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A wide range of microorganisms can cause IE, but only a few species account for the vast majority of cases. Streptococci and staphylococci are the cause of greater than 80% of IE cases in which a responsible organism is identified. Streptococcal species were historically the most common group of pathogens, but more recent data identify Staphylococcus aureus as the most frequently isolated microbial agent worldwide.26 Moreover, the rate of antibiotic resistance among causative organisms is increasing.26,65
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Native Valve Endocarditis
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Viridans group streptococci, or α-hemolytic streptococci, are a frequent cause of community-acquired NVE. Viridans streptococci are responsible for 30% to 65% of cases of NVE in older children and adults.65,66 They are normal residents of the oropharynx and easily gain access to the circulation after dental or gingival trauma. The viridans streptococci comprise several species, of which Streptococcus sanguinis, Streptococcus gallolyticus (formerly bovis), Streptococcus mutans, and Streptococcus mitior are most commonly isolated in cases of IE. The viridans streptococci are usually highly sensitive to penicillin, as defined by a minimum inhibitory concentration of < 0.1 μg/mL, and thus can often be eradicated with penicillin monotherapy.66
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S gallolyticus, a normal inhabitant of the human gastrointestinal (GI) tract, is noteworthy because IE caused by this organism is strongly suggestive of GI malignancy,67 polyp formation, or diverticular disease. Colonoscopy should be performed when this organism is detected in the blood. When meticulously investigated, GI pathology is discovered in as many as 60% of patients with S gallolyticus IE.60
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Nutritionally deficient streptococci, now known as Abiotrophia species and Granulicatella species, require specialized isolation and culture techniques for growth (supplemental thiol compounds or active forms of vitamin B6) and now account for approximately 5% to 7% of streptococcal IE cases.68 IE caused by these organisms is virtually always indolent in onset and associated with pre-existing heart disease. Therapy remains difficult, and prognosis is poor because these organisms are generally less sensitive to penicillin than the viridans group streptococci.69 Treatment often requires synergistic therapy with an aminoglycoside.
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The Enterococcus species, formerly classified as group D streptococci, are now defined as a distinct genus. They are responsible for 5% to 18% of cases of native valve IE, the vast majority of which are caused by E faecalis (80%) or Enterococcus faecium (10%). These organisms are normal inhabitants of the GI and genitourinary tracts, and may enter the bloodstream after manipulation of the colon, urethra, or bladder (eg, Foley catheterization, colonoscopy). The incidence of enterococcal endocarditis appears to be rising, likely as a result of the increased genitourinary and GI instrumentation in older adults and the increased use of indwelling central venous catheters and prosthetic implants. These organisms can infect both normal and diseased heart tissue, as well as prosthetic materials. Indeed, among the most relevant risk factors for development of enterococcal IE is the presence of an implanted device. The pathogenesis of such infections is poorly understood, but several virulence factors have been proposed. The ability to form biofilm has recently been shown to be one of the most prominent features of this microorganism, allowing colonization of inert and biological surfaces and preventing antibiotic penetrance. The disease typically runs an indolent course, and cure is challenging because the organism has limited susceptibility to many antibiotics, including β-lactam drugs. There is an alarming incidence of nosocomial bacteremia with these organisms and a growing problem with drug resistance (to both vancomycin and aminoglycosides). Although synergistic antibiotic therapy, as predicated by susceptibility testing, should be considered,69 there is some debate regarding its efficacy.69
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Group A Streptococcus rarely causes IE. Streptococcus pyogenes, the causative organism in childhood pharyngitis, scarlet fever, impetigo, cellulitis, erysipelas, fasciitis, and myositis, is not associated with IE in adults. Before 1945, Streptococcus pneumoniae caused approximately 10% of IE cases; however, the current incidence of pneumococcal IE is very low. Streptococcus pneumoniae bacteremia often begins with respiratory infection, and nearly half of patients with pneumococcal IE suffer from chronic alcoholism.70 Streptococcus pneumoniae can infect normal valve tissue and usually results in an acute, fulminant illness often associated with severe valve damage, perivalvular extension, embolic complications, pericarditis, meningitis, and high mortality (25%-50%).63
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Group B streptococci (eg, Streptococcus agalactiae) are chiefly responsible for infections in the neonate and parturient, although these organisms can be isolated from diabetic foot ulcers. Risk factors for group B streptococcal bacteremia in adults include obstetric complications,71 diabetes, carcinoma, liver failure, alcoholism, and IDU.72 These organisms are generally less sensitive to penicillin than group A isolates and require higher doses for treatment.
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Staphylococcus aureus causes 80% to 90% of staphylococcal IE and is the most common cause of acute IE. Recent prospective data from the International Collaboration on Endocarditis (ICE) suggest that Staphylococcus aureus has become the leading cause of IE worldwide and more often presents as an acute disease.2,26 The mucous membranes of the anterior nasopharynx are the most common sites of colonization, and approximately 30% of normal persons carry Staphylococcus aureus. Carrier rates are higher among persons with more frequent exposures to the organism and those who are at risk for breakdown of the normal mucocutaneous barrier. Rates of Staphylococcus aureus infection, particularly bacteremia associated with healthcare contact, have increased in hospitalized patients and among those receiving outpatient medical therapy.73,74 Although only a fraction of patients with Staphylococcus aureus bacteremia will develop NVE,75 populations at increased risk include patients on dialysis,37 patients with type 1 diabetes, burn victims, persons with HIV,32 IDUs,27 patients with certain chronic dermatologic conditions, and patients with recent surgical incisions (including median sternotomy for valve replacement). Despite the frequency of nosocomial Staphylococcus aureus acquisition, community-acquired infection appears to be an independent risk factor for the development of IE and metastatic disease.76,77 Staphylococcus aureus is respected as a highly virulent organism and has the capacity to infect and destroy normal endocardial surfaces (see Fig. 67–2). A number of virulence factors help this organism enter the bloodstream, adhere to endothelial and prosthetic surfaces, and evade host defense.55 Staphylococcus aureus IE is frequently fulminant when it involves left-sided cardiac valves and often results in major complications such as valve destruction, heart failure, perivalvular extension with conduction disturbances, embolization, and metastatic infection.78 Not surprisingly, Staphylococcus aureus as a causative organism is an independent predictor of poor prognosis in IE78 and is associated with a 25% to 30% mortality.1,26 As many as 50% of patients with left-sided NVE as a result of Staphylococcus aureus will require surgery. Right-sided (tricuspid valve) IE with Staphylococcus aureus, by contrast, is most frequently associated with IDUs and is associated with a high incidence of septic pulmonary embolization, but only a 2% to 4% case fatality rate.
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The detection of Staphylococcus aureus bacteremia should prompt echocardiography to look for evidence of IE, especially if bacteremia is persistent. Although most patients undergo TTE first, an initial TEE should be considered for patients with catheter-associated Staphylococcus aureus bacteremia as a cost-effective means of determining the duration of antibiotic therapy (ie, 2 weeks vs 4 weeks).79 A semisynthetic, β-lactamase–resistant penicillin (eg, nafcillin) is preferred for initial treatment of susceptible Staphylococcus aureus in non–penicillin-allergic individuals, often with a short course of an aminoglycoside. Antibiotic resistance can be a particular challenge with Staphylococcus aureus because more than 90% of clinical isolates produce β-lactamase and are thus penicillin resistant. Semisynthetic penicillin analogs that are unaffected by β-lactamase, such as methicillin, oxacillin, and nafcillin, are first-line agents. Increasing rates of MRSA in both hospital and community settings,26 and the recovery of clinical Staphylococcus aureus isolates resistant to vancomycin,80 have complicated the treatment of Staphylococcus aureus IE. Increasing hospital use of vancomycin for the treatment of MRSA is likely one additional reason for the growing incidence of vancomycin resistance among enterococci. Vancomycin, although the best available antibiotic for treatment of MRSA, is only weakly bactericidal and predominantly bacteriostatic. Recently, Staphylococcus aureus isolates with varying levels of vancomycin resistance have been cultured from infected patients and have been associated with IE treatment failures.81 The new lipopeptide antistaphylococcal agent daptomycin has been approved for treatment of Staphylococcus aureus bacteremia and right-sided IE,82 and may have promise for the treatment of left-sided IE caused by resistant organisms. Cases of resistant Staphylococcus aureus IE should always be managed in close collaboration with an infectious diseases specialist.
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The CoNS are constituents of normal human skin flora and are much less likely to infect normal endocardial surfaces. Staphylococcus epidermidis is an important causative agent in PVE and device-related endocarditis. NVE caused by CoNS occurs mainly in patients with pre-existing valvular heart disease,83 although exceptions to this generalization do occur (see Fig. 67–3). NVE caused by CoNS has historically been regarded as an indolent disease; however, recent data from the ICE have demonstrated equal rates of heart failure and death for CoNS and Staphylococcus aureus NVE.83 Staphylococcus epidermidis infections of intracardiac devices are extremely difficult to eradicate, and the addition of adjunctive course of rifampin therapy is often recommended. Rare cases of IE caused by other CoNS (eg, Staphylococcus saprophyticus, Staphylococcus capitis) have been reported,84,85 including a growing number of reports of IE caused by community-acquired Staphylococcus lugdunensis.86 S lugdunensis may cause a more virulent form of IE with high morbidity despite uniform in vitro susceptibility to most antibiotics.
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Gram-Negative Bacilli
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IE caused by gram-negative bacilli is uncommon and tends to occur in IDUs, immunocompromised patients, patients with advanced liver disease, and prosthetic heart valve recipients. The fastidious gram-negative rods of the HACEK group (Haemophilus species, Actinobacillus, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) reside normally in the oropharynx and are responsible for a very small (approximately 1%) proportion of cases of NVE, usually involving abnormal valve tissue. Because of their growth requirements (carbon dioxide), they may take 3 to 4 weeks to grow in culture and have gained notoriety for their implicated role in certain cases of culture-negative IE. The Haemophilus species (Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus) are the most common etiologic agents from this group. They typically form large and friable vegetations that have a tendency to embolize. There are numerous case reports of IE caused by other members of the HACEK group.87 The Enterobacteriaceae (eg, Escherichia coli, Klebsiella, Enterobacter, Serratia) are rare causes of IE. Salmonella species have a particular predilection for atherosclerotic plaque and may infect arterial aneurysms.88 The vast majority of patients with P aeruginosa endocarditis are IDUs.89 The source of Pseudomonas appears to be from standing water that contaminates needles and other drug paraphernalia. Left-sided endocarditis caused by P aeruginosa is difficult to eradicate with antibiotics alone, has a high rate of complications, and often requires early surgery.89
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The rickettsial organism Coxiella burnetii is the causative agent of Q fever and is a relevant cause of IE in areas where cattle, sheep, and goat farming are common. Cases of IE caused by C burnetii are well documented in the developed world.90 The aortic valve is affected in more than 80% of cases, and the infection is difficult to eradicate with antibiotics. Because the organism is extremely difficult to culture, the diagnosis is best made serologically using antibody titers.90 Bartonella species (Bartonella quintana, Bartonella henselae, Bartonella elizabethae), the etiologic agents in cat scratch disease, have been recently described as an important cause of IE among both homeless men and HIV-infected patients. The diagnosis can be suspected serologically and confirmed with special culture techniques or by polymerase chain reaction.91 Brucellae have been implicated in approximately 4% of cases of IE in Spain. These organisms are usually ingested in unpasteurized milk or cheese, and are occupational hazards for veterinarians, shepherds, and livestock handlers. IE is the most common cause of death in patients with brucellosis, and surgery is usually required for cure.92
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Fungal Infective Endocarditis
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Fungal endocarditis is a relatively new syndrome associated with exceedingly high mortality (survival rates of < 20%). Patients who develop fungal IE have multiple predisposing conditions that include an immunocompromised state, the use of endovascular devices, and previous reconstructive cardiac surgery. Candida and Aspergillus species are the most common causes of fungal IE and are associated with large, bulky vegetations that can obstruct valve orifices and can also embolize to large vessels (eg, the femoral artery). Blood cultures are usually positive in cases of Candida IE, whereas they are rarely positive with Aspergillus. Fungal endocarditis is an indication for surgical replacement of an infected valve. Cure usually requires combination fungicidal (amphotericin) and surgical treatment, followed by long-term suppressive therapy with an oral antifungal agent.93,94,95
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Culture-Negative Infective Endocarditis
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Blood cultures are negative in up to 20% of patients with IE diagnosed by strict criteria.93,94 Failure to isolate a microorganism may be the result of inadequate culture technique, a highly fastidious organism or a nonbacterial pathogen as the causative agent, or previous administration of antimicrobial therapy before blood culture acquisition. The latter is an extremely important consideration, because the administration of antibiotics before drawing blood cultures can reduce the recovery rate of bacterial pathogens by nearly one-third.93,94,95,96 There are numerous noninfectious causes of endocarditis that may behave like culture-negative IE, including those that are related to neoplasia (nonbacterial thrombotic endocarditis), autoimmune diseases (antiphospholipid antibody syndrome, systemic lupus erythematosus), or the postcardiac surgical state (thrombi, sutures).88,93,94,95 Empiric therapy for culture-negative IE remains extremely challenging because the patient may be exposed to potentially toxic antimicrobial therapy while awaiting what is often delayed identification of a causative organism, if one is identified at all. Consultation with an infectious disease specialist to define the most appropriate therapy is recommended.
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Prosthetic Valve Endocarditis
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PVE represents approximately 10% to 30% of all IE cases.9,15,65 Although many of the general principles applicable to native valve IE are relevant, there are important considerations specific to PVE. After valve replacement, the incidence of PVE is approximately 1% to 3% at 1 year and 3% to 6% at 5 years. Although the current evidence is not definitive, PVE can be broadly divided into two groups based on the time of onset of the infection after valve surgery—early PVE and late PVE. Early PVE is defined as endocarditis that develops within the first 2 months to 1 year after valve surgery. During this period, the vast majority of causative organisms are nosocomially acquired, with a predominance of staphylococci, notably coagulase-negative species (Staphylococcus epidermidis). Gram-negative bacilli, diphtheroids, and fungal species, although uncommon causes of IE overall, have a predilection to cause PVE during this early period. Late PVE is defined as that occurring beyond 1 year postoperatively. In contrast to early PVE, the spectrum of causative organisms in late PVE resembles that of NVE. In late PVE, cases are predominantly a result of streptococci and enterococci, with a significant decrease in the rate of CoNS and a continued rate of infection with Staphylococcus aureus. Between 2 and 12 months after valve replacement surgery, there is a gradual transition between the early and late microbiologic causes of PVE.
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TEE imaging is recommended in cases of suspected PVE (see below). In some cases, both TTE and TEE are performed to provide optimal characterization of the infection, prosthetic valve function, and cardiac performance. Empiric therapy for suspected PVE is similar to that for NVE; however, staphylococcal coverage should always be provided until definitive culture data are available, with particular attention to the likelihood of antibiotic resistance (MRSA). Complication rates with PVE are high, and surgery is often required even in the absence of documented perivalvular extension. For example, Staphylococcus aureus PVE is rarely eradicated with antibiotics alone, and retrospective analyses suggest that combined medical and surgical therapy is more effective than medical therapy alone.95,96 With proper timing of antibiotic therapy and surgery, the imputed risk of early reinfection of a newly implanted valve is only 2% to 3%.97