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Guidelines on Prevention, Diagnosis and Treatment of Infective Endocarditis Executive Summary
The Task Force on Infective Endocarditis of the European Society of Cardiology

Dieter Horstkotte , Ferenc Follath , Erno Gutschik , Maria Lengyel , Ali Oto , Alain Pavie , Jordi Soler-Soler , Gaetano Thiene , Alexander von Graevenitz , Silvia G. Priori , Maria Angeles Alonso Garcia , Jean-Jacques Blanc , Andrzej Budaj , Martin Cowie , Veronica Dean , Jaap Deckers , Enrique Fernández Burgos , John Lekakis , Bertil Lindahl , Gianfranco Mazzotta , João Morais , Ali Oto , Otto A. Smiseth , John Lekakis , Alec Vahanian , François Delahaye , Alexander Parkhomenko , Gerasimos Filipatos , Jan Aldershvile , Panos Vardas
DOI: http://dx.doi.org/10.1016/j.ehj.2003.11.008 267-276 First published online: 1 February 2004

Table of contents

  • Preamble

  • Introduction

  • Definitions, terminology

  • Prevention of infective endocarditis

  •     Cardiac condit

  •     Patient-related non-cardiac conditions

  •     Predisposing diagnostic and therapeuticinterventions

  • Prophylactic antibiotic regimens

  • Diagnosis

  •     History, symptoms, signs and laboratory tests

  •     Echocardiography

  •     Standard blood culture techniques

  •     Culture-negative endocarditis (CNE)

  • Treatment and management

  •     Antimicrobial therapy

  •     Drug level monitoring

  •     Empirical therapy

  •     Special subsets

  • Management of complications

  • Surgery for active NVE

  • Surgery for active PVE

  •     Postoperative antibiotic treatment

  • List of Abbreviations

  • Further Reading

1 Preamble

Guidelines and Expert Consensus documents aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making.

A great number of Guidelines and Expert Consensus Documents have been issued in recent years by different organizations, the European Society of Cardiology (ESC) and by other related societies. By means of links to web sites of National Societies several hundred guidelines are available. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents.

In spite of the fact that standards for issuing good quality Guidelines and Expert Consensus Documents are well defined, recent surveys of Guidelines and Expert Consensus Documents published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied within the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilisation of health resources.

The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups or consensus panels. The Committee is also responsible for the endorsement of these Guidelines and Expert Consensus Documents or statements.

Level of recommendations and evidence

Strength ofrecommendationDefinition
Class IEvidence and/or general agreement that a given treatment or a diagnostic approach is beneficial, useful and effective
Class IIConflicting evidence and/or a divergence of opinions about the usefulness/efficacy of a treatment or a diagnostic measure
IIaWeight of evidence/opinion is in favour of usefulness/efficacy
IIbUsefulness/efficacy is less well established by evidence/opinion
Class IIIEvidence or general agreement that the treatment/diagnostic measure is not useful/effective and in some cases may be harmful

Level ofevidenceAvailable evidence
AAt least two randomized trials supporting the recommendation
BSingle randomized trial and/or a meta-analysis of non-randomized studies supporting the recommendation
CConsensus opinion of experts based on trials and clinical experience

2 Introduction

If untreated, Infective Endocarditis (IE) is a fatal disease. Major diagnostic (first of all echocardiography) and therapeutic progress (mainly surgery during active IE) have contributed to some prognostic improvement during the last decades. If the diagnosis is delayed or appropriate therapeutic measures postponed, mortality is still high. In this respect, it is of utmost importance that (a) IE is considered early in every patient with fever or septicaemia and cardiac murmurs; (b) echocardiography is applied without delay in suspected IE; (c), cardiologists, microbiologists and cardiac surgeons cooperate closely if IE is suspected or definite.

3 Definitions, terminology

IE is an endovascular, microbial infection of intracardiac structures facing the blood including infections of the large intrathoracic vessels and of intracardiac foreign bodies. The early characteristic lesion is a variably sized vegetation, although destruction, ulceration or abscess formation may be seen earlier by echocardiography.

Terminology (Table 1) should give the following information: (a), activity of the disease and recurrence; (b), diagnostic status; (c), pathogenesis; (d), anatomical site; and (e), microbiology.

4 Prevention of infective endocarditis

For prophylactic reasons, antibiotics should be given before a bacteraemia is expected. If antibiotic prophylaxis is not given prior to this event, antibiotics may help a late clearance if administered intravenously within 2–3h.

4.1 Cardiac conditions/patients at risk

A previous history of IE, the presence of prosthetic heart valves or otherforeign material, surgically created conduits, and complex cyanotic congenital abnormalities are considered high-risk situations. Only patients with high or moderate risk (Table 2) should receive prophylaxis. This is a class I recommendation based on level C evidence.

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Table 1

Terminology for infective endocarditis (IE). Examples: active mitral valve IE due to Enterococcus faecalis; healed recurrent prosthetic aortic valve endocarditis due to Staphylococcus epidermidis; suspected culture-negative late prosthetic mitral valve endocarditis

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Table 2

Cardiac conditions in which antimicrobial prophylaxis is indicated

4.2 Patient-related non-cardiac conditions

Older age, conditions (a), promoting non-bacterial thrombotic vegetation; (b), compromising host defense; (c), compromising local non-immune defence mechanisms; and (d), increased risk/frequency/amount of bacteraemia are considered patient related, non-cardiac risk conditions.

4.3 Predisposing diagnostic and therapeutic interventions

Procedures which may cause bacteraemia and for which antimicrobial prophylaxis is recommended are given in Table 3. Prophylaxis is not recommended for cardiac catheterization.

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Table 3

Diagnostic and therapeutic interventions likely to produce bacteraemia

Dental hygiene is of major importance for the prevention of IE.

5 Prophylactic antibiotic regimens

Prophylaxis aims primarily at viridans streptococci and HACEK organisms before dental, oral, respiratory, and oesophageal procedures, and at enterococci and Streptococcus bovis before gastrointestinal and genitourinary procedures. Despite a lack of convincing evidenceantibiotic prophylaxis (Table 4) is a class I recommendation (based on level C evidence).

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Table 4

Prophylactic antibiotic regimens

6 Diagnosis

6.1 History, symptoms, signs and laboratory tests

The diagnosis of IE is established (definite IE) if during a systemic infection involvement of the endocardium is demonstrated. If, in addition, bacteraemia (positive blood cultures) or bacterial DNA are found, IE is definite and culture/microbiologically positive, otherwise IE is definite but culture/microbiologically negative (Table 5). Duke or modified Duke criteria may be used to make the diagnosis in otherwise unclear cases.

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Table 5

Criteria that should raise suspicion of IE

6.2 Echocardiography

Any patient suspected of having NVE by clinical criteria should be screened by transthoracic echocardiography (TTE). When images are of good quality and prove to be negative and there is only a low clinical suspicion of IE, endocarditis is unlikely and other diagnoses are to be considered. If suspicion of IE is high, transoesophageal echocardiography (TEE) should be performed in all TTE-negative cases, in suspected PVE, and if TTE is positive but complications are suspected or likely and before cardiac surgery during active IE. If TEE remains negative and there is still suspicion, it should be repeated within one week. A repeatedly negative study should virtually exclude the diagnosis (Fig. 1). These class I recommendations are based on level B evidence.

Fig. 1

Algorithm for the use of transthoracic (TTE) and transoesophageal echocardiography (TEE) in suspected IE. N.B. TTE “positive” indicates finding typical of IE (e.g. fresh vegetation or abscess formation)

Three echocardiographic findings are considered to be major criteria in the diagnosis of IE: (a), a mobile, echodense mass attached to the valvular or the mural endocardium or to implanted prosthetic material; (b), demonstration of abscesses or fistulas; (c), a new dehiscence of a valve prosthesis, especially when occurring late after implantation.

6.3 Standard blood culture techniques

Three or more blood cultures (BC) should be taken irrespective of body temperature at least 1h apart. If the patient has been on short-term antibiotics, one should wait, if possible, at least for three days after discontinuing antibiotic treatment before new BCs are taken. Blood cultures after long-term antibiotic treatment may not become positive after treatment has been discontinued for 6–7 days.

One BC consists of one aerobic and one anaerobic bottle, each containing approx. 50ml of medium (less in pediatric BC bottles). Venous blood, minimally 5ml and better 10ml in adults and 1–5ml in children should be added to each bottle. Minimum inhibitory concentrations should be determined for the drugs of choice.

6.4 Culture-negative endocarditis (CNE)

The most frequent cause of CNE is previous antimicrobial treatment. If traditional (non-automatic) BC systems are used, longer incubation periods (>6 days) are required when organisms of the HACEK group, Propionibacterium spp., Neisseria spp., Brucella, Abiotrophia spp., or Campylobacter spp. are suspected. Especially in CNE all material excised during cardiac surgery for active IE should also be cultured and examined.

The value of serology has been proven for IE due to Bartonella, Legionella, Chlamydia (immunofluorescence) and Coxiella burnetii.

The use of broad-spectrum polymerase chain reaction (PCR) provides a significant improvement in thecapability to detect difficult-to-culture organisms and even dead bacteria.

7 Treatment and management

7.1 Antimicrobial therapy

For treatment strategies refer to Tables 6–9.

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Table 6

Decision making for antibiotic treatment of native (NVE) and prosthetic valve endocarditis (PVE) due to streptococci

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Table 7

Decision-making for antibiotic treatment of IE due to enterococci and penicillin-resistant streptococci

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Table 8

Decision-making for antibiotic treatment of IE due to staphylococci

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Table 9

Antimicrobial treatment in CNE or if therapy is urgent and the causative organism unidentified

All patients with streptococcal IE should be treated for at least 2 weeks in hospital and observed for cardiac and non-cardiac complications. Patients may then be candidates for outpatient and home parenteral antibiotic therapy. Treatment recommendations for streptococcal IE are based on consistent results of a large number of studies (class I recommendation based on level B evidence).

IE caused by methicillin-resistant S. aureus (MRSA) is a therapeutic challenge as most strains are also resistant to most aminoglycosides. If the clinical course is complicated, treatment should be as for PVE.

Coagulase-negative species (CONS) causing PVE within the first year after valve replacement are usually methicillin-resistant. Therapy of choice is a combination of vancomycin and rifampicin for at least 6 weeks with the addition of gentamicin for the initial 2 weeks.

Despite lacking randomized studies and thus level A evidence, the scientific material available is convincing and allows for a class I recommendation.

Enterococci are generally resistant to a wide range of antimicrobial agents including aminoglycosides (MIC for gentamicin 4–64mg/l). (Table 7)

Duration of treatment should be at least 4 weeks for the combination and at least 6 weeks in complicated cases, in patients having symptoms for more than 3 months, and in patients with PVE. These class IIarecommendations are based on level B evidence.

7.2 Drug level monitoring

Gentamicin trough levels should be less than 0.1mg/l to avoid renal or ototoxic effects.

Optimum vancomycin effects are achieved if serum concentrations are continuously kept at least 2–4 times above the MIC of the causative organism. Trough levels should be at least 10–15mg/l. In patients with normal renal function, drug levels should be controlled once, but 2–3 times weekly if combined with aminoglycosides.

7.3 Empirical therapy

In cases complicated by sepsis, severe valvular dysfunction, conduction disturbances, or embolic events, empirical antimicrobial therapy should be started after three blood cultures have been taken (see standard blood culture techniques section).

Recommendations for empirical antibiotic treatment (before microbiologic test results are available) and CNE are given in Table 9.

7.4 Special subsets

Antimicrobial therapy for infections of permanently implanted pacemakers or ICD leads are based on culture and susceptibility results. Duration of therapy should be 4–6 weeks in most cases. Removal of the entire system is generally recommended.

In intravenous drug abusers (IVDAs), a methicillin-susceptible S. aureus (MSSA) is the causative organism in about 60–70% of cases. The tricuspid valve is affected in more than 70%. The most common organism (S. aureus) must always be covered by the antibiotic regimen. Treatment will include either penicillinase-resistant penicillins or vancomycin, depending on the local prevalence of MRSA. If the patient is a pentazocine addict, an antipseudomonas agent should be added. If IVDAs use brown heroine dissolved in lemon juice, Candida should be considered and antifungal treatment added. In IVDAs with underlying valve lesions and/or left-sided involvement, antibiotic treatment against streptococci and enterococci must be added.

8 Management of Complications

Rapid and effective antimicrobial treatment may help to prevent embolism. If the patient is on long-term oral anticoagulation, coumarin therapy should be discontinued and replaced by heparin immediately after thediagnosis of IE has been established.

After an embolic complication, the risk for recurrent episodes is high. After manifestation of a cerebral embolism, cardiac surgery to prevent a recurrent episode is not contraindicated if performed early (best within 72h) and cerebral haemorrhage has been excluded by cranialcomputed tomography immediately before the operation. If surgery is not performed early it is advisable to be postponed for 3–4 weeks.

9 Surgery for active NVE

The following indications for urgent valve surgery are accepted:

  • Heart failure due to acute aortic regurgitation;

  • Heart failure due to acute mitral regurgitation;

  • Persistent fever and demonstration of bacteremia for more than 8 days despite adequate antimicrobial therapy;

  • Demonstration of abscesses, pseudoaneurysms, abnormal communications like fistulas or rupture of one or more valves, conduction disturbances, myocarditis or other findings indicating local spread (locally uncontrolled infection);

  • Involvement of microorganisms which are frequently not cured by antimicrobial therapy (e.g. fungi; Brucella and Coxiella) or microorganisms which have a high potential for rapid destruction of cardiac structures (e.g. S. lugdunensis).

If vegetations are larger than 10mm on the mitral valve or if they are increasing in size despite antibiotic therapy or if they represent mitral kissing vegetations, early surgery should also be considered.

The prognosis of right-sided IE is favourable. Surgery is necessary if tricuspid vegetations are larger than 20mm after recurrent pulmonary emboli.

10 Surgery for active PVE

The following indications are accepted:

  • Early PVE (less than 12 months after surgery)

  • Late PVE complicated by prosthesis dysfunction including significant perivalvular leaks or obstruction, persistent positive blood cultures, abscess formation, conduction abnormalities, and large vegetations, particularly if staphylococci are the infecting agents.

10.1 Postoperative antibiotic treatment

A full course of antimicrobial treatment should be completed regardless of the duration of treatment prior to surgery, but at least 7–15 days postoperatively.

11 List of Abbreviations

  • Atrial septal defect

  • Blood culture

  • Culture-negative endocarditis

  • Coagulase-negative staphylococci

  • Group of bacteria consistent of Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae

  • High level resistance

  • Implantable cardioverter defibrillator

  • Infective endocarditis

  • Intravenous drug abuser

  • Minimal inhibitory concentration

  • Methicillin-resistant Staphylococcus aureus

  • Methicillin-sensitive Staphylococcus aureus

  • Native valve endocarditis

  • Polymerase chain reaction

  • Prosthetic valve endocardits

  • Plural of ‘species’

  • Transoesophageal echocardiography

  • Transthoracic echocardiography