Infective endocarditis (IE) is an infection of the endocardium, valves, or related structures of the heart and walls. It may arise following more frequent and prolonged bacteremia in a patient with or without a predisposing cardiac lesion. Infective endarteritis is a similar process. It may involve patent ductus arteriosus, shunts (native and constructed), aneurysms, stretching devices (stents), collateral closing devices, neonatal umbilical lines, and damaged arterial walls. The term infective endarteritis is now avoided, and all of these are united under IE.
Despite advances in diagnosis and treatment, IE of the 21st century may still be a life-threatening disease with significant mortality and morbidity. Pediatric IE has a lower incidence and better outcomes than IE in adults. The predisposing factors for IE in high-income countries have changed: although rheumatic heart disease–related IE has dramatically declined, there is a rise of the congenital heart disease (CHD)-related, postprocedural, and device-related pediatric IE. The mainstay of management of IE is the multidisciplinary approach coordinated by the endocarditis team: cardiologist, clinical microbiologist/infectious diseases specialist, and cardiothoracic surgeon.
All information is outlined in detail in the guidelines, recommendations, reviews, and updates.
Incidence of Pediatric Infective Endocarditis
The IE incidence in children is lower than in adults and reported stable at approximately 0.43 per 100,000 children/year, which is far below those in adults, who have an incidence of approximately 3 to 12 per 100,000 people/year. A New Zealand study showed increased incidence of pediatric IE from 0.46 per 100,000/year in 1994–2002 to 0.76 per 100,000/year in 2003–2012.
CHD-related pediatric IE is approximately 60% to 68% of the cases. A large population-based 1988–2010 study on a large cohort of Canadian children with CHD reported an IE incidence of 4.1 cases/10,000 person-years, which is much lower than that in adults with CHD of 10.6 cases/10,000 person-years. However, a more recent study from Taiwan similarly reported 11.13 cases/10,000 person-years.
The cumulative observed risk of IE is 6.1 cases/1000 CHD patients 0 to 18 years of age.
Cyanotic CHD lesions, left-sided lesions, and atrioventricular septal defects were associated with increased risk of IE acquisition in childhood. The relative risk of developing IE was substantially elevated during the 6-month postoperative period of cardiac surgery and in children younger than 3 years of age.
There is a comparable IE frequency in boys and girls because high-risk behaviors and other lifestyle factors may be less likely to differ between boys and girls during childhood.
Mortality Risk
Despite significant improvements, pediatric IE remains a disease with significant mortality risk, varying from 5% to 10% but is much lower than in the adult IE, which is still reported at approximately 25%.
Pediatric IE–related mortality is much lower in native valve endocarditis 3.5% than in patients with underlying heart disease 6.7%. Risk factors for mortality include some forms of CHD, premature/neonatal age, fungus, and Staphylococcus aureus as etiologic agents.
Epidemiology
The changing epidemiology and unique features of pediatric IE have been well outlined. Before the 1970s, up to 50% of the pediatric IE was rheumatic heart disease–related IE. After the 1970s, in high-income countries, there has been a gradual decrease and almost complete disappearance of rheumatic heart disease–related pediatric IE but with a concomitant rise of CHD-related IE; the rise of degenerative valvulopathies and intravenous drug abuse–related IE in adults is not seen in children. Pediatric IE changes are also marked by the rise of S. aureus as a causative agent, as well as device-related IE and postprocedural IE. Multiple site (dual valve) IE is being seen more often. The changing epidemiology is summarized in Box 56.1 .
- 1.
Changing underlying predisposing factor:
- ■
↓ Acquired rheumatic heart disease related
- ■
↑ Congenital heart disease related
- ■
↑ Device/prosthesis related
- ■
↑ Degenerative valve disease related in elderly
- ■
↑ Intravenous drug abuse related in adults
- ■
↑ Previous infective endocarditis (recurrence, reinfection)
- ■
- 2.
Changing microbiology:
- ■
↑ Staphylococcal
- ■
↓ Streptococcal
- ■
↑ Blood-culture positive (>70%) (improved diagnosis: techniques, fastidious organisms)
- ■
↑ Intracellular organisms (improved diagnosis: sensitive serology, PCR from vegetations)
- ■
- 3.
Changing way of acquisition:
- ■
↓ Community acquired
- ■
↑ Health care associated
- ■
- 4.
Changing localization of lesions:
- ■
↑ Multiple site (neighboring and nonneighboring)
- ■
↑ Right sided
- ■
↑ Recurrent
- ■
PCR , Polymerase chain reaction.
Classification
The classification of IE is outlined in Table 56.1 . Currently, only approximately 10% of pediatric IE is a native valve endocarditis (NVE).
| ACCORDING TO LOCALIZATION AND PRESENCE/ABSENCE OF INTRACARDIAC MATERIAL | |
| Left-sided native valve IE | |
| Left-sided prosthetic valve IE | |
| Early | <1 year after replacement |
| Late | >1 year after replacement |
| Right-sided IE a | |
| Cardiac device–related IE b | |
| ACCORDING TO MODE OF ACQUISITION | |
| Health care–associated IE | |
| Nosocomial | Hospitalized >48 h prior to onset of symptoms |
| Nonnosocomial | Hospitalized <48 h prior to onset of symptoms if:
|
| Community-acquired IE | Onset of symptoms out of hospital or <48 h after hospitalization if criteria for health care–associated not fulfilled |
| Intravenous drug abuse–associated IE | IE in active injection drug user without alternative source of infection |
| ACTIVE IE | |
| IE with persistent fever or positive blood culture | |
| Active inflammatory morphology at surgery | |
| Still under antibiotic therapy | |
| Histopathologic evidence of active IE | |
| RECURRENCE OF IE | |
| Relapse | Repeat episode with same microorganism <6 months after the initial episode |
| Reinfection | Repeat episode with same microorganism >6 months after the initial episode Infection with different microorganism |
a Including tricuspid valve supporting/additional tissue at partially closed or residual ventricular septal defect, transcatheter and surgical pulmonary valve replacement (prosthetic valve, homograft, valved conduit).
b Cardiac implantable electronic device (CIED) like permanent pacemakers (PPMs) and implantable cardioverter-defibrillator (ICD); Transcatheter introduced valves and closure devices (ASD/VSD/PDA closing) before endothelization; Long-term catheter related (Portacath, Hickman line and Peripherally inserted central line), other central lines reaching the heart.
Clinical Manifestations
The heterogeneous clinical manifestations with regard to signs and course, as well as the possible multiorgan involvement, explain why IE still presents a diagnostic challenge. The signs are related to:
- 1.
Infection: fever (>90%), positive markers of inflammation (elevated erythrocyte sedimentation rate/C-reactive protein, anemia normocytic or microcytic with low serum iron and normal or high ferritin, leukocytosis with neutrophilia), positive blood culture (BC) (>70%).
- 2.
Destruction (>90%): new cardiac murmur, heart failure (30% to 60%), conduction abnormality. Because children with congenital heart defects often have a preceding murmur, a new murmur is difficult to differentiate. Heart failure is caused by acute severe aortic or mitral insufficiency or intracardiac fistulae and only rarely by valve obstruction. Conduction abnormality (right and left bundle branch block, as well as complete heart block) can be observed and is due to spread of infection to the conduction system.
- 3.
Embolism (20% to 50%): systemic (brain, spleen, kidney, peripheral) or pulmonary. Pulmonary thromboembolism (PTE) is almost universally present in right-sided endocarditis. Neurologic complications (local brain involvement in the area of the embolization, ischemic stroke, mycotic aneurysm, subarachnoid hemorrhage secondary to mycotic aneurysm rupture) might be more often seen than the currently reported 30%. These continue occurring usually up to the first 2 weeks after start of antibiotic treatment.
- 4.
Immunologic phenomena (positive antinuclear antibody and rheumatoid factor, low C3/C4). Hematuria may be related both to immunologic complex deposition or small renal emboli.
The classical subacute presentation over weeks and sometimes months is characteristic for viridans group streptococci (VGS) and is less often seen. Acute presentation is now prevailing as IE caused by staphylococci, particularly S. aureus has become more frequent. We do not use the type of presentation for classification purposes.
Clinical manifestations leading to suspicion of IE are summarized in Box 56.2 .
IE must be suspected in the following situations:
- 1.
New regurgitant heart murmur.
- 2.
Embolic events of unknown origin.
- 3.
Sepsis of unknown origin (especially if associated with IE causative organism)
- 4.
Fever (>90% of patients). IE must be suspected if fever is associated with:
- a.
Intracardiac prosthetic material (e.g., prosthetic valve, pacemaker, implantable cardioverter defibrillator, surgical baffle/conduit)
- b.
Previous history of IE.
- c.
Previous valvar or congenital heart disease.
- d.
Other predisposition for IE (e.g., immunocompromised, intravenous drug users).
- e.
Predisposition and recent intervention with associated bacteremia.
- f.
New congestive heart failure.
- g.
New conduction disturbance.
- h.
Positive blood culture with typical IE causative organism or positive serology for Q-fever or Bartonella (microbiologic findings may precede cardiac manifestations).
- i.
Vascular or immunologic phenomena: embolic event, Roth spots, splinter hemorrhages, Janeway lesions, Osler nodes.
- j.
Focal or nonspecific neurologic symptoms and signs.
- k.
Evidence of pulmonary embolism/infiltration (right-sided IE).
- l.
Peripheral abscesses (renal, splenic, cerebral, vertebral) of unknown cause.
- a.
IE , Infective endocarditis.
Imaging
Echocardiography
Transthoracic echocardiography (TTE) has much higher sensitivity in children (>85%) than in adults. Two-dimensional (2D) images have high spatial resolution and high quality and diagnostic yield. The interplay between 2D and color Doppler (CD) imaging for visualization of structures and flow, respectively, are of greatest significance. Pulsed wave Doppler and continuous wave Doppler have importance in assessing stenosis and gradients between cavities. Tissue harmonic imaging provides improved image quality. Currently, the negative predicted value of the absence of echo signs of IE even in adults can reach 97%.
Transesophageal echocardiography (TEE) may only occasionally be indicated in technical difficulties in acquisition of transthoracic images, abscesses, or negative TTE in strong clinical suspicion of IE. Unlike adults, TEE is only rarely required and is usually not necessary because the sensitivity of TTE is greater than 90% for vegetations and greater than 85% in total.
A summary of echocardiography findings and rules and indications for TEE are summarized in Box 56.3 . Echocardiography images of signs of IE as well as matching intraoperative findings are shown in to .
Echocardiography Signs of IE:
- ■
Vegetation: mobile hyperechogenic mass attached to valve, device, or wall (2D)
- ■
Regurgitation due to:
- ■
perforation: regurgitant jet (CD) across an interruption of leaflet echo (2D)
- ■
fistula: communication (CD) between neighboring cavities through perforation (2D)
- ■
chordal rupture of AV valve: central regurgitant jet (CD) with gap, free floating chord prolapsing to the atrium, leaflet prolapse (2D)
- ■
dehiscence of prosthetic mechanical valve: paravalvar leak (CD) with/without rocking motion of the prosthesis
- ■
aneurysm: saccular bulging (2D)
- ■
- ■
Abscess: perivalvar thickened, nonhomogeneous, hyperechogenic (echodense), or hypoechogenic (echolucent) area (2D) not communicating with any cavity (CD)
- ■
Pseudoaneurysm: pulsatile perivalvar echolucent area (2D) with flow communicating with lumen (CD)
- ■
Intracardiac fistula: communication between a vessel and a cardiac chamber
- ■
Blocked shunt or stented vessel
Echocardiography rules of IE:
- ■
Neither sensitivity nor specificity of echocardiography is 100% and therefore negative echocardiogram does not 100% exclude IE.
- ■
Echogenicity does not differ significantly between vegetation, thrombus, and tumor.
- ■
Compare to previous images, if available, as dysplasia myxomatous changes may imitate vegetations.
- ■
Do not rely on still images, review loops of at least one complete cycle at low speed.
- ■
If the initial echocardiography was negative and the clinical suspicion remains high, repeated echo in 7–10 days or earlier if S. aureus infection.
- ■
Serial examinations have significance for guiding the management.
Echocardiography report should include:
- ■
Location and size of vegetation, perforation, abscess, aneurysm
- ■
Severity of stenosis or regurgitation
- ■
Hemodynamic consequences of stenosis or regurgitation including cavity size, ventricular function, and pulmonary artery pressure assessment.
- ■
Relation to presumed underlying cause: valvar abnormality, ventricular septal defect, prosthetic material etc.
- ■
In case of multisite IE, proximity each location to each other.
TEE may be indicated in:
- ■
Negative transthoracic echo in high clinical suspicion of IE
- ■
Prosthetic valve endocarditis
- ■
Suspected paravalvar abscess
- ■
Children and adolescents with inadequate transthoracic imaging because of overweight/obesity and chest wall deformities
2D , Two-dimensional; CD , color Doppler; IE , infective endocarditis; TEE , transesophageal echocardiography.
The added value of three-dimensional echocardiography remains to be established: it might remain low due to the currently low spatial resolution.
Targeted emergency echo may be lifesaving. It is becoming increasingly important to have a timely diagnosis and manage the emergency conditions related to embolic complications of IE or to heart failure related to acute valvar regurgitations. Guidelines for urgent targeted echo have been adopted.
Intracardiac echo may have added value for visualizing intrastent vegetations. It has been shown to be useful for visualizing vegetations in IE related to transcatheter implanted pulmonary valves, as up to 50% remain not visualized with TTE and TEE. It is rarely used because of the rare indications and relatively high price.
Computed Tomography
High-resolution multislice gated cardiac computed tomography (CT) with contrast is one of the added major IE criteria in the new 2015 IE guidelines. The newest third-generation dual source turboflash CT equipment not only has superior spatial resolution but also allows the acquisition of images in minimal amounts of time, thus enabling the investigation to be performed without general anesthesia and at very low radiation exposure.
CT has high added value for diagnosing IE in the following:
- ■
Paravalvar complications, including aortic abscess
- ■
Intrastent vegetations
- ■
PTE
- ■
Systemic peripheral thromboembolism, including cerebral
- ■
Subarachnoid hemorrhage in ruptured mycotic aneurysms
It is reasonable to screen patients with right-sided IE for possible PTE prior to operation.
Serial CT images show progression of disease and are an invaluable tool to guide management and are becoming more widely used.
There are currently no large comprehensive studies for the use of CT in pediatric IE, and this is a field of future interest.
Positron Emission Tomography–Computed Tomography
Positron emission tomography (PET)/CT is another new imaging strategy included in the 2015 European Society of Cardiology (ESC) IE diagnostic criteria. It is a nuclear imaging method that uses 18 F-fluorodeoxyglucose ( 18 F-FDG) and capitalizes on the fact that infectious and inflammatory foci are metabolically active and have higher uptake of 18 F-FDG. The addition of 18 F-FDG PET/CT as a major criterion increases the sensitivity of the modified Duke score from 70% up to 97% for prosthetic valve endocarditis (PVE) and implantable cardiac electrical device–related IE (ICED-IE).
PET/CT has great added value for diagnosing IE in the case of unconvincing outcome of the rest of the imaging in suspected IE, especially in prosthetic valve IE or cardiac device–related IE.
The role of PET/CT for the previously mentioned indications has been characterized and confirmed in recent larger studies. The role of PET/CT in pediatric cardiac patients and patients with congenital heart defects in general has recently been reviewed.
There are currently no large comprehensive studies for the use of PET/CT in pediatric IE, and this is a field of future interest.
Brain Imaging
Patients with IE and neurologic symptoms should undergo brain imaging, magnetic resonance imaging (MRI), or, if not possible, CT. Brain MRI has great significance for visualizing the cerebral complications of IE.
It is reasonable to screen patients with left-sided IE for possible brain involvement prior to operation.
Serial brain imaging is excellent to show whether there is an increasing number of mycotic aneurysms and other changes that will indicate early surgery.
Diagnosis
The diagnosis of IE still uses the modified Duke criteria. Under the current revision, following the advances in imaging, the ESC 2015 guidelines have added the positive CT and the PET/CT to the major criteria under the list of positive imaging modalities. The currently used version of the diagnostic criteria with revisions and recent amendments is shown in Table 56.2 .
| Major Criteria | Minor Criteria |
|---|---|
|
|
The criteria are very helpful, but they should be used for diagnosis in addition to clinical judgement.
Differential Diagnosis
It may require differential diagnosis with chronic infection, rheumatologic, and autoimmune diseases or tumors.
Intracardiac Masses
Tumors, although rare, should always be considered. It should be noted that cardiac myxomas quite often manifest with low-grade fever, immune phenomena, and positive markers of inflammation and mimic IE to a great extent. The nonbacterial thrombotic endocarditis (NBTE) described as a paraneoplastic process for multiple adult cancers seems not to be characteristic of pediatric tumors. However, there might be direct extension into the right heart by hepatoblastoma, neuroblastoma, and Wilms tumor. Extension to the left heart via the pulmonary vein for pulmonary metastasis of hepatoblasoma or Wilms tumor, as well as direct metastasis to the left ventricle of neuroblastoma, have also been described.
Granulomatous polyangiitis (GPA, previously Wegener granulomatosis) is reported to cause intracardiac thrombus, as well as valve perforations, which might mimic IE.
Liebmann-Sachs endocarditis may be the first manifestation of systemic lupus erythematosus (SLE) in children : it usually involves the mitral or aortic valve but may involve both or may also be located on the tricuspid valve. Although it may have a favorable evolution after starting treatment, it may require urgent surgery because excessive growth may create obstruction.
In Churg-Strauss eosinophilic polyangiitis, cardiac manifestations usually occur with severe myocarditis but intracardiac thrombi have also been reported.
Hypereosinophilic syndrome in childhood may have cardiac manifestations that are particularly notorious for initial infiltration, including mural and apical, that progresses quickly to fibrosis, thus leading to worsening regurgitation with little possibility for repair and almost universal need of replacement. It might also cause myocardial infiltration with restrictive cardiomyopathy as a concomitant feature. Biopsy might not always be helpful: echocardiograms and endomyocardial biopsies agree for presence or absence of cardiac involvement 60% of the time.
Hyperhomocysteinemia due to a heterozygous C677T polymorphism in the methylenetetrahydrofolate reductase gene is a well-recognized thrombophilia condition that is phenotypically most well expressed in the homozygous recessively inherited metabolic disorder that has severe hyperhomocysteinemia and may potentiate intracardiac and valvar thrombi formation. It should be taken into account that for unknown reasons patients with IE may have mild hyperhomocysteinemia without necessarily having the polymorphism itself; this does not relate to bigger vegetations or increased embolic risk. From the other thrombophilias studied, it has been confirmed that mutations G20210A of the prothrombin gene and G1691A of factor V Leiden gene do not contribute to the susceptibility to IE.
Periaortic Thickening
Surgically related echocardiographic findings can appear like glue after valve replacement or hyperechogenicity of homografts (unpublished). Chronic periaortitis has been studied in detail and described in GPA, eosinophilic granulomatous polyangiitis, and polyarteritis nodosa, and it might very well mimic aortic root abscess.
Pyrexia
Line infections are the most frequent cause of echo request for ruling out IE.
Pyrexia of unknown origin and bacteremia have become major indications for echo to rule out IE. The number of requests has risen exponentially in the past 2 decades. Different tools have been designed to indicate when an urgent echo is required. An approximately 20% and 10% positive yield for IE diagnosis in community and nosocomial acquired staphylococcal bacteremia, respectively, justifies echo as a screening tool ; the percentage of pediatric IE cases among children with S. aureus bacteremia is approximately 12%. It should be underlined that one of the most frequent causes of persistent bacteremia besides IE and line infection is osteomyelitis; tooth abscess has also been described.
Differential diagnosis is shown on Box 56.4 .
Intracardiac Masses
Tumors
- ■
Myxomas
- ■
Extension via the inferior vena cava (neuroblastoma and Wilms tumor)
- ■
Nonbacterial thrombotic endocarditis in distant tumors (not characteristic of pediatric age)
Noninfectious Intracardiac Thrombi
- ■
Acute rheumatic fever
- ■
Autoimmune diseases (GPA, SLE, APS, Churge-Strauss eosinophilic GPA)
- ■
Hypereosinophilic syndrome (acute leukemia, parasitic disease)
- ■
Thrombophilia (homocystinemia)
Periaortic Masses
- ■
Surgical (glue)
- ■
Homograft after recent implantation
- ■
Chronic periaortitis (GPA, EGPA)
Pyrexia
- ■
Chronic infections
- ■
Line infections
- ■
Pyrexia of unknown origin
- ■
Bacteremia from different focus
APS , Antiphospholipid syndrome; EGPA, eosinophilic granulomatous polyangiitis; GPA , granulomatous polyangiitis; SLE , systemic lupus erythematosus.
Pathogenesis
Intact vascular endothelium is resistant to microbial adhesion in most circumstances. In order for IE to develop there are a number of distinct pathophysiologic events that need to occur.
- 1.
Vascular endothelial damage with subsequent exposure of the subendothelial matrix can lead to fibrin and platelet deposition and the formation of NBTE. This lesion can act as a nidus for microbial (fungal) adhesion and establishment of an infected endovascular lesion. Vascular damage can occur via a number of different ways:
- ■
High velocity, turbulent jets occur with regurgitant and stenotic valves.
- ■
Mechanical friction, or interruption to normal flow resulting in turbulence, can result in endothelial damage when there are either abnormal structures, or due to the presence of foreign indwelling devices.
- ■
Prosthetic material used to repair CHD can act as a substrate for bacterial adhesion and biofilm formation, and this can last up to 6 months post procedure, after which they are relatively protected through endothelialization.
- ■
Children with artificial valves and those with palliative shunts are more at risk because there are residual defects causing flow problems and often incomplete endothelialization.
- ■
- 2.
Bacteria (or fungi) must either gain access to the circulation or directly infect material for an NBTE or a prosthetic device to become infected. The routes by which this can happen, and the various ways to prevent or mitigate against this occurring, are summarized in Table 56.3 .
Table 56.3
Routes of Entry of Microbial Pathogens
Route/Source of Entry
Prevention/Procedures to Mitigate
Activities of daily living (e.g., tooth brushing, flossing, chewing)
- 1.
Low-level cumulative bacteremia is likely to pose a risk that will be potentially worse when dental health is poor.
- 2.
Recommended regular dental review (twice yearly in high-risk patients) with emphasis on dental hygiene
Dental procedures:
- 1.
High-risk manipulation of gingival or periapical region or perforation of oral mucosa
- 2.
Low-risk treatment of superficial caries, local anesthetic injection, removal of sutures, orthodontic procedures
Prophylaxis given only in high-risk procedures in high-risk patient (see Box 56.6 )
Bacterial carriage (e.g., Staphylococcus aureus , group A streptococcus)
Preoperative screening for S. aureus , with eradication offered presurgery
High-risk procedures:
- 1.
Insertion of pacemaker or implantable defibrillator (recommended)
- 2.
Implantation of prosthetic valve, graft (consider)
Appropriate perioperative antimicrobial prophylaxis recommended (1) or considered (2).
Optimal surgical technique, including sterility of devices, instruments, theater air quality
Low- or minimal-risk procedures:
- 1.
Respiratory (bronchoscopy, laryngoscopy)
- 2.
Gastrointestinal/genitourinary (endoscopy, colonoscopy)
- 1.
No prophylaxis routinely required.
- 2.
Antimicrobial only required when procedure is done in the context of infection.
Bacterial infections/abscesses, empyema, other
- 1.
Prompt drainage of any abscess/and optimal antimicrobial therapy for systemic infections.
- 2.
Potential sources of sepsis eliminated ≥2 weeks prior to elective surgery.
Indwelling venous catheters
- 1.
Avoid long-term placement of central venous line in high-risk patients unless medically required.
- 2.
Strict indwelling venous catheter care and adherence to protocols to prevent exit and tunnel infections and luminal contamination should be observed.
Body piercing and tattooing
Probable increased risk with piercing of the oral mucosa; minimal data exist for skin tattoos done with aseptic technique. Risks of potential infection should be explained, as well as the fact that the efficacy of antibiotic prophylaxis has not been studied. Aseptic technique for skin piercing and body art should be used.
- 1.
- 3.
Neutrophil extracellular traps are a recently proven mechanism in which the IE pathogen promotes vegetation formation. Neutrophil extracellular traps were discovered in 2004 as a protective neutrophil mechanism independent of phagocytosis by forming a network of fibers outside the cell and may promote and expand vegetation formation through enhancing and entrapping bacteria-platelet aggregates on the injured heart valves. The suggested possibility of DNAse use to counteract this mechanism has not had any clinical test.
Microbiology
The majority of both native and prosthetic valve IE is caused by gram-positive bacteria. The likely reason for this is the specific capacity of these organisms to bind to surface-exposed host receptors in denuded injured subendothelial matrix. Work has further elucidated the complex mechanisms and interrelationships between bacterial binding and the formation of biofilm on host subendothelial surfaces.
Streptococci and Enterococci Species
- 1.
One of the best-characterized bacteria that cause IE is the viridans streptococcus, Streptococcus gordonii . The multifunctional fibrillar adhesin CshA can promote binding of bacteria to host cell matrix by forming molecular bridge to host cell integrin in the subendothelial matrix.
- 2.
Initial binding of S. gordonii to two cell surface proteins, Hsa and platelet adherence protein A, mediates adherence and activation of platelets, mediating binding to subendothelial matrix proteins vitronectin and fibronectin, promoting biofilm formation.
- 3.
In Enterococci spp., common causative pathogens in adults, it has been shown that the gene product of bepA, a carbohydrate phosphotransferase system permease, is linked to metabolism of glycosaminoglycan-injured heart valves.
Staphylococcus Aureus and Other Staphylococci
- 1.
S. aureus expresses cell wall–anchored (CWA) proteins. The most common group of these are the microbial surface components recognizing adhesive matrix molecules. These are multifunctional receptors (such as clumping factor A, fibronectin-binding proteins) involved in adhesion to subendothelial matrix proteins such as fibronectin but are also involved in tissue invasion, immune deviation, and establishment of biofilm formation. S. aureus expresses up to 24 different CWA proteins, whereas coagulase-negative strains often express a smaller number of these proteins. It is very likely that the increased virulence of S. aureus is likely to involve the plethora of CWA proteins it is able to utilize in host cell and matrix interactions.
- 2.
sarA, a global regulator of many S. aureus virulence factors, may be intricately involved in both regulation of biofilm production but also resistance to oxacillin, via its regulation of penicillin-binding protein 2b in methicillin-resistant strains, because sarA-deficient mutants produced significantly less biofilm and were more susceptible to oxacillin-mediated killing in experimental endocarditis models.
These investigations provide further rationale to develop novel interventions, such as vaccines designed to elicit antibodies that block microbial host cell interactions or compounds designed to interrupt microbial regulatory mechanisms. Vaccine strategies to induce protective antibodies in S. aureus and Enterococcus faecalis have been shown to be effective in experimental endocarditis. In animal models, vaccination strategies to induce antibody to Hsa and platelet adherence protein A protected against experimental endocarditis. In the longer term, such strategies could be more effective than antimicrobial prophylaxis, especially in high cases.
Infective Endocarditis Causative Agents: Drivers for Changing Epidemiology
- ■
As the underlying risk factors for IE have changed over the past 4 decades, there have been changes in the proportion of the microbial agents responsible.
- ■
There has been a reduction in rheumatic heart disease in developed countries in particular, with a concomitant rise in survival, and surgical intervention and management of children with CHD.
- ■
Heath care interventions and increasing survival of preterm neonates and other children requiring long-term central venous access (such as treatment of malignancy) has increased risk factors for IE in the absence of CHD.
- ■
In adults, large-scale epidemiologic studies have demonstrated a significant increase in staphylococcal spp., both S. aureus and so-called coagulase-negative staphylococci (CONS), in keeping with changing risk factors over the past 3 to 4 decades.
- ■
Relatively few studies have looked at the incidence and changes in risk factors and causative agents in children. There has been a similar trend in increase in staphylococcal IE in the past few decades. However, one factor that may have driven this in adults, namely intravenous drug abuse, is very uncommon in children.
Comments on the causative agents in pediatric IE and studies on these are summarized in Tables 56.4 and 56.5 .
| Causative Agent(s) | Notes and Comments |
|---|---|
| Staphylococcus aureus | Predominant and one of the most virulent causes of IE. Associated with tissue destruction and root abscesses. More common in absence of CHD. Highest mortality rates, especially in neonates. |
Coagulase-negative staphylococci:
| More likely to affect indwelling cardiac implants such as shunts and artificial valves. Often associated with indwelling central venous lines, though can be implanted at surgery. Can cause NVE, but very rare in children compared with adults. |
Oral Streptococcal species ( Viridans group)
| Most common cause in CHD. Often sensitive to penicillin and third-generation cephalosporin, but resistance to both agents has been observed. |
Enterococci
| More common in adults. Difficult to treat due to relative tolerance to β-lactam antimicrobials and increasing resistance in E. faecium. |
Nutritionally variant organism
| Difficult to isolate and culture. Concerns over relative resistance to β-lactams. High relapse rate, need to treat as for enterococcal IE. |
Other streptococcal species
| Infrequent but very aggressive cause if IE with severe tissue destruction requiring surgical intervention. |
HACEK
| Affects both prosthetic valves and native valves. Generally better prognosis than some causes of IE. Some strains are β-lactamase positive. Hard to grow in laboratory, often require prolonged culture. Good pick-up on resected material by molecular methods. |
Gram negative
| More likely in immune-compromised and neonates. Antimicrobial resistance an issue. Specialist advice on combination therapy and length. |
| Fungal | Candida spp. Cause of both NVE and PVE; very difficult to treat, requiring surgical resection in most cases, apart from mural IE in neonates. Filamentous fungi. Very difficult to manage, almost always requires surgical debridement and aggressive antifungal therapy. |
Other causes
| Often part of noncultivable or culture-negative endocarditis. Serologic testing available for some. Good rate of pick-up on molecular testing of resected material. Combine with epidemiologic exposure for optimal diagnosis |
Emerging pathogens
| M. chimaera recently identified as a cause of IE due to contaminated heater cooler units and bypass circuits used in cardiac surgery. |
| Study | Time Period, Study Type | Number of IE Episodes | % of Patients With Preexisting Cardiac Disease/None | Findings/Comments |
|---|---|---|---|---|
| Day et al | 2000 and 2003, US retrospective cohort | N = 1588 (causative organisms in 662 cases) | 42%/58% | IE episodes with coded organisms, n = 622
|
| Gupta et al | 2000–2010, US CHD Retrospective cohort | N = 3840 estimated | 53.5%/46.5% |
|
| Sakai Bizmark et al | 2001–2012, interrupted time series retrospective cohort | N = 3748 (weighted according to whether IE appears in any primary, secondary, or tertiary discharge code) | 50.2%/49.8% |
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Laboratory Diagnostic Procedures
BC remains the gold standard investigation for patients with suspected IE; however, optimal sampling techniques, volumes (based on age of child), and culture conditions are essential for an accurate diagnosis. In children the following volumes and frequency are recommended:
Volumes:
- 1.
Infants and young children: 1 to 3 mL per bottle
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Older children: 5 to 7 mL per bottle (up to 30 mL blood/day).
Frequency:
- 1.
Three sets of separate venipunctures over 24 hours, ideally with one set 12 hours apart, but with at least the first and last set 1 hour apart
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If the patient is unstable and presentation is acute, take two BCs at separate sites immediately and a third at least 1 hour later and commence empiric therapy as soon as feasible.
New Laboratory Diagnostic Techniques
Techniques such as broad-range bacterial (16S rDNA) and fungal (18s rDNA) polymerase chain reactions (PCRs), pathogen-specific real-time PCRs, and proteomics (matrix-assisted laser desorption/ionization time-of-flight analysis [MALDI-TOF]) have become widely available and should be used in conjunction with standard culture techniques. Gene-specific primers and amplification are more sensitive and do not always require a sequence step and so are more rapid.
- 1.
Molecular methodologies can detect bacterial DNA directly in blood, and, although they have advanced in recent years,
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They are still somewhat insensitive, the likely reason due to the low circulating load of bacteria in IE.
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Broad-range PCR techniques, bacterial (16S rDNA) and fungal (18S rDNA), are designed to amplify both conserved and variable regions of ribosomal DNA but in general are rather insensitive and in addition require a sequencing step to identify the pathogen.
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Contamination with environmental DNA can be problematic, particularly for fungal 18S DNA. Optimal sampling, extraction, and setup techniques are critical to performance of these broad-range techniques
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Single gene targets that can identify genus or species level are more sensitive than broad-range 16S rDNA PCR. They are more likely to be successful in acute sepsis and endocarditis, where circulating bacterial numbers may be much higher than in subacute IE. However, multiple primers sets are required to amplify the range of pathogens that could be present, increasing complexity and expense.
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In addition to species identification, genetic determinants of antimicrobial resistance, such as mecA (conferring resistance to majority of β-lactam antibiotics) in S. aureus , can also be rapidly detected.
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In the future, high-throughput sequencing (or next-generation sequencing) will be routinely available, which can theoretically provide whole-genome analysis of organisms in situ.
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Proteomic technology
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The majority of currently available techniques utilize MALDI-TOF.
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Can identify causative agent both rapidly and accurately once a BC is positive.
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Direct identification of bacteria in blood (without a culture step) by MALDI-TOF is possible, although not yet developed enough to be useful in clinical practice.
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Accurate determination of minimum inhibitory concentration to key antibiotics used in definitive therapy often still requires isolation and culture of the organism.
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Future developments include use of sophisticated mass spectrometry and proteomic techniques that not only detect the pathogen but also resistance and virulence determinants.
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- 3.
Investigation of resected material, by both broad-range and pathogen-specific PCRs and mass spectrometry techniques, can be particularly informative in identifying the etiologic agent. This can be useful to confirm a causative agent where blood (or tissue) cultures may have not been conclusive or may have been mixed, or in blood culture negative–endocarditis (BCNE).
Blood Culture–Negative Endocarditis
BCNE can occur due to:
- 1.
Prior antibiotic administration
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Suboptimal culture techniques
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Fastidious, intracellular or factitively intracellular, or require specialized culture techniques or rarely cultivable from BCs, including:
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Coxiella burnetii
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Bartonella spp.
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Brucella spp.
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Nutritional variant gram-positive (formerly Streptococci) organisms Abiotrophia sp., Granulicatella spp.
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Mycobacteria spp.
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Mycoplasma spp.
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Legionella spp.
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Tropheryma whipplei
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Filamentous fungi
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In such cases, a combined approach, using serologic assays, direct PCR on blood, and molecular testing on resected material can establish the causative agent, which allows for reasonable accuracy of detection rates.
The proportion of BCNE varies quite widely between studies: 26.6% in a mixed adult and pediatric cohort, 30.2% in a pediatric cohort. These might become identified on molecular studies on resected material. It is clear that further development of sensitive and accurate diagnostic tests, including molecular and proteomic techniques, are warranted.
Antimicrobial Therapy
Principles
- 1.
Effective management of IE requires at least one bactericidal antimicrobial to be used in high doses that is corrected for age, weight, and adjusted for renal function.
- 2.
Treatment of IE is necessarily prolonged because infection is established in a biofilm matrix. Organisms contained therein are either tolerant to bactericidal killing or can exist as “persisters.” This is especially relevant for prosthetic material IE; therefore duration of treatment is long (6 weeks or longer). In addition, biofilm and vegetation protect microorganisms from host-mediated clearance mechanisms.
- 3.
Current American Heart Association (AHA) and ESC guidelines provide comprehensive protocols for pathogen-specific therapy, but there are important differences, which are detailed in Table 56.6 . The suggested antibiotic treatment for streptococcal IE is shown in Table 56.7 and for staphylococcal IE is shown in Table 56.8 . The therapy should always be advised by a clinical microbiologist/infectious diseases specialist.
Table 56.6
Differences and Similarities Between 2015 ESC and Pediatric AHA Guidelines in Antimicrobial Therapy for Infective Endocarditis
AHA 2
ESC 1
For treatment of streptococcal IE:
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Short-course (2 weeks) standard regimen for treatment of uncomplicated IE due to oral streptococci in children not recommended due to lack of effectiveness data
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MICs for highly penicillin susceptibility ≤0.1 mg/L
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MICs for relatively resistant strains ≥0.2 mg/L
For treatment of streptococcal IE:
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Short-course (2 weeks) standard regimen for treatment of uncomplicated IE not explicitly ruled out
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MICs for highly penicillin susceptibility ≤0.0125 mg/L
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MICs for relatively resistant strains 0.250–2.0 mg/L
Treatment of Staphylococcus spp.:
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Treat native valve IE with oxacillin (methicillin)-sensitive strains; gentamicin can be used for first 3–5 days of initial treatment, but this may increase likelihood of ototoxicity or renal toxicity
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No mention of delay of rifampicin to either flucloxacillin or vancomycin in treatment of prosthetic valve endocarditis
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Daptomycin is now recommended as an alternative agent for treatment of staphylococcal IE for penicillin allergic (anaphylaxis) patients and in treatment of methicillin-resistant staphylococci when vancomycin cannot be used
Treatment of Staphylococcus spp.:
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Treat native valve IE with oxacillin (methicillin)-sensitive strains; gentamicin not recommended due to lack of evidence of efficacy and toxicity concerns
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For prosthetic valve endocarditis, addition of rifampicin to either flucloxacillin or vancomycin can be delayed until 3–5 days of effective therapy with either of these agents. The rationale supporting this recommendation is based on the antagonistic effect of the antibiotic combinations with rifampin against planktonic/replicating bacteria and the synergy seen against dormant bacteria within the biofilm.
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Daptomycin is now recommended as an alternative agent for treatment of staphylococcal IE for penicillin-allergic (anaphylaxis) patients and in treatment of methicillin-resistant staphylococci when vancomycin cannot be used. Daptomycin may be superior to vancomycin for treatment of either MSSA (if penicillin allergic) or MRSA IE when MIC to vancomycin is >1 mg/L.
Treatment of enterococcal spp.:
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Ampicillin plus ceftriaxone (for aminoglycoside-resistant enterococci or aminoglycoside-intolerant patient) given as alternative therapy.
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Aminoglycoside give for whole duration of therapy
Treatment of enterococcal spp.:
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Use of ampicillin and ceftriaxone in the therapy of E. faecalis IE, whether there is high-level resistance to gentamicin or not, although the combination of ampicillin and gentamicin is still advocated, with some experts saying only 2 weeks of gentamicin needs to be given; this could be given as a single daily dose.
Local policies should be adjusted for the specific testing methodologies used in their lab (CLSI or EUCAST).
High doses of daptomycin are required (10 mg/kg) and, due to increase clearance of this drug in very young children and infants, specialist dosing advice needs to be sought.
AHA, American Heart Association; ESC , European Society of Cardiology; IE , infective endocarditis; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus ; MSSA, methicillin-sensitive Staphylococcus aureus .
Table 56.7
Antibiotic Treatment of Infective Endocarditis Due to Viridans Oral and Gastrointestinal Streptococci
Antibiotic
Dose
Comments
HIGHLY SUSCEPTIBLE STRAINS (MIC ≤0.1 MG/L) STANDARD 4-WEEK REGIMEN
Penicillin G
200,000–300,000 U/kg/day divided 4 hourly doses
Give 6 weeks if PVE
Amoxicillin
200–300 mg/kg/day in 4–6 divided doses
Ceftriaxone
100 mg/kg/day 1/day
β-LACTAM ALLERGIC
Vancomycin
40–45 mg/kg/day in 2–3 divided doses
Serum trough levels should be 10–15 mg/L
RELATIVELY RESISTANT STRAINS (MIC 0.2–2 MG/L)
Penicillin G
200,000–300,000 U/kg/day divided in 4 hourly doses
Give 6 weeks if PVE
Serum trough levels <1 mg/L peak 3–5 mg/L
Amoxicillin
200–300 mg/kg/day in 4–6 divided doses
Ceftriaxone
plus
100 mg/kg/day 1/day
Gentamicin (for first 2 weeks)
3–5 mg/kg/day in 3 divided doses
β-LACTAM ALLERGIC OR STRAINS HIGHLY RESISTANT TO PENICILLIN MIC >2 MG/L
Vancomycin
plus
40–45 mg/kg/day in 2–3 divided doses
Give 6 weeks if PVE
Serum trough levels should be 10–15 mg/L
Gentamicin (for first 2 weeks
3–5 mg/kg/day 3 divided doses
Serum trough levels <1 mg/L peak 3–5 mg/L
ANTIBIOTIC TREATMENT OF INFECTIVE ENDOCARDITIS DUE TO ENTEROCOCCUS SPP.
Amoxicillin-Sensitive Strains (Mainly E. Faecalis)
Amoxicillin
plus
200–300 mg/kg/day in 4–6 divided doses
Give 6 weeks if PVE
Serum trough levels <1 mg/L peak 3–5 mg/L
Gentamicin (for full duration of therapy)
3–5 mg/kg/day in 3 divided doses
Amoxicillin-Resistant Strains (Mainly E. Faecium ) or β-Lactam Allergy
Vancomycin
plus
40–45 mg/kg/day in 2–3 divided doses
Give 6 weeks if PVE
Serum trough levels should be 10–15 mg/L
Gentamicin (for full duration of therapy)
3–5 mg/kg/day in 3 divided doses
Serum trough levels <1 mg/L peak 3–5 mg/L
MIC, Minimum inhibitory concentration; PVE , prosthetic valve endocarditis.
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