Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

89. Infective Endocarditis

Angie Veverka, Michael A. Crouch, and Brian L. Odle


KEY CONCEPTS

 Images Infective endocarditis is an uncommon infection usually occurring in persons with preexisting cardiac valvular abnormalities (e.g., prosthetic heart valves) or with other specific risk factors (e.g., IV drug abuse).

 Images Three groups of organisms cause a majority of infective endocarditis cases: streptococci, staphylococci, and enterococci.

 Images The clinical presentation of infective endocarditis is highly variable and nonspecific, although a fever and murmur are usually present. Classic peripheral manifestations (e.g., Osler’s nodes) may or may not occur.

 Images The diagnosis of infective endocarditis requires the integration of clinical, laboratory, and echocardiographic findings. The two major diagnostic criteria are bacteremia and echocardiographic changes (e.g., valvular vegetation).

 Images Treatment of infective endocarditis involves isolation of the infecting pathogen and determination of antimicrobial susceptibilities, followed by high-dose, parenteral, bactericidal antibiotics for an extended period.

 Images Surgical replacement of the infected heart valve is an important adjunct to endocarditis treatment in certain situations (e.g., patients with acute heart failure).

 Images β-Lactam antibiotics, such as penicillin G (or ceftriaxone), nafcillin, and ampicillin, remain the drugs of choice for streptococcal, staphylococcal, and enterococcal endocarditis, respectively.

 Images Aminoglycoside antibiotics are essential to obtain a synergistic bactericidal effect in the treatment of enterococcal endocarditis. Adjunctive aminoglycosides also may decrease the emergence of resistant organisms (e.g., prosthetic valve endocarditis caused by coagulase-negative staphylococci) and hasten the pace of clinical and microbiologic response (e.g., some streptococcal and staphylococcal infections).

 Images Vancomycin is reserved for patients with immediate β-lactam allergies and the treatment of resistant organisms.

 Images Antimicrobial prophylaxis is used as an attempt to prevent infective endocarditis for patients who are at the highest risk (such as persons with prosthetic heart valves) before a bacteremia-causing procedure (e.g., dental extraction).


Endocarditis is an inflammation of the endocardium, the membrane lining the chambers of the heart and covering the cusps of the heart valves.1,2 More commonly, endocarditis refers to infection of the heart valves by various microorganisms. Although it typically affects native valves, it also may involve nonvalvular areas or implanted mechanical devices (e.g., mechanical heart valves). Bacteria primarily cause endocarditis, but fungi and other atypical microorganisms can lead to the disease; hence, the more encompassing term infective endocarditis is preferred.2,3

Endocarditis is often referred to as acute or subacute depending on the pace and severity of the clinical presentation. The acute, fulminating form is associated with high fevers and systemic toxicity. Virulent bacteria, such as Staphylococcus aureus, frequently cause this syndrome, and if untreated, death may occur within days to weeks. On the other hand, subacute infective endocarditis is more indolent, and it is caused by less invasive organisms, such as viridans streptococci, usually occurring in preexisting valvular heart disease. Although infective endocarditis is often referred to as acute or subacute, it is best classified based on the etiologic organism, the anatomic site of infection, and pathogenic risk factors.1,4,5 Infection also may follow surgical insertion of a prosthetic heart valve, resulting in prosthetic valve endocarditis (PVE), or insertion of a cardiac implantable electronic device, resulting in cardiac device infective endocarditis (CDIE).6,7

EPIDEMIOLOGY AND ETIOLOGY

Infective endocarditis is an uncommon, but not rare, infection. Population-based studies have reported incidence rates of 2 to 15 cases per 100,000 person-years.1,8,9 In the United States, the infection is listed as the primary or secondary diagnosis of 28,000 hospital discharges.10 The mean male-to-female ratio is approximately 2:1.11 As the population ages and as valve replacement surgery becomes more common, the mean age of patients with infective endocarditis increases. Overall, most cases occur in individuals older than 50 years of age, and it is uncommon in children.1114 PVE and CDIE account for 20% and 6.4% of cases of infective endocarditis, respectively.11,15 Those with a history of IV drug abuse (IVDA) are also at high risk. Of note, the incidence of healthcare-associated infective endocarditis is rising, especially in the elderly population.11,12 Other conditions associated with a higher incidence of infective endocarditis include diabetes, long-term hemodialysis, and poor dental hygiene.5

Images Most persons with infective endocarditis have risk factors, such as preexisting cardiac valvular abnormalities. Many types of structural heart disease result in turbulent blood flow that increases the risk for infective endocarditis. A predisposing risk factor, however, may be absent in up to 25% of cases. Some of the more important risk factors include5,7,11,13,16:

   1. Presence of a prosthetic valve (highest risk)

   2. Previous endocarditis (highest risk)

   3. Congenital heart disease (CHD)

   4. Chronic IV access

   5. Diabetes mellitus

   6. Healthcare-related exposure

   7. Acquired valvular dysfunction (e.g., rheumatic heart disease)

   8. Cardiac implantable device

   9. Chronic heart failure

   10. Mitral valve prolapse with regurgitation

   11. IVDA

In the past, rheumatic heart disease was a prevalent risk factor for infective endocarditis, but the incidence of this disease continues to decline. The risk of infective endocarditis in persons with mitral valve prolapse and regurgitation is small; however, because the condition is prevalent, it is an important contributor to the overall number of infective endocarditis cases.5,11 PVE occurs in 1% to 3% of patients undergoing valve replacement surgery in the first postoperative year.11,17

Images Nearly every organism causing human disease may cause infective endocarditis, but three groups of organisms result in a majority of cases: streptococci, staphylococci, and enterococci (Table 89–1).1,3,4,11,16 The incidence of staphylococci, particularly S. aureus, continues to increase, and case series have documented that staphylococci have surpassed viridans streptococci as the leading cause of infective endocarditis.11,16 In general, streptococci cause infective endocarditis in patients with community-acquired disease and underlying cardiac abnormalities, such as mitral valve prolapse or rheumatic heart disease. Staphylococci (S. aureus and coagulase-negative staphylococci) are the most common cause of PVE within the first year after valve surgery, and S. aureus is common in those with a history of IVDA. Although polymicrobial infective endocarditis is uncommon, it is encountered most often in association with IVDA.1,11,16 Enterococcal endocarditis tends to follow genitourinary manipulations or obstetric procedures.17 There are many exceptions to the preceding generalizations; thus, isolation of the causative pathogen and determination of its antimicrobial susceptibilities offer the best chance for successful therapy.

TABLE 89-1 Etiologic Organisms in Infective Endocarditisa

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The mitral and aortic valves are affected most commonly in cases involving a single valve. Subacute endocarditis tends to involve the mitral valve, whereas acute disease often involves the aortic valve. Up to 35% of cases involve concomitant infections of both the aortic and the mitral valves. Infection of the tricuspid valve is less common, with a majority of these cases occurring in patients with a history of IVDA. It is rare for the pulmonary valve to be infected.11,16,17

Pathophysiology

The development of infective endocarditis via hematogenous spread, the most common route, requires the sequential occurrence of several factors. These components are complex and not fully elucidated.18,19

   1. The endothelial surface of the heart is damaged. This injury occurs with turbulent blood flow associated with the valvular lesions previously described.

   2. Platelet and fibrin deposition occurs on the abnormal epithelial surface. These platelet–fibrin deposits are referred to as nonbacterial thrombotic endocarditis.

   3. Bacteremia gives organisms access to and results in colonization of the endocardial surface. Bacteremia is the result of trauma to a mucosal surface with a high concentration of resident bacteria, such as the oral cavity and GI tract. Transient bacteremia commonly follow certain dental, GI, urologic, and gynecologic procedures. Staphylococci, viridans streptococci, and enterococci are most likely to adhere to nonbacterial thrombotic endocarditis, probably because of production of specific adherence factors, such as dextran by some oral streptococci and glycocalyx for staphylococci. Gram-negative bacteria rarely adhere to heart valves and are uncommon causes of infective endocarditis.

   4. After colonization of the endothelial surface, a “vegetation” of fibrin, platelets, and bacteria forms. The protective cover of fibrin and platelets allows unimpeded bacterial growth to concentrations as high as 109 to 1010organisms per gram of tissue.

The pathogenesis of early PVE or CDIE differs from infective endocarditis acquired by the hematogenous route because surgery may directly inoculate prosthetic material with bacteria from the patient’s skin or operating room personnel. In the case of early PVE, a recently placed nonendothelialized valve is more susceptible to bacterial colonization than are native valves. Bacteria also may colonize the new valve from contaminated bypass pumps, cannulas, and pacemakers or from a nosocomial bacteremia subsequent to an intravascular catheter.7,16,17 The mechanism of bacterial colonization and pathogenesis in late PVE is similar to native valve endocarditis (NVE).17

The vegetations seen in infective endocarditis may be single or multiple and vary in size from a few millimeters to centimeters. Bacteria within the vegetation grow slowly and are protected from antibiotics and host defenses. The adverse effects of infective endocarditis and the resulting lesions can be far-reaching and include (a) local perivalvular damage, (b) embolization of septic fragments with potential hematogenous seeding of remote sites, and (c) formation of antibody complexes.17,19

Formation of vegetations may destroy valvular tissue, and continued destruction can lead to acute heart failure via perforation of the valve leaflet, rupture of the chordae tendineae or papillary muscle, or, for patients with PVE, valve dehiscence. Occasionally, valvular stenosis may occur. Abscesses can develop in the valve ring or in myocardial tissue itself. Even with resolution of the process, fibrosis of tissue with some residual dysfunction is possible.

Vegetations may be friable, and fragments may be released downstream. These infected particles, termed septic emboli, can result in organ abscess or infarction. Septic emboli from right-sided endocarditis commonly lodge in the lungs, causing pulmonary abscesses. Emboli from left-sided vegetations commonly affect organs with high blood flow, such as the kidneys, spleen, and brain.17,19

Circulating immune complexes consisting of antigen, antibody, and complement may deposit in organs, producing local inflammation and damage (e.g., glomerulonephritis in the kidneys). Other potential pathologic changes that result from immune-complex deposition or septic emboli include the development of “mycotic” aneurysms (although the aneurysm is usually bacterial in origin, not fungal), cerebral infarction, splenic infarction and abscess, and skin manifestations such as petechiae, Osler’s nodes, and Janeway’s lesions.5,17,19

CLINICAL PRESENTATION

Images The clinical presentation of infective endocarditis is highly variable and nonspecific. Fever is the most common finding and is often accompanied by other vague symptoms (Table 89–2). Fever may be relatively low grade, particularly in subacute cases. Heart murmurs are found in a majority of patients, most often preexisting, with some documented as new or changing. Infective endocarditis usually begins insidiously and worsens gradually. Patients may present with nonspecific findings, such as fever, chills, weakness, dyspnea, night sweats, weight loss, or malaise. In contrast, patients with acute disease, such as those with a history of IVDA and S. aureus infective endocarditis, may appear with classic signs of sepsis.

TABLE 89-2 Clinical Presentation of Infective Endocarditis

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Splenomegaly is a frequent finding for patients with prolonged endocarditis. Other important clinical signs especially prevalent in subacute illness may include the following peripheral manifestations (“stigmata”) of endocarditis5,11,12,16:

   1. Osler’s nodes: Purplish or erythematous subcutaneous papules or nodules on the pads of the fingers and toes. These lesions are 2 to 15 mm in size and are painful and tender. These nodes are not specific for infective endocarditis and may be the result of embolism, immunologic phenomena, or both.

   2. Janeway’s lesions: Hemorrhagic, painless plaques on the palms of the hands or soles of the feet. These lesions are believed to be embolic in origin.

   3. Splinter hemorrhages: Thin, linear hemorrhages found under the nail beds of the fingers or toes. These lesions are not specific for infective endocarditis and more commonly are the result of traumatic injuries. Distal lesions are more likely the result of trauma, whereas proximal lesions tend to be associated with infective endocarditis.

   4. Petechiae: Small (usually 1 to 2 mm in diameter), erythematous, painless, hemorrhagic lesions. These lesions appear anywhere on the skin but more frequently on the anterior trunk, buccal mucosa and palate, and conjunctivae. Petechiae are nonblanching and resolve after a few days.

   5. Clubbing of the fingers: Proliferative changes in the soft tissues about the terminal phalanges observed in long-standing endocarditis.

   6. Roth’s spots: Retinal infarct with central pallor and surrounding hemorrhage.

   7. Emboli: Embolic phenomena occur in up to one third of cases and may result in significant complications. Left-sided endocarditis can result in renal artery emboli causing flank pain with hematuria, splenic artery emboli causing abdominal pain, and cerebral emboli, which may result in hemiplegia or alteration in mental status. Right-sided endocarditis may result in pulmonary emboli, causing pleuritic pain with hemoptysis.

Patients with infective endocarditis typically have laboratory abnormalities; however, none of these changes is specific for the disease. Anemia (normocytic, normochromic), leukocytosis, and thrombocytopenia may be present. The white blood cell count is often normal or only slightly elevated, sometimes with a mild left shift. Acute bacterial endocarditis, however, may present with an elevated white blood cell count, consistent with a fulminant infection. The erythrocyte sedimentation rate and C-reactive protein may be elevated in approximately 60% of patients. Often the urinary analysis is abnormal, with proteinuria and microscopic hematuria occurring in approximately 25% of individuals.5,11

The hallmark of infective endocarditis is a continuous bacteremia caused by bacteria shedding from the vegetation into the bloodstream; 90% to 95% of patients with infective endocarditis have positive blood cultures.1,11,17Three sets of blood cultures, each from separate venipuncture sites, should be collected over 24 hours, and antibiotics should be withheld until adequate blood cultures are obtained. On the other hand, if a patient has a toxic appearance, several blood cultures should be collected promptly, followed by immediate empirical antimicrobial treatment. The blood cultures for patients who have received previous antibiotics should be monitored more closely because pathogen growth may be suppressed.1 “Culture-negative” endocarditis describes a patient in whom a clinical diagnosis of infective endocarditis is likely but blood cultures do not yield a pathogen. This condition is often the consequence of previous antibiotic therapy, improperly collected blood cultures, or unusual organisms.4 When blood cultures from patients suspected of having infective endocarditis show no growth after 48 to 72 hours, the laboratory should be advised and cultures held for up to a month to detect growth of fastidious organisms.4

An electrocardiogram, chest radiograph, and echocardiogram are performed for patients suspected of endocarditis. The electrocardiogram rarely shows important diagnostic findings but may reveal heart block, suggesting extension of the infection. The chest radiograph may provide more diagnostic information, especially in a patient with right-sided endocarditis. Septic pulmonary emboli may occur, leading to multiple lung foci. The echocardiogram is the most important test and should be performed for all patients suspected of this infection.

Echocardiography plays an important role in the diagnosis and management of infective endocarditis.4 The chosen approach, transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE), depends on the clinical setting. The TEE technique is more sensitive for detecting vegetations (90% to 100%) as compared with TTE (58% to 63%), and TEE maintains good specificity (85% to 95%).1,4 TTE appears reasonable in the evaluation of children or adults in whom the clinical suspicion of infective endocarditis is relatively low.4,20 TEE is preferred in high-risk patients such as those with prosthetic heart valves, many CHDs, previous endocarditis, new murmur, heart failure, or other stigmata of endocarditis.4,21,22 The lack of vegetation on echocardiogram does not exclude infection even if the transesophageal approach is used. Conversely, the test may reveal an unsuspected large vegetation, extension of the disease into surrounding tissue, valvular defects, abscess formation, cordial rupture, or an intracardiac fistula. Thus, in addition to helping in the diagnosis of infective endocarditis, the echocardiogram allows the physician to evaluate hemodynamic stability and the need for urgent surgical intervention; it also provides a rough estimate of the likelihood of embolism.4,22

DIAGNOSIS

Images The signs and symptoms of infective endocarditis are not specific, and the diagnosis is often unclear. The identification of infective endocarditis requires the integration of clinical, laboratory, and echocardiographic findings. The Duke diagnostic criteria include major and minor variables (Table 89–3).23,24 Based on the number of major and minor criteria that are fulfilled, patients suspected of infective endocarditis are categorized into three separate groups: definite infective endocarditis, possible infective endocarditis, or infective endocarditis rejected.24

TABLE 89-3 Diagnosis of Infective Endocarditis According to the Modified Duke Criteria

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PROGNOSIS

The outcome for endocarditis is improved with rapid diagnosis, appropriate treatment (i.e., antimicrobial therapy, surgery, or both), and prompt recognition of complications should they arise. Factors associated with increased mortality include (a) heart failure, (b) increasing age, (c) endocarditis caused by resistant organisms such as fungi or gram-negative bacteria, (d) left-sided endocarditis caused by S. aureus, (e) paravalvular complications, (f) healthcare-acquired infection, and (g) PVE.4,5,11,16 The presence of heart failure has the greatest negative impact on the short-term prognosis.4 For left-sided native valve infective endocarditis, mortality rates range from 15% to 45%; lower rates (4% to 16%) occur with community-acquired disease that is most commonly caused by viridans streptococci. Higher rates (25% to 45%) occur with healthcare-associated disease that is more commonly caused by enterococci and staphylococci.1 Even higher rates of mortality are seen with unusually encountered organisms (e.g., mortality greater than 50% for Pseudomonas aeruginosa).4 The mortality rate for right-sided infective endocarditis associated with IVDA is generally low (e.g., less than 10%).1,4 For those who relapse after treatment for infective endocarditis, most will do so within the first 2 months after discontinuation of antimicrobials. Relapse rates for viridans streptococcus are generally low (2%), whereas relapse is more likely in those with enterococcal infection (8% to 20%) and PVE (10% to 15%).5,17 After appropriate treatment and recovery, the risk of morbidity and mortality following infective endocarditis persists for years, although it gradually declines annually. Morbidity remains elevated because of a greater likelihood of recurrent infective endocarditis, heart failure, and embolism or, if a valve is replaced, the risk of anticoagulation, valve thrombosis, or additional valve surgery.5,21

TREATMENT

Desired Outcomes

The desired outcomes for treatment and prophylaxis of infective endocarditis are to:

  1. Relieve the signs and symptoms of the disease

  2. Decrease morbidity and mortality associated with the infection

  3. Eradicate the causative organism with minimal drug exposure

  4. Provide cost-effective antimicrobial therapy determined by the likely or identified pathogen, drug susceptibilities, hepatic and renal function, drug allergies, and anticipated drug toxicities

  5. Prevent infective endocarditis from occurring or recurring in high-risk patients with appropriate prophylactic antimicrobials

General Approach to Treatment

Images The most important approach in the treatment of infective endocarditis is isolation of the infecting pathogen and determination of antimicrobial susceptibilities, followed by high-dose, parenteral, bactericidal antibiotics for an extended period.1,5,17 Identification of susceptibilities is crucial given the escalating level of antibiotic resistance to commonly encountered pathogens. Treatment usually is started in the hospital, but for select patients it is often completed in the outpatient setting so long as defervescence has occurred and followup blood cultures show no growth.5,25 Large doses of parenteral antimicrobials usually are necessary to achieve bactericidal concentrations within vegetations. An extended duration of therapy is required, even for susceptible pathogens, because microorganisms are enclosed within valvular vegetations and fibrin deposits. These barriers impair host defenses and protect microbes from phagocytic cells. In addition, high bacterial concentrations within vegetations may result in an inoculum effect that further resists killing (see eChap. 24 for additional discussion). Many bacteria are not actively dividing, further limiting the rate of bacterial death. For most patients, a minimum of 4 to 6 weeks of therapy is required.4

Nonpharmacologic Therapy

Images Surgery is an important adjunct in the management of both NVE and PVE. In most surgical cases, valvectomy and valve replacement are performed to remove infected tissue and to restore hemodynamic function. Indications for surgery include heart failure, persistent bacteremia, persistent vegetation, an increase in vegetation size, or recurrent emboli despite prolonged antibiotic treatment, valve dysfunction, paravalvular extension (e.g., abscess), or endocarditis caused by resistant organisms (e.g., fungi or gram-negative bacteria).4,26,27 More controversial is the appropriate timing of surgery as American and European guidelines have different criteria for emergent or urgent surgical intervention.26,27 Additionally, studies evaluating postsurgical outcomes and associated mortality are limited such that a specific risk prediction system has not been established.2832 Early surgery (e.g., within 48 hours) may be appropriate in patients with severe heart failure and large vegetations, whereas patients with septic shock, advanced age, or neurologic complications of infective endocarditis may have more detrimental outcomes.28,29,33,34


Clinical Controversy…

The role of surgery in the management of infective endocarditis has expanded; however, criteria to select patients and appropriate timing of surgery have not been well defined. Additionally, more studies are needed to evaluate postsurgical outcomes.

Pharmacologic Therapy

Specific treatment recommendations from the American Heart Association (AHA) provide guidance for the management of infective endocarditis, and these were updated in 2005.4 Guidelines published in 2009 by the European Society of Cardiology are consistent with the AHA guidelines.27 Both guidelines use an evidence-based scoring system where recommendations are given a classification as well as level of evidence. Class I recommendations are conditions for which there is evidence, general agreement, or both that a given procedure or treatment is useful and effective. Class II recommendations are conditions for which there is conflicting evidence, a divergence of opinion, or both about the usefulness/efficacy of a procedure or treatment (IIa implies the weight of evidence/opinion is in favor of usefulness/efficacy, whereas IIb implies usefulness/efficacy is less well established by evidence/opinion). Class III recommendations are conditions for which there is evidence, general agreement, or both that the procedure/treatment is not useful/effective and in some cases may be harmful. Level of evidence is listed as A (data derived from multiple randomized clinical trials), B (data derived from a single randomized trial or nonrandomized studies), and C (consensus opinion of experts).

Imagesβ-Lactam antibiotics, such as penicillin G (or ceftriaxone), nafcillin, and ampicillin, remain the drugs of choice for streptococcal, staphylococcal, and enterococcal endocarditis, respectively. Tables 89–4to 89-7 summarize these recommendations, which are discussed in more detail in the following sections. Tables 89–8 and 89-9 list drug dosing and monitoring recommendations for adult and pediatric patients. Because these guidelines focus on common causes of endocarditis, readers are referred to other references for more in-depth discussion of unusually encountered organisms.4,27,3537

TABLE 89-4 Treatment Options for Native Valve Endocarditis by Causative Organism

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TABLE 89-5 Treatment Options for Prosthetic Valve Endocarditis (PVE) by Causative Organism

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TABLE 89-6 Treatment Options for Native or Prosthetic Valve Endocarditis Caused by Enterococci

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TABLE 89-7 Treatment Options for Culture-Negative Endocarditis and Endocarditis Caused by Gram-Negative Organismsa

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TABLE 89-8 Drug Dosing Table for Treatment of Infective Endocarditisa

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TABLE 89-9 Drug Monitoring of Select Agents

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Images For some pathogens, such as enterococci, the use of synergistic antimicrobial combinations (including an aminoglycoside) is essential to obtain a bactericidal effect. Combination antibiotics also may decrease the emergence of resistant organisms during treatment (e.g., PVE caused by coagulase-negative staphylococci) and hasten the pace of clinical and microbiologic response (e.g., some streptococcal and staphylococcal infections). Occasionally, combination treatment will result in a shorter treatment course.

Streptococcal Endocarditis

Streptococci are a common cause of infective endocarditis, with most isolates being viridans streptococci. Viridans streptococci refer to a large number of different species, such as Streptococcus sanguinis, Streptococcus oralis, Streptococcus salivarius, Streptococcus mutans, and Gemella morbillorum.4 These bacteria are common inhabitants of the human mouth and gingiva, and they are especially common causes of endocarditis involving native valves.1,4,16 During dental surgery, and even when brushing the teeth, these organisms can cause a transient bacteremia. In susceptible individuals, this may result in infective endocarditis. Streptococcal endocarditis is usually subacute, and the response to medical treatment is very good. Streptococcus bovis is not a viridans streptococcus, but it is included in this treatment group because it is penicillin sensitive and requires the same treatment as viridans streptococci. S. bovis is a nonenterococcal group D Streptococcus that resides in the GI tract. Infective endocarditis caused by this organism is often associated with a GI pathology, especially colon carcinoma. Endocarditis caused by Streptococcus pneumoniae, Streptococcus pyogenes, and group B, C, and G streptococci are uncommon, and their treatment is not well defined.4,19

Antimicrobial regimens for viridans streptococci are well studied, and in uncomplicated cases, response rates as high as 98% can be expected. Viridans streptococci are penicillin susceptible, although some are more susceptible than others. Most are exquisitely sensitive to penicillin G and have minimal inhibitory concentrations (MICs) of less than 0.12 mcg/mL (mg/L).4,19 Approximately 10% to 20% are moderately susceptible (MIC 0.12 to 0.5 mcg/mL [mg/L]). This difference in in vitro susceptibility led to recommendations that the MIC be determined for all viridans streptococci and that the results be used to guide therapy. Some streptococci are deemed tolerant to the killing effects of penicillin, where the minimal bactericidal concentration (MBC) exceeds the MIC by 32 times. A tolerant organism is inhibited but not killed by an antibiotic normally considered bactericidal.4 Bactericidal activity is required for successful treatment of infective endocarditis; therefore, infections with a tolerant organism may relapse after treatment. Despite some animal studies of endocarditis suggesting that tolerant strains do not respond as readily to β-lactam therapy as nontolerant ones, this phenomenon is primarily a laboratory finding with little clinical significance.4,19 Treatment for tolerant strains is identical to that for nontolerant organisms, and measurement of the MBC is not recommended.4

An assortment of regimens can be used to treat uncomplicated NVE caused by fully susceptible viridans streptococci (Table 89–4). Two single-drug regimens consist of high-dose parenteral penicillin G or ceftriaxone for 4 weeks. If a shorter course of therapy is desired, the guidelines suggest either high-dose parenteral penicillin G or ceftriaxone in combination with an aminoglycoside.4 When used in select patients, this combination is as effective as 4 weeks of penicillin alone. Although streptomycin was listed in previous guidelines, gentamicin is the preferred aminoglycoside because serum drug concentrations are obtained easily, clinicians are more familiar with its use, and the few strains of streptococci resistant to the effects of streptomycin–penicillin remain susceptible to gentamicin–penicillin. Other aminoglycosides are not recommended.

The decision of which regimen to use depends on the perceived risk versus benefit. For example, a 2-week course of gentamicin in an elderly patient with renal impairment may be associated with ototoxicity, worsening renal function, or both. Furthermore, the 2-week regimen is not recommended for patients with known extracardiac infection. On the other hand, a 4-week course of penicillin alone generally entails greater expense, especially if the patient remains in the hospital. Monotherapy with once-daily ceftriaxone offers ease of administration, facilitates home healthcare treatment, and may be cost-effective.1,4,25

The British Society for Antimicrobial Chemotherapy guidelines suggest that all of the following conditions be present to consider a 2-week treatment regimen for penicillin-sensitive streptococcal endocarditis35:

   1. Penicillin-sensitive viridans streptococcus or S. bovis (penicillin MIC <0.1 mcg/mL [mg/L])

   2. No cardiovascular risk factors such as heart failure, aortic insufficiency, or conduction abnormalities

   3. No evidence of thromboembolic disease

   4. Native valve infection

   5. No vegetation of greater than 5 mm diameter on echocardiogram

   6. Clinical response within 7 days (the temperature should return to normal, the patient should feel well, and the patient’s appetite should return to normal)

Images When a patient has a history of an immediate-type hypersensitivity to penicillin, vancomycin should be chosen for infective endocarditis caused by viridans streptococci. When vancomycin is used, the addition of gentamicin is not recommended.4 Most patients who report a penicillin allergy have a negative penicillin skin test and consequently are at low risk of anaphylaxis.38 The published experience with penicillin is more extensive than with alternative regimens; consequently, a thorough allergy history must be obtained before a second-line therapy is administered.

For patients with complicated infections (e.g., extracardiac foci) or when the streptococcus has an MIC of 0.12 to less than or equal to 0.5 mcg/mL (mg/L), combination therapy with an aminoglycoside for the first 2 weeks and penicillin (higher dose) or ceftriaxone is recommended, followed by penicillin or ceftriaxone alone for an additional 2 weeks (Table 89–4).4 Some viridans streptococci have biologic characteristics that complicate diagnosis and treatment, previously referred to as nutritionally variant streptococci. Abiotrophia defectiva and Granulicatella species have nutritional deficiencies that hinder growth in routine culture media.4,5,19 These organisms require special broth supplemented with pyridoxal hydrochloride or cysteine. For patients infected with nutritionally variant streptococci or when the Streptococcus has an MIC of more than 0.5 mcg/mL (mg/L), treatment should follow the enterococcal endocarditis treatment guidelines.4

The rationale for combination therapy of penicillin-susceptible viridans streptococci is that enhanced activity against these organisms usually is observed when cell-wall–active agents are combined with aminoglycosides in vitro.39 Combined treatment results in quicker sterilization of vegetations in animal models of endocarditis and probably explains the high response rates observed for patients treated for a total of 2 weeks.4,40 The combined treatment, however, is not superior to penicillin alone. Some authors question the need for combination therapy in relatively resistant streptococci, emphasizing that few human data suggest that patients with endocarditis caused by these organisms respond less well to penicillin alone.39,41

For patients with endocarditis of prosthetic valves or other prosthetic material caused by viridans streptococci and S. bovis, choices of treatment are similar to those without prosthetic material (e.g., penicillin or ceftriaxone); however, treatment courses are extended to 6 weeks (Table 89–5). In fact, if the organism is relatively resistant, gentamicin is recommended for 6 weeks.

Whether extended-interval aminoglycoside dosing has a role in infective endocarditis continues to be debated. At this time, data support extended-interval dosing for the treatment of streptococcal infective endocarditis, and as compared with three-times-daily dosing this approach may have greater efficacy.4245 One study specifically evaluated the combination of ceftriaxone (2 g daily) with gentamicin (3 mg/kg daily) for 2 weeks compared with ceftriaxone (2 g daily) alone for 4 weeks for penicillin-sensitive streptococci. Both regimens were safe and effective with similar clinical cure rates at 3 months following treatment.40


Clinical Controversy…

In the past, the AHA guidelines recommended traditional aminoglycoside dosing (three times daily) whenever clinicians use these antibiotics. Extended-interval dosing (once-daily administration) is an intriguing dosing strategy, but data only support this approach for the treatment of streptococcal infective endocarditis.

Staphylococcal Endocarditis

Endocarditis caused by staphylococci has become more prevalent, mainly because of increased IVDA, more frequent use of peripheral and central venous catheters, and increased frequency of valve replacement surgery.46,47 S. aureus is the most common organism causing infective endocarditis among those with IVDA and persons with venous catheters. Coagulase-negative staphylococci (usually Staphylococcus epidermidis) are prominent causes of PVE.

Staphylococcal endocarditis is not a homogeneous disease; appropriate management requires consideration of several questions: Is the organism methicillin resistant? Should combination therapy be used? Is the infection on a native or prosthetic valve? Does the patient have a history of IVDA? Is the infection on the left or right side of the heart? Another consideration in staphylococcal endocarditis is that some organisms may exhibit tolerance to antibiotics. Similar to streptococci, however, the concern for tolerance among staphylococci should not affect antibiotic selection.4

Any patient who develops staphylococcal bacteremia is at risk for endocarditis. Many investigators have attempted to develop criteria that identify the bacteremic patient likely to have infective endocarditis.46In the past, patients were considered to be at high risk for infective endocarditis if S. aureus bacteremia was community acquired versus hospital acquired; however, nosocomial S. aureus bacteremia is now considered as a major criterion for development of infective endocarditis.23,24 The prevalence of infective endocarditis in patients with S. aureus bacteremia is approximately 25%, leading some authors to suggest that screening echocardiography be performed in all patients.48 In hospitalized patients with S. aureus bacteremia and an identified focus of infection, such as a vascular catheter, the risk of concomitant infective endocarditis is low, and treatment of the bacteremia can be reduced to 2 weeks. This approach applies only if the patient does not have a prosthetic valve or additional clinical evidence for endocarditis.49 Additionally, the following parameters predict higher risk of infective endocarditis for patients with S. aureus bacteremia: (a) the absence of a primary site of infection, (b) metastatic signs of infection, and (c) valvular vegetations detected by echocardiography.24,48

The recommended therapy for patients with left-sided, native valve infective endocarditis caused by methicillin-sensitive S. aureus (MSSA) is 6 weeks of nafcillin or oxacillin, often combined with a short course of gentamicin (Table 89–4). Four weeks of monotherapy with nafcillin or oxacillin may be sufficient for uncomplicated infections (no perivalvular abscess or septic metastatic complications). From in vitro studies, the combination of an aminoglycoside and penicillinase-resistant penicillin or vancomycin enhances the activity of these drugs for MSSA. In animal models of endocarditis, combinations of penicillin with an aminoglycoside eradicate organisms from vegetations more rapidly than penicillins alone.39,50 In most human studies, the addition of an aminoglycoside to nafcillin hastens the resolution of fever and bacteremia, but it does not affect survival or relapse rates and can increase renal toxicity.39,51,52 One small cohort study has demonstrated a decrease in recurrent bacteremia with combination therapy.53 Traditional twice- or three-times-daily dosing of aminoglycosides is recommended when administered for staphylococcal infective endocarditis; however, there is a report with gentamicin given once a day.54

If a patient has a mild, delayed allergy to penicillin, first-generation cephalosporins (such as cefazolin) are effective alternatives, but they should be avoided for patients with a history of immediate-type hypersensitivity reactions to penicillins (see Table 89–4). The potential for a true immediate-type allergy should be assessed carefully. A penicillin skin test should be conducted before giving antibiotic treatment to any patient with infective endocarditis caused by MSSA if there is a questionable penicillin allergy.55 Images For a patient with a positive skin test or a history of immediate hypersensitivity to penicillin, vancomycin is chosen. Vancomycin, however, kills S. aureus slowly and is regarded as inferior to penicillinase-resistant penicillins for MSSA.56 Alternatively, patients with immediate-type hypersensitivity reactions to penicillin who fail to respond to vancomycin therapy should be considered for penicillin desensitization.4 Generally, antibiotic therapy should be continued for 6 weeks. Unfortunately, left-sided infective endocarditis caused by S. aureus continues to have a poor prognosis, with a mortality rate between 17% and >50%.1,47 For reasons discussed in the following section, those with infective endocarditis associated with IVDA have a more favorable response to therapy.

During the past decade, staphylococci more commonly have become resistant to penicillinase-resistant penicillins (e.g., methicillin). Images Although vancomycin is still the most commonly selected alternative in these cases (see Table 89–4), susceptibility reports with MIC >2 mcg/mL (mg/L) and reports of vancomycin-resistant S. aureus strains are increasing.20 Literature has emerged documenting success with daptomycin or linezolid for these patients.5762 Based on available data, daptomycin (at a dose of 6 mg/kg/day) was approved by the FDA in 2006 for the treatment of S. aureus bacteremia associated with right-sided NVE and is now a recommended alternative.20,58 Higher doses of daptomycin (8 to 10 mg/kg/day) have been used in clinical practice and may be preferred by some experts, although prospective, randomized clinical trials are lacking.20,6365 To date, linezolid has not been approved by the FDA for use in endocarditis as most available data are based on case reports, and there is concern regarding use of a bacteriostatic agent for this condition.20,57,66 Furthermore, the FDA issued a warning for linezolid in 2007 following reports from one study that patients with catheter-related bacteremia treated with linezolid had an increased incidence of death due to gram-negative bacillary infections.67 The presence or lack of a prosthetic heart valve in patients with a methicillin-resistant organism guides therapy and determines whether vancomycin should be used alone or, if a prosthetic valve is present, whether combination therapy is necessary (Table 89–5).4

Staphylococcus Endocarditis: IV Drug Abuser

Infective endocarditis in those with IVDA is frequently (60% to 70%) caused by S. aureus, although other organisms may be common in certain geographic locations.1 In this setting, the tricuspid valve is frequently infected, resulting in right-sided infective endocarditis. Most patients have no history of valve abnormalities, are usually otherwise healthy, and have a good response to medical treatment. Nonetheless, surgery may be required.

An uncomplicated, left-sided MSSA endocarditis may be treated sufficiently with 4 weeks of monotherapy with penicillinase-resistant penicillin.4 For the IV drug abuser, however, the clinical response with right-sided MSSA endocarditis is usually excellent. These patients may be treated effectively (clinical and microbiologic cure exceeding 85%) with a 2-week course of nafcillin or oxacillin plus an aminoglycoside.6874 There are limited data on using short-course vancomycin, in place of nafcillin or oxacillin.69,74 Another trial suggested that a 2-week regimen of a penicillinase-resistant penicillin alone, without the addition of an aminoglycoside, is as effective as combined therapy in MSSA tricuspid valve endocarditis.75 Although these data suggest that an aminoglycoside is unnecessary for short-course treatment in the IV drug abuser with right-sided infective endocarditis, most clinicians are uncomfortable with monotherapy and choose combination treatment so long as there are no reasons to avoid an aminoglycoside. Short-course therapy should not be used in left-sided endocarditis, and it is inappropriate for patients with underlying acquired immunodeficiency syndrome, renal failure, meningitis, or substantial pulmonary complications, such as lung abscess from right-sided infective endocarditis.4

An intriguing therapeutic approach for staphylococcal endocarditis in those with IVDA is oral treatment. One study indicated that short-course IV treatment (primarily nafcillin; mean: 16 days) followed by oral treatment (dicloxacillin or oxacillin; mean: 26 days) might be effective for tricuspid valve MSSA endocarditis.76 The positive results of this trial can be explained by the duration of IV antibiotics (>2 weeks) being longer than sufficient. Two other studies that predominantly used oral therapy (ciprofloxacin and rifampin) demonstrated efficacy (cure rates exceeding 90%) in addicts with uncomplicated right-sided endocarditis caused by MSSA.77,78 At this time, concerns with resistance (e.g., ciprofloxacin) and limited published data preclude routine use of oral antibacterial regimens for the treatment of infective endocarditis in the IV drug abuser.4

Staphylococcal Endocarditis: Prosthetic Valves

PVE accounts for approximately 15% of all infective endocarditis cases.8 An episode of PVE occurring within 2 months of surgery strongly suggests that the cause is staphylococci implanted during the procedure. Yet the risk of staphylococcal endocarditis remains elevated for up to 12 months after valve replacement.79 Because this type of infective endocarditis is typically a nosocomial infection, methicillin-resistant organisms are common, and vancomycin is the cornerstone of therapy. Combination antimicrobials are recommended because of the high morbidity and mortality associated with PVE and its refractoriness to therapy.4,11,20 Although the addition of rifampin to a penicillinase-resistant penicillin or vancomycin does not result in predictable bacterial synergism, rifampin may have unique activity against staphylococcal infection that involves prosthetic material, where its addition results in a higher microbiologic cure rate.66 Combination therapy also decreases the emergence of resistance to rifampin, which frequently occurs when it is used alone. For methicillin-resistant staphylococci (both methicillin-resistant S. aureus[MRSA] and coagulase-negative staphylococci), vancomycin is recommended with rifampin for 6 weeks or more (see Table 89–5). An aminoglycoside is added for the first 2 weeks if the organism is aminoglycoside susceptible. For MSSA, penicillinase-resistant penicillin is administered in place of vancomycin. PVE responds poorly to medical treatment and has a higher mortality compared with NVE. Valve dehiscence and incompetence can result in acute heart failure, and surgery is often a component of treatment.4,33

Twelve months or more after valve replacement, the likely organism for PVE parallels that of NVE. As with NVE, antimicrobial therapy should be based on the identified organism and in vitro susceptibility. If an organism is identified other than staphylococci, the treatment regimen should be guided by susceptibilities and should be at least 6 weeks in duration.4 Additionally, a concomitant aminoglycoside is recommended if streptococci or enterococci are identified. Once-daily aminoglycoside regimens have not been adequately evaluated in PVE and are not recommended.4

The use of anticoagulation is controversial in PVE. In general, those who require anticoagulation for a prosthetic valve should continue the anticoagulant cautiously during endocarditis therapy, unless a contraindication to therapy exists. It is recommended to hold all anticoagulation for at least 2 weeks for patients with S. aureus PVE if a recent CNS embolic event has occurred.4

Enterococcal Endocarditis

Enterococci are normal inhabitants of the human GI tract and, occasionally, of the anterior urethra. These organisms are usually of low virulence but can become pathogens in predisposed patients following genitourinary manipulations (older men) or obstetric procedures (younger women).19 Historically, enterococci were considered group D streptococci, but they have been reclassified into the genus Enterococcus (E. faecalis and E. faecium). E. faecalis is the most common clinical isolate (approximately 90%) of the two species. Enterococci cause 5% to 18% of endocarditis cases, but they are more resistant to therapy than staphylococci and streptococci. Enterococci are noteworthy for the following reasons: (a) no single antibiotic is bactericidal, (b) MICs to penicillin are relatively high (1 to 25 mcg/mL [mg/L]), (c) intrinsic resistance occurs to all cephalosporins and relative resistance occurs to aminoglycosides (e.g., “low-level” aminoglycoside resistance), (d) combinations of a cell-wall–active agent such as a penicillin or vancomycin and an aminoglycoside are necessary for killing, and (e) resistance to all available drugs is increasing.4,80,81

Monotherapy with penicillin for infective endocarditis caused by enterococci results in relapse rates of 50% to 80%. When used alone, penicillins are only bacteriostatic against enterococci, and combination therapy is always recommended for susceptible strains.4 The relapse rate following penicillin–gentamicin therapy for susceptible strains is less than 15%.5 The killing of enterococci by the bactericidal combination of an aminoglycoside antibiotic and a penicillin is the best clinical example of antibiotic synergy. Because the aminoglycoside cannot penetrate the bacterial cell in the absence of the penicillin, enterococci usually will appear to be resistant to aminoglycosides by routine susceptibility testing (low-level resistance). However, in the presence of an agent that disrupts the cell wall such as penicillin, the aminoglycoside can gain entry, attach to bacterial ribosomes, and cause rapid cell death. An aminoglycoside–vancomycin combination is also synergistic against enterococci and is appropriate therapy for the penicillin-allergic patient.4,19

Enterococcal endocarditis ordinarily requires 4 to 6 weeks of ampicillin or high-dose penicillin G plus an aminoglycoside for cure (Table 89–6). Ampicillin has greater in vitro activity than penicillin G, although there are no clinical data to document differences in efficacy. A 6-week course is recommended for patients with symptoms lasting longer than 3 months and those with PVE. Streptomycin has been the most extensively studied aminoglycoside, but gentamicin is presently favored. Because of resistance, other aminoglycosides, such as tobramycin and amikacin, cannot be substituted routinely. In the treatment of enterococcal endocarditis, relatively low serum concentrations of aminoglycosides appear adequate for successful therapy, such as a gentamicin peak concentration of approximately 3 to 4 mcg/mL (mg/L; 6.3 to 8.4 μmol/L).4,82 Treatment of enterococcal endocarditis does not have the high success rate seen with infective endocarditis caused by viridans streptococci, presumably because the organism is more resistant to killing.

Although some data support the use of extended-interval aminoglycoside dosing for other types of endocarditis (i.e., streptococci), the data are more vague regarding this strategy in enterococcal infective endocarditis.83 Even though some studies suggest that extended-interval aminoglycoside dosing and short-interval (traditional) dosing are clinically equivalent,8486 discordant studies imply otherwise.87,88 The paucity of human data precludes routine use of extended-interval aminoglycoside dosing in this setting and the guidelines recommend three-times-daily dosing.4

Resistance among enterococci to penicillins and aminoglycosides is increasing.4 Enterococci that exhibit high-level resistance to streptomycin (MIC >2,000 mcg/mL [mg/L]) are not synergistically killed by penicillin and streptomycin because the aminoglycoside either no longer binds to the ribosome or is inactivated by an aminoglycoside-modifying enzyme, streptomycin adenylase. Because enterococci will appear resistant to aminoglycosides on routine susceptibility testing, the only way to distinguish high-level from low-level resistance is by performing special susceptibility tests using 500 to 2,000 mcg/mL (mg/L) of the aminoglycoside. High-level streptomycin-resistant enterococci occur with a frequency approaching 60%, and high-level resistance to gentamicin is now found in 10% to 50% of isolates. Although most gentamicin-resistant enterococci are resistant to all aminoglycosides (including amikacin), 30% to 50% remain susceptible to streptomycin.19,80 High-level gentamicin resistance is mediated by a bifunctional aminoglycoside-modifying enzyme, 6-acetyltransferase/2-phosphotransferase, and most strains also possess streptomycin adenylase. These organisms do not commonly cause infective endocarditis; data on appropriate therapy are sparse, and therapeutic options are few.80,81,89

In addition to isolates with high-level aminoglycoside resistance, β-lactamase–producing enterococci (especially E. faecium) have been reported. If these organisms are discovered, use of vancomycin or ampicillin–sulbactam in combination with gentamicin should be considered. Vancomycin-resistant enterococci are reported increasingly, primarily with E. faecium. Vancomycin resistance occurs when the bacterium replaces the normal vancomycin target with a peptidoglycan precursor that does not bind vancomycin.81

Treating multidrug-resistant enterococci is difficult, and data on appropriate therapy are sparse. Current guidelines suggest either linezolid or quinupristin–dalfopristin for resistant strains of E. faecium and combination β-lactam therapy (ampicillin with either imipenem–cilastatin or ceftriaxone) for E. faecalis.4 Daptomycin has produced conflicting results.9094 Surgery and replacement of the infected cardiac valve may be the only cure.

HACEK Group

Fastidious gram-negative bacteria from the group of bacteria including Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae (HACEK group) account for 5% to 10% of native valve, community-acquired infective endocarditis.4 Frequently, these types of infective endocarditis present as subacute illnesses with large vegetations and emboli.19 These oropharyngeal organisms typically are slow growing and should be considered as possible causes of “culture-negative” endocarditis. In the past, high-dose ampicillin with gentamicin for 4 weeks was an acceptable treatment regimen for HACEK endocarditis, but β-lactamase–producing organisms are occurring more often; hence, HACEK organisms should be considered resistant to ampicillin alone. Numerous treatments are reasonable for the treatment of HACEK infective endocarditis, including ceftriaxone and ampicillin–sulbactam; the newest addition to the guidelines is oral ciprofloxacin for select patients (Table 89–7).4 Treatment is usually for 4 weeks, but it should be extended to 6 weeks in PVE caused by one of these organisms.

Less Common Types of Infective Endocarditis

Atypical Microorganisms

Endocarditis caused by organisms such as BartonellaCoxiella burnetiiBrucella, Candida, and Aspergillus spp.; Legionella; and gram-negative bacilli (e.g., Pseudomonas) is relatively uncommon. Medical therapy for infective endocarditis caused by these organisms is usually unsuccessful.4,5 Consultation with an infectious disease expert is warranted when these microorganisms are identified.

In addition to Pseudomonas spp., other gram-negative bacilli that have been implicated include Salmonella spp., Escherichia coli, Citrobacter spp., Klebsiella–Enterobacter spp., Serratia marcescens, Proteusspp., and Providencia spp.36 Generally, these infections have a poor prognosis, with mortality rates as high as 60% to 80%.36 Cardiac surgery in concert with extended-course antibacterial therapy is the recommended course (class IIa; level of evidence: B) for most patients with gram-negative bacillary infective endocarditis. Readers are referred to the AHA guidelines for more extensive review of Pseudomonas spp. infective endocarditis and unusual gram-negative bacteria treatment regimens.4

Fungi cause between 2% and 4% of endocarditis cases; most patients with fungal endocarditis have undergone recent cardiovascular surgery, are IV drug abusers, have received prolonged treatment with IV catheters or antibiotics, or are immunocompromised.19,95 Candida spp. and Aspergillus spp. are the most commonly involved, and the mortality rate is high (greater than 80%) for the following reasons: (a) large, bulky vegetations that often form, (b) systemic septic embolization that may occur, (c) the tendency of fungi to invade the myocardium, (d) poor penetration of vegetations by antifungals, (e) the low toxic-to-therapeutic ratio of agents such as amphotericin B, and (f) the lack of consistent fungicidal activity of available antifungal agents.3,96 When fungal infective endocarditis is identified, the combined medical–surgical approach is recommended. Because these infections occur infrequently, scant clinical data are available to make solid treatment recommendations; however, the use of antifungal agents alone has been globally unsuccessful. Amphotericin B has been the mainstay pharmacologic approach. The availability of newer antifungal agents challenges this historical approach, although clinical trial data are lacking.4

C. burnetii (Q fever) may be recovered from blood cultures, but infection is more likely to be identified via serologic tests. It is a common cause of infective endocarditis in certain areas of the world where goat, cattle, and sheep farming are widespread. The most favorable therapy for Q fever is unknown but may include doxycycline with trimethoprim–sulfamethoxazole, rifampin, or fluoroquinolones.19Brucella are facultative intracellular gram-negative bacilli. Humans are infected by this organism after ingesting infected unpasteurized milk or undercooked meat, inhalation of infectious aerosols, or contact with infected tissues. This type of infective endocarditis is more common in veterinarians and livestock handlers. Cure requires valve replacement and antimicrobial agents including doxycycline with streptomycin or gentamicin or doxycycline with trimethoprim–sulfamethoxazole or rifampin for an extended period (8 weeks to months).19

Culture-Negative Endocarditis

Sterile blood cultures are reported in 5% to 20% of patients with infective endocarditis if strict diagnostic criteria are used.5,11 This type of infective endocarditis may occur as a result of unidentified subacute right-sided infective endocarditis, previous antibiotic therapy, slow-growing fastidious organisms, nonbacterial etiologies (e.g., fungi), and improperly collected blood cultures. When blood cultures from patients suspected of infective endocarditis show no growth after 48 to 72 hours, the laboratory should be advised, and cultures should be held for up to a month to detect growth of fastidious organisms.4

The AHA guidelines provide general recommendations for culture-negative infective endocarditis (Table 89–7), although clinicians should individualize therapy, as necessary. Selection of treatment can be difficult, balancing the need to cover all likely organisms against potential toxic drug effects (e.g., aminoglycosides). Antimicrobial selection should be in consultation with an infectious disease specialist. Irrespective of the chosen treatment, extended antimicrobial therapy is required. The empirical approaches for culture-negative infective endocarditis highlight the need for proper collection and monitoring of blood cultures and an extensive medication history.

PERSONALIZED PHARMACOTHERAPY

Infective endocarditis remains an uncommon disease, but the cost of treatment can be substantial. In the past, the long duration of hospitalization required to administer IV antimicrobials was the major expense. In select cases, abbreviated and/or outpatient, oral antimicrobial therapy may appreciably reduce the cost of care.

Shorter-course antimicrobial regimens are advocated when possible. For instance, in exquisitely sensitive streptococcal endocarditis (MICs less than 0.12 mcg/mL [mg/L]), a 2-week regimen of high-dose parenteral penicillin G or ceftriaxone in combination with an aminoglycoside is as effective as 4 weeks of penicillin alone.4 Uncomplicated right-sided MSSA endocarditis in the IV drug abuser may be treated with a 2-week course. Treatment with nafcillin or oxacillin in combination with an aminoglycoside appears to be cost-effective.

The initiation of outpatient parenteral antibiotics should be considered early in the treatment of infective endocarditis, after the patient is stable clinically and responds favorably to initial antibiotics. Outpatient treatment is safe and cost-effective in select situations.26,97 Patients considered for home therapy must be hemodynamically stable, compliant with therapy, have careful medical monitoring, understand the potential complications of the disease, and have immediate access to medical care. Advances in technology allow for the outpatient administration of complex antibiotic regimens that significantly reduce the cost of therapy. Simple regimens, such as single daily doses of ceftriaxone for streptococcal infective endocarditis, are particularly attractive. Although endocarditis is common in those with a history of IVDA and home healthcare would substantially reduce the cost of treatment, many clinicians are uncomfortable with outpatient IV therapy because central venous access is required. Sudden cardiac decompensation in an outpatient setting is also of concern.4,98

EVALUATION OF THERAPEUTIC OUTCOMES

The evaluation of patients treated for infective endocarditis includes assessment of disease signs and symptoms, blood cultures, microbiologic tests, serum drug concentrations, and other tests that evaluate organ function.

Signs and Symptoms

Fever usually subsides within 1 week of initiating therapy.5,17,98 Persistence of fever may indicate ineffective antimicrobial therapy, emboli, infections of intravascular catheters, or drug reactions. For some patients, low-grade fever may persist even with appropriate antimicrobial therapy. With defervescence, the patient should begin to feel better, and other symptoms, such as lethargy or weakness, should subside. Echocardiography should be performed when antibiotic therapy has been completed to determine new baseline cardiac function (i.e., ventricular size and function). A TTE is usually sufficient.

Blood Cultures

Blood cultures should be negative within a few days, although microbiologic response to vancomycin may be slower. If bacteria continue to be isolated from blood beyond the first few days of therapy, it may indicate that the antimicrobials are inactive against the pathogen or that the doses are not producing adequate concentrations at the site of infection. After the initiation of therapy, blood cultures should be rechecked until negative. During the remainder of therapy, frequent blood culturing is not necessary. Additional blood cultures should be rechecked after successful treatment (e.g., once or twice within the 8 weeks after treatment) to ensure cure.4

Microbiologic Tests

For all isolates from blood cultures, MICs should be determined; MBCs are no longer recommended.4 The agent currently being used should be tested, as well as alternatives that may be required if intolerance, allergy, or resistance occurs. Occasionally, it is useful to determine whether synergy exists for antimicrobial combinations, although synergistic regimens usually can be predicted from the literature. eChapter 24 summarizes the methods for in vitro determinations of synergy.

Serum bactericidal titers (SBTs; also called Schlichter’s tests) have been used in the past in association with a number of infectious diseases. The SBT is the greatest dilution of a patient’s serum sample that is obtained while receiving antimicrobial treatment that kills greater than 99.9% of an inoculum of the infecting pathogen in vitro over 18 to 24 hours.

Although specific SBTs have been evaluated in endocarditis, at present, SBTs have little value in monitoring treatment of common types of infective endocarditis and should not be recommended routinely.4,99This test may be useful when the causative organisms are only moderately susceptible to antimicrobials, when less-well-established regimens are used, or when response to therapy is suboptimal and dosage escalation is being considered.

Serum Drug Concentrations

Of the agents used commonly for infective endocarditis, measurement of serum drug concentrations is routinely available for aminoglycosides (except streptomycin) and vancomycin. Few data, however, support attaining any specific serum concentrations for patients with infective endocarditis. In general, serum concentrations of the antimicrobial should exceed the MBC of the organisms. Aminoglycoside concentrations rarely exceed the MBC for certain organisms, such as streptococci and enterococci, and concentrations of aminoglycosides and vancomycin for staphylococci have not been correlated with response.99,100

When aminoglycosides are administered for infective endocarditis caused by gram-positive cocci with a traditional three-times-daily regimen, peak serum concentrations are recommended to be on the low side of the traditional ranges (3 to 4 mcg/mL [mg/L; 6.3 to 8.4 μmol/L] for gentamicin). If extended-interval dosing is used, which is only recommended in streptococcal infective endocarditis, the most appropriate method of monitoring has not been determined. When vancomycin is administered, the most recent treatment guidelines for infective endocarditis recommend serum drug monitoring of peak and trough concentrations.4 However, it is now generally accepted that peak concentrations of vancomycin have limited clinical applicability and the primary goal of serum vancomycin monitoring is to ensure adequate trough concentrations, in this case 15 to 20 mcg/mL (mg/L; 10 to 14 μmol/L), are achieved.101

PREVENTION

Images Antimicrobial prophylaxis is used as an attempt to prevent infective endocarditis for patients who are at the highest risk.6,18 The use of antimicrobials for this purpose requires consideration of (a) cardiac conditions associated with endocarditis, (b) procedures causing bacteremia, (c) organisms likely to cause endocarditis, and (d) pharmacokinetics, spectrum, cost, adverse effects, and ease of administration of available antimicrobial agents. The objective of prophylaxis is to diminish the likelihood of infective endocarditis in high-risk individuals from procedures that result in bacteremia. Although there are no prospective, controlled human trials demonstrating that prophylaxis in high-risk individuals protects against the development of endocarditis during bacteremia-induced procedures, animal studies suggest possible benefit.18 Many causes of infective endocarditis, however, appear not to be secondary to an invasive procedure. Bacteremia as a consequence of daily activities may, in fact, be the major culprit, and the value of antibiotic prophylaxis before bacteremia-causing procedures has been questioned.102 Retrospective human studies, though, support that a reduction of endocarditis occurs for select patients following dental surgery where prophylaxis is employed.18 The common practice of using antimicrobial therapy in this setting remains controversial. The mechanism of a beneficial effect in humans is unclear, but antibiotics may decrease the number of bacteria at the surgical site, kill bacteria after they are introduced into the blood, and prevent adhesion of bacteria to the valve. Prophylaxis does not reduce the frequency of bacteremia immediately following tooth extraction as compared with a control group, suggesting that a reduction in adhesion or effects after the bacteria adhere to the endocardium are more likely mechanisms.103,104 Other studies have further questioned the benefit of antibiotic prophylaxis.105


Clinical Controversy…

The common practice of administering antibiotics to high-risk individuals before a bacteremia-causing procedure is controversial. Despite limited data supporting this approach and the fact that 100% compliance with AHA preventative guidelines would have only a modest benefit, the use of single-dose antibiotics for the prevention of endocarditis remains a standard of care.

Regardless of the controversy about whether prophylactic antibiotics should be used, infective endocarditis prophylaxis is recommended in select situations, specifically dental procedures, in those with underlying high-risk cardiac conditions. The AHA released updated guidelines that better define who should and should not receive infective endocarditis prophylaxis.18 This update is important as data show overuse of infective endocarditis prophylaxis occurs in low-risk patients and underuse occurs in those at greater risk.106

Key points of this report are that (a) only a small number of cases of infective endocarditis might be prevented with antibiotic prophylaxis for dental procedures, even if 100% effective; (b) infective endocarditis prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk; (c) for those with high-risk underlying cardiac conditions, prophylaxis is recommended for all dental procedures involving manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa; (d) prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of infective endocarditis; and (e) administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or GI tract procedure.

To determine whether a patient should receive prophylactic antibiotics, one needs to assess the patient’s risk and whether he or she is undergoing a procedure resulting in bacteremia. When antibiotic prophylaxis is appropriate, a single 2 g dose of amoxicillin is recommended for adult patients at risk, given 30 to 60 minutes before undergoing procedures associated with bacteremia. Because the duration of antimicrobial prophylaxis appears to be relatively short, guidelines do not advocate a second oral dose of amoxicillin, which was recommended previously. Alternative prophylaxis regimens for patients allergic to penicillins or those unable to take oral medications are also provided. A summary of guideline recommendations is available in Table 89–10. Consultation of the full AHA guideline is suggested for more detailed information.18

TABLE 89-10 Prophylaxis of Infective Endocarditis

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ABBREVIATIONS

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REFERENCES

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