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
- 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
- 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] <0.1 mg/L) |
| Patients <65 years, normal serum creatinine levels |
Penicillin G 12–20 million units/24 h IV, divided into 4–6 doses for 4 weeks plus gentamicin 3 mg/kg/24 h IV (maximum 240 mg/day), divided into 2–3 doses for 2 weeks |
| Same conditions as above with uncomplicated courses and rapid clinical response to therapy |
Penicillin G 12–20 million units/24 h IV, divided into 4–6 doses for 2 or 4 weeks with ambulatory treatment after 7 days treatment in hospitala |
| Patients >65 years and/or serum creatinine levels elevated or allergy to penicillin |
Penicillin G adapted to renal function for 4 weeks or ceftriaxone 2 g/24 h IVb as single dose for 4 weeks |
| Patients allergic to penicillin and cephalosporins |
Vancomycin 30 mg/kg/24 h IV divided into 2 doses for 4 weeks |
| 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 orb 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 weeksc 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/Ld |
| |
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 >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 <8 mg/L) and gentamicin (MIC <500 mg/L) |
Penicillin G, 16–20 million units in 4–6 divided doses plus gentamicin 3 mg/kg, IV, divided in 2 doses for 4-6 weeks |
| Penicillin-allergic patients and penicillin/gentamicin susceptible enterococcal isolates |
Vancomycin 30 mg/kg/day IV in two divided doses plus gentamicin (dosage as above) for 6 weeks |
| Penicillin-resistant strains (MIC >8 mg/L)a |
Vancomycin plus gentamicin (dosage as above) for 6 weeks |
| Vancomycin-resistant strains including strains with low resistance to vancomycin (MIC 4-16 mg/L) or highly resistance to gentamicina |
Assistance of an experienced microbiologist is mandatory. If antimicrobial therapy fails, 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 |
| MSSAa no allergy to penicillin |
Oxacillinb 8–12 g/24 h IV, divided into 4 doses for at least 4 weeksc 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 |
| MSSAa "allergy" to penicillind |
Vancomycin 30 mg/kg/24 h IV divided into 2 dosese for 4–6 weeksf, 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 |
| MRSAg
| Vancomycin 30 mg/kg/24 h IV divided into 2 dosese for 6 weeks |
| Regimen B: Endocarditis involving prosthetic material/cardiac valve prostheses |
| MSSAa |
Oxacillinb 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 |
| MRSAg,CONSh,i |
Vancomycin 30 mg/kg/24 h IV divided into 2 dosese for 6 weeks, plus rifampicin 900 mg/24 h IV divided into 3 doses, plus gentamicinj 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 hoursa, 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
