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## Complete Summary

#### GUIDELINE TITLE

Guidelines on prevention, diagnosis and treatment of infective
endocarditis. The task force on infective endocarditis of the European
Society of Cardiology.

#### BIBLIOGRAPHIC SOURCE(S)

Horstkotte D, Follath F, Gutschik E, Lengyel M, Oto A, Pavie A,
Soler-Soler J, Thiene G, von Graevenitz A. Guidelines on prevention,
diagnosis and treatment of infective endocarditis. The Task Force on
Infective Endocarditis of the European Society of Cardiology. France:
European Society of Cardiology; 2004. 37 p. \[390 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse (NGC)**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [July 08, 2008, Fluoroquinolones (ciprofloxacin, norfloxacin,
    ofloxacin, levofloxacin, moxifloxacin,
    gemifloxacin)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#Fluoroquinolone):
    A BOXED WARNING and Medication Guide are to be added to the
    prescribing information to strengthen existing warnings about the
    increased risk of developing tendinitis and tendon rupture in
    patients taking fluoroquinolones for systemic use.

-   [February 28, 2008, Heparin Sodium
    Injection](http://www.fda.gov/medwatch/safety/2008/safety08.htm#HeparinInj2):
    The U.S. Food and Drug Administration (FDA) informed the public that
    Baxter Healthcare Corporation has voluntarily recalled all of their
    multi-dose and single-use vials of heparin sodium for injection and
    their heparin lock flush solutions. Alternate heparin manufacturers
    are expected to be able to increase heparin production sufficiently
    to supply the U.S. market. There have been reports of serious
    adverse events including allergic or hypersensitivity-type
    reactions, with symptoms of oral swelling, nausea, vomiting,
    sweating, shortness of breath, and cases of severe hypotension.

-   [September 11, 2007, Rocephin (ceftriaxone
    sodium)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Rocephin):
    Roche informed healthcare professionals about revisions made to the
    prescribing information for Rocephin to clarify the potential risk
    associated with concomitant use of Rocephin with calcium or
    calcium-containing solutions or products.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Infective endocarditis (IE)

#### GUIDELINE CATEGORY

Diagnosis\
Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Cardiology\
Dentistry\
Family Practice\
Infectious Diseases\
Internal Medicine\
Surgery

#### INTENDED USERS

Hospitals\
Physicians

#### GUIDELINE OBJECTIVE(S)

To provide recommendations regarding adequate diagnosis, treatment, and
prevention of infective endocarditis (IE)

#### TARGET POPULATION

Patients with and patients at risk for infective endocarditis (IE)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Prevention**

1.  Identification of patients at risk

2.  Antibiotic prophylaxis, including amoxicillin, ampicillin,
    clindamycin, azithromycin, gentamicin, and vancomycin

3.  Patient education

**Diagnosis**

1.  History, symptoms, signs, and laboratory tests

2.  Echocardiography, including transthoracic (TTE) and transoesophageal
    echocardiography (TEE)

3.  Standard blood culture (BC) techniques, including susceptibility
    testing by disk diffusion and the determination of minimum
    inhibitory concentration (MIC) for drugs of choice

4.  Culture-negative endocarditis (CNE): BC, serology,
    immunofluorescence, polymerase chain reaction (PCR)

**Treatment/Management**

1.  Antibiotic treatment

    -   Penicillin G

    -   Gentamicin

    -   Ceftriaxone

    -   Vancomycin

    -   Netilmicin

    -   Teicoplanin

    -   Oxacillin

    -   Rifampicin

    -   Amphotericin B or ambisome

    -   5-fluorocytosine

2.  Drug level monitoring

3.  Surgery for native valve endocarditis

4.  Surgery for prosthetic valve endocarditis

5.  Management of complications, including embolic events, pulmonary
    complications of right-sided endocarditis, cardiac failure,
    myocarditis, renal failure, arrhythmias and conduction disturbances,
    and relapsing endocarditis

#### MAJOR OUTCOMES CONSIDERED

-   Incidence of bacteraemia

-   Predictive value of diagnostic tests

-   Sensitivity and specificity of diagnostic tests

-   Clinical effectiveness and safety of antibiotic drug regimens

-   Antibiotic susceptibility and resistance of microorganisms

-   Incidence of complications of infective endocarditis

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Levels of Evidence**

**A**: Data derived from multiple randomised clinical trials or
meta-analyses

**B**: Data derived from a single randomised trial or nonrandomised
studies

**C**: Consensus opinion of the experts and/or small studies

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The European Society of Cardiology Task Force on Infective Endocarditis
(IE) was formed to prepare recommendations regarding adequate diagnosis,
treatment and prevention of IE. The advice of additional experts (see
appendix 2 of the original guideline document) was obtained whenever the
core group felt that additional specific knowledge was mandatory. The
document was read by all members of the Task Force twice, redrafted and
approved by the Board of the European Society of Cardiology in 2003.

To end up with a readable paper, including a maximum of information and
covering the majority of issues frequently associated with IE, the text
has been condensed to essential information accompanied by key
references to allow for the information. The text is thus not a
substitute for textbooks.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Strength of Recommendation**

**Class I**: Conditions for which there is evidence or general agreement
that a given procedure or treatment is useful and effective

**Class II**: Conditions for which there is conflicting evidence or a
divergence of opinion about the usefulness/efficacy of a procedure or
treatment

-   **Class IIa**: Weight of evidence/efficacy is in favor or
    usefulness/efficacy

-   **Class IIb**: Usefulness/efficacy is less well established by
    evidence/opinion

**Class III**: Conditions for which there is evidence and/or general
agreement that the procedure/treatment is not useful/effective and in
some cases may be harmful

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

A review coordinator is appointed with the Committee for Practice
Guidelines (CPG). The document is reviewed by the members of the CPG,
the European Society of Cardiology Board Members, and other experts in
the field chosen from joint societies, working groups, and other
sources.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The class of recommendations (I-III) and level of evidence (A-C) are
defined at the end of the \"Major Recommendations\" field.

The following is the Executive Summary of the Guidelines on Prevention,
Diagnosis, and Treatment of Infective Endocarditis (IE) (See \"Companion
Documents\" field). Please refer to the Full Text of the guidelines for
the complete set of recommendations and supporting evidence.

**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 to 3 h.

**Cardiac conditions/Patients at risk**

A previous history of IE, the presence of prosthetic heart valves or
other foreign material, surgically created conduits, and complex
cyanotic congenital abnormalities are considered high-risk situations.
Only patients with high or moderate risk (See below and refer to table 2
in the \"Executive Summary\" \[See \"Companion Documents\" field\])
should receive prophylaxis. This is a **class I recommendation based on
level C evidence**.

[Cardiac conditions in which antimicrobial prophylaxis is
indicated]{.underline}

-   Prosthetic heart valves (high-risk group)

-   Complex congenital cyanotic heart diseases (high-risk group)

-   Previous IE (high-risk group)

-   Surgically constructed systemic or pulmonary conduits (high-risk
    group)

-   Acquired valvular heart diseases

-   Mitral valve prolapse with valvular regurgitation or severe valve
    thickening

-   Non-cyanotic congenital heart diseases (except for secundum type
    atrial septal defect) including bicuspid aortic valves

-   Hypertrophic obstructive cardiomyopathy

**Patient-related noncardiac conditions**

Older age, conditions (a) promoting nonbacterial thrombotic vegetation;
(b) compromising host defense; (c) compromising local nonimmune defense
mechanisms; and (d) increased risk/frequency/amount of bacteraemia are
considered patient related, noncardiac risk conditions.

**Predisposing diagnostic and therapeutic interventions**

Procedures which may cause bacteraemia and for which antimicrobial
prophylaxis is recommended are given below (Also refer to Table 3 in the
\"Executive Summary\" \[See \"Companion Documents\" field\]).
Prophylaxis is not recommended for cardiac catheterization.

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

[Diagnostic and therapeutic interventions likely to produce
bacteraemia]{.underline}

-   Bronchoscopy (rigid instrument)

-   Cystoscopy during urinary tract infection

-   Biopsy of urinary tract/prostate

-   Dental procedures with the risk of gingival/mucosal trauma

-   Tonsillectomy and adenoidectomy

-   Oesophageal dilation/sclerotherapy

-   Instrumentation of obstructed biliary tracts

-   Transurethral resection of prostate

-   Urethral instrumentation/dilation

-   Lithotripsy

-   Gynecologic procedures in the presence of infection

**Prophylactic antibiotic regimens**

Prophylaxis aims primarily at viridans streptococci and a group of
bacteria consistent of *Haemophilus* spp., *Actinobacillus
actinomycetemcomitans*, *Cardiobacterium hominis*, *Eikenella
corrodens*, *Kingella kingae* (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 evidence, antibiotic
prophylaxis (See below and refer to table 4 in the \"Executive Summary\"
\[See the \"Companion Documents\" field\]) is a **class I recommendation
based on level C evidence**.

-   Dental, oral, respiratory, and esophageal procedures (P)

    -   Not allergic to penicillin

        -   Amoxicillin 2.0 g (children 50 mg/kg) orally (p.o.) 1 h
            before P

        -   Unable to take oral medication: amoxicillin or ampicillin
            2.0 g (children 50 mg/kg) intravenously (i.v.) 1/2 to 1 h
            before P

    -   Allergic to penicillin: clindamycin 600 mg (children 20 mg/kg)
        or azithromycin/clarithromycin 500 mg (children 15 mg/kg) 1 h
        before P

-   Genitourinary and gastrointestinal procedures (P)

    -   Not allergic to penicillin

        -   High-risk group: ampicillin or amoxicillin 2.0 g i.v. plus
            gentamicin 1.5 mg/kg i.v. 1/2 to 1 h before P; 6 h later,
            ampicillin or amoxicillin 1.0 g p.o.

        -   Moderate-risk group: ampicillin or amoxicillin 2.0 g i.v.
            (children 50 mg/kg) ½ to 1 h before P; or amoxicillin 2.0 g
            (children 50 mg/kg) p.o. 1 h before P

    -   Allergic to penicillin

        -   High-risk group: vancomycin 1.0 g (children 20 mg/kg) over 1
            to 2 h before P plus gentamicin 1.5 mg/kg i.v. or
            intramuscularly (i.m.)

        -   Moderate-risk group: vancomycin (see above) without
            gentamicin

**Diagnosis**

**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
deoxyribonucleic acid (DNA) are found, IE is definite and
culture/microbiologically positive; otherwise IE is definite but
culture/microbiologically negative (Please refer to table 5 of the
\"Executive Summary\" \[See the \"Companion Documents\" field\] for
information on criteria that should raise suspicion of IE). Duke or
modified Duke criteria may be used to make the diagnosis in otherwise
unclear cases.

**Echocardiography**

Any patient suspected of having native valve endocarditis (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 prosthetic valve endocarditis (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 (Please
refer to figure 1 of the original guideline document for an algorithm
for the use of TTE and TEE in suspected IE). These **class I
recommendations are based on level B evidence**.

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; and (c) a new dehiscence of
a valve prosthesis, especially when occurring late after implantation.

**Standard blood culture (BC) techniques**

Three or more BCs should be taken irrespective of body temperature at
least 1 h 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 to 7 days.

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

**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 the capability to detect difficult-to-culture
organisms and even dead bacteria.

**Treatment and management**

**Antimicrobial therapy**

For treatment strategies refer to the following tables 6-8 from the
\"Executive Summary\" (see the \"Companion Documents\" field).

**Table 6: Decision making for antibiotic treatment of native (NVE) and
prosthetic valve endocarditis (PVE) due to streptococci**

+----------------------+-----------------------------------------------+
| *Regimen A: NVE;     |                                               |
| full susceptibility  |                                               |
| to penicillin        |                                               |
| (Minimal inhibitory  |                                               |
| concentration        |                                               |
| \[MIC\]              |                                               |
| [\<]{.underline}0.1  |                                               |
| mg/L)*               |                                               |
+----------------------+-----------------------------------------------+
| Patients             | Penicillin G 12--20 million units/24 h IV,    |
| [\<]{.underline}65   | divided into 4--6 doses for 4 weeks plus      |
| years, normal serum  | gentamicin 3 mg/kg/24 h IV (maximum 240       |
| creatinine levels    | mg/day), divided into 2--3 doses for 2 weeks  |
+----------------------+-----------------------------------------------+
| Same conditions as   | Penicillin G 12--20 million units/24 h IV,    |
| above with           | divided into 4--6 doses for 2 or 4 weeks with |
| uncomplicated        | ambulatory treatment after 7 days treatment   |
| courses and rapid    | in hospital^a^                                |
| clinical response to |                                               |
| therapy              |                                               |
+----------------------+-----------------------------------------------+
| Patients             | Penicillin G adapted to renal function for 4  |
| [\>]{.underline}65   | weeks or ceftriaxone 2 g/24 h IV^b^ as single |
| years and/or serum   | dose for 4 weeks                              |
| creatinine levels    |                                               |
| elevated or allergy  |                                               |
| to penicillin        |                                               |
+----------------------+-----------------------------------------------+
| Patients allergic to | Vancomycin 30 mg/kg/24 h IV divided into 2    |
| penicillin and       | doses for 4 weeks                             |
| cephalosporins       |                                               |
+----------------------+-----------------------------------------------+
| *Regimen B:          |                                               |
| Susceptibility to    |                                               |
| penicillin (MIC 0.1  |                                               |
| mg/L--0.5 mg/L) or   |                                               |
| PVE*                 |                                               |
+----------------------+-----------------------------------------------+
|                      | -   Penicillin G 20--24 million units/24 h IV |
|                      |     divided into 4--6 doses or^b^ ceftriaxone |
|                      |     2 g/24 h IV as single dose both for 4     |
|                      |     weeks plus gentamicin 3 mg/kg/24 h IV,    |
|                      |     divided into 2--3 doses for 2 weeks^c^    |
|                      |     followed by ceftriaxone 2 g/24 h IV for   |
|                      |     additional 2 weeks                        |
|                      |                                               |
|                      | -   Vancomycin as single drug treatment for 4 |
|                      |     weeks (dosage see above)                  |
+----------------------+-----------------------------------------------+
| *Regimen C:          |                                               |
| Resistance to        |                                               |
| penicillin; MIC      |                                               |
| \>0.5 mg/L^d^*       |                                               |
+----------------------+-----------------------------------------------+
|                      | Treatment like IE due to enterococci (Refer   |
|                      | to full version of original guideline         |
|                      | document)                                     |
+----------------------+-----------------------------------------------+

**Notes**:

^a^ For 2 weeks regimen see table 5 in the original guideline document

^b^ Especially for patients allergic to penicillin

^c^ 2--3 mg/kg netilmicin once daily may be an alternative (peak serum
level \<16 mg/L).

^d^ High level resistance (HLR) to penicillin or ceftriaxone (MIC \>8
mg/l) and HLR to gentamicin (MIC \>500 mg/l) or resistance to vancomycin
or teicoplanin (MIC [\>]{.underline}4 mg/L) are rare among strains of
streptococci. In such situations, extended susceptibility testing and a
close cooperation with the clinical microbiologist are mandatory.

**Table 7: Decision-making for antibiotic treatment of IE due to
enterococci and penicillin-resistant streptococci**

  ------------------------------------- ---------------------------------
  Penicillin (MIC [\<]{.underline}8     Penicillin G, 16--20 million
  mg/L) and gentamicin (MIC \<500 mg/L) units in 4--6 divided doses plus
                                        gentamicin 3 mg/kg, IV, divided
                                        in 2 doses for 4-6 weeks

  Penicillin-allergic patients and      Vancomycin 30 mg/kg/day IV in two
  penicillin/gentamicin susceptible     divided doses plus gentamicin
  enterococcal isolates                 (dosage as above) for 6 weeks

  Penicillin-resistant strains (MIC \>8 Vancomycin plus gentamicin
  mg/L)^a^                              (dosage as above) for 6 weeks

  Vancomycin-resistant strains          Assistance of an experienced
  including strains with low resistance microbiologist is mandatory. If
  to vancomycin (MIC 4-16 mg/L) or      antimicrobial therapy fails,
  highly resistance to gentamicin^a^    valve replacement should be
                                        considered early
  ------------------------------------- ---------------------------------

**Note**:

^a^ For resistant enterococci, treatment with oxazolidinone may be an
option but should be initiated only after advice from a reference centre
has been taken.

**Table 8: Decision-making for antibiotic treatment of IE due to
staphylococci**

  ------------------- -----------------------------------------------------
  *Regimen A: Native  
  valve endocarditis* 

  MSSA^a^ no allergy  Oxacillin^b^ 8--12 g/24 h IV, divided into 4 doses
  to penicillin       for at least 4 weeks^c^ plus gentamicin 3 mg/kg/24 h
                      IV (maximum 240 mg/d), divided into 2-3 doses for the
                      first 3--5 days of treatment

  MSSA^a^ \"allergy\" Vancomycin 30 mg/kg/24 h IV divided into 2 doses^e^
  to penicillin^d^    for 4--6 weeks^f^, plus gentamicin 3 mg/kg/24 h IV
                      (maximum 240 mg/d) divided into 2-3 doses for the
                      first 3--5 days of treatment

  MRSA^g^             Vancomycin 30 mg/kg/24 h IV divided into 2 doses^e^
                      for 6 weeks

  *Regimen B:         
  Endocarditis        
  involving           
  prosthetic          
  material/cardiac    
  valve prostheses*   

  MSSA^a^             Oxacillin^b^ 8--12 g/24 h IV, divided into 3--4 doses
                      plus rifampicin 900 mg/24 h IV divided into 3 doses,
                      both for 6--8 weeks, plus gentamicin 3 mg/kg/24 h IV
                      (maximum 240 mg/d) divided into 2--3 doses for the
                      first 2 weeks of treatment

  MRSA^g^,CONS^h,i^   Vancomycin 30 mg/kg/24 h IV divided into 2 doses^e^
                      for 6 weeks, plus rifampicin 900 mg/24 h IV divided
                      into 3 doses, plus gentamicin^j^ 3 mg/kg/24 h IV
                      (maximum 240 mg/d) divided into 2--3 doses, all for
                      6--8 weeks
  ------------------- -----------------------------------------------------

**Notes**:

^a^ Methicillin-susceptible *Staphylococcus aureus*

^b^ Or its congeners

^c^ Except for drug addicts for whom a two-week regimen may be
sufficient

^d^ For both immediate (immunoglobulin E \[IgE\]) type and
hypersensitivity reaction during treatment

^e^ Infusion over at least 60 min

^f^ Total treatment duration for patients initially treated with
oxacillin should be at least 4 weeks. These patients should not have a
second course of gentamicin treatment.

^g^ Methicillin-resistant *S. aureus*

^h^ Coagulase-negative staphylococci. In oxacillin-susceptible CONS,
vancomycin should be replaced by oxacillin.

^i^ For resistant staphylococci, treatment with oxazolidinone may be an
option but should be initiated only after advice from a reference centre
has been taken.

^j^ If gentamicin susceptibility has been shown in vitro, gentamicin is
added in MRSA for the full course but for CONS only for the first two
weeks of treatment. If the organism is resistant to all aminoglycosides,
gentamicin may be substituted by a fluoroquinolone.

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 (minimum inhibitory concentration
\[MIC\] for gentamicin 4 to 64 mg/L). (Refer to the table above for
information on decision-making for antibiotic treatment of IE due to
enterococci and penicillin-resistant streptococci).

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 IIa
recommendations are based on level B evidence**.

**Drug level monitoring**

Gentamicin trough levels should be less than 0.1 mg/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--15 mg/L. In patients with
normal renal function, drug levels should be controlled once, but 2--3
times weekly if combined with aminoglycosides.

**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 above).

Recommendations for empirical antibiotic treatment (before microbiologic
test results are available) and CNE are given below and in table 9 of
the \"Executive Summary\" (See \"Companion Documents\" field).

**Table 9: Antimicrobial treatment in CNE or if therapy is urgent and
the causative organism unidentified**

  ------------------ ------------------------------------- ---------------
  **NVE**                                                  

  Vancomycin         15 mg/kg i.v. every 12 hours^a,\ b^   4-6 weeks

  \+ Gentamicin      1.0 mg/kg i.v. every 8 h              2 weeks

  **PVE**                                                  

  Vancomycin         15 mg/kg i.v. every 12 h              4-6 weeks

  \+ Rifampicin      300-450 mg p.o. every 8 h             4-6 weeks

  \+ Gentamicin      1.0 mg/kg i.v. every 8 h              2 weeks
  ------------------ ------------------------------------- ---------------

**Notes**:

^a^ Maximum 2 g/day; for drug level monitoring see above and refer to
full text in the original guideline document

^b^ Aminopenicillin may be added.

**Special subsets**

Antimicrobial therapy for infections of permanently implanted pacemakers
or implantable cardioverter defibrillator (ICD) leads is based on
culture and susceptibility results. Duration of therapy should be 4 to 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 to 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.

**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
the diagnosis 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
72 h) and cerebral haemorrhage has been excluded by cranial-computed
tomography immediately before the operation. If surgery is not performed
early, it is advisable to be postponed for 3 to 4 weeks.

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

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

**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

**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 to 15 days
postoperatively.

**Definitions**

**Class Strength of Recommendations**

**Class I**: Conditions for which there is evidence or general agreement
that a given procedure or treatment is useful and effective

**Class II**: Conditions for which there is conflicting evidence or a
divergence of opinion about the usefulness/efficacy of a procedure or
treatment

-   **Class IIa**: Weight of evidence/efficacy is in favor or
    usefulness/efficacy

-   **Class IIb**: Usefulness/efficacy is less well established by
    evidence/opinion

**Class III**: Conditions for which there is evidence and/or general
agreement that the procedure/treatment is not useful/effective and in
some cases may be harmful

**Levels of Evidence**

**A**: Data derived from multiple randomised clinical trials or
meta-analyses

**B**: Data derived from a single randomised trial or nonrandomised
studies

**C**: Consensus opinion of the experts and/or small studies

#### CLINICAL ALGORITHM(S)

Clinical algorithms are provided in the original guideline document for
the use of transthoracic (TTE) and transoesophageal echocardiography
(TEE) in suspected infective endocarditis (IE) and for empiric
antibiotic treatment before identification of causative
microorganism(s).

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for selected
recommendations (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

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.
Differences in morbidity and mortality recently reported point to the
importance of an early and proper diagnosis and adequate treatment.

#### POTENTIAL HARMS

-   Vancomycin, gentamicin, and other aminoglycosides may cause renal
    dysfunction.

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

-   Aminoglycosides should be used in special indications only during
    pregnancy because of the potential of eighth cranial nerve toxicity
    in the fetus.

-   Amphotericin may cause drug-associated fever.

-   Fluconazole use during pregnancy has produced dose-dependent
    teratogenic effects (grossly dysmorphic infants).

-   Cardiac surgery during pregnancy poses the risk of fetal distress,
    growth retardation, and fetal death.

-   Prolonged high-dose beta-lactam antibiotics may inhibit
    granulopoiesis and result in neutropenia.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   Quinolones are contraindicated during pregnancy.

-   In patients with the antecedent of immediate type (immunoglobulin E
    \[IgE\]-type) hypersensitivity to penicillin, any beta-lactam
    antibiotic should be avoided.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

The term \"bacterial endocarditis\" has been replaced by \"infective
endocarditis\" (IE) since fungi are also involved as causative
pathogens.

**Classification and terminology**

In contrast to older classifications distinguishing between acute,
subacute, and chronic IE, the present classification refers to (a)
activity of the disease and recurrence; (b) diagnostic status; (c)
pathogenesis; (d) anatomical site; and (e) microbiology.

-   **A**: With respect to activity, differentiation between active and
    healed IE is especially important for patients undergoing surgery.
    Active IE is present if positive blood cultures and fever are
    present at the time of surgery, or positive cultures are obtained at
    surgery, or active inflammatory morphology is found
    intraoperatively, or surgery has been performed before completion of
    a full course of antibiotic therapy. More recently, it has been
    recommended to call IE active if the diagnosis has been established
    two months or less before surgery.

> IE is recurrent if it develops after eradication of a previous IE,
> while in persistent IE, the infection has never been truly eradicated.
> It can be difficult or even impossible to differentiate between the
> two unless another episode of IE is caused by a different organism.
> Endocarditis developing more than one year after operation is usually
> considered recurrent. Recurrent IE is a dreaded complication with high
> mortality.

-   **B**: The diagnosis of IE is established (definite IE) if during
    septicaemia or systemic infection involvement of the endocardium can
    be demonstrated, preferably by multiplane transoesophageal
    echocardiography (TEE). If IE is strongly suspected clinically (see
    Section 4.4 of the original guideline document) but involvement of
    the endocardium has not been proven so far, endocarditis should be
    classified as \"suspected\" to express a more or less high suspicion
    of IE. If IE is only a potential differential diagnosis in febrile
    patients, a situation which is of special importance when applying
    the Duke criteria, one should describe this as \"possible\" IE.

-   **C**: Native (NVE), prosthetic valve endocarditis (PVE) and IE in
    intravenous drug abuse (IE in IVDA) differ with respect to
    pathology. PVE should be classified as an infection more likely to
    have been acquired perioperatively and thus being nosocomial (early
    PVE), or more likely to have been community-acquired (late PVE).
    Because of significant differences in the microbiology of PVE
    observed within one year of operation and later, the cut-off between
    early and late PVE should be at one year.

-   **D**: Due to the differences in clinical manifestation and
    prognosis, IE involving structures of the left and the right heart
    should be distinguished and referred to as right heart or left heart
    IE, respectively. If the anatomical site of the infection has been
    identified properly (e.g., by transoesophageal echocardiography), it
    should be part of the definition (e.g., mitral, aortic, mural).

-   **E**: When the causative organism has been identified, it should be
    included in the terminology, as it provides crucial information
    regarding clinical presentation, treatment and prognosis. As long as
    cultures, serological tests, histological and/or molecular
    biological methods (e.g., broad-spectrum polymerase chain reaction
    \[PCR\]) have remained negative, this information should also be
    included in the terminology (e.g., culture, serology,
    histologically, PCR-negative or -positive IE). If all techniques
    have been applied and were negative, the term \"microbiologically
    negative\" is considered appropriate.

-   **F**: Classification referring to the population involved (e.g. IE
    in addicts, in patients with congenital heart disease, neonates,
    children, in the elderly; nosocomial NVE) is helpful for
    epidemiological purposes and clinical management.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Personal Digital Assistant (PDA) Downloads\
Pocket Guide/Reference Cards\
Slide Presentation

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Horstkotte D, Follath F, Gutschik E, Lengyel M, Oto A, Pavie A,
Soler-Soler J, Thiene G, von Graevenitz A. Guidelines on prevention,
diagnosis and treatment of infective endocarditis. The Task Force on
Infective Endocarditis of the European Society of Cardiology. France:
European Society of Cardiology; 2004. 37 p. \[390 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2004 Jan

#### GUIDELINE DEVELOPER(S)

European Society of Cardiology - Medical Specialty Society

#### SOURCE(S) OF FUNDING

European Society of Cardiology (ESC). The Task Force on Infective
Endocarditis was supported financially in its entirety by The European
Society of Cardiology and was developed without any involvement of the
pharmaceutical industry.

#### GUIDELINE COMMITTEE

Task Force on Infective Endocarditis of the European Society of
Cardiology

European Society of Cardiology (ESC) Committee for Practice Guidelines

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Task Force Members*: Dieter Horstkotte, (Chairperson) (Germany); Ferenc
Follath (Switzerland); Erno Gutschik (Denmark); Maria Lengyel (Hungary);
Ali Oto (Turkey); Alain Pavie (France); Jordi Soler-Soler (Spain);
Gaetano Thiene (Italy); Alexander von Graevenitz (Switzerland)

*European Society of Cardiology (ESC) Committee for Practice Guidelines
Members*: Silvia G. Priori (Chairperson) (Italy); Maria Angeles Alonso
Garcia (Spain); Jean-Jacques Blanc (France); Andrzej Budaj (Poland);
Martin Cowie (UK); Veronica Dean (France); Jaap Deckers (The
Netherlands); Enrique Fernandez Burgos (Spain); John Lekakis (Greece);
Bertil Lindahl (Sweden); Gianfranco Mazzotta (Italy); Joao Morais
(Portugal); Ali Oto (Turkey); Otto A. Smiseth (Norway)

*Document Reviewers*: John Lekakis (CPG Review Coordinator) (Greece);
Alec Vahanian (France); Francois Delahaye (France); Alexander
Parkhomenko (Ukraine); Gerasimos Filipatos (Greece); Jan Aldershvile
(Denmark); Panos Vardas (Greece)

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The Task Force makes every effort to avoid any actual or potential
conflicts of interest that might arise as a result of an outside
relationship or personal interest of a member of the writing panel.
Specifically, all members of the writing panel, before final approval by
the Committee for Practice Guidelines (CPG), are asked to provide
disclosure statements of all such relationships that might be perceived
as real or potential conflicts of interest. Once they have verbally
accepted to become members of the Task Force, a written consent form is
signed as well as this \"Disclosure form\" and this for all Guidelines.
The disclosure form must be updated if any changes occur during the
elaboration to the document.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [European Society of Cardiology
(ESC) Web
site](http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/infective-endocarditis.aspx).

Print copies: Available from Elsevier Science Ltd. European Heart
Journal, ESC Guidelines - Reprints, 32 Jamestown Road, London, NW1 7BY,
United Kingdom. Tel: +44.207.424.4422; Fax: +44 207 424 4515; Web site:
[http://www.eurheartj.org](http://www.eurheartj.org/)

#### AVAILABILITY OF COMPANION DOCUMENTS

The following is available:

-   Guidelines on prevention, diagnosis and treatment of infective
    endocarditis. Executive summary. 2004. Electronic copies: Available
    in Portable Document Format (PDF) from the [European Society of
    Cardiology (ESC) Web
    site](http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-IE-ES.pdf).

-   Prevention, diagnosis and treatment of infective endocarditis.
    Pocket guidelines. Available from the [ESC Web
    site](http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/IE-pocket.aspx).
    Also available for PDA download from the [ESC Web
    site](http://pocketgram.net/escardio/).

-   Prevention, diagnosis and treatment of infective endocarditis. Slide
    set. Available from the [ESC Web
    site](http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-IE-slides.pdf).

Print copies: Available from Elsevier Science Ltd., 32 Jamestown Road,
London, NW1 7BY, United Kingdom. Tel: +44.207.424.4422; Fax: +44 207 424
4433; Web site: [http://www.eurheartj.org](http://www.eurheartj.org/)

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on July 26, 2004. The information
was verified by the guideline developer on September 24, 2004. This
summary was updated by ECRI Institute on June 22, 2007 following the
U.S. Food and Drug Administration (FDA) advisory on heparin sodium
injection. This summary was updated by ECRI Institute on October 3, 2007
following the U.S. Food and Drug Administration (FDA) advisory on
Rocephin (ceftriaxone sodium). This summary was updated by ECRI
Institute on March 13, 2008 following the updated FDA advisory on
heparin sodium injection. This summary was updated by ECRI Institute on
July 28, 2008 following the U.S. Food and Drug Administration advisory
on fluoroquinolone antimicrobial drugs.

#### COPYRIGHT STATEMENT

This summary is based on the original guideline, which is subject to the
guideline developer\'s copyright restrictions.

### DISCLAIMER

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