Infective Endocarditis

Outline
Introduction Classification Signs and Symptoms Cause Pathogenesis Diagnosis Echocardiography Modified Duke Criteria Micro-organisms Responsible Treatment Dental Prophylaxis References

A mitral valve vegetation caused by bacterial endocarditis

Introduction
Infective endocarditis is a form of endocarditis, or inflammation, of the inner tissue of the heart, such as its valves, caused by infectious agents. The agents are usually bacterial, but other organisms can also be responsible. The valves of the heart do not receive any dedicated blood supply. As a result, defensive immune mechanisms (such as white blood cells) cannot directly reach the valves via the bloodstream. If an organism (such as bacteria) attaches to a valve surface and forms a vegetation, the host immune response is blunted. The lack of blood supply to the valves also has implications on treatment, since drugs also have difficulty reaching the infected valve. Normally, blood flows smoothly through these valves. If they have been damaged - from rheumatic fever, for example - the risk of bacterial attachment is increased. Fortunately, preventing IE is simple. Maintain good dental hygiene. Brushing, flossing, and visiting your dentist regularly prevents tooth and gum infections that could lead to endocarditis.

Classification
1-By duration Historically, infective endocarditis has been clinically divided into acute and subacute presentations (because untreated patients tended to live longer with the subacute as opposed to the acute form). This classifies both the rate of progression and severity of disease. Subacute bacterial endocarditis (SBE) is often due to streptococci of low virulence and mild to moderate illness which progresses slowly over weeks and months and has low propensity to hematogenously seed extracardiac sites.

Acute bacterial endocarditis (ABE) is a fulminant illness over days to weeks, and is more likely due to Staphylococcus aureus which has much greater virulence, or disease-producing capacity and frequently causes metastatic infection. This classification is now discouraged, because the ascribed associations (in terms of organism and prognosis) were not strong enough to be relied upon clinically. The terms short incubation (meaning less than about six weeks), and long incubation (greater than about six weeks) are preferred.

2-By culture results Infective endocarditis may also be classified as culture-positive or culturenegative. By far the most common cause of a "culture-negative" endocarditis is prior administration of antibiotics. Sometimes micro-organisms can take a longer period of time to grow in the culture media, such organisms are said to be fastidious because they have demanding growth requirements. Some examples include pathogens like Aspergillus species, Brucella species, Coxiella burnetii, Chlamydia species, & HACEK bacteria. Due to delay in growth and identification in these cases, patients may be erroneously classified as "culture-negative" endocarditis. 3-By heart side Endocarditis can also be classified by the side of the heart affected: Patients who inject narcotics or other drugs intravenously may introduce infection which will travel to the right side of the heart classically affecting the tricuspid valve, and most often caused by Streptococcus aureus.

In other patients without a history of intravenous exposure, endocarditis is more frequently left-sided.

4-By infection setting Another form of endocarditis is healthcare associated endocarditis when the infecting organism is believed to be transmitted in a health care setting like hospital, dialysis unit or a residential nursing home. Nosocomial endocarditis is a form of healthcare associated endocarditis in which the infective organism is acquired during stay in a hospital and it is usually secondary to presence of intravenous catheters, Total parenteral nutrition lines, pacemakers, etc. 5-By valve type Finally, the distinction between native-valve endocarditis and prosthetic-valve endocarditis is clinically important. Prosthetic valve endocarditis can be early (< 60 days of valvular surgery), intermediate (60 days to 1 year) or late (> 1 year following valvular surgery). Early prosthetic valve endocarditis is usually due to intraoperative contamination or a postoperative bacterial contamination which is usually nosocomial in nature.

Late prosthetic valve endocarditis is usually due to community acquired microorganisms.

Signs and symptoms
Fever occurs in 97% of people; malaise and endurance fatigue in 90% of people.

A new or changing heart murmur, weight loss, and coughing occurs in 35% of people.

Vascular phenomena: septic embolism (causing thromboembolic problems such as stroke in the parietal lobe of the brain or gangrene of fingers), Janeway lesions (painless hemorrhagic cutaneous lesions on the palms and soles), intracranial hemorrhage, conjunctival hemorrhage, splinter hemorrhages, renal infarcts, and splenic infarcts.

Immunologic phenomena: Glomerulonephritis which allows for blood and albumin to enter the urine, Osler's nodes (painful subcutaneous lesions in the distal fingers), Roth's spots on the retina, positive serum rheumatoid factor

Other signs may include; night sweats, rigors, anemia, splenomegaly

A common mnemonic for the signs and symptoms of endocarditis:

• • • • • • • •

Fever Roth's spots Osler's nodes Murmur Lesions Anemia Splinter hemorrhage (splinter) hemorrhages Emboli

Cause
In a healthy individual, a bacteremia (where bacteria get into the blood stream through a minor cut or wound) would normally be cleared quickly with no adverse consequences. If a heart valve is damaged and covered with a piece of a blood clot, the valve provides a place for the bacteria to attach themselves and an infection can be established. In the past, bacteremia caused by dental procedures (in most cases due to viridans streptococci, which reside in oral cavity), such as a cleaning or extraction of a tooth was thought to be more clinically significant than it actually was. However, it is important that a dentist or a dental hygienist be told of any heart problems before commencing treatment. Antibiotics are administered to patients with certain heart conditions as a precaution, although this practice has changed in the US, with new American Heart Association guidelines released in 2007, and in the UK as of March 2008 due to new NICE guidelines. Everyday tooth brushing and flossing will similarly cause bacteremia. Although there is little evidence to support antibiotic prophylaxis for dental treatment, the current American Heart Association guidelines are highly accepted by clinicians and patients. Other conditions that results in high number of bacteria entering into the bloodstream include Colorectal cancer (mostly Streptococcus bovis), serious urinary tract infections (mostly enterococci), and drug injection (Staphylococcus aureus). With a large number of bacteria, even a normal heart valve may be infected. A more virulent organism (such as Staphylococcus aureus can cause infective endocarditis by infecting even a normal heart valve. Intravenous drug users tend to get their right-sided heart valves infected because the veins that are injected drain into the right side of the heart. In rheumatic heart disease infection occurs on the aortic and the mitral valves, on the left side of the heart. Other factors that increase the risk of developing infective endocarditis are low levels of white blood cells, immunodeficiency or immunosuppression, malignancy, diabetes, and alcohol abuse.

Pathogenesis
As previously mentioned, altered blood flow around the valves contributes to development of endocarditis. The valves may be damaged congenitally, from surgery, by auto-immune mechanisms, or simply as a consequence of old age. The damaged part of a heart valve leads to formation of a local blood clot, a condition known as non-bacterial thrombotic endocarditis (NBTE). Altered blood flow, and thus infective endocarditis, are more likely in high pressure areas. Consequently, ventricular septal defects create more susceptibility than atrial septal defects. Damaged vascular endothelium will also promote platelet and fibrin deposition, upon which bacteria can take hold. Valvular lesions are a major cause of such damage, as are jet lesions resulting from ventricular septal defects or patent ductus arteriosus.

Diagnosis
In general, a patient should fulfill the Duke criteria in order to establish the diagnosis of endocarditis. As the Duke criteria rely heavily on the results of echocardiography, research has addressed when to order an echocardiogram by using signs and symptoms to predict occult endocarditis among patients with intravenous drug abuse and among non drug-abusing patients. Unfortunately, this research is over 20 years old and it is possible that changes in the epidemiology of endocarditis and bacteria such as staphylococci make the following estimates incorrect. Among patients who do not use intravenous drugs and have a fever in the emergency room, there is a less than 5% chance of occult endocarditis. Mellors in 1987 found no cases of endocarditis nor of staphylococcal bacteremia among 135 febrile patients in the emergency room. The upper confidence interval for 0% of 135 is 5%, so for statistical reasons alone, there is up to a 5% chance of endocarditis among these patients. In contrast, Leibovici found that among 113 non-selected adults admitted to the hospital because of fever there were two cases (1.8% with 95%CI: 0% to 7%) of endocarditis. Among patients who do use intravenous drugs and have a fever in the emergency room, there is about a 10% to 15% prevalence of endocarditis. This estimate is not substantially changed by whether the doctor believes the patient has a trivial explanation for their fever. Weisse found that 13% of 121 patients had endocarditis. Marantz also found a prevalence of endocarditis of 13% among such patients in the emergency room with fever. Samet found a 6% incidence among 283 such patients, but after excluding patients with initially apparent major illness to explain the fever (including 11 cases of manifest endocarditis), there was a 7% prevalence of endocarditis.

Among patients with staphylococcal bacteremia (SAB), one study found a 29% prevalence of endocarditis in community-acquired SAB versus 5% in nosocomial SAB. However, only 2% of strains were resistant to methicillin and so these numbers may be low in areas of higher resistance.

Vegetation on the tricuspid valve by echocardiography.Arrow denotes the vegetation.

Echocardiography
The transthoracic echocardiogram has a sensitivity and specificity of approximately 65% and 95% if the echocardiographer believes there is 'probable' or 'almost certain' evidence of endocarditis .

Modified Duke Criteria
Established in 1994 by the Duke Endocarditis Service and revised in 2000, the Duke criteria is a collection of major and minor criteria used to establish a diagnosis of endocarditis. A definite diagnosis of infective endocarditis can be established if the following conditions are fulfilled: two major criteria, one major and three minor criteria, or five minor criteria. Diagnosis of infective endocarditis can only be said to be "possible" if only 1 major and 1 minor criteria are fulfilled or if only 3 minor criteria are fulfilled. Major criteria include: 1. Positive blood culture with typical IE microorganism, defined as one of the following:  Typical microorganism consistent with IE from 2 separate blood cultures, as noted below: Viridans-group streptococci Or Streptococcus bovis including nutritional variant strains  Or HACEK group
 

Or Staphylococcus aureus Or Community-acquired Enterococci, in the absence of a primary focus
 

 Microorganisms consistent with IE from persistently positive blood cultures defined as: Two positive cultures of blood samples drawn >12 hours apart, or  All of 3 or a majority of 4 separate cultures of blood (with first and last sample drawn 1 hour apart)  Coxiella burnetii detected by at least one positive blood culture or antiphase I IgG antibody titer >1:800

2. Evidence of endocardial involvement with positive echocardiogram defined as  Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation  Or Abscess  Or New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Minor criteria include: 1. Predisposing factor: known cardiac lesion, recreational drug injection 2. Fever >38°C 3. Evidence of embolism: arterial emboli, pulmonary infarcts, Janeway lesions, conjunctival hemorrhage 4. Immunological problems: glomerulonephritis, Osler's nodes 5. Positive blood culture (that doesn't meet a major criterion) or serologic evidence of infection with organism consistent with IE but not satisfying major criterion

Micro-organisms Responsible
Many microorganisms can cause infective endocarditis. These are generally isolated by blood culture, where the patient's blood is removed, and any growth is noted and identified. The term bacterial endocarditis (BE) commonly is used, reflecting the fact that most cases of IE are due to bacteria; however, Infective Endocarditis (IE) has become the preferred term.

Bacterial Staphylococcus aureus followed by Streptococci of the viridans group and Coagulase negative Staphylococci are the three most common organisms responsible for infective endocarditis. Other Streptococci and Enterococci are also a frequent cause of infective endocarditis. HACEK group of microorganisms and Fungi are seen less frequently.

Yellow colonies of S. aureus on a blood agar plate, note regions of clearing around colonies caused by lysis of red cells in the agar (beta hemolysis) Viridans Alpha-hemolytic streptococci , that are present in the mouth are the most frequently isolated micro-organisms when the infection is acquired in a community setting. In contrast, Staphylococcus blood stream infections are frequently acquired in a health care setting where they can enter the blood stream through procedures that cause break in the integrity of skin like surgery, catheterisation or during access of long term indwelling catheters or secondary to intravenous injection of recreational drugs. Enterococcus can enter the bloodstream as a consequence of abnormalities in the gastrointestinal or genitourinary tracts. Some organisms, when isolated, give valuable clues to the cause, as they tend to be specific. Pseudomonas species, which are very resilient organisms that thrive in water, may contaminate street drugs that have been contaminated with drinking water. P. aeruginosa can infect a child through foot punctures, and can cause both endocarditis and septic arthritis. • S. bovis and Clostridium septicum, which are part of the natural flora of the bowel, are associated with colonic malignancies. When they present as the causative agent in endocarditis, it usually call for a concomitant colonoscopy due to concerns regarding hematogenous spread of bacteria from the colon due to the neoplasm breaking down the barrier between the gut lumen and the blood vessels which drain the bowel. • HACEK organisms are a group of bacteria that live on the dental gums, and can be seen with IV drug users who contaminate their needles with saliva. Patients may also have a history of poor dental hygiene, or pre-existing valvular disease.

Less commonly reported etiological bacteria are responsible for so called "culture negative endocarditis". Such bacteria can be identified by serology, culture of the excised valve tissue, sputum, pleural fluid, and emboli; and by polymerase chain reaction or and sequencing of bacterial 16S ribosomal RNA. Such bacteria include Bartonella, Chlamydia psittaci, and Coxiella.

Fungal and Viral Candida albicans, a yeast , is associated with endocarditis in IV drug users and immunocompromised patients. Other fungi demonstrated to cause endocarditis are Histoplasma capsulatum and Aspergillus. Endocarditis with Tricosporon asahii has also ben reported in a case report.

Candida albicans growing on Sabouraud agar Viral infections of the heart are usually associated with viral myocarditis or viral pericarditis. The existence of viral endocarditis is disputed, but there is some evidence that it can occur.

Treatment
High dose antibiotics are administered by the intravenous route to maximize diffusion of antibiotic molecules into vegetation(s) from the blood filling the chambers of the heart. This is necessary because neither the heart valves nor the vegetations adherent to them are supplied by blood vessels. Antibiotics are continued for a long time, typically two to six weeks depending on the characteristics of the infection and the causative micro-organisms. In acute endocarditis, due to the fulminant inflammation empirical antibiotic therapy is started immediately after the blood has been drawn for culture. This usually includes vancomycin and ceftriaxone IV infusions until the microbial identification and susceptibility report with the minimum inhibitory concentration becomes available allowing for modification of the antimicrobial therapy to target the specific microorganism. In subacute endocarditis, where patient's hemodynamic status is usually stable, antibiotic treatment can be delayed till the causative microorganism can be identified.

The most common organism responsible for infective endocarditis is Staphylococcus aureus , which is resistant to penicillin in most cases. High rates of resistant to oxacillin are also seen, in which cases treatment with vancomycin is required. Viridans group streptococci and Streptococcus bovis are usually highly susceptible to penicillin and can be treated with penicillin or ceftriaxone. Relatively resistant strains of viridans group streptococci and Streptococcus bovis are treated with penicillin or ceftriaxone along with a shorter 2 week course of an aminoglycoside during the initial phase of treatment.

Dental Prophylaxis
American Heart Association Guidelines
1-All dental procedures that involve manipulation of gingival tissue or the peri-apical region of teeth or perforation of the oral mucosa 2-Suture Removal 3-Extractions 4-Periodontal Procedures (Scaling, Root Planning, Probing, Surgery, Recall maintenance) 5-Implant placement or re-implantation of avulsed teeth 6-Endodontic instrumentation or surgery when beyond the apex 7-Subgingival placement of antibiotic fibers or strips 8-Intraligamentary local anaesthetic injections 9-Prophylactic cleaning of teeth or implants 10-Biopsies 11-Placement of orthodontic bands 1-Restorative dentistry without retraction cord 2-Local anaesthetic injections through non-infected tissue 3-Intracanal endodontic treatment 4-Post placement and build-up 5-Rubber dam placement 6-Making of oral impressions 7-Fluoride treatments 8-Taking radiographs 9-Placement or Removal of orthodontic or prosthetic appliances 10-Placement of orthodontic brackets 11-Adjustment of orthodontic appliances 12-Shedding of deciduous teeth 13-Bleeding from trauma to the lips or oral mucosa

References
1-Mitchell RS, Kumar V, Robbins SL, Abbas AK, Fausto N (2007). Robbins Basic Pathology (8th ed.). Saunders/Elsevier. pp. 406–8. 2-Morris AM (January 2006). "How best to deal with endocarditis". 3-Durack D, Lukes A, Bright D (1994). "New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service". Am J Med 96 (3): 200–9. 4-Erbel R, Rohmann S, Drexler M, et al. (1988). "Improved diagnostic value of echocardiography in patients with infective endocarditis by trans-oesophageal approach. A prospective study". 5-Murdoch, DR; et. al. (9). "Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study". Archives of Internal Medicine 169 (5) 6-Lamas, CC; Eykyn, SJ (March 2003). "Blood culture negative endocarditis: analysis of 63 cases presenting over 25 years". 7-Baddour, LM; et. al. (14). "Infective Endocarditis Diagnosis, Antimicrobial Therapy, and Management of Complications: A Statement for Healthcare Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of America".

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