The incidence of PVE ranges from 1% to 6% of prosthetic valve implantations, or 0.3% to 0.6% per patient-year.^1–3 PVE accounts for 16% to 33% of all definite cases of infective endocarditis (IE), according to data from retrospective studies of single and multicenter tertiary care units in developed countries,^3–10 and from prospective national,^11–13 European,⁹ and international multicenter observational¹⁴ studies. Risk factors associated with the development of PVE include male sex, previous native valve endocarditis, and long cardiopulmonary bypass time for prosthetic valve placement.¹⁵ The cumulative risk of developing PVE is highest within the initial 12 months after replacement surgery, with a peak during the first 2 months.^14,16

The prosthetic valve is vulnerable to secondary microbial seeding during the early postimplantation period when valve endothelialization has yet to occur. The mean age of patients with PVE is 65 years; the range is 50 to 74 years.^{8–11,14,17,18} The risk of PVE is higher in patients who undergo valve replacement surgery during active IE, especially in the setting of an unknown pathogen or insufficient antibiotic treatment.^19–23

The mechanical prostheses appear to have a slightly higher risk during the first 3 months postsurgery, and the bioprosthetic valves appear to have a slightly higher risk after 12 months postsurgery,^20,21,24 likely as a result of degenerative changes in the bioprosthetic leaflets. However, the cumulative risk of PVE appears similar between mechanical and bioprosthetic valves.^22,24–27 The frequency of PVE also appears to be similar for both aortic and mitral prosthetic valves.

Microbiology

The microbiology of prosthetic valve endocarditis depends on (1) time of onset of PVE (early vs. late PVE) and (2) site of acquisition (community vs. health care associated).

Early- and Late-Onset Prosthetic Valve Endocarditis

PVE has been categorized as early-onset PVE and late-onset PVE on the basis of the time period between prosthetic valve replacement and the manifestation of endocarditis. The microbiology of early- and late-onset PVE is different.^14,19,28,29 Early-onset PVE has been due to infections acquired intraoperatively or during the immediate postoperative period. Staphylococcus aureus, coagulase-negative staphylococci (CoNS), diphtheroids, fungi, and nosocomial aerobic gram-negative bacilli are the most common pathogens in early PVE.^{10,14,29–34} In the past, the time limit was arbitrarily chosen as 60 days,^7,14,19 to differentiate perioperative infections from late community-acquired infections. However, less virulent organisms acquired perioperatively may manifest many months after surgery. The peak incidence of CoNS endocarditis is between 60 and 365 days after valve implantation.¹⁴ Hence, 1 year appears to be a better reference point to distinguish between early and late PVE.^10,18,29,35 There has been a sharp decline in the proportion of early PVE from 60% of all PVE cases in studies published in the 1970s^31,32,34 to about 10% to 20% in more recent studies^10,14,30 without significantly affecting the overall rate of PVE.^{2,10,14,24,33} The reduced early PVE rate is the consequence of better infection prevention and control practices, appropriate use of antimicrobial prophylaxis, improvements in design of prosthetic valves, and better surgical techniques.

Late PVE is usually considered acquired in the community, unrelated to surgery or perioperative period. However, as a result of changes in the health care delivery system and the longer survival of patients with PVE, health care–associated PVE cases are increasing in the late period.¹⁰ In some regions of the world, staphylococci have surpassed streptococci as the most frequent causative organisms of late PVE. In some hospitals, enterococci have surpassed viridans group streptococci and thus are the third most common etiologic agent of late PVE.^10,14,30

Health Care–Associated Prosthetic Valve Endocarditis

Health care–associated infections have become the most important risk factor for development of PVE in recent years.* Health care–associated PVE constituted about 37% of all cases in a prospective, multinational cohort. S. aureus is now the leading causative organism of PVE, with increases in frequency of methicillin-resistant strains across geographic regions.¹⁴ Major risk factors for health care–associated PVE include intravascular devices and hemodialysis. About 70% of health care–associated PVE cases are diagnosed within the first year after prosthetic valve implantation and more than 60% occur beyond 60 days postsurgery. Many aerobic gram-negative bacilli can cause health care–associated PVE, and multidrug resistance is common. Among this group, Pseudomonas, Serratia, Acinetobacter, and Stenotrophomonas spp. predominate. Fungal PVE due to Candida spp. can occur with health care exposure. Candida albicans and Candida parapsilosis are the most frequently isolated fungal pathogens of PVE. Other non-albicans Candida spp. such as Candida glabrata and Candida krusei can cause PVE.

Most community-acquired PVE is caused by enterococci, viridans group streptococci, and fastidious organisms including the HACEK group (Haemophilus parainfluenzae, Aggregatibacter aphrophilus, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella spp.).^{11–13,42–47}

Late-onset PVE is rarely caused by Mycobacterium, Coxiella, Tropheryma, Bartonella, and Legionella spp.^48–56 Aspergillus spp. have been noted in few infections and can be difficult to identify as causative pathogens because blood cultures are usually negative. Fungal stains of the resected tissue can show characteristic fungal hyphal elements. Other rare fungal pathogens include Cryptococcus neoformans and Histoplasma capsulatum.

Pathogenesis

PVE can occur due to direct microbial contamination of a prosthetic valve at the time of surgery or as a consequence of secondary hematogenous seeding from a distant infectious focus. The prosthetic valve and perivalvular tissue are vulnerable for secondary microbial seeding during the early postimplantation period when they lack protective endothelial lining.

The pathogenesis of PVE consists of several steps including (1) microbial adherence to the prosthetic valve, damaged endothelium, platelet-fibrin aggregate, and/or periprosthetic tissue; (2) recruitment and activation of monocytes, platelets, activation of extrinsic coagulation cascade resulting in an infected coagulum called a vegetation, the characteristic lesion of endocarditis; (3) persistence and growth of the microorganism within cardiac lesions leading to local tissue destruction and invasion; and (4) dislodgement of the vegetations may occur, resulting in septic emboli in distant organs such as the brain, skin, spleen, and kidneys or in the musculoskeletal system.^57,58

Formation and Growth of Vegetations

The microbial growth within a platelet-fibrin aggregate leads to activation of the extrinsic coagulation cascade, recruitment of monocytes, and platelets that result in the formation of vegetation. The adherent bacteria activate the extrinsic coagulation pathway by triggering release of tissue factor from monocytes that adhere to early vegetations^85,86 and from endothelial cells surrounding the infected valves.^87,88 They also influence recruitment and activation of monocytes.^89–91 For example, the FnBPA proteins of staphylococci interact with the endothelial cells and help in recruitment of monocytes by triggering the expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1), interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP-1), and tissue factor.

Microorganisms also engage and activate platelets either directly or through bridging molecules. For example, S. aureus induces platelet activation by several surface proteins. ClfA/clumping factor B (ClfB) and FnBPA/fibronectin-binding protein B (FnBPB) are the major platelet activating modulins.^92–95 ClfA and FnBPA/FnBPB bind to the low-activity platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor through fibrinogen and fibronectin bridges. The circulating specific ClfA or FnBPA/FnBPB antibodies engage the crystallizable fragment γ receptor IIA (FcγRIIA). Activation of both receptors on quiescent platelets initiates a signal transduction cascade resulting in platelet activation and aggregation. S. sanguis activates platelets by either direct interaction between the serine-rich glycoprotein A (SrpA) and the glycoprotein Ib receptor (von Willebrand factor [vWF])⁹⁶ or specific antibody and complement assembly that link the surface proteins to platelet FcγRIIA and complement receptors.^94,97 Strains of S. gordonii stimulate platelet aggregation directly by binding to glycoproteins Ib and IIb through the serine-rich surface glycoproteins GspB and the sialic acid–binding adhesins (Hsa).^98–102

These processes result in an enhanced procoagulant and inflammatory activity in the vicinity of the infection. The thrombus serves as a focus for adherence of additional bacteria and platelets leading to growth of the vegetation.

Pathology

The clinicopathologic findings of PVE usually differ between mechanical and bioprosthetic valves. Mechanical heart valves are primarily made of metal or carbon alloys and are classified according to their structure as caged-ball, single-tilting disk, or bileaflet-tilting disk valves.¹¹⁰ Metal or carbon alloys are usually not well suited for microbial adherence. The infection of mechanical prostheses usually starts at the interface between the sewing cuff and the native tissue. The perivalvular tissue invasion can result in loosening of the sutures, causing periprosthetic leaks, or in ring abscesses (Fig. 83-1). Annular abscess or paravalvular leak was more common in mechanical PVE than bioprosthetic PVE.¹¹¹ In a retrospective multicenter study at 16 tertiary referral hospitals, 148 (17%) of 872 patients with PVE had perivalvular complications of the aortic ring, including aortocavitary fistulas in 19% and nonruptured abscess in 81%.¹¹² The ring abscess may dislodge the prosthesis from its anchorage (Fig. 83-2) and give rise to the echocardiographic appearance of a “dancing” prosthesis. Acute ventricular decompensation and congestive heart failure, due to either valve obstruction or incompetence, are important complications of PVE requiring surgery. In one study, 45% of all patients with PVE developed prosthetic dehiscence with moderate or severe valve regurgitation.¹¹² Aortic PVE may also result in third-degree heart block if the infectious process extends to the conducting system of the heart. Ruptured ring abscesses may form fistulous tracks into cardiac chambers or into the intraventricular septum and lead to intracardiac shunting.¹¹² The aortic PVE may result in aneurysms of the sinus of Valsalva by extending to the aortic root or aneurysms of the anterior leaflet of the mitral valve by extending through mitral-aortic fibrous continuity. The infection may also extend to involve the other valves resulting in multivalvular endocarditis (Fig. 83-3).

Bioprosthetic valves are homografts (preserved human aortic valves) or heterografts (bovine pericardial or porcine valve tissue mounted on a metal support), and the infection is usually restricted to the cusps (Fig. 83-4). The growth of thrombotic vegetations in the biosynthetic material can lead to cusp rupture, perforation, leak, and vegetations. However, if the sewing cuff is involved in infection, the pathologic process is similar to that of mechanical prosthetic valve infection.

The sizes and types of vegetations appear to be correlated with the virulence of the causative microorganism. S. aureus usually results in smaller vegetations but causes significant destruction and invasion of the tissue. Viridans group streptococci have been associated with larger vegetations with slower, milder destruction of tissue. Fungi form large, bulky vegetations.¹¹² Large vegetations are also associated with HACEK group of organisms.

Clinical Presentation

The clinical presentation of prosthetic valve endocarditis is variable, determined by the virulence of the pathogen and the time of presentation. Common clinical presentations include fever, new/changing murmur, heart block, congestive heart failure (CHF), and embolic events. Fever is the most common symptom and sign of PVE that is present in 73% to 92% of patients. However, fever is often absent in patients with renal failure, elderly patients, and those taking antibiotic or antipyretic medications. New or changing murmur or congestive heart failure may be indicative of complications of PVE such as prosthetic valve dehiscence, fistulas, or perivalvular abscess.^113–116 New ventricular dysrhythmias or conduction abnormalities may arise if the infectious process (perivalvular abscess) extends into the electrical conduction system of the heart. Perivalvular extension of the aortic PVE into the intraventricular septum can disrupt the proximal ventricular conduction system and result in complete heart block. Embolic stroke or brain abscess, or both, may be the initial presentation of PVE. In patients with left-sided endocarditis, both symptomatic (35%) and clinically silent (30%) cerebrovascular complications are common.¹¹⁷ Mycotic aneuryms involving the cerebral vasculature are uncommon but serious complications of PVE. The mortality rate associated with ruptured intracranial mycotic aneurysm approaches 80%^118–120 and can result in intracranial hemorrhage. Secondary metastatic abscess can develop in the musculoskeletal system (psoas abscess, vertebral osteomyelitis, and diskitis), kidneys, spleen, joints, etc. Right-sided endocarditis involving the tricuspid or pulmonic prosthesis may result in septic pulmonary emboli. Glomerulonephritis or arthritis can be a manifestation of systemic immune response but is uncommon in acute presentations.

Diagnosis

Classic Oslerian manifestations may often be absent in acute PVE because patients present during the early stage of the disease before the evolution of immunologic and embolic manifestations. The diagnosis of prosthetic valve endocarditis can be challenging because atypical presentations are common in the elderly populations with prosthetic valves. High index of suspicion and comprehensive clinical, microbiologic, and echocardiographic evaluations are important for prompt diagnosis of PVE and its complications. Modified Duke criteria should be used as a clinical guide to evaluate all patients suspected to have prosthetic valve endocarditis.^121,122 It should be noted that the Duke criteria were established for epidemiologic and clinical research purposes rather than to assist in clinical practice. Hence, clinical judgment should be used when they are applied in the management of patients.

Echocardiography

Transesophageal echocardiography (TEE) is recommended in all cases of suspected PVE.¹²² One of the two major criteria in the modified Duke diagnostic schema is echocardiographic evidence of oscillating intracardiac mass on the valve or supporting structures, new partial dehiscence of prosthetic valve, or intracardiac abscess.¹²¹ The utility of transthoracic echocardiography (TTE) is limited in the evaluation of patients with suspected PVE for two reasons. First, reverberations and other artifacts created by the prosthesis hamper the quality of the TTE images. Secondly, TTE is not sensitive enough to evaluate for perivalvular complications, which is critical in the management of PVE. TEE has a higher sensitivity of 84% to 94% to detect vegetations when compared with TTE (33% to 68%).^123–125 TEE is also superior to TTE for the detection of complications such as perforations, prosthetic valve dehiscence, perivalvular abscesses, and fistulas.¹²⁶ Thus, TEE is important to both establish the diagnosis of PVE and identify high-risk patients who may require early surgery.

False-negative TEE may occur in the early course of illness if the vegetations or perivalvular abscesses are too small to be detected.¹²⁷ TEE images may be limited if the abscess is localized around calcification in the posterior mitral annulus and in patients with a Bentall procedure (composite graft placement of the aortic valve, aortic root, and ascending aorta, with reimplantation of the coronary arteries into the graft). If the clinical suspicion persists despite negative TEE, TEE should be repeated after 2 to 7 days. In experienced laboratories, the specificity of an abnormal TEE is about 95%. The interpretation of TEE is sometimes difficult because differentiation among thrombus, vegetation, or degenerative strand is not always obvious.

Complications of PVE such as valve dehiscence, perivalvular abscess, fistulas, and pseudoaneurysm may evolve over time despite negative initial TEE. Persistent fever despite appropriate antibiotic treatment and/or new conduction abnormalities should raise the suspicion for intracardiac perivalvular abscess. New or worsening heart failure may suggest mechanical valve dehiscence or perforation/rupture of the bioprosthetic valve cusp. TEE should be repeated promptly whenever there is a change in clinical condition that raises the suspicion of PVE complications. TEE may identify pseudoaneurysms as pulsatile, echocardiographic-free sac around the prosthesis communicating with a cardiac chamber (Fig. 83-5).

A new imaging modality, multislice computed tomography (Fig. 83-6), was shown in one study to have excellent sensitivity (97%) when compared with TEE and provided more accurate anatomic detail about the perivalvular extent of abscess/pseudoaneuryms than TEE.¹²⁸ This and other newer tools require additional investigation as to how they should be used in patients with PVE.

Management

The management of PVE consists of effective pathogen-specific antimicrobial therapy and timely surgical intervention, when indicated. TEE is used to assess prosthetic valve function and vegetation size and to identify perivalvular complications that may require surgical intervention. It should be repeated during antimicrobial therapy when clinically indicated to monitor for development of complications of PVE. TEE is thus important to determine if a patient can be managed with medical therapy alone or if surgical intervention is necessary.

All patients suspected of having PVE should be hospitalized initially for close clinical monitoring. As previously discussed, pathogen identification, usually by isolation from blood cultures, is critical in defining an optimal treatment regimen. Because the infection is life threatening, it is reasonable to initiate empirical antimicrobial therapy targeting the most likely pathogens after obtaining at least three sets of blood cultures, especially in patients with acute-onset PVE and in hemodynamically unstable patients. It is suggested that the empirical antimicrobial regimen be chosen to target the most likely pathogens of PVE, considering the time of onset of PVE and the likely site of acquisition.

Staphylococcal Prosthetic Valve Endocarditis

The antimicrobial regimens recommended for S. aureus and coagulase-negative staphylococcal PVE are identical—based mainly on in vitro susceptibility testing (Table 83-1). A triple-drug combination antimicrobial regimen is recommended for the optimal treatment of staphylococcal PVE.¹²² The principal drug is a cell wall–active agent, chosen on the basis of methicillin susceptibility. Vancomycin is the principal drug of choice for methicillin-resistant organisms, whereas semisynthetic penicillin (nafcillin, oxacillin) should be chosen for methicillin-susceptible organisms. Isolates of Staphylococcus epidermidis with oxacillin minimal inhibitory concentration (MIC) of 0.25 µg/mL or less may be treated with oxacillin or nafcillin. The second drug in combination therapy is rifampin, which is important in the treatment of staphylococcal foreign body–related infections. In vitro studies, animal models of staphylococcal prosthetic device infections, and clinical studies provide evidence supporting the role of rifampin in eradicating staphylococci adherent to prosthetic devices.^162–167 Rifampin resistance can easily develop due to mutation of the ribosomal gene responsible for rifampin site of action.¹⁶⁶ The probability of this mutation and hence selection of rifampin-resistant strains is high when a large, highly dense, rapidly dividing bacterial population is exposed to ineffective rifampin-containing regimens. Hence, it is reasonable to initiate rifampin only after an effective two-drug combination antistaphylococcal therapy has been administered for at least 2 days. If the Staphylococcus is not susceptible to two other drugs, a single agent can be used for 3 to 5 days before initiation of rifampin. The goal of this strategy is to reduce the number of organisms and hence lower the risk of selection of rifampin-resistant subpopulation. The third drug in the combination regimen is either an aminoglycoside or a fluoroquinolone. Gentamicin is recommended for the initial 2 weeks of therapy, though there are only limited clinical data to support this addition. In case of gentamicin resistance or intolerance to an aminoglycoside, a fluoroquinolone may be used as a substitute if the strain is susceptible.^166–168

In vitro susceptibility testing should be repeated when there is failure of an antimicrobial regimen. Clinical failure with vancomycin therapy for methicillin-resistant S. aureus (MRSA) PVE can occur due to heterogeneous-type VISA (vancomycin-intermediate S. aureus) strains¹⁶⁹ and the optimal antimicrobial therapy in such cases is unknown. Clinical experience is limited in the treatment of PVE with newer agents such as high-dose daptomycin and linezolid.^{170,171,172–175} No cases of PVE treated with telavancin or ceftaroline have been published to date. Staphylococcal PVE is often complicated by perivalvular extension or prosthetic valve dysfunction, requiring surgical intervention for optimal management.

Streptococcal Prosthetic Valve Endocarditis

The antimicrobial regimens recommended by the American Heart Association (AHA) for the treatment of PVE caused by viridans group streptococci, Streptococcus gallolyticus, Streptococcus pneumoniae, or other penicillin-susceptible streptococci are listed in Table 83-2. The primary drug for treatment of streptococcal PVE is either penicillin or ceftriaxone, given for a minimum of 6 weeks. For PVE caused by highly penicillin-susceptible streptococci (MIC ≤0.12 µg/mL), the addition of gentamicin for the initial 2 weeks is optional because combination regimen has not been shown to have superior cure rates compared with β-lactam monotherapy.¹²² If the strain does not have high-level gentamicin resistance, intravenous once-daily gentamicin may be administered for the initial 2 weeks in patients who can tolerate aminoglycosides. For patients with PVE caused by streptococci with relative or high-level penicillin resistance (MIC >0.12 µg/mL), Gemella, Abiotrophia, or Granulicatella spp., a combination of penicillin or ceftriaxone with gentamicin is recommended for a minimum duration of 6 weeks. It is suggested to continue gentamicin for 6 weeks if the patient can tolerate it without significant nephrotoxicity. Monotherapy with vancomycin for a minimum of 6 weeks is recommended only for patients who cannot tolerate both penicillin and ceftriaxone.

TABLE 83-2

Therapy of Prosthetic Valve Endocarditis Caused by Streptococci as Suggested by American Heart Association

REGIMEN	DOSAGE AND ROUTE	DURATION	COMMENTS
Penicillin-Susceptible (MIC ≤0.12 µg/mL) Strain of Viridans Streptococci, Streptococcus bovis, Streptococcus pneumoniae
Either aqueous crystalline penicillin G Or	24 million units/24 hr IV either continuously or in 4-6 equally divided doses	6 wk	Gentamicin is optional. Combination of penicillin or ceftriaxone with gentamicin has not been shown to be superior to monotherapy.
Ceftriaxone	2 g IV/IM q24h	6 wk
With or without Gentamicin	3 mg/kg IM or IV single daily dose	2 wk
Relatively or Fully Resistant to Penicillin (MIC >0.12 µg/mL) Strain of Streptococcus or Gemella spp., Streptococcus agalactiae, Abiotrophia defectiva, Granulicatella spp.
Either Aqueous crystalline penicillin G Or	24 million units/24 hr IV either continuously or in 4-6 equally divided doses	6 wk	See below for patients with β-lactam allergy*
Ceftriaxone Plus	2 g IV/IM q24h	6 wk
Gentamicin	3 mg/kg IM or IV single daily dose	6 wk

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