By Brian K. Yorkgitis, PA-C

Editor's Note

ADVANCE for Physician Assistants and the Eugene Applebaum College of Pharmacy and Health Sciences, and Wayne State University School of Medicine, are pleased to offer this continuing education opportunity.

The Wayne State University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Wayne State University School of Medicine designates this educational activity for a maximum of one AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

To receive 1 hour of AMA PRA Category 1 CME credit, read this article and follow the directions on the answer form at the end of the article.

Learning Objectives

1. Review the pathogenesis of infective endocarditis.

2. Review the epidemiology of infective endocarditis.

3. Explain the role and risk of antibiotic prophylaxis for infective endocarditis.

4. Discuss the recommendations of the 2007 American Heart Association guidelines for prevention of infective endocarditis.

Disclosure of Conflict of Interest

The author(s) have indicated no relationships to disclose related to the contents of this article.

The CME coordinator for ADVANCE for Physician Assistants, John McGinnity, MS, PA-C, discloses receiving honoraria from Novartis and Omron Healthcare and that he is on the speakers' bureau for Pfizer.

For more than 50 years, the American Heart Association (AHA) has made recommendations for the prevention of infective endocarditis (IE), a life-threatening infection. Until recently, the rationale for prophylaxis was based heavily on expert opinion. However, the latest guidelines, released in April 2007, acknowledge that recommendations for IE prophylaxis must be evidence-based.

Prophylaxis for IE can be confusing for patients and health care providers alike, and the 2007 prevention recommendations provide more concise guidelines for clinical practice. The document recommends that only the individuals with the highest risk of complications receive antimicrobial prophylaxis.¹

Pathogenesis

IE is caused by infected vegetations that occur on previously damaged or congenitally distorted valvular tissue.² Additionally, IE can affect the chordae, chamber walls, paraprosthetic tissue, implanted shunts, conduits and fistulas.³ Approximately 70% of patients with IE have cardiac abnormalities, including rheumatic valvular disease and degenerative valvular conditions.⁴ Common cardiac abnormalities that place a person at risk for IE include previous endocarditis, prosthetic heart valves, valvular stenosis, ventricular septal defect and valvular damage secondary to rheumatic fever.² In the past, rheumatic heart disease (RHD) had been the most common predisposing factor to endocarditis; with the reduced incidence of RHD in developed nations, mitral valve prolapse now is the most common underlying condition.¹

The pathogenesis of IE results from interaction between matrix molecules and platelets at the sites of endocardial damage and pathogens in the bloodstream.¹ Injury to the endothelium is influenced by aberrant intracardiac flow. This injury occurs where a high-velocity jet directly impacts the endothelium. Additionally, areas of increased shear stress secondary to flow across a narrowed orifice or flow from a high-pressure cavity to a low-pressure cavity can result in endothelial injury.³ The aberrant flow predisposes deposition of platelets and fibrin on the surface of the endothelium. The material deposition results in the formation of nonbacterial thrombotic endocarditis (NBTE).¹ The Venturi effect causes pathogens to be deposited at the low-pressure sink, just beyond an orifice, or at the site where the jet stream directly strikes the surface.³ Pathogenic bacteria in the bloodstream adhere to areas of NBTE and proliferate within a vegetation. Microbial adherence to vegetations stimulates additional deposition of platelets and fibrin to the endothelial surface.¹

The bacteria are derived commonly from mucosal surfaces populated by dense endogenous microflora. Studies suggest that more than 700 identified species of bacteria can be present in the human mouth. Commonly, the pathogenic microflora is of the viridans group streptococci species, which accounts for at least 50% of community-acquired native-valve IE in non-intravenous drug users.⁵ Anaerobic microorganisms are commonly the causative agent for periodontal disease and frequently cause transient bacteremia but rarely cause endocarditis. Trauma to the mucosa, particularly gingival crevices around the teeth, the oropharynx, the gastrointestinal (GI) tract, the urethra and the vagina, release the microbes into the bloodstream transiently. This transient bacteremia can occur through activities of daily living (ADLs) such as chewing food, brushing teeth, flossing, using a toothpick or through procedures to the mucosal surfaces.¹

One study showed a cumulative exposure of an estimated 5,370 minutes of bacteremia over a one-month period in dentulous patients from chewing food and daily oral hygiene. This exposure time is much longer than the six to 30 minutes of bacteremia associated with single tooth extraction.⁶ The cumulative exposure during a single year from ADLs may be as high as 5.6 million times greater than the bacteremia from a single tooth extraction.⁷ Thus, it is likely that the frequency and cumulative duration of exposure to bacteremia resulting from ADLs are much higher than those from procedures.

Recent studies have shown that procedures may cause only a small number of cases of IE. Therefore, prophylaxis for these patients would prevent few cases, even assuming that the regimens were 100% effective at eliminating the risk of IE. In some cases of IE, prophylaxis had been given, indicating that prophylaxis was not 100% effective. It is difficult to determine with certainty whether the transient bacteremia from a procedure caused the IE or whether it was a result of bacteremia stemming from ADLs.¹

A variety of respiratory tract procedures reportedly have caused transient bacteremia with a wide variety of organisms. To date, no published data have conclusively linked these procedures and IE. The GI and genitourinary (GU) tracts have various normal microflora; enterococci are the most likely of these organisms to cause IE.¹

Epidemiology

IE is a major cause of morbidity and mortality, with 10,000 to 20,000 newly diagnosed cases in the United States each year. Even with advances in medical and surgical therapy, approximately 15% to 20% of patients with IE die during their initial hospitalization. Additionally, nonfatal complications of IE include stroke, heart failure and the need for valvular replacement.⁴

Risks

There are risks associated with prophylaxis. Nonfatal adverse reactions include rash, diarrhea and GI upset. Fatal anaphylactic reactions are estimated to occur in 15 to 25 individuals per 1 million patients receiving a single dose of penicillin, and one case per 1 million for cephalosporin. Widespread antibiotic use promotes emergence of resistant organisms. The frequency of multidrug-resistant viridans group streptococci and enterococci has increased dramatically over the past 20 years. The induced resistance has reduced the efficacy of and the number of antibiotics useful in the treatment and prophylaxis of IE.¹

Recommendations

Given the questionable efficacy, risk and benefit of prophylaxis, the AHA has changed its recommendations for prophylaxis. Only cardiac conditions with the highest risk of adverse outcome from endocarditis should receive prophylaxis. Those patients (Figure 1) include prosthetic cardiac valve, previous IE and cardiac transplantation patients who develop cardiac valvulopathy. Additionally, congenital heart disease (CHD), including unrepaired cyanotic CHD, repaired CHD with prosthetic material/device (during the first six months postoperatively), repaired CHD with residual defect at the site or adjacent to the site of repair with patch or prosthetic device.¹

The 2007 AHA guidelines for IE prophylaxis for dental procedures include patients with the above conditions who are undergoing a procedure that involves the manipulation of gingival tissue or the periapical region of the teeth or perforation of the oral mucosa. This does not include anesthetic injections through noninfective tissue, placement of orthodontic appliances including brackets, placement of removable prosthetics or orthodontic appliances and bleeding from trauma to the lips or oral mucosa.¹

The recommended agents (Figure 2) include amoxicillin 2 g in adults who are able to take oral therapy. In pediatric patients, 50 mg/kg of amoxicillin is recommended. In adult patients unable to take oral therapy, ampicillin 2 g IV or IM or cefazolin or ceftriaxone 1 g IV or IM may be given. In pediatric patients, the dose for ampicillin, cefazolin or ceftriaxone is 50 mg/kg IM or IV. If the adult patent is intolerant to penicillins or ampicillin, cephalexin 2 g orally or 50 mg/kg in children, clindamycin 600 mg or 20 mg/kg in children orally, IM or IV, or azithromycin or clarithromycin each 500 mg or 15 mg/kg in children orally can be used as alternatives.¹

The guidelines for respiratory tract procedures for patients with the conditions in Figure 1 receive appropriate prophylaxis from Figure 2 for procedures that involve incision of the respiratory tract mucosa. In patients who undergo invasive respiratory tract procedures to treat an established infection, the antibiotic regimen to the patients previously listed (Figure 1) must contain an active agent against viridans group streptococci. If the infectious agent is Staphylococcus aureus, an anti-staphylococcal penicillin or cephalosporin should be used. Vancomycin may be used if the patient has intolerance to beta-lactams or is suspected to have methicillin-resistant S. aureus (MRSA).¹

Prophylaxis for GI and GU procedures solely for prevention of IE is not recommended. It may be reasonable for patients to receive an antibiotic regimen that includes an agent active against enterococci if the patients have established infections of the GI or GU tract with conditions listed in Figure 1. However, no published studies demonstrate this therapy would prevent enterococcal IE. If the patient with an established infection is to undergo an elective procedure that calls for manipulation of the urinary tract, antimicrobial therapy to eradicate enterococci from the urine prior to the procedure is reasonable. If the procedure is not elective, empiric antimicrobials may be warranted against enterococci. Amoxicillin or ampicillin is the preferred agent (Figure 2). Vancomycin may be used if the patient is intolerant of beta-lactam antibiotics.¹

Procedures on infected skin, soft tissue and musculoskeletal tissue often are polymicrobial. Of the common microbes, staphylococci and beta-hemolytic streptococci are the most pathogenic for IE. If a patient with the previously listed conditions (Figure 1) is to undergo a procedure that involves infected skin, soft tissue or musculoskeletal tissue, it is reasonable that the antimicrobial therapy contain activity against staphylococci and beta-hemolytic streptococci. These agents are anti-staphylococcal penicillin or cephalosporin. Vancomycin or clindamycin may be used if the patient is suspected to have MRSA or is intolerant to beta-lactams (Figure 2).¹

Cardiac surgery patients are recommended to undergo preoperative dental evaluation when possible. This may decrease the incidence of late valvular endocarditis by viridans streptococci. Additionally, perioperative prophylactic antibiotics are recommended for patients undergoing placement of prosthetic valves or placement of prosthetic intravascular or intracardiac materials. Prophylaxis should be given immediately prior to the procedure and repeated during prolonged procedures to maintain serum concentration intraoperatively. They should not be continued for more than 48 hours after the procedure's conclusion to minimize emergence of resistance.¹

If a patient is receiving antimicrobial therapy with an agent that is also recommended for IE prophylaxis, it is prudent to select an antibiotic from a different class rather than increase the dose of the current treatment.1 This helps protect against organisms that may have developed resistance to the previous medications.

Intramuscular injections for IE prophylaxis should be avoided in patients receiving anticoagulation treatment due to the risk of bleeding at the injection site. Oral antibiotics should be given whenever feasible. Intravenous antibiotics should be given to patients who are unable to tolerate or absorb oral therapy.¹

The above therapies should be given to the high-risk patients previously identified in Figure 1 approximately 30 to 60 minutes prior to the procedure. If the antibiotic dose is inadvertently not given prior to the onset of the procedure, the therapy may be administered up to two hours after the procedure.¹

It is important to remember that there is cross-reactivity in patients allergic to penicillins to other beta-lactams, including cephalosporins. The frequency of cross-allergenicity is approximately 1% to 8%.⁸ In these patients, the non-beta-lactam therapies should be used.

Highest Risk, Greatest Benefit

The recommendations set forth by the AHA in the 2007 guidelines are a paradigm shift from the previous recommendations. The guidelines may present difficulty to the health care provider and the patient, given the long history of more stringent guidelines for the prophylaxis of IE.

It is important to understand that the risk of IE is present daily through regular activities for which we do not offer prophylaxis. Additionally, antimicrobial therapy presents a risk for patients. Thus, those at the highest risk of IE complications are the patients that receive the greatest benefit from prophylactic therapy. Those at low risk for IE may have higher risk of adverse events and propagation of resistant microorganism than the risk of IE resulting from a single procedure.¹

References

1. Wilson W, Taubert KA, Gewitz M, et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group. Prevention of infective endocarditis: guidelines from the American Heart Association. Circulation. 2007;116(15):1736-1754.

2. Oliver R, Roberts GJ, Hooper L. Penicillins for the prophylaxis of bacterial endocarditis in dentistry. Cochrane Database Syst Rev. 2004;(2):CD003813. doi:10.1002/14651858.CD003813.pub2.

3. Lester SJ, Wilansky S. Endocarditis and associated complications. Crit Care Med. 2007;35(8 suppl):S384-S391.

4. Seto TB. The case for infectious endocarditis prophylaxis: time to move forward. Arch Intern Med. 2007;167(4):327-330.

5. Fowler VG Jr, Scheld WM, Bayer AS. Endocarditis and intravascular infections. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:975-1022.

6. Guntheroth WG. How important are dental procedures as a cause of infective endocarditis? Am J Cardiol. 1984;54,(7):797-801.

7. Roberts GJ. Dentists are innocent! "Everyday" bacteremia is the real culprit: a review and assessment of the evidence that dental surgical procedures are the principal cause of bacterial endocarditis in children. Pediatr Cardiol. 1999;20:317-325.

8. Madaan A, Li JT. Cephalosporin allergy. Immunol Allergy Clin North Am. 2004;24(3):463-476.

Brian Yorkgitis is a physician assistant at Abington Emergency Physician Associates in Abington, Pa.