Endocarditis antibiotic prophylaxis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-in-Chief: Cafer Zorkun, M.D., Ph.D. [2];Michael W. Tempelhof, M.D.

ACC/AHA 2008 Guideline Update on Valvular Heart Disease: Focused Update on Infective Endocarditis (DO NOT EDIT)

Class I

1. "Modified recommendation (changed class of recommendation from I to IIa, changed text). There are no Class I recommendations for infective endocarditis prophylaxis."

Class III (Harm)

1. "Prophylaxis against infective endocarditis is not recommended for nondental procedures (such as transesophageal echocardiogram, esophagogastroduodenoscopy, or colonoscopy) in the absence of active infection. (Level of Evidence: B) "

Class IIa

1. "Prophylaxis against infective endocarditis is reasonable for the following patients at highest risk for adverse outcomes from infective endocarditis who undergo dental procedures that involve manipulation of either gingival tissue or the periapical region of teeth or perforation of the oral mucosa4: "

1a. "Patients with prosthetic cardiac valves or prosthetic material used for cardiac valve repair. (Level of Evidence: B) "

1b. "Patients with previous infective endocarditis. (Level of Evidence: B) "

1c. "Patients with CHD. (Level of Evidence: B) "

1d. "Unrepaired cyanotic CHD, including palliative shunts and conduits. (Level of Evidence: B) "

1e. "Completely repaired congenital heart defect repaired with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure. (Level of Evidence: B) "

1f. "Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (both of which inhibit endothelialization). (Level of Evidence: B) "

1g. "Cardiac transplant recipients with valve regurgitation due to a structurally abnormal valve. (Level of Evidence: C) "

ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease (DO NOT EDIT)

Class I

1. "Prophylaxis against infective endocarditis is recommendedfor the following patients:"

1a. "Patients with prosthetic heart valves and patients with a history of infective endocarditis.(Level of Evidence: C)"

1b. "Patients who have complex cyanotic congenital heart disease (e.g., single-ventricle states, transposition of the great arteries, tetralogy of Fallot). (Level of Evidence: C)"

1c. "Patients with surgically constructed systemic pulmonary shunts or conduits. (Level of Evidence: C)"

1d. "Patients with congenital cardiac valve malformations, particularly those with bicuspid aortic valves, and patients with acquired valvular dysfunction (e.g., rheumatic heart disease). (Level of Evidence: C)"

1e. "Patients who have undergone valve repair.(Level of Evidence: C)"

1f. "Patients who have hypertrophic cardiomyopathy when there is latent or resting obstruction.(Level of Evidence: C)"

1g. "Patients with MVP and auscultatory evidence of valvular regurgitation and/or thickened leaflets on echocardiography. (Level of Evidence: C)"

Class III (Harm)

1. "Prophylaxis against infective endocarditis is not recommended for the following patients: "

1a. "Patients with isolated secundum atrial septal defect. (Level of Evidence: C) "

1b. "Patients 6 or more months after successful surgical or percutaneous repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus. (Level of Evidence: C) "

1c. "Patients with MVP without MR or thickened leaflets on echocardiography. (Level of Evidence: C) "

1d. "Patients with physiological, functional, or innocent heart murmurs, including patients with aortic valve sclerosis as defined by focal areas of increased echogenicity and thickening of the leaflets without restriction of motion and a peak velocity less than 2.0 m per second. (Level of Evidence: C) "

1e. "Patients with echocardiographic evidence of physiologic MR in the absence of a murmur and with structurally normal valves. (Level of Evidence: C) "

1f. "Patients with echocardiographic evidence of physiological TR and/or pulmonary regurgitation in the absence of a murmur and with structurally normal valves. (Level of Evidence: C) "

Patients Requiring Antibiotic Prophylaxis Prior to Dental Procedures

The presumed correlation between endodontic induced bacteremia and new onset endocarditis made pre-procedural antibiotic prophylaxis a reasonable practice for the preceding 60 years. However, there is a paucity of evidence in support of providing chemoprophylaxis for effective endocarditis prevention. Chewing, dental hygiene practices, kidney disease, diabetes, and skin colonization present a greater risk of significant bacteremia and greater cumulative endocarditis risk than any single invasive dental procedure. The AHA recommends reducing the incidence of bacteremia with the optimization of oral hygiene in at-risk patients and does not recommend indiscriminant pre-procedural chemoprophylaxis as a safe practice to prevent endocarditis. The AHA acknowledges that even if chemoprophylaxis conferred 100% efficacy, few cases of endocarditis would be prevented as the incidence of endodontic induced endocarditis is so low.

The AHA now recommends the administration of pre-endodontic procedural prophylactic antibiotics to patients with the highest risk of adverse outcomes subsequent to the development of endocarditis:

• Patients with a prosthetic cardiac valve
• Patients with a prior history of infective endocarditis
• Cardiac transplantation recipients who develop cardiac valvulopathy
• Patients with congenital heart disease:

• Patients with unrepaired cyanotic congenital heart disease in which shunts and conduits are present
• Patients who have undergone completely repair of a congential heart defect within the past 6 months
• Patient with repaired congenital heart disease with residual defects at the site of a prosthetic patch or device

The following endodontal procedures require coverage in this high risk population:

• Any type of dental extractions
• Any type of periodontal procedures and gingival surgery
  • Placement of dental implants and avulsed teeth replantation
  • Dental canal or root surgery
  • Antibiotic fibres or strips placement at subgingival area
  • Initial placement of orthodontic brackets
  • Intraligamentous injection of local anesthetic drugs
  • Bleeding during prophylactic cleaning of teeth or implants

Other scenarios that are not dental procedures and for which prophylaxis is not recommended include shedding of deciduous teeth and trauma to the lips and oral mucosa. Routine anesthetic injections through non-infected tissue, the taking of dental radiographs, placement of removable prosthodontic or orthodontic appliances, placement of orthodontic brackets, or adjustment of orthodontic appliances do not require prophylaxis.

In this high risk population, prophylactic antimicrobial therapy should be directed against Streptococcus viridans. Acknowledging an estimated 10-20 fold greater risk of single-dose fatal anaphylaxis with amoxicillin compared to single dose cephalosporin, macrolide and clindamycin regimens, the AHA believes prophylaxis with amoxicillin is a safe practice as there have been no reports of fatal anaphylaxis arising from a single-dose of pre-dental endocarditis prophylaxis using oral amoxicillinwhich is well absorbed in the gastrointestinal tract and provides high and sustained serum concentrations.

For those patients who have an allergy to penicillins or amoxicillin, then the use of cephalexin or another first-generation oral cephalosporin, clindamycin, azithromycin, or clarithromycin is recommended. For those patients who cannot tolerate oral antibiotics, treatment with ampicillin, ceftriaxone, or cefazolin administered either intramuscularly or intravenously is recommended. Finally, for those patients who are ampicillin allergic and who are also unable to take an oral antibiotic, therapy with either parenteral cefazolin, ceftriaxone, or clindamycin is recommended.

A complete list of antibiotics that are acceptable for use as prophylaxis of infective endocarditis include the following:

• Amoxicillin
• Ampicillin
• Cefazolin
• Ceftriaxone
• Cephalexin
• Clindamycin
• Azithromycin
• Clarithromycin

Recommendations Regarding Antibiotic Prophylaxis Prior to Procedures on Infected Skin or Musculoskeletal Tissue

These infections are often polymicrobial, but only staphylococci and beta hemolytic beta-hemolytic streptococci are likely to cause Infective Endocarditis. For patients with high risk conditions who undergo a surgical procedure that involves infected skin, skin structure, or musculoskeletal tissue, it may be reasonable that the therapeutic regimen administered for treatment of the infection contain an agent active against staphylococci and beta-hemolytic streptococci, such as an antistaphylococcal penicillin or a cephalosporin. Vancomycin or clindamycin may be administered to patients unable to tolerate a beta-lactam or who are known or suspected to have an infection caused by a methicillin-resistant staphylococcus aureus.

Antibiotic Prophylaxis For Respiratory Tract Procedures

It is recommended that the same individuals at the highest risk cited in the section on endodontic procedures who require the procedures listed below should receive antibiotic prophylaxis:

• Tonsillectomy
• Adenoidectomy
• Rigid bronchoscopic manipulations
• Respiratory mucosa related surgery
• Invasive respiratory tract procedures to treat an established infection, such as drainage of an abscess or [[empyema]

Although there is no published data conclusively demonstrate a link between these procedures and infective endocarditis, antibiotic prophylaxis is reasonable for these select high risk patients who undergo an invasive procedure of the respiratory tract that involves incision or biopsy of the respiratory mucosa such as those listed above. Bronchoscopy does not usually require antibiotic prophylaxis unless there is incision of the respiratory tract mucosa.

Antibiotic Prophylaxis for Gastrointestinal (GI) and Genitourinary (GU) Procedures

Routine administration of prophylactic antibiotics prior to GI and GU procedures including diagnostic esophagogastroduodenoscopy or colonoscopy is not recommended. However, for the high risk patients listed in the endodontic section who already have an established GI or GU tract infection, it is reasonable to administer antibiotics against enterococci which includes the following: penicillin,ampicillin, piperacillin, or vancomycin. Despite the reasonable nature of this approach, it should be noted that there are no published studies that demonstrate that this approach prevents enterococcal endocarditis. The preferred agents for enterococcal coverage are amoxicillin or ampicillin, and vancomycin can be administered to those patients who cannot tolerateampicillin.

Patients Already Receiving Antibiotics

It is recommended that an antibiotic from another class be administered to those patients who are already on long-term therapy with an antibiotic, such as those patients on antibiotics to prevent recurrent acute rheumatic fever. The chronic antibiotic dose is usually lower than what is required for prevention of endocarditis. Furthermore, these indiividuals oftin are colonized with viridans group streptococci in their oral that are relatively resistant to either penicillin or amoxicillin. In high risk patients, eitherclindamycin, azithromycin, or clarithromycin are recommended for prophylaxis prior to a dental procedure. In so far as there is the potential for cross-resistance among strep viridans groups, cephalosporins, are not recommended. Finally, if possible it is recommended that elective procedures be delayed for 10 days to allow for recolonization with the usual flora.

Antibiotic Prophylaxis in Patients Who are Undergoing Cardiac Surgery

Peri-operative antibiotics are recommended for those patients who are undergoing placement of prosthetic heart valves, prosthetic intravascular devices and intracardiac materials. The basis for this recommendation is the high risk of infection and the morbidity and mortality associated with such a complication.

The most common causative agents in the development of early prosthetic valve endocarditis are S. aureus, coagulase-negative staphylococci, or diphtheroids. Unfortunately there is no single antibiotic that eradicates all three organisms, and the prophylaxis is therefore directed primarily at the staphylococci and not the diptheroids. While it is common to administer a first-generation cephalosporin, consideration should be given to the antibiotic susceptibility patterns at a given hospital. If the hospital has a high incidence of methicillin-resistant Staphylococcus aureus (MRSA), then prophylaxis with vancomycin should be considered. On the other hand, even though most nosocomial coagulase-negative staphylococci are methicillin-resistant, a first-generation cephalosporin is recommended as vancomycin has not been shown to be superior to a cephalosporin. Likewise, if methicillin-resistant S. epidermidis is prevalent at a hospital, prophylaxis with vancomycin is reasonable.

Prophylaxis should be administered immediately before surgery. In so far as renal function and extracorporeal circulation may alter drug concentrations, antibiotic concentrations should be monitored during and after the procedure. In order to prevent the emergence of resistant organisms, antibiotic therapy should be continued for only 48 hours.

Basis for AHA Recommendations Regarding Antibiotic Prophylaxis for Dental Procedures

Endodontic procedures have been associated with a high incidence of bacteremia since the 1920s. Therefore, dental procedures were implicated as an independent risk factor for the development of bacterial endocarditis. However, only 4%-7.5% of all bacterial endocarditis cases are related to endodontic associated bacteremia. In 1955, the American Heart Association (AHA) published the first of ten subsequent endocarditis prevention guidelines. The most recent, 2007 guidelines underwent changes intended to clarify patient eligibility criteria for receiving endocarditis prophylaxis. Major changes include:

• Bacteremias associated with daily activities (which are frequent) are considered more likely to cause endocarditis than are endodontic-procedural induced bacteremias.
• Optimal oral hygiene is emphasized as an important practice to prevent endocarditis.
• A patient’s lifetime risk of endocarditis is no longer a consideration for initiating prophylactic antibiotic therapy.
• The AHA now recommends the administration of single-dose prophylactic antibiotics prior to endodontic procedure only to patients with cardiac conditions associated with the highest risk of adverse outcomes following the acquisition of bacterial endocarditis (see the list above).

The Risk of Endocarditis Following Endodontic Procedures

Based in the findings below, the AHA has concluded that the cumulative background bacteremia associated with chewing, daily dental hygiene practices, kidney disease, diabetes, and skin colonization present a greater risk of significant bacteremia than any single invasive dental procedure.

• Following dental intervention, the absolute risk for developing endocarditis is estimated at 1 case per 14 million dental procedures.
• The risk of endocarditis following an endodontic induced bacteremia in high risk patients is as follows:

• Congenital heart disease: 1 per 475,000
• Rheumatic heart disease: 1 per 142,000;
• Patients with a prosthetic heart valve, 1 per 114,000
• Patients with previous endocarditis: 1 per 95,000 dental procedures.

• Inocula of 1 x 108 (100 million) colony forming units [cfu]/mL or greater are required to consistently induce experimental endocarditis.
  • Recent human quantitative blood culture data support the implication that endodontic associated bacteremia inocula are of insufficient magnitude to induce endocarditis. Bacteremia intensities immediately following invasive human dental procedures are 1.5 cfu/ml-5.9 cfu/ml, 10 fold less then necessary to induce endocarditis in animal models.

• The most recent case-control study of 104 patients with known, high-risk structural heart disease discovered that patients who developed endocarditis were actually less likely to have experienced an endodontic procedure within the 180 days prior to diagnosis of endocarditis than did control patients who did not develop endocarditis (OR 0.2 [95% CI 0.04-0.7]).

• Among high-risk patients with underlying structural heart disease, kidney disease (OR 16.9 [95% CI 1.5-193.0]), diabetes (OR 2.7 [95% CI 1.4-5.2]) and skin flora infection (OR 3.5 [95% CI 0.7-17.0]) were associated with a greater risk for the development of bacterial endocarditis.

• Daily activities such as chewing and oral hygiene practices result in bacteremias more frequently, of longer duration and of greater magnitude in comparison to high-risk endodontic procedures.

The Efficacy of Prophylactic Antibiotic

• The efficacy of antibiotic regimens for endocarditis prophylaxis has never been assessed under the scrutiny of a randomized controlled trial.
• Evidence supporting pre-endodontic chemoprophylaxis efficacy is extrapolated from data demonstrating reductions in bacteremia magnitudes immediately following the administration of antibiotics.
• The Cochran Collaboration assessed whether prophylactic administration of penicillin to moderate- to high-risk patients prior to endodontic intervention conferred a mortality, serious illness or endocarditis incidence benefit. The pooled, adjusted Odds Ratio across all studies for the development of IE among patients receiving prophylaxis was non-significant (0.56 [95% CI (0.15-2.15)]). The Cochrane Collaboration concluded that it is unclear whether antibiotic prophylaxis is effective and there is a lack of evidence to support published guidelines using penicillin as chemoprophylaxis for IE.
• To date, only 4 case-control studies have assessed antibiotic efficacy for endocarditis prevention.

1. Strom et al discovered the administration pre-endodontic procedural antibiotics did not provide a protective benefit against the development of IE (OR 0.5 [CI .01-9.6]).
2. Van Der Meer et al,8/48 case patients (16%) received antibiotics while 26/200 of control patients (13%) received antibiotics. Stratified Odds Ratio: 0.51 (0.11-2.29).Protective Efficacy 49%.
3. Lacassin et al6/37 case patients (23%) received antibiotics while 6/33 control patients (27%) received antibiotics. Matched and Adjusted Odds Ratio: 0.2 (0-0.8) Protective Efficacy 20%.
4. Imperiale et al 1/8 case pts (13%) received antibiotics.15/24 control patients (63%) received antibiotics. Matched Odds Ratio: .09 (CI upper limit of 0.93) (p=.025). Protective Efficacy 91%.

Safety Concerns with Antibiotic Prophylaxis

Adverse reactions associated with the administration of beta-lactam antibiotics are common.

• The adverse events range in severity from purititus to fatal anaphylactic shock, the frequency of all adverse reactions from the administration of penicillin to the general population is 0.7% to 10%.
• Fatal anaphylaxis among patients receiving single-dose penicillin, ampillicin or amoxicillin therapy is approximately 20 cases per 1 million patients treated.
• Single-dose, cephalosporin-associated fatal anaphylaxis risk is estimated at 0.5-5.7 cases per 10 million patients treated.
• Macrolide and clindamycin single-dose fatal anaphylaxis risk is estimated at 0-5 cases per 1 million patients treated.
• The risk of mortality associated with the single-dose administration of beta-lactam antibiotics for IE prophylaxis is estimated at 1-3 anaphylactic deaths per 1 million patients treated.
• According to the AHA, single dose administration of a beta-lactam antibiotic for IE prophylactic therapy is a safe practice as it has never resulted in a reportable case of fatal anaphylaxis.

Cost Effectiveness of Oral Antibiotic Prophylaxis

To date, one report has addressed the cost-effectiveness of providing chemoprophylaxis to patients of moderate- and high-risk of IE acquisition prior to endodontic procedure.

• The risk of drug-induced anaphylaxis and associated loss of QALYs with prophylactic oral amoxicillin or ampicillin to moderate-risk patients rendered this practice ineffective and therefore the authors did not complete a cost-effectiveness analysis.
• The estimated cost-effectiveness ratio for the prophylaxis of 10 million moderate-risk patients with clarithromycin, clindamycin or cephalexin, was $88,007, $101,142 and $99,373 per QALY saved, respectively.
• Cost-effectiveness ratio for the use of clarithromycin in patients with the prior diagnosis of endocarditis was $40,334, and in patients with prosthetic valves, $16,818 per QALY saved.
• Cost-effectiveness ratio of treating 10 million high-risk patients administered single dose clindamycin was $46,678 (prior endocarditis) and $19,936 (prosthetic valve) per QALY saved. #Cephalexin was associated with a cost-effectiveness of $37,916 per QALY saved in patients with a history of IE and $14,060 per QALY saved, in patients with a prosthetic valves.
• The cost-effective analyses suggest that the 2007 AHA IE prevention guidelines advocating chemoprophylaxis to patients with a high-risk of adverse outcomes upon acquisition of IE is a reasonable, cost-effective practice.