Paula A. Teichner, Pharm.D.
By the end of this lecture, the student should be able to:
Pharmacotherapy. A Pathophysiologic Approach. 3rd Edition, 1996. Chapter 104. Infective Endocarditis. Pages 2081-2099. or 2nd Edition. 1992. Chapter 99. Pages 1614-31.
Endocarditis is defined as an infection of the heart valves or mural endocardium. In the past was classified as acute or subacute based on the clinical presentation of the disease. Although useful conceptually, this classification is no longer used, but is now based on the etiologic agent. This classification system is preferable since it has implications for the course usually followed, the likelihood of underlying heart disease and the appropriate antimicrobial agents to use.
Acute Bacterial Endocarditis typically is associated with a fulminant course, usually with high fever, systemic toxicity, leucocytosis, and death within a few days to weeks if untreated. This infection is classically caused by virulent organisms such as S. aureus which occurs in patients with previously normal valves.
Subacute Bacterial Endocarditis usually occurs in patients with prior valvular disease and is characterized by a slow, indolent course associated with low grade fever, night sweats, weight loss and vague systemic complaints. Classically caused by viridans streptococci.
PATHOGENESIS
Acute endocarditis - usually acute onset of fever, chills back pain, myalgias. Patients look ill.
Subacute endocarditis - insidious onset of a variety of symptoms such as weakness, fatigue, anorexia, night sweats, weight loss, fever. Symptoms may be present for weeks to months. Onset may be related to antecedent events such as dental work.
1. Cardiac signs
Heart murmur - present in 85% or more of cases. Vegetations on heart valve may be single or multiple and consist of fibrin, platelet aggregates, and bacterial masses. Usually affects aortic or mitral valves. CHF may be present if significant valvular insufficiency.
2. Embolic phenomena
-hematuria (emboli to kidneys)
3. Central Nervous System
-stroke, sensory loss, aphasia, altered mental status
4. Splenomegaly (25-60% of patients)
5. Musculoskeletal
-arthralgias, myalgias, low back pain
6. Skin Manifestations
-Petechiae (20-40% of cases)
-Osler nodes - small painful nodular lesions usually in pads of fingers/toes.
-Janeway lesions - hemorrhagic, macular plaques usually seen on palms and soles. -Splinter hemorrhages - found in nail beds.
7. Eye
-Roth Spots - retinal lesions surrounded by hemorrhage.
A. Non-Specific Findings
1. Increased Erythrocyte Sedimentation Rate (ESR).
2. Anemia - normochromic, normocytic
3. WBC - usually normal or moderately increased.
4. Thrombocytopenia
5. Rheumatoid Factor - present in 40-50% of patients with disease > several weeks.
6. Microscopic hematuria and proteinuria - detected on urinalysis.
B. Blood Cultures
The single most important laboratory test! Must be obtained if endocarditis is suspected. Cultures are positive in 85-95% of cases. 3-4 blood cultures should be obtained, taken from separate venipuncture sites, at 15-30 minute intervals. Blood cultures should be held for 3 weeks. Usually a continuous, low-grade bacteremia.
C. Echocardiography (ECHO) - 2D ECHO will reveal vegetations in 40-80% of patients. A negative ECHO does not rule out bacterial endocarditis. Transesophageal ECHO (TEE) more sensitive than 2D in detecting vegetations (85-90%).
The diagnosis of endocarditis should be considered in any patient with fever for several days and no obvious source of infection and in association with a significant heart murmur.
ETIOLOGIC AGENTS CAUSING ENDOCARDITIS
1. Streptococci- occur in 60-80% of cases of endocarditis. Usually seen in children and young women with mitral valve involvement.
-35% of cases caused by viridans streptococci (S. mitis, sanguis, mutans, salivarius, intermedius, bovis, mitior).
-10% of cases caused by enterococcus.
-10% of cases due to S. pneumoniae (seen in alcoholics) or other streptococci..
2. Staphylococci - Approximately 35% of cases of infective endocarditis. Of these, 80- 90% are caused by S. aureus.
3. Other - Minority of cases caused by enteric gram negative bacilli, P. aeruginosa, fungi, anaerobes, etc.
4. Culture Negative - May be due to slow-growing, fastidious organisms (HACEK) or can occur in patients who have received prior antibiotics
Bacteria in vegetations are surrounded by fibrin >> inaccessible to phagocytic cells. Also bacteria within vegetations are in high density (108-1010 org/gram of tissue). At these densities, there is decreased metabolism and cell division >> decreased bactericidal effects of penicillins.
Basic Principles: Bactericidal antibiotics necessary
Prolonged therapy (to eradicate all organisms from valve)
Need IV therapy
High doses to produce sustained, bactericidal levels
May use antimicrobial combinations (synergy)
Selection of antibiotics should be based on susceptibilities
The ease of bacteriologic cure generally tends to be related to the degree of antibiotic susceptibility of the infecting organism.
Laboratory Aids in Treating Endocarditis
1. MIC/MBC of organism - should be determined by tube dilution tests, in addition to the usual disc susceptibilities.
2. Serum Bactericidal Test (SBT) - is the highest dilution of the patients' serum (obtained while they are receiving antibiotic therapy) that kills a standard inoculum of the patients' organism in vitro. Peak SBT >greater than or equal to 1:8 is desirable. Not routinely used, but may be helpful when response to treatment is suboptimal, endocarditis is due to an unusual organism, or when unconventional treatment is used.
3. Drug Levels - should be monitored for specific antimicrobials. When aminoglycosides are used for synergy, peak levels of 3 g/ml for gentamicin and 20 g/ml for streptomycin are desirable.
Initiating Therapy
For acute bacterial endocarditis, get 3-4 blood cultures over a 1 hour period start therapy promptly to prevent progression. In a patient with a subacute presentation, obtain blood cultures over a 1-2 day period. Await culture results before starting antimicrobial therapy.
ANTIBIOTIC THERAPY FOR SPECIFIC ORGANISMS CAUSING ENDOCARDITIS
A. VIRIDANS STREPTOCOCCI (See Table 104.3, page 2086)
Most common in subacute endocarditis in patients with native valves and underlying heart disease. Strep bovis is not a viridans streptococci, but a non-enterococcal Group D streptococci. Will include in this section because it is penicillin sensitive and the treatment regimen is the same as that for viridans streptococci.
Penicillin Sensitive (MIC < 0.1 g/ml) -Penicillin G is the drug of choice, either alone or in combination with an aminoglycoside.
1. Penicillin alone. Dose of 12-18 million units/day given q4 hours x 4 weeks. Bacteriologic cure in 99% of patients. Use in patients with impaired renal function or at risk for nephrotoxicity.
2. Penicillin plus an aminoglycoside. Combination results in synergistic killing of bacteria. Penicillin 12-18 million units/day given q4 hours plus either streptomycin 7.5 mg/kg (not to exceed 500 mg) IM q12 hours OR gentamicin 1.0 mg/kg (not to exceed 80 mg dose) IV/IM, for 2 weeks. This can be the total length of therapy, or this regimen can be followed by another 2 weeks of penicillin alone. The 2-week combination-therapy regimen is the most cost-effective, but should only be used in uncomplicated, penicillin-sensitive cases where the patient is at low risk for nephrotoxicity. The 4 week course should be used in patients with a complicated course or history of disease > 3 months.
3. Aminoglycoside use. Aminoglycosides are used for synergy against streptococci. Although streptomycin and gentamicin are interchangeable, gentamicin is preferred due to cost, drug availability, physician familiarity, and the ability to obtain serum levels. Serum peak concentrations of 3 g/ml for gentamicin and 20 g/ml for streptomycin. {These are significantly lower than those typically used for the treatment of serious gram (-) infections.}
4. Ceftriaxone 2 gram IV or IM qd x 4 weeks. Bacteriologic cure of up to 98%. Useful for patients treated in outpatient setting.
Tolerant Streptococci (MIC >0.1 and < 0.5) (See Table 104.4, page 2086)
Penicillin 20 million units/day in 6 divided doses X 4 weeks PLUS either gentamicin 1.0 mg/kg (not to exceed 80 mg) IV/IM q8 hours or streptomycin 7.5 mg/kg (not to exceed 500 mg ) IM q12 hours for at least 2 weeks.
Penicillin resistant strep viridans (MIC > 0.5) - uncommon.
Treat with both penicillin and aminoglycoside. Treatment is the same as for enterococcal endocarditis (See Below).
Penicillin Allergic Patients - Make sure patient really has a true allergy because experience with penicillin is far more favorable. May consider skin-testing to determine if true allergy.
(See Table 104.5, page 2087).
1. Penicillin hypersensitivity (not immediate hypersensitivity)
Cephalothin 2 gm IV q4 hours or cefazolin 1 gm IV q8 hours x 4 weeks. Aminoglycoside may be added for the first 2 weeks.
2. Immediate-Type PCN hypersensitivity
Vancomycin 30 mg/kg/day given in 2 divided doses x 4 weeks. Dosage adjustment may be required in patients with renal dysfunction. Serum peak concentrations of 30-45 g/ml are desirable.
B. STAPHYLOCOCCI (See Table 104.6, page 2088)
Staphylococcal endocarditis is seen in patients with intravenous catheters, patients who use intravenous drugs, and in patients with prosthetic valves. Management of this disease requires consideration of several factors:
1. Is the organism methicillin-resistant?
2. Should combination therapy be used?
3. Is the infection on a native or prosthetic heart valve?
4. Is the patient an intravenous drug abuser?
Absence of Prosthetic Material (Native Valve) ( Both S. aureus and S. epidermidis)
1. Methicillin Susceptible. Give Nafcillin 2 gm IV q4 hours X 4-6 weeks, PLUS gentamicin 1.0 mg/kg (not to exceed 80 mg) IV/IM q8 hours for 3-5 days (aminoglycoside optional). Although combination therapy trials have failed to show an improved outcome, combination therapy causes a more rapid killing of the bacteria and sterilization of the valve.
2. Penicillin Allergic (not immediate hypersensitivity). Cephalothin 2 gm IV q4 hours or Cefazolin 2 gm IV q8 hours X 4-6 weeks, with the option of gentamicin for the first 3-5 days (dose as above).
3. Penicillin Allergic (immediate hypersensitivity reaction). Vancomycin 30 mg/kg/day in 2 divided doses X 4-6 weeks. Avoid aminoglycoside due to concern of increased nephrotoxicity. Vancomycin is less rapidly bactericidal than nafcillin in vitro against Staph aureus. Failure rates up to 40%.
4. Methicillin-Resistant Staphylococci (MRSA). Vancomycin 30 mg/kg/day in 2 divided doses X 4-6 weeks. Levels as above.
5. Oral Therapy. After 2 weeks of parenteral therapy, may try high doses of oral semisynthetic penicillins. Give X 4 weeks, after 2 weeks IV. SBT may be of benefit to assure adequate bactericidal activity.
Ciprofloxacin plus rifampin given orally also shown to have some benefit in staphylococcal endocarditis. Further studies needed before this therapy can be recommended.
C. ENTEROCOCCI (See Table 104.8, page 2090).
When treating enterococcal infections, there are several key things to remember:
a. No single antibiotic is bactericidal against E. faecalis (ie. B-lactams and vancomycin are bacteriostatic).
b. Effective bactericidal therapy requires addition of aminoglycoside for full treatment course.
c. Cell-wall antibiotics PLUS aminoglycosides act synergistically against enterococci.
d. Low dose aminoglycoside is as good as high dose (ie. peak level 3 g/ml).
e. Enterococci are NOT inhibited by cephalosporins.
Non-Penicillin Allergic
Penicillin G 20-30 million units/day in 6 divided doses OR Ampicillin 2 gm IV q4 X 4-6 weeks PLUS streptomycin 7.5 mg/kg (not to exceed 500 mg) IM q12 hours OR gentamicin 1 mg/kg (not to exceed 80 mg) IV/IM q8 hours X 4-6 weeks.
If streptomycin MIC > 2000 g/ml, use gentamicin. If strain of enterococcus exhibits high-level resistance to all aminoglycosides >> DO NOT use. Unlikely to provide any clinical benefit.
Peak level of streptomycin = 20 g/ml. Peak levels of gentamicin should be 3
g/ml.
Penicillin Allergic Patient
Vancomycin 30 mg/kg/day in 2 divided doses for 4-6 weeks PLUS aminoglycoside (regimens same as above) X 4-6 weeks. Serum levels for vancomycin and aminoglycoside as mentioned above.
CANNOT USE CEPHALOSPORINS TO TREAT ENTEROCOCCAL INFECTIONS
Incidence 1-2%. Divided into 2 categories:
1. Early - those infections occurring within 12 months (usually first 2 months) of valve replacement. Infections acquired at the time of surgery or early post-op. Usually caused by S. epidermidis. Can be gram negative bacilli, fungi or S. aureus.
2. Late - occur > 12 months post-op. Usually due to streptococci.
Regimen for Methicillin Susceptible Staphylococci (Epidermidis and aureus) (Table 104.7, Page 2089)
Nafcillin 2 gm IV q4 hours PLUS rifampin 300 mg po q8 hours X at least 6 weeks, PLUS gentamicin 1.0 mg/kg IV q8 hours for the first 2 weeks. Gentamicin levels as above.
Regimen for Methicillin-Resistant Staphylococci (Epidermidis and aureus) (Table 104.7, Page 2089)
Vancomycin 30 mg/kg/day given in 2 divided doses PLUS rifampin 300 mg po q8 hours for at least 6 weeks PLUS gentamicin X 2 weeks.
Use of rifampin for S. aureus infections associated with prosthetic valves is based on favorable clinical experience.
ENDOCARDITIS IN INTRAVENOUS DRUG ABUSERS
Microbiology
1. Staphylococcus aureus is the most common cause on endocarditis in this population. Occurs in 60-80% of cases.
2. Streptococci (20%) - usually causes left-sided endocarditis.
3. Gram negative bacilli and Pseudomonas (10-15%).
4. Candida spp. (5%).
Features of Endocarditis
1. Infection usually localized to the tricuspid valve causes Right-sided endocarditis.
2. Death and serious complications of heart failure and stroke are less likely to occur.
3. Usually no prior history of heart disease.
4. Symptoms usually 1-2 weeks in duration, fever almost always present.
5. May have increased risk for MRSA.
6. Patients often have cough, dyspnea, pleuritic chest pain associated with pneumonia.
Antimicrobial Therapy
Treatment is the same as for other patients with staphylococcal endocarditis (without prosthetic material). Right-sided endocarditis may be easier to cure 2 fewer organisms present.
Shorter courses (2 weeks) of therapy have been shown to be successful in IVDA with right sided endocarditis:
Nafcillin 1.5 gm IV q4 hours PLUS tobramycin 1 mg/kg IV q8 hours X 2 WEEKS. (Was studied with tobramycin; gentamicin is also acceptable).
As vancomycin appears less effective than B-lactams, not recommended for use in short-course treatment of staph endocarditis
Short-course therapy should only be considered in patients without evidence of renal failure, extrapulmonary complications, aortic or mitral valve involvement, meningitis or infection with MRSA.
ROLE OF SURGERY IN THE MANAGEMENT OF ENDOCARDITIS
Sometimes antimicrobial therapy alone is inadequate to sterilize the cardiac valve. In these cases, valve replacement may be indicated. Below are some reasons for surgical intervention.
1. Fungal endocarditis
2. Progressive or significant CHF that doesn't respond to medical therapy.
3. Persistent bacteremia (7-10 days) despite appropriate antibiotics.
4. Septic emboli - > 1 serious embolic event.
5. Prosthetic valve endocarditis.
6. Relapse of infection.
7. Evidence of extension of infection ie. pericarditis, valvular ring abscess, etc.
8. Vegetations - depends on size, location, and clinical assessment.
Improvement in symptoms, decreased fever and negative blood cultures occurs fairly quickly with sensitive organisms (24-48 hours), but with organisms such as S. aureus >> may take days to a week before definite improvement is noted.
If fever recurrence, may be caused by:
1. Failure to control infection
2. Phlebitis
3. Metastatic abscess formation
4. Recurrent emboli
5. Superimposed infection
6. Drug fever