Infectious Disease I - 11 (2) - Infective Endocarditis (Courses in Therapeutics and Disease State Management)

Infectious Disease I:
Infective Endocarditis
Courses in Therapeutics and Disease State Management
Author: Michael W. Perry PharmD, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy
http://accesspharmacy.mhmedical.com/LearningModuleGroup.aspx?id=8
Copyright © 2017 McGraw-Hill Education. All rights reserved
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
Risk Factors
• Presence of a prosthetic valve • Healthcare-related exposure
(highest risk) • Acquired valvular dysfunction
• Previous endocarditis (highest • Cardiac implantable device
risk)
• Chronic heart failure
• Congenital heart disease (CHD)
• Mitral valve prolapse with
• Chronic IV access regurgitation
• Diabetes mellitus • IV drug abuse
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
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
Clinical Presentation (Slide 1 of 3)
Symptoms Signs
• Fever • Fever
• Chills • New or changing heart murmur
• Night Sweats • Embolic Phenomena
• Weakness • Skin manifestations
• Dyspnea • Clubbing of extremities
• Weight Loss
• Myalgia or arthralgia
Laboratory Tests Diagnostic Tests
• WBC count normal or elevated • Electrocardiogram
• Anemia • Chest radiograph
• Elevated C-reactive protein (CRP) • Echocardiogram
• Elevated erythrocyte sedimentation • Transthoracic (TTE)
rate (ESR) • Transesophogeal (TEE)
• Altered urinary analysis
• Blood Cultures
• 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
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)
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
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
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
Nonpharmacological Treatment
• Surgical removal, repair, and/ or replacement of infected valves or
cardiac hardware
• Support of vital functions
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
Pathogen Specific Therapies (Slide 1 of 7)
Native Valve Endocarditis caused by highly penicillin- susceptible (MIC≤ 0.12
mcg/mL) viridans group streptococci and Streptococcus gallolyticus (bovis)
Regimen Duration Adult Dose
(weeks)
Aqueous crystalline penicillin G sodium 4 12-18 million units/24 hours
Ceftriaxone 4 2 grams/24 hours
Vancomycin 4 Trough goal 10-15

plus
Gentamicin (traditional dosing peak of 3-4 mcg/ml)
plus
Gentamicin (traditional dosing peak of 3-4 mcg/ml)
Native Valve Endocarditis caused by Streptococcus gallolyticus (bovis)
and viridans group streptococci relatively resistant to penicillin (MIC>
0.12 mcg/mL)
(weeks)
Aqueous crystalline penicillin G sodium 4 24 million units/24 hours
Plus
Gentamicin (traditional dosing peak of 3-4 mcg/ml) 2
Prosthetic Valve Endocarditis caused by highly penicillin- susceptible (MIC≤ 0.12 mcg/mL) viridans
group streptococci and Streptococcus gallolyticus (bovis)
(weeks)

plus

plus
Prosthetic Valve Endocarditis caused by Streptococcus gallolyticus
(bovis) and viridans group streptococci relatively resistant to penicillin
(MIC> 0.12 mcg/mL)
(weeks)
Aqueous crystalline penicillin G sodium 6 24 million units/24 hours
Plus

Plus
Native Valve Endocarditis caused by Staphylococci
(weeks)
MSSA
Oxacillin or Nafcillin 6 12g/24 hours
Cefazolin 6 6 gm/24 hours
MRSA
Daptomycin 6 ≥ 8 mg/kg/dose
Prosthetic Valve Endocarditis caused by Staphylococci
(weeks)
MSSA
Oxacillin or Nafcillin 6+ 12g/24 hours
Plus Rifampin 6+ 900 mg/24 hours
Plus gentamicin 2 Traditional dosing Peak goal
3-4 mcg/ml
MRSA
Vancomycin 6+ Trough goal 10-20
Plus Rifampin 6+ 900 mg/24 hours
Plus gentamicin 2 Traditional dosing Peak goal
3-4 mcg/ml
Prosthetic or Native Valve Endocarditis caused by Enterococci
(weeks)
Ampicillin 4-6 12g/24 hours
Plus gentamicin 4-6 Traditional dosing Peak goal 3-4 mcg/ml
OR
Aqueous crystalline penicillin G sodium 4-6 18-30 million units/24 hours
OR
Ampicillin 4-6 12g/24 hours

Plus Ceftriaxone 4-6 2 gm IV Q 12H
OR
Vancomycin 4-6 Trough goal 10-15
Pathogen Specific Therapies
Native and Prosthetic Valve Endocarditis caused by HACEK
Microorganisms
(weeks)
Ceftriaxone 4-6 12g/24 hours
Ampicillin 4-6 6 gm/24 hours
Ciprofloxacin 4-6 400 mg IV Q12H
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
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 •4–6
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 •6
Vancomycin plus gentamicin plus ciprofloxacin plus rifampin •6
Suspected Bartonella, Culture-Negative
Ceftriaxone plus gentamicin with or without doxycycline •6
•2
•6
Culture-Positive Bartonella
Doxycycline plus gentamicin •6
•2
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
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
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 2g 50
IM or IV ampicillinc 2g 50
IM or IV cefazolin or ceftriaxonec,d,e 1g 50
Oral cephalexind,e,f 2g 50
Oral clindamycine 600 mg 20
Oral azithromycin or clarithromycine 500 mg 15
IV or IM clindamycinc,e 600 mg 20
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 - 11 (2) - Infective Endocarditis (Courses in Therapeutics and Disease State Management)

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Infectious Disease I:

Ceftriaxone 4 2 grams/24 hours

Vancomycin 4 Trough goal 10-15

Aqueous crystalline penicillin G sodium 2 12-18 million units/24 hours

Vancomycin 4 Trough goal 10-15

Ceftriaxone 6 2 grams/24 hours

Vancomycin 6 Trough goal 10-15

Aqueous crystalline penicillin G sodium 6 12-18 million units/24 hours

Ceftriaxone 6 2 grams/24 hours

Ceftriaxone 6 2 grams/24 hours

Vancomycin 4 Trough goal 10-15

Cefazolin 6 6 gm/24 hours

Ampicillin 4-6 12g/24 hours

Ampicillin 4-6 6 gm/24 hours

Ciprofloxacin 4-6 400 mg IV Q12H

Culture-Negative Endocarditis, Early (<1 Year) Prosthetic Valve

Vancomycin plus gentamicin plus ciprofloxacin plus rifampin •6

Antimicrobial Options Adult Dosesb Pediatric Dosesb (mg/kg)

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