How to achieve infective endocarditis prophylaxis

Introduction

Infective endocarditis is a rare condition; however, the high mortality and morbidity rates, as well as the difficulty of treatment, mandate preventive measures. Earlier guidelines recommended antibiotic prophylaxis in patients with underlying cardiac conditions at moderate or high risk of infective endocarditis undergoing a wide range of invasive procedures that might cause bacteraemia, including (but not limited to) invasive dental procedures [1,2].

Over the last 10 to 15 years, the approach of recommending antibiotic prophylaxis for invasive dental procedures has been put in question as patients experience a higher burden of recurrent bacteraemia in their everyday dental and buccal activities such as brushing, flossing, and chewing than they do during sporadic dental interventions. The patients with poor oral hygiene are more prone to bacteraemia during daily activities [3].

The low incidence of the disease makes it almost impossible to conduct an adequately powered prospective randomised controlled trial investigating the efficacy of prophylactic antibiotics in preventing infective endocarditis. The data about prophylaxis are mainly derived from studies where bacteraemia is regarded as a surrogate for endocarditis. In the absence of randomised controlled trials and other high-quality data favouring the routine use of antibiotic prophylaxis, there has been a paradigm shift in major society guidelines.

The European Society of Cardiology (ESC) [4] and American Heart Association (AHA) [5] guidelines have each restricted prophylactic antibiotics to those patients with the highest risk of adverse outcomes. The National Institute for Health and Clinical Excellence (NICE) guidelines went one step further and advised against prophylactic antibiotics totally [6].

High-risk individuals to whom antibiotic prophylaxis should be provided are as follows [4,5]:

• Patients with prosthetic valves (including transcatheter valves) and patients who have undergone valve repair in whom a prosthetic material is used.
• Patients with a history of previous infective endocarditis.
• Patients with cyanotic congenital heart defects.
• Patients for the first six months after surgical or percutaneous repair of a congenital heart disease with a prosthetic material (indefinitely in case of residual shunt or valvular regurgitation).

ESC guidelines differ from AHA guidelines as the latter recommend prophylaxis in cardiac transplant recipients who develop cardiac valvulopathy.

The guidelines define the high-risk individuals as those who are likely to suffer from a poor outcome rather than the cumulative risk of endocarditis. Recent epidemiological data have been in agreement that the highest odds of developing endocarditis or dying from endocarditis in five years were in those with previous infective endocarditis, prosthetic or repaired valves, congenital heart disease treated with a palliative shunt or conduit, and cyanotic congenital heart disease. However, the data also showed that the odds of developing or dying from endocarditis were significantly high in certain intermediate-risk conditions such as rheumatic valve disease and congenital valve anomalies, comparable to several high-risk conditions, and even higher than in those with congenital defects repaired with prosthetic material, even in the first six months [7].

Time trend studies after the introduction of these guidelines and case cohort studies of contradictory results have kept the debate alive for more than a decade after their first introduction. Meanwhile, endocarditis in the elderly and cases related to healthcare have been increasing with a shift in causative microorganisms to staphylococci [8,9]. The most important steps in endocarditis prevention remain educating patients to maintain good oral and cutaneous hygiene, as well as adhering strictly to sterile techniques during invasive procedures in the healthcare setting.

Risks related to antibiotic prophylaxis

Major drawbacks that led to restriction of routine antibiotic prophylaxis were emerging antibiotic resistance, potential adverse drug reactions, and the costs of treating a large population to prevent a single case of endocarditis. Prophylactic antibiotics were associated with an increase in antibiotic resistance, especially when administered repeatedly. No fatal reactions related to 3-gram amoxicillin prescriptions were reported in England between 2004 and 2014; there were 22.62 non-fatal reactions/million prescriptions. Six hundred (600) mg clindamycin caused 13 fatal and 149 non-fatal reactions/million prescriptions, mostly related to super infections with clostridium difficile [10].

A recent case-crossover study has shown that a variety of invasive procedures preceded endocarditis, and 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 [11]. 

Cost-effectiveness of antibiotic prophylaxis

Although the cost of administering a single dose of prophylactic antibiotic to a single person is not high, the cumulative number of prescriptions in the community could lead to a high economic burden. A study from the USA reported that antibiotic prophylaxis before dental procedures in a patient population thought to be at risk of distant site infections could cost up to $145 million per year [12]. In a cost-effectiveness study after the NICE guidelines, antibiotic prophylaxis for those at intermediate or high risk of endocarditis when compared to no antibiotics was estimated to save £2.47 per patient with amoxicillin and £3.65 with clindamycin. In the higher-risk group, the savings are nearly £40 per patient. This would lead to a cumulative saving of between £5.5-8.2 million with gains of 2,687 quality-adjusted life years annually [13]. The recommendation for administration of prophylactic antibiotics to a high-risk population seems reasonable. 

Antibiotic regimens for infective endocarditis prophylaxis

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 [4,5]. Australian guidelines have provided a list of dental procedures that are likely to cause a high incidence of bacteraemia that always require prophylaxis. These areas follows [14]:

• Tooth extraction.
• Periodontal surgery, subgingival scaling and root planning.
• Replantation of avulsed teeth.
• Other surgical procedures such as implant placement or apicoectomy.

Procedures that cause a moderate incidence of bacteraemia might be considered for prophylaxis if multiple procedures are being conducted, in cases where the procedure is prolonged, or in the setting of periodontal disease.

Antibiotic prophylaxis is not recommended for procedures with a low possibility of bacteraemia such as:

• Local anaesthetic injections.
• Dental X-rays.
• Treatment of superficial caries.
• Orthodontic appliance placement and adjustment.
• Following shedding of deciduous teeth.
• After lip or oral trauma.

The prophylactic antibiotic should be effective against viridans group streptococci. The guidelines recommend 2 grams of amoxicillin given orally as a single dose 30-60 minutes before the procedure as the drug of choice for infective endocarditis prophylaxis. Amoxicillin has been shown to be effective in reducing bacteraemia related to dental procedures [15]. Amoxicillin is a semisynthetic aminopenicillin, which can be inactivated by beta-lactamases. It has bactericidal activity against streptococci and enterococci. It reaches peak concentrations within one to two hours of oral administration, it has a short half-life of 1.5 hours, but therapeutic levels are maintained for nearly six hours. It has high oral bioavailability. The usual paediatric dosage is 50 mg/kg, with a maximum up to 2 gr. If the patient is unable to take oral medications, parenteral administration of 2 gr amoxicillin or ampicillin is considered as an alternative.

Oral or parenteral administration of cephalexin 2 gr for adults or 50 mg/kg for children, or parenteral administration of cefazolin or ceftriaxone 1 gr i.m./i.v. for adults or 50 mg/kg i.m./i.v for children are other alternatives. Cephalexin can be replaced by another first- or second-generation oral cephalosporin of equivalent dosage.

In patients hypersensitive to penicillin, guidelines are in agreement that the alternative drug of choice is clindamycin 600 mg (15-20 mg/kg up to 600 mg for children). It can be administered orally or intravenously 30-60 minutes before the procedure. Clindamycin is a bacteriostatic protein synthesis inhibitor. Peak serum concentrations are achieved within 45 to 60 minutes after oral administration. Clindamycin is effective against streptococci and methicillin-sensitive staphylococci. However, some studies have questioned the potency of clindamycin prophylaxis [15]. While ESC guidelines recommend solely clindamycin in penicillin-allergic patients, the AHA and Australian guidelines provide a variety of alternatives in this group of patients. The AHA guidelines recommend macrolides, 500 mg of azithromycin or clarithromycin (15 mg/kg for children). The Australian guidelines recommend glycopeptides; however, the ESC guidelines do not recommend glycopeptides and fluoroquinolones due to the lack of evidence on their efficacy. Cephalosporins should be refrained from use in patients who have encountered anaphylaxis, angioedema or urticaria related to penicillins.

It is important to administer prophylaxis before the procedure so that minimal inhibitory concentrations of the drugs will be present from the beginning of the procedure. If the patient cannot receive a prophylactic antibiotic before the procedure, it can be administered up to two hours after the procedure; however, delay in the treatment might lead to increased bacteraemia. If the patient needs multiple interventions, prophylaxis should be repeated with each. It is advised to finish necessary interventions in one or two sessions if possible. Given that consecutive exposures to the same antibiotic increase resistance rates, the healthcare provider might opt to choose different antibiotics for subsequent sessions. These might be the second-line alternative therapies mentioned in the guidelines or administering the patient a combination beta lactamase inhibitor such as amoxicillin-clavulanate or sulbactam-ampicillin [16]. If the patient is already on antibiotic therapy with penicillins, the operation could be delayed until after the cessation of the antibiotic and restoration of the oral flora. If this is not possible, an alternative group of antibiotics could be preferred.

Non-dental, non-cardiac invasive procedures

ESC guidelines recommend against routine prophylaxis for infective endocarditis during respiratory tract, gastrointestinal, genitourinary, dermatological or musculoskeletal procedures unless performed at an infected or colonised 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 not known, the empirical prophylaxis should cover the most commonly encountered pathogens in that site. The decision to administer prophylaxis for surgical site infections should be made independently according to relevant guidelines.

For respiratory procedures that involve infected tissue, anti-staphylococcal penicillins or first- or second-generation cephalosporins such as oral cephalexin 2 gr (50 mg/kg for children up to a maximum of 2 gr) or i.v. cefazolin 1 gr, can be administered 30-60 minutes before the procedure. Clindamycin can be an alternative drug against staphylococci.

Gastrointestinal and genitourinary procedures have a higher risk of enterococci and other gram-negative bacilli. However, gram-negative bacilli rarely cause endocarditis. Asymptomatic urinary colonisations should be treated before surgery. If the procedures are urgent or involve infected tissue, the antibiotic of choice should be effective against enterococci. Amoxicillin and ampicillin are the drugs of choice; vancomycin can be administered to penicillin-hypersensitive patients.

If infection involves the skin or subcutaneous tissue, staphylococcus aureus (methicillin-susceptible or methicillin-resistant), beta haemolytic streptococci or coagulase-negative staphylococci could be the pathogens. Vancomycin 15 mg/kg (1-1.5 gr) given as a slow infusion of 1 hour before the procedure is the drug of choice for the prevention of methicillin-resistant s.aureus or pathogenic s. epidermidis [17]. 

Cardiac implantable device infection prophylaxis

The expanding population who are candidates for cardiac implantable device therapies has led to an increase in cardiac implantable device infections.

Device-related infective endocarditis (involving the lead and/or the tricuspid valve) is a part of the spectrum of cardiac implantable device infections and can occur in patients without other cardiac abnormalities. Staphylococci, both s.aureus and coagulase-negative staphylococci, are the most prevalent microorganisms involved[ 18]. Rates of methicillin resistance might differ between institutions. In a large randomised placebo-controlled trial, a single dose of cefazolin 1 gr i.v. immediately before the procedure as prophylaxis significantly reduced device-related infections [19]. Cefazolin 1 gr i.v. within 60 minutes of device implantation seems reasonable as the drug of choice where methicillin resistance is not widespread. Vancomycin given as a slow infusion (1gr/hour) could be preferred in institutions where methicillin resistance could be a problem, or the patient is known to be colonised with methicillin-resistant staphylococci. Vancomycin can also be administered in case of penicillin hypersensitivity. British guidelines for the diagnosis, prevention and management of intracardiac device infection prefer glycopeptides over cephalosporins as first-line antibiotics[20].

Table 1. Summary of antibiotic use in endocarditis prophylaxis.

Adapted with permission from [8].

* Vancomycin should be given as a slow infusion 1 gr/hr dose. Initiate infusion 60-90 minutes before the procedure.

Conclusions

Infective endocarditis is rare but has a high mortality rate. Guidelines have not been in complete agreement about antibiotic prophylaxis in the prevention of endocarditis. Controversies regarding prophylactic antibiotic use for prevention have not ceased over the last decade. Providing prophylaxis to individuals at high risk of adverse outcomes undergoing high-risk procedures seems efficient and cost-effective.