Guidelines for the prevention, diagnosis, and treatment of infective endocarditis in adults^†: The Task Force for the Prevention, Diagnosis, and Treatment of Infective Endocarditis in Adults of Chinese Society of Cardiology of Chinese Medical Association, and of the Editorial Board of Chinese Journal of Cardiology

Introduction

The pathogenesis of infective endocarditis (IE) is a complex process which can include tissue damage to the valves during bacteraemia, pathogen adherence leading to the formation of non-bacterial thrombotic vegetations, platelet aggregation at sites of tissue damage, and a variety of biological interactions between pathogens and host matrix molecules (e.g. platelets).^1,2 In the past few decades, the incidence of IE has increased significantly, which may be the result of an aging population, delayed diagnosis of valvular heart disease, and even new methods of valve implantation, including transcatheter therapies. The incidence of IE of the right heart has also increased due to the prevalence of intravenous drug use. Overall, the epidemiological profile of IE in China remains inadequately characterized, and the precise epidemiology differs between geographic location and study populations. For example, in Europe, the incidence of IE is reported to be 3–10 episodes/100 000 person-years and increases with age—the peak incidence being 14.5 episodes/100 000 person-years in patients between 70 and 80 years of age, with a male : female ratio of ≥2 : 1. Over the course of the 20th century, due to effective antibiotic treatment, the major cause of IE has changed from rheumatic valve disease, which mainly affects young adults, to a variety of other aetiologies. In many locations, the most common pathogen of IE has changed from Streptococcus to Staphylococcus. In the USA, staphylococcal infection has become the most prevalent, and, in China, case reports show that Streptococcus and Staphylococcus are the most common pathogens.^3–6 Despite advances in its management, IE is still considered a severe disease with a high mortality rate and poor prognosis.

This consensus is written by the Chinese Society of Cardiology, and the Heart Failure Group is responsible for the implementation of its recommendations. Importantly, this document is the first version of a consensus on the management of IE in China. It is based on advanced scientific principles and evidence-based medicine, and it is written with the goal of benefiting patients and informing clinicians. The Heart Failure Group studied the most recent domestic and international guidelines relevant to IE, including those published by the European Society of Cardiology and the British Institute of Antibiotics, as well as the diagnostic criteria proposed by the Chinese Academy of Pediatrics. After review and analysis of related studies, a consensus was reached after vigorous discussion. The Heart Failure Group organized a taskforce to draft these guidelines, including experts in infectious disease, cardiology, cardiac surgery, radiology, clinical laboratory medicine, and pathology. The recommendations herein have undergone both a nationwide commenting period and a 2-year revising period. We are convinced that the publication of this consensus statement will positively impact the diagnosis and treatment of adult IE.

According to international standards, this consensus statement designates recommendation and evidence levels for therapeutic strategies, including the efficacy of antibiotic regimens. The Classes of Recommendation are defined as follows: Class I, evidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effective; Class II, conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure (Class IIa represents weight of evidence/opinion that is in favour of usefulness/efficacy, while Class IIb represents usefulness/efficacy that is less well-established by evidence/opinion); Class III, evidence or general agreement that the given treatment or procedure is not useful/effective and may even be harmful in certain situations. The Levels of Evidence are defined as follows: Level of Evidence A, data derived from multiple randomized clinical trials or meta-analyses; Level of Evidence B, data derived from a single randomized clinical trial or large non-randomized studies; Level of Evidence C, consensus of opinion of the experts and/or small studies, retrospective studies, or registries.

The prevention of infective endocarditis

The primary focus of preventive are aimed at the association between bacteraemia and structural heart diseases. Bacteraemia is a prerequisite for the occurrence of IE, and patients with structural heart abnormalities are highly susceptible to IE if they become bacteraemia.

To prevent and reduce the incidence of bacteraemia in patients with structural heart disease, general measures include emphasizing the importance of good oral hygiene and regular dental examinations, as well as skin hygiene, so as to prevent secondary infection caused by skin or mucosal injury. It is recommended to try to avoid traumatic examinations and operations and to strictly follow aseptic technique if possible.

Antibiotic prophylaxis

Antibiotic prophylaxis is recommended when a high-risk procedure is performed in the patients with any of the following conditions: valvular heart disease, congenital heart disease (CHD), hypertrophic obstructive cardiomyopathy, rheumatological disorders requiring glucocorticoid or immunosuppressive therapy,^1,2,7–10 and drug addicts.¹

Patient populations and surgical operations requiring prophylaxis

Specific patient populations and operations requiring prophylaxis include: (i) patients with a prosthetic valve or prosthetic material used for cardiac valve repair; (ii) patients with previous IE; (iii) patients with cyanotic CHD, either without surgical repair or with residual defects, palliative shunts or conduits; CHD with complete repair with prosthetic material, whether placed by surgery or by percutaneous technique, up to 6 months after the procedure; and in the setting of a residual defect which persists at the site of implantation of prosthetic material or a device, either by cardiac surgery or percutaneous technique.^1,11

Examinations and routine procedures requiring prophylaxis

The reported incidence of transient bacteraemia after dental procedures is highly variable and ranges from 10 to 100%. Therefore, antibiotic prophylaxis is recommended 30 min before certain procedures (see Table 1).^1,11 Antibiotic prophylaxis for other procedures should refer to regulations published by the health department. There is no compelling evidence that bacteraemia may result from common procedures involving the respiratory tract (e.g. bronchoscopy, laryngoscopy, or transnasal/endotracheal intubation), gastrointestinal tract (e.g. upper endoscopy, colonoscopy, and transesophageal echocardiogram) or urogenital tract (e.g. cystoscopy or catheterization). Therefore, antibiotic prophylaxis is not recommended in patients undergoing these procedures.

Diagnosis of infective endocarditis

Clinical features of infective endocarditis

The clinical presentation of IE is diverse and can be complicated. Infection may lead to valvular ulceration or perforation, valvular insufficiency, or decreased tenacity of the heart valve, leading to the formation of a luminal tumour-like bulge that may impede blood flow and, in some cases, perforation of the bulging valve which will exacerbate regurgitation.¹² When infection spreads to neighbouring tissues, valvular abscesses may occur. An abscess located at the root of the aortic valve may compress the coronary artery and lead to angina pectoris or myocardial infarction. An abscess located at the proximal end of the mitral valve may spread to the left atrial wall, atrial septum, left ventricle, or even more distally. Pathogens proliferating in the blood stream may result in bacteraemia or septicaemia. Meanwhile, the proliferation of pathogens may induce antibody production and lead to immune-mediated diseases, including polyangiitis, focal, or systemic glomerular nephritis, arthritis, and pericarditis. Embolic events are a frequent complication related to the shedding of cardiac vegetations, with spread most common to the brain, spleen, lung, heart, and kidney. Clinical manifestations are related to the size of the emboli, the diameter of the blocked blood vessel, the existence of end-organ collateral circulation, and whether the vegetation contains pathogens or not. Micro-emboli may not demonstrate overt clinical symptoms and may only be discovered at the time of autopsy. Large emboli can cause organ ischaemia or even necrosis. Infective emboli may lead to local infection with progression to abscess formation. Alternatively, embolization can result in infective vasculitis and angioma formation, most commonly involving the cerebral arteries, mesenteric artery, splenic artery, coronary artery, and pulmonary artery.

Clinical manifestations of infective endocarditis

Clinical manifestations are highly variable. Fever is the most common symptom, which is typically associated with chills, decreased appetite, and weight loss. Heart murmurs are also frequent. Other symptoms include those arising from vascular and immune system disorders and embolization to the brain, lungs, and spleen.¹³ Clinical presentations among the elderly and immunosuppressed patients are usually less typical,¹⁴ and fever is less commonly observed.

Clinical presentation of IE: (A) New regurgitant heart murmur. (B) Embolic events of unknown origin. (C) Sepsis of unknown origin (especially if associated with an IE causative organism). (D) Fever. In the latter case, IE should be suspected if fever is associated with: (i) intra-cardiac prosthetic material (e.g. prosthetic valve, pacemaker, implantable defibrillator, and surgical baffle/conduit); (ii) a prior history of IE; (iii) previous valvular or CHD; (iv) a predisposition for IE (e.g. immunocompromised state or IV drug use); (v) predisposition and/or recent invasive intervention with associated bacteraemia; (vi) evidence of congestive heart failure; (vii) the presence of a new conduction disturbance by EKG or echocardiography; (viii) positive blood cultures with a typical IE causative organism or positive serology for chronic Q fever(microbiological findings may precede cardiac manifestations); (ix) the presence of vascular or immunologic abnormalities indicative of an embolic event, including Roth spots, splinter haemorrhages, Janeway lesions, and Osler's nodes; (x) focal or non-specific neurological symptoms and signs that may suggest a CNS embolic event; (xi) evidence of pulmonary embolism/infiltration (right-sided IE); (xii) peripheral abscesses (renal, splenic, cerebral, and vertebral).

Clinical and laboratory diagnosis of infective endocarditis

1. Blood cultures: Blood cultures remain the cornerstone of diagnosis and provide live bacteria for susceptibility testing. Blood samples should be obtained using strict aseptic technique before antibiotic therapy is administered.¹⁵Figure 1 shows the detection algorithm.¹⁶

   Blood-culture-negative IE occurs in 2.5–31% of all cases, often delaying diagnosis and the initiation of treatment, with profound impact on clinical outcomes.¹⁷ This circumstance arises most commonly as a consequence of prior antibiotic administration, and may necessitate antibiotic withdrawal and repeat blood cultures in these situations. Another common scenario is infection by fastidious organisms with limited proliferation under conventional culture conditions.¹⁸ This is particularly common in IE affecting patients with prosthetic valves, indwelling venous lines, pacemakers, renal failure, or immune-compromised states. Detection methods should be modified when blood-culture-negative IE is suspected (see Table 2).

2. Echocardiography: The sensitivity of transthoracic and transoesophageal echocardiography (TTE/TEE) are 40–63% and 90–100%, respectively. The findings on echocardiography that are major criteria for the diagnosis of IE include the observation of vegetations, abscess, and new dehiscence of prosthetic valves (Table 3). Figure 2 illustrates the preferred detection algorithm with regard to echocardiography.

3. Histological/immunological techniques: Pathological examination of resected valvular tissue or embolic fragments remains the gold standard for the diagnosis of IE and can also be helpful in guiding antimicrobial treatment. Electron microscopy has a high sensitivity and may help to characterize new microorganisms, but it is not recommended time-consuming and expensive. Direct immunofluorescence or enzyme-linked immunosorbent assay may also allow the detection of microorganisms,¹⁹ but their significance remains uncertain.

Culture of homogenized valvular tissue is required for patients who have undergone surgery for IE in order to accurately identify the responsible pathogens. For tissue culture-negative patients, polymerase chain reaction (PCR) can be used for the rapid and reliable detection of fastidious pathogens in these patients.^20,21 Although there are several advantages to PCR, including a high sensitivity, inherent limitations to this technique include a lack of reliable application to whole blood samples. Although PCR positivity has been proposed as a major diagnostic criterion for IE, the technique seems unlikely to supersede blood cultures as a primary diagnostic tool.

Figure 1

Microbiological diagnosis of infective endocarditis.

Open in new tabDownload slide

Figure 2

Indications for echocardiography in suspected infective endocarditis.

Open in new tabDownload slide

Diagnostic criteria

Modified Duke criteria are now recommended for diagnostic classification.²² Diagnosis of IE is considered definitive in the presence of (i) two major criteria; (ii) one major and three minor criteria; (iii) five minor criteria. Diagnosis of IE is possible in the presence of (i) one major and one minor criteria and (ii) three minor criteria.

Major criteria

(i) Blood-cultures positive for IE: (a) the presence of typical microorganisms consistent with IE from two separate blood cultures, which include Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus, or community-acquired enterococci, in the absence of a separate primary focus; (b) microorganisms consistent with IE from persistently positive blood cultures (at least two positive blood cultures from blood samples drawn >12 h apart; or all of three or a majority of ≥4 separate blood cultures, with the first and last sample drawn at least 1 h apart); (c) a single positive blood culture for Coxiella burnetii or phase I IgG antibody titer >1 : 800. (ii) Evidence of endocardial involvement by (a) Echocardiography positive for IE with vegetation, abscess, or new partial dehiscence of prosthetic valve; (b) new valvular regurgitation.

Minor criteria

(i) Predisposition (including a predisposing heart condition or history of injection drug use). (ii) Fever (with a temperature >38°C). (iii) Vascular phenomena (including major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intra-cranial haemorrhages, conjunctival haemorrhages, or Janeway lesions). (iv) Immunologic phenomena (including glomerulonephritis, Osler's nodes, Roth's spots, or positive rheumatoid factor). (v) Microbiological evidence (defined as either a positive blood culture that does not meet a major criterion or serological evidence of active infection with an organism consistent with IE).

Antimicrobial therapy for infective endocarditis

Successful treatment of IE relies on the eradication of pathogens using antimicrobial drugs. The principles of antimicrobial therapy include: (i) the application of bactericidal agents, (ii) the combination of two cooperative antimicrobial drugs, (iii) large dosage of therapy to guarantee effective tissue concentration, (iv) intravenous delivery of therapy, (v) prolongation of therapy (4–6 weeks). In the case of prosthetic valve endocarditis (PVE), treatment should last for at least 6–8 weeks in order to reduce the rate of recurrence. Antimicrobial administration should be applied according to pharmacokinetics. Fractionation and intravenous therapy is recommended for large doses of penicillin to prevent central nervous system toxicity, such as penicillin encephalopathy.^1,2,23 Surgery is recommended for some patients, in order to remove infected tissue or drain abscesses, thus eliminating the focus of infection.

Empirical therapy of suspected infective endocarditis

For patients who are diagnosed with possible IE and in unstable condition, empirical therapy is recommended before positive blood culture reports are obtained. The initial choice of empirical treatment depends on several considerations including the severity of infection, the location of the affected valves, and the risk of uncommon or drug-resistant pathogen infection. There are two main types of IE, native valve endocarditis (NVE) and PVE. Empirical therapy should cover the most common pathogens of IE. See Table 4 for recommended empirical therapy.

Therapy for staphylococcal endocarditis

See Table 5 for recommended therapy. Therapeutic regimen should be determined by the susceptibility of the pathogen to methicillin. As over 90% of Staphylococcus are resistant to methicillin, oxacillin, and cloxacillin combined with aminoglycosides are recommended for empirical treatment.

Therapy of streptococcal endocarditis

See Table 6 for recommended therapy. Regimens against Streptococcus viridians differ according to the susceptibility of pathogens to penicillin. Streptococcus viridians infections are classified according to the susceptibility of the cultured strain as susceptible (penicillin MIC ≤0.125 mg/L), relatively resistant (MIC 0.125–0.5 mg/L), and fully resistant (MIC >0.5 mg/L). For infection by resistant strains, a combination therapy of gentamicin and vancomycin or teicoplanin is recommended in the cases of either NVE or PVE.

Therapy of enterococcal endocarditis

See Table 7 for recommended therapy. Enterococci are highly resistant to antibiotics in general, and eradication requires prolonged administration of synergistic bactericidal combinations of antimicrobial agents. Enterococcus faecalis is sometimes susceptible to ampicillin and penicillin, though the susceptibility is lower than that of S. viridians, while Enterococcus faecium has ever lower susceptibility.

Infective endocarditis caused by G ram-negative bacteria

Combination therapy of penicillins or cephalosporins with anti-pseudomonal activity and aminoglycosides is recommended (e.g. combination of piperacillin and gentamycin or tobramycin, and combination of ceftazidime and aminoglycosides). Selection of appropriate antimicrobial treatment is based on susceptibility testing, as susceptibility differs between Gram-negative bacteria. Long-term therapy (≥6 weeks) is recommended.

HACEK Gram-negative bacilli infection may also cause IE. In the past, HACEK-related species have been susceptible to ampicillin. Recently, however, the prevalence of β-lactamase-producing strains has increased, and third generation cephalosporins such as ceftriaxone and cefotaxime are now recommended. As for strains that do not produce β-lactamase, combined therapy of amoxicillin or ampicillin, and aminoglycosides is recommended. The recommended duration of therapy is 4 weeks for NVE and 6 weeks for PVE. If gentamycin is chosen as a component of the initial therapeutic strategy, the recommended duration is 2 weeks. Ciprofloxacin may be chosen as a possible substitute.

Infective endocarditis due to other pathogens

Candida endocarditis: Initial treatment with an echinocandin or lipid-associated amphotericin is first line. Many authorities recommend the addition of flucytosine to amphotericin B.³⁴ Initial duration of therapy is 6–10 weeks. When patients are stabilized and blood cultures become negative, it is recommended that patients with susceptible organisms undergo oral therapy with fluconazole 400–800 mg qd. Surgical valve replacement is highly desirable if clinically indicated, and antimicrobial therapy should last for 6 weeks after operative treatment. For those with valvular abscess or other complications, the duration of antimicrobial therapy should be extended.

1. Q fever: C. burnetii is the causative microorganism of Q fever. Primary manifestations of Q fever are fever, headache, myalgias, and interstitial lung disease, and some patients present chronic symptoms. Infective endocarditis is the most common manifestation of chronic infection.²⁴ Patients likely to develop Q-fever IE are those with predisposing valvular damage or prosthetic heart valves.²⁵Coxiella burnetii is the most common cause of culture-negative IE,²⁶ and typically vegetation of the valve can be detected. Higher doses have been recommended in patients whose phase I antibody titers are slow to decrease.²⁷

   Recommended therapy includes prompt administration of antibiotics and surveillance of antibody titers until cure. Possible antibiotic regimens include (i) doxycycline 100 mg q12 h po, combined with hydroxychloroquine 200 mg q8 h po, for a duration of at least 18 months and up to 3 years according to some guidelines and (ii) doxycycline 100 mg q12 h po, combined with ciprofloxacin 200 mg q12 h po, for at least. Surveillance of antibody titers of C. burnetii should be conducted every 6 months during the treatment period and after 3 months once in the following 2 years. The criterion of cure is considered to be phase I IgG antibody titers <1 : 800 and phase I IgA and IgM titers <1 : 50.²⁸

2. Bartonella endocarditis: Bartonella spp. are facultative intra-cellular Gram-negative aerobic bacteria that are a common causative pathogen for blood-culture-negative IE. Bartonella quintana is the most common pathogen, followed by B. henselae. Bartonella quintana can cause trench fever and IE and is transmitted by the body louse. Predisposing factors to infection include homelessness, immune disorder, drug abuse, and alcoholism.²⁹Bartonella henselae rarely cause IE. Infective endocarditis is a feature of chronic Bartonella infection.³⁰

   Recommended therapy includes combined gentamycin and β-lactams or doxycycline for treatment.³¹ Gentamicin 1 mg/kg q8 h iv (duration 4 weeks) should be combined with amoxicillin 2 g q4 h or ceftriaxone 2 g qd iv (duration 6 weeks). The blood concentration of gentamicin should be monitored throughout treatment.

3. Fungal endocarditis: Fungi cause endocarditis in 1–6% of cases.³² The most common pathogens are Candida and Aspergillus spp., followed by Histoplasma, Cryptococcus and other budding fungi. Diagnosis of fungal endocarditis is rather difficult. If IE is suspected, and, whenever blood cultures show negative results, fungal endocarditis should be included in the differential diagnosis. For Candida endocarditis, blood cultures are positive in 83–95% of cases. Blood cultures are also frequently positive in Cryptococcus and yeast fungus infections.³³ For fungal endocarditis, the duration of treatment is long, the prognosis is relatively poor, and the recurrence rate is high.

Aspergillus endocarditis: Initial treatment should be with voriconazole for at least 4 weeks, with therapeutic drug monitoring. Lipid-associated amphotericin B is a possible substitution for patients who are intolerant to voriconazole. Long-term oral therapy with voriconazole is recommended for at least 2 years. Surgical valve replacement is mandatory for survival.

Endocarditis due to other fungi: For other pathogenic fungi, drug selection is as above and determined according to susceptibility testing.³⁵

Surgical management of infective endocarditis

Indications and timing of surgery

In general, surgical management of IE is reserved for left-sided disease. Approximately 50–56% of left-sided IE affects the mitral valve, and 35–49% affects the aortic valve.^36,37 In ∼15% of cases, both valves are affected. Half of patients require surgery because of severe complications.³⁸ Indications for early phase surgery (during antimicrobial therapy) include heart failure, uncontrolled infection, and prevention of embolism (Table 8).^1,23,39 Early phase surgery is associated with high risk. Age alone is not considered a contraindication.

1. Heart failure: Heart failure is an indication for surgery in most IE cases,²³ and acute heart failure is the main reason for emergency surgery in patients with IE.³⁹ This includes severe acute regurgitation or valve obstruction causing refractory pulmonary oedema/shock, severe acute regurgitation or valve obstruction with persistent heart failure or echocardiographic signs of poor haemodynamic tolerance, and severe regurgitation in the absence of heart failure.

2. Uncontrolled infection, including persisting infections (>7 days), infections caused by multi-resistant microorganisms, and locally uncontrolled infections.

3. Prevention of embolism: Most embolic events occur before hospitalization, and prevention of embolization is currently difficult.⁴⁰ The first week of antimicrobial therapy is the most frequent period for embolic events, and this is considered the best time for surgery in order to prevent complications of embolic events. Evidence shows that risk is clearly related to the size and mobility of vegetations,¹³ but the decision to operate in the early phase is a difficult one and should take into account previous embolism, other complications of IE, the size and mobility of the vegetation, and duration of antibiotic therapy.^39,41,42 The general condition of the patient and complications should be evaluated on an individual basis.^4,13,40–43

Mortality, morbidity, and complications of surgery

The rate of operative mortality in IE lies between 5 and 15%,^1,44 although domestic research reports it to be 4.1%. When surgery must be performed within the first week of antimicrobial therapy, in-hospital mortality is 15%, with risks of recurrence and non-infective post-operative valvular dysfunction occurring in 12 and 7% of surgical patients,⁴⁵ respectively. In less complex cases, where disease is limited to the valve structures alone (allowing complete excision of infected tissue), mortality should be similar to routine valve surgery. The mortality rate of mitral annuloplasty is 2.3%, and the long-term infection rate is 1.8%, which significantly exceeds that of mitral valve replacement.⁴⁶ Causes of death are often multi-factorial, but the major causes of death include multi-organ failure, heart failure, intractable sepsis, coagulopathy, and stroke.⁴⁷

Immediate post-operative complications are relatively common, and among the most frequent are: severe coagulopathy requiring treatment with clotting factors, re-exploration of the chest for bleeding or tamponade, acute renal failure requiring haemodialysis, stroke, low cardiac output syndrome, pneumonia, and atrioventricular block following radical resection of an aortic root abscess with need for pacemaker implantation.⁴⁷ A pre-operative ECG demonstrating left bundle branch block predicts the need for a post-operative permanent pacemaker.⁴⁸

Complications of infective endocarditis

Neurological complications

Neurological events develop in 20–40% of all patients with IE and are mainly the consequence of vegetation embolism. The clinical spectrum of these complications is wide and includes ischaemic or haemorrhagic stroke, transient ischaemic attacks, silent cerebral embolism, symptomatic or asymptomatic infectious aneurysm, brain abscess, meningitis, toxic encephalopathy, and seizure.

Staphylococcus aureus causes higher overall rates of neurological complications than other organisms.⁴⁹ Ischaemic stoke is not a contraindication to surgery, but the timing of surgery in these patients remains controversial.⁵⁰ If cerebral haemorrhage has been excluded, surgery is indicated for patients with heart failure, uncontrolled infection, abscess, or persistent high embolic risk.⁵¹ In patients with intra-cranial haemorrhage, the neurological prognosis is worse, and surgery must be postponed for at least 1 month. Neurosurgery or interventional therapy is recommended if intra-cranial aneurysms grow or are at higher risk of rupture.

Acute renal failure

Acute renal failure is a common complication of IE which occurs in ∼30% of patients.⁵² Causes are often multi-factorial and include: (i) immune complex and vasculitic glomerulonephritis; (ii) renal infarction; (iii) haemodynamic impairment, particularly in cases associated with heart failure, severe sepsis, or cardiac surgery; (iv) antibiotic toxicity (acute interstitial nephritis), notably related to aminoglycosides, vancomycin (which has synergistic toxicity with aminoglycosides), and even high dose penicillin; (v) nephrotoxicity of contrast agents used during radiologic imaging.

Rheumatic complications

Musculoskeletal symptoms (e.g. arthralgia, myalgia, and back pain) are frequent during IE, and rheumatic complications may be the first manifestations of the disease. Peripheral arthritis occurs in ∼14% and spondylodiscitis in 3–15% of cases. In one study, IE was diagnosed in 30.8% of patients with pyogenic spondylodiscitis. Magnetic resonance imaging (MRI) or computer tomography (CT) of the spine should be performed in IE patients with back pain.

Splenic abscess

Splenic infarction occurs in 40% cases, of which 5% of cases may progress to splenic abscess.⁵³Streptococcus virdans and S. aureus are the most frequent pathogens, and Enterococcus spp. are also causative pathogens. Gram-negative bacteria and fungi are not commonly observed in splenic abscesses. Persistent or recurrent fever and bacteraemia are suggestive of abscess formation, and these patients should be evaluated by abdominal CT, MRI, and/or ultrasound. Sensitivity of abdominal CT and MRI is 90–95%. Splenectomy may be considered for splenic rupture or large abscesses which respond poorly to antibiotics alone. Percutaneous drainage is an alternative for high-risk surgical candidates.

Myocarditis and pericarditis

Cardiac failure may also be due to myocarditis. Ventricular arrhythmias can indicate myocardial involvement and imply a poor prognosis. Myocardial involvement is best assessed using TTE. Pericarditis may be associated with an abscess, myocarditis, or bacteraemia (often as a result of S. aureus infection). When infection affects the bicuspid valve or the tricuspid valve, purulent pericarditis must be considered. Purulent pericarditis is a rare occurrence and may necessitate surgical drainage. Additionally, ruptured pseudo-aneurysms or fistulae may communicate with the pericardium, with fatal consequences.

Assessment on admission and follow-up at discharge

Assessment on admission

The in-hospital mortality rate of IE has been reported to be 9.6–26%.¹ Quick identification of high-risk patients can facilitate the initiation of increased monitoring and aggressive treatment. The main factors that affect prognosis include the background clinical status of the patient, whether co-morbidities exist, and the species of pathogen. When there is >1 risk factor present in each of the three aspects mentioned above, the risk of death or disability can be >70%. For example, IE with heart failure, paravalvular abscess, and pathogen of S. aureus is at the greatest risk of mortality. Surgery in this patient would be necessary even if the infection has not been controlled.⁵⁴

• Elements of a patient's background clinical status can indicate a poor prognosis, including the following: a history of heart disease, valve replacement, intra-cardiac devices, insulin-independent diabetes mellitus, renal diseases and pulmonary diseases, old age, autoimmune diseases (systemic lupus erythematosus, etc.), malignant tumours (colon cancers, etc.), persistent fever after conventional antibiotic therapy, or persistent positive blood cultures over 10 days.

• Co-morbidities that portend a worse prognosis include the following: cardiovascular failure, structural heart disease,² renal failure, strokes, multi-organ embolism, aneurysm, septic shock, locally uncontrolled infections (myocardial or paravalvular abscesses, false aneurysms), and large vegetations (>10 mm).

• The infectious organism associated with a patient's disease can suggest a more dire clinical course, which include: S. aureus, fungus, gram-negative bacillus, some rarely seen microorganisms difficult to identify by blood culture (Aerococc^us urinae, etc.), and especially co-infection with HIV.

Follow-up after discharge

The prognosis of IE is greatly affected by the presence of late complications. Common complications include the recurrence of infection, cardiac failure, valvular damage requiring replacement, and death.

• Recurrence: The rate of recurrence of IE is reported to be between 2.7 and 22.5%. Recurrence is defined as relapsing disease or later reinfection. Relapse is indicated if the pathogen is the same as with the former IE, while reinfection is used to describe a situation when the second IE is caused by another pathogen. It is hard to determine whether the new IE is relapse or reinfection when the pathogen detected in recurrent patients is the same as the last one. Molecular methods for typing of the pathogen may help in most cases. When there is difficulty in determining the pathogens or performing molecular typing, the time interval between the two episodes can help to distinguish the aetiology. Generally, the time to relapse is shorter than the time to reinfection. Recurrence occurring within 6 months of the first infection is usually due to relapse, and those occurring after 6 months are mostly reinfections. Thus, it is suggested that isolations of IE be preserved over 1 year.⁵⁵

• Factors that increase the risk of recurrence include: (i) inappropriate antimicrobial therapy (drug types, doses, and duration of therapy); (ii) infection by resistant pathogens such as Brucella, Legionella, Chlamydia, Mycoplasma, Mycobacterium tuberculosis, Bartonella, Coxiella bumetii, or fungi; (iii) multiple microbial infection in intravenous drug users; (iv) patients who receives empiric therapy with negative blood cultures; (v) the development of paravalvular infection; (vi) PVE; (vii) persistent appearance of a metastasis focus; (viii) resistance to conventional treatment regimens; (ix) positive valve cultures.

• Reinfections are mostly found in intravenous drug users (especially within 1 year after the first infection), patients with PVE, and patients who remain on haemodialysis with multiple risk factors for IE. Reinfected patients are at a higher risk of death, and often in need of valve replacement.⁵⁶ Antibiotics should be selected based on the pathogen and results of antimicrobial susceptibility test when recurrence is due to insufficient duration of therapy or inadequate selection of drugs. An additional 4–6 weeks of antimicrobial therapy is also needed.

• Heart failure and valve replacement: In a patient whose infection has been well controlled, if heart failure progresses due to destruction of the valves, indications for surgery are the same as those in traditional valvular diseases.

• Long-term mortality: Long-term mortality after discharge is mainly determined by age, co-morbidities, and cardiac function. In patients who do not undergo surgery, these factors affect mortality rate more than reinfection rate.^57,58 Only 6.5% of long-term mortality is caused by reinfection.⁵⁷

• Follow-up: Patients should be educated about symptoms and signs of IE. They should be alerted to the possibility of IE recurrence and present to the hospital if they develop fever, chills or other signs of infection. Blood cultures should be obtained before antimicrobial therapy. Preventive actions should be performed in high-risk patients. In order to monitor heart function, clinical assessment of cardiac function and TTE should be performed when antimicrobial therapy is finished and on regular follow-ups, especially during the first year of follow-up. Clinical assessment, blood tests including WBC counts and CRP, and TTE are recommended on the first, third, sixth, and twelfth month after the completion of antimicrobial therapy.

Special types of infective endocarditis

Prosthetic valve endocarditis

Prosthetic valve endocarditis is a type of IE that occurs in prosthetic or repaired native valves. Prosthetic valve endocarditis occurs at an incidence of 0.3 to 1.2% per year and is similar with mechanical and bioprosthetic valves. Studies show that PVE accounts for 10 to 30% of IE cases in Europe.¹ This percentage is closer to 2 to 4% in China^3,9 but has increased to 13.9% recently.⁸ Prosthetic valve endocarditis is different from NVE in its microbiological profile, extent of pathological changes, diagnosis, and clinical outcome.

• Microbiology: PVE is mainly caused by coagulase-negative staphylococcus, Gram-negative bacilli and fungi.⁸

• Pathological changes: Early-stage PVE, such as in perioperative infection cases, typically involves the junction of the suture ring and the annuloplasty ring, leading to paravalvular abscess, thus resulting in seam cracking, pseudoaneurysm, and fistula formation. Late-stage PVE, for instance with bioprosthetic valves, often compromises prosthetic valve leaflets, leading to valve perforation and rupture.

• Diagnosis: Clinical manifestations can be atypical. The basic features of infection and abnormality of mechanical valve structure and function on echocardiography are necessary to diagnose PVE, and TEE is more accurate than TTE.

• Prognosis: In-hospital mortality rate is ∼20–40% abroad,¹ but domestic data demonstrate a mortality rate of 13.5% with regard to PVE.⁸ Complications like heart failure and stroke as well as staphylococcal infection are the most powerful predictive factors for a poor prognosis.

Infective endocarditis associated with intra-cardiac electronic device

This type of IE is mainly caused by pathogenic bacteria introduced directly during the process of device placement. Other sources of infection occurs by retrograde infection along the electrode catheter or by transmission from other infectious foci to the endocardium and head of the electrode through the bloodstream.^59,60

• Microbiology: S. aureus and coagulase-negative staphylococcus are common pathogens.^61,62 However, with the widespread adoption of broad-spectrum antibiotics and the growing population of intravenous drug abusers, the elderly and people of low immunity, cases of Gram-negative bacteria, multi-resistant bacteria, and fungal infection have also been reported.⁶³ Infectious foci are typically distributed in the subcutaneous tissue, pocket, blood vessels, right atrium, right ventricle, tricuspid valve, apex of the electrode, or vena cava.

• Diagnosis: TTE, especially TEE, and blood cultures form the foundation for definitive diagnosis.⁶⁴ CT and radioisotope scanning of the lung may help to find pulmonary septic emboli.

• Treatment: See above section for information on antibiotic therapy of IE associated with electronic intra-cardiac devices.

• Removal of the intra-cardic electronic device: The intra-cardic electronic device, including the pulse transmitter and electrode catheter, should be removed entirely as expected. Transvenous catheter removal is also recommended. If this is difficult to accomplish, there is serious damage to the tricuspid valve, or an associated lesion is >25 mm, surgery must be considered.

• Partial treatment of abscess: Treatment of an abscess may include the following: (i) removal of dead tissue and local granulation tissue clearly (under general anesthesia if necessary); (ii) a complete stop to any bleeding, preferably with the use of a radioknife (in some instances, thrombin can be applied to an oozing wound), (iii) washing of the pocket after exhaustive debridement and haemostasis. The suggested order for the washing of wounds is: hydrogen peroxide → metronidazole → gentamicin → saline, each for at least two or three times.

Infective endocarditis of the right atrium

Infective endocarditis of the right atrium represents 5–10% of the total number of IE events, mainly occurring in intravenous drug abusers.

• Microbiology: The most common cause is of IE of the right atrium is S. aureus (60–90%). Other aetiologies include Pseudomonas aeruginosa, Gram-negative bacilli, fungi, enterococcus, among others. The pathological changes chiefly involve the tricuspid valve, often the pulmonary valve, and rarely the left heart valves.⁶⁵

• Diagnosis: Clinical manifestations include persistent fever, bacteraemia, and multiple pulmonary bacterial emboli, occurring secondary to pulmonary arterial hypertension and severe valvular regurgitation and stenosis. The prognosis is relatively good. Factors contributing to poor prognosis include vegetations >20 mm, fungal infection and severe immunosuppression status of HIV patients (CD4 <200 mL⁻¹).^66,67

• Treatment: Empirical choice of antibiotics depends on the suspected microbial species, drug and solvent used by the addict, as well as the involved site of the heart lesion. The course of antibiotic therapy can be reduced to 2 weeks if the following conditions are fulfilled: (i) the infection is due to methicillin-sensitive S. aureus, (ii) there is an adequate response to treatment, (iii) there is an absence of extra-cardiac infection or abscess, (iv) there are no intra- or extra-cardiac complications, (v) there is no involvement of a prosthetic or left heart valve involvement, (vi) vegetation length is <20 mm, and (vii) severe immunosuppression is absent (CD4 >200 mL⁻¹). Surgical treatment can usually be avoided. The indications for surgical treatment are: (i) severe tricuspid valve regurgitation leading to right heart failure that is refractory to diuretic drugs; (ii) difficulty eradicating pathogenic bacteria or fungi, or bacteraemia persisting after an adequate antibiotic regimen for 7 days; (iii) length of tricuspid valve vegetation >20 mm, causing repeated pulmonary embolism, regardless of the presence of right heart failure.⁶⁸

Infective endocarditis associated with congenital heart disease

Congenital heart diseases are the main cause of IE in young adults and account for 8–15% of cases of IE according to data from our country.⁶⁹ Worldwide, the reported proportion of CHD in patients with IE varies between 2 and 18%, with a consistent minor male dominance.^1,70

• Type of CHD vs. the degree of IE: Types of CHD conferring increased risk include patent ductus arteriosus, malformation of the aortic valve, mitral insufficiency, ventricular septal defect, coarctation of the aorta, Marfan's syndrome with aortic valve insufficiency, and tetralogy of Fallot. Secondary types of CHD are mitral valve prolapse, simple mitral valve stenosis, obstructive hypertrophic cardiomyopathy, primum atrial septal defect, artificial intra-cardiac device and prior history of IE. Simple pulmonary artery valvular disease, ostium secundum defect, and heart diseases cured by operation (without artificial implantation, >6 months after surgery) are less dangerous. The risk of IE increases in patients who suffer from complex cardiac abnormalities.⁷¹

• Microbiology: The pathogenic profile remains the same as with acquired diseases. Staphylococci and streptococci are the most common pathogens.⁷² Infection by other agents have also been described (see Infective endocarditis of the right atrium for further information).

• Diagnosis and treatment: The diagnosis, treatment, and surgical indications are identical to other causes.

• Prevention: Prevention can be accomplished in the following ways: (i) by raising awareness in clinicians to screen for certain types of high-risk CHD, (ii) by promoting good oral and skin hygiene, (iii) by properly observing strict aseptic methods in any venous catheterization or invasive operation, (iv) by limiting the use of preventive antibiotics use to patients and operations of high risk, and (v) through complete surgical repair of CHD to reduce future risk of IE.^73,74

Pregnant patients with infective endocarditis

The incidence rate of IE during pregnancy is ∼0.006%,⁷⁵ while that of pregnant women with cardiac valve disease or CHD is 0.5%.⁷⁶ The fatality rate of pregnant women with IE is 33%, while that of foetus is 29%. The most common complication is cardiac dysfunction due to valve insufficiency, followed by arterial embolism.⁷⁷Conflict of interest: none declared.

• Diagnosis: The criteria for diagnosis of IE in pregnant women are the same as those in the non-pregnant population. Preventive antibiotics should be administered to high-risk pregnant women receiving treatment in the department of stomatology. Foetal heart rates should be monitored when necessary during diagnostic procedures, for example, when pregnant women undergo TEE under sedation.⁷⁸

• Treatment: The principles are similar as with non-pregnant patients, but the impact of antibiotics on the foetus should be taken into consideration. The choice of antibacterial drugs is not only based on susceptibility results but also on the foetal toxicity. Surgical valve operation and termination of pregnancy are suggested if the disease cannot be controlled by medical therapy. Thirteen to 28 weeks of gestation is the best time for surgery. For women >26 weeks pregnant, it is recommended to perform valve surgery on cardiopulmonary bypass after caesarean delivery.

References