Overview of the management of chronic mitral regurgitation
Author
William H Gaasch, MD
Section Editor
Catherine M Otto, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC
Last literature review version 16.2: May 2008 | This topic last updated: April 24, 2008 (More)
INTRODUCTION — Modern management of patients with chronic mitral regurgitation (MR) requires an understanding of multiple factors: These include:
• The pathophysiology and natural history of the disease
• The severity of the valvular lesion
• The development of atrial fibrillation
• The therapeutic potential of chronic vasodilator therapy
• The indications for endocarditis prophylaxis
• The indications for mitral valve repair and mitral valve replacement
While our knowledge of these areas is not yet complete, it is possible to develop a rational plan for the management of patients with chronic MR [1,2] . These management issues will be reviewed here. The management of functional and ischemic MR are addressed elsewhere. (See "Functional mitral regurgitation" and see "Ischemic mitral regurgitation").
PATHOPHYSIOLOGY AND NATURAL HISTORY — An elusive and poorly understood aspect of the pathophysiology of MR is the nature of the transition from the chronic compensated stage to a decompensated stage. This evolution generally occurs over many years, even decades, depending upon the severity of the regurgitant lesion and the cardiovascular response to the regurgitant volume. The etiology of MR also plays a role in the natural history of this process. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet").
Stages of MR — Left ventricular (LV) chamber size and function have been used to define a compensated, transitional, and decompensated stage in patients with chronic MR (show table 1) [3-9] . (See "Pathophysiology and stages of chronic mitral regurgitation").
• The compensated stage is defined largely on the basis of natural history and other data that indicate a benign prognosis when the end-diastolic dimension is less than 60 mm and the end-systolic dimension is less than 40 mm (as measured by echocardiography).
• The natural history of the transitional stage is not precisely defined, but most published data indicate that a good clinical result can be achieved if surgery is performed at this time.
• The decompensated stage is based upon data derived from patients who have undergone valvular surgery, which indicates that patients who exhibit one or more markers of a decompensated ventricle are at risk for a poor or suboptimal clinical result after valve replacement. These markers include LV end-diastolic dimension greater than 70 mm, LV end-systolic dimension greater than 45 to 47 mm, or a left ventricular ejection fraction (LVEF) less than 50 to 55 percent. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Reduced left ventricular function).
While these considerations do not identify the optimal time for mitral valve replacement or repair, they do enable the clinician to predict a poor LV response to corrective surgery and, in this fashion, provide a picture of the options of surgical or nonsurgical treatment. In principle, corrective surgery should be performed during the transition from a compensated to decompensated stage of the disease (ie, before the decompensated stage is established). (See "Mitral valve surgery" below).
Early identification of progression avoids the development of irreversible changes in LV function that may preclude an optimal response to corrective surgery. Patients with chronic MR and severe LV dysfunction (eg, LVEF <40 percent) are at very high risk of a suboptimal postoperative result. Many of these patients exhibit characteristics of a dilated cardiomyopathy with increased LV afterload and depressed myocardial contractility. Their initial management includes aggressive medical therapy with digitalis, diuretics, and vasodilators.
Cardiac catheterization and coronary angiography should be performed in preparation for surgery. Corrective surgery (and continued medical therapy) generally provides symptomatic relief, but chamber enlargement and a low LVEF usually persist despite technically successful surgery.
Etiology of mitral regurgitation — The major causes of MR are primary diseases of the valve leaflets (eg, mitral valve prolapse and, in developing countries, rheumatic heart disease) and secondary MR due to cardiomyopathy or coronary disease. (See "Etiology, clinical features, and evaluation of chronic mitral regurgitation", section on Etiology).
The best natural history data that are currently available have come from studies of patients with mitral valve prolapse and flail mitral valve leaflet. It is generally assumed that these findings may be applied to MR of other causes. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet").
Summarized briefly, the following factors may be useful for stratifying patients into groups that can be managed medically versus those that require surgical intervention. Older age, male gender, and auscultatory evidence of severe MR are prognostic clues that identify patients with mitral valve prolapse who are at a relatively high risk of complications. Echocardiographic evidence of LV enlargement provides further evidence of high risk that requires careful follow-up.
MR due to flail leaflet — Severe MR due to a flail leaflet, an LVEF <60 percent, and presence of symptoms are predictive of excess mortality. The risk of death was reduced by mitral valve surgery (adjusted hazard ratio 0.42, 95% CI 0.21-0.84) in a series of 394 patients of varying baseline symptom status (36 percent with severe symptoms). For asymptomatic patients with flail leaflet and severe MR (as for other asymptomatic patients with severe MR), surgical correction should be considered early in the course of the disease if valve repair is feasible with a >90 percent likelihood of success. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet" and see "Mitral valve surgery" below).
Effect of pregnancy — Chronic MR is usually well tolerated during pregnancy. The normal fall in systemic vascular resistance tends to reduce the degree of regurgitation. Issues related to the management of mitral regurgitation during pregnancy are discussed separately. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet", section on Effect of pregnancy).
SEVERITY OF MR — In addition to the stage of MR (show table 1), decisions regarding the timing of surgery depend upon the severity of MR. This can be assessed by both clinical and echocardiographic criteria. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation")
Symptoms — Patients with severe chronic MR often experience exercise intolerance, dyspnea, or fatigue during the transition from a compensated to a decompensated stage. Because of the importance of identifying such a transition, a careful history is important to establish an estimate of baseline exercise tolerance [1] . (See "Etiology, clinical features, and evaluation of chronic mitral regurgitation", section on Clinical manifestations).
Most experts and the ACC/AHA guidelines recommend that patients with chronic MR who become symptomatic are candidates for corrective mitral surgery, even if the symptoms improve with medical therapy or the left ventricle appears to be compensated (show table 2) [1,2] . If there is uncertainty about the presence or absence of symptoms, exercise testing may provide objective information that may not be available from the medical history alone. (See "Indications" below).
There has traditionally been reluctance to treat asymptomatic patients with chronic MR surgery. With nothing to gain in the way of symptomatic improvement, early surgery exposes the patient to perioperative morbidity and mortality as well as the long-term complications of a prosthetic valve if a valve repair procedure cannot be performed. (See "Complications of prosthetic heart valves").
On the other hand, there may be benefit from surgery prior to the onset of symptoms. As an example, left ventricular decompensation may develop in the setting of severe MR despite the absence of symptoms. Thus, waiting for the patient to experience dyspnea or exercise intolerance may allow time for the development of irreversible depression of LV function. For this reason, it is important to have an objective measure of LV function in patients with asymptomatic MR.
Echocardiography — The severity of MR can be assessed semiquantitatively by Doppler echocardiography; the results of these two methods correlate highly in grading MR [1,10] . Transthoracic echocardiography usually provides the desired information and is preferred to routine transesophageal echocardiography because it is noninvasive (show table 3 and show table 4).
Based upon the 2003 American Society of Echocardiography guidelines [11] , the following findings, in order or priority, are consistent with severe MR (show table 5):
• A vena contracta width ≥7 mm
• A regurgitant orifice area ≥0.40 cm2
• A regurgitant volume ≥60 mL
• A regurgitant fraction ≥50 percent
• A jet area >40 percent of left atrial area, but this is not so reproducible and less often used
These values are based on an average adult size and may need to be adjusted for body size in small or large patients; however, there is no specific formula for making this adjustment. (See "Etiology, clinical features, and evaluation of chronic mitral regurgitation", section on Severity of MR).
Regardless of echo-Doppler grading, severe chronic MR does NOT exist (with rare exceptions) without clear evidence of left atrial or left ventricular enlargement. If the left ventricular end-diastolic dimension (by echocardiography) is less than 60 mm (approximately 35 mm/m2), the diagnosis of severe chronic MR should be seriously questioned. Left atrial size may reflect the "history" (severity and duration) of chronic MR [12] .
Cardiac catheterization is primarily indicated when echocardiography does not provide diagnostic information or the echocardiographic findings are discrepant from the clinical features (show table 6) [1] .
Serial monitoring — In addition to the initial evaluation, serial monitoring is warranted in patients with chronic MR. The goals of monitoring are to assess changes in clinical status by history and physical examination and to assess changes in left ventricular function, which can occur in the absence of symptoms, by echocardiography.
The 2006 ACC/AHA guidelines included recommendations for clinical and transthoracic echocardiographic monitoring in asymptomatic patients with chronic MR (show table 3) [1] . Echocardiography is performed to assess the left ventricular ejection fraction and end-systolic dimension.
The recommendations varied with the severity of MR:
• Patients with mild MR and no evidence of left ventricular enlargement, left ventricular dysfunction, or pulmonary hypertension should be seen yearly for history and physical examination with instructions to contact the physician if symptoms occur. Repeat echocardiography at these visits is not necessary in the absence of clinical evidence of worsening MR.
• Patients with moderate MR should be seen yearly or sooner if symptoms occur. Repeat transthoracic echocardiography should be obtained at these visits.
• Patients with severe MR should be seen every 6 to 12 months or sooner if symptoms occur. Repeat transthoracic echocardiography should be obtained at these visits. The six month interval is preferred if stability has not been documented, there is evidence of progression, or measurements are close to the echocardiographic cutoff values for mitral valve surgery (show table 2). (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation").
Exercise stress testing may add objective evidence about symptoms and a change in exercise tolerance; it may be particularly useful if a good history of exercise capacity is difficult to obtain. Measurement of MR severity and pulmonary artery pressure during exercise also may be helpful.
Transesophageal echocardiography is NOT ndicated for routine follow-up (show table 4). It does, however, have a role in preoperative and intraoperative evaluation when mitral valve surgery is being considered.
A separate issue, the indications for repeat echocardiography in patients with mitral valve prolapse independent of MR, is discussed elsewhere. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet", section on Monitoring).
PHYSICAL ACTIVITY AND EXERCISE — Exercise has a variable effect on the regurgitant fraction in patients with chronic MR [13] . The reduction in systemic vascular resistance may result in no change or a mild reduction in the regurgitant fraction. On the other hand, an elevation in blood pressure, as occurs with static exercise, can lead to marked increases in regurgitant volume and pulmonary capillary pressure.
The 2006 ACC/AHA guidelines concluded that there are no exercise restrictions in asymptomatic patients who are in sinus rhythm and have normal left ventricular and left atrial dimensions and a normal pulmonary artery pressure [1] . Specific recommendations for participation in competitive sports in patients with MR were made by the 36th Bethesda Conference [13] , which also included a classification of sports (show table 7) [14] :
• Patients with mild to moderate MR who are in sinus rhythm, have normal left ventricular size and function, and normal pulmonary artery pressures can participate in all competitive sports.
• Patients with mild to moderate MR who are in sinus rhythm, have normal left ventricular systolic function at rest, and mild left ventricular enlargement can participate in low and moderate static and all dynamic competitive sports (class IA, IB, IIA, IIB, and IIC) (show table 7).
• Patients with severe MR and definite left ventricular enlargement, pulmonary hypertension, or any reduction in left ventricular systolic function at rest should not participate in any competitive sports.
• Patients with atrial fibrillation or a history of atrial fibrillation who are treated with long-term anticoagulation therapy should not engage in sports with any for bodily contact or risk of trauma (show table 7).
Recommendations for exercise after mitral repair for chronic MR are described below. (See "Exercise after valve repair" below).
ATRIAL ENLARGEMENT AND FIBRILLATION — Chronic MR is often complicated by the development of left atrial enlargement and atrial fibrillation (AF), both of which can have an impact on patient outcome.
Atrial fibrillation — If the ventricle is compensated and the heart rate is not excessive, the patient with AF merely notices palpitations. There is little or no disability in these cases except for an increased risk of stroke or other sign of systemic embolization. These patients are candidates for direct current cardioversion and antiarrhythmic drug therapy to maintain sinus rhythm. (See "Restoration of sinus rhythm in atrial fibrillation: Recommendations" and see "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations").
It can be argued, however, that mitral valve surgery should be performed before AF is persistent or resistant to cardioversion. This notion is based upon the observation that persistent AF after surgery places the patient at particularly high risk for atrial thrombus and arterial embolism.
Preoperative variables that are associated with the persistence of AF after surgery are a prolonged duration of the arrhythmia (exceeding one year) and moderate to severe left atrial enlargement [12,15,16] . When the preoperative left atrial size exceeds 50 mm (by echocardiography), fewer than one-half of the patients return to normal sinus rhythm after surgery; in contrast, when left atrial dimension is normal, 85 percent of patients return to normal sinus rhythm [15] .
These data and anecdotal clinical experience support the concept that, if postoperative AF and its complications are to be minimized, corrective surgery should be considered within months of the development of AF or before substantial left atrial enlargement is present. The 2006 ACC/AHA guidelines concluded that the weight of evidence was in favor of the efficacy of mitral valve surgery in asymptomatic patients with severe chronic MR and preserved left ventricular function who have new onset AF (show table 2) [1] . The 2007 ESC guidelines thought that this was a debatable point [2] .
Although AF is not necessarily an indication for surgery in an asymptomatic patient with preserved left ventricular function, the burden of this arrhythmia in a patient with borderline left ventricular function (LVEF 55 to 60 percent) might be used as an indication for surgery, especially if the risk of surgery is low and the valve appears to be amenable to repair. (See "Mitral valve replacement versus repair" below).
The use of the maze procedure or radiofrequency or cryoablation as an adjunct to mitral valve repair or replacement is an effective approach to reduce the incidence of postoperative AF. (See "Surgical approaches to prevent recurrent atrial fibrillation").
Left atrial enlargement — Left atrial enlargement itself, in the absence of AF, may be a risk factor for an adverse outcome following mitral valve surgery. In one study, for example, measures of left ventricular systolic function and left atrial size were equally important in predicting postoperative cardiac-related mortality in patients with symptomatic chronic MR [12] . The authors concluded that left atrial size may reflect the "history" (severity and duration) of MR. This observation again supports the notion that surgery should be considered prior to the development of significant left atrial enlargement.
USE OF VASODILATORS — The indications for vasodilator therapy in patients with chronic MR depend upon the presence or absence of symptoms and the functional state of the left ventricle. These issues are discussed in detail elsewhere and will be briefly reviewed here. (See "Vasodilator therapy in chronic mitral regurgitation").
Asymptomatic patients — There are no published studies that support the hypothesis that vasodilator therapy is beneficial in asymptomatic patients with chronic MR. In addition, the administration of vasodilators in patients with normal LV function might limit the development of symptoms due to increasing LV dysfunction, thereby masking an indication for surgery. Thus, with some exceptions (eg, the hypertensive patient), vasodilators are not recommended for use in asymptomatic patients with chronic MR due to primary valve disease [1,2] .
Symptomatic patients — Several studies confirm a beneficial effect of acute vasodilator therapy in patients with chronic MR. Intravenous nitroprusside, for example, decreases left ventricular end-diastolic pressure and volume while increasing forward stroke volume and cardiac index. Hydralazine has similar salutary effects. In contrast, the acute effect of angiotensin converting enzyme (ACE) inhibitors or nitrates is usually a decrease or no change in the cardiac index.
Data regarding the chronic effect of vasodilators are less impressive. Chronic therapy provides the most benefit for patients with the largest hearts, the poorest systolic function, and the most disabling symptoms. When combined with digitalis and diuretics, for example, hydralazine can produce substantial symptomatic and hemodynamic improvement in patients who are in NYHA functional class II-IV [17] . ACE inhibitors may also be beneficial in this setting [18] . However, because of the substantial improvement in outcome associated with surgery in patients with symptomatic MR, chronic vasodilator therapy is only indicated in those who are not surgical candidates.
In patients for whom chronic vasodilator therapy is warranted, the following recommendations can be made based upon the etiology of MR and whether or not the patient is a candidate for surgery. (See "Vasodilator therapy in chronic mitral regurgitation").
• In symptomatic patients with primary MR (eg, myxomatous or rheumatic), there is little potential to induce a change in the regurgitant orifice area via preload reduction and the therapeutic goal should be a reduction in systolic pressure. Thus, a beta blocker, diuretic, hydralazine, or calcium channel blocker should be used. However, medical therapy is not a substitute for surgical intervention in patients with chronic symptomatic MR.
• Chronic vasodilator therapy is indicated in symptomatic patients who are not candidates for surgery. The evidence of benefit is best in patients with secondary (functional) MR due to left ventricular dysfunction. Treatment of such patients should consist of optimal medical therapy of heart failure and, in appropriate patients, cardiac resynchronization therapy. With respect to ACE inhibitors and/or angiotensin II receptor blockers, the dose titration and monitoring schedules are the same as for heart failure due to left ventricular systolic dysfunction in the absence of moderate to severe MR. (See "Functional mitral regurgitation" and see "Overview of the therapy of heart failure due to systolic dysfunction" and see "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use").
CARDIAC RESYNCHRONIZATION — In selected patients with functional MR, cardiac resynchronization therapy (CRT) with biventricular pacing may be helpful. At this time, however, standard indications for CRT in patients with heart failure are based upon left ventricular (LV) function, functional class, and measures of LV dyssynchrony. (See "Functional mitral regurgitation", section on Cardiac resynchronization therapy, and see "Cardiac resynchronization therapy (biventricular pacing) in heart failure")
ANTICOAGULATION — The risk of an embolic event is increased in patients with rheumatic or nonrheumatic MR, particularly when atrial fibrillation is also present. The presence of mitral annular calcification, which if often associated with MR, also increases the risk of embolism, even in the absence of atrial fibrillation. It was estimated by the Framingham Heart Study that the risk of stroke associated with mitral annular calcification was 2.1-fold greater compared to the absence of mitral valve calcification [19] . (See "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation" and see "Echocardiography in detection of intracardiac sources of embolism", section on Mitral annular calcification).
The Seventh ACCP Consensus Conference on Antithrombotic Therapy published in 2004 included the following recommendations for anticoagulation in patients with chronic MR [20] . These recommendations are essentially the same as for patients without mitral valve disease who have atrial fibrillation and/or systemic embolic events:
Rheumatic MR — Anticoagulation with warfarin (target INR 2.5, range 2.0 to 3.0) is indicated in patients with rheumatic MR who have a history of systemic embolism, intermittent (paroxysmal) or persistent (chronic) atrial fibrillation, or sinus rhythm with a left atrial diameter greater than 5.5 cm. Since the risk of embolism may be increased in other patients with MR who are in sinus rhythm, a decision about the use of warfarin should also be based on comorbid risk factors, including age and the hemodynamic severity of the lesion.
If recurrent systemic embolism occurs despite adequate anticoagulation, aspirin (75 to 100 mg/day) should be added. For patients unable to take aspirin, alternative therapies are dipyridamole (400 mg/day) or clopidogrel (75 mg per day).
Nonrheumatic MR/mitral annular calcification — Long-term anticoagulation with warfarin (target INR 2.5, range 2.0 to 3.0) is recommended in patients with nonrheumatic MR who have atrial fibrillation or a history of systemic embolism and in patients with mitral annular calcification complicated by systemic embolism.
Mitral valve prolapse — The 2006 ACC/AHA guidelines on the management of valvular heart disease included recommendations for aspirin and warfarin therapy in patients with mitral valve prolapse (show table 8) [1] . When warfarin is given, the target INR is usually 2.5 (range 2.0 to 3.0). (See "Nonarrhythmic complications of mitral valve prolapse").
ENDOCARDITIS PROPHYLAXIS — The 2007 American Heart Association guidelines on infective endocarditis revised prior recommendations for patients with acquired valvular disease, including those with chronic MR [21] . As a result, antibiotic prophylaxis is no longer recommended when such patients undergo dental or other invasive procedures that produce significant bacteremia with organisms associated with endocarditis. (See "Antimicrobial prophylaxis for bacterial endocarditis").
MITRAL VALVE SURGERY — Two issues must be addressed when considering mitral valve surgery in patients with chronic MR: the indications for intervention; and the choice of procedure. These issues are discussed in detail separately but will be briefly reviewed here. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation").
This discussion will be limited to chronic MR due to primary valve disease. The management of functional and ischemic MR are reviewed elsewhere. (See "Functional mitral regurgitation" and see "Ischemic mitral regurgitation").
Indications — Among patients with severe chronic MR, surgery is indicated in patients with symptoms and in asymptomatic patients with abnormalities in LV size or function, pulmonary hypertension, or new onset atrial fibrillation (show figure 1A-1B and show table 9) [1] . Surgery may also be reasonable in asymptomatic patients with preserved left ventricular function if mitral valve repair is performed in experienced centers and it is estimated that the likelihood of successful repair without residual MR is greater than 90 percent.
Asymptomatic patients with severe chronic MR who do not meet criteria for intervention can be safely treated with watchful waiting as long as the patient is carefully monitored [22] . Such patients should be seen every 6 to 12 months or sooner if symptoms occur. Repeat transthoracic echocardiography should be obtained at these visits. The six month interval is preferred if stability has not been documented, there is evidence of progression, or measurements are close to the echocardiographic cutoff values for mitral valve surgery (show table 3). (See "Serial monitoring" above).
Surgery may be offered early in patients with borderline values for LV size or function in whom access to such monitoring is limited. On the other hand, a somewhat higher threshold for surgery is used if valve replacement is required. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Outcomes with watchful waiting).
Mitral valve replacement versus repair — Two surgical procedures confined to the mitral valve itself are available for the treatment of chronic MR: valve repair and valve replacement. The choice of procedure depends, at least in part, upon the cause of the MR, the anatomy of the mitral valve, and the degree of left ventricular dysfunction.
In most patients, mitral valve repair at experienced surgical centers is the preferred approach because of both functional and survival benefits compared to valve replacement (show figure 2). (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Valve repair versus valve replacement).
When required, mitral valve replacement can be performed with a mechanical or bioprosthetic valve. Mechanical valves have the disadvantage of requiring lifelong warfarin therapy, while bioprosthetic valves have the disadvantage of limited durability due to valve degeneration, particularly in patients under age 65. (See "Complications of prosthetic heart valves").
When valve replacement is necessary, the following recommendations for the selection of a bioprosthetic or mechanical mitral valve were made by the 2006 ACC/AHA guidelines when valve replacement (show table 10) [1] :
• Bioprosthetic valves are recommended in patients who cannot or will not take warfarin or have a clear contraindication to warfarin therapy.
• Among patients who can take warfarin, the weight of evidence supports the following approach:
- A mechanical valve in patients under age 65 who have long-standing AF.
- A bioprosthetic valve in patients ≥65 years of age.
Among patients under age 65 who are in sinus rhythm, patient preference plays a central role in the choice of valve. The guidelines suggested that a bioprosthetic valve should only be considered after a detailed discussion with the patient of the risks of warfarin therapy compared to the likelihood of repeat valve replacement in the future.
Concurrent coronary disease — Many patients with nonischemic chronic MR requiring surgery also have significant coronary artery disease. Obstructive coronary lesions are usually revascularized at the time of mitral valve surgery, since concurrent bypass surgery typically adds little morbidity or mortality to the procedure [1] . A separate issue, which is discussed elsewhere, is the management of ischemic mitral regurgitation. (See "Ischemic mitral regurgitation").
Assuming that the patient is not severely hemodynamically unstable, coronary angiography was recommended by the ACC/AHA guidelines in patients who have or are suspected to have coronary disease (and who may have ischemic MR) and in those at risk for coronary disease (show table 11) [1] . At risk was defined as men ≥35 years of age, women ≥35 years of age with coronary risk factors, and postmenopausal women. A higher age threshold of ≥45 years was recommended in patients without ischemic symptoms or coronary risk factors in whom MR is due to mitral valve prolapse because of a very low rate of significant coronary disease in younger patients with mitral valve prolapse. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Predicting coronary disease).
Exercise after valve repair — The effect of exercise in patients with repaired mitral valves has not been well studied. The 36th Bethesda conference cited above recommended that such patients should not participate in sports that are associated with a risk of bodily contact or trauma that might disrupt the repair [13] . They can participate in low-intensity competitive sports (class IA) and selected patients can participate in low and moderate static and low and moderate dynamic competitive sports (class IA, IB, and IIA) (show table 7).
Sunday, August 31, 2008
Antimicrobial therapy of prosthetic valve endocarditis
Antimicrobial therapy of prosthetic valve endocarditis
Author
Adolf W Karchmer, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 16.2: May 2008 | This topic last updated: May 12, 2008 (More)
INTRODUCTION — Infection of a prosthetic heart valve can be difficult to diagnose and manage. Optimal treatment of prosthetic valve endocarditis (PVE) requires:
• Identification of the causative microorganism.
• Selection of a bactericidal antimicrobial regimen of proven efficacy.
• A clear understanding of the intracardiac pathology and attendant complications of PVE.
• Surgical intervention, especially when infection has extended beyond the valve to contiguous cardiac tissue.
The antimicrobial therapy of prosthetic valve endocarditis will be reviewed here. The pathogenesis, microbiology, pathology, clinical features, diagnosis, prevention, and surgical management of PVE are discussed separately. (See "Presentation and diagnosis of prosthetic valve endocarditis" and see "Surgery for prosthetic valve endocarditis").
GENERAL PRINCIPLES — Treatment of PVE with antimicrobial agents alone frequently fails, and invasive infection with subsequent valve dysfunction often arises before or during therapy. Thus, all treatment for PVE should be initiated in the hospital, preferably in an institution where cardiac surgery is available. Patients should remain hospitalized until fever resolves and it is clear that surgery can be safely avoided.
It is essential to isolate the causative organism in patients with suspected PVE. For patients who are hemodynamically stable with an indolent clinical course, antibiotic therapy should be delayed pending the blood culture results. This delay allows additional blood cultures to be obtained without the confounding effect of antibiotics, which is particularly important for patients who have received recent antimicrobial agents and whose initial blood cultures may be negative.
However, patients presenting with hemodynamic instability or acute disease should receive empiric antibiotics promptly after three sets of blood cultures have been obtained. Empiric antibiotic therapy with three agents should be initiated: vancomycin, gentamicin, and either cefepime or a carbapenem. Subsequent therapy should be adjusted based on culture results; if cultures remain negative, therapy as outlined for culture negative PVE should be used (See "Culture-negative" below).
Antimicrobial treatment regimens for PVE are based upon clinical experience. The antimicrobials used to treat a specific pathogen causing PVE are generally the treatment used for that organism when it causes native valve endocarditis (NVE). Staphylococci, which commonly cause PVE, are an exception to this dictum. (See "Antimicrobial therapy of native valve endocarditis").
No randomized controlled studies have evaluated the optimal duration of therapy for PVE. Treatment guidelines from the American Heart Association (AHA) and the European Society for Cardiology (ESC) recommend that PVE should be treated with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks [1-3] . We generally agree with these guidelines and recommend a minimum of six weeks of treatment.
There are small differences, described under each specific microorganism below, in recommended guidelines between the AHA and the ESC [1-3] . We are in general agreement with these guidelines.
STAPHYLOCOCCI — Treatment choices for staphylococcal PVE are not contingent on whether the pathogen is coagulase-negative or S. aureus, unlike most other types of staphylococcal infections [4,5] (show table 1). The primary consideration in choosing therapy hinges upon whether or not the organism is sensitive to methicillin and other beta-lactam antibiotics. In addition, PVE caused by S. aureus frequently requires prompt surgical intervention. (See "Surgery for prosthetic valve endocarditis" section on "Microorganisms usually requiring surgery").
Antimicrobial treatment of staphylococcal PVE requires combination therapy. We agree with the AHA and ESC who recommend a triple drug regimen, as described below.
Evidence to support a triple-drug regimen (with one drug being rifampin) comes from animal models of prosthetic device infection and retrospective clinical series [6-10] . A retrospective study of valve cultures from 61 patients with staphylococcal PVE treated surgically found that valves from patients receiving combination therapy were 5.9 times more likely to be culture-negative than those receiving monotherapy when results were adjusted for duration of therapy before surgery [6] . Although the numbers are too small to analyze, all six patients who received a triple-drug regimen that included rifampin, had negative valve cultures at surgery.
Methicillin susceptibility — Vancomycin is the critical drug for isolates resistant to methicillin, while a semisynthetic penicillinase-resistant penicillin (nafcillin, oxacillin) is the mainstay of therapy for isolates susceptible to methicillin. In patients with penicillin allergy that does not involve anaphylaxis, swelling, or hives, the AHA recommends that a first generation cephalosporin can substitute for nafcillin or oxacillin. We agree with this recommendation.
If the organism is susceptible to gentamicin by routine testing, this should be the second agent, with rifampin as the third agent. (See "Rifampin" below). The aminoglycoside should be administered for the initial two weeks of treatment, after which it can be discontinued and the other two agents continued for at least four additional weeks. If the organism is resistant to gentamicin, an alternative aminoglycoside should be sought based upon antibiotic susceptibilities.
If the isolate is resistant to all available aminoglycosides, a fluoroquinolone to which the strain is highly susceptible should be used [11-13] . If a fluoroquinolone is used in lieu of an aminoglycoside, we prefer to continue the three-drug regimen for the entire course of treatment. When the isolate is resistant to all aminoglycosides and fluoroquinolones, daptomycin [14] , linezolid [15] , or trimethoprim-sulfamethoxazole could be considered as a third drug for the initial two weeks of therapy. If breakthrough bacteremia or microbiologic failure occurs in patients receiving daptomycin, the isolate recovered from the breakthrough bacteremia should be tested for the development of daptomycin resistance [16] .
Optimal therapy of PVE caused by methicillin-resistant S. aureus with reduced vancomycin susceptibility, has not been established. Although linezolid and daptomycin are often active against these organisms, clinical experience in the treatment of PVE is limited [14,17] .
Rifampin — Rifampin appears to have the unique ability to kill staphylococci that are adherent to foreign material, based upon in vitro data, evidence from animal model experiments, and clinical observations [4,8-13,18] . This drug is an essential component of regimens used to treat staphylococcal PVE. However, bacterial cells have a relatively high intrinsic mutation rate for the gene controlling the rifampin site of action. These mutations allow the selection of a rifampin-resistant subpopulation when large numbers of staphylococci are exposed to ineffective rifampin-containing regimens [4,11] .
To protect against the emergence of resistance, the recommended regimens for staphylococcal PVE (see "Staphylococci" above) ideally contain two additional antimicrobials, which should be identified prior to the initiation of rifampin, if at all possible. Thus, a regimen with two other drugs to which the staphylococci are susceptible should be in place at the time rifampin is begun. If the isolate is not sensitive to two additional antimicrobials, therapy with a single antistaphylococcal agent should be administered for three to five days before beginning rifampin. This strategy may reduce the total number of staphylococci at the site of infection and thus diminish the probability that a rifampin-resistant subpopulation will emerge. Nevertheless, susceptibility to rifampin should be reassessed when regimens containing rifampin fail [8] .
STREPTOCOCCI — Combination therapy with a beta-lactam antibiotic and an aminoglycoside (if the isolate is susceptible) is the preferred regimen for streptococcal endocarditis due to synergistic killing of the organism when two antibiotics are used in combination [19] .
Based on in vitro studies, clinical series, and experience of experts, penicillin plus gentamicin is recommended for the therapy of PVE caused by penicillin-susceptible streptococci (minimum inhibitory concentration [MIC] <0.12 mcg/mL) (show table 2) [5,20] . Gentamicin, if the isolate does not exhibit high level resistance (see "Enterococci" below), should be given only during the initial two weeks of treatment. Streptomycin, if the isolate does not possess high level resistance, may be given in lieu of gentamicin to achieve the same effect, but gentamicin is more commonly used in clinical practice due to the wider availability of gentamicin serum levels, and because dosing regimens for gentamicin are more familiar to most clinicians than for streptomycin [21,22] . For these reasons, we recommend gentamicin if the isolate is susceptible. Penicillin, a cephalosporin, or vancomycin can be used alone if aminoglycoside therapy is relatively contraindicated [4] .
If the streptococcus is relatively resistant to penicillin (MIC ≥0.12 mcg/mL), the AHA recommends that the aminoglycoside should be continued for the entire four to six weeks of therapy, if not precluded by nephrotoxicity (show table 3). We agree with the AHA that the aminoglycoside be continued for the duration of treatment. In contrast, the ESC recommends that the aminoglycoside only be given during the initial two weeks of treatment even when the isolate is relatively resistant to penicillin. Although the AHA recommends that gentamicin be dosed once daily, we, as well as the ESC, advocate three equally divided doses.
Among patients who are allergic to penicillin, vancomycin is advised for those with immediate type reactions (urticaria or anaphylaxis). Cefotaxime or ceftriaxone may be used in non-immediate allergies. (See "Penicillin and related antibiotic allergy; skin testing; and desensitization" section on "Cephalosporins").
ENTEROCOCCI — To achieve bactericidal activity against enterococci requires the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin) [19] . (See "Antimicrobial therapy of native valve endocarditis"). To achieve this interaction the organism must not be resistant to the cell wall active agent at achievable serum concentrations and must not be resistant to gentamicin at 500 mcg/mL or streptomycin at 1000 mcg/mL in broth or at 2000 mcg/mL when using cultures on agar. Growth in the presence of the aminoglycoside at these concentrations indicates high-level resistance and precludes synergy when the aminoglycoside is used. Resistance to gentamicin at this concentration also indicates that synergy cannot be achieved with netilmicin, tobramycin, amikacin, or kanamycin. High-level resistance to gentamicin and streptomycin are mediated by two independently acquired genes; hence, organisms should be tested for high-level resistance to each of these drugs.
Based on in vitro studies, animal models, and clinical series [23] , we, along with the AHA and ESC recommend combination therapy with a cell wall active agent (penicillin, ampicillin, or vancomycin) plus an aminoglycoside (usually gentamicin or streptomycin) for treatment of PVE caused by enterococci (as long as the strain is confirmed to be susceptible).
Cephalosporins are not usually active against enterococci and also do not interact with aminoglycosides to result in bactericidal synergy. The cephalosporins should not be used alone as the cell wall active agent in the treatment of enterococcal PVE. In past years, the regimens outlined for treatment of enterococcal PVE in the following tables had been predictably bactericidal (show table 4 and show table 5) [23] . However, antibiotic resistance among enterococci has become significantly more common, necessitating that each strain causing endocarditis be carefully tested in order to select a synergistic regimen [24,25] .
Penicillin/ampicillin resistance will most commonly be due to alterations in penicillin-binding proteins. In that situation, vancomycin is the cell-active agent of choice. Occasionally, E. faecalis may be resistant to penicillin and ampicillin by virtue of beta-lactamase production. In this instance vancomycin or ampicillin-sulbactam could be used. (See "Mechanisms of antibiotic resistance in enterococci").
If the enterococcus has high-level resistance to both streptomycin and gentamicin, synergy is not feasible and an aminoglycoside should not be administered. When resistance precludes bactericidal therapy, a prolonged course of 8 to 12 weeks of one of the cell wall active agents should be administered instead, but therapy in patients with native valve endocarditis has only a 40 percent chance of being successful [26] .
Although the data are limited, in the setting of progressive nephrotoxicity, the duration of aminoglycoside administration may be reduced to less than six weeks with no decrease in cure rates. This was illustrated in a prospective study from Sweden of 93 episodes of enterococcal endocarditis that included 27 cases of prosthetic valve endocarditis [27] . Clinical cure was achieved in 75 of 93 episodes (81 percent) overall, and in 21 of 27 (78 percent) with PVE. In patients who achieved clinical cure, a cell wall-active antimicrobial therapy was given for a median of 42 days, and a synergistic aminoglycoside was added for a median of 15 days.
Optimal therapy of PVE caused by vancomycin-resistant E. faecium (VRE) organisms, which often are also resistant to penicillin and ampicillin, and highly resistant to gentamicin and streptomycin, has not been established. VRE are occasionally susceptible to penicillin and ampicillin and may not have high-level resistance to streptomycin and gentamicin. A full evaluation of the isolates resistance profile is required to select optimal therapy.
Although quinupristin-dalfopristin (E. faecium only) and linezolid (E. faecium and E. faecalis) are often active against these organisms, their effectiveness in the treatment of PVE caused by VRE is not known [28] . The following table outlines possible regimens for PVE caused by VRE (show table 6). Surgical intervention during suppressive bacteriostatic therapy should be strongly considered when PVE is caused by highly resistant enterococci. (See "Treatment options for infections caused by vancomycin-resistant enterococci — Human studies").
HACEK — Because some of these organisms are ampicillin-resistant due to the production of beta-lactamase, and all are highly susceptible to third generation cephalosporins, we, along with the AHA recommend therapy for HACEK PVE with one of the following antibiotics: ceftriaxone, cefotaxime, or a comparable third generation cephalosporin; ampicillin-sulbactam; or ciprofloxacin (recommended only for patients unable to tolerate cephalosporin or ampicillin therapy), administered for six weeks (show table 7). The ESC recommends ampicillin (if the organism is susceptible) or a third generation cephalosporin. Patients with HACEK PVE, who do not have valvular dysfunction, generally can be cured with antibiotics alone [29] .
CORYNEBACTERIA (DIPHTHEROIDS) — If the strain is susceptible to gentamicin (MIC <4.0 mcg/mL), penicillin plus gentamicin will result in synergistic bactericidal activity and is recommended as therapy. Gentamicin resistance precludes bactericidal synergy [30] . Vancomycin is bactericidal against diphtheroids and is recommended for therapy when strains are resistant to gentamicin or when patients are allergic to penicillin.
GRAM-NEGATIVE BACILLI — We recommend treatment of PVE caused by gram-negative bacilli be based upon the susceptibility of the causative organism. Where possible, a synergistic bactericidal regimen should be used. Treatment for Pseudomonas aeruginosa is based upon experience in patients with NVE. If the organism is susceptible, high dose tobramycin (8 mg/kg per day in three equally divided doses IV or IM to achieve peak concentrations approaching 15 mcg/mL) plus ticarcillin, piperacillin, cefepime, or ceftazidime is recommended. (See "Antimicrobial therapy of native valve endocarditis").
Surgery to excise the infected valve is often required in gram-negative bacillus endocarditis, especially that caused by P. aeruginosa or when infection involves the left-sided heart valves. (See "Surgery for prosthetic valve endocarditis").
FUNGI — No randomized, controlled studies have evaluated the optimal therapy for fungal PVE. We, along with most infectious disease specialists, recommend a combined approach that utilizes both antifungal agents and valve replacement [31] . Amphotericin B (daily doses ranging from 0.7 to 1.0 mg/kg per day) is the antimicrobial of choice for treatment of fungal PVE as the greatest clinical experience in treating fungal PVE is with this agent.
For the treatment of endocarditis caused by mycelial fungi, such as Aspergillus or Mucor species, somewhat larger doses are used (1.0 to 1.5 mg/kg per day). We recommend for the treatment of fungal endocarditis, amphotericin B be combined with flucytosine (150 mg/kg per day divided into four doses with adjustments for renal dysfunction) in an attempt to achieve a synergistic effect. This initial phase of treatment is usually given for at least six weeks. (See "Clinical use of flucytosine").
The use of a lipid formulation of amphotericin B in lieu of amphotericin B desoxycholate for the treatment of fungal endocarditis has not been evaluated. Nevertheless, if renal dysfunction complicates amphotericin B treatment, substitution of a lipid formulation is justified.
Early surgical intervention is considered by most experts to be a standard element of treatment for fungal PVE. (See "Surgery for prosthetic valve endocarditis" section on "Microorganisms usually requiring surgery").
Since the potential for relapse is high in Candida PVE, even with surgical intervention, we along with most infectious disease specialists recommend a suppressive second phase of oral therapy with fluconazole (200 to 400 mg daily or another triazole) for prolonged periods, if not indefinitely [32-34] . (See "Candida endocarditis").
Successful treatment of Candida PVE without surgery has been reported in a few case reports using a combination regimen of fluconazole and caspofungin or fluconazole and amphotericin B [35,36] .
CULTURE-NEGATIVE — Many native and prosthetic valve endocarditis patients with negative blood cultures have been rendered culture-negative by virtue of prior antibiotic therapy. The therapy to which they have been exposed is a clue and consideration in selecting empiric treatment. (See "Culture-negative endocarditis").
In the absence of clinical clues to a specific etiology, we along with the AHA recommend that treatment for culture-negative PVE, with onset within the first year following valve surgery, should include vancomycin, gentamicin, cefepime, and rifampin [1] . For patients with the onset of disease 12 months or more after valve implantation, the AHA and we recommend treatment with ceftriaxone, gentamicin, and doxycycline [1] . Aggressive efforts must be made to identify a causative agent. (See "Diagnostic approach to infective endocarditis" section on "Culture-negative IE"). Epidemiologic considerations should be weighed carefully. As an example, in some regions of the world Coxiella burnetii is a common cause of culture-negative PVE. The possibility of fungal endocarditis should be considered, especially in patients with a complex perioperative course. If unexplained fever persists in the face of empiric therapy, surgery to obtain a vegetation for microbiologic evaluation should be considered [4,20] . (See "Q fever endocarditis").
SUMMARY AND RECOMMENDATIONS
• Treatment of prosthetic valve endocarditis is more difficult than treatment of native valve endocarditis and may require surgical replacement of the prostheses in addition to antibiotic therapy. (See "Introduction" above).
• The antimicrobial regimens used are targeted to a specific pathogen, thus identification of the causative organism is critical. (See "Introduction" above and see "Diagnostic approach to infective endocarditis").
• We recommend the same treatment regimens for a specific pathogen causing PVE as is used for that organism when it causes native valve endocarditis (Grade 1B). An exception is staphylococcal endocarditis; we recommend treatment with three agents for this microorganism. (Grade 1B). (See "General principles" above and see "Staphylococci" above).
• We recommend treatment of PVE with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks (Grade 1C). (See "General principles" above).
• Treatment choices for staphylococcal PVE are the same regardless of whether the pathogen is coagulase-negative staphylococci or S. aureus. The primary consideration in choosing therapy hinges upon whether or not the organism is sensitive to methicillin and other beta-lactam antibiotics. (See "Staphylococci" above).
• We recommend a treatment regimen for enterococcal PVE that includes the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin). (Grade 1B). (See "Enterococci" above).
Author
Adolf W Karchmer, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 16.2: May 2008 | This topic last updated: May 12, 2008 (More)
INTRODUCTION — Infection of a prosthetic heart valve can be difficult to diagnose and manage. Optimal treatment of prosthetic valve endocarditis (PVE) requires:
• Identification of the causative microorganism.
• Selection of a bactericidal antimicrobial regimen of proven efficacy.
• A clear understanding of the intracardiac pathology and attendant complications of PVE.
• Surgical intervention, especially when infection has extended beyond the valve to contiguous cardiac tissue.
The antimicrobial therapy of prosthetic valve endocarditis will be reviewed here. The pathogenesis, microbiology, pathology, clinical features, diagnosis, prevention, and surgical management of PVE are discussed separately. (See "Presentation and diagnosis of prosthetic valve endocarditis" and see "Surgery for prosthetic valve endocarditis").
GENERAL PRINCIPLES — Treatment of PVE with antimicrobial agents alone frequently fails, and invasive infection with subsequent valve dysfunction often arises before or during therapy. Thus, all treatment for PVE should be initiated in the hospital, preferably in an institution where cardiac surgery is available. Patients should remain hospitalized until fever resolves and it is clear that surgery can be safely avoided.
It is essential to isolate the causative organism in patients with suspected PVE. For patients who are hemodynamically stable with an indolent clinical course, antibiotic therapy should be delayed pending the blood culture results. This delay allows additional blood cultures to be obtained without the confounding effect of antibiotics, which is particularly important for patients who have received recent antimicrobial agents and whose initial blood cultures may be negative.
However, patients presenting with hemodynamic instability or acute disease should receive empiric antibiotics promptly after three sets of blood cultures have been obtained. Empiric antibiotic therapy with three agents should be initiated: vancomycin, gentamicin, and either cefepime or a carbapenem. Subsequent therapy should be adjusted based on culture results; if cultures remain negative, therapy as outlined for culture negative PVE should be used (See "Culture-negative" below).
Antimicrobial treatment regimens for PVE are based upon clinical experience. The antimicrobials used to treat a specific pathogen causing PVE are generally the treatment used for that organism when it causes native valve endocarditis (NVE). Staphylococci, which commonly cause PVE, are an exception to this dictum. (See "Antimicrobial therapy of native valve endocarditis").
No randomized controlled studies have evaluated the optimal duration of therapy for PVE. Treatment guidelines from the American Heart Association (AHA) and the European Society for Cardiology (ESC) recommend that PVE should be treated with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks [1-3] . We generally agree with these guidelines and recommend a minimum of six weeks of treatment.
There are small differences, described under each specific microorganism below, in recommended guidelines between the AHA and the ESC [1-3] . We are in general agreement with these guidelines.
STAPHYLOCOCCI — Treatment choices for staphylococcal PVE are not contingent on whether the pathogen is coagulase-negative or S. aureus, unlike most other types of staphylococcal infections [4,5] (show table 1). The primary consideration in choosing therapy hinges upon whether or not the organism is sensitive to methicillin and other beta-lactam antibiotics. In addition, PVE caused by S. aureus frequently requires prompt surgical intervention. (See "Surgery for prosthetic valve endocarditis" section on "Microorganisms usually requiring surgery").
Antimicrobial treatment of staphylococcal PVE requires combination therapy. We agree with the AHA and ESC who recommend a triple drug regimen, as described below.
Evidence to support a triple-drug regimen (with one drug being rifampin) comes from animal models of prosthetic device infection and retrospective clinical series [6-10] . A retrospective study of valve cultures from 61 patients with staphylococcal PVE treated surgically found that valves from patients receiving combination therapy were 5.9 times more likely to be culture-negative than those receiving monotherapy when results were adjusted for duration of therapy before surgery [6] . Although the numbers are too small to analyze, all six patients who received a triple-drug regimen that included rifampin, had negative valve cultures at surgery.
Methicillin susceptibility — Vancomycin is the critical drug for isolates resistant to methicillin, while a semisynthetic penicillinase-resistant penicillin (nafcillin, oxacillin) is the mainstay of therapy for isolates susceptible to methicillin. In patients with penicillin allergy that does not involve anaphylaxis, swelling, or hives, the AHA recommends that a first generation cephalosporin can substitute for nafcillin or oxacillin. We agree with this recommendation.
If the organism is susceptible to gentamicin by routine testing, this should be the second agent, with rifampin as the third agent. (See "Rifampin" below). The aminoglycoside should be administered for the initial two weeks of treatment, after which it can be discontinued and the other two agents continued for at least four additional weeks. If the organism is resistant to gentamicin, an alternative aminoglycoside should be sought based upon antibiotic susceptibilities.
If the isolate is resistant to all available aminoglycosides, a fluoroquinolone to which the strain is highly susceptible should be used [11-13] . If a fluoroquinolone is used in lieu of an aminoglycoside, we prefer to continue the three-drug regimen for the entire course of treatment. When the isolate is resistant to all aminoglycosides and fluoroquinolones, daptomycin [14] , linezolid [15] , or trimethoprim-sulfamethoxazole could be considered as a third drug for the initial two weeks of therapy. If breakthrough bacteremia or microbiologic failure occurs in patients receiving daptomycin, the isolate recovered from the breakthrough bacteremia should be tested for the development of daptomycin resistance [16] .
Optimal therapy of PVE caused by methicillin-resistant S. aureus with reduced vancomycin susceptibility, has not been established. Although linezolid and daptomycin are often active against these organisms, clinical experience in the treatment of PVE is limited [14,17] .
Rifampin — Rifampin appears to have the unique ability to kill staphylococci that are adherent to foreign material, based upon in vitro data, evidence from animal model experiments, and clinical observations [4,8-13,18] . This drug is an essential component of regimens used to treat staphylococcal PVE. However, bacterial cells have a relatively high intrinsic mutation rate for the gene controlling the rifampin site of action. These mutations allow the selection of a rifampin-resistant subpopulation when large numbers of staphylococci are exposed to ineffective rifampin-containing regimens [4,11] .
To protect against the emergence of resistance, the recommended regimens for staphylococcal PVE (see "Staphylococci" above) ideally contain two additional antimicrobials, which should be identified prior to the initiation of rifampin, if at all possible. Thus, a regimen with two other drugs to which the staphylococci are susceptible should be in place at the time rifampin is begun. If the isolate is not sensitive to two additional antimicrobials, therapy with a single antistaphylococcal agent should be administered for three to five days before beginning rifampin. This strategy may reduce the total number of staphylococci at the site of infection and thus diminish the probability that a rifampin-resistant subpopulation will emerge. Nevertheless, susceptibility to rifampin should be reassessed when regimens containing rifampin fail [8] .
STREPTOCOCCI — Combination therapy with a beta-lactam antibiotic and an aminoglycoside (if the isolate is susceptible) is the preferred regimen for streptococcal endocarditis due to synergistic killing of the organism when two antibiotics are used in combination [19] .
Based on in vitro studies, clinical series, and experience of experts, penicillin plus gentamicin is recommended for the therapy of PVE caused by penicillin-susceptible streptococci (minimum inhibitory concentration [MIC] <0.12 mcg/mL) (show table 2) [5,20] . Gentamicin, if the isolate does not exhibit high level resistance (see "Enterococci" below), should be given only during the initial two weeks of treatment. Streptomycin, if the isolate does not possess high level resistance, may be given in lieu of gentamicin to achieve the same effect, but gentamicin is more commonly used in clinical practice due to the wider availability of gentamicin serum levels, and because dosing regimens for gentamicin are more familiar to most clinicians than for streptomycin [21,22] . For these reasons, we recommend gentamicin if the isolate is susceptible. Penicillin, a cephalosporin, or vancomycin can be used alone if aminoglycoside therapy is relatively contraindicated [4] .
If the streptococcus is relatively resistant to penicillin (MIC ≥0.12 mcg/mL), the AHA recommends that the aminoglycoside should be continued for the entire four to six weeks of therapy, if not precluded by nephrotoxicity (show table 3). We agree with the AHA that the aminoglycoside be continued for the duration of treatment. In contrast, the ESC recommends that the aminoglycoside only be given during the initial two weeks of treatment even when the isolate is relatively resistant to penicillin. Although the AHA recommends that gentamicin be dosed once daily, we, as well as the ESC, advocate three equally divided doses.
Among patients who are allergic to penicillin, vancomycin is advised for those with immediate type reactions (urticaria or anaphylaxis). Cefotaxime or ceftriaxone may be used in non-immediate allergies. (See "Penicillin and related antibiotic allergy; skin testing; and desensitization" section on "Cephalosporins").
ENTEROCOCCI — To achieve bactericidal activity against enterococci requires the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin) [19] . (See "Antimicrobial therapy of native valve endocarditis"). To achieve this interaction the organism must not be resistant to the cell wall active agent at achievable serum concentrations and must not be resistant to gentamicin at 500 mcg/mL or streptomycin at 1000 mcg/mL in broth or at 2000 mcg/mL when using cultures on agar. Growth in the presence of the aminoglycoside at these concentrations indicates high-level resistance and precludes synergy when the aminoglycoside is used. Resistance to gentamicin at this concentration also indicates that synergy cannot be achieved with netilmicin, tobramycin, amikacin, or kanamycin. High-level resistance to gentamicin and streptomycin are mediated by two independently acquired genes; hence, organisms should be tested for high-level resistance to each of these drugs.
Based on in vitro studies, animal models, and clinical series [23] , we, along with the AHA and ESC recommend combination therapy with a cell wall active agent (penicillin, ampicillin, or vancomycin) plus an aminoglycoside (usually gentamicin or streptomycin) for treatment of PVE caused by enterococci (as long as the strain is confirmed to be susceptible).
Cephalosporins are not usually active against enterococci and also do not interact with aminoglycosides to result in bactericidal synergy. The cephalosporins should not be used alone as the cell wall active agent in the treatment of enterococcal PVE. In past years, the regimens outlined for treatment of enterococcal PVE in the following tables had been predictably bactericidal (show table 4 and show table 5) [23] . However, antibiotic resistance among enterococci has become significantly more common, necessitating that each strain causing endocarditis be carefully tested in order to select a synergistic regimen [24,25] .
Penicillin/ampicillin resistance will most commonly be due to alterations in penicillin-binding proteins. In that situation, vancomycin is the cell-active agent of choice. Occasionally, E. faecalis may be resistant to penicillin and ampicillin by virtue of beta-lactamase production. In this instance vancomycin or ampicillin-sulbactam could be used. (See "Mechanisms of antibiotic resistance in enterococci").
If the enterococcus has high-level resistance to both streptomycin and gentamicin, synergy is not feasible and an aminoglycoside should not be administered. When resistance precludes bactericidal therapy, a prolonged course of 8 to 12 weeks of one of the cell wall active agents should be administered instead, but therapy in patients with native valve endocarditis has only a 40 percent chance of being successful [26] .
Although the data are limited, in the setting of progressive nephrotoxicity, the duration of aminoglycoside administration may be reduced to less than six weeks with no decrease in cure rates. This was illustrated in a prospective study from Sweden of 93 episodes of enterococcal endocarditis that included 27 cases of prosthetic valve endocarditis [27] . Clinical cure was achieved in 75 of 93 episodes (81 percent) overall, and in 21 of 27 (78 percent) with PVE. In patients who achieved clinical cure, a cell wall-active antimicrobial therapy was given for a median of 42 days, and a synergistic aminoglycoside was added for a median of 15 days.
Optimal therapy of PVE caused by vancomycin-resistant E. faecium (VRE) organisms, which often are also resistant to penicillin and ampicillin, and highly resistant to gentamicin and streptomycin, has not been established. VRE are occasionally susceptible to penicillin and ampicillin and may not have high-level resistance to streptomycin and gentamicin. A full evaluation of the isolates resistance profile is required to select optimal therapy.
Although quinupristin-dalfopristin (E. faecium only) and linezolid (E. faecium and E. faecalis) are often active against these organisms, their effectiveness in the treatment of PVE caused by VRE is not known [28] . The following table outlines possible regimens for PVE caused by VRE (show table 6). Surgical intervention during suppressive bacteriostatic therapy should be strongly considered when PVE is caused by highly resistant enterococci. (See "Treatment options for infections caused by vancomycin-resistant enterococci — Human studies").
HACEK — Because some of these organisms are ampicillin-resistant due to the production of beta-lactamase, and all are highly susceptible to third generation cephalosporins, we, along with the AHA recommend therapy for HACEK PVE with one of the following antibiotics: ceftriaxone, cefotaxime, or a comparable third generation cephalosporin; ampicillin-sulbactam; or ciprofloxacin (recommended only for patients unable to tolerate cephalosporin or ampicillin therapy), administered for six weeks (show table 7). The ESC recommends ampicillin (if the organism is susceptible) or a third generation cephalosporin. Patients with HACEK PVE, who do not have valvular dysfunction, generally can be cured with antibiotics alone [29] .
CORYNEBACTERIA (DIPHTHEROIDS) — If the strain is susceptible to gentamicin (MIC <4.0 mcg/mL), penicillin plus gentamicin will result in synergistic bactericidal activity and is recommended as therapy. Gentamicin resistance precludes bactericidal synergy [30] . Vancomycin is bactericidal against diphtheroids and is recommended for therapy when strains are resistant to gentamicin or when patients are allergic to penicillin.
GRAM-NEGATIVE BACILLI — We recommend treatment of PVE caused by gram-negative bacilli be based upon the susceptibility of the causative organism. Where possible, a synergistic bactericidal regimen should be used. Treatment for Pseudomonas aeruginosa is based upon experience in patients with NVE. If the organism is susceptible, high dose tobramycin (8 mg/kg per day in three equally divided doses IV or IM to achieve peak concentrations approaching 15 mcg/mL) plus ticarcillin, piperacillin, cefepime, or ceftazidime is recommended. (See "Antimicrobial therapy of native valve endocarditis").
Surgery to excise the infected valve is often required in gram-negative bacillus endocarditis, especially that caused by P. aeruginosa or when infection involves the left-sided heart valves. (See "Surgery for prosthetic valve endocarditis").
FUNGI — No randomized, controlled studies have evaluated the optimal therapy for fungal PVE. We, along with most infectious disease specialists, recommend a combined approach that utilizes both antifungal agents and valve replacement [31] . Amphotericin B (daily doses ranging from 0.7 to 1.0 mg/kg per day) is the antimicrobial of choice for treatment of fungal PVE as the greatest clinical experience in treating fungal PVE is with this agent.
For the treatment of endocarditis caused by mycelial fungi, such as Aspergillus or Mucor species, somewhat larger doses are used (1.0 to 1.5 mg/kg per day). We recommend for the treatment of fungal endocarditis, amphotericin B be combined with flucytosine (150 mg/kg per day divided into four doses with adjustments for renal dysfunction) in an attempt to achieve a synergistic effect. This initial phase of treatment is usually given for at least six weeks. (See "Clinical use of flucytosine").
The use of a lipid formulation of amphotericin B in lieu of amphotericin B desoxycholate for the treatment of fungal endocarditis has not been evaluated. Nevertheless, if renal dysfunction complicates amphotericin B treatment, substitution of a lipid formulation is justified.
Early surgical intervention is considered by most experts to be a standard element of treatment for fungal PVE. (See "Surgery for prosthetic valve endocarditis" section on "Microorganisms usually requiring surgery").
Since the potential for relapse is high in Candida PVE, even with surgical intervention, we along with most infectious disease specialists recommend a suppressive second phase of oral therapy with fluconazole (200 to 400 mg daily or another triazole) for prolonged periods, if not indefinitely [32-34] . (See "Candida endocarditis").
Successful treatment of Candida PVE without surgery has been reported in a few case reports using a combination regimen of fluconazole and caspofungin or fluconazole and amphotericin B [35,36] .
CULTURE-NEGATIVE — Many native and prosthetic valve endocarditis patients with negative blood cultures have been rendered culture-negative by virtue of prior antibiotic therapy. The therapy to which they have been exposed is a clue and consideration in selecting empiric treatment. (See "Culture-negative endocarditis").
In the absence of clinical clues to a specific etiology, we along with the AHA recommend that treatment for culture-negative PVE, with onset within the first year following valve surgery, should include vancomycin, gentamicin, cefepime, and rifampin [1] . For patients with the onset of disease 12 months or more after valve implantation, the AHA and we recommend treatment with ceftriaxone, gentamicin, and doxycycline [1] . Aggressive efforts must be made to identify a causative agent. (See "Diagnostic approach to infective endocarditis" section on "Culture-negative IE"). Epidemiologic considerations should be weighed carefully. As an example, in some regions of the world Coxiella burnetii is a common cause of culture-negative PVE. The possibility of fungal endocarditis should be considered, especially in patients with a complex perioperative course. If unexplained fever persists in the face of empiric therapy, surgery to obtain a vegetation for microbiologic evaluation should be considered [4,20] . (See "Q fever endocarditis").
SUMMARY AND RECOMMENDATIONS
• Treatment of prosthetic valve endocarditis is more difficult than treatment of native valve endocarditis and may require surgical replacement of the prostheses in addition to antibiotic therapy. (See "Introduction" above).
• The antimicrobial regimens used are targeted to a specific pathogen, thus identification of the causative organism is critical. (See "Introduction" above and see "Diagnostic approach to infective endocarditis").
• We recommend the same treatment regimens for a specific pathogen causing PVE as is used for that organism when it causes native valve endocarditis (Grade 1B). An exception is staphylococcal endocarditis; we recommend treatment with three agents for this microorganism. (Grade 1B). (See "General principles" above and see "Staphylococci" above).
• We recommend treatment of PVE with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks (Grade 1C). (See "General principles" above).
• Treatment choices for staphylococcal PVE are the same regardless of whether the pathogen is coagulase-negative staphylococci or S. aureus. The primary consideration in choosing therapy hinges upon whether or not the organism is sensitive to methicillin and other beta-lactam antibiotics. (See "Staphylococci" above).
• We recommend a treatment regimen for enterococcal PVE that includes the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin). (Grade 1B). (See "Enterococci" above).
Complications and outcome of infective endocarditis
http://www.uptodateonline.com/online/content/topic.do?topicKey=endocard/5997&selectedTitle=36~150&source=search_result
Complications and outcome of infective endocarditis
Author
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Daniel J Sexton, MD
Section Editor
Stephen B Calderwood, MD
Gabriel S Aldea, MD
Scott E Kasner, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Susan B Yeon, MD, JD, FACC
Last literature review version 16.2: May 2008 | This topic last updated: May 19, 2008 (More)
INTRODUCTION — Infective endocarditis (IE) is associated with a myriad of complications, one or more of which occur in the majority of patients. This was illustrated in a review of 223 episodes of IE in which 57 percent of patients had one complication, 26 percent two, 8 percent three or more, and 6 percent six or more complications [1] . Complications such as heart failure and stroke are relatively common and feared outcomes of IE, while other complications such as blindness and septic arthritis are, fortunately, rare in modern practice.
The frequency and type of complications due to IE has changed with advances in diagnosis and therapy. Renal failure and uncontrolled intracardiac or metastatic infection, for example, which were previously common complications of IE, are infrequent in the antibiotic era. The frequency of specific complications depends upon variables such as the infecting pathogen, duration of illness prior to therapy, and the type of treatment facility (eg, referral versus community hospital). It is often difficult to assess the true incidence of complications despite extensive literature on the subject because different reviews and case series were generally based upon retrospective chart reviews and used different diagnostic criteria to define cases of IE. (See "Infective endocarditis: Historical and Duke criteria").
The major complications of IE will be reviewed here but will only attempt to describe the frequency of these complications as relatively common, rare, or very rare because accurate numbers are not available. Complications can occur before, during and, rarely, even after the end of therapy (eg, ruptured mycotic aneurysm).
DEFINITIONS — Complications of IE can be broadly categorized as:
• Cardiac
• Septic
• Embolic
• Neurologic
• Musculoskeletal
• Renal
• Associated with medical treatment
While these categories are broad and organize the complications in an understandable fashion, they do not take into account significant overlapping features. As an example, patients with neurologic involvement can simultaneously have embolic and septic processes.
One can also consider complications in terms of their pathogenesis, which leads to different groupings:
• Embolic (eg, cerebral infarct)
• Local spread of infection (eg, heart valve destruction)
• Metastatic infection (eg, vertebral osteomyelitis)
• Immune-mediated damage (eg, glomerulonephritis)
CARDIAC COMPLICATIONS — Cardiac complications are the most common complications seen in IE, occurring in one-third to one-half of patients in most recent case series [2] .
Heart failure — Heart failure (HF) remains the most common cause of death due to IE in the modern era and is the most frequent reason for cardiac surgery in patients with IE. (See "Surgery for native valve endocarditis").
The usual cause of HF in patients with IE is valvular insufficiency resulting from infection-induced valvular damage. Rarely, embolism of fragments of valvular vegetations or vegetation-induced stenosis of the coronary ostia can cause acute myocardial infarction and subsequent HF [2] .
Perivalvular abscesses — Among patients with IE, the reported incidence of perivalvular abscess at surgery or autopsy has ranged from about 30 to 40 percent [3-5] . The aortic valve and its adjacent annulus are more susceptible to abscess formation and the complications of perivalvular extension of infection than are the mitral valve and ring [3-5] . This was illustrated in an autopsy study of patients with native valve endocarditis: annular extension of infection was far more common in patients with aortic valve compared to mitral valve endocarditis (41 versus 6 percent) [3] .
Injection drug use may be another risk factor for perivalvular abscess [4] . In contrast, although large vegetation size had been implicated as a risk factor in some series, subsequent studies have shown no correlation between the presence or size of the vegetation and the development of periannular extension [4,6] .
Paravalvular abscesses can extend into adjacent cardiac conduction tissues, possibly leading to various forms of heart block. Involvement of the conducting system is most common with infection of the aortic valve, especially when there is involvement of the valve ring between the right and non-coronary cusp (this anatomic site overlies the intraventricular septum that contains the proximal ventricular conduction system).
Paravalvular abscess should be suspected when fever persists despite appropriate antimicrobial therapy and/or when conduction abnormalities appear on the ECG [7] . Transesophageal echocardiography (TEE) has a much greater likelihood of detecting a myocardial abscess than transthoracic echocardiography (TTE). One study, for example, evaluated 118 patients with IE, 37 percent of whom had an abscess documented at surgery or autopsy [5] . The sensitivity, specificity, and positive and negative predictive values of TEE imaging were 87, 95, 91, and 92 percent, respectively; the sensitivity of TTE was much lower (28 versus 87 percent) although the specificity was 99 percent. However, some perivalvular abscesses may be missed by TEE. (See "Role of echocardiography in infective endocarditis", section on Perivalvular abscess or fistula).
Patients with perivalvular abscesses appear to have higher rates of systemic embolization and fatal outcomes. In one study comparing outcomes of patients with and without perivalvular abscesses, the rate of embolization was approximately twice as high (64 versus 30 percent) [4] . These patients also have a higher mortality rate (23 versus 14 percent in those without abscesses in a report of 118 patients, 44 of whom had a perivalvular abscess) [5] . Mortality may be particularly high in patients with at least moderate valvular regurgitation [8] .
Other extravalvular complications — Other rare extravalvular cardiac complications of IE include:
• Pericarditis, which may be suppurative or nonsuppurative, can rarely cause pain or even cardiac tamponade [9,10] . (See "Purulent pericarditis" and see "Evaluation and management of acute pericarditis").
• Fistulous intracardiac connections (eg, aorta-atrial or aorta-ventricular) due to extension of infection from the valve to adjacent myocardium may rarely result in large aneurysms, a pseudoaneurysm if the aortic wall is involved [11] , or even myocardial perforation.
The incidence of fistulous intracardiac complications was 1.6 percent in a retrospective, multicenter study of 4681 episodes of IE [12] . Surgery was performed in 66 of the 76 patients with a mortality of 41 percent. Multivariate analysis identified heart failure (odds ratio [OR] 4.3), prosthetic IE (OR 4.6), and urgent or emergent surgical treatment (OR 4.3) as being significantly associated with an increased risk of death.
• Aortic valve dissection [13] .
• Descending thoracic aorta intraluminal infectious masses [14] .
EMBOLIZATION — Embolization remains a distressingly common complication of IE and can occur even after appropriate therapy is well underway. This section will provide a general discussion of embolization in patients with IE. Issues related to embolization in patients with IE who undergo surgery are discussed separately (See "Surgery for native valve endocarditis" section on Embolization, and see "Surgery for prosthetic valve endocarditis" section on Embolization).
Systemic emboli most commonly complicate left-sided IE, but rarely can occur in tricuspid valve endocarditis via a patent foramen ovale [15] . However, emboli to the lung with subsequent abscess formation occur frequently in patients with tricuspid endocarditis. Small, clinically inapparent embolization probably occurs in most, if not all, patients with IE, but clinically recognized embolism has been reported in 13 to 44 percent of patients in published reports [16,17] .
Emboli consisting of vegetation fragments can occlude or damage virtually any blood vessel, large or small, in the systemic or pulmonary arterial circulation. As a result, emboli can produce:
• Stroke
• Blindness
• Painful ischemic or frankly gangrenous extremities
• Unusual pain syndromes (eg, due to splenic or renal infarction)
• Hypoxia (due to pulmonary emboli in right-sided endocarditis)
• Paralysis (due to embolic infarction of either the brain or spinal cord)
Emboli can occasionally cause symptoms or signs that mimic other common conditions such as kidney stones, Bell's palsy, dizziness, or pleurisy.
Endocarditis should be considered as a possible etiology in virtually all patients who present with signs or symptoms of systemic arterial embolization. In one study, cerebral infarction was the presenting sign of IE in 4 to 14 percent of all cases of IE [15] . The vast majority of patients with an acute stroke do not have endocarditis although the occurrence of a stroke in a younger patient or evidence of simultaneous or sequential cerebral and systemic arterial embolization, increase the probability of IE. As an example, in one report of 60 patients with IE and cerebral complications, 28 (47 percent) also had clinically identifiable systemic emboli [18] compared to only 2 percent of all stroke patients in a different large series [19] .
Symptomatic embolization appears to be more common with IE due to fungal pathogens. Whenever emboli to large systemic arterial vessels occur in a patient with IE, the possibility of a fungal etiology should be entertained. In a literature review of 270 patients with fungal endocarditis, peripheral arterial embolization occurred in 45 percent. The most common sites were the cerebral circulation (17 percent) and femoral artery (16 percent) [20] .
Histopathologic or microbiologic examination of occluding embolic material in such large vessels may lead to a diagnosis of an underlying fungal IE. Haemophilus species and other slow growing fastidious gram-negative organisms also seem to predispose to embolization with some frequency. (See "Candida endocarditis").
Effect of antibiotic therapy on embolic risk — The risk of embolization tends to decline after the institution of effective antimicrobial therapy, and serious embolic events rarely occur several weeks after such therapy is instituted [16,21,22] . The relationship between the initiation of antibiotic therapy and the risk of embolism is illustrated by the following observations:
In a series of 629 patients with left sided endocarditis, 131 patients (21 percent) had one or more embolic events [21] . The event occurred before the initiation of antimicrobial therapy in 42 percent, on the day therapy commenced in 14 percent, and within 15 days of initiating therapy in 82 percent.
In a study that used TTE to detect vegetations, the rate of embolization fell from 13 per 1000 patient days during the first week of therapy to less than 1.2 per 1000 patient days after two weeks of therapy [16] .
These findings suggest that surgery may not be necessary for prevention of embolic stroke in the early weeks following initiation of appropriate antibiotic therapy, if there are no other indications for surgery (such as a large mobile vegetation or congestive heart failure due to valvular leak) [22] .
Predictors of embolization — The size of a vegetation as determined by echocardiography has been assessed as a risk factor for embolization in IE. Although some data are conflicting, vegetation size is generally a risk factor for embolization. (See "Role of echocardiography in infective endocarditis", section on Echocardiographic estimation of outcome).
However, the presence or absence of vegetations, the location of the vegetations, the characteristics of vegetations by TEE, the specific etiologic microorganism, or antiphospholipid antibodies may have predictive value [23-29] :
• A multicenter prospective European study of 384 patients with definite IE by Duke criteria found that emboli were more frequently observed in cases due to Streptococcus bovis and S. aureus by multivariate analysis [29] . Multivariate analysis identified vegetation size >10 mm and severe vegetation mobility as additional risk factors for embolic events that occurred in 28 patients after the initiation of antibiotic therapy.
• Embolization occurs more frequently with left-sided than right-sided vegetations [24] . In a review of 281 patients with clinically suspected IE, the incidence of embolic events was greater with mitral than aortic valve vegetations (25 versus 10 percent) [25] . The risk was highest with vegetations on the anterior mitral leaflet (37 percent), suggesting that the mechanical effects of broad and abrupt leaflet excursion may contribute to the risk of embolization [24] .
• A prospective study of patients with IE due to S. aureus suggested that the risk of embolization was significantly greater in patients who had visible vegetations by both TTE and TEE compared to patients who had vegetations visualized only by TEE [26] .
• The absence of valvular abnormalities on TTE may be associated with a decreased incidence of complications [27] .
• The presence of antiphospholipid antibodies were correlated with an increased risk of embolization (62 versus 23 percent) in a series of 91 patients with IE, perhaps due to increased endothelial cell activation, generation of thrombin, and defective fibrinolysis [28] .
Effect of prior antiplatelet therapy — The possible protective effect of prior antiplatelet therapy (one or more of aspirin, dipyridamole, clopidogrel, or ticlopidine) on embolism in IE was evaluated in a retrospective cohort of 600 patients with IE, 147 of whom (25 percent) had a symptomatic embolic event [30] . The patients who had received continuous daily antiplatelet therapy for at least six months prior to hospitalization for IE had a significantly lower rate of a symptomatic embolic event (12 versus 28 percent without such therapy, adjusted odds ratio 0.36, 95% CI 0.19-0.68). The presumed mechanism is that platelet aggregation plays a role in vegetation formation.
In contrast to prior therapy, the initiation of aspirin after the diagnosis of IE is of no benefit and may be harmful. This was illustrated in randomized trial in which 115 patients with IE were assigned to aspirin (325 mg/day) or placebo for four weeks [31] . Aspirin did not reduce the incidence of embolic events, was associated with a trend toward an increased incidence of bleeding (odds ratio 1.92, 95% CI 0.76-4.86), and had no effect on vegetation resolution or valve function.
NEUROLOGIC COMPLICATIONS — Neurologic complications rank second to cardiac in importance, occurring in approximately 25 to 35 percent of patients [15,32-36] , although a lower rate of 10 percent was noted in one series [37] . In a review of 260 nondrug addicts with IE due to Staphylococcus aureus, 91 patients (35 percent) developed neurologic manifestations including 61 (23 percent) who presented with these symptoms [34] . (See "Complications of Staphylococcus aureus bacteremia").
Manifestations — The mechanism for and types of neurologic complications are diverse and include:
• Embolic stroke
• Acute encephalopathy
• Meningoencephalitis
• Purulent or aseptic meningitis
• Cerebral hemorrhage (due to stroke or a ruptured mycotic aneurysm)
• Brain abscess or cerebritis
• Seizures (secondary to abscess or embolic infarction)
Neurologic complications may be the presenting symptom in patients with IE. In a series of 68 patients with stroke and endocarditis, for example, two-thirds presented to the hospital with stroke, before the diagnosis of endocarditis was made [37] . Thus, the possibility of IE should be considered in all patients who present with strokes, meningitis, or a brain abscess. Unexplained fever accompanying a stroke in a patient with valvular disease is an important clue in some patients. (See "Diagnostic approach to infective endocarditis").
Outcomes — Reported patient outcomes after a neurologic complication are variable. The following findings have been noted in different series:
• Among survivors of cardiac surgery for IE, 70 percent of patients with a preoperative stroke experienced a full neurologic recovery [36] . Outcomes were worse in patients with stroke complicated by meningitis, abscess, or intracerebral hemorrhage.
• Patient mortality in more contemporary series has varied from approximately 20 to 50 percent at one year [36,37] to as high as 74 percent (time of follow-up not given) in patients with Staphylococcus aureus endocarditis [34] .
One of the dilemmas that often arises is whether neurologic complications of IE are a contraindication to valve replacement. This important issue is discussed elsewhere. (See "Surgery for native valve endocarditis", section on Effect of recent cerebral embolization).
MYCOTIC ANEURYSMS — Mycotic aneurysms can occur in the cerebral or systemic circulation of patients with IE, usually at points of vessel bifurcation. (See "Mycotic aneurysms").
RENAL DISEASE — Renal infarction (due to emboli), drug-induced acute interstitial nephritis, glomerulonephritis (due to deposition of immunoglobulins and complement in the glomerular membrane) and, rarely, renal abscess can occur in patients with IE. (See "Renal disease in infective endocarditis").
Acute renal failure, defined as a serum creatinine of 2 mg/dL (177 µmol/L) or greater, has been reported in up to one-third of patients [38] . By contrast, chronic renal failure due to immune-complex mediated glomerulonephritis, which was a common contributing cause of death in patients who presented with classic IE in the preantibiotic era, is now rare. Immune complex-mediated renal disease is also uncommon in the antibiotic era, especially in patients whose infection is detected and treated early.
METASTATIC ABSCESSES — Rarely, metastatic abscesses develop in the kidneys, spleen, brain or soft tissues (eg, the psoas muscle) in the setting of IE. There is a strong association between IE and splenic abscess, even though otherwise splenic abscesses are less frequently observed than other types intraabdominal abscesses.
Patients with splenic abscesses usually do not have marked abdominal pain or splenomegaly; persistent fever during or after treatment for IE and occasionally recurrent bacteremia after cure of the valvular infection may be the only clue to the presence of this complication [39] . Splenic abscesses are often diagnosed only at autopsy and generally require splenectomy for cure. In one study of 27 patients with splenic abscesses, mortality was 100 percent in the patients who did not have a splenectomy compared to 18 percent in the patients who had the procedure [40] .
Discrete microabscesses or larger solitary brain abscesses can rarely occur in patients with IE. Abscess formation occurs as a sequela of septic embolization. Some patients with IE and brain abscesses also have purulent meningitis. In fact, the presence of meningitis due to S. aureus should suggest the possibility of concomitant S. aureus endocarditis. In one case series of 33 patients with S. aureus meningitis, seven (21 percent) also had endocarditis [41] .
Appropriate treatment, including drainage of such abscesses, is needed not only to control the local infection but also to prevent ongoing bacteremia, which is of particular concern among patients who may require surgical treatment of endocarditis with implantation of a prosthetic valve.
MUSCULOSKELETAL COMPLICATIONS — Vertebral osteomyelitis is a well known but relatively rare complication of IE. Although the majority of patients with IE and back pain do not have vertebral osteomyelitis, protracted, severe back pain in any patient with IE should alert the clinician to this possibility. Plain films are insensitive for diagnosing vertebral osteomyelitis, especially if taken early in the course of illness [42] . (See "Vertebral osteomyelitis"). Osteomyelitis more frequently complicates S. aureus endocarditis than IE due to other microorganisms [42] .
Acute septic arthritis, involving one or more joints, may be the first clue to the presence of IE in a small percentage of patients. IE should be strongly considered in selected cases of septic arthritis:
• When infections spontaneously arise in joints of the axial skeleton (eg, sacroiliac, pubic, or manubriosternal joints).
• When organisms with a known propensity to cause IE (eg, S. aureus, viridans streptococci or non-group A beta-hemolytic streptococci) grow from a joint aspirate, particularly in patients without a history of recent surgery, joint infection, or trauma.
• When multiple joints are infected.
COMPLICATIONS OF MEDICAL OR SURGICAL THERAPY — Patients with IE can develop a number of the complications associated with prolonged parenteral antimicrobial therapy or surgery:
• Aminoglycoside-induced ototoxicity or nephrotoxicity (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity")
• Secondary bacteremia due to central vascular lines (See "Pathogenesis of and risk factors for central venous catheter-related infections")
• Mediastinitis or early postoperative prosthetic valve endocarditis (See "Postoperative mediastinitis after cardiac surgery")
• Intravenous catheter-associated phlebitis
• Drug fever (See "Drug fever")
• Allergic or idiosyncratic reactions to various antimicrobial agents
• Bleeding due to disturbances in coagulation caused by anticoagulants (in prosthetic valve endocarditis)
MORTALITY — Multiple studies have evaluated death rates in patients with both native and prosthetic valve endocarditis [43-47] :
• The in-hospital mortality rate is between 18 and 23 percent
• The six month mortality rate is between 22 and 27 percent
The outcomes in patients with neurologic complications are described above. (See "Outcomes" above).
Predictors of death — Several studies have attempted to identify predictors of death in patients with IE. Each patient may have one or more of the following:
• Infection with S. aureus [44,46,48] , while mortality is lower with streptococcal infection (8 versus 33 percent with S. aureus in one series) [46]
• Heart failure [45,47]
• Diabetes mellitus [44]
• Embolic events [44,48]
• Perivalvular abscess [5,8,47]
• Vegetation size [29,48]
• Female gender [29]
• Contraindication to surgery [46]
• Low serum albumin [43]
• Persistent bacteremia [47]
• Abnormal mental status [46]
• Poor surgical candidacy [46]
All but two of the preceding studies [44,46] were retrospective. Because the clinical and echocardiographic features of patients with endocarditis change during the course of illness, some of the above findings should be interpreted with caution. In one of the reports using a prospective study design, neither heart failure as defined by the Framingham criteria nor cardiac surgery was independently associated with in-hospital mortality [44] . However, among patients with moderate to severe heart failure, cardiac surgery in other studies has been associated with a lower rate of long-term mortality compared to medical therapy alone. The data supporting this conclusion are presented separately. (See "Surgery for native valve endocarditis", section on Efficacy).
In view of the wide disparity in the methods used in the preceding studies, one should be cautious about making prognostic predictions in individual patients with IE.
Complications and outcome of infective endocarditis
Author
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Daniel J Sexton, MD
Section Editor
Stephen B Calderwood, MD
Gabriel S Aldea, MD
Scott E Kasner, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Susan B Yeon, MD, JD, FACC
Last literature review version 16.2: May 2008 | This topic last updated: May 19, 2008 (More)
INTRODUCTION — Infective endocarditis (IE) is associated with a myriad of complications, one or more of which occur in the majority of patients. This was illustrated in a review of 223 episodes of IE in which 57 percent of patients had one complication, 26 percent two, 8 percent three or more, and 6 percent six or more complications [1] . Complications such as heart failure and stroke are relatively common and feared outcomes of IE, while other complications such as blindness and septic arthritis are, fortunately, rare in modern practice.
The frequency and type of complications due to IE has changed with advances in diagnosis and therapy. Renal failure and uncontrolled intracardiac or metastatic infection, for example, which were previously common complications of IE, are infrequent in the antibiotic era. The frequency of specific complications depends upon variables such as the infecting pathogen, duration of illness prior to therapy, and the type of treatment facility (eg, referral versus community hospital). It is often difficult to assess the true incidence of complications despite extensive literature on the subject because different reviews and case series were generally based upon retrospective chart reviews and used different diagnostic criteria to define cases of IE. (See "Infective endocarditis: Historical and Duke criteria").
The major complications of IE will be reviewed here but will only attempt to describe the frequency of these complications as relatively common, rare, or very rare because accurate numbers are not available. Complications can occur before, during and, rarely, even after the end of therapy (eg, ruptured mycotic aneurysm).
DEFINITIONS — Complications of IE can be broadly categorized as:
• Cardiac
• Septic
• Embolic
• Neurologic
• Musculoskeletal
• Renal
• Associated with medical treatment
While these categories are broad and organize the complications in an understandable fashion, they do not take into account significant overlapping features. As an example, patients with neurologic involvement can simultaneously have embolic and septic processes.
One can also consider complications in terms of their pathogenesis, which leads to different groupings:
• Embolic (eg, cerebral infarct)
• Local spread of infection (eg, heart valve destruction)
• Metastatic infection (eg, vertebral osteomyelitis)
• Immune-mediated damage (eg, glomerulonephritis)
CARDIAC COMPLICATIONS — Cardiac complications are the most common complications seen in IE, occurring in one-third to one-half of patients in most recent case series [2] .
Heart failure — Heart failure (HF) remains the most common cause of death due to IE in the modern era and is the most frequent reason for cardiac surgery in patients with IE. (See "Surgery for native valve endocarditis").
The usual cause of HF in patients with IE is valvular insufficiency resulting from infection-induced valvular damage. Rarely, embolism of fragments of valvular vegetations or vegetation-induced stenosis of the coronary ostia can cause acute myocardial infarction and subsequent HF [2] .
Perivalvular abscesses — Among patients with IE, the reported incidence of perivalvular abscess at surgery or autopsy has ranged from about 30 to 40 percent [3-5] . The aortic valve and its adjacent annulus are more susceptible to abscess formation and the complications of perivalvular extension of infection than are the mitral valve and ring [3-5] . This was illustrated in an autopsy study of patients with native valve endocarditis: annular extension of infection was far more common in patients with aortic valve compared to mitral valve endocarditis (41 versus 6 percent) [3] .
Injection drug use may be another risk factor for perivalvular abscess [4] . In contrast, although large vegetation size had been implicated as a risk factor in some series, subsequent studies have shown no correlation between the presence or size of the vegetation and the development of periannular extension [4,6] .
Paravalvular abscesses can extend into adjacent cardiac conduction tissues, possibly leading to various forms of heart block. Involvement of the conducting system is most common with infection of the aortic valve, especially when there is involvement of the valve ring between the right and non-coronary cusp (this anatomic site overlies the intraventricular septum that contains the proximal ventricular conduction system).
Paravalvular abscess should be suspected when fever persists despite appropriate antimicrobial therapy and/or when conduction abnormalities appear on the ECG [7] . Transesophageal echocardiography (TEE) has a much greater likelihood of detecting a myocardial abscess than transthoracic echocardiography (TTE). One study, for example, evaluated 118 patients with IE, 37 percent of whom had an abscess documented at surgery or autopsy [5] . The sensitivity, specificity, and positive and negative predictive values of TEE imaging were 87, 95, 91, and 92 percent, respectively; the sensitivity of TTE was much lower (28 versus 87 percent) although the specificity was 99 percent. However, some perivalvular abscesses may be missed by TEE. (See "Role of echocardiography in infective endocarditis", section on Perivalvular abscess or fistula).
Patients with perivalvular abscesses appear to have higher rates of systemic embolization and fatal outcomes. In one study comparing outcomes of patients with and without perivalvular abscesses, the rate of embolization was approximately twice as high (64 versus 30 percent) [4] . These patients also have a higher mortality rate (23 versus 14 percent in those without abscesses in a report of 118 patients, 44 of whom had a perivalvular abscess) [5] . Mortality may be particularly high in patients with at least moderate valvular regurgitation [8] .
Other extravalvular complications — Other rare extravalvular cardiac complications of IE include:
• Pericarditis, which may be suppurative or nonsuppurative, can rarely cause pain or even cardiac tamponade [9,10] . (See "Purulent pericarditis" and see "Evaluation and management of acute pericarditis").
• Fistulous intracardiac connections (eg, aorta-atrial or aorta-ventricular) due to extension of infection from the valve to adjacent myocardium may rarely result in large aneurysms, a pseudoaneurysm if the aortic wall is involved [11] , or even myocardial perforation.
The incidence of fistulous intracardiac complications was 1.6 percent in a retrospective, multicenter study of 4681 episodes of IE [12] . Surgery was performed in 66 of the 76 patients with a mortality of 41 percent. Multivariate analysis identified heart failure (odds ratio [OR] 4.3), prosthetic IE (OR 4.6), and urgent or emergent surgical treatment (OR 4.3) as being significantly associated with an increased risk of death.
• Aortic valve dissection [13] .
• Descending thoracic aorta intraluminal infectious masses [14] .
EMBOLIZATION — Embolization remains a distressingly common complication of IE and can occur even after appropriate therapy is well underway. This section will provide a general discussion of embolization in patients with IE. Issues related to embolization in patients with IE who undergo surgery are discussed separately (See "Surgery for native valve endocarditis" section on Embolization, and see "Surgery for prosthetic valve endocarditis" section on Embolization).
Systemic emboli most commonly complicate left-sided IE, but rarely can occur in tricuspid valve endocarditis via a patent foramen ovale [15] . However, emboli to the lung with subsequent abscess formation occur frequently in patients with tricuspid endocarditis. Small, clinically inapparent embolization probably occurs in most, if not all, patients with IE, but clinically recognized embolism has been reported in 13 to 44 percent of patients in published reports [16,17] .
Emboli consisting of vegetation fragments can occlude or damage virtually any blood vessel, large or small, in the systemic or pulmonary arterial circulation. As a result, emboli can produce:
• Stroke
• Blindness
• Painful ischemic or frankly gangrenous extremities
• Unusual pain syndromes (eg, due to splenic or renal infarction)
• Hypoxia (due to pulmonary emboli in right-sided endocarditis)
• Paralysis (due to embolic infarction of either the brain or spinal cord)
Emboli can occasionally cause symptoms or signs that mimic other common conditions such as kidney stones, Bell's palsy, dizziness, or pleurisy.
Endocarditis should be considered as a possible etiology in virtually all patients who present with signs or symptoms of systemic arterial embolization. In one study, cerebral infarction was the presenting sign of IE in 4 to 14 percent of all cases of IE [15] . The vast majority of patients with an acute stroke do not have endocarditis although the occurrence of a stroke in a younger patient or evidence of simultaneous or sequential cerebral and systemic arterial embolization, increase the probability of IE. As an example, in one report of 60 patients with IE and cerebral complications, 28 (47 percent) also had clinically identifiable systemic emboli [18] compared to only 2 percent of all stroke patients in a different large series [19] .
Symptomatic embolization appears to be more common with IE due to fungal pathogens. Whenever emboli to large systemic arterial vessels occur in a patient with IE, the possibility of a fungal etiology should be entertained. In a literature review of 270 patients with fungal endocarditis, peripheral arterial embolization occurred in 45 percent. The most common sites were the cerebral circulation (17 percent) and femoral artery (16 percent) [20] .
Histopathologic or microbiologic examination of occluding embolic material in such large vessels may lead to a diagnosis of an underlying fungal IE. Haemophilus species and other slow growing fastidious gram-negative organisms also seem to predispose to embolization with some frequency. (See "Candida endocarditis").
Effect of antibiotic therapy on embolic risk — The risk of embolization tends to decline after the institution of effective antimicrobial therapy, and serious embolic events rarely occur several weeks after such therapy is instituted [16,21,22] . The relationship between the initiation of antibiotic therapy and the risk of embolism is illustrated by the following observations:
In a series of 629 patients with left sided endocarditis, 131 patients (21 percent) had one or more embolic events [21] . The event occurred before the initiation of antimicrobial therapy in 42 percent, on the day therapy commenced in 14 percent, and within 15 days of initiating therapy in 82 percent.
In a study that used TTE to detect vegetations, the rate of embolization fell from 13 per 1000 patient days during the first week of therapy to less than 1.2 per 1000 patient days after two weeks of therapy [16] .
These findings suggest that surgery may not be necessary for prevention of embolic stroke in the early weeks following initiation of appropriate antibiotic therapy, if there are no other indications for surgery (such as a large mobile vegetation or congestive heart failure due to valvular leak) [22] .
Predictors of embolization — The size of a vegetation as determined by echocardiography has been assessed as a risk factor for embolization in IE. Although some data are conflicting, vegetation size is generally a risk factor for embolization. (See "Role of echocardiography in infective endocarditis", section on Echocardiographic estimation of outcome).
However, the presence or absence of vegetations, the location of the vegetations, the characteristics of vegetations by TEE, the specific etiologic microorganism, or antiphospholipid antibodies may have predictive value [23-29] :
• A multicenter prospective European study of 384 patients with definite IE by Duke criteria found that emboli were more frequently observed in cases due to Streptococcus bovis and S. aureus by multivariate analysis [29] . Multivariate analysis identified vegetation size >10 mm and severe vegetation mobility as additional risk factors for embolic events that occurred in 28 patients after the initiation of antibiotic therapy.
• Embolization occurs more frequently with left-sided than right-sided vegetations [24] . In a review of 281 patients with clinically suspected IE, the incidence of embolic events was greater with mitral than aortic valve vegetations (25 versus 10 percent) [25] . The risk was highest with vegetations on the anterior mitral leaflet (37 percent), suggesting that the mechanical effects of broad and abrupt leaflet excursion may contribute to the risk of embolization [24] .
• A prospective study of patients with IE due to S. aureus suggested that the risk of embolization was significantly greater in patients who had visible vegetations by both TTE and TEE compared to patients who had vegetations visualized only by TEE [26] .
• The absence of valvular abnormalities on TTE may be associated with a decreased incidence of complications [27] .
• The presence of antiphospholipid antibodies were correlated with an increased risk of embolization (62 versus 23 percent) in a series of 91 patients with IE, perhaps due to increased endothelial cell activation, generation of thrombin, and defective fibrinolysis [28] .
Effect of prior antiplatelet therapy — The possible protective effect of prior antiplatelet therapy (one or more of aspirin, dipyridamole, clopidogrel, or ticlopidine) on embolism in IE was evaluated in a retrospective cohort of 600 patients with IE, 147 of whom (25 percent) had a symptomatic embolic event [30] . The patients who had received continuous daily antiplatelet therapy for at least six months prior to hospitalization for IE had a significantly lower rate of a symptomatic embolic event (12 versus 28 percent without such therapy, adjusted odds ratio 0.36, 95% CI 0.19-0.68). The presumed mechanism is that platelet aggregation plays a role in vegetation formation.
In contrast to prior therapy, the initiation of aspirin after the diagnosis of IE is of no benefit and may be harmful. This was illustrated in randomized trial in which 115 patients with IE were assigned to aspirin (325 mg/day) or placebo for four weeks [31] . Aspirin did not reduce the incidence of embolic events, was associated with a trend toward an increased incidence of bleeding (odds ratio 1.92, 95% CI 0.76-4.86), and had no effect on vegetation resolution or valve function.
NEUROLOGIC COMPLICATIONS — Neurologic complications rank second to cardiac in importance, occurring in approximately 25 to 35 percent of patients [15,32-36] , although a lower rate of 10 percent was noted in one series [37] . In a review of 260 nondrug addicts with IE due to Staphylococcus aureus, 91 patients (35 percent) developed neurologic manifestations including 61 (23 percent) who presented with these symptoms [34] . (See "Complications of Staphylococcus aureus bacteremia").
Manifestations — The mechanism for and types of neurologic complications are diverse and include:
• Embolic stroke
• Acute encephalopathy
• Meningoencephalitis
• Purulent or aseptic meningitis
• Cerebral hemorrhage (due to stroke or a ruptured mycotic aneurysm)
• Brain abscess or cerebritis
• Seizures (secondary to abscess or embolic infarction)
Neurologic complications may be the presenting symptom in patients with IE. In a series of 68 patients with stroke and endocarditis, for example, two-thirds presented to the hospital with stroke, before the diagnosis of endocarditis was made [37] . Thus, the possibility of IE should be considered in all patients who present with strokes, meningitis, or a brain abscess. Unexplained fever accompanying a stroke in a patient with valvular disease is an important clue in some patients. (See "Diagnostic approach to infective endocarditis").
Outcomes — Reported patient outcomes after a neurologic complication are variable. The following findings have been noted in different series:
• Among survivors of cardiac surgery for IE, 70 percent of patients with a preoperative stroke experienced a full neurologic recovery [36] . Outcomes were worse in patients with stroke complicated by meningitis, abscess, or intracerebral hemorrhage.
• Patient mortality in more contemporary series has varied from approximately 20 to 50 percent at one year [36,37] to as high as 74 percent (time of follow-up not given) in patients with Staphylococcus aureus endocarditis [34] .
One of the dilemmas that often arises is whether neurologic complications of IE are a contraindication to valve replacement. This important issue is discussed elsewhere. (See "Surgery for native valve endocarditis", section on Effect of recent cerebral embolization).
MYCOTIC ANEURYSMS — Mycotic aneurysms can occur in the cerebral or systemic circulation of patients with IE, usually at points of vessel bifurcation. (See "Mycotic aneurysms").
RENAL DISEASE — Renal infarction (due to emboli), drug-induced acute interstitial nephritis, glomerulonephritis (due to deposition of immunoglobulins and complement in the glomerular membrane) and, rarely, renal abscess can occur in patients with IE. (See "Renal disease in infective endocarditis").
Acute renal failure, defined as a serum creatinine of 2 mg/dL (177 µmol/L) or greater, has been reported in up to one-third of patients [38] . By contrast, chronic renal failure due to immune-complex mediated glomerulonephritis, which was a common contributing cause of death in patients who presented with classic IE in the preantibiotic era, is now rare. Immune complex-mediated renal disease is also uncommon in the antibiotic era, especially in patients whose infection is detected and treated early.
METASTATIC ABSCESSES — Rarely, metastatic abscesses develop in the kidneys, spleen, brain or soft tissues (eg, the psoas muscle) in the setting of IE. There is a strong association between IE and splenic abscess, even though otherwise splenic abscesses are less frequently observed than other types intraabdominal abscesses.
Patients with splenic abscesses usually do not have marked abdominal pain or splenomegaly; persistent fever during or after treatment for IE and occasionally recurrent bacteremia after cure of the valvular infection may be the only clue to the presence of this complication [39] . Splenic abscesses are often diagnosed only at autopsy and generally require splenectomy for cure. In one study of 27 patients with splenic abscesses, mortality was 100 percent in the patients who did not have a splenectomy compared to 18 percent in the patients who had the procedure [40] .
Discrete microabscesses or larger solitary brain abscesses can rarely occur in patients with IE. Abscess formation occurs as a sequela of septic embolization. Some patients with IE and brain abscesses also have purulent meningitis. In fact, the presence of meningitis due to S. aureus should suggest the possibility of concomitant S. aureus endocarditis. In one case series of 33 patients with S. aureus meningitis, seven (21 percent) also had endocarditis [41] .
Appropriate treatment, including drainage of such abscesses, is needed not only to control the local infection but also to prevent ongoing bacteremia, which is of particular concern among patients who may require surgical treatment of endocarditis with implantation of a prosthetic valve.
MUSCULOSKELETAL COMPLICATIONS — Vertebral osteomyelitis is a well known but relatively rare complication of IE. Although the majority of patients with IE and back pain do not have vertebral osteomyelitis, protracted, severe back pain in any patient with IE should alert the clinician to this possibility. Plain films are insensitive for diagnosing vertebral osteomyelitis, especially if taken early in the course of illness [42] . (See "Vertebral osteomyelitis"). Osteomyelitis more frequently complicates S. aureus endocarditis than IE due to other microorganisms [42] .
Acute septic arthritis, involving one or more joints, may be the first clue to the presence of IE in a small percentage of patients. IE should be strongly considered in selected cases of septic arthritis:
• When infections spontaneously arise in joints of the axial skeleton (eg, sacroiliac, pubic, or manubriosternal joints).
• When organisms with a known propensity to cause IE (eg, S. aureus, viridans streptococci or non-group A beta-hemolytic streptococci) grow from a joint aspirate, particularly in patients without a history of recent surgery, joint infection, or trauma.
• When multiple joints are infected.
COMPLICATIONS OF MEDICAL OR SURGICAL THERAPY — Patients with IE can develop a number of the complications associated with prolonged parenteral antimicrobial therapy or surgery:
• Aminoglycoside-induced ototoxicity or nephrotoxicity (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity")
• Secondary bacteremia due to central vascular lines (See "Pathogenesis of and risk factors for central venous catheter-related infections")
• Mediastinitis or early postoperative prosthetic valve endocarditis (See "Postoperative mediastinitis after cardiac surgery")
• Intravenous catheter-associated phlebitis
• Drug fever (See "Drug fever")
• Allergic or idiosyncratic reactions to various antimicrobial agents
• Bleeding due to disturbances in coagulation caused by anticoagulants (in prosthetic valve endocarditis)
MORTALITY — Multiple studies have evaluated death rates in patients with both native and prosthetic valve endocarditis [43-47] :
• The in-hospital mortality rate is between 18 and 23 percent
• The six month mortality rate is between 22 and 27 percent
The outcomes in patients with neurologic complications are described above. (See "Outcomes" above).
Predictors of death — Several studies have attempted to identify predictors of death in patients with IE. Each patient may have one or more of the following:
• Infection with S. aureus [44,46,48] , while mortality is lower with streptococcal infection (8 versus 33 percent with S. aureus in one series) [46]
• Heart failure [45,47]
• Diabetes mellitus [44]
• Embolic events [44,48]
• Perivalvular abscess [5,8,47]
• Vegetation size [29,48]
• Female gender [29]
• Contraindication to surgery [46]
• Low serum albumin [43]
• Persistent bacteremia [47]
• Abnormal mental status [46]
• Poor surgical candidacy [46]
All but two of the preceding studies [44,46] were retrospective. Because the clinical and echocardiographic features of patients with endocarditis change during the course of illness, some of the above findings should be interpreted with caution. In one of the reports using a prospective study design, neither heart failure as defined by the Framingham criteria nor cardiac surgery was independently associated with in-hospital mortality [44] . However, among patients with moderate to severe heart failure, cardiac surgery in other studies has been associated with a lower rate of long-term mortality compared to medical therapy alone. The data supporting this conclusion are presented separately. (See "Surgery for native valve endocarditis", section on Efficacy).
In view of the wide disparity in the methods used in the preceding studies, one should be cautious about making prognostic predictions in individual patients with IE.
Surgery for prosthetic valve endocarditis
Surgery for prosthetic valve endocarditis
Author
Adolf W Karchmer, MD
Section Editor
Catherine M Otto, MD
Scott E Kasner, MD
Gabriel S Aldea, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Susan B Yeon, MD, JD, FACC
Last literature review version 16.2: May 2008 | This topic last updated: April 29, 2008 (More)
INTRODUCTION — Infection of a prosthetic heart valve can be difficult to diagnose and manage. Optimal treatment of prosthetic valve endocarditis (PVE) requires:
• Identification of the causative microorganism.
• Selection of a bactericidal antimicrobial regimen of proven efficacy.
• A clear understanding of the intracardiac pathology and attendant complications of PVE. (See "Presentation and diagnosis of prosthetic valve endocarditis").
• Surgical intervention in nearly all cases, especially that in which infection has extended beyond the valve to contiguous cardiac tissue.
The surgical management of prosthetic valve endocarditis will be reviewed here. The antimicrobial treatment of prosthetic valve endocarditis and the role of surgery in native valve endocarditis are discussed separately. (See "Antimicrobial therapy of prosthetic valve endocarditis" and see "Surgery for native valve endocarditis").
GENERAL PRINCIPLES — Cardiac surgery plays a major role in the effective therapy of many patients with PVE. Heart failure, persistent fever for 10 or more days despite appropriate antibiotic therapy, systemic embolization, and new onset electrocardiographic conduction abnormalities are associated with high mortality rates in patients with PVE and are clinical indications of invasive infection [1-4] . (See "Presentation and diagnosis of prosthetic valve endocarditis" and see "Surgery for native valve endocarditis").
Invasive infection is demonstrated far more predictably by transesophageal echocardiography than by a transthoracic evaluation. (See "Role of echocardiography in infective endocarditis").
Invasive infection is common in PVE, especially when infection arises within 12 months of surgery or involves an aortic prosthesis [2] . For patients with complicated PVE, the survival rates are higher among surgically than medically treated patients, and relapses, rehospitalization for valve surgery, and delayed mortality due to endocarditis are less common among those treated surgically [2,3,5-7] .
INDICATIONS — Indications for cardiac surgery in patients with PVE have been developed based upon the intracardiac pathology of PVE and the risk of recrudescent infection on the new prosthesis. The 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of valvular heart disease included recommendations for surgery in patients with prosthetic and native valve endocarditis (show table 1A-1B) [8] .
Some of the indications for surgical treatment are absolute, while others are relative and require careful risk benefit analysis. Persistent bacteremia despite optimal antimicrobial treatment requires surgical intervention.
A multicenter prospective study of 104 patients with PVE examined the influence of medical versus surgical therapy on outcome in order to identify patients for whom surgery may be beneficial [9] . Multivariate analysis identified the following independent predictors of in-hospital mortality:
• Severe heart failure (odds ratio [OR] 5.5; 95% CI, 1.9-16.1)
• S. aureus infection (OR 6.1; 95% CI, 1.9-19.2)
Independent predictors of long-term mortality (32 month follow-up) included:
• Comorbidity (risk ratio [RR] 3; 95% CI, 1.4-6.6)
• Early PVE (<60 days post-surgery, RR 2.1; 95% CI, 1.1-4.3)
• Severe heart failure (RR 4.2; 95% CI, 2.2-8.0)
• Staphylococcus infection (RR 2.0; 95% CI, 1.0-4.0)
• New prosthetic dehiscence (RR 2.4; 95% CI, 1.3-4.7)
Mortality was not significantly different between surgical and nonsurgical patients overall (17 versus 25 percent), however, in-hospital mortality was reduced by a surgical approach in patients with staphylococcal (27 versus 73 percent) or complicated PVE (18 versus 48 percent).
An international multi-center prospective study of 355 patients with prosthetic valve endocarditis found the following variables independently associated with surgical therapy: intracardiac abscess, heart failure, younger age, coagulase negative staphylococci, and S. aureus. Unadjusted in-hospital mortality rates in this study were similar for surgical and medical treatment, 25 and 23 percent, respectively. When a propensity analysis was performed to compare surgically treated patients with a population of medically treated patients selected to have similar clinical features, there was a trend toward reduced in-hospital mortality with surgical treatment (OR 0.51; 95% CI 0.23-1.36). A similar trend was noted when all patients with high propensity score for cardiac surgery were examined [10] .
In contrast, antibiotic therapy alone is often successful in patients with PVE who have no evidence of heart failure, significant prosthetic valve dysfunction, or invasive infection, and who are infected by less virulent organisms. These patients are characterized by later onset of infection (more than 12 months after prosthesis implantation), and infection by viridans streptococci, HACEK, or enterococci (that can be treated with bactericidal therapy) [9,11,12] .
Valve dysfunction — The outcome of PVE in patients who experience moderate to severe heart failure due to prosthesis dysfunction is improved if patients are treated surgically. Few survive beyond six months if treated with antibiotics alone, whereas 44 to 64 percent survive with timely surgical intervention [1,3,11,13,14] .
An unstable hypermobile prosthesis due to dehiscence of anchoring sutures is a surgical emergency, requiring urgent intervention, because the valve is likely to become increasingly unstable with acute severe valve regurgitation.
As with NVE, surgical intervention to correct valve dysfunction and heart failure must be performed before it becomes severe and intractable. There is no evidence that delaying surgery in this setting improves outcome or reduces the frequency of recurrent endocarditis [15-17] . In fact, the operative mortality of these patients is proportional to the severity of hemodynamic disability at the time of surgery [15,18] .
Patients with PVE complicated by perivalvular invasion experience high mortality rates and are rarely curable with medical treatment alone. By contrast, complex reconstructive procedures have been associated with survival rates of 80 percent [6,19] . Echocardiographic findings are enhanced with transesophageal (versus transthoracic) but can still be limited by "shadowing" from prosthetic valve sewing rings. Echocardiographic findings of perivalvular invasion include [1,2] :
• Valve dehiscence
• Paravalvular abscess
• Aortic aneurysm or pseudoaneurysm
• Fistula formation
Relapse after optimal medical therapy — If PVE relapses after appropriate antimicrobial therapy, surgical intervention should usually be performed since relapses often reflect unrecognized perivalvular infection [1,2] .
Microorganisms usually requiring surgery — Retrospective studies suggest that S. aureus PVE is associated with significant mortality, up to 70 percent in patients treated with antibiotics alone [20-24] . While mortality outcomes in patients who had surgery in these studies have varied, intracardiac complications in patients with S. aureus PVE are consistently associated with an increased mortality and surgical intervention reduces mortality in this group. In one study, for example, mortality was reduced 20-fold by surgical intervention during antimicrobial therapy (odds ratio [OR] 0.5, 95% CI 0.005-0.42) [23] . Multiple studies have concluded that PVE caused by S. aureus is most effectively treated by antibiotics and prompt surgical intervention [3,9,20,21,25] .
Another study, while not finding an improvement in overall mortality with surgical treatment of S. aureus PVE, noted that patients who developed cardiac complications defined as heart failure and/or intracardiac abscess (a group that would be considered at high risk for endocarditis related death) and underwent early valve replacement had the lowest mortality rate (28.6 percent) [24] .
Early surgical intervention is considered by most experts to be a standard element of treatment for fungal PVE [26] . Among 15 patients with fungal PVE treated with antifungal agents and with surgery, 10 (67 percent) survived with an average follow-up of 4.5 years [27] . One review of 17 patients suggested that survival rates for Candida PVE were comparable with and without surgery (46 versus 50 percent) [28] . However, only patients with uncomplicated PVE survived in this review, and many remained on long term suppressive oral therapy. Patients who have fungal PVE have significant co-morbidities (such as end-stage renal disease on hemodialysis or immunosuppressed states from chemotherapy or HIV for example). Timing and duration of medical therapy and surgical intervention are frequently complex.
Some other pathogens, such as P. aeruginosa and probably multi-resistant enterococci for which there is no synergistic bactericidal regimen, are also less amenable to medical therapy. Surgery is generally advised for PVE caused by these microorganisms.
Embolization — The frequency of embolic complications is higher in patients with NVE who have vegetations exceeding 10 mm in diameter compared to those with smaller vegetations. Comparable data are not available for patients with PVE. However, the overall rate of embolic complications is similar for patients with PVE and NVE, and emboli decrease rapidly with effective therapy in both [29] . While prevention of emboli that cause highly morbid, irreversible end-organ damage (eg, central nervous system and myocardial infarction) is a laudable goal, it has not been established that surgical intervention achieves this aim in patients with PVE, large vegetations, and no other complications. The risk of emboli in this setting, rather than constituting an indication for surgery, should be weighed with other findings that might benefit from surgical intervention and then factored into the overall management plan. Recurrent emboli despite appropriate antibiotic therapy are an indication for surgical intervention.
OUTCOME — Complex reconstruction of the aortic or mitral valve apparatus and the supporting structures is often required to achieve an optimal outcome of PVE [19,30-32] . In the hands of experienced cardiac surgeons, operative mortality rates for patients with invasive PVE, treated with valve replacement and surgical reconstruction of paravalvular tissue, range from 10 to 30 percent; in contrast the projected mortality would approach 100 percent without surgery [6,19,30-33] . These data suggest that surgical intervention for PVE complicated by extensive invasion and tissue disruption should be performed in centers with extensive experience, when possible. Earlier surgical reintervention in patients with invasive organisms may also significantly limit morbidity by avoiding the need for complex reconstructions (such as root replacement for annular abscess or atrial-ventricular reconstructions for mitral valve prosthetic valve endocarditis).
The rate of recrudescent PVE after surgery is six to 15 percent; repeat surgery is required for recurrent PVE or for dysfunction of the newly implanted prosthesis in 18 to 26 percent [2,6,15,19,30,33] . While these figures are not insignificant, they are relatively small compared with the anticipated mortality with antibiotic therapy alone. Five-year survival rates ranging from 54 to 82 percent have been reported for patients undergoing surgery for PVE [15,19,30,32,34] .
ANTIBIOTIC TREATMENT FOLLOWING SURGERY — Following valve replacement for active bacterial endocarditis, the Task Force on Infective Endocarditis of the European Society of Cardiology (ESC) recommends another full course (six weeks) of antimicrobial treatment if the intraoperative valve culture is positive [35] . If the culture is negative, the ESC recommends that the full treatment course be completed (counting the duration of preoperative antibiotics).
ANTICOAGULANT THERAPY — Among patients with prosthetic valve IE, the potential benefit of preventing embolization with anticoagulation must be weighed against the increased risk of intracerebral hemorrhage. This issue is discussed in detail separately. (See "Anticoagulant and antiplatelet therapy in patients with infective endocarditis").
SUMMARY AND RECOMMENDATIONS
• Treatment of prosthetic valve endocarditis is more difficult than treatment of native valve endocarditis and often requires surgical replacement of the prostheses in addition to antibiotic therapy. (See "Introduction" above).
• Invasive infection is common in PVE, especially when infection arises within 12 months of surgery or involves an aortic prosthesis. (See "General principles" above).
• Some of the indications for surgical treatment are absolute, while others are relative and require careful risk benefit analysis (show table 1A). (See "General principles" above).
• The outcome of PVE in patients who experience moderate to severe heart failure due to prosthesis dysfunction or who have evidence of valve dehiscence, paravalvular abscess, or fistula formation is improved if patients are treated surgically. There is no evidence that delaying surgery in this setting improves outcome or reduces the frequency of recurrent endocarditis. (See "Valve dysfunction" above).
• Surgery is generally advised for PVE caused by S. aureus when accompanied by intracardiac complications, and also for fungi, gram-negative (nonHACEK) microorganisms (particularly P. aeruginosa), and multi-drug resistant enterococci. (See "Microorganisms usually requiring surgery" above).
• In the hands of experienced cardiac surgeons, operative mortality rates for patients with invasive PVE, treated with valve replacement and surgical reconstruction of paravalvular tissue, range from 10 to 30 percent; in contrast the projected mortality approaches 100 percent without surgery. (See "Outcome" above).
• The rate of recurrent PVE after surgery is six to 15 percent. (See "Outcome" above).
Author
Adolf W Karchmer, MD
Section Editor
Catherine M Otto, MD
Scott E Kasner, MD
Gabriel S Aldea, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Susan B Yeon, MD, JD, FACC
Last literature review version 16.2: May 2008 | This topic last updated: April 29, 2008 (More)
INTRODUCTION — Infection of a prosthetic heart valve can be difficult to diagnose and manage. Optimal treatment of prosthetic valve endocarditis (PVE) requires:
• Identification of the causative microorganism.
• Selection of a bactericidal antimicrobial regimen of proven efficacy.
• A clear understanding of the intracardiac pathology and attendant complications of PVE. (See "Presentation and diagnosis of prosthetic valve endocarditis").
• Surgical intervention in nearly all cases, especially that in which infection has extended beyond the valve to contiguous cardiac tissue.
The surgical management of prosthetic valve endocarditis will be reviewed here. The antimicrobial treatment of prosthetic valve endocarditis and the role of surgery in native valve endocarditis are discussed separately. (See "Antimicrobial therapy of prosthetic valve endocarditis" and see "Surgery for native valve endocarditis").
GENERAL PRINCIPLES — Cardiac surgery plays a major role in the effective therapy of many patients with PVE. Heart failure, persistent fever for 10 or more days despite appropriate antibiotic therapy, systemic embolization, and new onset electrocardiographic conduction abnormalities are associated with high mortality rates in patients with PVE and are clinical indications of invasive infection [1-4] . (See "Presentation and diagnosis of prosthetic valve endocarditis" and see "Surgery for native valve endocarditis").
Invasive infection is demonstrated far more predictably by transesophageal echocardiography than by a transthoracic evaluation. (See "Role of echocardiography in infective endocarditis").
Invasive infection is common in PVE, especially when infection arises within 12 months of surgery or involves an aortic prosthesis [2] . For patients with complicated PVE, the survival rates are higher among surgically than medically treated patients, and relapses, rehospitalization for valve surgery, and delayed mortality due to endocarditis are less common among those treated surgically [2,3,5-7] .
INDICATIONS — Indications for cardiac surgery in patients with PVE have been developed based upon the intracardiac pathology of PVE and the risk of recrudescent infection on the new prosthesis. The 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of valvular heart disease included recommendations for surgery in patients with prosthetic and native valve endocarditis (show table 1A-1B) [8] .
Some of the indications for surgical treatment are absolute, while others are relative and require careful risk benefit analysis. Persistent bacteremia despite optimal antimicrobial treatment requires surgical intervention.
A multicenter prospective study of 104 patients with PVE examined the influence of medical versus surgical therapy on outcome in order to identify patients for whom surgery may be beneficial [9] . Multivariate analysis identified the following independent predictors of in-hospital mortality:
• Severe heart failure (odds ratio [OR] 5.5; 95% CI, 1.9-16.1)
• S. aureus infection (OR 6.1; 95% CI, 1.9-19.2)
Independent predictors of long-term mortality (32 month follow-up) included:
• Comorbidity (risk ratio [RR] 3; 95% CI, 1.4-6.6)
• Early PVE (<60 days post-surgery, RR 2.1; 95% CI, 1.1-4.3)
• Severe heart failure (RR 4.2; 95% CI, 2.2-8.0)
• Staphylococcus infection (RR 2.0; 95% CI, 1.0-4.0)
• New prosthetic dehiscence (RR 2.4; 95% CI, 1.3-4.7)
Mortality was not significantly different between surgical and nonsurgical patients overall (17 versus 25 percent), however, in-hospital mortality was reduced by a surgical approach in patients with staphylococcal (27 versus 73 percent) or complicated PVE (18 versus 48 percent).
An international multi-center prospective study of 355 patients with prosthetic valve endocarditis found the following variables independently associated with surgical therapy: intracardiac abscess, heart failure, younger age, coagulase negative staphylococci, and S. aureus. Unadjusted in-hospital mortality rates in this study were similar for surgical and medical treatment, 25 and 23 percent, respectively. When a propensity analysis was performed to compare surgically treated patients with a population of medically treated patients selected to have similar clinical features, there was a trend toward reduced in-hospital mortality with surgical treatment (OR 0.51; 95% CI 0.23-1.36). A similar trend was noted when all patients with high propensity score for cardiac surgery were examined [10] .
In contrast, antibiotic therapy alone is often successful in patients with PVE who have no evidence of heart failure, significant prosthetic valve dysfunction, or invasive infection, and who are infected by less virulent organisms. These patients are characterized by later onset of infection (more than 12 months after prosthesis implantation), and infection by viridans streptococci, HACEK, or enterococci (that can be treated with bactericidal therapy) [9,11,12] .
Valve dysfunction — The outcome of PVE in patients who experience moderate to severe heart failure due to prosthesis dysfunction is improved if patients are treated surgically. Few survive beyond six months if treated with antibiotics alone, whereas 44 to 64 percent survive with timely surgical intervention [1,3,11,13,14] .
An unstable hypermobile prosthesis due to dehiscence of anchoring sutures is a surgical emergency, requiring urgent intervention, because the valve is likely to become increasingly unstable with acute severe valve regurgitation.
As with NVE, surgical intervention to correct valve dysfunction and heart failure must be performed before it becomes severe and intractable. There is no evidence that delaying surgery in this setting improves outcome or reduces the frequency of recurrent endocarditis [15-17] . In fact, the operative mortality of these patients is proportional to the severity of hemodynamic disability at the time of surgery [15,18] .
Patients with PVE complicated by perivalvular invasion experience high mortality rates and are rarely curable with medical treatment alone. By contrast, complex reconstructive procedures have been associated with survival rates of 80 percent [6,19] . Echocardiographic findings are enhanced with transesophageal (versus transthoracic) but can still be limited by "shadowing" from prosthetic valve sewing rings. Echocardiographic findings of perivalvular invasion include [1,2] :
• Valve dehiscence
• Paravalvular abscess
• Aortic aneurysm or pseudoaneurysm
• Fistula formation
Relapse after optimal medical therapy — If PVE relapses after appropriate antimicrobial therapy, surgical intervention should usually be performed since relapses often reflect unrecognized perivalvular infection [1,2] .
Microorganisms usually requiring surgery — Retrospective studies suggest that S. aureus PVE is associated with significant mortality, up to 70 percent in patients treated with antibiotics alone [20-24] . While mortality outcomes in patients who had surgery in these studies have varied, intracardiac complications in patients with S. aureus PVE are consistently associated with an increased mortality and surgical intervention reduces mortality in this group. In one study, for example, mortality was reduced 20-fold by surgical intervention during antimicrobial therapy (odds ratio [OR] 0.5, 95% CI 0.005-0.42) [23] . Multiple studies have concluded that PVE caused by S. aureus is most effectively treated by antibiotics and prompt surgical intervention [3,9,20,21,25] .
Another study, while not finding an improvement in overall mortality with surgical treatment of S. aureus PVE, noted that patients who developed cardiac complications defined as heart failure and/or intracardiac abscess (a group that would be considered at high risk for endocarditis related death) and underwent early valve replacement had the lowest mortality rate (28.6 percent) [24] .
Early surgical intervention is considered by most experts to be a standard element of treatment for fungal PVE [26] . Among 15 patients with fungal PVE treated with antifungal agents and with surgery, 10 (67 percent) survived with an average follow-up of 4.5 years [27] . One review of 17 patients suggested that survival rates for Candida PVE were comparable with and without surgery (46 versus 50 percent) [28] . However, only patients with uncomplicated PVE survived in this review, and many remained on long term suppressive oral therapy. Patients who have fungal PVE have significant co-morbidities (such as end-stage renal disease on hemodialysis or immunosuppressed states from chemotherapy or HIV for example). Timing and duration of medical therapy and surgical intervention are frequently complex.
Some other pathogens, such as P. aeruginosa and probably multi-resistant enterococci for which there is no synergistic bactericidal regimen, are also less amenable to medical therapy. Surgery is generally advised for PVE caused by these microorganisms.
Embolization — The frequency of embolic complications is higher in patients with NVE who have vegetations exceeding 10 mm in diameter compared to those with smaller vegetations. Comparable data are not available for patients with PVE. However, the overall rate of embolic complications is similar for patients with PVE and NVE, and emboli decrease rapidly with effective therapy in both [29] . While prevention of emboli that cause highly morbid, irreversible end-organ damage (eg, central nervous system and myocardial infarction) is a laudable goal, it has not been established that surgical intervention achieves this aim in patients with PVE, large vegetations, and no other complications. The risk of emboli in this setting, rather than constituting an indication for surgery, should be weighed with other findings that might benefit from surgical intervention and then factored into the overall management plan. Recurrent emboli despite appropriate antibiotic therapy are an indication for surgical intervention.
OUTCOME — Complex reconstruction of the aortic or mitral valve apparatus and the supporting structures is often required to achieve an optimal outcome of PVE [19,30-32] . In the hands of experienced cardiac surgeons, operative mortality rates for patients with invasive PVE, treated with valve replacement and surgical reconstruction of paravalvular tissue, range from 10 to 30 percent; in contrast the projected mortality would approach 100 percent without surgery [6,19,30-33] . These data suggest that surgical intervention for PVE complicated by extensive invasion and tissue disruption should be performed in centers with extensive experience, when possible. Earlier surgical reintervention in patients with invasive organisms may also significantly limit morbidity by avoiding the need for complex reconstructions (such as root replacement for annular abscess or atrial-ventricular reconstructions for mitral valve prosthetic valve endocarditis).
The rate of recrudescent PVE after surgery is six to 15 percent; repeat surgery is required for recurrent PVE or for dysfunction of the newly implanted prosthesis in 18 to 26 percent [2,6,15,19,30,33] . While these figures are not insignificant, they are relatively small compared with the anticipated mortality with antibiotic therapy alone. Five-year survival rates ranging from 54 to 82 percent have been reported for patients undergoing surgery for PVE [15,19,30,32,34] .
ANTIBIOTIC TREATMENT FOLLOWING SURGERY — Following valve replacement for active bacterial endocarditis, the Task Force on Infective Endocarditis of the European Society of Cardiology (ESC) recommends another full course (six weeks) of antimicrobial treatment if the intraoperative valve culture is positive [35] . If the culture is negative, the ESC recommends that the full treatment course be completed (counting the duration of preoperative antibiotics).
ANTICOAGULANT THERAPY — Among patients with prosthetic valve IE, the potential benefit of preventing embolization with anticoagulation must be weighed against the increased risk of intracerebral hemorrhage. This issue is discussed in detail separately. (See "Anticoagulant and antiplatelet therapy in patients with infective endocarditis").
SUMMARY AND RECOMMENDATIONS
• Treatment of prosthetic valve endocarditis is more difficult than treatment of native valve endocarditis and often requires surgical replacement of the prostheses in addition to antibiotic therapy. (See "Introduction" above).
• Invasive infection is common in PVE, especially when infection arises within 12 months of surgery or involves an aortic prosthesis. (See "General principles" above).
• Some of the indications for surgical treatment are absolute, while others are relative and require careful risk benefit analysis (show table 1A). (See "General principles" above).
• The outcome of PVE in patients who experience moderate to severe heart failure due to prosthesis dysfunction or who have evidence of valve dehiscence, paravalvular abscess, or fistula formation is improved if patients are treated surgically. There is no evidence that delaying surgery in this setting improves outcome or reduces the frequency of recurrent endocarditis. (See "Valve dysfunction" above).
• Surgery is generally advised for PVE caused by S. aureus when accompanied by intracardiac complications, and also for fungi, gram-negative (nonHACEK) microorganisms (particularly P. aeruginosa), and multi-drug resistant enterococci. (See "Microorganisms usually requiring surgery" above).
• In the hands of experienced cardiac surgeons, operative mortality rates for patients with invasive PVE, treated with valve replacement and surgical reconstruction of paravalvular tissue, range from 10 to 30 percent; in contrast the projected mortality approaches 100 percent without surgery. (See "Outcome" above).
• The rate of recurrent PVE after surgery is six to 15 percent. (See "Outcome" above).
Diagnostic approach to infective endocarditis
http://www.uptodateonline.com/online/content/topic.do?topicKey=endocard/6293&selectedTitle=10~150&source=search_result
Diagnostic approach to infective endocarditis
Author
Daniel J Sexton, MD
Section Editor
Catherine M Otto, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 16.2: May 2008 | This topic last updated: March 21, 2008 (More)
INTRODUCTION — The diagnosis of infective endocarditis (IE) is usually based upon a constellation of clinical findings rather than a single definitive test result. The diagnosis is usually obvious when a patient has the characteristic findings of IE:
• Numerous positive blood cultures in the presence of a well recognized predisposing cardiac lesion
• Evidence of endocardial involvement
However, some patients with IE do not have positive blood cultures (ie, culture-negative endocarditis), and approximately one-third to one-fourth of patients have no identifiable predisposing cardiac lesion at disease onset. The presence of atypical features may result in misdiagnosis or a correct diagnosis that is greatly delayed. (See "Culture-negative endocarditis" below).
The general approach to the diagnosis of IE will be reviewed here. Risk factors for IE and antibiotic prophylaxis and treatment of IE are discussed separately. (See "Infective endocarditis: Epidemiology and risk factors" and see "Antimicrobial prophylaxis for bacterial endocarditis" and see "Antimicrobial therapy of native valve endocarditis" and see "Antimicrobial therapy of prosthetic valve endocarditis").
DIAGNOSTIC CRITERIA — The diagnosis of IE is based upon a careful history and physical examination, blood culture and laboratory results, an electrocardiogram (ECG), a chest radiograph, and an echocardiogram.
Debate persists as to the optimal case definition for IE. Practical and logical case definitions are important since underdiagnosis can lead to clinical catastrophe and death, while overdiagnosis can result in weeks of unnecessary antimicrobial therapy with excessive costs and potentially avoidable drug-related side effects. It can, for example, be difficult to distinguish between IE and an alternate source of infection in a bacteremic patient with underlying heart disease.
Several sets of criteria for IE have been described. The most commonly accepted are the Duke criteria (show table 1 and show table 2 and show Calculator). (See "Infective endocarditis: Historical and Duke criteria", section on Duke criteria).
HISTORY — During the initial assessment of patients with suspected endocarditis, a careful history should be performed with special attention given to a history of prior cardiac lesions and historical clues pointing toward a recent source of bacteremia, such as indwelling intravascular catheters or intravenous drug use.
PHYSICAL EXAMINATION — The physical examination should include a careful cardiac examination for signs of new regurgitant murmurs or heart failure (see "Auscultation of cardiac murmurs").
A vigorous search should be undertaken for the classic clinical stigmata of endocarditis, including evidence of small and large emboli with special attention to the fundi, conjunctivae, skin, and digits. A neurologic evaluation may reveal evidence of focal neurologic impairment; it can also be used as a baseline examination should such abnormalities appear later. (See "Complications and outcome of infective endocarditis").
Associated peripheral cutaneous or mucocutaneous lesions of IE include petechiae, splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots. Petechiae are not specific for IE but are its most common skin manifestation. They may be present on the skin, usually on the extremities, or on mucous membranes such as the palate or conjunctivae, the latter usually as hemorrhages best seen with eversion of either upper or lower eyelids. Splinter hemorrhages, also nonspecific for endocarditis, are nonblanching, linear reddish-brown lesions found under the nail bed (show picture 1).
Janeway lesions, Osler's nodes, and Roth spots are more specific (but still not diagnostic) for IE. They are also less common, and Roth spots are rare.
• Janeway lesions are macular, blanching, nonpainful, erythematous lesions on the palms and soles (show picture 2).
• Osler's nodes are painful, violaceous nodules found in the pulp of fingers and toes and are seen more often in subacute than acute cases of IE (show picture 3).
• Roth spots are exudative, edematous hemorrhagic lesions of the retina.
In addition to these physical findings, patients with IE may have involvement of other organs due to embolic events (eg, focal neurologic deficits, renal and splenic infarcts) or a systemic immune reaction (eg, glomerulonephritis, arthritis). In right-sided endocarditis, septic pulmonary infarcts may be seen (show picture 4). (See "Complications and outcome of infective endocarditis" and see "Renal disease in infective endocarditis").
LABORATORY STUDIES
Blood cultures
Collection — Blood cultures should be obtained prior to antibiotic therapy. This was illustrated in a prospective study of 348 patients with suspected culture-negative endocarditis; among the 73 patients without an identifiable etiologic agent, 58 (79 percent) received antibiotics before blood cultures were obtained [9] .
A minimum of three blood cultures should be obtained over a time period based upon the severity of the illness. If the tempo of illness is subacute and the patient is not critically ill, it is reasonable and often preferable to delay therapy for one to three days while awaiting the results of blood cultures and other diagnostic tests. However, if the patient is acutely ill, three blood cultures should be obtained over a one hour time span before beginning empiric therapy. Almost all cases of bacterial IE are due to aerobic organisms; thus, culturing for anaerobes is rarely useful. (See "Blood cultures for the detection of bacteremia").
The additional diagnostic yield of more than three cultures is minimal in patients who have not recently received antimicrobial therapy. In a series of 206 cases of endocarditis, for example, the initial blood culture in patients with streptococcal endocarditis was positive in 96 percent and one of the first two blood cultures was positive in 98 percent; in patients with IE caused by bacteria other than streptococci, the first blood culture was positive in 82 percent and one of the first two cultures was positive in 100 percent [1] . Additional blood cultures are occasionally useful in patients who have been treated recently with antibiotics.
The bacteriologic diagnosis of IE is facilitated by the relative constancy, rather than random, release of bacteria from the cardiac vegetations [2] . However, since many patients with bacterial endocarditis have low grade bacteremia (eg, 1 to 10 CFU/mL of blood) [1] , a minimum of 10 mL (and preferably 20 mL) of blood should be obtained from adults and 0.5 to 5 mL from infants and children. In one study, blood cultures inoculated with at least 5 mL of blood had a significantly higher detection rate for bacteremia than bottles inoculated with less than 5 mL of blood (92 versus 69 percent) [3] . The estimated yield of blood cultures in bacteremic adults increased approximately 3 percent per mL of blood cultured.
Each set of cultures should be obtained from separate venipuncture sites. Blood cultures can be taken at any time; they do not need to be obtained with the appearance of chills or fever since patients with IE typically have a continuous bacteremia. (See "Blood cultures for the detection of bacteremia").
Organism — Not all microorganisms have the same propensity to cause endocarditis. As an example, organisms such as viridans streptococci and Staphylococcus aureus are more likely to cause endocarditis than are gram-negative rods such as Escherichia coli and Proteus spp. This distinction is important. The Duke Criteria for the diagnosis of endocarditis define the following organisms as "typical causes" of IE (show table 1 and show table 2) [4] :
• Staphylococcus aureus
• Viridans streptococci and Streptococcus bovis
• Enterococci
• HACEK group organisms (show table 2)
It was previously thought that patients who present with community-acquired enterococcal bacteremia are significantly more likely to have endocarditis than patients who develop enterococcal bacteremia while hospitalized for another cause [5] . However, this conclusion has been questioned as a result of a case-control study that compared the clinical and demographic characteristics of all patients with enterococcal endocarditis seen at a single center over eight years with controls randomly chosen from 455 patients with enterococcal bacteremia without endocarditis [6] . Community acquisition of bacteremia was not a risk factor for IE.
The probability of endocarditis varies by species of bacteria. As examples:
• S. sanguis bacteremia is more often indicative of endocarditis than is bacteremia due to S. milleri (also known as S. anginosus).
• Bacteremia with groups A or C streptococci are seldom associated with IE whereas group G streptococcal infection is often indicative of endocarditis [7] . (See "Group C and group G streptococcal infection").
• In a study of enterococcal bacteremia cited above, infection with E. faecalis, compared to other enterococcal species, was associated with IE by both univariate and multivariate analysis [6] .
The risk of endocarditis in patients with S. aureus bacteremia (regardless of source or residence at the time of onset) is particularly high. As a result, all patients with S. aureus recovered from the blood should be clinically evaluated for IE. (See "Complications of Staphylococcus aureus bacteremia").
Positive cultures — The interpretation of positive blood cultures in patients with suspected endocarditis is confounded by the fact that false-positive results occasionally occur despite use of the most exacting techniques for collection and processing. When organisms such as Propionibacterium spp., Corynebacterium spp., Bacillus spp., and coagulase-negative staphylococci are recovered from a single blood culture or a minority of blood culture bottles, the result is probably falsely positive. However, since all of these organisms are capable of causing endocarditis, it is important to determine if the bacteremia is persistent. (See "Endocarditis due to coagulase-negative staphylococci").
The definition of persistent bacteremia varies with the likelihood that the organism is a cause of endocarditis [4] :
• For an organism likely to cause endocarditis (eg, S. aureus, viridans streptococci), two positive samples collected more than 12 hours apart
• For an organism that is more commonly a skin contaminant, three or a majority of four or more separate blood cultures are positive and the first and last samples are collected at least one hour apart
Additional tests — The utility of other laboratory tests in the diagnosis of endocarditis is limited, other than the finding of an antiphase I IgG titer >1:800 for Coxiella burnetii [8] .
The following findings may be identified among patients with IE but are relatively nonspecific:
• An elevated erythrocyte sedimentation rate and/or an elevated level of C-reactive protein.
• A normochromic normocytic anemia.
• The white blood cell count may be normal or elevated in patients with subacute presentations of endocarditis; however, most patients with staphylococcal endocarditis have leukocytosis and some may have thrombocytopenia.
• Hyperglobulinemia, cryoglobulins, circulating immune complexes, hypocomplementemia, elevated rheumatoid factor titers, and false positive serologic tests for syphilis all occur in some patients.
An elevated rheumatoid factor titer in patients without a known prior rheumatologic disorder is one of six minor criteria in the Duke diagnostic scheme (show table 2) [4] . (See "Origin and utility of measurement of rheumatoid factors").
Most patients with endocarditis have an abnormal urinalysis, as manifested by microscopic or gross hematuria, proteinuria, and/or pyuria. Each of these findings lacks specificity. However, the presence of red blood cell casts on urinalysis is generally indicative of glomerulonephritis (often in association with hypocomplementemia) and is a minor diagnostic criterion for IE (show table 2) [4] . (See "Renal disease in infective endocarditis").
Electrocardiogram — We recommend that a baseline electrocardiogram be performed as part of the initial evaluation of all patients with suspected endocarditis even though this test rarely shows diagnostic findings. The presence or subsequent appearance of changes suggestive of ischemia or infarction on the electrocardiogram may provide useful clues to the presence of emboli to the coronary circulation. In addition, the initial presence or new appearance of heart block or conduction delay may provide an important clue to extension of infection to the valve annulus and adjacent septum. (See "Complications and outcome of infective endocarditis").
Chest radiograph — Chest radiographs occasionally reveal important diagnostic clues. As an example, patients with tricuspid valve endocarditis often present with radiographic evidence of septic pulmonary emboli. In such cases, there may be a few or multiple focal lung infiltrates, which may reveal central cavitation. Rarely, chest radiographs show calcification in a cardiac valve, which may raise suspicions of endocarditis in a febrile patient.
Echocardiography — The 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of patients with valvular heart disease included recommendations for the use of transthoracic and transesophageal echocardiography in patients with suspected or proven native or prosthetic valve endocarditis (show table 3) [10] . These recommendations are generally consistent with the 2005 AHA guidelines on infective endocarditis, which were endorsed by the Infectious Diseases Society of America [11] .
The information that can be obtained by echocardiography includes:
• Evaluation of patients in settings in which endocarditis is suspected (such as persistent bacteremia without a known source or high clinical suspicion with negative cultures)
• Detection and characterization of vegetations on valves and in other sites (as in patients with congenital heart disease)
• Detection of valvular dysfunction and assessment of hemodynamic severity
• Detection of associated abnormalities such as shunts or abscesses
• Re-evaluation of patients in complex settings (such as those with virulent organisms, severe hemodynamic effects, persistent or recurrent fever or bacteremia, or clinical deterioration)
An echocardiogram should be performed in all patients with a moderate or high suspicion of endocarditis (show table 1 and show table 2). In comparison, among patients with a low clinical probability of endocarditis, the diagnostic yield of both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) is very low, and neither should be performed [12] . (See "Infective endocarditis: Historical and Duke criteria", section on Case definitions).
Role of TTE — Transthoracic echocardiography may provide confirmation of the diagnosis of endocarditis. Detection of a vegetation is a positive test show echocardiogram 1 show echocardiogram 2 show echocardiogram 3. (See "Role of echocardiography in infective endocarditis").
However, TTE has relatively low sensitivity for vegetation in IE (29 to 63 percent in different series) [13-15] . Thus, the absence of vegetation does not preclude the diagnosis and, as described in the next section, TEE is usually warranted. However, the finding of normal valves (both morphology and function) substantially reduces the probability of IE. In one study, 96 percent of patients with normal valves and no vegetation on TTE also had a negative TEE [16] .
In contrast to the variable sensitivity, TTE has a specificity (the likelihood of a negative result in a patient without disease) approaching 100 percent, indicating very few false positive studies [13] .
Role of TEE — Transesophageal echocardiography has a higher spatial resolution than TTE and is much more sensitive for the detection of endocarditis show echocardiogram 4 show echocardiogram 5. TEE is especially useful for the detection of vegetations, diagnosis of prosthetic valve endocarditis, detection of a valve abscess, and assessment of embolic risk.
• Detection of vegetations — Two series with a total of 162 episodes of suspected IE demonstrated the greater sensitivity of TEE compared to TTE (100 versus 63 percent and 94 versus 44 percent, respectively) [13,14] . In a third report of 103 patients with S. aureus bacteremia, TTE revealed valvular abnormalities in 33 patients and vegetations in seven; in contrast, TEE identified vegetations in 22 patients and abscesses in two [15] .
• Diagnosis of IE on prosthetic valves — TEE is especially important for prosthetic valves in the mitral or aortic position, because acoustic shadowing frequently makes the transthoracic approach suboptimal. TEE has superior spatial resolution, and bacteremic patients with these prostheses are at increased risk for endocarditis show echocardiogram 6. Few data are available regarding the superiority of TEE for suspected endocarditis of tricuspid and pulmonic prostheses, but presumably it would be similar. (See "Role of echocardiography in infective endocarditis", section on Prosthetic valve endocarditis).
The greater value of TEE in patients with prosthetic heart valves was demonstrated in a prospective study that compared TTE and TEE in 114 episodes of IE suspected on clinical grounds (80 on native valves and 34 on prosthetic valves) [17] . The results of the two tests were concordant in 55 percent of cases; TEE led to a reclassification in 11 percent of patients with native valves and 34 percent with prosthetic valves.
The negative predictive value of TEE is nearly 100 percent for patients with native valves, but IE can be missed in patients with prosthetic valves. In the latter patients, clinical assessment is especially important.
• Detection of a valve abscess — TEE is much more sensitive than TTE for the detection of valve abscess. This was illustrated in a series of 44 patients with IE complicated by abscess formation (sensitivity 87 versus 28 percent with TTE) [18] .
While TEE is generally much more sensitive than TTE for detection of abscess, even TEE may miss a significant number of abscesses in some populations. This was illustrated in a report of 44 patients with endocarditis by Duke criteria who had valvular abscesses identified intraoperatively. Endocarditis was detected by TEE in only 48 percent of cases; prosthetic heart valves were present in 32 percent of patients. Indications for surgery included severe valvular dysfunction (with or without heart failure), embolization during antibiotic therapy, or concommitant pacemaker infection [19] . Abscesses not visualized by TEE were located at the posterior mitral annulus in 61 percent of cases; the majority of these were associated with a large calcification, which may have interfered with detection.
• Assessment of embolic risk — In general, larger vegetation size is associated with increased risk of embolization. This issue is discussed separately. (See "Role of echocardiography in infective endocarditis" section on Echocardiographic estimation of outcome).
Recommended use — We generally perform a TTE as the first diagnostic test in most patients with suspected IE. However, it is reasonable to begin with TEE in selected settings:
• Limited transthoracic windows (eg, due to obesity, chest wall deformity, or mechanical ventilation)
• Prosthetic valves, especially prosthetic aortic or mitral valves in which shadowing may make visualization difficult by TTE
• A prior valvular abnormality (including previous endocarditis)
• S. aureus bacteremia [15]
• Bacteremia due to an organism known to be a common cause of IE such as viridans streptococci
For patients with a normal TTE (both morphology and function), the likelihood of IE is very low [16] . A subsequent TEE is not necessary unless one or more of the following is present:
• A high clinical suspicion of IE (persistently positive blood cultures and/or multiple minor criteria for endocarditis) (show table 1 and show table 2)
• A technically limited TTE study
Some patients with abnormal on findings on TTE may require further evaluation by TEE. These include patients with significant valvular regurgitation in whom surgery is contemplated and patients who have one or more of the following risk factors for paravalvular abscess:
• Conduction delay by ECG that is not known to be old
• Persistent fever despite appropriate antimicrobial therapy
• Aortic valve endocarditis
(See "Complications and outcome of infective endocarditis", section on Paravalvular abscesses).
Controversies — There are a number of unresolved controversies related to the use of echocardiography in the diagnosis and management of patients with IE:
• Some experts recommend that all patients with suspected IE, especially those with staphylococcal bacteremia should have a TEE as the initial study [20] . However, we regard the steps outlined above as sufficient to exclude IE without TEE in many cases, and do not require that all patients undergo this invasive procedure.
• Some experts believe that patients with staphylococcal bacteremia associated with a condition (such as vertebral osteomyelitis) that will require a protracted course of antimicrobial therapy do not require echocardiography to rule out associated IE, especially if there are no hemodynamic signs or symptoms of IE. However, we recommend that echocardiography be performed in such patients, since a positive result will influence the type and intensity of follow-up examinations. (See "Complications and outcome of infective endocarditis").
• On theoretical grounds, some physicians delay echocardiography for several days after the onset of bacteremia, because both TTE and TEE can be falsely negative if vegetations are small (and, occasionally, if previously present vegetations have embolized). In addition, even TEE can miss a paravalvular abscess, especially if the study is done in the first few days of illness [21] .
The 2005 AHA guidelines on the diagnosis and management of IE, which were endorsed by the Infectious Diseases Society of America, recommend that echocardiography be performed as soon as possible after the diagnosis of IE is suspected [11] .
Histologic examination — Histologic demonstration of microorganisms, vegetations, or active endocarditis in cardiac valve tissue obtained at surgery is included in the Duke criteria and is considered to be a criterion of confirmed infective endocarditis (show table 1). The histologic features that characterize endocarditis were defined in a retrospective pathologic analysis of tissue adjoining mechanical cardiac valves in 90 patients who underwent surgical removal of a mechanical valve for suspected IE (21 patients) or noninfectious dysfunction (69 patients) [22] .
IE was characterized by microorganisms, vegetations, and significant neutrophil-rich inflammatory infiltrates with extensive neovascularization. In contrast, tissue adjoining valves from noninfectious complications showed extensive fibrosis and, when present, inflammatory infiltrates that were mainly composed of macrophages and lymphocytes.
Thus, when no microorganisms are detected and vegetations are lacking in tissue adjacent to a mechanical valve, neutrophil-rich inflammation and extensive neovascularization may allow differentiation between IE and inflammatory noninfectious valve processes in patients with mechanical cardiac valves who undergo surgery.
CULTURE-NEGATIVE ENDOCARDITIS — Culture-negative endocarditis should be considered in patients with negative blood cultures and persistent fever with one or more clinical findings consistent with IE (eg, stroke or other manifestations of emboli). Culture-negative IE should also be considered in patients with a vegetation on echocardiogram with no clear microbiologic diagnosis. Issues related to culture-negative IE are discussed separately. (See "Culture-negative endocarditis").
TREATMENT — Standard antimicrobial therapy for infective endocarditis is generally administered to patients characterized as definite or probable by the Duke criteria. Patients in whom the diagnosis is "rejected" by these criteria are not usually treated with prolonged antimicrobial therapy. (See "Antimicrobial therapy of native valve endocarditis").
SUMMARY
• The diagnosis of infective endocarditis (IE) is usually based upon a constellation of history, clinical findings, laboratory studies (particularly blood cultures), and echocardiography. (See "Introduction" above).
• Physical examination findings supporting a diagnosis of IE include new regurgitant murmurs or heart failure, evidence of embolic events (eg, focal neurologic impairment, glomerulonephritis, renal and splenic infarcts, and septic pulmonary infarcts), and peripheral cutaneous or mucocutaneous lesions (eg, petechiae, conjunctival or splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots). (See "Physical examination" above).
As part of the initial evaluation of all patients with suspected endocarditis the following studies should be performed:
- At least three blood cultures from separate sites over a time period ranging from a few hours to one to two days depending upon the severity of illness and urgency of the need for treatment. (See "Blood cultures" above).
- An electrocardiogram to evaluate for the presence of changes suggestive of ischemia or infarction or the presence or new appearance of heart block or conduction delay. (See "Electrocardiogram" above).
- Echocardiography. (See "Echocardiography" above).
Cultures remain negative in 2 to 5 percent of patients with endocarditis, which is referred to as culture-negative endocarditis. (See "Culture-negative endocarditis").
Diagnostic approach to infective endocarditis
Author
Daniel J Sexton, MD
Section Editor
Catherine M Otto, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 16.2: May 2008 | This topic last updated: March 21, 2008 (More)
INTRODUCTION — The diagnosis of infective endocarditis (IE) is usually based upon a constellation of clinical findings rather than a single definitive test result. The diagnosis is usually obvious when a patient has the characteristic findings of IE:
• Numerous positive blood cultures in the presence of a well recognized predisposing cardiac lesion
• Evidence of endocardial involvement
However, some patients with IE do not have positive blood cultures (ie, culture-negative endocarditis), and approximately one-third to one-fourth of patients have no identifiable predisposing cardiac lesion at disease onset. The presence of atypical features may result in misdiagnosis or a correct diagnosis that is greatly delayed. (See "Culture-negative endocarditis" below).
The general approach to the diagnosis of IE will be reviewed here. Risk factors for IE and antibiotic prophylaxis and treatment of IE are discussed separately. (See "Infective endocarditis: Epidemiology and risk factors" and see "Antimicrobial prophylaxis for bacterial endocarditis" and see "Antimicrobial therapy of native valve endocarditis" and see "Antimicrobial therapy of prosthetic valve endocarditis").
DIAGNOSTIC CRITERIA — The diagnosis of IE is based upon a careful history and physical examination, blood culture and laboratory results, an electrocardiogram (ECG), a chest radiograph, and an echocardiogram.
Debate persists as to the optimal case definition for IE. Practical and logical case definitions are important since underdiagnosis can lead to clinical catastrophe and death, while overdiagnosis can result in weeks of unnecessary antimicrobial therapy with excessive costs and potentially avoidable drug-related side effects. It can, for example, be difficult to distinguish between IE and an alternate source of infection in a bacteremic patient with underlying heart disease.
Several sets of criteria for IE have been described. The most commonly accepted are the Duke criteria (show table 1 and show table 2 and show Calculator). (See "Infective endocarditis: Historical and Duke criteria", section on Duke criteria).
HISTORY — During the initial assessment of patients with suspected endocarditis, a careful history should be performed with special attention given to a history of prior cardiac lesions and historical clues pointing toward a recent source of bacteremia, such as indwelling intravascular catheters or intravenous drug use.
PHYSICAL EXAMINATION — The physical examination should include a careful cardiac examination for signs of new regurgitant murmurs or heart failure (see "Auscultation of cardiac murmurs").
A vigorous search should be undertaken for the classic clinical stigmata of endocarditis, including evidence of small and large emboli with special attention to the fundi, conjunctivae, skin, and digits. A neurologic evaluation may reveal evidence of focal neurologic impairment; it can also be used as a baseline examination should such abnormalities appear later. (See "Complications and outcome of infective endocarditis").
Associated peripheral cutaneous or mucocutaneous lesions of IE include petechiae, splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots. Petechiae are not specific for IE but are its most common skin manifestation. They may be present on the skin, usually on the extremities, or on mucous membranes such as the palate or conjunctivae, the latter usually as hemorrhages best seen with eversion of either upper or lower eyelids. Splinter hemorrhages, also nonspecific for endocarditis, are nonblanching, linear reddish-brown lesions found under the nail bed (show picture 1).
Janeway lesions, Osler's nodes, and Roth spots are more specific (but still not diagnostic) for IE. They are also less common, and Roth spots are rare.
• Janeway lesions are macular, blanching, nonpainful, erythematous lesions on the palms and soles (show picture 2).
• Osler's nodes are painful, violaceous nodules found in the pulp of fingers and toes and are seen more often in subacute than acute cases of IE (show picture 3).
• Roth spots are exudative, edematous hemorrhagic lesions of the retina.
In addition to these physical findings, patients with IE may have involvement of other organs due to embolic events (eg, focal neurologic deficits, renal and splenic infarcts) or a systemic immune reaction (eg, glomerulonephritis, arthritis). In right-sided endocarditis, septic pulmonary infarcts may be seen (show picture 4). (See "Complications and outcome of infective endocarditis" and see "Renal disease in infective endocarditis").
LABORATORY STUDIES
Blood cultures
Collection — Blood cultures should be obtained prior to antibiotic therapy. This was illustrated in a prospective study of 348 patients with suspected culture-negative endocarditis; among the 73 patients without an identifiable etiologic agent, 58 (79 percent) received antibiotics before blood cultures were obtained [9] .
A minimum of three blood cultures should be obtained over a time period based upon the severity of the illness. If the tempo of illness is subacute and the patient is not critically ill, it is reasonable and often preferable to delay therapy for one to three days while awaiting the results of blood cultures and other diagnostic tests. However, if the patient is acutely ill, three blood cultures should be obtained over a one hour time span before beginning empiric therapy. Almost all cases of bacterial IE are due to aerobic organisms; thus, culturing for anaerobes is rarely useful. (See "Blood cultures for the detection of bacteremia").
The additional diagnostic yield of more than three cultures is minimal in patients who have not recently received antimicrobial therapy. In a series of 206 cases of endocarditis, for example, the initial blood culture in patients with streptococcal endocarditis was positive in 96 percent and one of the first two blood cultures was positive in 98 percent; in patients with IE caused by bacteria other than streptococci, the first blood culture was positive in 82 percent and one of the first two cultures was positive in 100 percent [1] . Additional blood cultures are occasionally useful in patients who have been treated recently with antibiotics.
The bacteriologic diagnosis of IE is facilitated by the relative constancy, rather than random, release of bacteria from the cardiac vegetations [2] . However, since many patients with bacterial endocarditis have low grade bacteremia (eg, 1 to 10 CFU/mL of blood) [1] , a minimum of 10 mL (and preferably 20 mL) of blood should be obtained from adults and 0.5 to 5 mL from infants and children. In one study, blood cultures inoculated with at least 5 mL of blood had a significantly higher detection rate for bacteremia than bottles inoculated with less than 5 mL of blood (92 versus 69 percent) [3] . The estimated yield of blood cultures in bacteremic adults increased approximately 3 percent per mL of blood cultured.
Each set of cultures should be obtained from separate venipuncture sites. Blood cultures can be taken at any time; they do not need to be obtained with the appearance of chills or fever since patients with IE typically have a continuous bacteremia. (See "Blood cultures for the detection of bacteremia").
Organism — Not all microorganisms have the same propensity to cause endocarditis. As an example, organisms such as viridans streptococci and Staphylococcus aureus are more likely to cause endocarditis than are gram-negative rods such as Escherichia coli and Proteus spp. This distinction is important. The Duke Criteria for the diagnosis of endocarditis define the following organisms as "typical causes" of IE (show table 1 and show table 2) [4] :
• Staphylococcus aureus
• Viridans streptococci and Streptococcus bovis
• Enterococci
• HACEK group organisms (show table 2)
It was previously thought that patients who present with community-acquired enterococcal bacteremia are significantly more likely to have endocarditis than patients who develop enterococcal bacteremia while hospitalized for another cause [5] . However, this conclusion has been questioned as a result of a case-control study that compared the clinical and demographic characteristics of all patients with enterococcal endocarditis seen at a single center over eight years with controls randomly chosen from 455 patients with enterococcal bacteremia without endocarditis [6] . Community acquisition of bacteremia was not a risk factor for IE.
The probability of endocarditis varies by species of bacteria. As examples:
• S. sanguis bacteremia is more often indicative of endocarditis than is bacteremia due to S. milleri (also known as S. anginosus).
• Bacteremia with groups A or C streptococci are seldom associated with IE whereas group G streptococcal infection is often indicative of endocarditis [7] . (See "Group C and group G streptococcal infection").
• In a study of enterococcal bacteremia cited above, infection with E. faecalis, compared to other enterococcal species, was associated with IE by both univariate and multivariate analysis [6] .
The risk of endocarditis in patients with S. aureus bacteremia (regardless of source or residence at the time of onset) is particularly high. As a result, all patients with S. aureus recovered from the blood should be clinically evaluated for IE. (See "Complications of Staphylococcus aureus bacteremia").
Positive cultures — The interpretation of positive blood cultures in patients with suspected endocarditis is confounded by the fact that false-positive results occasionally occur despite use of the most exacting techniques for collection and processing. When organisms such as Propionibacterium spp., Corynebacterium spp., Bacillus spp., and coagulase-negative staphylococci are recovered from a single blood culture or a minority of blood culture bottles, the result is probably falsely positive. However, since all of these organisms are capable of causing endocarditis, it is important to determine if the bacteremia is persistent. (See "Endocarditis due to coagulase-negative staphylococci").
The definition of persistent bacteremia varies with the likelihood that the organism is a cause of endocarditis [4] :
• For an organism likely to cause endocarditis (eg, S. aureus, viridans streptococci), two positive samples collected more than 12 hours apart
• For an organism that is more commonly a skin contaminant, three or a majority of four or more separate blood cultures are positive and the first and last samples are collected at least one hour apart
Additional tests — The utility of other laboratory tests in the diagnosis of endocarditis is limited, other than the finding of an antiphase I IgG titer >1:800 for Coxiella burnetii [8] .
The following findings may be identified among patients with IE but are relatively nonspecific:
• An elevated erythrocyte sedimentation rate and/or an elevated level of C-reactive protein.
• A normochromic normocytic anemia.
• The white blood cell count may be normal or elevated in patients with subacute presentations of endocarditis; however, most patients with staphylococcal endocarditis have leukocytosis and some may have thrombocytopenia.
• Hyperglobulinemia, cryoglobulins, circulating immune complexes, hypocomplementemia, elevated rheumatoid factor titers, and false positive serologic tests for syphilis all occur in some patients.
An elevated rheumatoid factor titer in patients without a known prior rheumatologic disorder is one of six minor criteria in the Duke diagnostic scheme (show table 2) [4] . (See "Origin and utility of measurement of rheumatoid factors").
Most patients with endocarditis have an abnormal urinalysis, as manifested by microscopic or gross hematuria, proteinuria, and/or pyuria. Each of these findings lacks specificity. However, the presence of red blood cell casts on urinalysis is generally indicative of glomerulonephritis (often in association with hypocomplementemia) and is a minor diagnostic criterion for IE (show table 2) [4] . (See "Renal disease in infective endocarditis").
Electrocardiogram — We recommend that a baseline electrocardiogram be performed as part of the initial evaluation of all patients with suspected endocarditis even though this test rarely shows diagnostic findings. The presence or subsequent appearance of changes suggestive of ischemia or infarction on the electrocardiogram may provide useful clues to the presence of emboli to the coronary circulation. In addition, the initial presence or new appearance of heart block or conduction delay may provide an important clue to extension of infection to the valve annulus and adjacent septum. (See "Complications and outcome of infective endocarditis").
Chest radiograph — Chest radiographs occasionally reveal important diagnostic clues. As an example, patients with tricuspid valve endocarditis often present with radiographic evidence of septic pulmonary emboli. In such cases, there may be a few or multiple focal lung infiltrates, which may reveal central cavitation. Rarely, chest radiographs show calcification in a cardiac valve, which may raise suspicions of endocarditis in a febrile patient.
Echocardiography — The 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of patients with valvular heart disease included recommendations for the use of transthoracic and transesophageal echocardiography in patients with suspected or proven native or prosthetic valve endocarditis (show table 3) [10] . These recommendations are generally consistent with the 2005 AHA guidelines on infective endocarditis, which were endorsed by the Infectious Diseases Society of America [11] .
The information that can be obtained by echocardiography includes:
• Evaluation of patients in settings in which endocarditis is suspected (such as persistent bacteremia without a known source or high clinical suspicion with negative cultures)
• Detection and characterization of vegetations on valves and in other sites (as in patients with congenital heart disease)
• Detection of valvular dysfunction and assessment of hemodynamic severity
• Detection of associated abnormalities such as shunts or abscesses
• Re-evaluation of patients in complex settings (such as those with virulent organisms, severe hemodynamic effects, persistent or recurrent fever or bacteremia, or clinical deterioration)
An echocardiogram should be performed in all patients with a moderate or high suspicion of endocarditis (show table 1 and show table 2). In comparison, among patients with a low clinical probability of endocarditis, the diagnostic yield of both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) is very low, and neither should be performed [12] . (See "Infective endocarditis: Historical and Duke criteria", section on Case definitions).
Role of TTE — Transthoracic echocardiography may provide confirmation of the diagnosis of endocarditis. Detection of a vegetation is a positive test show echocardiogram 1 show echocardiogram 2 show echocardiogram 3. (See "Role of echocardiography in infective endocarditis").
However, TTE has relatively low sensitivity for vegetation in IE (29 to 63 percent in different series) [13-15] . Thus, the absence of vegetation does not preclude the diagnosis and, as described in the next section, TEE is usually warranted. However, the finding of normal valves (both morphology and function) substantially reduces the probability of IE. In one study, 96 percent of patients with normal valves and no vegetation on TTE also had a negative TEE [16] .
In contrast to the variable sensitivity, TTE has a specificity (the likelihood of a negative result in a patient without disease) approaching 100 percent, indicating very few false positive studies [13] .
Role of TEE — Transesophageal echocardiography has a higher spatial resolution than TTE and is much more sensitive for the detection of endocarditis show echocardiogram 4 show echocardiogram 5. TEE is especially useful for the detection of vegetations, diagnosis of prosthetic valve endocarditis, detection of a valve abscess, and assessment of embolic risk.
• Detection of vegetations — Two series with a total of 162 episodes of suspected IE demonstrated the greater sensitivity of TEE compared to TTE (100 versus 63 percent and 94 versus 44 percent, respectively) [13,14] . In a third report of 103 patients with S. aureus bacteremia, TTE revealed valvular abnormalities in 33 patients and vegetations in seven; in contrast, TEE identified vegetations in 22 patients and abscesses in two [15] .
• Diagnosis of IE on prosthetic valves — TEE is especially important for prosthetic valves in the mitral or aortic position, because acoustic shadowing frequently makes the transthoracic approach suboptimal. TEE has superior spatial resolution, and bacteremic patients with these prostheses are at increased risk for endocarditis show echocardiogram 6. Few data are available regarding the superiority of TEE for suspected endocarditis of tricuspid and pulmonic prostheses, but presumably it would be similar. (See "Role of echocardiography in infective endocarditis", section on Prosthetic valve endocarditis).
The greater value of TEE in patients with prosthetic heart valves was demonstrated in a prospective study that compared TTE and TEE in 114 episodes of IE suspected on clinical grounds (80 on native valves and 34 on prosthetic valves) [17] . The results of the two tests were concordant in 55 percent of cases; TEE led to a reclassification in 11 percent of patients with native valves and 34 percent with prosthetic valves.
The negative predictive value of TEE is nearly 100 percent for patients with native valves, but IE can be missed in patients with prosthetic valves. In the latter patients, clinical assessment is especially important.
• Detection of a valve abscess — TEE is much more sensitive than TTE for the detection of valve abscess. This was illustrated in a series of 44 patients with IE complicated by abscess formation (sensitivity 87 versus 28 percent with TTE) [18] .
While TEE is generally much more sensitive than TTE for detection of abscess, even TEE may miss a significant number of abscesses in some populations. This was illustrated in a report of 44 patients with endocarditis by Duke criteria who had valvular abscesses identified intraoperatively. Endocarditis was detected by TEE in only 48 percent of cases; prosthetic heart valves were present in 32 percent of patients. Indications for surgery included severe valvular dysfunction (with or without heart failure), embolization during antibiotic therapy, or concommitant pacemaker infection [19] . Abscesses not visualized by TEE were located at the posterior mitral annulus in 61 percent of cases; the majority of these were associated with a large calcification, which may have interfered with detection.
• Assessment of embolic risk — In general, larger vegetation size is associated with increased risk of embolization. This issue is discussed separately. (See "Role of echocardiography in infective endocarditis" section on Echocardiographic estimation of outcome).
Recommended use — We generally perform a TTE as the first diagnostic test in most patients with suspected IE. However, it is reasonable to begin with TEE in selected settings:
• Limited transthoracic windows (eg, due to obesity, chest wall deformity, or mechanical ventilation)
• Prosthetic valves, especially prosthetic aortic or mitral valves in which shadowing may make visualization difficult by TTE
• A prior valvular abnormality (including previous endocarditis)
• S. aureus bacteremia [15]
• Bacteremia due to an organism known to be a common cause of IE such as viridans streptococci
For patients with a normal TTE (both morphology and function), the likelihood of IE is very low [16] . A subsequent TEE is not necessary unless one or more of the following is present:
• A high clinical suspicion of IE (persistently positive blood cultures and/or multiple minor criteria for endocarditis) (show table 1 and show table 2)
• A technically limited TTE study
Some patients with abnormal on findings on TTE may require further evaluation by TEE. These include patients with significant valvular regurgitation in whom surgery is contemplated and patients who have one or more of the following risk factors for paravalvular abscess:
• Conduction delay by ECG that is not known to be old
• Persistent fever despite appropriate antimicrobial therapy
• Aortic valve endocarditis
(See "Complications and outcome of infective endocarditis", section on Paravalvular abscesses).
Controversies — There are a number of unresolved controversies related to the use of echocardiography in the diagnosis and management of patients with IE:
• Some experts recommend that all patients with suspected IE, especially those with staphylococcal bacteremia should have a TEE as the initial study [20] . However, we regard the steps outlined above as sufficient to exclude IE without TEE in many cases, and do not require that all patients undergo this invasive procedure.
• Some experts believe that patients with staphylococcal bacteremia associated with a condition (such as vertebral osteomyelitis) that will require a protracted course of antimicrobial therapy do not require echocardiography to rule out associated IE, especially if there are no hemodynamic signs or symptoms of IE. However, we recommend that echocardiography be performed in such patients, since a positive result will influence the type and intensity of follow-up examinations. (See "Complications and outcome of infective endocarditis").
• On theoretical grounds, some physicians delay echocardiography for several days after the onset of bacteremia, because both TTE and TEE can be falsely negative if vegetations are small (and, occasionally, if previously present vegetations have embolized). In addition, even TEE can miss a paravalvular abscess, especially if the study is done in the first few days of illness [21] .
The 2005 AHA guidelines on the diagnosis and management of IE, which were endorsed by the Infectious Diseases Society of America, recommend that echocardiography be performed as soon as possible after the diagnosis of IE is suspected [11] .
Histologic examination — Histologic demonstration of microorganisms, vegetations, or active endocarditis in cardiac valve tissue obtained at surgery is included in the Duke criteria and is considered to be a criterion of confirmed infective endocarditis (show table 1). The histologic features that characterize endocarditis were defined in a retrospective pathologic analysis of tissue adjoining mechanical cardiac valves in 90 patients who underwent surgical removal of a mechanical valve for suspected IE (21 patients) or noninfectious dysfunction (69 patients) [22] .
IE was characterized by microorganisms, vegetations, and significant neutrophil-rich inflammatory infiltrates with extensive neovascularization. In contrast, tissue adjoining valves from noninfectious complications showed extensive fibrosis and, when present, inflammatory infiltrates that were mainly composed of macrophages and lymphocytes.
Thus, when no microorganisms are detected and vegetations are lacking in tissue adjacent to a mechanical valve, neutrophil-rich inflammation and extensive neovascularization may allow differentiation between IE and inflammatory noninfectious valve processes in patients with mechanical cardiac valves who undergo surgery.
CULTURE-NEGATIVE ENDOCARDITIS — Culture-negative endocarditis should be considered in patients with negative blood cultures and persistent fever with one or more clinical findings consistent with IE (eg, stroke or other manifestations of emboli). Culture-negative IE should also be considered in patients with a vegetation on echocardiogram with no clear microbiologic diagnosis. Issues related to culture-negative IE are discussed separately. (See "Culture-negative endocarditis").
TREATMENT — Standard antimicrobial therapy for infective endocarditis is generally administered to patients characterized as definite or probable by the Duke criteria. Patients in whom the diagnosis is "rejected" by these criteria are not usually treated with prolonged antimicrobial therapy. (See "Antimicrobial therapy of native valve endocarditis").
SUMMARY
• The diagnosis of infective endocarditis (IE) is usually based upon a constellation of history, clinical findings, laboratory studies (particularly blood cultures), and echocardiography. (See "Introduction" above).
• Physical examination findings supporting a diagnosis of IE include new regurgitant murmurs or heart failure, evidence of embolic events (eg, focal neurologic impairment, glomerulonephritis, renal and splenic infarcts, and septic pulmonary infarcts), and peripheral cutaneous or mucocutaneous lesions (eg, petechiae, conjunctival or splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots). (See "Physical examination" above).
As part of the initial evaluation of all patients with suspected endocarditis the following studies should be performed:
- At least three blood cultures from separate sites over a time period ranging from a few hours to one to two days depending upon the severity of illness and urgency of the need for treatment. (See "Blood cultures" above).
- An electrocardiogram to evaluate for the presence of changes suggestive of ischemia or infarction or the presence or new appearance of heart block or conduction delay. (See "Electrocardiogram" above).
- Echocardiography. (See "Echocardiography" above).
Cultures remain negative in 2 to 5 percent of patients with endocarditis, which is referred to as culture-negative endocarditis. (See "Culture-negative endocarditis").
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