Infectious Disease I: Infective Endocarditis

Infectious Disease I: Infective Endocarditis
Courses in Therapeutics and Disease State Management

Learning Objectives (Slide 1 of 3)
List patient populations at increased risk for developing infective endocarditis (IE) Delineate bacteria that commonly cause IE as well as situations where certain bacteria are more likely Describe the sequential steps necessary to develop hematogenous spread of IE Identify the clinical manifestations of the disease, including physical findings, laboratory abnormalities, blood cultures, and other diagnostic test (e.g., echocardiography) Argue the importance of correctly obtained blood cultures and state situations that may lead to “culture-negative” IE

Justify the rationale for high-dose parenteral, bactericidal, extended- duration antibiotics for IE treatment Summarize the role of nonpharmacologic approaches (i.e., surgery) in the treatment of IE and identify situations where this approach is preferred Design drug regimens for the following types of infective endocarditis: streptococci, staphylococci, enterococci, the HACEK microorganisms, and “culture-negative” IE Describe why β-lactam antibiotics are preferred for the treatment of IE and classify situations where vancomycin is appropriate Evaluate the role of penicillin skin tests in patients with a documented penicillin allergy

Outline specific monitoring parameters during IE treatment, including signs and symptoms, blood cultures, microbiologic tests, serum drug concentrations, and tests that evaluate organ function Identify patients who should receive antimicrobials for IE prophylaxis as well as bacteremia-causing procedures that can lead to IE in predisposed individuals In high-risk groups receiving bacteremia-causing procedures, devise a prophylactic antimicrobial regimen and list alternative regimens in those with an immediate-type penicillin allergy

Required Reading Veverka A, Crouch MA, Odle BL. Chapter 89. Infective Endocarditis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015; 132:1435–86. Gerber MA, Baltimore RS, Eaton CB, et. Al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation. 2009;119:1541–15

Overview Serious infection involving the lining and valves of the heart Acute Disease High fevers Elevated WBC counts Systemic toxicity Sub-acute Disease Slower and more subtle presentation Low grade fevers Night sweats Fatigue Endocarditis is an inflammation of the endocardium, the membrane lining the chambers of the heart and covering the cusps of the heart valves While it commonly affects native valves, it also may involve nonvalvular areas or implanted mechanical devices Differentiation between acute and subacute depends on the severity of symptoms on presentation Most commonly due to bacterial pathogens, but fungal and other atypical pathogens can be the cause of infective endocarditis

Risk Factors Presence of a prosthetic valve (highest risk)
Previous endocarditis (highest risk) Congenital heart disease (CHD) Chronic IV access Diabetes mellitus Healthcare-related exposure Acquired valvular dysfunction Cardiac implantable device Chronic heart failure Mitral valve prolapse with regurgitation IV drug abuse Endocarditis is rare, but not uncommon Most persons with infective endocarditis have risk factors, such as preexisting cardiac valvular abnormalities The mitral and aortic valves are affected most commonly in cases involving a single valve. Infections of the tricuspid valve occur less often and are associated with IV drug abusers

Pathophysiology Hematogenous spread is the most common pathway
Endothelial surface of the heart must be damages Platelet and fibrin depositions occur on the damaged epithelial surface Bacteremia gives organisms access to and results in colonization of the endocardial surface After colonization of the endothelial surface, a “vegetation” of fibrin, platelets, and bacteria forms Implantation of prosthetic values or other cardiac hardware that has been contaminated with pathogens is another pathway for endocarditis The mitral and aortic valves are affected most commonly in cases involving a single valve. Infections of the tricuspid valve occur less often and are associated with IV drug abusers prosthetic material may be contaminated with bacteria from the patient’s skin or operating room personnel Bacteria within the vegetations grow slowly and are protected from antibiotics and host defense. a) local perivalvular damage b) embolization of septic fragments with potential hematogenous seeding of remote sites c) formation of antibody complexes Vegetations may be friable, and fragments may be released downstream

Pathophysiology: Most Common Pathogens
Agent Percentage of Cases Staphylococci 30–70 Coagulase positive 20–68 Coagulase negative 3–26 Streptococci 9–38 Viridans streptococci 10–28 Other streptococci 3–14 Enterococci 5–18 Gram-negative aerobic bacilli 1.5–13 Fungi 1–9 Miscellaneous bacteria <5 Mixed infections 1–2 “Culture negative” <5–17 Table 89-1 Etiologic Organisms in Infective Endocarditis Values encompass community-acquired, healthcare-associated, native valve, and prosthetic valve infective endocarditis Nearly every organism causing human disease may cause infective endocarditis, but three groups of organisms result in a majority of cases: streptococci, staphylococci, and enterococci

Clinical Presentation (Slide 1 of 3)
Symptoms Signs Fever Chills Night Sweats Weakness Dyspnea Weight Loss Myalgia or arthralgia Fever New or changing heart murmur Embolic Phenomena Skin manifestations Clubbing of extremities Presentation of endocarditis can be variable and non specific making early identification of this infection difficult for clinicians Skin manifestation examples :Osler’s nodes, Janeway’s lesions Osler’s nodes: Purplish or erythematous subcutaneous papules or nodules on the pads of the fingers and toes. These lesions are 2 to 15 mm in size and are painful and tender. These nodes are not specific for infective endocarditis and may be the result of embolism, immunologic phenomena, or both. Janeway’s lesions: Hemorrhagic, painless plaques on the palms of the hands or soles of the feet. These lesions are believed to be embolic in origin. Splinter hemorrhages: Thin, linear hemorrhages found under the nail beds of the fingers or toes. These lesions are not specific for infective endocarditis and more commonly are the result of traumatic injuries. Distal lesions are more likely the result of trauma, whereas proximal lesions tend to be associated with infective endocarditis. Petechiae: Small (usually 1 to 2 mm in diameter), erythematous, painless, hemorrhagic lesions. These lesions appear anywhere on the skin but more frequently on the anterior trunk, buccal mucosa and palate, and conjunctivae. Petechiae are nonblanching and resolve after a few days. Clubbing of the fingers: Proliferative changes in the soft tissues about the terminal phalanges observed in long-standing endocarditis. Roth’s spots: Retinal infarct with central pallor and surrounding hemorrhage. Emboli: Embolic phenomena occur in up to one third of cases and may result in significant complications. Left-sided endocarditis can result in renal artery emboli causing flank pain with hematuria, splenic artery emboli causing abdominal pain, and cerebral emboli, which may result in hemiplegia or alteration in mental status. Right-sided endocarditis may result in pulmonary emboli, causing pleuritic pain with hemoptysis.

Laboratory Tests Diagnostic Tests WBC count normal or elevated Anemia Elevated C-reactive protein (CRP) Elevated erythrocyte sedimentation rate (ESR) Altered urinary analysis Blood Cultures Electrocardiogram Chest radiograph Echocardiogram Transthoracic (TTE) Transesophogeal (TEE) Presentation of endocarditis can be variable and non specific making early identification of this infection difficult for clinicians Urinalysis alterations: Proteinuria/microscopic hematuria The hallmark laboratory finding is continuous bacteremia; three sets of blood cultures should be collected over 24 hours Three sets of blood cultures, each from separate venipuncture sites, should be collected over 24 hours, and antibiotics should be withheld until adequate blood cultures are obtained unless the patient is acutely septic “Culture-negative” endocarditis describes a patient in whom a clinical diagnosis of infective endocarditis is likely but blood cultures do not yield a pathogen. This condition is often the consequence of previous antibiotic therapy, improperly collected blood cultures, or unusual organisms Some pathogens may take longer than 5 days to grow in the laboratory Echocardiography to determine the presence of valvular vegetations plays a key role in the diagnosis of infective endocarditis; it should be performed in all suspected cases TEE technique is more sensitive for detecting vegetations

The signs and symptoms of infective endocarditis are not specific, and the diagnosis is often unclear The Duke diagnostic criteria integrate clinical, laboratory, and echocardiographic findings to identify the likelihood a patient has endocarditis Patients are grouped into one of three categories Definite infective endocarditis Possible infective endocarditis Infective endocarditis rejected

Modified Duke Criteria: Major Criteria (Slide 1 of 2)
Blood culture positive for IE Typical microorganisms consistent with IE from 2 separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or community-acquired enterococci in the absence of a primary focus; or Microorganisms consistent with IE from persistently positive blood cultures defined as follows: At least 2 positive cultures of blood samples drawn 12 h apart; or all of 3 or a majority of 4 separate cultures of blood (with first and last sample drawn at least 1 h apart) Single positive blood culture for Coxiella burnetii or anti–phase 1 IgG antibody titer >1:800

Modified Duke Criteria: Major Criteria (Slide 2 of 2)
Evidence of endocardial involvement Echocardiogram positive for IE (TEE recommended for patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE paravalvular abscess; TTE as first test in other patients) defined as follows: 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; new valvular regurgitation (worsening or changing or preexisting murmur not sufficient)

Modified Duke Criteria: Minor Criteria
Predisposition, predisposing heart condition, or IVDA Fever, temperature >38°C Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s lesions Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor Microbiological evidence: positive blood culture but does not meet a major criterion as noted above* or serological evidence of active infection with organism consistent with IE

Modified Duke Criteria: Diagnostic Scoring (Slide 1 of 2)
Definite Infective Endocarditis Pathological criteria Microorganisms demonstrated by culture or histological examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen Pathological lesions; vegetation or intracardiac abscess confirmed by histological examination showing active endocarditis Clinical criteria 2 major criteria 1 major criterion and 3 minor criteria 5 minor criteria

Modified Duke Criteria: Diagnostic Scoring (Slide 2 of 2)
Possible IE 1 major criterion and 1 minor criterion 3 minor criteria Rejected Firm alternative diagnosis explaining evidence of IE; or Resolution of IE syndrome with antibiotic therapy for 4 days; or No pathological evidence of IE at surgery or autopsy, with antibiotic therapy for 4 days; or Does not meet criteria for possible IE as above

Goal Outcomes Relieve the signs and symptoms of the disease
Decrease morbidity and mortality associated with the infection Eradicate the causative organism with minimal drug exposure Provide cost-effective antimicrobial therapy determined by the likely or identified pathogen, drug susceptibilities, hepatic and renal function, drug allergies, and anticipated drug toxicities Prevent infective endocarditis from occurring or recurring in high-risk patients with appropriate prophylactic antimicrobials

Treatment Overview Empiric antibiotic treatment until an infecting pathogen is isolated High dose, parenteral, bactericidal pathogen specific antibiotics for an extended period A minimum of 4 to 6 weeks of antibiotic therapy is generally required The outcome for endocarditis is improved with rapid diagnosis, appropriate treatment (, and prompt recognition of complications should they arise An extended duration of therapy is required, even for susceptible pathogens, because microorganisms are enclosed within valvular vegetations and fibrin deposits. These barriers impair host defenses and protect microbes from phagocytic cells. In addition, high bacterial concentrations within vegetations may result in an inoculum effect that further resists killing

Nonpharmacological Treatment
Surgical removal, repair, and/ or replacement of infected valves or cardiac hardware Support of vital functions valvectomy and valve replacement are performed to remove infected tissue and to restore hemodynamic function

Pharmacological Treatment
β-Lactam antibiotics, such as penicillin G (or ceftriaxone), nafcillin, and ampicillin, remain the drugs of choice The use of synergistic antimicrobial combinations may be required for certain pathogens to obtain a bactericidal effect Once the infecting pathogen is identified, there are detailed guidelines for the treatment of each specific bacteria Bactericidal activity is required for successful treatment of infective endocarditis

Pathogen Specific Therapies (Slide 1 of 7)
Native Valve Endocarditis caused by highly penicillin- susceptible (MIC≤ mcg/mL) viridans group streptococci and Streptococcus gallolyticus (bovis) Regimen Duration (weeks) Adult Dose Aqueous crystalline penicillin G sodium 4 12-18 million units/24 hours Ceftriaxone 2 grams/24 hours Vancomycin Trough goal 10-15 plus Gentamicin (traditional dosing peak of 3-4 mcg/ml) 2 Vancomycin therapy is reasonable only for patients unable to tolerate penicillin or ceftriaxone; Streptococci are a common cause of infective endocarditis, with most isolates being viridans streptococci. Streptococci are normal flora in the mouth and gingiva. Manipulation of the gums and teeth during normal brushing and dental procedures may cause a transient bacteremia. Bacteria can adhere to damaged endocardial tissues and develop into endocarditis in susceptible patients. Combined treatment results in quicker sterilization of vegetations in animal models of endocarditis and probably explains the high response rates observed for patients treated for a total of 2 weeks

Native Valve Endocarditis caused by Streptococcus gallolyticus (bovis) and viridans group streptococci relatively resistant to penicillin (MIC> 0.12 mcg/mL) Regimen Duration (weeks) Adult Dose Aqueous crystalline penicillin G sodium 4 24 million units/24 hours Plus Gentamicin (traditional dosing peak of 3-4 mcg/ml) 2 Vancomycin Trough goal 10-15 Vancomycin therapy is reasonable only for patients unable to tolerate penicillin or ceftriaxone Ceftriaxone may be a reasonable alternative treatment option for VGS isolates that are susceptible to ceftriaxone

Prosthetic Valve Endocarditis caused by highly penicillin- susceptible (MIC≤ 0.12 mcg/mL) viridans group streptococci and Streptococcus gallolyticus (bovis) Regimen Duration (weeks) Adult Dose Aqueous crystalline penicillin G sodium 6 12-18 million units/24 hours Ceftriaxone 2 grams/24 hours Vancomycin Trough goal 10-15 plus Gentamicin (traditional dosing peak of 3-4 mcg/ml) 2 Vancomycin therapy is reasonable only for patients unable to tolerate penicillin or ceftriaxone; Ampicillin 2 g IV every 4 h is a reasonable alternative to penicillin if a penicillin shortage exists

Prosthetic Valve Endocarditis caused by Streptococcus gallolyticus (bovis) and viridans group streptococci relatively resistant to penicillin (MIC> 0.12 mcg/mL) Regimen Duration (weeks) Adult Dose Aqueous crystalline penicillin G sodium 6 24 million units/24 hours Plus Gentamicin (traditional dosing peak of 3-4 mcg/ml) 2 Ceftriaxone 2 grams/24 hours Vancomycin 4 Trough goal 10-15 Vancomycin therapy is reasonable only for patients unable to tolerate penicillin or ceftriaxone Ceftriaxone may be a reasonable alternative treatment option for VGS isolates that are susceptible to ceftriaxone

Native Valve Endocarditis caused by Staphylococci Regimen Duration (weeks) Adult Dose MSSA Oxacillin or Nafcillin 6 12g/24 hours Cefazolin 6 gm/24 hours MRSA Vancomycin Trough goal 10-20 Daptomycin ≥ 8 mg/kg/dose For MSSA infections cefazolin is an acceptable alternative to nafcillin or oxacillin in patients with a history of nonanaphylactoid reactions to penicillin. For MSSA infections vancomycin and daptomycin are both acceptable alternatives to nafcillin or oxacillin or cefazolin in patients with a history of anaphylactoid reactions to penicillin. hVISA, VISA or VRSA infections should be managed by an ID specialist Endocarditis caused by staphylococci has become more prevalent, mainly because of increased IVDA, more frequent use of peripheral and central venous catheters, and increased frequency of valve replacement surgery

Prosthetic Valve Endocarditis caused by Staphylococci Regimen Duration (weeks) Adult Dose MSSA Oxacillin or Nafcillin 6+ 12g/24 hours Plus Rifampin 900 mg/24 hours Plus gentamicin 2 Traditional dosing Peak goal 3-4 mcg/ml MRSA Vancomycin Trough goal 10-20 6 + The addition of rifampin to a penicillinase-resistant penicillin or vancomycin does not result in predictable bacterial synergism, rifampin may have unique activity against staphylococcal infection that involves prosthetic material, where its addition results in a higher microbiologic cure rate

Prosthetic or Native Valve Endocarditis caused by Enterococci Regimen Duration (weeks) Adult Dose Ampicillin 4-6 12g/24 hours Plus gentamicin Traditional dosing Peak goal 3-4 mcg/ml OR Aqueous crystalline penicillin G sodium 18-30 million units/24 hours Plus Ceftriaxone 2 gm IV Q 12H Vancomycin Trough goal 10-15 Monotherapy with penicillin for infective endocarditis caused by enterococci results in relapse rates of 50% to 80%. When used alone, penicillins are only bacteriostatic against enterococci, and combination therapy is always recommended for susceptible strains

Pathogen Specific Therapies
Native and Prosthetic Valve Endocarditis caused by HACEK Microorganisms Regimen Duration (weeks) Adult Dose Ceftriaxone 4-6 12g/24 hours Ampicillin 6 gm/24 hours Ciprofloxacin 400 mg IV Q12H Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae All patients with prosthetic valves should be treated for 6 weeks

Endocarditis Culture Negative Therapies (Slide 1 of 2)
A patient with an acute clinical presentation of native valve infection should be started on antibiotic coverage for S aureus, β-hemolytic streptococci, and aerobic Gram negative bacilli A patient with an subacute clinical presentation of native valve infection should be started on antibiotic coverage for S aureus, viridans group streptococci, HACEK, and enterococci Vancomycin plus cefepime is a reasonable option for acute presentation Vancomycin plus ampicillin/sulbactam is a reasonable option for subacute presentation

Endocarditis Culture Negative Therapies (Slide 2 of 2)
Regimen Duration Culture-Negative Endocarditis, Native Valve Ampicillin–sulbactam plus gentamicin 4–6 Vancomycin plus gentamicin plus ciprofloxacin Culture-Negative Endocarditis, Early (<1 Year) Prosthetic Valve Vancomycin plus cefepime plus rifampin plus gentamicin 6 2 Culture-Negative Endocarditis, Late (>1 Year) Prosthetic Valve Ampicillin–sulbactam plus gentamicin plus rifampin Vancomycin plus gentamicin plus ciprofloxacin plus rifampin Suspected Bartonella, Culture-Negative Ceftriaxone plus gentamicin with or without doxycycline Culture-Positive Bartonella Doxycycline plus gentamicin

Overall Monitoring of Infective Endocarditis
Fever usually subsides within 1 week of initiating therapy Echocardiography should be completed after completion of antibiotic therapy to establish a new baseline heart function Blood cultures should be negative within a few days of starting antibiotic therapy Persistence of fever may indicate ineffective antimicrobial therapy, emboli, infections of intravascular catheters, or drug reactions. For some patients, low-grade fever may persist even with appropriate antimicrobial therapy. With defervescence, the patient should begin to feel better, and other symptoms, such as lethargy or weakness, should subside.

Patients at Highest Risk of Endocarditis
Prosthetic cardiac valve or prosthetic material used for cardiac valve repair Previous infective endocarditis Congenital heart disease (CHD) Unrepaired cyanotic CHD, including palliative shunts and conduits Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure† Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization) Cardiac transplantation recipients who develop cardiac valvulopathy only a small number of cases of infective endocarditis might be prevented with antibiotic prophylaxis for dental procedures, even if 100% effective infective endocarditis prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk for those with high-risk underlying cardiac conditions, prophylaxis is recommended for all dental procedures involving manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of infective endocarditis administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or GI tract procedure.

Prophylaxis of Infective Endocarditis
Highest Risk Cardiac Conditions Presence of a prosthetic heart valve Prior diagnosis of infective endocarditis Cardiac transplantation with subsequent valvulopathy Congenital heart disease (CHD)a Types of procedures Any that require perforation of the oral mucosa or manipulation of the periapical region of the teeth of gingival tissue Antimicrobial Options Adult Dosesb Pediatric Dosesb (mg/kg) Oral amoxicillin 2 g 50 IM or IV ampicillinc IM or IV cefazolin or ceftriaxonec,d,e 1 g Oral cephalexind,e,f Oral clindamycine 600 mg 20 Oral azithromycin or clarithromycine 500 mg 15 IV or IM clindamycinc,e aIncludes only the following: unrepaired cyanotic CHD, prophylaxis within the first 6 months of implanting prosthetic material to repair a congenital heart defect, and repaired CHD with residual defects at or adjacent to prosthetic material. bAll one-time doses administered 30–60 minutes prior to initiation of the procedure. cFor patients unable to tolerate oral medication. dShould be avoided in patients with immediate-type hypersensitivity reaction to penicillin or ampicillin (e.g., anaphylaxis, urticaria, or angioedema). eOption for patients with nonimmediate hypersensitivity reaction to penicillin or ampicillin. fMay substitute with an alternative first- or second-generation cephalosporin at an equivalent dose.

Summary Endocarditis typically presents as fever
Antibiotic treatment durations differ significantly when treating native vs. prosthetic valve infections There are specific guidelines for each pathogen causing endocarditis Patients at the highest risk of infective endocarditis should receive prophylactic antibiotic therapy

References Veverka A, Crouch MA, Odle BL. Chapter 89. Infective Endocarditis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015; 132:1435–86. Gerber MA, Baltimore RS, Eaton CB, et. Al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation. 2009;119:1541–15

Infectious Disease I: Infective Endocarditis

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