* Monitor patients for the development of complications, including (1) valvular dysfunction, usually insufficiency of the mitral or aortic valves; (2) myocardial or septal abscesses; (3) congestive heart failure; (4) metastatic infection; (5) embolic phenomenon; and (6) organ dysfunction resulting from immunological processes. Note that the diagnosis of developing congestive heart failure or valvular insufficiency is based on clinical findings, not solely on echocardiographic measurements.
* The onset of valve dysfunction or moderate-to-severe congestive heart failure should lead to an evaluation for immediate valve replacement.
* Complications such as congestive heart failure resulting from valvular insufficiency and embolization may occur after bacteriologic cure has been achieved.
* In general, infected vascular catheters should be removed and should not be replaced over a guidewire. Surgically implanted devices, such as Broviac or Hickman catheters, do not necessarily need to be removed unless evidence of IE, a tunnel infection, or suppurative thrombophlebitis is present or if the infecting organism is a Corynebacteria species, a Pseudomonas species, a fungus, S aureus, or a Mycobacterium species. If bacteremia persists longer than a few days, the catheter must be removed.55,56
Further Outpatient Care
* Patients must be closely monitored for delayed development of congestive heart failure.
Inpatient & Outpatient Medications
* Orally administered antibiotics have been used as suppressive therapy for incurable valvular infections (ie, inoperable prosthetic valve endocarditis [PVE]).
Transfer
* Transfer the patient to a tertiary care cardiovascular center for surgical intervention in the following situations:
o Significant congestive heart failure that develops in association with valve dysfunction
o Conduction disturbances or echocardiogram findings that suggest the presence of a myocardial abscess
o Recurrent emboli with vegetations larger than 1 cm in diameter remaining on the valve
o Lack of response to antimicrobial therapy
Deterrence/Prevention
* Approximately 15-25% of cases of IE are a consequence of invasive procedures that produce a significant bacteremia. Because only 50% of those who developed valvular infection following a procedure were identified as being candidates for antibiotic prophylaxis, only approximately 10% of cases of IE can be prevented by the administration of preprocedure antibiotics.
* Maintaining good oral hygiene is probably more effective in the overall prevention of valvular infection because gingivitis is the most common source of spontaneous bacteremias.
* The American Heart Association periodically compiles recommendations for IE prophylaxis. Updated guidelines (October 2007) are detailed here. Remembering that these are guidelines and not standards is important. They may be modified in particular circumstances. The guidelines remain unproven by randomized controlled clinical trials. Indeed, many examples of failure of these recommendations have been noted, even when they are applied appropriately.
o The 3 major steps in the pathogenesis of IE that are vulnerable to antibiotic prophylaxis are (1) killing of the pathogen in the bloodstream before it can adhere to the valve, (2) preventing adherence to the valve/fibrin-platelet thrombus, and (3) eradicating any organisms that have attached to the thrombus.
o Successful antibiotic prophylaxis requires (1) identifying those patients who are at risk, (2) prioritizing the procedures that require prophylaxis, and (3) selecting an appropriate antibiotic regimen. In general, bactericidal antibiotics are used. However, bacteristatic agents are probably effective in most circumstances.
o Although the 2007 guidelines are a marked improvement because they prioritize the cardiac conditions and procedures that require antibiotic prophylaxis and emphasize the importance of promoting good oral hygiene, they offer little direction in dealing with the ever-growing problem of antibiotic-resistance patterns of S viridans and enterococci.
o The importance of antibiotic prophylaxis of calcific valvular disease in elderly patients also needs to be more fully discussed. Calcific valvular disease is the most common underlying cardiac risk factor for the development of IE in this age group.
o The author's preference is to administer parenteral prophylactic antibiotics to patients with prosthetic valves because of the severe consequences of PVE.
* Prevention of vascular catheter infections is an important prophylactic approach in preventing nosocomial infective endocarditis (NIE). Protective factors include the insertion and maintenance of catheters by an infusion therapy team, the use of topical disinfectants and antibiotics, and the practice of coating catheters with antimicrobial agents.
* No double-blind studies have been performed to support the use of systemically administered antibiotics for the prevention of pacemaker or intracardiac defibrillator infections. However, awaiting definitive studies, the authors recommend prophylactic antibiotics, as with any implantable device. Of course, strict sterile technique must be followed. Antibiotic prophylaxis is not recommended in patients with pacemakers or intracardiac defibrillators during other types of invasive procedures. Pacemaker infection due to transient bacteremias is uncommon.57
Complications
* Monitor patients for the development of the following complications:
o Valvular dysfunction, usually insufficiency of the mitral or aortic valves
o Myocardial or septal abscesses
o Congestive heart failure
o Metastatic infection
o Embolic phenomenon
o Organ dysfunction resulting from immunological processes
* Complications, such as congestive heart failure resulting from valvular insufficiency and embolization, may occur after bacteriologic cure has been achieved.
Prognosis
* Cure rates for appropriately managed (including both medical and surgical therapies) native-valve endocarditis (NVE) are as follows:
o For S viridans and S bovis infection, the rate is 98%.
o For enterococci and S aureus infection in individuals who abuse intravenous drugs, the rate is 90%.
o For community-acquired S aureus infection in individuals who do not abuse intravenous drugs, the rate is 60-70%.
o For infection with aerobic gram-negative organisms, the rate is 40-60%.
o For infection with fungal organisms, the rate is lower than 50%.
* For PVE, the cure rates are as follows:
o Rates are 10-15% lower for each of the above categories, for both early and late PVE.
o Surgery is required far more frequently.
o Approximately 60% of early CoNS PVE cases and 70% of late CoNS PVE cases are curable.
* The fatality rate of pacemaker IE ranges up to 34%.58
Patient Education
* Surveys indicate that an appallingly small number of patients who are at risk for developing IE have an understanding of antibiotic and nonpharmacologic (ie, appropriate oral hygiene) principles.
* For excellent patient education resources, visit eMedicine's Heart Center. Also, see eMedicine's patient education article Tetralogy of Fallot.
Miscellaneous
Medicolegal Pitfalls
* Infective endocarditis (IE) is a fatal disease, but effective therapy is available. Seek expert advice as needed.
* As a rule for primary care clinics, do not administer antimicrobial agents to febrile patients with heart murmurs without first obtaining at least 2 sets of blood cultures.
* Many malpractice suits are caused by a failure to diagnose and a delay in diagnosis accompanied by a poor outcome for the patient.
* The perception that most IE is preventable is wrong. Frequent episodes of transient bacteremia occur with chewing and other activities of daily life. Proving that a failure to give prophylaxis before dental and surgical procedures resulted in IE is difficult. However, this does not prevent legal action alleging IE as a consequence of failing to give the antimicrobial prophylaxis recommended by the American Heart Association.
* When a central venous line is needed, not inserting the line when a patient is known to be bacteremic is advisable. If no alternative to placing the line is available, bactericidal antimicrobial agents should be administered to try to prevent the development of IE
http://emedicine.medscape.com/article/216650-print
John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
Updated: Aug 23, 2009
Introduction
Background
Infective endocarditis (IE) is an infection of the endocardial surface of the heart. The intracardiac effects of this infection include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. IE also produces a wide variety of systemic signs and symptoms through several mechanisms, including both sterile and infected emboli and various immunological phenomena.
Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must not be misdiagnosed or overlooked. The history of IE can be divided into several eras. Lazaire Riviere first described gross autopsy findings of the disease in 1723. In 1885, William Osler presented the first comprehensive description of endocarditis in English. Lerner and Weinstein presented a thorough discussion of this disease in modern times in their landmark series of articles, "Infective Endocarditis in the Antibiotic Era," published in 1966 in the New England Journal of Medicine.1,2,3
IE currently can be described as infective endocarditis in the era of intravascular devices, as infection of intravascular lines has been determined to be the primary risk factor for Staphylococcus aureus bloodstream infections (BSIs). S aureus is the primary pathogen of endocarditis.4
Acute bacterial endocarditis caused by Staphy...
Acute bacterial endocarditis caused by Staphylococcus aureus with perforation of the aortic valve and aortic valve vegetations. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Administration Medical Center.
Acute bacterial endocarditis caused by Staphy...
Acute bacterial endocarditis caused by Staphylococcus aureus with aortic valve ring abscess extending into myocardium. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Administration Medical Center.
Since the 1960s, the clinical characteristics of IE have changed significantly. The dramatic "graying" of the disease and the increase in recreational drug use and proliferation of invasive vascular procedures underlie this phenomenon. Varieties of IE that were uncommon in the early antibiotic era have become prominent. Cases of nosocomial infective endocarditis (NIE), intravenous drug abuse (IVDA) IE, and prosthetic valve endocarditis (PVE) have markedly increased. Valvular infections have entered the era of IE caused by intravascular devices and procedures.
The underlying valvular pathology has also changed. Rheumatic heart disease currently accounts for less than 20% of cases, and 6% of patients with rheumatic heart disease eventually develop IE. Approximately 50% of elderly patients have calcific aortic stenosis as the underlying pathology. Congenital heart disease accounts for 15% of cases, with the bicuspid aortic valve being the most common example.
Other contributing congenital abnormalities include ventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot. Atrial septal defect (secundum variety) is rarely associated with IE. Mitral valve prolapse is the most common predisposing condition found in young adults and is the predisposing condition in 30% of cases of native valve endocarditis (NVE) in this age group.
IE complicates 5% of cases of asymmetrical septal hypertrophy, usually involving the mitral valve.
The most significant risk factor for IE is residual valvular damage caused by a previous attack of endocarditis.5,6
In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of these infections involve the tricuspid valve.7
PVE accounts for 10-20% of cases of IE. Eventually, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and, after 1 year, bioprosthetic valves are more likely to be infected. The valves in the mitral valve position are more susceptible than those in the aortic areas.8
Analogous to PVE are infections of implantable pacemakers and cardioverter-defibrillators. Usually, these devices are infected within a few months of implantation. Infection of pacemakers includes that of the generator pocket (the most common), infection of the proximal leads, and infection of the portions of the leads in direct contact with the endocardium. This last category represents true pacemaker IE, is the least common infectious complication of pacemakers (0.5% of implanted pacemakers), and is the most challenging to treat. Of pacemaker infections, 75% are produced by staphylococci, both coagulase-negative and coagulase-positive.
NIE is defined as an infection that manifests 48 hours after the patient is hospitalized or that is associated with a hospital, based on a procedure performed within 4 weeks of clinical disease onset. The term health care?associated infective endocarditis (HCIE) is preferable to NIE, since it is inclusive of all sites that deliver patient care, such as hemodialysis centers. The term NIE should be applied to cases of IE acquired in the hospital. An appropriate alternative term would be iatrogenic IE.
Two types of NIE have been described. The right-sided variety affects a valve that has been injured by placement of an intravascular line (eg, Swan-Ganz catheter). Subsequently, the valve is infected by a nosocomial bacteremia. The second type develops in a previously damaged valve and is more likely to occur on the left side. S aureus has been the predominant pathogen of NIE/HCIE since the recent prevalence of intravascular devices. Enterococci are second most commonly isolated pathogens. These usually arise from a genitourinary source.
The classic clinical presentation and clinical course of IE has been characterized as either acute or subacute. Acute IE frequently involves normal valves. It is a rapidly progressive illness in persons who are healthy or debilitated. Subacute IE typically affects only abnormal valves. Its course, even in untreated patients, may extend over many months. Indiscriminate antibiotic usage and an increase in immunosuppressed patients have blurred the distinction between these 2 major types of IE (see below). However, the classification still has clinical merit.9
Organism clinical features
* S aureus
o Overall, S aureus infection is the most common cause of IE, including PVE, acute IE, and IVDA IE.
o Approximately 35-60.5% of staphylococcal bacteremias are complicated by IE.
o More than half the cases are not associated with underlying valvular disease.
o The mortality rate of S aureus IE is 40-50%.
o S aureus infection is the second most common cause of nosocomial BSIs, second only to coagulase-negative staphylococci (CoNS) infection.
o The incidence of methicillin-resistant S aureus (MRSA) infections, both the hospital- and community-acquired varieties, has dramatically increased (50% of isolates). Sixty percent of individuals are intermittent carriers of MRSA or methicillin-sensitive S aureus.
o The primary risk factor for S aureus BSI is the presence of intravascular lines. Other risk factors include cancer, diabetes, corticosteroid use, IVDA, alcoholism, and renal failure.
o The realization that approximately 50% of hospital- and community-acquired staphylococcal bacteremias arise from infected vascular catheters has led to the reclassification of staphylococcal BSIs. BSIs are acquired not only in the hospital but also in any type of health care facility (eg, nursing home, dialysis center).
o Of S aureus bacteremia cases in the United States, 7.8% (200,000) per year are associated with intravascular catheters.
* Streptococcus viridans
o This organism accounts for approximately 50-60% of cases of subacute disease.
o Most clinical signs and symptoms are mediated immunologically.
* Streptococcus intermedius group
o These infections may be acute or subacute.
o S intermedius infection accounts for 15% of streptococcal IE cases.
o S intermedius is unique among the streptococci; it can actively invade tissue and can cause abscesses.
* Abiotrophia species (formerly known as nutritionally variant streptococci)
o Approximately 5% of subacute cases of IE are due to infection with Abiotrophia species.
o They require metabolically active forms of vitamin B-6 for growth.
o This type of IE is associated with large vegetations that lead to embolization and a high rate of posttreatment relapse.
* Group D streptococci
o Most cases are subacute.
o The source is the gastrointestinal or genitourinary tract.
o It is the third most common cause of IE.
o They pose major resistance problems for antibiotics.
* Nonenterococcal group D organisms
o The clinical course is subacute.
o Infection often reflects underlying abnormalities of the large bowel (eg, ulcerative colitis, polyps, cancer).
o The organisms are sensitive to penicillin.
* Group B streptococci
o Acute disease develops in pregnant patients and older patients with underlying diseases (eg, cancer, diabetes, alcoholism).
o The mortality rate is 40%.
o Complications include metastatic infection, arterial thrombi, and congestive heart failure.
o It often requires valve replacement for cure.
* Group A, C, and G streptococci
o Acute disease resembles that of S aureus IE (30-70% mortality rate), with suppurative complications.
o Group A organisms respond to penicillin alone.
o Group C and G organisms require a combination of synergistic antibiotics (as with enterococci).
* Coagulase-negative S aureus
o This causes subacute disease.
o It behaves similarly to S viridans infection.
o It accounts for approximately 30% of PVE cases and less than 5% of NVE cases.10
* Pseudomonas aeruginosa
o This is usually acute, except when it involves the right side of the heart in IVDA IE.
o Surgery is commonly required for cure.
* HACEK organisms (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)
o These organisms usually cause subacute disease.
o They account for approximately 5% of IE cases.
o They are the most common gram-negative organisms isolated from patients with IE.
o Complications may include massive arterial emboli and congestive heart failure.
o Cure requires ampicillin, gentamicin, and surgery.
* Fungi
o These usually cause subacute disease.
o The most common organism of both fungal NVE and fungal PVE is Candida albicans.
o Fungal IVDA IE is usually caused by Candida parapsilosis or Candida tropicalis.
o Aspergillus species are observed in fungal PVE and NIE.
* Bartonella species
o The most commonly involved species is Bartonella quintana.
o IE typically develops in homeless males who have extremely substandard hygiene. Bartonella must be considered in cases of culture-negative endocarditis among homeless individuals.
* Polymicrobial infective endocarditis
o Pseudomonas and enterococci are the most common combination of organisms.
o It is observed in cases of IVDA IE
o The cardiac surgery mortality rate is twice that associated with single-agent IE.11
Approximately 5% of cases of possible IE yield negative blood culture results (ie, culture-negative IE). These may have noninfectious causes (eg, vasculitis) or may be caused by fastidious organisms. Modern blood culture systems recover the vast majority of pathogens within 4-5 days, including members of the HACEK group and Abiotrophia species. Overall, the most common cause of culture-negative IE is the prior use of antibiotics. In certain populations, infections with Coxiella burnetii (in southern France and Israel) and Bartonella species (among homeless persons) have become more frequent causes of culture-negative IE. The blood culture results in fungal valvular infections are often sterile. In S aureus IE, the blood cultures results may be negative when the organism burrows deep within the thrombus, leaving the surface of the valvular thrombus sterile (surface sterilization).12
IE remains a diagnostic and therapeutic challenge. Its manifestations may be muted by the indiscriminate use of antimicrobial agents or by underlying conditions in frail and elderly individuals or immunosuppressed persons. Effective therapy has become progressively more difficult to achieve because of the proliferation of implanted biomechanical devices and the rise in the number of resistant organisms. Antibiotic prophylaxis has probably had little effect in decreasing the incidence of IE.
Pathophysiology
All cases of IE develop from a commonly shared process, as follows:
1. Bacteremia (nosocomial or spontaneous) that delivers the organisms to the surface of the valve
2. Adherence of the organisms
3. Eventual invasion of the valvular leaflets
The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis, a sterile fibrin-platelet vegetation. The development of subacute IE depends on a bacteria inoculum sufficient to allow invasion of the preexistent thrombus. This critical mass is the result of bacterial clumping produced by agglutinating antibodies.
In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma from intravenous catheters or pacing wires (ie, NIE). S aureus can invade the endothelial cells (endotheliosis) and increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. Nonbacterial thrombotic endocarditis may result from stress, renal failure, malnutrition, systemic lupus erythematosus, or neoplasia.
The Venturi effect also contributes to the development and location of nonbacterial thrombotic endocarditis. This principle explains why bacteria and the fibrin-platelet thrombus are deposited on the sides of the low-pressure sink that lies just beyond a narrowing or stenosis. In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial surface of the valve. In patients with aortic insufficiency, they are located on the ventricular side. In these examples, the atria and ventricles are the low-pressure sinks. In the case of a ventricular septal defect, the low-pressure sink is the right ventricle and the thrombus is found on the right side of the defect. Nonbacterial thrombotic endocarditis may also form on the endocardium of the right ventricle, opposite the orifice that has been damaged by the jet of blood flowing through the defect (ie, the MacCallum patch).
IE develops most commonly on the mitral valve, closely followed in descending order of frequency by the aortic valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve. Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection.
The microorganisms that most commonly produce endocarditis (ie, S aureus; S viridans; group A, C, and G streptococci; enterococci) resist the bactericidal action of complement and possess fibronectin receptors for the surface of the fibrin-platelet thrombus. Among the many other characteristics of IE-producing bacteria demonstrated in vitro and in vivo, some features include the following:
* Increased adherence to aortic valve leaflet disks by enterococci, S viridans, and S aureus
* Mucoid-producing strains of S aureus
* Dextran-producing strains of S viridans
* S viridans and enterococci that possess FimA surface adhesin
* Platelet aggregation by S aureus and S viridans and resistance of S aureus to platelet microbicidal proteins
The pathogenesis of pacemaker IE is similar. Shortly after implantation, the development of a fibrin-platelet thrombus (similar to the nonbacterial thrombotic endocarditis described above) involves the generator box and conducting leads. After 1 week, the connective tissue proliferates, partially embedding the leads in the wall of the vein and endocardium. This layer may offer partial protection against infection during a bacteremia.
Many possible risk factors for the development of pacemaker infection have been described, including diabetes mellitus, age, and use of anticoagulants and corticosteroids. The evidence for these is conflicting. The major risk factor is probably surgical intervention to any part of the pacemaker system, especially elective battery replacements. The rate of infection associated with battery replacements is approximately 5 times that of the initial implantation (6.5% vs 1.4%). Other significant risk factors include the development of a postoperative hematoma, the inexperience of the surgeon, and a preceding temporary transvenous pacing.
Bacteremia (either spontaneous or due to an invasive procedure) infects the sterile fibrin-platelet vegetation. BSIs develop from various extracardiac types of infection, such as pneumonias or pyelonephritis, but most commonly from gingival disease. Of those with high-grade gingivitis, 10% have recurrent transient bacteremias (usually streptococcal species). Most cases of subacute disease are secondary to the bacteremias that develop from the activities of daily living (eg, brushing teeth, bowel movements).
Bacteremia can result from various invasive procedures, ranging from oral surgery to sclerotherapy of esophageal varices to genitourinary surgeries to various abdominal operations. The potential for invasive procedures to produce a bacteremia varies greatly. Procedures, rates, and organisms are as follows:
* Endoscopy
o Rate of 0-20%
o CoNS, streptococci, diphtheroids
* Colonoscopy
o Rate of 0-20%
o Escherichia coli, Bacteroides species
* Barium enema
o Rate of 0-20%
o Enterococci, aerobic and anaerobic gram-negative rods
* Dental extractions
o Rate of 40-100%
o S viridans
* Transurethral resection of the prostate
o Rate of 20-40%
o Coliforms, enterococci, S aureus
* Transesophageal echocardiography
o Rate of 0-20%
o S viridans, anaerobic organisms, streptococci
The incidence of nosocomial bacteremias, mostly associated with intravascular lines, has more than doubled in the last few years. Up to 90% of BSIs caused by these devices are secondary to the placement of various types of central venous catheters. Hickman and Broviac catheters are associated with the lowest rates, presumably because of their Dacron cuffs. Peripherally placed central venous catheters are associated with similar rates.
Intravascular catheters are infected from 1 of 4 sources, including (1) infection of the insertion site, (2) infection of the catheter, (3) bacteremia arising from another site, and (4) contamination of the infused solution. Bacterial adherence to intravascular catheters depends on the response of the host to the presence of this foreign body, the properties of the organism itself, and the position of the catheter. Within a few days of insertion, a sleeve of fibrin and fibronectin is deposited on the catheter. S aureus adheres to the fibrin component.
S aureus also produces an infection of the endothelial cells (endotheliosis), which is important in producing the continuous bacteremia of S aureus BSIs. Endotheliosis may explain many cases of persistent methicillin-susceptible S aureus (MSSA) and MRSA catheter-related BSIs without an identifiable cause. S aureus catheter-related BSIs occur even after an infected catheter is removed, apparently attributable to specific virulence factors of certain strains of S aureus that invade the adjacent endothelial cells. At some point, the staphylococci re-enter the bloodstream, resulting in bacteremia.13
Four days after placement, the risk of infection markedly increases. Lines positioned in the internal jugular are more prone to infection than those placed in the subclavian vein. Colonization of the intracutaneous tract is the most likely source of short-term catheter-related BSIs. Among lines in place for more than 2 weeks, infection of the hub is the major source of bacteremia. In some cases, the infusion itself may be a reservoir of infection.
Colonization of heart valves by microorganisms is a complex process. Most transient bacteremias are short-lived, are without consequence, and are often not preventable. Bacteria rarely adhere to an endocardial nidus before the microorganisms are removed from the circulation by various host defenses.
Once microorganisms establish themselves on the surface of the vegetation, platelet aggregation and fibrin deposition accelerate at the site. As the bacteria multiply, they are covered by ever-thickening layers of platelets and thrombin, which protect them from neutrophils and other host defenses. Organisms deep in the vegetation hibernate because of the paucity of available nutrients and are therefore less susceptible to bactericidal antimicrobials that interfere with bacterial cell wall synthesis (see Treatment).
Complications of subacute endocarditis result from embolization, slowly progressive valvular destruction, and various immunological mechanisms. The pathological picture of subacute IE is marked by valvular vegetations in which bacteria colonies are present both on and below the surface.
The cellular reaction occurs primarily with mononuclear cells and lymphocytes, with few polymorphonuclear cells. The surface of the valve beneath the vegetation shows few organisms. Proliferation of capillaries and fibroblasts is marked. Areas of healing are scattered among areas of destruction. Over time, the healing process falls behind, and valvular insufficiency develops secondary to perforation of the cusps and damage to the chordae tendineae. Compared with acute disease, little extension of the infectious process usually occurs beyond the valvular leaflets.
Levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins are markedly increased in patients with subacute endocarditis. Many of the extracardiac manifestations of this form of the disease are due to circulating immune complexes. Among these include glomerulonephritis, peripheral manifestations (eg, Osler nodes, Roth spots, subungual hemorrhages), and, possibly, various musculoskeletal abnormalities. Janeway lesions usually arise from infected microemboli.
The complication of arterial embolization is second in frequency to congestive heart failure for both subacute and acute IE. The frequency of this complication has decreased, from 80% in the preantibiotic era to 15-35% today. The emboli are usually sterile because of the minimally invasive nature of the causative organisms (eg, S viridans). The persons most at risk are younger (20-40 y), have mitral or aortic valve (native or prosthetic) involvement, and are infected with certain organisms such as Candida or Aspergillus species, S aureus, Haemophilus parainfluenzae, group B streptococci, and nutritionally variant streptococci.
The prevalence of embolization appears to be the same for both types of disease. The most common areas of deposition include the coronary arteries, kidneys, brain, and spleen. Infarction at the site of embolization is common; abscess formation is not. Cerebral emboli occur in 33% of patients. The middle cerebral artery is involved most often.
Other neurological embolic damage includes cranial nerve palsies, cerebritis, and mycotic aneurysms caused by weakening of the vessel walls and produced by embolization to the vasa vasorum. Mycotic aneurysms may occur in the abdominal aorta and the splenic, coronary, and pulmonary arteries.
Congestive heart failure due to aortic valve insufficiency is the most common intracardiac complication of subacute endocarditis. It develops after months of untreated disease but may occur a full year following microbiological cure.
The microscopic appearance of acute bacterial endocarditis differs markedly from that of subacute disease. Vegetations that contain no fibroblasts develop rapidly, with no evidence of repair. Large amounts of both polymorphonuclear leukocytes and organisms are present in an ever-expanding area of necrosis. This process rapidly produces spontaneous rupture of the leaflets, of the papillary muscles, and of the chordae tendineae. The complications of acute bacterial endocarditis result from intracardiac disease and metastatic infection produced by suppurative emboli. Because of their shortened course, immunological phenomena are not a part of acute IE.
The frequency of aneurysms and other suppurative intracardiac complications is high. In addition to valvular insufficiency, other intracardiac complications of acute IE include (1) aortocardiac and other fistulas, (2) aneurysms of the sinus of Valsalva, (3) intraventricular abscesses, (4) ring abscesses, (5) myocardial abscesses, (6) mycotic aneurysms, (7) septic coronary arterial emboli, and (8) pericarditis.
In patients with acute disease, especially disease caused by S aureus infection, emboli almost inevitably lead to abscesses in the areas where they are deposited. Multiple abscesses can occur in almost every organ, including the kidneys, heart, and brain. Mycotic aneurysms may occur in almost any artery. Paradoxically, they are less common in patients with acute IE.14,15
Frequency
United States
The incidence of IE is approximately 2-4 cases per 100,000 persons per year. This rate has not changed in the past 50 years.16
International
The incidence of IE in other countries is similar to that in the United States.
Mortality/Morbidity
* If left untreated, IE is generally fatal. Anecdotal reports describe the resolution of right-sided valvular infection caused by S aureus infection in individuals who abuse intravenous drugs after just a few days of oral antibiotics.
* Early detection and appropriate treatment of this uncommon disease can be lifesaving.
Race
* IE has no racial predilection.
Sex
* IE is 3 times as common in males as in females.
Age
* IE may occur in a person of any age. Its frequency is increasing in elderly individuals, with 25-50% of cases occurring in those older than 60 years.
Clinical
History
The diagnosis of subacute infective endocarditis (IE) is suggested by a history of an indolent process characterized by fever, fatigue, anorexia, back pain, and weight loss. Less common developments include a cerebrovascular accident or congestive heart failure.
The patient should be questioned about invasive procedures and recreational drug use that may be causing the bacteremia. Most subacute disease caused by S viridans infection is related to dental disease. However, most cases are not caused by dental procedures but by transient bacteremias caused by gingivitis. In 85% of patients, symptoms of endocarditis appear within 2 weeks of dental or other procedures. The interval between the onset of disease and diagnosis averages approximately 6 weeks. The fact that less than 50% of patients have previously diagnosed underlying valvular disease significantly limits the effectiveness of antibiotic prophylaxis.
Acute IE is a much more aggressive disease. The patient notices an acute onset of high-grade fevers and chills and a rapid onset of congestive heart failure. Again, a history of antecedent procedures or illicit drug use must be investigated.
The distinction between these 2 polar types of IE has become less clear. Intermittent use of antibiotics aimed at treating misdiagnosed endocarditis can suppress bacterial growth within the valvular thrombus, giving rise to the state of muted IE. This is often the case in nosocomial infective endocarditis (NIE), which commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis fever, leukocytosis, and multiple organ failure). The source of the bacteremia may be an infection in another organ (eg, pneumonia, pyelonephritis) or in a central venous catheter. Most often, these patients are in the intensive care unit. Approximately 45% of cases of NIE occur in patients with prosthetic valves. Muted IE due to S aureus infection may resemble IE that results from S viridans infection.
* The symptoms of early subacute native valve endocarditis (NVE) are usually subtle and nonspecific. They include low-grade fever (absent in 3-15% of patients), anorexia, weight loss, influenzalike syndromes, polymyalgialike syndromes, pleuritic pain, syndromes similar to rheumatic fever (eg, fever, dulled sensorium as in typhoid, headaches), and abdominal symptoms (eg, right upper quadrant pain, vomiting, postprandial distress, appendicitislike symptoms).
o When appropriate therapy is delayed for weeks or months, additional clinical features, embolic or immunological in origin, develop.
o Signs and symptoms secondary to emboli include acute meningitis with sterile spinal fluid, hemiplegia in the distribution of the middle cerebral artery, regional infarcts that cause painless hematuria, infarction of the kidney or spleen, unilateral blindness caused by occlusion of a retinal artery, and myocardial infarction due to embolization of a coronary artery.
o The emboli of right-sided IE commonly produce pulmonary infarcts. The rate of embolization is related to the organism, the size of the vegetation and its rate of growth or resolution, and its location.
o The vegetations of S aureus, Haemophilus influenzae, H parainfluenzae, and the fungi are much more likely to embolize than those of S viridans. Those larger than 10 mm in diameter and mobile or prolapsing have a high rate of embolization. A vegetation that grows during therapy is associated with a significant increase in the risk of embolization but with the persistence of bacteremia.
o Clinically separating the importance of the absolute size and the rate of change in the size of the vegetation from the causative organism is difficult. The vegetations of the mitral valve are much more likely to embolize than those in any other location (see Echocardiographic predictors of embolization). The risk of embolization markedly decreases after 1 week of appropriate antibiotic therapy.
o The deposition of circulating immune complexes in the kidney may produce interstitial nephritis or proliferative glomerulonephritis, with renal failure progressing to the point of uremia at the time of the patient's presentation. Similarly, various musculoskeletal symptoms (44% of patients) arise from immunologically mediated synovitis.
o Osler nodes and Roth spots arise from immune-mediated vasculitis. Patients may experience palpitations, ie, the symptoms of an immune-mediated myocarditis.
o The origin of lumbosacral back pain in patients with subacute IE (15%) is unclear but probably results from the deposition of immune complexes in the disk space. However, antibiotic therapy rapidly abolishes these symptoms. In 50% of patients with cerebral emboli, this event is the first manifestation of IE and is associated with a 2- to 4-times higher mortality rate. Stroke in younger people should always raise the possibility of underlying IE.
* Rarely observed today, the bacteria-free state of IE is one in which patients have multiple negative blood culture results in the presence of severe congestive heart failure, renal failure, multiple sterile emboli, massive splenomegaly, severe anemia, brown facial pigmentation, bilateral thigh pain, and massive leg edema. These patients are usually afebrile. This process appears to indicate prolonged and unchecked stimulation of the immune system.
* The clinical symptoms of acute IE result from either embolic or intracardiac suppurative complications. The onset of illness is abrupt, with rapidly progressive destruction of the infected valve. The valvular leaflets are quickly destroyed by bacteria that multiply rapidly within the ever-growing friable vegetations. Complications develop within a week. These include the dyspnea and fatigue of severe congestive heart failure and a wide spectrum of neuropsychiatric complications resulting from CNS involvement.
* Patients with right-sided IVDA IE (53% of cases) frequently present with pleuropulmonary (pneumonia and/or empyema) manifestations.
o Symptoms due to metastatic infection develop early disease course caused by S aureus.
o Infection with P aeruginosa has a high rate of neurological involvement, with 2 distinctive features: (1) mycotic aneurysms with a higher-than-average rate of rupture and (2) panophthalmitis (10% of patients). The course of infection with P aeruginosa is much slower than that of S aureus.
o Right-sided disease is associated with a low rate of congestive heart failure and valvular perforation.
o The course of left-sided IVDA IE is similar to that of non-IVDA disease.
o Approximately 5-8% of febrile individuals who abuse intravenous drugs have underlying IE. Many users of illicit drugs may lose their fever within a few hours of hospitalization. This phenomenon, termed cotton wool fever, is probably caused by the presence of adulterants contained within the injected drugs.
* Early prosthetic valve endocarditis (PVE) is defined as infection occurring within 60 days of valve implantation. Late PVE occurs after this period. For valvular infection with CoNS, this division should be extended to 12 months.
o Clinical features of PVE closely resemble those of NVE.
o Congestive heart failure occurs earlier and is more severe in persons with PVE. The patient may present with symptoms of myocarditis or pericarditis. The rate of embolic stroke is high in the first 3 days of PVE.
* The clinical presentation in a person with a pacemaker infection and pacemaker IE depends on several factors, including the site of infection (eg, generator pocket vs intravascular leads or epicardial leads), the type of organism, and the origin of the infection (eg, pocket erosion, localized infection of the generator pocket, bacteremia from a remote site).
o Early infections, within a few months of implantation, manifest as acute or subacute infections of the pulse-generator pocket. Bacteremia may be present even in the absence of clinical signs and symptoms. Fever is the most common finding and may be the only finding in approximately 33% of patients.
o Late infections of the pocket may be due to erosion of the overlying skin without systemic involvement. Such erosions always indicate infection of the underlying device.
o The most significant late infections involve the transvenous or epicardial leads. With epicardial infection, signs and symptoms of pericarditis or mediastinitis may be present along with bacteremia. Infection of the transvenous electrode produces signs and symptoms of right-sided endocarditis. Those that occur early after implantation (33% of cases) show prominent systemic signs of infection, often with obvious localization to the pacemaker pocket.
o Late infections have much more subtle manifestations. They may occur up to several years after implantation or reimplantation.
o Fever is almost universal in persons with pacemaker IE. Signs of right-sided endocarditis (ie, pneumonia, septic emboli) are observed in up to 50% of patients.
* NIE commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis fever, leukocytosis, and multiple organ failure).
o The source of bacteremia may develop from an infection in another organ (eg, pneumonia, pyelonephritis) or from a central venous catheter.
o Most often, these patients are in the intensive care unit.
o Approximately 45% of cases of NIE/health care?associated infective endocarditis (HCIE) occur in patients with prosthetic valves.
Physical
Approximately 3-15% of patients with subacute IE (primarily elderly and chronically ill individuals) have normal or subnormal temperatures. The vast majority of patients have detectable heart murmurs. The presence of a murmur is so common (99% of cases) that its absence should cause clinicians to reconsider the diagnosis of IE. The major exception is right-sided IE, in which only one third of patients have a detectable murmur. Because many of these murmurs are hemodynamically insignificant and have been present for years, their role in the patient's illness may be underestimated. The saying "a changing murmur is extremely helpful in diagnosing subacute IE" is a myth. Only 15% do so early in the course of infection.
* The peripheral lesions of subacute IE are observed in only approximately 20% of patients, compared with 85% in the preantibiotic era. Currently, the most common of these is petechiae. They may occur on the palpebral conjunctivae, the dorsa of the hands and feet, the anterior chest and abdominal walls, the oral mucosa, and the soft palate.
* Subungual hemorrhages (ie, splinter hemorrhages) are linear and red. They are usually caused by workplace trauma to the hands and feet rather than by valvular infection. Hemorrhages that do not extend for the entire length of the nail are more likely the result of infection rather than trauma.
* Osler nodes are smallish tender nodules that range from red to purple and are located primarily in the pulp spaces of the terminal phalanges of the fingers and toes, soles of the feet, and the thenar and hypothenar eminences of the hands. Their appearance is often preceded by neuropathic pain. They last from hours to several days. They remain tender for a maximum of 2 days. The underlying mechanism is probably the circulating immunocomplexes of subacute IE. They have been described in various noninfectious vasculitides.
* Clubbing of fingers and toes was found almost universally, but it is now observed in less than 10% of patients. It primarily occurs in those patients who have an extended course of untreated IE.
* The arthritis associated with subacute IE is asymmetrical and is limited to 1-3 joints. Clinically, it resembles the joint changes found in patients with rheumatoid arthritis, Reiter syndrome, or Lyme disease. The fluid is usually sterile.
* Splenomegaly is observed more commonly in patients with long-standing subacute disease. It may persist long after successful therapy.
* Roth spots are retinal hemorrhages with pale centers. The Litten sign represents cotton-wool exudates.
* Murmurs are absent in approximately one third of patients with acute IE. The most common type is an aortic regurgitation murmur. Because of the suddenness of onset, the left ventricle does not have a chance to dilate. In this situation, the classic finding of increased pulse pressure in significant valvular insufficiency is absent.
* Fever is always present and is usually high.
* Janeway lesions are irregular erythematosus and painless macules (1-4 mm in diameter). They most often are located on the thenar and hypothenar eminences of the hands and feet. They usually represent an infectious vasculitis of acute IE resulting from S aureus infection.
* Acute septic monoarticular arthritis in patients with acute IE most often is caused by S aureus infection.
* Purulent meningitis may be observed in patients with acute IE, compared with the aseptic type observed in patients with subacute disease. Other neurological findings are similar to those observed in patients with subacute disease.17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32
Causes
The following is a summary of particular pathogens associated with subtypes of IE.
* S aureus is the most common bacteria found in patients with IVDA IE. Groups A, C, and G streptococci and enterococci are also recovered from patients with IVDA IE. Currently, gram-negative organisms are involved infrequently. P aeruginosa and the HACEK family are the most common examples.
* CoNS are the most frequent cause of PVE (30%). S aureus causes 17% of early PVE and 12% of late PVE. Corynebacterium, nonenterococcal streptococci, fungi (eg, C albicans, Candida stellatoidea, Aspergillus species), Legionella, and the HACEK organisms cause the remaining cases.
* The organisms that cause NIE obviously are related to the type of underlying bacteremia. The gram-positive cocci (ie, S aureus, CoNS, enterococci, nonenterococcal streptococci) are the most common pathogens.
Differential Diagnoses
Antiphospholipid Syndrome
Reactive Arthritis
Atrial Myxoma
Systemic Lupus Erythematosus
Cardiac Neoplasms, Primary
Lyme Disease
Polymyalgia Rheumatica
Other Problems to Be Considered
Thrombotic nonbacterial endocarditis
Vasculitis
Temporal arteritis
Marantic endocarditis
Workup
Laboratory Studies
* The criterion standard test for diagnosing infective endocarditis (IE) is the documentation of a continuous bacteremia (>30 min in duration) based on blood culture results.
o Exceptions are observed in patients with prosthetic valve endocarditis (PVE) and right-sided IE. Approximately 5-10% of patients with IE have false-negative blood culture results. Prior use of antibiotics is the most common cause of false-negative blood culture results (see Organism clinical features). Other causes include fastidious organisms and inadequate blood volume; a blood-to-broth ratio of 1:10 is needed. Currently, with modern automated blood culture systems, fastidious organisms such as nutritionally variant streptococci and members of the HACEK group rarely cause culture-negative IE.
o As many as 50% of positive blood culture results have been estimated to be falsely positive. This rate has probably decreased, but false-positive blood culture results remain a major diagnostic challenge. One such result can lead to 4 days of unnecessary patient hospitalization. The significance of positive blood culture results correlates with (1) the type of organism, (2) the clinical setting (CoNS are significant in patients with prosthetic valves but not in those with native valves.), (3) multiple blood cultures positive for the same organism, (4) shorter incubation time for recovery, and (5) the degree of severity of clinical illness.
o Never draw only one set of blood cultures; one is worse than none. For diagnosing subacute IE, draw 3-5 sets of blood cultures over 24 hours. This helps detect 92-98% of cases in patients who have not recently received antibiotics. In the case of acute IE, 3 sets may be drawn over 30 minutes (with separate venipunctures) to help document a continuous bacteremia.
o Using various types of blood culture bottles (with resins added to interfere with antibiotic action) probably has little advantage. Some of these may interfere with bacterial growth.
o When blood culture results fail to show an infectious agent after blood is drawn 48 hours after antibiotic therapy has been stopped, the second set of blood for cultures must be drawn approximately 7 days later. If these later culture results remain negative, the diagnosis of IE must be reconsidered. In general, blood for culture should not be drawn through intravenous lines unless this is part of an approach for diagnosing line infection.
* The diagnosis of catheter infection may be made in 1 of 2 ways, as follows:
o Culturing the device via the roll-plate semiquantitative method is the most common approach but requires a catheter removal. In the case of long-term catheters, blood may be drawn simultaneously through the line and the peripheral vein. If it is impossible to draw blood from a peripheral vein in the presence of a multilumen catheter, one sample may be obtained through each of 2 catheter lumens. In a catheter infection, the colony count of the sample obtained from the suspected port is 3-fold greater than that drawn from a peripheral vein or from another port of the catheter. Retrieval of organisms from blood drawn from a catheter hub at least two hours earlier before their growth is detected in the blood obtained from peripheral vein meets the differential time to positivity criteria of a catheter infection.
o A sterile culture of the insertion site has a highly negative predictive value for line infection.
* Patients with culture-negative IE occasionally present with signs and symptoms highly suggestive of IE, but the blood cultures remain negative.
o Valvular vegetations may be detected during cardiac ultrasonographic examinations, but the blood culture results are persistently negative. In this situation, 3 separate blood cultures spaced over a 24-hour period are usually sufficient to detect microorganisms in the blood. Additional blood cultures are not usually helpful.
o The most common cause of culture-negative IE is prior antimicrobial therapy that can suppress bacterial growth within the vegetation but is insufficient to eliminate the valvular infection.
o Many pathogens once considered to be fastidious are no longer classified as such (see above). Bartonella, Legionella, and C burnetii remain significant causes of culture-negative IE. These require special culture media or a prolonged incubation period for retrieval. C burnetii IE is usually diagnosed with serological testing. Buffered charcoal and yeast agar are required for the isolation of Legionella. Brucella species require up to 6 weeks.
* Serologic tests are often the most practical means for diagnosing valvular infection with fastidious organisms (eg, C burnetii and Chlamydia, Brucella, and Legionella species).
* Most types of fungal IE have a low rate of positive blood culture results. At best, only 50% of Candida species are associated with positive blood culture results. Histoplasma and Aspergillus are almost never retrieved from the bloodstream. Fungal endocarditis must always be considered in the clinical setting of culture-negative IE that fails to respond to appropriate antibiotic therapy.
* Establishing the diagnosis of pacemaker IE is difficult because of its subtle presentation, especially late-onset disease. The addition of pocket infection and the presence of pulmonary emboli to the Duke criteria have increased the rate of diagnosis from 16% to 87.5% of cases. Importantly, fever and/or a positive blood culture result without evidence of a primary source in patients with a pacemaker or implantable cardioverter-defibrillator represents device-associated IE until proven otherwise.33,34,35,36,37,38,39
Imaging Studies
* Although blood cultures remain key in making the diagnosis of IE, the need for indirect diagnostic techniques that are both specific and sensitive is increasing. This is because the nature of valvular infections has changed over the years. The numbers of fastidious organisms have increased, and the rate of the classic peripheral stigmata of IE is much lower. Patients who are elderly, chronically ill, or immunosuppressed are often afebrile and unable to mount a significant fever or exhibit the classic stigmata of valvular infection.
* Echocardiography has become the indirect diagnostic method of choice, especially in patients who present with a clinical picture of IE but who have nondiagnostic blood culture results. Echocardiography is useful for predicting the potential complications of IE, especially those that are embolic in nature (see Complications). The diagnosis of IE can never be excluded based on negative echocardiogram findings, either transthoracic or transesophageal.
o Transthoracic echocardiography (TTE) can detect vegetations in approximately 60% of patients with native valve endocarditis (NVE) but in only 20% of patients with PVE.
o Transesophageal echocardiography (TEE) was developed to overcome the problems in visualizing prosthetic valve thrombi and right-sided events. TEE eliminates the need for the operator to find a clear field for the beam. The use of higher-frequency waveforms is permitted because of the decreased distance between the heart and the probe. The sensitivity of TEE in detecting the vegetations of NVE is 90-100%. In patients with PVE, the sensitivity of TEE under optimal circumstances is greater than 90%. TEE is far more sensitive than TTE for detecting myocardial abscesses (95% vs 28%).
o TEE successfully visualizes vegetations of the leads or of the tricuspid valve in more than 90% of cases of pacemaker IE, compared with less than the 50% achieved by TTE.
o Neither TEE nor TTE should be used for screening purposes (ie, patients with fever of unknown origin or those with positive blood culture results and no other signs or symptoms of IE) because nearly 60% of vegetations revealed are sterile. Approximately 15% of positive study results are false-positive results because the images are, in reality, not those of vegetations but of thickened valves, nodules, or valvular calcifications.
o Echocardiographic predictors of systemic embolization in patients with IE are (1) large valvular vegetations (>10 mm in diameter), (2) multiple vegetations, (3) mobile but pedunculated vegetations, (4) noncalcified vegetations, (5) vegetations that are increasing in size, and (6) prolapsing vegetations.
o In summary, the indications for performing echocardiography with Doppler in patients with IE are (1) to provide a baseline in proven or highly suggestive cases of IE and (2) to provide a means of documenting complications during therapy.
+ In most cases, TTE is sufficient.
+ TEE is indicated (1) when mechanical prosthetic valves are present, (2) to detect right-sided lesions, and (3) to visualize myocardial abscesses. Because of the endoscopic portion of the test, TEE carries the risk factor of inducing bacteremias.
+ Approximately 15% of cases of IE do not demonstrate any detectable vegetations at the time of the echocardiographic study.
* Two-dimensional cardiac ultrasound Doppler testing has been a significant advance for diagnosing and evaluating IE. It provides information about the presence and size of vegetations, which helps in diagnosis and, to some extent, in predicting embolization.
o The Doppler method can detect distorted blood flow and certain types of cardiac pathology not otherwise visualized by standard echocardiography.
o It is good for visualizing jet lesions and differentiating cusp perforation from valvular insufficiency.
o The combination of TEE and color Doppler is excellent for detecting intracardiac fistulas.
o The resolution of either TEE or TTE in real life is approximately 2 mm.
o Conditions that are positively related to the detection of valvular thrombi are (1) the location, ie, right-sided structures are poorly visualized, especially by TTE; (2) disease lasting longer than 2 weeks; (3) abscesses of the valves or myocardium; and (4) aneurysms of the sinus of Valsalva.
* Various radionuclide scans using, for example, gallium Ga 67?tagged white cells and indium In 111?tagged white cells, have proven to be of little use in diagnosing IE. Radionuclide scans of the spleen are useful to help rule out a splenic abscess, which is a cause of bacteremia that is refractory to antibiotic therapy.
* A CT scan of the head should be obtained in patients who exhibit CNS symptoms or findings consistent with a mass effect (eg, macroabscess of the brain).40,41,42
Other Tests
* Electrocardiography may help detect the 10% of patients who develop a conduction delay during IE by documenting an increased P-R interval.
* Rheumatoid factor (ie, "poor man's" circulating immune complex) becomes positive in 50% of patients with subacute disease. It becomes negative after successful treatment.
* Durack and colleagues developed diagnostic criteria that combine the clinical, microbiological, pathological, and echocardiographic characteristics of a specific case.43
o Major blood culture criteria
+ Two blood cultures positive for organisms typically found in patients with IE (ie, S viridans, Streptococcus bovis, a HACEK group organism, community-acquired S aureus, or enterococci in the absence of a primary focus)
+ Blood cultures persistently positive for one of the above organisms from cultures drawn more than 12 hours apart
+ Three or more separate blood cultures drawn at least 1 hour apart
o Major echocardiographic criteria
+ Echocardiogram positive for IE, documented by an oscillating intracardiac mass on a valve or on supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomical explanation
+ Myocardial abscess
+ Development of partial dehiscence of a prosthetic valve
+ New-onset valvular regurgitation
o Minor criteria
+ Predisposing heart condition or intravenous drug use
+ Fever of 38?C (100.4?F) or higher
+ Vascular phenomenon, including major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, or Janeway lesions
+ Immunological phenomenon such as glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor
+ Positive blood culture results not meeting major criteria or serologic evidence of active infection with an organism consistent with IE (eg, Brucella, C burnetii [ie, Q fever], Legionella)
+ Echocardiogram results consistent with IE but not meeting major echocardiographic criteria
o Definitive pathological diagnosis is established by demonstrating microorganisms, by culture or histology, in vegetations removed by surgery, embolectomy, or drainage of an intracardiac abscess. Alternatively, a definitive clinical diagnosis is made based on the presence of 2 major criteria, 1 major criterion and 3 minor criteria, or by 5 minor criteria.
o A diagnosis of possible IE is made when findings consistent with IE fall short of the criteria for definite IE but do not meet the criteria for rejection.
o Rejection criteria for the diagnosis of IE are as follows:
+ The presence of a firm alternative diagnosis of the manifestations of endocarditis
+ Resolution of manifestations of endocarditis after 4 or fewer days of antimicrobial therapy
+ No pathologic evidence of IE at surgery or autopsy after 4 or fewer days of antimicrobial therapy
o These criteria may, at times, overdiagnose IE and may not be as applicable in patients with subacute disease.
* A major clinical challenge is that at least 25% of S aureus BSIs represent IE or metastatic infections. The question is whether a continuous bacteremia in the presence of an intravascular line is representative of IE.
o Blood cultures should only be drawn through intravascular lines for the purpose of diagnosing catheter-related BSIs and have limited value for answering this clinical challenge.
o Because of the ability of S aureus to produce an endotheliosis, the presence of a continuous bacteremia does not necessarily imply an infected valvular vegetation.
o An important clue to continuous bacteremia/IE is the presence of S aureus bacteruria associated with hematuria. Hematuria in the setting of IE is due to embolic renal infarction or immunologically mediated glomerulonephritis. Echocardiography has developed into a useful tool for meeting this clinical challenge.
o Twenty-five percent of patients with staphylococcal bacteremia and 23% of those with catheters as the primary focus have evidence of IE based on TEE findings, in the absence of clinical and TTE findings.43
Procedures
* Catheterization of the heart is rarely required for the diagnosis of IE or any of its complications. The findings from echocardiography correlate well with the findings from cardiac catheterization.
Histologic Findings
The characteristic findings of IE are intravascular endocardial vegetations that contain microorganisms surrounded by fibrin and platelets (see Pathophysiology).
Treatment
Medical Care
The major goals of therapy for infective endocarditis (IE) are to eradicate the infectious agent from the thrombus and to address the complications of valvular infection. The latter includes both the intracardiac and extracardiac consequences of IE. Much of the discussion of dealing with the effects of IE is in Surgical Care.
* Mild congestive heart failure resulting from valvular insufficiency or myocarditis may be managed with standard medical therapy. Often, this is progressive, and, despite achieving a microbiological cure, it requires valvular surgery.
* Although thrombosis is a key element of IE, anticoagulation with heparin (Coumadin) is controversial. Indeed, evidence indicates patients who are anticoagulated have worse outcomes than those who are not anticoagulated. Patients who are treated with anticoagulation appear to have a higher rate of intracerebral bleeding. If an established reason for anticoagulation (eg, deep venous thrombosis, presence of a mechanical prosthetic valve) exists, a standard regimen of anticoagulation should be followed.
* Antibiotics remain the mainstay of treatment for IE.
o In the setting of acute IE, institute antibiotic therapy as soon as possible to minimize valvular damage. Three to 5 sets of blood cultures are obtained within 60-90 minutes, followed by the infusion of the appropriate antibiotic regimen. By necessity, the initial antibiotic choice is empiric in nature, determined by clinical history and physical examination findings.
o In the case of subacute IE, treatment may be safely delayed until culture and sensitivity results are available. Waiting does not increase the risk of complications in this form of the disease.
o Eradicating bacteria from the fibrin-platelet thrombus is extremely difficult because (1) the high concentration of organisms present within the vegetation (ie, 10-100 billion bacteria per gram of tissue), (2) their position deep within the thrombus, (3) their location in both a reduced metabolic and reproductive state, and (4) the interference of fibrin and white cells with antibiotic action. For all of these reasons, bactericidal antibiotics are considered necessary for cure of valvular infection.
o Intravenous administration is preferred because more reliable therapeutic levels are achieved with this route.
o Treat all patients in a hospital or skilled nursing facility to allow adequate monitoring of the development of complications and the response to antibiotic therapy.
* Management of S aureus bacteremia in the presence of an intravascular catheter includes (1) promptly removing the catheter, (2) initiating appropriate antibiotic therapy, (3) monitoring of blood culture results in 24-48 hours, and (4) performing a TEE.
o If the follow-up blood culture and TEE findings are negative and no evidence of metastatic infection is found, then 2 weeks of antistaphylococcal therapy is appropriate.
o If the follow-up blood culture findings are positive and the TEE results indicate the presence of IE, then the patient is treated for 4-6 weeks with antistaphylococcal antibiotics.
o If the follow-up blood culture results are positive and the TEE findings show no evidence of IE, then metastatic infection, such as a splenic abscess or osteomyelitis, must be considered while appropriate antibiotic therapy is continued and while the extracardiac source of infection is sought.
* It is important to recognize that, in up to one third of cases, a cause of persistent BSI is not identified. A good deal of these may be explained by endotheliosis. For the time being, the duration of antibiotic therapy for each case of S aureus catheter-related BSI must be individualized. The author and others would treat cases that meet the criteria of continuous bacteremia for a total of 4 weeks despite a negative TEE result.44,45,46
Surgical Care
Approximately 15-25% of patients with IE eventually require surgery.
* Indications for surgical intervention in patients with native valve endocarditis (NVE) are as follows:
o Congestive heart failure refractory to standard medical therapy
o Fungal IE (except that caused by Histoplasma capsulatum)
o Persistent sepsis after 72 hours of appropriate antibiotic treatment
o Recurrent septic emboli, especially after 2 weeks of antibiotic treatment
o Rupture of an aneurysm of the sinus of Valsalva
o Conduction disturbances caused by a septal abscess
o Kissing infection of the anterior mitral leaflet in patients with IE of the aortic valve
* Congestive heart failure in a patient with NVE is the primary indication for surgery. A second relapse, during or after completion of treatment, requires replacement of the valve.
* Paravalvular abscess and intracardiac fistula almost always require surgical intervention. Patients with culture-negative NVE who remained febrile for more than 10 days should be considered surgical candidates. Persistent hypermobile vegetations, especially those with a history of embolization beyond 7 days of antibiotic therapy, should be treated with surgery. Cardiac surgery should be considered in patients with multiresistant organisms (eg, enterococci).
* The indications for surgery in patients with prosthetic valve endocarditis (PVE) are the same as those for patients with NVE, with the addition of the conditions of valvular dehiscence and early PVE.
* Surgery is often required for treatment of metastatic infections (eg, cerebral and other types of aneurysms and macroabscesses of the brain and spleen). Many cerebral abscesses may not be accessible. If this is the case, they can be monitored because 30% may heal when treated medically.
* Occasionally, local debridement and the administration of appropriate antibiotics may be sufficient to cure an uncomplicated pacemaker pocket infection. However, most studies indicate that complete removal of the system is necessary for cure in most cases. Many patients in whom this is not possible eventually die of complications from relapsing infection. This aggressive approach is especially necessary when dealing with pacemaker IE.
o After removal of the infected device, placing a temporary transvenous pacer is best. Immediate insertion of a permanent pacemaker at a new site can be safely accomplished.
o In the past, removal of the intracardiac leads that had been in place for several months often necessitated open heart surgery. The use of laser technology to dissolve the pacemaker lead adhesions has proven successful, with a 94% success rate. The risk of dislodging vegetations during removal of infected leads is negligible.
o Patients whose leads cannot be removed are started on permanent antibiotic suppression.47,48
Consultations
* Personnel in the clinical microbiology laboratory must have the skill to isolate the organism, properly identify it, and perform susceptibility testing appropriate for the growth characteristics and requirements of the organism (with determination of the minimum inhibitory concentration [MIC] of clinically relevant antimicrobial agents). To obtain the best possible information, the attending physician should work closely with the microbiology laboratory personnel.
* In general, both a cardiologist and an infectious diseases specialist should be involved in the care of patients with IE.
* Consulting a cardiothoracic surgeon may be necessary. See Surgical Care.
Diet
No special diets are recommended for patients with endocarditis; however, if the patient has congestive heart failure, administer a sodium-restricted diet.
Activity
Activity limitations are determined by the severity of the illness, complications (eg, stroke), and the presence of significant congestive heart failure.
Medication
Goals to maximize treatment success are (1) early diagnosis, (2) accurate microorganism identification, (3) reliable susceptibility testing, (4) prolonged intravenous administration of bactericidal antimicrobial agents, (5) proper monitoring of potentially toxic antimicrobial regimens, and (6) aggressive surgical management of correctable mechanical complications.
The American Heart Association has developed guidelines for treating infective endocarditis (IE) caused by the most frequently encountered microorganisms. Updated guidelines (October 2007) are detailed here. Antibiotic doses are predicated on normal renal function.
Adult native valve endocarditis (NVE) caused by penicillin-susceptible S viridans, S bovis, and other streptococci (MIC of penicillin of ? 0.1 mcg/mL) should be treated with one of the following regimens:
* Administer penicillin G at 12-18 million U/d intravenously (IV) by continuous pump or in 6 equally divided doses for 4 weeks.
* Administer ceftriaxone at 2 g/d IV for 4 weeks. It may be given intramuscularly (IM) for short periods if venous access problems develop. Ceftriaxone allows once-a-day outpatient intravenous therapy for clinically stable patients.
* Administer penicillin G and gentamicin at 1 mg/kg (based on ideal body weight) every 8 hours for 2 weeks. Short-course therapy with ceftriaxone and gentamicin for 2 weeks is a cost-effective regimen and is effective in selected patients. Short-course therapy is recommended for those with uncomplicated NVE caused by sensitive S viridans and of less than 3 months' duration.
* In patients who are allergic to penicillin, use vancomycin at 30 mg/kg/d IV in 2 equally divided doses for 4 weeks. The vancomycin dose should not exceed 2 g/d unless serum levels are monitored and can be adjusted to attain a peak vancomycin level of 30-45 mcg/mL 1 hour after completion of the intravenous infusion of vancomycin.
For NVE caused by relatively resistant streptococci (MICs of penicillin of 0.1-0.5 mcg/mL), the following regimens are recommended:
* Administer penicillin G at 18 million U/d IV, either by continuous pump or in 6 equally divided doses, for 4 weeks.
* Administer cefazolin at 6 g/d IV in 3 equally divided doses for 4 weeks.
* Both of these alternatives are combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for the first 2 weeks of therapy.
* For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d IV in 2 equally divided doses (usually, do not exceed 2 g/d unless serum levels are monitored) for 4 weeks. Peak vancomycin levels of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
IE caused by nonresistant enterococci, resistant S viridans (MICs of penicillin G of >0.5 mcg/mL), or nutritionally variant S viridans and prosthetic valve endocarditis (PVE) caused by penicillin-G?susceptible S viridans or S bovis should be treated as follows:
* Administer penicillin G at 18-30 million U/d IV, either by continuous pump or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
* Alternatively, administer ampicillin at 12 g/d by continuous infusion or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
* In patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d in 2 equally divided doses (usually, do not exceed 2 g/24 h unless serum levels are monitored). This may be combined with gentamicin for 4-6 weeks of treatment. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
Enterococcal PVE generally responds as well as disease involving native valves. Six weeks of treatment is recommended for patients with symptoms of enterococcal IE of more than 3 months' duration, with relapsed infection, or with PVE.
A combination of an inhibitor of cell wall synthesis (ie, penicillin, vancomycin) with an aminoglycoside (ie, gentamicin, streptomycin) is necessary to achieve bactericidal activity against the enterococci. Tobramycin or amikacin does not act synergistically with antibiotics active against the bacterial cell wall.
Increasing numbers of enterococci have aminoglycoside-inactivating enzymes that make them relatively resistant to the usual synergistic combinations. These aminoglycoside-resistant strains have an MIC of 2000 mcg/mL or more for streptomycin and 500 mcg/mL or more for gentamicin. Of gentamicin-resistant enterococcal strains, 25% are susceptible to streptomycin. Continuously infused ampicillin (serum level of 16 mcg/mL) is probably the best therapy for aminoglycoside-resistant enterococci. Alternative choices are imipenem, ciprofloxacin, or ampicillin with sulbactam. Vancomycin does not appear to be as useful as the aforementioned antibiotics.
Enterococcus faecalis may become resistant to the penicillins because of their production of beta-lactamases. These strains can be treated with ampicillin combined with sulbactam or with vancomycin combined with gentamicin.
High peak levels of gentamicin are not necessary to establish synergistic bactericidal activity against enterococci. Peak gentamicin levels of 3-5 mcg/mL, with a trough of less than 2 mcg/mL, frequently can be obtained with a dose of gentamicin of 1 mg/kg IV every 8 hours. Once-a-day gentamicin dosing should not be used because a prolonged postantibiotic effect against gram-positive organisms does not occur, and synergistic killing requires the simultaneous presence of an agent active in the cell wall and an aminoglycoside.
A recent study indicates that gentamicin usage, even for synergy, is associated with decreasing renal function. However, overall mortality does not appear to be increased. Certainly, gentamicin therapy should be continued to achieve synergy against enterococci, but the practice of administering gentamicin for 5 days in the treatment of S aureus IVDA IE should be questioned.
Vancomycin-resistant isolates of Enterococcus faecium and Enterococcus faecalis (ie, vancomycin-resistant enterococci [VRE]) produce some of the most challenging nosocomial infections. Presently, no therapy has been proven highly effective for IE caused by strains of VRE. Quinupristin/dalfopristin (ie, Synercid) may suppress E faecium bacteremia but frequently is not bactericidal. Other options for therapy include linezolid, a combination of ampicillin and imipenem, and chloramphenicol. In one small series, the combination of ampicillin and ceftriaxone was found to be useful against VRE. Often, the valve must be replaced to achieve a cure.
NVE caused by methicillin-sensitive S aureus should be treated as follows:
* Administer nafcillin or oxacillin at 2 g IV every 4 hours for 4-6 weeks.
* Administer cefazolin at 2 g IV every 8 hours for 4-6 weeks.
* For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg (usually, do not to exceed 2 g/24 h unless serum levels are monitored) for 4-6 weeks. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
Vancomycin therapy is associated with a significant failure rate (up to 35%) in the treatment of MSSA and MRSA BSI/IE. It appears that vancomycin should not be used to treat infections with staphylococci with an MIC of greater than 1.5-2 mcg/mL. In these cases, alternative agents such as linezolid or daptomycin should be used.
PVE caused by MRSA should be treated with vancomycin at 30 mg/kg/d in 2 equally divided doses (usually, do not exceed 2 g unless serum levels are monitored) for 4-6 weeks. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.
PVE caused by methicillin-sensitive S aureus should be treated as follows:
* Administer nafcillin or oxacillin at 2 g IV every 4 hours for 6 weeks or longer.
* Alternatively, administer cefazolin at 2 g IV every 8 hours for 6 weeks or longer.
* Each of these options should be combined with rifampin at 300 mg orally every 8 hours for 6 weeks or longer and with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for the first 2 weeks.
PVE caused by MRSA should be treated with vancomycin at 30 mg/kg (not to exceed 2 g/d unless serum levels are monitored) for 6 weeks or longer combined with rifampin and gentamicin as outlined above. A significant concern is that MRSA may become resistant to vancomycin.
Treatment with linezolid appears to result in outcomes superior to those with vancomycin against many types of infections caused by MRSA and methicillin-sensitive S aureus. The use of linezolid should be strongly considered instead of vancomycin in patients who are seriously ill. Another advantage of linezolid is that its dose does not need to be adjusted in patients with renal failure. White blood cell counts, red blood cell counts, and platelet counts need to be monitored frequently while the patient is on this drug. The risk of developing serotonin syndrome is low. After the fourth week of therapy, the risk of hematological and neuropathic complications rapidly increases.
Daptomycin (6 mg/kg/24 h) has recently been approved for the treatment of S aureus BSI and right-sided IE. Higher doses of daptomycin (12 mg/kg/24 h) are more effective, with little increase in adverse effects. Patients who have received vancomycin have a higher rate of resistance to daptomycin.
HACEK microorganisms should be treated as follows:
* Administer ceftriaxone at 2 g/d IV for 4 weeks.
* Alternatively, administer ampicillin at 12 g/d by continuous pump or in 6 equally divided doses daily. This may be combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4 weeks.
Culture-negative NVE is usually treated with vancomycin and gentamicin. In patients who have previously received antibiotics, initial therapy should consist of either ampicillin-sulbactam plus gentamicin (3 mg/kg/d) or vancomycin plus gentamicin and ciprofloxacin. Because of the increased risk of renal failure with gentamicin, the latter regimen is preferred.
Patients with culture-negative PVE are usually given vancomycin and gentamicin, targeting possible enterococcal or coagulase-negative staphylococcal infections. In patients with suspected PVE who have previously received antibiotics, enteric therapy should consist of vancomycin, gentamicin, cefepime, and rifampin. Because of the risk of developing resistance to rifampin, many clinicians would start this antibiotic only after the blood cultures results become negative.
Treatment of other microorganisms is as follows:
* For P aeruginosa, administer ceftazidime, cefepime, or imipenem, combined with high-dose tobramycin at 8 mg/kg/d in 3 divided doses, to attain peak blood levels of 15-20 mcg/mL, for 6 weeks.
* For enteric gram-negative rods (eg, E coli, Proteus mirabilis), administer ampicillin, ticarcillin-clavulanic acid (Timentin), piperacillin, piperacillin-tazobactam, ceftriaxone, or cefepime combined with gentamicin or amikacin for 4-6 weeks.
* For Streptococcus pneumoniae, administer ceftriaxone at 2 g/d IV or vancomycin (if penicillin allergy or high-level penicillin G resistance [MIC of 2 mcg/mL or more]) for 4 weeks.
* For diphtheroids, administer penicillin G at 18-24 million U/d in 6 divided doses or vancomycin combined with gentamicin for 4 weeks.
* For Q fever (C burnetii infection), administer doxycycline combined with rifampin, sulfamethoxazole-trimethoprim, or a fluoroquinolone for 3-4 years.
PVE is especially difficult to treat because the microorganisms adhere to the foreign body and may make them impervious to the bactericidal action of agents active in the cell wall. All patients with PVE require at least 6 weeks of antimicrobial therapy. Rifampin is the key drug in the treatment of PVE, as it is one of the only antimicrobial agents that penetrate the biofilm laid down by S aureus and CoNS. Because of the risk of these organisms developing resistance to rifampin, many clinicians withhold the addition of rifampin until blood cultures have cleared.
Penicillin-sensitive S viridans PVE should be treated with 2 weeks of penicillin G or ceftriaxone combined with gentamicin, followed by 4 weeks of penicillin G or ceftriaxone.
If the S viridans PVE is caused by an organism with a penicillin MIC of 0.2 mcg/mL or more, penicillin G or ceftriaxone combined with gentamicin combination therapy should be administered for 4-6 weeks. If the combination therapy is administered for only 4 weeks, penicillin G or ceftriaxone should be continued for an additional 2 weeks. Vancomycin is substituted for penicillin or ceftriaxone if the patient has a history of severe, immediate penicillin hypersensitivity, such as urticaria, anaphylaxis, or angioedema.
Enterococcal PVE therapy is complicated by the multiple types of enterococcal antimicrobial resistance, including beta-lactamase production (rare), different types of aminoglycoside-inactivating enzymes (more common), and VRE (increasingly common). If the enterococci are highly resistant to both gentamicin and streptomycin, ampicillin should be administered for 8-12 weeks by continuous infusion.
No effective therapy is known for VRE PVE.
Patients with PVE must be monitored carefully for signs of valve dysfunction, congestive heart failure, and heart block. They should also be monitored for clinical response to therapy, conversion of positive blood culture results, renal function status, and serum blood levels of vancomycin and aminoglycosides. Valve replacement surgery should be performed promptly if any of the following occurs: (1) moderate-to-severe congestive heart failure, (2) valve dysfunction, (3) perivalvular or myocardial abscess formation, (4) the presence of an unstable valve that is becoming detached from the valve ring, (5) more than one embolic episode with persistent vegetations observed on transtracheal echocardiogram, or (6) the presence of vegetations larger than 1 cm in diameter.
If PVE does not respond to antimicrobial therapy and blood cultures results remain positive or if a relapse of bacteremia occurs after infection, the prosthetic valve should be replaced. In the presence of microorganisms that have no microbicidal agent (eg, VRE, fungi) or in the presence of other recalcitrant organisms (eg, P aeruginosa, S aureus, enteric gram-negative rods, Brucella species, C burnetii), past clinical experience shows that early replacement of the prosthetic valve improves the chances for cure.
Fungal endocarditis is rare and primarily occurs after prosthetic valve surgery and in individuals who abuse intravenous drugs. Candida species and Aspergillus species are the organisms most frequently encountered. Currently available antifungal agents have not been successful in eliminating fungal IE. The only cures for proven fungal IE have resulted when surgical excision of the infected valves was combined with amphotericin B therapy.
Empiric therapy of IVDA IE should be aimed at S aureus. Whether to use vancomycin or oxacillin/nafcillin depends on the incidence of MRSA in the community. Generally, gram-negative organisms occur infrequently, and delay in covering them initially is acceptable.
Some clinicians obtain peak and trough blood samples during the course of antimicrobial therapy of IE in order to run serum bactericidal tests. These tests are performed by incubating serial 2-fold dilutions of serum that contains antimicrobials with an inoculum of 100,000 colony-forming units per milliliter of the target microorganism that has been previously isolated from the patient's blood for 24-48 hours.
Peak antimicrobial concentrations that inhibit and kill the bacteria at a 1:32 or greater dilution in serum are a consistent predictor of a favorable clinical response. Antimicrobial dosages are adjusted to try to attain this goal. However, many clinicians feel that the serum bactericidal test does not have a reproducible result, and these clinicians rely on standardized tests of antimicrobial susceptibility (ie, MICs) and serum antimicrobial assays of peak and trough levels to determine whether sufficient amounts of antimicrobial agents are being administered.49,50,51,52,53,54
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Penicillin G (Pfizerpen)
For IE caused by S viridans or S bovis with penicillin G MIC of 0.1 mcg/mL or less.
Dosing
Adult
MIC <0.1 mcg/mL: 12-18 million U/d IV by pump or divided into 6 equal doses for 4 wk (duration 2 wk if combined with gentamicin)
MIC 0.1-0.5 mcg/mL: 18 million U/d IV by continuous pump or divided into 6 equal doses for 4 wk
MIC >0.5 mcg/mL or enterococci: 18-30 million U/d IV by continuous pump or in 6 equally divided doses, with gentamicin for 4-6 wk
Pediatric
<20 kg: 12.5 mg/kg IV q6h
>20 kg: Administer as in adults
Interactions
Probenecid can increase effects; coadministration of tetracyclines can decrease effects
Contraindications
Documented hypersensitivity; do not mix with gentamicin (mutual interaction will occur)
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired renal function; phlebitis may develop with potassium penicillin G
Ceftriaxone (Rocephin)
Once-daily treatment of S viridans or HACEK IE. Third-generation cephalosporin with broad-spectrum gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Dosing
Adult
2 g IV qd for 4 wk; may be given IM for short periods if central access is lost
Pediatric
37.5 mg/kg IV q12h
Interactions
Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity; do not mix in the same bag as gentamicin because of mutual inactivation
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal impairment; caution in breastfeeding and allergy to penicillin; may form biliary sludge and cause biliary colic; monitor for Clostridium difficile colitis
Vancomycin (Vancocin, Lyphocin, Vancoled)
DOC for patients who are allergic to penicillin who have streptococcal or enterococcal endocarditis, those with MRSA IE, and those with other beta-lactam?resistant gram-positive IE infections.
Duration of treatment is 4 wk in penicillin-susceptible streptococcal IE and 4-6 wk for staphylococcal infections, prosthetic valve infections, or enterococcal IE.
Dosing
Adult
30 mg/kg IV qd divided bid; not to exceed 2 g/d unless serum levels are monitored and dose is adjusted to attain peak level of 30-45 mcg/mL 1 h after completion of infusion
Pediatric
Infants (aged 1 mo) and children: 20 mg/kg IV q12h
Interactions
Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal failure and neutropenia; red man syndrome is caused by an IV infusion that is too rapid (dose given over a few min) but rarely happens when dose given as 2-h administration, PO, or with intraperitoneal administration; red man syndrome is not an allergic reaction; monitor blood levels, with a goal of 30-40 mcg/mL 1 h after completion of IV dose
Administer slowly; rapid administration is associated with hypotension and histamine release, ie, red man syndrome
Gentamicin (Garamycin, Gentacidin)
Combination therapy used to attain bactericidal activity against enterococci and resistant streptococcal species, to shorten treatment of penicillin-susceptible streptococcal IE, and for prosthetic staphylococcal IE
Duration for penicillin-susceptible streptococcal IE is 2 wk. For penicillin-resistant streptococci and enterococci, 4-6 wk.
Dosing
Adult
1 mg/kg (calculated based on ideal body weight) IV q8h
Pediatric
Infants and children: 2.5 mg/kg IV q8h
Interactions
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus, prolonged respiratory depression may occur
Coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Contraindications
Documented hypersensitivity; non ? dialysis-dependent renal insufficiency
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment
Monitor blood levels to reduce toxicity; a peak level of 3-4 mcg/mL is sought tid in order to sustain synergistic killing of gram-positive organisms; maximum allowable peak level is 10 mcg/mL; maximum trough level is 2 mcg/mL; once-a-day administration not recommended because a sustained level is required for synergistic killing of gram-positive bacteria; change dose in renal failure; calculate doses based on ideal body weight rather than actual weight in patients who are obese
Ampicillin (Marcillin, Omnipen, Polycillin, Principen)
For treatment of enterococcal IE, IE caused by HACEK organisms, or as penicillin G substitute for penicillin-susceptible organisms.
For enterococcal endocarditis, duration is 4-6 wk in combination with gentamicin.
Dosing
Adult
12 g IV qd by continuous pump or in 6 equally divided doses
Pediatric
<20 kg: 50 mg/kg, IV q6h
>20 kg: Administer as in adults
Interactions
Probenecid and disulfiram elevate levels; allopurinol decreases effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction
Cefazolin (Ancef, Kefzol, Zolicef)
Used for staphylococcal endocarditis susceptible to methicillin/oxacillin. Substitute for penicillin G or ampicillin for penicillin-susceptible streptococcal endocarditis.
Used if develop mild rash to penicillins but no anaphylaxis or severe immediate hypersensitivity reactions.
Dosing
Adult
2 g IV q8h for 4-6 wk
Pediatric
Infants and children: 25 mg/kg IV q6h
Interactions
Probenecid prolongs effects; coadministration with aminoglycosides may increase renal toxicity; may yield false-positive urine-dip test results for glucose
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal impairment; superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy
Nafcillin (Nafcil, Unipen, Nallpen)
Used for staphylococcal IE caused by organisms susceptible to methicillin/oxacillin.
Dosing
Adult
2 g IV q4h for 4-6 wk
Pediatric
Older infants and children: 20 mg/kg IV q4h
Interactions
Associated with warfarin resistance when administered concurrently; effects may decrease with bacteristatic action of tetracycline derivatives
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
To optimize therapy, determine causative organisms and susceptibility; treatment of 10 d or longer needed to eliminate infection and prevent sequelae (eg, endocarditis, rheumatic fever); take cultures after treatment to confirm infection is eradicated
Linezolid (Zyvox)
Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteristatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of VRE.
Dosing
Adult
600 mg PO/IV q12h for 14-28 d
Pediatric
Not established
Interactions
May cause hypertension when used concomitantly with adrenergic agents, including pseudoepinephrine, sympathomimetic agents, or vasopressor or dopaminergic agents (reduce dose of dopamine or epinephrine if concurrent use required); serotonin syndrome may occur if used concomitantly with serotonergic agents, including TCAs, meperidine, dextromethorphan, trazodone, venlafaxine, and selective serotonin reuptake inhibitors
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Has mild MAOI properties and potential to have same interactions as other MAOIs; caution in uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism and in patients who are at increased risk for bleeding, have preexisting thrombocytopenia, receive concomitant medications that may decrease platelet count or function, or who may require > 2 wk of therapy (monitor platelet counts); unnecessary use may lead to development of resistance
Follow-up
Further Inpatient Care
* Patients should have blood cultures taken after 3-4 days of treatment to document eradication of the bacteremia.
o Blood cultures during treatment are essential if persistent fever or other signs develop that suggest failing treatment.
o Failure to sterilize the bloodstream, despite adequate serum levels of appropriate antibiotics, should prompt a search for metastatic infection (eg, abscesses, especially splenic, or mycotic aneurysm).
o Fever lasting longer than 10 days into therapy with an indicated antibiotic regimen should be of concern and should prompt a search for suppurative complications. Approximately 30% of patients have a return of fever after the initial response. This is usually caused by an intracardiac abscess or metastatic infection. Causes of unresponsive fever include myocardial or septal abscesses, large vegetations that resist sterilization, and metastatic infection. Occasionally, fever in patients with uncomplicated infective endocarditis (IE) may take as long as 3 weeks to abate.
* Relapse of IE usually occurs within 2 months of finishing clinically effective therapy.
o Infection with S aureus, enterococci, and gram-negative organisms (especially P aeruginosa) is associated with a high rate of relapse.
o Those with pretreatment symptoms of IE of more than 3 months' duration are at greater risk for relapse.
o Enterococcal infection of the mitral valve has the greatest potential for relapse.
o Recurrent IE occurs most often in individuals who abuse intravenous drugs. Valvular infections in these patients recur at a rate of 40%.
o Other significant risk factors for recurrence include a previous episode of IE, the presence of a prosthetic valve, and congenital heart disease.
* Monitor patients for the development of complications, including (1) valvular dysfunction, usually insufficiency of the mitral or aortic valves; (2) myocardial or septal abscesses; (3) congestive heart failure; (4) metastatic infection; (5) embolic phenomenon; and (6) organ dysfunction resulting from immunological processes. Note that the diagnosis of developing congestive heart failure or valvular insufficiency is based on clinical findings, not solely on echocardiographic measurements.
* The onset of valve dysfunction or moderate-to-severe congestive heart failure should lead to an evaluation for immediate valve replacement.
* Complications such as congestive heart failure resulting from valvular insufficiency and embolization may occur after bacteriologic cure has been achieved.
* In general, infected vascular catheters should be removed and should not be replaced over a guidewire. Surgically implanted devices, such as Broviac or Hickman catheters, do not necessarily need to be removed unless evidence of IE, a tunnel infection, or suppurative thrombophlebitis is present or if the infecting organism is a Corynebacteria species, a Pseudomonas species, a fungus, S aureus, or a Mycobacterium species. If bacteremia persists longer than a few days, the catheter must be removed.55,56
Further Outpatient Care
* Patients must be closely monitored for delayed development of congestive heart failure.
Inpatient & Outpatient Medications
* Orally administered antibiotics have been used as suppressive therapy for incurable valvular infections (ie, inoperable prosthetic valve endocarditis [PVE]).
Transfer
* Transfer the patient to a tertiary care cardiovascular center for surgical intervention in the following situations:
o Significant congestive heart failure that develops in association with valve dysfunction
o Conduction disturbances or echocardiogram findings that suggest the presence of a myocardial abscess
o Recurrent emboli with vegetations larger than 1 cm in diameter remaining on the valve
o Lack of response to antimicrobial therapy
Deterrence/Prevention
* Approximately 15-25% of cases of IE are a consequence of invasive procedures that produce a significant bacteremia. Because only 50% of those who developed valvular infection following a procedure were identified as being candidates for antibiotic prophylaxis, only approximately 10% of cases of IE can be prevented by the administration of preprocedure antibiotics.
* Maintaining good oral hygiene is probably more effective in the overall prevention of valvular infection because gingivitis is the most common source of spontaneous bacteremias.
* The American Heart Association periodically compiles recommendations for IE prophylaxis. Updated guidelines (October 2007) are detailed here. Remembering that these are guidelines and not standards is important. They may be modified in particular circumstances. The guidelines remain unproven by randomized controlled clinical trials. Indeed, many examples of failure of these recommendations have been noted, even when they are applied appropriately.
o The 3 major steps in the pathogenesis of IE that are vulnerable to antibiotic prophylaxis are (1) killing of the pathogen in the bloodstream before it can adhere to the valve, (2) preventing adherence to the valve/fibrin-platelet thrombus, and (3) eradicating any organisms that have attached to the thrombus.
o Successful antibiotic prophylaxis requires (1) identifying those patients who are at risk, (2) prioritizing the procedures that require prophylaxis, and (3) selecting an appropriate antibiotic regimen. In general, bactericidal antibiotics are used. However, bacteristatic agents are probably effective in most circumstances.
o Although the 2007 guidelines are a marked improvement because they prioritize the cardiac conditions and procedures that require antibiotic prophylaxis and emphasize the importance of promoting good oral hygiene, they offer little direction in dealing with the ever-growing problem of antibiotic-resistance patterns of S viridans and enterococci.
o The importance of antibiotic prophylaxis of calcific valvular disease in elderly patients also needs to be more fully discussed. Calcific valvular disease is the most common underlying cardiac risk factor for the development of IE in this age group.
o The author's preference is to administer parenteral prophylactic antibiotics to patients with prosthetic valves because of the severe consequences of PVE.
* Prevention of vascular catheter infections is an important prophylactic approach in preventing nosocomial infective endocarditis (NIE). Protective factors include the insertion and maintenance of catheters by an infusion therapy team, the use of topical disinfectants and antibiotics, and the practice of coating catheters with antimicrobial agents.
* No double-blind studies have been performed to support the use of systemically administered antibiotics for the prevention of pacemaker or intracardiac defibrillator infections. However, awaiting definitive studies, the authors recommend prophylactic antibiotics, as with any implantable device. Of course, strict sterile technique must be followed. Antibiotic prophylaxis is not recommended in patients with pacemakers or intracardiac defibrillators during other types of invasive procedures. Pacemaker infection due to transient bacteremias is uncommon.57
Complications
* Monitor patients for the development of the following complications:
o Valvular dysfunction, usually insufficiency of the mitral or aortic valves
o Myocardial or septal abscesses
o Congestive heart failure
o Metastatic infection
o Embolic phenomenon
o Organ dysfunction resulting from immunological processes
* Complications, such as congestive heart failure resulting from valvular insufficiency and embolization, may occur after bacteriologic cure has been achieved.
Prognosis
* Cure rates for appropriately managed (including both medical and surgical therapies) native-valve endocarditis (NVE) are as follows:
o For S viridans and S bovis infection, the rate is 98%.
o For enterococci and S aureus infection in individuals who abuse intravenous drugs, the rate is 90%.
o For community-acquired S aureus infection in individuals who do not abuse intravenous drugs, the rate is 60-70%.
o For infection with aerobic gram-negative organisms, the rate is 40-60%.
o For infection with fungal organisms, the rate is lower than 50%.
* For PVE, the cure rates are as follows:
o Rates are 10-15% lower for each of the above categories, for both early and late PVE.
o Surgery is required far more frequently.
o Approximately 60% of early CoNS PVE cases and 70% of late CoNS PVE cases are curable.
* The fatality rate of pacemaker IE ranges up to 34%.58
Patient Education
* Surveys indicate that an appallingly small number of patients who are at risk for developing IE have an understanding of antibiotic and nonpharmacologic (ie, appropriate oral hygiene) principles.
* For excellent patient education resources, visit eMedicine's Heart Center. Also, see eMedicine's patient education article Tetralogy of Fallot.
Miscellaneous
Medicolegal Pitfalls
* Infective endocarditis (IE) is a fatal disease, but effective therapy is available. Seek expert advice as needed.
* As a rule for primary care clinics, do not administer antimicrobial agents to febrile patients with heart murmurs without first obtaining at least 2 sets of blood cultures.
* Many malpractice suits are caused by a failure to diagnose and a delay in diagnosis accompanied by a poor outcome for the patient.
* The perception that most IE is preventable is wrong. Frequent episodes of transient bacteremia occur with chewing and other activities of daily life. Proving that a failure to give prophylaxis before dental and surgical procedures resulted in IE is difficult. However, this does not prevent legal action alleging IE as a consequence of failing to give the antimicrobial prophylaxis recommended by the American Heart Association.
* When a central venous line is needed, not inserting the line when a patient is known to be bacteremic is advisable. If no alternative to placing the line is available, bactericidal antimicrobial agents should be administered to try to prevent the development of IE
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