RHEUMATIC FEVER, CRITERIA FOR RHEUMATIC FEVER, DIFFERENTIAL DIAGNOSIS, TREATMENT,

 

Acute rheumatic fever. Chronic rheumatic heart disease. Definition. Ethioliogy. Pathogenesis. Clinical pattern. Diagnostics. Treatment. Prophylaxis. Infectious endocarditis. Ethioliogy. Pathogenesis. Clinical pattern. Diagnostics. Treatment. Prophylaxis. Role of a doctor-dentist in prophylaxis.

Structure of the heart. (a) an anterior view, (b) a posterior view

Rheumatic fever (acute rheumatic fever or ARF) is an autoimmune disease that may occur after a group A streptococcal throat infection that causes inflammatory lesions in connective tissue, especially that of the heart, joints, blood vessels, and subcutaneous tissue. This condition may permanently damage the heart valves. The disease has been described since the 1500s, but the association between a throat infection and rheumatic fever symptom development was not described until the 1880s. It was associated with scarlet fever (rash caused by streptococcal exotoxins) in the 1900s. Prior to the broad availability of penicillin, rheumatic fever was a leading cause of death in children and one of the leading causes of acquired heart disease in adults. Symptoms of valve damage often don’t appear for 10-30 years after the initial event.  In many developing countries, which account for almost two-thirds of the world’s population, streptococcal infections, rheumatic fever, and rheumatic heart disease remain a very significant public health problem. The most severe complication is rheumatic heart disease.

The disease has many symptoms and can affect different parts of the body, including the heart, joints, skin, and brain. There is no simple diagnostic test for rheumatic fever, so the American Heart Association’s modified Jones criteria (first published in 1944 and listed below) are used to assist the physician in making the proper diagnosis.

EPIDEMIOLOGY The epidemiology of acute rheumatic fever is identical to that of group A streptococcal upper respiratory tract infections. Lancefield’s group A consists of a single species, S. pyogenes. As its species name implies, this organism is associated with a variety of suppurative infections. In addition, group A streptococci can trigger the postinfectious syndromes of acute rheumatic fever. As is the case for streptococcal sore throat, acute rheumatic fever most often occurs in children; the peak age-related incidence is between 5 and 15 years. Most initial attacks in adults take place at the end of the second and beginning of the third decades of life. Rarely, initial attacks occur as late as the fourth decade and recurrent attacks have been documented as late as the fifth decade.

Studies have shown that approximately 3% of individuals with untreated group A streptococcal pharyngitis will develop rheumatic fever. The epidemiology of rheumatic fever is also influenced by the serotypes of group A streptococci present in a population. The concept of “rheumatogenecity” of specific strains is largely based upon epidemiologic evidence associating certain serotypes with rheumatic fever (e.g., serotypes 1, 3, 5, 6, 18, etc.). Mucoid isolates are frequently associated with virulence and with rheumatic fever.

 

Strep throat is the most common bacterial cause of sore throat. Because strep throat can occasionally lead to rheumatic fever, antibiotics are given. Strep throat often includes a fever, white draining patches on the throat, and swollen or tender lymph glands in the neck.

 

 

 

Group A streptococcus (GAS) infections of the pharynx are the precipitating cause of rheumatic fever. Proper diagnosis and adequate antibiotic treatment of GAS infections can prevent acute rheumatic fever in most cases.

DIAGNOSIS OF STREPTOCOCCAL PHARYNGITIS

Acute pharyngitis is caused much more often by viruses than by bacteria. However, differentiation of GAS pharyngitis from other causes of acute pharyngitis is often difficult because none of the clinical findings suggestive of GAS infection is specific enough on its own for diagnosis (Table 1). A history of recent exposure is helpful in making the diagnosis, as is an awareness of the prevalence of GAS infections in the community.

 

TABLE 1.
GAS vs. Viral Pharyngitis: Clinical and Epidemiologic Findings

 

Features suggestive of GAS infection

Beefy, swollen, red uvula

Fever

Headache

History of exposure to GAS

Nausea, vomiting, and abdominal pain

Pain with swallowing

Patient 5 to 15 years of age

Presentation in winter or early spring (in temperate climates)

Scarlet fever rash

Soft palate petechiae (“doughnut lesions”)

Sudden onset of sore throat

Tender, enlarged anterior cervical nodes

Tonsillopharyngeal erythema

Tonsillopharyngeal exudates

Features suggestive of viral infection

Characteristic enanthems

Characteristic exanthems

Conjunctivitis

Coryza

Cough

Diarrhea

Hoarseness

 

GAS = group A streptococcus.

 

PATHOGENESIS

 More than half a century ago the pioneering studies of Lancefield differentiated beta-hemolytic streptococci into serologic groups. This ultimately led to the association of infection by the group A organism of the pharynx and tonsils (not of the skin) and the subsequent development of acute rheumatic fever. However, the mechanism(s) responsible for the development of rheumatic fever after an infection remains incompletely defined. Historically, approaches to understanding the pathogenesis of rheumatic fever have been grouped into three major categories:

1. direct infection by the group A streptococcus;

2. toxic effect of streptococcal extracellular products on the host tissues;

3. an abnormal or dysfunctional immune response to one or more as yet unidentified somatic or extracellular antigens produced by all (or perhaps only by some) group A streptococci.

There is insufficient evidence to support direct infection of the heart as the inciting event. Additionally, while toxins such as streptolysin O and others have been postulated to have a pathogenetic role, there is relatively little convincing evidence of this at the present time. Major efforts have focused on an abnormal immune response by the human host to one or more group A streptococcal antigens.

The hypothesis of “antigenic mimicry” between human and group A streptococcal antigens has been studied extensively and has concentrated on two interactions. The first is the similarity between the group-specific carbohydrate of the group A streptococcus and the glycoprotein of heart valves; the second involves the molecular similarity among the streptococcal cell membrane, streptococcal M protein sarcolemma, and other moieties of the human myocardial cell.

The possibility of a predisposing genetic influence in some individuals is one of the most tantalizing of the incompletely understood factors that might contribute to susceptibility to rheumatic fever. The precise genetic factors influencing the attack rate have never been adequately defined. Observations have been described that support the concept that this nonsuppurative sequel to a group A streptococcal upper respiratory tract infection results from an abnormal immune response by the human host. Thus, differences in immune responses to streptococcal antigens have been reported. Further, new data suggest that a unique surface marker oon-T lymphocytes in patients with rheumatic fever and rheumatic heart disease may prove helpful in defining which individuals are susceptible to developing rheumatic fever after a streptococcal infection because of abnormal immune responses.

 

Schematic representation of the aetiopathogenic events occurring during the development of carditis

 

 

 Classification of rheumatic fever.

Phase:

A. Acute: I degree – minimum, II degree – moderate, III degree – maximum

B. nonacute

Clinical-Anatomical characteristic of involvement of the heart:

1. Acute phase:

a. primary rheumocarditis without valvular involvement.

b. recurrent rheumocarditis with cardiac defect

c. rheumatic fever without obvious cardiac  involvement.

2. nonacute phase:

a. rheumatic myocardiosclerosis

b. cardiac defect

 

Clinical-Anatomical characteristic of involvement of visceral organs and systems:

1. Acute phase: carditis, polyathritis, serositis (pleuritis, peritonitis,abdominal syndrome), chorea, encephalitis, meningoencephalitis, cerebral vasculitis, vasculitis, nephritis, hepatitis, pneumonia, skin alteration, iritis, iridocyclitis, thyroiditis.

2. nonacute phase: results of the outcardiac involvement.

Course: Acute, subacute, recurrent, latent

 

Functional condition of blood circulation:

HF0 – heart failure is absent

HF1 – the first grade of heart failure

HF2 – the second grade of heart failure

HF3 – the third grade of heart failure

3. Structure of clinical diagnosis.

I. Rheumatic fever

II. Phase

a.) acute:

I degree – minimum, II degree – moderate, III degree – maximum

b.) nonacute

IV. Cardiac involvement: 1. Acute phase:

a.) primary rheumocarditis without valvular involvement,

b.) recurrent rheumocarditis with cardiac defect,

c). rheumatic fever without obvious cardiac involvement.

2. nonactive phase:

a.) rheumatic myocardiosclerosis,

b.) cardiac defect

V. Involvement of visceral organs and systems:

1.) Acute phase: polyathritis, serositis (pleuritis, peritonitis,abdominal syndrome), chorea, encephalitis, meningoencephalitis, cerebral vasculitis, vasculitis, nephritis, hepatitis, pneumonia, skin alteration, iritis, iridocyclitis, throiditis

2.) Nonacute phase: results of the outcardiac involvement.

VI. Functional condition of blood circulation:

a) HF0 – heart failure is absent

b) HF1 – the first grade of heart failure

c) HF2 – the second grade of heart failure

d) HF3 – the third grade of heart failure

 

Criteria for the grades of activity of rheumatic fever

 

There is no specific laboratory test that can establish a diagnosis of rheumatic fever. The diagnosis, therefore, is a clinical one but requires supporting evidence from the clinical microbiology and clinical immunology laboratories. Because of the variety of signs and symptoms associated with the rheumatic fever syndrome, in 1944 Jones first proposed criteria to assist the clinician in standardizing the diagnosis of rheumatic fever. The most recent modification of the Jones criteria (Updated Jones Criteria) was published in 1992 by a Special Writing Group of the American Heart Association.  Оnes criteria are guidelines decided on by the American Heart Association to help doctors clinically diagnose rheumatic fever. Two major criteria or one major and two minor plus a history of a streptococcal throat infection are required to make the diagnosis of rheumatic fever.

There are five criteria termed major because they are most commonly found in patients with rheumatic fever:

·        Carditis (heart inflammation, there is pancarditis Le. pericarditis, myocarditis, endocarditis):

1.     Pericarditis: There is very little serous effusion like butter on bread (bread and butter appearance) and no constriction, pericardial friction rub.,

 

 

2.     Endocarditis:There is inflammation of heart valves leading to murmur of mitral stenosis (Care’s Coomb’s murmur-blowin mid-diastolic murmur at the a ex murmur of aortic regurgitation, and mitral regurgitation.

3.     Myocarditis: There is sinus tachycardia, mitral regurgitation, S3 gallop, MR, TR, increased PR interval, heart failure.

·        Arthritis in several joints (migratory polyarthritis):

The arthritis lasts for a few days in one joint and then occurs in another joint, even before it is cured in the first joint.

When the joint is cured, there is no sequelae or residual deformity of the joint.

Arthritis is migratory, affecting the ankles, wrists, knees, and elbows.

Usually the small joints of the hand and feet are not involved.

Big joints like hip joints are not involved.

Typically the arthritis lasts for a day or two in one joint. It flits from one joint to another. This migrating polyarthritis lasts for a few days to weeks affecting one or two joints at a time.

The pain of rheumatic arthritis responds dramatically to 2 g of aspirin given 4 times a day (3-4 tablets given 4-6 hou rly).

·        Chorea. In children the chorea starts with restlessness, change in handwriting, irritability, and later typical rapid, jerky movements of the trunk and whole body. Rheumatic chorea is called Sydenham‘s chorea or St. Vitus Dance. It occurs several months after the streptococcal infection. It is very rare.

·        Subcutaneous nodules. These are small and found over extensor surface of joints in long-standing Rheumatic heart disease (RHD). They may disappear in few days.

·         

·        Skin rash (erythema marginatum).These are transient macular eruptions with rounded borders, may be with irregular margins, specially on the trunk, pink in color, non pruritic (do not itch). They are very uncommon in Indians.

 

The minor criteria include:

1.     fever,

2.     high ESR (erythrocyte sedimentation rate, an laboratory sign of inflammation),

3.     joint pain (arthralgia),

4.     EKG changes (electrocardiogram), and

5.     other laboratory findings (elevated C-reactive protein, elevated or rising streptococcal antigen test).

 

 

 

Molecular Structure: C-REACTIVE PROTEIN

 

MOLECULAR DIAGRAM OF NATIVE C-REACTIVE PROTEIN PENTAMER,

which is very sensitive to the activity of the rheumatic fever

 

The minor criteria are nonspecific and may be present in many clinical conditions.

To fulfill the Jones criteria, either two major criteria, or one major criterion and two minor criteria, plus evidence of an antecedent streptococcal infection are required. The latter may be provided by recovery of the organism on culture or by evidence of an immune response to one of the commonly measured group A streptococcal antibodies (e.g., anti-streptolysin O, anti-deoxyribonuclease B, anti-hyaluronidase). Since the accurate diagnosis of rheumatic fever has future medical and financial implications, the clinician is obligated to evaluate any patient completely until the suspected diagnosis is either established or excluded.

Both the clinical microbiology and the clinical immunology laboratories have important roles in confirming the diagnosis of rheumatic fever. An attempt should be made to recover the organism from a throat culture, although group A streptococci can be recovered from the upper respiratory tract of only 25 to 40% of patients at the time the diagnosis is made. If a rapid antigen detection test is used but is negative, a confirmatory throat culture must be performed. It is helpful to obtain two or three cultures from the throat at the time the diagnosis is suspected but before initiating antibiotic therapy in order to confirm the presence of the organism.

At least 80% of patients with acute rheumatic fever have an elevated anti-streptolysin O titer at presentation. If one employs two additional streptococcal antibody tests such as the anti-DNAse B or anti-hyaluronidase test, the percentage of patients who show evidence of a preceding group A streptococcal infection will rise to more than 95%. While an initially elevated titer is convincing, being able to demonstrate a rise in titer from the acute to the convalescent phase is a more reliable means of documenting the recent infection. If three antibody tests are done and there is no evidence of a preceding infection, the diagnosis must be seriously reconsidered.

The carditis of acute rheumatic fever is a pancarditis involving the pericardium, myocardium, and endocardium.

 

 

In most published series, between 40 and 60% of patients with acute rheumatic fever have evidence of carditis, which is characterized by one or more of the following: sinus tachycardia, the murmur of mitral regurgitation  an S3 gallop, a pericardial friction rub, and cardiomegaly. The introduction of echocardiography has assisted in the identification of subtle abnormalities of the mitral valve, and these may be present in an additional 20% of patients who do not have an audible heart murmur. A prolonged PR interval and evidence of heart failure may be present as well, but these are nonspecific and may be found in a number of other diseases.

Healing of the rheumatic valvulitis may cause fibrous thickening and adhesion, resulting in the most serious complication of rheumatic fever, i.e., valvular stenosis and/or regurgitation. The mitral valve is involved most frequently, followed by the aortic valve.

                                                        

                                 

      

 

Aortic Stenosis

Mitral Stenosis

 

However, isolated aortic valve disease as a consequence of acute rheumatic fever is quite rare. In patients with aortic valve disease due to rheumatic fever, the mitral valve is almost always simultaneously affected. Even minor degrees of rheumatic valvular involvement can lead to susceptibilities to infective endocarditis. Although rheumatic pericarditis can cause a serous effusion, fibrin deposits, and even pericardial calcification, it does not lead to constrictive pericarditis.

Carditis is the most serious manifestation of rheumatic fever, involves all the layers of the heart wall simultaneously. It occurs in as many as 40% of patients and may include cardiomegaly, new murmur, congestive heart failure, and pericarditis, with or without a rub and valvular disease. The inflammation of the pericardium (outer coating of the heart) is called pericarditis. The inflammation of the myocardium (heart muscle) is called myocarditis. The inflammation of the endocardium (internal lining of the heart wall) is called endocarditis. The involvement of the heart is revealed by the occurrence of new mitral and aortic murmurs and cardiomegaly. Very severe rheumatic heart disease may lead to heart failure. The heart lesions may remain and worsen with every recurrence of the acute rheumatic fever.

Aortic valve showing active valvulitis. The valve is slightly thickened and displays small vegetations – “verrucae”

 

Myocardial Aschoff body – the cells are large, elongated, with large nuclei; some are multinucleate

 

The clinical picture includes high pulse rate, congestive heart failure, arrhytmias and pericardial friction rubs. On the first attack, valvulitis is suspected in the presence of a new apical systolic murmur of mitral regurgitation (associated or not with an apical mid-diastolic murmur) and/or a basal diastolic murmur of aortic regurgitation. Cardiomegaly is noted on X-Ray and on echocardiogram. Myocarditis and/or pericarditis in the absence of valvular involvement is unlikely due to acute RF. It is contentious if myocardial disfunction in acute RF is valvular or myocardial in origin. In fact, in a subset of patients, the initial presentation may be quite severe, with overt heart failure, fever and toxaemia, making the differential diagnosis with infective endocarditis very difficult, in particular in patients with recurrent rheumatic heart disease.

Chest radiograph of an 8 year old patient with acute carditis before treatment

 

Same patient after 4 weeks

The valvular lesions in RF often result in residual damage. Nevertheless, in milder forms of rheumatic carditis patients may recover from valvulitis without sequelae. In the first attack, the lesions are predominantly regurgitant, due to ring dilatation, swollen cusps, chordal rupture or papillary muscle dysfunction. In the chronic phase, obstructive lesions are more frequent.

 

 

A migratory polyarthritis is present in as many as 75% of cases, most often affecting the ankles, wrists, knees, and elbows over a period of days. It usually does not affect the small joints of the hands or feet and seldom involves the hip joints. Since salicylates and other anti-inflammatory drugs usually cause prompt resolution of joint symptoms, it is important that the cliniciaot prescribe these medications until it is determined whether the arthritis is migratory. The arthritis of acute rheumatic fever is extremely painful. Pain can be controlled with codeine or similar analgesics until the diagnosis is established.  The arthritis lasts 1-5 weeks and subsides without residual deformity. The difference between arthralgia (subjective joint pain) and arthritis (joint pain and swelling) must be understood. Too often, arthralgia is used (incorrectly) as a major criterion.

Sydenham’s chorea occurs in fewer than 10% of patients with rheumatic fever. The latent period between the onset of the initiating streptococcal infection and the onset of Sydenham’s chorea may be as long as several months. While differing from the other manifestations, this central nervous system disorder is a part of the rheumatic fever complex and should be managed as such. Many patients who appear to have only chorea may present several decades later with evidence of typical rheumatic valvular disease. There is no definitive laboratory test for establishing a diagnosis of Sydenham’s chorea, and the diagnosis is one of exclusion. Patients with Sydenham’s chorea should be given secondary prophylaxis for prevention of recurrent attacks, even if they do not appear to have rheumatic heart disease. Sydeman’s chorea – involuntary choreoathetoid movements primarily of the face, tongue, and upper extremities – may be the sole manifestation; only half of cases have other overt signs of rheumatic fever. Girls are more frequently affected, and occurrence in adults is rare.

 

 

 

Erythema marginatum

 

Subcutaneous nodules and erythema marginatum are rare major manifestations, usually present in fewer than 10% of cases. Subcutaneous nodules are found over extensor surfaces of joints, are seen most often in patients with long-standing rheumatic heart disease, and are extremely rare in patients experiencing an initial attack. They are small (≤ 2 cm in diameter), firm, and nontender and are attached to fascia or sheaths over bony prominences.  They persist for days or weeks, are recurrent, and are indistinguishable from rheumatoid nodules.

Subcutaneous nodules

Subcutaneous nodule on the extensor surface of elbow of a patient with acute RF Subcutaneous nodules are rarely seen and when present, they are usually associated with severe carditis. They are painless, firm, movable, measuring around 0.5 to 2 cm. They are usually located over extensor surfaces of the joints, particularly knees, wrists and elbows

 

Erythema marginatum is an uncommon manifestation. It is an evanescent macular eruption with rounded borders-usually concentrated on the trunk and proximal extremities. The former begin as rapidly enlarging macules that assume the shape of rings or crescents with clear centers. They may be confluent, and either transient or persistent.

Erythema marginatum
This is an evanescent, erythematous, non-pruritic rash with pale centers and rounded or serpiginous margins. Lesions occur mainly on the trunk and proximal extremities and may be induced by application of heat.

Erythema marginatum on the trunk, showing erythematous lesions with pale centers and rounded or serpiginous margins
Closer view of erythema marginatum in the same patient

The minor criteria are nonspecific and may be present in many clinical conditions. These include fever, polyarthralgias, reversible prolongation of the PR interval, rapid erythrocyte sedimentation rate, evidence of an antecedent b-hemolytic streptococcal infection, or a history of rheumatic fever.

There is non-specific evidence of inflammatory disease, as shown by a rapid sedimentation rate. High or increasing titers of antistreptococcal antibodies (antistreptolysin O and anti-DNAse B0 are used to confirm recent infection; 10 % of cases lack this serologic evidence.

Investigations

These are listed in Box. The ESR and CRP are non-specific markers of systemic inflammation, and are useful for monitoring progress of the disease. ASO titres are normal in about one-fifth of adult cases of rheumatic fever and most cases of chorea. Echocardiography typically shows mitral regurgitation with dilatation of the mitral annulus and prolapse of the anterior mitral leaflet; other common findings are aortic regurgitation and pericardial effusion.

 

 

 

Laboratory studies
Acute phase reactants are useful in helping to recognize acute RF and also to exclude other diseases. C-reactive protein and erythrocyte sedimentation rates are helpful in monitoring inflammatory activity.

Laboratory evidence of a preceding GAS infection should be sought, either by demonstration of GAS in the throat by culture or rapid streptoccocal antigen test, or using streptococcal antibody tests. Elevated or rising titers of antistreptolysin O (ASO) occur in more than 80% of patients with acute GAS pharyngitis. There is a remarkable response during the acute phase of RF. The test specificity has been shown to be 93% with ASO titers above 960 IU/ml.

Prolonged P-R interval relative to heart rate is a nonspecific finding, present in more than one third of the patients. Low-voltage QRS complexes and ST segment changes may be found in the presence of pericarditis and pericardial effusion.

Endomyocardial biopsy is invasive and does not appear to provide additional diagnostic information where there is a clinical consensus about the diagnosis of RF, with a diagnostic sensitivity in one relatively large study of 27%. It should be limited to clinical investigation.

 Differential diagnosis
The differential diagnosis is extensive because of the lack of specificity of many of the clinical and laboratory findings in RF and also the unavailability of a laboratory test to confirm the diagnosis. Several diseases need to be considered. Table  includes those more often presenting clinical difficulties to the clinician. Juvenile rheumatoid arthritis (JRA) and other connective tissue diseases often should be considered. The articular involvement in JRA usually lasts longer than in RF. It is generally polyarticular and symmetrical, typically affecting the small joints of the hands. Patients complain of increased pain in the morning or after long periods of immobility. Arthritis of the cervical spine occurs in about half of the cases but is also quite frequent in acute RF. 

Differential diagnosis of rheumatic fever

 
 
 

Cardiac involvement presents primarily as pericarditis therefore infective endocarditis should be considered in patients with recurrent RF presenting with persistent fever of unknown origin. Sometimes the differential diagnosis can be difficult, especially in those presenting with a more severe clinical presentation. Splenomegaly, vascular and immmunologic phenomena, demonstration of vegetations on echocardiogram and positive blood cultures are indicative of infective endocarditis. Gallium-67 cardiac scintigraphy can be helpful in this setting.

Systemic lupus erythematosus (SLE) shares clinical characteristics with acute RF. Arthralgia and transient arthritis are common. SLE affects multiple organs, including kidney, central nervous system, skin, and blood. Diagnosis is made on clinical grounds and confirmed by serologic studies.

Differentiation between rheumatic fever and myocarditis:

Myocarditis (nonrheumatic) is an inflammatory disease of the heart muscle which may be acute, subacute, or chronic. It may be focal, multifocal, or diffuse. The myocarditides may be divided into the acute and chronic forms. Myocarditis also should be suspected when there is new onset of heart failure, arrhythmia, or conduction disturbance in an individual not known to have heart disease.

Classification of myocarditides:

1.) Acute a) with known aetiology (infective, viral, bacterial myocarditis, fungal  and others); b) with unknown aetiology.

2.) chronic, unknown; 3.) myocardiofibrosis; 4.) widening: a) focal, b) diffuse; 5.) course: minimal, mild, severe; 6.) clinical variants:  cardialgia, arrhythmias and others; 7.) heart failure

Classification (Ministry of Health of Ukraine (February 14)

1. Acute

a. With defined etiology (infectious, bacterial, viral, parasitogenic, due to other etiology)

b. Of unknown etiology

2. Chronic, of unknown etiology

3. Myocardiofibrosis

4. Dissemination

a. Diffusive

b. Focal

5. Course: mild, moderate, severe

6. Clinical variants: arrhythmia, injured repolarization, cardialgia

7. Heart failure

The clinical manifestations range from an asymptomatic state, with the presence of myocarditis inferred only by the finding of transient electrocardiographic ST-T-wave abnormalities, to a fulminant condition with arrhythmias, heart failure, and death. In some patients, myocarditis simulates acute myocardial infarction, with chest pain, electrocardiographic changes, and elevated serum levels of myocardial enzymes.

The ECG changes of myocarditis are usually nonspecific. Almost all systemic infections may produce minor myocardial involvement. Measeles, mumps, influenza, hepatitis, infectious mononucleosis, and scarlet fever, the coxackievirus A and B strains, the poliomyelitis, rubeola viruses   just to name a few diseases, may be associated with ECG abnormalities and with histologic evidence of myocardial inflammation. When the myocardial involvement is subclinical, the ECG changes are usually subtle and nonspecific. There are minor T-wave changes, manifested as flattening or perhaps shallow inversion of the T waves in multiple leads. The conducting system may be involved, and prolongation of the PR interval may be noted.

In more obvious myocarditis, the ECG demonstrates symmetrically inverted T waves in most of the standard limb leads and in lateral precordial leads. When the special conducting system is involved, bundle branch block may occur, and patterns of diffuse nonspecific intraventricular conduction defects may occur.

The physical examination is ofteormal, although more severe cases may show a muffled first heart sound, along with a third heart sound and a murmur of mitral regurgitation. A pericardial friction rub may be audible in patients with associated pericarditis.

Though viral myocarditis is most often self-limited and without sequelae, severe involvement may recur, and it is likely that acute viral myocarditis occasionally progresses to a chronic form and to dilated cardiomyopathy. Patients with viral myocarditis often give a history of a preceding upper respiratory febrile illness or a flulike syndrome, and viral nasopharyngitis or tonsillitis may be evident clinically. The isolation of virus from the stool, pharyngeal washings, or other body fluids and changes in specific antibody titers are helpful clinically. Endomyocardial biopsy, carried out early in the illness, may show round-cell infiltration and necrosis of adjacent myocytes.

Experimental studies suggest that exercise may be deleterious in patients with viral myocarditis, and strenuous activity should be proscribed until the electrocardiogram has returned to normal. Patients who develop congestive heart failure respond to the usual measures (ACE inhibitors, diuretics, and salt restriction), but they appear to be unusually sensitive to digitalis. Arrhythmias are common and are occasionally difficult to manage. Deaths attributed to heart failure, tachyarrhythmias, and heart block have been reported, and it seems prudent to monitor the electrocardiogram of patients with arrhythmias, especially during the acute illness.

Myocarditis also should be suspected when there is new onset of heart failure, arrhythmia, or conduction disturbance in an individual not known to have heart disease.

Clues that should lead to the consideration of acute myocarditis include tachycardia out of proportion to the body temperature in any acute infectious illness, especially if accompanied by myalgias and tenderness of muscles; dyspnea, palpitation, gallop rhythms, or evidence of heart failure during or following an acute viral illness; and new electrocardiograhic or echocardiographic abnormalities following an acute illness. Evidence of acute pericarditis should always lead the physician to question myocardial involvement. Sometimes myocarditis, which may develop either during or several weeks after the respiratory illness, may lead to acute heart failure which may be fatal, more frequently in infants than in adults, or it may lead to a variety of cardiac arrythmias. Myocarditis is frequently associated with acute pericarditis, especially when it is caused by coxackievirus B strains or echoviruses. Chronic myocarditis should be suspected in any individual who presents with cardiomyopathy, idiopathic arrhythmias, or conduction distur­bances of relatively recent onset.

A presumptive diagnosis of myocarditis may be made when there is evidence of new or relatively recent onset of heart disease in the absence of evidence for coronary, valvular, congenital, hypertensive, or specific heart muscle disease. A definitive diagnosis requires histopathologic confirmation by means of myocardial biopsy.

Criteria for myocarditis (New York Heart Association 1964, 1973)

Significant indices

The infection lasting for 10 days and resulting in:

1.                 signs of congestive cardiac failure

2.                 cardiogenic shock

3.                 complete AV block with Morgans – Adems – Stokes Syndrome

4.                 pathologic transpormations of  ESI

5.                 increased activity of myocardial enzymes in the serum

Insignificant Values

1.                 laboratory Confirmation of a suffered viral infection

2.                 tachycardia

3.                 the first heart sound weakening on the apex of the heart

4.                 gallop rhythm

5.                 subendomiocardial biopsy findings

To diagnose mild myocardibis it is quite enough to take into consideration a suffered infection and 2 significant indices on 1 significant  and 2 insignificant ones.

The presences of one of 3 first significant values testify it an average severe or a severe course of the disease.

Bellow the typical features myocarditis forms are presented:

Infectious Allergic Myocarditis

V.A. Nasonova and I.A.Bronzov (1978) determined the following diagnostic criteria of infectious allergic myocarditis:

1.                   The conveetion of the disease with acute rhinopharyngeal infection, chronic tonsillitis exacerbations.

2.                   The absence of the latent period (less than 5-7 years) between clinical manifestations of rhinopharyngel infection and myocarditis onset.

3.                   The presence of the allergic syndrome accompanied by urticaria, vasomotor rhinitis, conjunctivitis, medicamental allergy.

4.                   Prevailing morbidity among middle aged people.

5.                   Slow progress of the disease, without evident progress, vnianifectations (taking into consideration lab. Finding)

6.                   Marked complaints of a cardiac nature (cardiac pain, palpitation, cardiac activity disorders, their resistance to antianginal pharmaceuticals, emotional colouring of the pain syndrome.

7.                   The absence of arthritis and rare cases of arthralgia.

8.                   Rare cases of pericarditis and the absence of valvulitis in all the cases.

9.                   Feebly marked laboratory findings activity or its lack in the presence of strongly pronounced signs of myocarditis.

10.              Quick development of asthenization which reaches the stage of adynamia, vegetative dystonia symptoms, thermoregulation disorders.

11.              Evident ECI transformations in all the patients.

12.              Slow symptom dynamics due to antic – inflammatory therapy.

 

Myocarditis, i.e., cardiac inflammation, is most commonly the result of an infectious process. Myocarditis may also result from a hypersensitivity to drugs or may be caused by radiation, chemicals, or physical agents. In an unknowumber of cases, acute myocarditis progresses to chronic dilated cardiomyopathy. While almost every infectious agent is capable of producing myocarditis, clinically significant acute myocarditis is caused most commonly by viruses, especially coxsackievirus B. The clinical manifestations range from an asymptomatic state, with the presence of myocarditis inferred only by the finding of transient electrocardiographic ST-T-wave abnormalities, to a fulminant condition with arrhythmias, heart failure, and death. In some patients, myocarditis simulates acute myocardial infarction, with chest pain, electrocardiographic changes, and elevated serum levels of myocardial enzymes.

The physical examination is ofteormal, although more severe cases may show a muffled first heart sound, along with a third heart sound and a murmur of mitral regurgitation. A pericardial friction rub may be audible in patients with associated pericarditis.

Though viral myocarditis is most often self-limited and without sequelae, severe involvement may recur, and it is likely that acute viral myocarditis occasionally progresses to a chronic form and to dilated cardiomyopathy. Patients with viral myocarditis often give a history of a preceding upper respiratory febrile illness or a flulike syndrome, and viral nasopharyngitis or tonsillitis may be evident clinically. The isolation of virus from the stool, pharyngeal washings, or other body fluids and changes in specific antibody titers are helpful clinically. Endomyocardial biopsy, carried out early in the illness, may show round-cell infiltration and necrosis of adjacent myocytes.

Experimental studies suggest that exercise may be deleterious in patients with viral myocarditis, and strenuous activity should be proscribed until the electrocardiogram has returned to normal. Patients who develop congestive heart failure respond to the usual measures (ACE inhibitors, diuretics, and salt restriction), but they appear to be unusually sensitive to digitalis. Arrhythmias are common and are occasionally difficult to manage. Deaths attributed to heart failure, tachyarrhythmias, and heart block have been reported, and it seems prudent to monitor the electrocardiogram of patients with arrhythmias, especially during the acute illness.

 

 Treatment of the acute attack

 

Benzathine penicillin 1.2 million units i.m. or oral phenoxymethylpenicillin 250 mg 6-hourly for 10 days should be given on diagnosis in order to eliminate any residual streptococcal infection. Treatment of acute rheumatic fever is then directed towards limiting cardiac damage and relieving symptoms. Bed rest and supportive therapy. Bed rest is important as it lessens joint pain and reduces cardiac workload in patients with carditis. The duration of bed rest should be guided by symptoms and markers of inflammation (e.g. temperature, leucocyte count and ESR) and should be continued until these indices of disease activity have settled. In patients who have had carditis, it is conventional to recommend bed rest for 2-6 weeks after the ESR and temperature have returned to normal. Prolonged bed rest, particularly in children or adolescents, produces problems of boredom and depression that need to be anticipated and managed. Cardiac failure should be treated as necessary. Some patients, particularly those in early adolescence, develop a fulminant form of the disease with severe mitral regurgitation and sometimes concomitant aortic regurgitation. If heart failure does not respond to medical treatment in these cases valve replacement may be necessary and is often associated with a dramatic decline in rheumatic activity. Heart block is seldom progressive, and pacemaker therapy is rarely needed.

Aspirin.  Aspirin will usually relieve the symptoms of arthritis rapidly and a prompt response (within 24 hours) helps to confirm the diagnosis. A reasonable starting dose is 60 mg/kg body weight per day, divided into six doses. In adults, 120 mg/kg per day may be needed up to the limits of tolerance or a maximum of 8 g per day. Mild toxic effects include nausea,  tinnitus and deafness; more serious ones are vomiting, tachypnoea and acidosis. Aspirin should be continued until the ESR has fallen, and then gradually tailed off.

Corticosteroids. These produce more rapid symptomatic relief than aspirin, and are indicated in cases with carditis or severe arthritis. There is no evidence that long-term steroids are beneficial. Prednisolone 1.0-2.0 mg/kg per day in divided doses should be continued until the ESR is normal, then gradually tailed off.

TREATMENT OF STREPTOCOCCAL PHARYNGITIS

Primary prevention of rheumatic fever requires adequate therapy for GAS pharyngitis. In selecting a

TABLE 2.
Primary Prevention of Rheumatic Fever

 

Agent	Dosage	Evidence rating*
Penicillins
Amoxicillin	50 mg per kg (maximum, 1 g) orally once daily for 10 days	1B
Penicillin G benzathine	Patients weighing 27 kg (60 lb) or less: 600,000 units IM once	1B
	Patients weighing more than 27 kg: 1,200,000 units IM once
Penicillin V potassium	Patients weighing 27 kg or less: 250 mg orally 2 or 3 times daily for 10 days	1B
	Patients weighing more than 27 kg: 500 mg orally 2 or 3 times daily for 10 days
For patients allergic to penicillin
Narrow-spectrum cephalosporin (cephalexin [Keflex], cefadroxil [formerly Duricef])†	Varies	1B
Azithromycin (Zithromax)	12 mg per kg (maximum, 500 mg) orally once daily for 5 days	2aB
Clarithromycin (Biaxin)‡	15 mg per kg orally per day, divided into 2 doses (maximum, 250 mg twice daily), for 10 days	2aB
Clindamycin (Cleocin)	20 mg per kg orally per day (maximum, 1.8 g per day), divided into 3 doses, for 10 days	2aB

 

OTHER RECOMMENDATIONS

Because most patients with GAS pharyngitis respond well to antimicrobial therapy, posttreatment throat cultures are indicated only in those who remain symptomatic, who have recurrent symptoms, or who have had rheumatic fever previously.

With the exception of persons who have had or whose family members have had rheumatic fever, repeated courses of antibiotics are typically not indicated in asymptomatic persons who continue to harbor GAS after appropriate therapy.

Although acute infections with group B and C beta-hemolytic streptococci can appear similar to GAS pharyngitis, rheumatic fever has not been documented as a complication of these infections.

Secondary Prevention of Rheumatic Fever

Continuous prophylaxis is recommended in patients with well-documented histories of rheumatic fever and in those with evidence of rheumatic heart disease (Tables 3 and 4). Prophylaxis should be initiated as soon as acute rheumatic fever or rheumatic heart disease is diagnosed. To eradicate residual GAS, a full course of penicillin should be given to patients with acute rheumatic fever, even if a throat culture is negative.

TABLE 3.
Duration of Secondary Prophylaxis for Rheumatic Fever

 

Type	Duration after last attack	Evidence rating*
Rheumatic fever with carditis and residual heart disease (persistent valvular disease†)	10 years or until age 40 years (whichever is longer); lifetime prophylaxis may be needed	1C
Rheumatic fever with carditis but no residual heart disease (no valvular disease†)	10 years or until age 21 years (whichever is longer)	1C
Rheumatic fever without carditis	5 years or until age 21 years (whichever is longer)	1C

 

 

TABLE 4.
Secondary Prevention of Rheumatic Fever

 

Agent	Dosage	Evidence rating*
Penicillin G benzathine	Patients weighing 27 kg (60 lb) or less: 600,000 units IM every 4 weeks†	1A
	Patients weighing more than 27 kg: 1,200,000 units IM every 4 weeks†
Penicillin V potassium	250 mg orally twice daily	1B
Sulfadiazine	Patients weighing 27 kg or less: 0.5 g orally once daily	1B
	Patients weighing more than 27 kg: 1 g orally once daily
Macrolide or azalide antibiotic (for patients allergic to penicillin and sulfadiazine)‡	Varies	1C

 

IM = intramuscularly.

 

 

 

 

Primary prevention of rheumatic fever.⁴²

 

 

Secondary prevention of rheumatic fever.⁴²

 

Secondary prevention

Patients are susceptible to additional attacks of rheumatic fever if further streptococcal infection occurs, and long-term prophylaxis with penicillin should be given as benzathine penicillin 1.2 million units i.m. monthly (if compliance is in doubt) or oral phenoxymethylpenicillin 250 mg 12-hourly. Erythromycin may be used if the patient is allergic to penicillin. Further attacks of rheumatic fever are unusual after the age of 21, at which age treatment may be stopped. However, treatment should be extended if an attack has occurred in the last 5 years, or the patient lives in an area of high prevalence, or has an occupation (e.g. teaching) with high exposure to streptococcal infection. It is important to appreciate that long-term antibiotic prophylaxis is intended to prevent another attack of acute rheumatic fever and does not protect against infective endocarditis.

 

INFECTIVE ENDOCARDITIS

The proliferation of microorganisms on the endothelium of the heart results in infective endocarditis. The prototypic lesion at the site of infection, the vegetation, is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells.

 

 

 

Infective endocarditis

Vegetations (arrows) due to viridans streptococcal endocarditis involving the mitral valve.

ETIOLOGY
Organisms Causing Major Clinical Forms     of Endocarditis:

n  Streptococci

n  Pneumococci

n  Enterococci

n  Staphylococcus aureus

n  Coagulase-negative staphylococci

n  Fastidious gram-negative coccobacilli (HACEK group) Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and Kingella kingae.

n  Gram-negative bacilli

n  Candida spp.

n  Polymicrobial/miscellaneous

n  Diphtheroids

n  Culture-negative

 

primary portals

n  oral cavity,

n  skin,

n  upper respiratory tract from the gastrointestinal tract

n  from the genitourinary tract

Clinical and Laboratory Features of Infective Endocarditis

n  Fever 80-90 %

n  Chills and sweats 40-75 %

n  Anorexia, weight loss, malaise 25-50 %

n  Myalgias, arthralgias 15-30 %

n  Back pain 7-15 %

n  Heart murmur 80-85 %

n  New/worsened regurgitant murmur 10-40 %

n  Arterial emboli 20-50 %

n  Splenomegaly 15-50 %

n  Clubbing 10-20 %

n  Neurologic manifestations 20-40 %

n  Peripheral manifestations (Osler’s nodes, subungual hemorrhages, Janeway lesions, Roth’s spots) 2-15 %

n  Petechiae 10-40 %

n  Laboratory manifestations:

n  Anemia 70-90 %

n  Leukocytosis 20-30 %

n  Microscopic hematuria 30-50 %

n  Elevated erythrocyte sedimentation rate>90 %

n  Rheumatoid factor 50 %

n  Circulating immune complexes 65-100 %

n  Decreased serum complement  5-40 %

 

Noncardiac Manifestations

Janeway lesions. Hemorrhagic, infarcted macules and papules on the volar fingers in a patient with S. aureus endocarditis.

 

Septic vasculitis associated with bacteremia. Dermal nodule with hemorrhage and necrosis on the dorsum of a finger. This type of lesion occurs with bacteremia (e.g., S. aureus) and fungemia (e.g., Candida tropicalis).

 

 

subconjunctival hemorrhage. Submucosal hemorrhage of the lower eyelid in an elderly diabetic with enterococcal endocarditis; splinter hemorrhages in the midportion of the nail bed and Janeway lesions were also present.

  

 

 

 

Splinter hemorrhages, embolic Subungual hemorrhages in the midportion of the nail bed (quite different in comparison to traumatic splinter hemorrhages) was noted in several fingernails in a 60-year-old female with enterococcal endocarditis, who had associated subconjunctival hemorrhage

 

Osler’s nodes. Violaceous, tender nodules on the volar fingers associated with minute infective emboli or immune complex deposition.

 

Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis

                                                      

Vasculitis

                          

 

Computed tomography of the abdomen showing large embolic infarcts in the spleen and left kidney of a patient with Bartonella endocarditis.

 

 

 

Clubbing. Seen in patients with chronic lung disease, cyanotic heart disease, cirrhosis and infective enocarditis.

 

Common Peripheral Manifestations of Infective Endocarditis.

Splinter hemorrhages(Panel A) are normally seen under the fingernails. They are usually linear and red for the firstr two to three days and brownish thereafter.
Panel B shows conjunctival petechiae.
Osler’s nodes (Panel C) are tender, subcutaneous nodules, often in the pulp of the digits or the thenar eminence.
Janeway’s lesions (Panel D) are nontender, erythematous, hemorrhagic, or pustular lesions, often on the palms or soles.

Janeway lesions are seen in people with acute bacterial endocarditis. They appear as flat, painless, red to bluish-red spots on the palms and soles.

 

Janeway lesions are seen in people with acute bacterial endocarditis. They appear as flat, painless, red to bluish-red spots on the palms and soles.

 

 

Infective endocarditis: metastatic infections due to emboli.

 

The Duke Criteria for the Clinical Diagnosis of Infective Endocarditis

n  MAJOR CRITERIA:

n   Positive blood culture

– Typical microorganism for infective endocarditis from two separate blood cultures

– Viridans streptococci, Streptococcus bovis, HACEK group, or

– Community-acquired Staphylococcus aureus or enterococci in the absence of a primary focus, or

n  Persistently positive blood culture, defined as recovery of a microorganism consistent with infective endocarditis from:

– Blood cultures drawn >12 h apart; or

– All of three or a majority of four or more separate blood cultures, with first and last drawn at least 1 h apart

n  Evidence of endocardial involvement

n  Positive echocardiogram

– Oscillating intracardiac mass on valve or supporting structures or in the path of regurgitant jets or in implanted material, in the absence of an alternative anatomic explanation, or

– Abscess, or

– New partial dehiscence of prosthetic valve, or

n  New valvular regurgitation (increase or change in preexisting murmur not sufficient)

n  MINOR CRITERIA :

n  Predisposition: predisposing heart condition or injection drug use

n  Fever ≥38.0◦C

n  Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions

n  Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, rheumatoid factor

n  Microbiologic evidence: positive blood culture but not meeting major criterion as noted previously or serologic evidence of active infection with organism consistent with infective endocarditis

n  Echocardiogram: consistent with infective endocarditis but not meeting major criterion

n  Documentation of two major criteria, of one major and three minor criteria, or of five minor criteria allows a clinical diagnosis of definite endocarditis.

 

Prosthetic valve endocarditis with valvular dehiscence. The 2D echocardiogram of a St. Jude mitral valve is shown in (A) and the color-flow Doppler is shown in (B). Note severe perivalvular mitral regurgitation into the LA due to dehiscence of the MVR. (Color version of figure is available online.

 
Characteristic sites of vegetations within the heart. In the presence of aortic insufficiency, vegetations characteristically occur on the ventricular surface of the aortic valve (A) or on the chordae tendinae or papillary muscles (B). In mitral regurgitation, the vegetations characteristically are located on the atrial surface of the mitral valve (C) or at sites of jet lesions (D) on the atrial wall.

 

Prior to the availability of antimicrobial therapy, infective endocarditis (IE) was invariably fatal. The majority of patients with endocarditis now survive their infections, although even today, a substantial percentage of patients infected with highly virulent organisms (such as Staphylococcus aureus) may die as a direct or indirect result of their valvular infection. An adverse outcome in these patients can occur despite having received appropriate antimicrobial therapy in a timely manner, and despite the skillful use of modern diagnostic techniques.
This card will review the major issues related to the medical therapy of IE. The indications for surgery in this disorder are discussed separately.

GENERAL CONSIDERATIONS — Soon after the discovery of sulfonamides and penicillins, it was realized that only bactericidal, not bacteriostatic therapy was effective in treating endocarditis. Thus, following the establishment of a diagnosis using microbiologic and echocardiographic methods, or by clinical deduction, antimicrobial therapy should be administered in a dose designed to give sustained bactericidal serum concentrations throughout much or all of the dosing interval. In vitro determination of the minimum inhibitory concentration of the etiologic cause of the endocarditis should be performed in all patients.

The duration of therapy has to be sufficient to eradicate microorganisms growing within the valvular vegetations.

 The initial microbiologic response to therapy should be assessed by obtaining repeat blood cultures 48 to 72 hours after antibiotics are begun. Thereafter, regular careful serial examinations should be performed to search for signs of congestive heart failure or other complications.

Most patients with IE generally become afebrile three to five days after treatment is begun with an appropriate antibiotic. Patients with Staphylococcal aureus endocarditis may respond somewhat more slowly, remaining febrile for five to seven days after the institution of therapy. Early consultation with a cardiac surgeon should be obtained for all cases in which complications are observed or expected (such as in infections involving prosthetic valves).

Duration of therapy — Although early clinical trials showed that a few patients with streptococcal endocarditis could be cured with low doses of penicillin administered for as short as six days, longer therapy was necessary to ensure cure in all patients. As an example, the results of two early landmark treatment trials performed in the 1940s and early 1950s revealed that approximately 20 percent of patients with viridans streptococcal endocarditis relapsed when penicillin was administered for only 14 days. By contrast, in a later study of 74 patients with viridans streptococcal endocarditis, none of 66 consecutive patients who survived a four week course of penicillin G relapsed, and no patient treated with this regimen died of active infection. Similarly, four to six weeks of bactericidal therapy with a single drug was shown to be highly effective as treatment for endocarditis due to other streptococcal species and for staphylococci.

Prolonged therapy was presumed to be necessary because bacterial concentrations within vegetations are as high as 10(9) to 10(11) CFUs/gram of tissue, and because organisms deep within vegetations are not accessible to phagocytic cells and often are in a state of reduced metabolic activity].Combination antimicrobial therapy — The need for prolonged therapy in treating endocarditis, and the problem of reduced in vitro sensitivity to commonly used antimicrobial agents, has stimulated interest in using combination therapy to treat endocarditis.  •  Combination therapy using a beta lactam agent such as penicillin, with an aminoglycoside, has been shown to be highly effective in streptococcal endocarditis, and of equivocal efficacy in patients with staphylococcal endocarditis (see below).  •  Combination therapy with a penicillin and an aminoglycoside, or and ceftriaxone an aminoglycoside for two weeks is highly effective in streptococcus viridans endocarditis

Combination therapy with nafcillin and an aminoglycoside for two weeks has been shown to be effective in patients with right-sided endocarditis due to Staphylococcus aureus. In contrast, combined therapy with vancomycin and an aminoglycoside administered for two weeks does not appear to be effective in these patients. In addition, combined therapy withnafcillin and an aminoglycoside is not effective in left-sided endocarditis if treatment is given for only two weeks. Oral antibiotic therapy — Recently, several reports have appeared that describe the successful use of oral regimens for selected patients with IE. In general, oral regimens should not be used as initial therapy, but may be used in highly selected cases if the following criteria are met: the causative organism is known; the antimicrobial susceptibility has been carefully studied; in vitro studies show high levels of susceptibility; and there is a compelling reason to give oral therapy rather than conventional intravenous therapy. As an example, a recent randomized prospective study of right-sided endocarditis in injection drug users showed that combination oral therapy with rifampin and ciprofloxacin was as effective as parenteral therapy in patients in whom oral therapy could be closely supervised.Home antibiotic therapy — Until recently, most patients with IE received the entire duration of their antimicrobial therapy while in the hospital. However, the development of systems and equipment that permit prolonged and safe administration of intravenous therapy in the home has made it acceptable to treat selected patients with endocarditis as outpatients during much or even all of their therapy. Patients selected for outpatient therapy should be hemodynamically stable, compliant, and capable of managing the technical aspects of intravenous therapy. Such patients still require careful and regular monitoring, and must have ready access to full medical care should complications such as drug allergy, emboli, or cardiac failure occur.

VIRIDANS STREPTOCOCCI AND STREPTOCOCCUS BOVIS — The various species of streptococci that make up the viridans group and Streptococcus bovis account for approximately 60 percent of all cases of native valve endocarditis in community practice. Most of these organisms are highly penicillin-susceptible (eg, have a minimum inhibitory concentration (MIC) 0.1 µg/mL).

Endocarditis due to these organisms can usually be microbiologically cured if one of four different regimens is used 

A regimen consisting of aqueous crystalline penicillin G at a dose of 12 to 18 million units daily for four weeks is reliably effective in patients with endocarditis due to highly penicillin-susceptible streptococci. This regimen, or an equally effective regimen consisting of ceftriaxone given as a 2 gm daily dose for one month, remain the preferred treatments for elderly patients, or in other patients in whom aminoglycoside therapy is considered risky or contraindicated.

Selected patients with native valve endocarditis who do not have evidence of intracardiac or extracardiac complications, or preexisting renal or otic disease, may be treated with shorter courses of combination therapy consisting of either aqueous crystalline penicillin G or ceftriaxone, plus gentamicin. The last agent should be given at a dose designed to give a peakgentamicin serum level of 3 µg/mL (usually 1 mg/kg). Although streptomycin may also be given with either of the above beta-lactam antibiotics to achieve the same effect, gentamicin is more commonly used in clinical practice due to the wider availability of gentamicin serum levels, and because dosing regimens for gentamicin are more familiar to most clinicians than forstreptomycin.

Patients with prior histories of penicillin allergy can usually be treated with other beta lactam antibiotics, such as cefazolin, if their prior history of penicillin allergy consists of rash without other signs of immediate-type hypersensitivity. Patients with histories of immediate-type hypersensitivity may either be treated with vancomycin for four weeks, or desensitized to penicillin and treated with a standard regimen.

Patients with endocarditis due to viridans streptococci that have MICs >0.1 µg/mL, and those with endocarditis due to streptococci with nutritional deficiencies that hinder their growth in routine laboratory culture media, should receive aqueous penicillin G at a dose of 12 to 18 million units daily for a total of four weeks. Gentamicin should be added to this regimen for the first two weeks. As for other patients with streptococcal endocarditis who have had an immediate-type hypersensitivity reaction to beta lactams, vancomycin is an acceptable alternative to penicillin.

 

OTHER STREPTOCOCCAL SPECIES — Other streptococcal species (eg, Groups A, B,C, and G, and Streptococcus pneumoniae) are occasional causes of endocarditis. Therapy should always be based on the results of susceptibility testing. Since most of these organisms are highly sensitive to penicillin, regimens used to treat endocarditis due to viridans streptococci are typically effective.

Pneumococcal endocarditis typically follows pneumonia in alcoholic patients and may be complicated by concurrent meningitis. However, increasing numbers of isolates of Streptococcus pneumoniae have become relatively or highly resistant to penicillin. These organisms may be simultaneously resistant to other beta lactams and other antimicrobial agents. Therapy in these cases usually requires the input of an infectious disease specialist or a microbiologist. A few strains of Streptococcus pneumoniae only respond to vancomycin therapy.

ENTEROCOCCI — Enterococci have a more narrow spectrum of sensitivity than streptococcal species. In particular, members of the genus Enterococcus are all resistant to, at the least, low concentrations of penicillin; they are also relatively resistant to expanded spectrum penicillins, resistant to cephalosporins, and typically resistant to aminoglycosides at concentrations achieved after standard dosing regimens. However, if penicillin, ampicillin, or vancomycin are given in synergistic combination with an aminoglycoside such as gentamicin, many strains of enterococci are killed both in vitro and in vivo.

During the past 10 to 15 years, a number of new trends in the resistance pattern of enterococci have appeared. A few strains, almost all Enterococcus faecalis, have acquired genetic material that allows them to produce beta lactamase. Other strains have acquired high level resistance to streptomycin and/or gentamicin. The latter is accompanied by high level resistance to and/or resistance to synergy with tobramycin, netilmicin, and amikacin. In addition, non-penicillinase mediated high level resistance to penicillin and ampicillin (MIC  128 µg/mL) has increased in some enterococci (primarily strains of Enterococcus faecium). Finally, increasing numbers of enterococci have acquired high level resistance to vancomycin as well as toampicillin. Some, but not all of these highly resistant strains, are also resistant to the investigational glycopeptide antibiotic, teicoplanin, which is available in Europe but not in the United States.

These patterns of resistance have a direct impact on the guidelines for treatment of enterococcal endocarditis:

 

The majority of cases of enterococcal endocarditis are caused by strains of E. faecalis. Therapy for an E. faecalis with typical low level penicillin resistance consists of a combination of intravenous aqueous penicillin G (18 to 30 million units per day) or ampicillin (2 gm q 4h) plus gentamicin. Although ampicillin is about one dilution more potent then penicillin in vitro, there is no evidence that this is necessary or beneficial for synergism in most instances. Because of the possibility of increased reactions to ampicillin, some experts prefer penicillin rather thanampicillin for synergistic therapy. Gentamicin therapy is usually given at doses of 1 mg/kg every eight hours to achieve peak serum levels of approximately 3 µg/mL, and trough serum concentrations <1 µg/mL. Tobramycin and amikacin are usually avoided. (See “Mechanisms of antibiotic resistance in enterococci”). In one study, patients with symptoms for less than three months were usually treated successfully with four weeks of therapy. By contrast, six weeks of therapy is preferred in patients with symptoms of more than three months duration prior to the initiation of treatment, with a relapsed infection, or with prosthetic valve infection. Patients with a history of penicillin allergy should be treated with a combination ofvancomycin and gentamicin for four to six weeks or considered for desensitization. Patients with enterococcal prosthetic valve endocarditis do not seem to fare worse than those with enterococcal native valve endocarditis and often can be cured with antibiotics alone Enterococcal endocarditis due to strains with intrinsic high-level penicillin resistance (MIC>16 µg/mL) may be treated with a combination of vancomycin and gentamicin. The usual dose of vancomycin is 30 mg/kg daily given intravenously in two divided doses (not to exceed 2 gm per day, unless serum levels are monitored).

  •  Based upon animal model data, organisms that are resistant to penicillin via the production of beta-lactamase should respond to the combination of either ampicillin-sulbactam, orvancomycin plus an aminoglycoside to which the organism is not highly resistant. Unfortunately, most beta-lactamase producing E. faecalis have been highly resistant to streptomycin andgentamicin.

  •  Endocarditis due to enterococci with high level aminoglycoside and/or vancomycin resistance may require special evaluation by microbiologists or infectious disease specialists. (See “Treatment options for infections caused by vancomycin-resistant enterococci”). Some strains of enterococci that are streptomycin-resistant lack high-level resistance (HLR) to gentamicin, and vice versa; however, HLR to gentamicin is conferred by a bifunctional enzyme that confers high level resistance to and/or resistance to synergism with tobramycin, netilmicin, andamikacin, as well as gentamicin. When endocarditis is due to enterococci that are highly resistant to both streptomycin and gentamicin, the addition of an aminoglycoside is not beneficial.

Optimal therapy for such patients has not been defined but possible regimens include high dose ampicillin (up to 24 gm/day has been used, perhaps by continuous infusion, for 8 to 12 weeks. Subsequent surgical resection of the involved valve may be necessary for cure.

STAPHYLOCOCCAL ENDOCARDITIS — The success of therapy for staphylococcal endocarditis is dependent upoumerous factors, including involvement of right versus left-sided valvular structures, whether the staphylococcus is coagulase negative or positive, the susceptibility of the staphylococcal isolate, and whether the infection occurs on a native or prosthetic valve.

Native valve endocarditis — Native valve endocarditis due to Staphylococcus aureus is best treated with a semisynthetic penicillin, such as nafcillin or oxacillin (2 gm given intravenously every four hours), for four to six weeks. Many authorities recommend the addition of gentamicin for the first three to five days of therapy, since methicillin-susceptible strains of Staphylococcus aureus are more rapidly killed with combined therapy in vitro and in experimental models of endocarditis. However, there is no consensus that this is the optimal approach. For example, a multicenter collaborative study of native valve endocarditis due to methicillin-susceptible strains of Staphylococci randomized patients to receive the combination of nafcillin plus gentamicin given for the first two weeks of therapy, or nafcillin alone. Although combination therapy was associated with more rapid clearing of the bacteremia, patients in this group did not have improved cure rates when compared to those receiving monotherapy. Furthermore, combination nafcillin and gentamicin therapy was associated with a higher incidence of renal dysfunction. We recommend adding gentamicin to beta lactam therapy only for the first three to five days of treatment.

Patients with native valve endocarditis due to Staphylococcus aureus who have a history of penicillin allergy, can be treated with either first generation cephalosporins, such as cefazolin (2 gm intravenously every eight hours if there is no prior history of penicillin reaction that is typical of an immediate-type allergy), or vancomycin. Vancomycin should not be used on the basis of convenience related to pharmacokinetics in patients without a history of penicillin allergy, since recent clinical experience and in vitro studies have suggested that vancomycin is a less effective antistaphylococcal antibiotic than nafcillin or oxacillin .

Selected patients with native valve right-sided endocarditis due to Staphylococcus aureus may be successfully treated with two week regimens utilizing the combination of nafcillin andgentamicin . Regimens that substitute vancomycin or cefazolin for nafcillin (eg, for penicillin allergic patients) are not considered to be reliably effective if only two weeks of therapy is given. Short course regimens utilizing combination therapy are also not suitable for patients with simultaneous infection of the left-side heart valves, isolates that demonstrate high-levelgentamicin resistance (MIC >500 µg/mL), or metastatic infections outside of the lungs.

Treatment regimens for coagulase-negative staphylococci (eg, Staphylococcus epidermidis) are identical to those for coagulase-positive organisms. However, most strains of coagulase-negative staphylococci are methicillin-resistant. Thus, unless susceptibility to methicillin can be conclusively demonstrated, coagulase-negative staphylococci should be assumed to bemethicillin-resistant and treated as described below.

Prosthetic valve endocarditis — Patients with prosthetic valve endocarditis due to methicillin-susceptible Staphylococcus aureus should be treated with nafcillin or an equivalent beta-lactamase resistant beta lactam antibiotic for at least six weeks. Most authorities recommend simultaneously treating with oral rifampin (300 mg orally every 8 h), as these infections are notoriously difficult to cure with medical therapy. In addition, we and many other experts advise the addition of gentamicin for the first two weeks of therapy. A first generation cephalosporin or vancomycin may be substituted for nafcillin in patients with a history of penicillin allergy.

Methicillin resistant staphylococci — The only effective therapy for patients with endocarditis due to methicillin-resistant staphylococci is vancomycin .

Monotherapy with vancomycin for four to six weeks is usually adequate for native valve endocarditis due to either methicillin-resistant Staphylococcus aureus or coagulase-negative staphylococci. When methicillin-resistant staphylococci cause infection in patients with prosthetic valves, or in the presence of other prosthetic material, combination therapy is generally used.

 

These patients can be treated with intravenous vancomycin and oral rifampin therapy for six to eight weeks. Gentamicin is also recommended for the first two weeks of this therapeutic regimen. Coagulase negative staphylococci — Treatment regimens for coagulase-negative staphylococci are identical to that for coagulase-positive staphylococci. Most strains of coagulase-negative staphylococci are methicillin-resistant. As a result, unless susceptibility to methicillin can be conclusively demonstrated, coagulase-negative staphylococci causing prosthetic valve endocarditis should be assumed to be methicillin-resistant and treated accordingly

. HACEK ORGANISMS — A number of fastidious Gram negative bacilli, collectively grouped by the acronym “HACEK,” account for 5 to 10 percent of all cases of native valve endocarditis in individuals who do not use illicit intravenous drugs. Organisms in this category include the following: Haemophilus parainfluenzae; Haemophilus aphrophilus; Actinobacillus actinomycetemcomitans; Cardiobacterium hominis; Eikenella corrodens; and Kingella kingae. All of these organisms grow slowly in blood culture media, and incubation for 7 to 14 days may be required to detect their growth. This delayed growth makes standard antibiotic susceptibility testing difficult.

Although most HACEK organisms were ampicillin-sensitive in the past, this is no longer true, as many species in this group have acquired the ability to produce beta-lactamase. However, virtually all of these organisms are highly susceptible to third generation cephalosporins, such as ceftriaxone (2 gm once daily, given IV or IM) or cefotaxime (6 gm per day in three divided doses, given IV). Either agent is usually effective when given for three to four weeks in patients with native valve endocarditis and four to six weeks in those with prosthetic valve endocarditis.