Infective endocarditis (IE) is a rare disease but with devastating consequences. In-hospital mortality rates of left-sided endocarditis are around 20%, and 5-year mortality rates are up to 40% despite the advances in diagnosis and treatment [ ]. High mortality and morbidity and difficulty in treatment mandate institution of effective preventive measures to lower the incidence of this life-threatening condition. Unfortunately, the low incidence of the disease makes it very hard to obtain high-quality prospective randomized trial data measuring the effects of preventive interventions.
Antibiotic prophylaxis for dental procedures was first recommended by the American Heart Association (AHA) more than 60 years ago [ ]. During the 50 years following the first recommendations, antibiotic prophylaxis was administered to patients with various underlying cardiac conditions undergoing different invasive procedures. Patients and procedures were stratified into high- and low-risk groups in 1977 [ ], and high-, moderate-, and low-risk categories were defined in 1997 guidelines. The latter recommended prophylaxis to the moderate- and high-risk patients undergoing various procedures, including dental procedures [ ]. However, these recommendations were based on animal studies or studies where bacteremia was regarded as a surrogate for endocarditis. In the years to follow, studies showing that patients are experiencing recurrent bacteremia due to daily oral hygiene activities such as brushing, flossing, and even chewing have been published [ ]. Bacteremia with IE causing microorganisms after toothbrushing was especially pronounced in those with poor oral hygiene [ ]. These led to the development of the concept that daily oral hygiene activities might be riskier than sporadic invasive dental procedures in patients with poor oral hygiene. The absence of high-quality data on the effectiveness of antibiotics in preventing IE as well as the potential risks related to antibiotic use have led to a shift in major society guidelines after the mid-2000s. However, the guidelines around the world are still not in complete agreement on whom to administer prophylactic antibiotics as well as which procedures require prophylaxis. European Society of Cardiology (ESC) [ ] and the AHA [ ] guidelines have restricted prophylactic antibiotics to the patients with the highest risk of adverse outcomes. National Institute for Health and Clinical Excellence (NICE) guidelines advised against prophylactic antibiotics completely [ ]. Time trend analysis of IE cases in the United Kingdom has shown that prescriptions of antibiotics for prophylaxis have decreased, and cases of IE have increased in the United Kingdom after the institution of these guidelines [ ]. In 2016 NICE amended the previous recommendations stating that ‘antibiotic prophylaxis is not recommended’ to “not ‘routinely’ recommended” for people undergoing dental procedures, which provided some flexibility to health-care providers in administering antibiotic prophylaxis in selected cases if they felt the patient is at high risk for adverse outcomes [ ]. On the other hand, Japanese Circulation Society guidelines still recommend antibiotic prophylaxis for both high-risk and moderate-risk patients [ ].
Meanwhile, the epidemiology of IE has been changing. More cases are seen in the older adults related to health care and intravenous drug users, leading to a shift in causative microorganisms from streptococci to staphylococci [ , ].
Risk associated with predisposing cardiovascular conditions
A high-risk patient is defined as someone who could suffer from a poor outcome from IE rather than a patient who has a higher lifetime risk of contracting endocarditis.
Guidelines specify high-risk individuals as follows [ , , ]:
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Patients with a history of previous IE
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Patients with prosthetic valves (including transcatheter valves) and patients who have undergone valve repair with prosthetic material such as rings or artificial chordae
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Patients with cyanotic congenital heart defects
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The first 6 months after surgical or percutaneous repair of congenital heart disease with a prosthetic material (indefinitely in case of a residual shunt or valvular regurgitation)
AHA additionally recommends prophylaxis in cardiac transplant recipients who develop cardiac valve regurgitation, whereas ESC guidelines do not, based on lack of strong evidence. Table 6.1 summarizes the high- and intermediate-risk conditions for IE. More recent epidemiological data have supported that patients with previous IE, prosthetic or repaired valves, congenital heart disease treated with a palliative shunt or conduit, and cyanotic congenital heart disease had the highest odds of developing endocarditis or dying from endocarditis in 5 years. However, the data also showed that patients with certain intermediate-risk conditions, such as rheumatic valve disease, had high odds of developing endocarditis comparable to cyanotic congenital heart disease. The risk of death was lower than the risk of death of cyanotic congenital heart disease. Congenital valve anomalies also have a risk of IE or dying from endocarditis that is as high as several high-risk conditions. On the other hand, patients with congenital heart disease repaired with prosthetic material who are currently stratified as high risk in the first 6 months had a lower risk of IE or death than all conditions currently considered to be moderate risk. Additionally, patients with cardiac implantable electronic devices (CIEDs) not stratified in a risk group had a 10-fold increase in endocarditis risk [ ].
| High risk |
| Prosthetic heart valves (bioprosthesis or mechanical) or valve repair with prosthetic material |
| Unrepaired cyanotic congenital heart disease, including palliative shunts/conduits |
| Previous infective endocarditis |
| First 6 months after repair of an intracardiac shunt, or lifelong if residual shunt remains |
| Heart transplant recipient with valvulopathy a |
| Intermediate risk |
| Rheumatic valve disease |
| Patients with any other form of native-valve disease (including bicuspid aortic valve, MVP, and calcific aortic stenosis) |
| Unrepaired congenital heart valve abnormalities |
| Hypertrophic CMP with obstruction a |
Noncardiac risk factors for endocarditis include older age, compromised immunity, hemodialysis, indwelling intravascular devices, malignancy, diabetes mellitus, chronic liver disease, poor dentition, and intravenous drug use [ ].
Risk associated with invasive procedures
Invasive dental procedures
Dental plaques are a biofilm of bacteria that can lead to dental caries and soft tissue infection. The microorganisms in the biofilm leading to dental caries are mostly viridans streptococci ( Streptococcus mutans and Streptococcus sanguinis ). They can be introduced to the bloodstream after invasive dental procedures that can cause bleeding and disruption of the gingival mucosa. Temporary bacteremia caused by invasive dental treatments is considered to be a risk factor for developing endocarditis. Case–control or case–crossover studies of IE patients have yielded controversial results in associating recent invasive dental procedures to endocarditis development [ ]. A similar controversy is also present about antibiotics’ efficacy in preventing IE [ , ]. Endocarditis risk due to invasive dental procedures seems very small; however, the consequences of endocarditis might be very severe. Most guidelines have decided to remain cautious and continue recommending prophylaxis for the highest risk patients undergoing certain invasive dental procedures.
Antibiotic prophylaxis is recommended for invasive dental procedures that involve the manipulation of gingival tissue or periapical region or perforation of the mucosa when performed on high-risk individuals [ , ]. Australian guidelines have provided a list of dental procedures that are likely to cause a high incidence of bacteremia that always require prophylaxis as follows [ ]:
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Tooth extraction
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Periodontal surgery, subgingival scaling, and root planning
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Replantation of avulsed teeth
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Other surgical procedures, such as implant placement or apicoectomy
Procedures that cause a moderate incidence of bacteremia might be considered for prophylaxis if multiple procedures are being conducted, the procedure is prolonged, or in the setting of periodontal disease.
Antibiotic prophylaxis is not recommended for procedures with a low possibility of bacteremia, such as
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Oral examination
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Local anesthetic injections
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Dental X-rays
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Restorative treatment of superficial caries
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Orthodontic appliance placement and adjustment
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Following the shedding of deciduous teeth
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After lip or oral trauma
Body art
Body piercing and tattooing have become very popular among young people. Increasing trends in tattooing and piercing have led to an increase in IE cases related to body art. The tongue, earlobe, and navel were common sites of piercing associated with IE. Tongue and nose piercings were shown to cause endocarditis in young patients without a history of underlying congenital heart disease [ ]. Endocarditis risk related to tattooing seems lower than that of piercing. ESC 2015 guidelines [ ] discourage tattooing and piercing in high-risk individuals. The patients and body art professionals should be informed about the risk of endocarditis. If the patient decides to have piercing/tattooing, it should be performed under strict sterile conditions. However, antibiotic prophylaxis is not recommended for ear and body piercing or tattooing.
Nondental, noncardiac invasive procedures
A quarter to one-third of IE patients reports a history of recent exposure to health care. The patients with health-care-acquired endocarditis are older and have higher rates of staphylococcal and enterococcal infections than those with community-acquired endocarditis [ , ]. Vascular manipulation, peripheral or central venous catheterization, is the primary source of bacteremia, causing health-care-related IE [ ]. Several inpatient and outpatient invasive procedures are shown to be associated with an increased risk of endocarditis in a recent case–crossover study. These include bone marrow puncture, transfusions, hemodialysis, cystoscopy, bronchoscopy, gastrointestinal endoscopic procedures, arterial puncture, therapeutic ENT procedures, genitourinary procedures, procedures of skin, and management of wounds. Most endoscopic procedures are associated with increased endocarditis risk regardless of a biopsy is taken or not. The number needed to treat was 476 to prevent a single endocarditis case if prophylaxis was 100% effective. This number was lower in some higher-risk interventions [ ].
ESC and Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease [ ] guidelines recommend against routine prophylaxis against IE during respiratory tract, gastrointestinal, genitourinary, dermatological, or musculoskeletal procedures unless performed at an infected or colonized site. These procedures may include incision or drainage of local abscesses or procedures performed through infected skin. If the pathogen is known, it should be treated accordingly. If the pathogen is unknown, the empirical prophylaxis should cover the most commonly encountered pathogens in that site. AHA, as well as JCS, guidelines find antibiotic prophylaxis of high-risk patients undergoing tonsillectomy or adenoidectomy reasonable.
Cardiovascular invasive procedures
The advances in medicine have led to a significant increase in the number of the prosthetic heart valve and intracardiac device implantations. Parallel to the increase in the procedures, IE cases related to transcatheter valve interventions such as transcatheter aortic valve implantation (TAVI) or MitraClip have also been increasing [ , ]. The risks of contracting or dying from IE are small but significant in patients with CIEDs [ ].
Early prosthetic valve endocarditis is mostly a result of perioperative contamination of the valve. Central or peripheral intravenous catheters, as well as deep sternal wound infections, can lead to endocarditis. Staphylococcus aureus , Staphylococcus epidermidis , enterococci, gram-negative bacteria, and fungi can be responsible for early surgical valve endocarditis. Recently contaminated water tanks of heater-cooler units used for the extracorporeal membrane oxygenation (ECMO) units, probably contaminated at manufacturing, have been associated with Mycobacterium chimaera outbreaks [ , ]. Bioaerosols from exhaust air from heater-cooler units of ECMO might be a potential source of infection [ ]. The infections have caused a spectrum of disorders, from surgical site infections to pulmonary or disseminated granulomatous disease and prosthetic valve endocarditis. Careful checking of tap water and operating room devices through periodic sampling might help prevent other local cases.
TAVI also is associated with a risk of IE. The most frequent causative microorganisms are S. epidermidis , S. aureus , and enterococci [ , ]. While enterococcal endocarditis is relatively rare when compared to staphylococci after surgical AVR, enterococcal endocarditis is as frequent as staphylococci after TAVI. The difference might be related to different bacterial colonization of the femoral access site. TAVI is generally performed in catheterization laboratories, which tend to have a less sterile environment than the operating rooms. There are also additional risks related to the procedure like the turbulent flow of paravalvular leaks causing a nidus of infection, trauma to the native-valve leaflets during manipulations of the valve, or use of pacemakers [ ].
Patients with CIEDs not stratified in a risk group had a 10-fold increase in endocarditis risk [ ]. CIED infections are a spectrum of infectious processes from local pocket infections to systemic IE. CIED can occur in patients without other cardiac abnormalities due to bacterial inoculation from the skin during implantation or secondary seeding from distant infections. Most infections are related to early bacterial colonization and biofilm formation. Preventing the periprocedural colonization will be able to prevent the majority of the CIED infections. CIED endocarditis can involve the lead and/or the tricuspid valve. Staphylococci, both coagulase-negative staphylococci and S. aureus , are the most prevalent microorganisms involved [ ]. Risk factors of CIED infections related to the procedure are lack of antibiotic prophylaxis, long duration of the procedure, hematoma formation, need for revision, as well as device characteristics like dual-chamber systems and presence of an abdominal pocket [ ].
Recent European Heart Rhythm Association international consensus document on how to prevent, diagnose, and treat CIED infections [ ] and British guidelines for the diagnosis, prevention, and management of intracardiac device infection [ ] recommend several periprocedural interventions to avoid CIED. They are summarized in Table 6.2 .
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Sources of dental sepsis should be eliminated at least 2 weeks before implanting a prosthetic valve or other intravascular/intracardiac foreign material.
25%–30% of the population are nasal carriers of S . aureus [ , ]. Preoperative screening of nasal carriage of S. aureus is recommended before elective cardiac surgery or CIED implantation. Treating carriers with mupirocin nasal ointment and chlorhexidine soap prevents staphylococcal surgical site infections, which might potentially lead to endocarditis [ ].
Measures for prevention of infective endocarditis
Nonpharmacological measures
Nonpharmacological measures are still the most critical interventions in the prevention of IE. The guidelines emphasize the importance of good dental and cutaneous hygiene practices for the prevention of IE. The patients should be educated about good hygiene practices and advised to have routine dental checkups once or twice a year, depending on their risk status. However, data from the European Heart Survey showed that the education level about IE prophylaxis is low. Only half of the patients with native-valve disease were educated on IE prevention, and only a third attended routine dental care visits [ ].
Other nonpharmacological measures include proper disinfection of wounds, consulting conditions like atopic dermatitis with a physician, limitation of venous catheter use, and aseptic measures during the insertion and manipulation of venous catheters and during any invasive procedure. Treatment of chronic bacterial colonization of skin and urine is advisable. Patients should be discouraged from self-treating with antibiotics and educated to consult their cardiologists in case of fever that does not resolve in a few days.
Antibiotic prophylaxis
Concerns about antibiotic prophylaxis
The efficacy of antibiotics in preventing endocarditis has been controversial. The low incidence of the disease makes it very challenging to conduct a high-quality randomized trial of antibiotics with an end point of IE development. The current data are derived from animal studies of endocarditis, trials identifying postprocedural bacteremia as a surrogate of endocarditis, case–control studies, and time trend analyses of endocarditis cases before and after guideline restrictions are implemented. It is well established that antibiotic prophylaxis effectively reduces procedure-associated bacteremia, but it is uncertain if the reduction of postprocedural bacteremia is a good surrogate for a reduction in IE development [ ]. Time trend studies after guideline restrictions of prophylactic antibiotics have also yielded controversial results. Oral streptococcal endocarditis cases were not increased in France after guideline changes [ ]; on the contrary, endocarditis cases were found to be increased in studies from the United States, Germany, the United Kingdom, and Canada [ , ].
Potential of anaphylaxis, emerging antibiotic resistance, and high costs of widespread prophylaxis were among other concerns besides the uncertainty in efficacy. Between 2004 and 2014, no fatal reactions were reported in the United Kingdom related to 3-gram amoxicillin prescriptions. There were 22.62 nonfatal reactions/million prescriptions. 600 mg clindamycin caused 13 fatal and 149 nonfatal reactions/million prescriptions, mostly related to superinfections with Clostridium difficile [ ]. Antibiotic prophylaxis before dental procedures to patients at risk could cost up to $145 million per year [ ]. The exact impact of prophylactic antibiotic use for IE on antibiotic resistance is not known. However, oral microorganisms already have a high antibiotic resistance rate. 45% of S. mutans species found in patients with dental infections are resistant to antibiotics. The resistance to clindamycin is more pronounced than resistance to amoxicillin-clavulanate [ ]. Microorganisms in biofilms are known to be more resistant to antibiotics [ ]. 10% of all antibiotic prescriptions are for the treatment of oral infections. High rates of resistance could result from high rates of repetitive therapeutic prescriptions rather than a single high-dose antibiotic used for prophylaxis. However, the high rate of resistance in the oral flora could impact prophylactic antibiotics’ choice in the future.
Antibiotic prophylaxis regimens
Invasive dental procedures
The prophylactic antibiotic should be effective against viridans group streptococci. 2 g of amoxicillin given orally as a single dose 30–60 min before the procedure is the drug of choice for IE prophylaxis [ , ]. Amoxicillin is shown to be effective in reducing bacteremia related to dental procedures [ ]. Amoxicillin is a moderate spectrum beta-lactam antibiotic that is bactericidal against streptococci and enterococci. It is preferred over ampicillin due to higher oral bioavailability. Oral administration results in a peak concentration in 1–2 h. The pediatric dosage is 50 mg/kg, with a maximum of 2 g. If the patient cannot take oral medications, parenteral administration of 2 g amoxicillin or ampicillin is considered an alternative.
Oral cephalexin or equivalent first- or second-generation cephalosporin or parenteral cefazolin or ceftriaxone are second-line alternatives.
Clindamycin 600 mg administered 30–60 min before the procedure is the drug of choice in penicillin-hypersensitive patients. It is not clear whether increasing antibiotic resistance rates in viridans streptococci will impact the choice of antibiotics in the future. The resistance of oral microorganisms to clindamycin is especially pronounced, and this should be considered when prescribing clindamycin to penicillin-hypersensitive patients. Currently, ESC guidelines recommend clindamycin as the only alternative in penicillin-allergic patients. On the other hand, the AHA guideline also recommends macrolides 500 mg of azithromycin or clarithromycin (15 mg/kg for children) as alternatives in the penicillin-hypersensitive group.
The antibiotics are administered 30–60 min before the procedures to ensure the antibacterial activity of the antibiotic is present from the beginning of the procedure. If the prophylaxis is inadvertently not administered in this time frame, it can be given within 2 h of the procedure. If the treatment will be done in several sessions, prophylaxis should be repeated at each session. It is advisable to limit the number of sessions as much as possible.
In patients who are already taking antibiotics, an antibiotic drug from a different class should be chosen. Alternatively, the procedure could be delayed for 10 days or more to restore the oral flora [ , ].
Cardiac implantable electronic device insertion
The most prevalent microorganisms causing CIED endocarditis are staphylococci. Antibiotic prophylaxis before CIED insertion should be done with an antistaphylococcal agent. Methicillin-susceptible species could easily be covered by a single dose of cefazolin given before the implantation. Cefazolin prophylaxis has been shown to reduce CIED infections significantly [ ]. Methicillin resistance is common in nosocomial staphylococcal infections. Institutions have different rates of methicillin resistance. Vancomycin 1–1.5 g (15 mg/kg) given as a slow infusion is the drug of choice when methicillin resistance is anticipated, or the patient is hypersensitive to penicillins [ ]. British Society of Antimicrobial Chemotherapy guidelines prefer glycopeptide teicoplanin with or without gentamycin over other antibiotics [ ]. Teicoplanin can be administered as 800 mg bolus within 60 min before the implantation.
Use of a minocycline and rifampin eluting mesh envelope during high-risk CIED implantations was associated with a lower incidence of CIED infections [ ] and is recommended by the recent guidelines for the high-risk population of patients undergoing pocket or lead revision, generator replacement, system upgrade, or an initial CRT-D implantation [ ]. Local instillation of antibiotics or antiseptics is not recommended due to a lack of benefit.
Transcatheter aortic valve implantation
Most patients undergoing TAVI are given first- or second-generation cephalosporins for prophylaxis. Cephalosporins could be effective in preventing methicillin-susceptible staphylococcal infections. However, data from the Swiss TAVI registry and a recent systematic review have shown that enterococci are becoming the most common microorganisms causing IE early after TAVI [ , ]. Therefore the prophylactic antibiotics should cover enterococci as well as staphylococci. Enterococci are intrinsically resistant to cephalosporins. Antimicrobial susceptibility testing revealed endocarditis prophylaxis was ineffective in 47.9% of patients who developed post-TAVI endocarditis mainly due to high rates of enterococcal infections [ ]. Ampicillin resistance in enterococci generally is not a significant problem. Amoxicillin/clavulanic acid, ampicillin/sulbactam, or vancomycin in patients allergic to penicillin may be preferred over cephalosporins to cover for enterococci.
Table 6.3 summarizes recommended antibiotic prophylaxis regimens for specific situations [ ].
