1. 2015 AHA Guidelines For the Management of Infective Endocarditis: An Update
Albina Ongari, PharmD
PGY-1 Pharmacy Resident
Kennedy University Hospitals
April 26th, 2016

2. Disclosure Statement I have no conflicts of interest to disclose
Anthony Fryckberg, PharmD, BCPS, BCCCP(Mentor)

3. Objectives Pharmacist Technicians
Describe recent changes to the guidelines for the treatment of infective endocarditis
Identify patients who require antimicrobial prophylaxis for infective endocarditis and recommend an appropriate antibiotic regimen
Technicians
Identify the signs and symptoms of infective endocarditis
Recognize the treatment regimens involved in the treatment of infective endocarditis

4. Infective Endocarditis (IE)
Infection of the endocardial surface of the heart (endocardium)
Includes one or more heart valves, mural endocardium, or septal defects
Associated with underlying cardiac defects
Valvular abnormalities
Heart failure and myocardial abscesses
Fatal if left untreated
Baddour LM, et al. Circulation 2015; 32:1-40.
Cahill TJ. Lancet 2016; 387:

5. Pathophysiology

6. Pathophysiology 1 2 3 4 Endothelial surface of heart is damaged
Turbulent blood flow associated with valvular damage 2
Platelet and fibrin adhere to damaged epithelial surface 3
Bacteria most commonly introduced hematogenously (bacteremia)
Attach to platelet and fibrin 4
A “vegetation” of platelets, fibrin, and bacteria forms; platelets and fibrin protect bacteria from antibiotics and immune system and allow for unimpeded growth
On prosthetic valves, gram-positive organisms (specifically Staphylococccus species) create biofilm; further protects bacteria
Cahill TJ. Lancet 2016; 387:

7. Epidemiology Incidence is rare High mortality and morbidity
3 to 7 per 100,000 people per year
High mortality and morbidity
20% mortality rate
3rd most common life threatening infection
More commonly in males
25-30 % of IE cases are caused by health care-acquired organisms
Baddour LM, et al. Circulation 2015; 32:1-40.
Cahill TJ. Lancet 2016; 387:

8. Risk Factors Degenerative valve disease (volvulopathy)
Rheumatic heart disease (low income countries)
Intravenous drug use
Congenital heart disease
Prosthetic heart valves
Dental procedures and poor dentation
Ages >60
Presence of intravascular device
Diabetes
Long term hemodialysis
Cahill TJ. Lancet 2016; 387:

9. Complications Heart failure Septic emboli Abscess formation Stroke
Conduction complications
Heart block
Circulating immune complexes
Brain, kidneys, spleen, skin lesions
Cahill TJ. Lancet 2016; 387:

10. Microbiology Microorganism Prevalence (%) Staphylococcus
Staphylococcus aureus: 26.6%
Coagulase-negative staphylococci: 9.7%
Streptococci and enterococci
Oral streptococci: 18.7%
Non-oral streptococci: 17.5%
Enterococci: 10.5%
Other: 1.6%
HACEK (haemophilus, aggregatibacter, cardiobacterium,
Eikenella corrodens, kingella) species
1to 2%
Candida species
Other 6%
Polymicrobial (≥2 microorganisms)
1.8%
No microorganism identified
5.2%
Baddour LM, et al. Circulation 2015; 32:1-40.
Cahill TJ. Lancet 2016; 387:

11. Microbiology Staphylococcal IE Coagulase-negative staphylococci
Both prosthetic and native valves
Coagulase-negative staphylococci
Indwelling lines and devices
Prosthetic valves
High rates of abscess formation and antimicrobial resistance
Streptococcal IE
Viridans group- oral, gastrointestinal, urogenital tract
Enterococcal IE
Elderly and chronic condition
Both native and prosthetic valves
Fungal endocarditis
Candida and Aspergillus- rare but fatal
Cahill TJ. Lancet 2016; 387:

12. Clinical Manifestations
Signs
Symptoms
Heart murmur (85% cases)
Tricuspid, mitral or aortic regurgitation
Skin lesions (rare)
Osler nodes
Janeway lesions
Roth spots
Splinter hemorrhages
Petechiae
Splenomegaly
WBC normal or slightly elevated
Persistent bacteremia (98%)
Vegetation on valve on echocardiography
Anemia, thrombocytopenia
Fever (90% cases)
Chills
Weakness
Dyspnea
Night sweats
Weight loss
Malaise
Baddour LM, et al. Circulation 2015; 32:1-40.
Cahill TJ. Lancet 2016; 387:

13. Assessment Question #1
Which of the following are risk factors for infective endocarditis?
Mitral valve regurgitation
Intravenous drug user
Poor dentation
Diabetes
All of the above
For technician???
Answer E. all of the above

14. Assessment Question #1
Which of the following are risk factors for infective endocarditis?
Mitral valve regurgitation
Intravenous drug user
Poor dentation
Diabetes
All of the above

15. Diagnosis Modified Duke Criteria Tool utilized for diagnosis of IE
Major and Minor criteria
Now lets talk about diagnosis,
Has anyone here heard about duke criteria? So this is a tool that we utilize to dx IE but before we talk in detail about that lest first review the major and minor components of duke criteria

16. Major Clinical Criteria
Blood cultures positive for IE
Typical microorganisms consistent with IE from two separate blood cultures
Single positive blood culture for Coxiella burnetii, or phase 1 IgG antibody titre >1:800
Evidence of endocardial involvement with echocardiography positive for IE
Presence of a vegetation, abscess, or new partial dehiscence of prosthetic valve
New valvular regurgitation
Baddour LM, et al. Circulation 2015; 32:1-40.
San Roman AJ, et al. Rev Esp Cardiol 2016; 69(1):7-10.

17. Minor Clinical Criteria
1. Predisposition
Predisposing heart condition, intravenous drug use
2. Fever
Temperature >38°C
3. Vascular phenomena
Major arterial emboli, septic, pulmonary infarcts, mycotic aneurysm, intracranial, janeway lesions
4. Immunological phenomena
Osler’s nodes, Roth spots, rheumatoid factor
5. Microbiological evidence not meeting major criteria
Baddour LM, et al. Circulation 2015; 32:1-40.
San Roman AJ, et al. Rev Esp Cardiol 2016; 69(1):7-10.

18. Diagnosis Modified Duke Criteria
Diagnosis of IE is definite in the presence of
One pathological criterion OR
Two major criteria OR
One major criteria and three minor criteria OR
Five minor criteria
Baddour LM, et al. Circulation 2015; 32:1-40.

19. Imaging Studies Transthoracic echocardiogram (TTE)
Easier to perform
Less sensitive
Transesophageal echocardiogram (TEE)
More sensitive
Invasive procedure
TTE is recommended for all patient
TEE is recommended for high risk patients
Prosthetic valve, congenital heart disease, previous IE, new murmur
Negative echo does not rule out IE
Baddour LM, et al. Circulation 2015; 32:1-40.
San Roman AJ, et al. Rev Esp Cardiol 2016; 69(1):7-10.

20. Echocardiography
Baddour LM, et al. Circulation 2015; 32:1-40.

21. Echocardiography
-for high risk patient such initial TTE, followed by TEE. Again everyone intially gets TTE bc non-invasive
Baddour LM, et al. Circulation 2015; 32:1-40.

22. Blood Cultures
Positive blood culture is the cornerstone of microbiological diagnosis
Cultures should be drawn before administration of antibiotics
Is this always achievable?
At least 2 sets of blood cultures obtained from different sites
Every 24 to 48 hours until blood stream infection is cleared
First and last drawn at least 1 hour apart
Just read this
Baddour LM, et al. Circulation 2015; 32:1-40.

23. Treatment of Infective Endocarditis

24. Background
Last AHA guidelines for diagnosis and management of IE were published 2005
August 2015, European Society of Cardiology (ESC) published guidelines for management of IE
October 2015, AHA released the new guidelines for diagnosis and management of IE
Lets focus on the updates!

25. Antimicrobial Therapy
Goals of therapy
Eradicate infection (bacteremia), including sterilization of the vegetation
Prolonged, parenteral, bactericidal therapy is required for treatment and cure of IE
Antimicrobial properties
Bactericidal drugs
Penetrate the cardiac vegetation
Break down the layers of fibrin of the biofilm
Addition of aminoglycosides and B-lactams
Combination of two bacteriostatic drugs for synergy
Baddour LM, et al. Circulation 2015; 32:1-40.
Thanavaro KL. Heart & Lung 2014; 43:

26. Approach to Regimen Selection
Organism and susceptibility (MIC)
Type of Valve
(Prosthetic vs. native )
Allergies
Here are some of the elements we want to consider before choosing therapy…
1. Organisms and suceptibility
Baddour LM, et al. Circulation 2015; 32:1-40.
Thanavaro KL. Heart & Lung 2014; 43:

27. Approach to Regimen Selection
Additional consideration
Patient specific characteristics
Previous antimicrobial therapy
Microbiological findings
Local antimicrobial resistance rates
Baddour LM, et al. Circulation 2015; 32:1-40.
Thanavaro KL. Heart & Lung 2014; 43:

28. Native valve, penicillin (PNC) susceptible strep bovis and viridans
Streptococcus IE
Native valve, penicillin (PNC) susceptible strep bovis and viridans
MIC ≤0.12mg/ml
Duration of therapy
Penicillin G million units/day (in 4 or 6 divided doses) OR
Ceftriaxone 2 g/day IV
4 weeks
PCN G or ceftriaxone
PLUS
Gentamicin 3 mg/kg IV q24h or 1 mg/kg IV q8h
2 weeks
Vancomycin
Beta-lactam allergic patients (IgE- mediated)
NO CHANGES !!!
Vancomycin 30 mg/kg per 24 hr in 2 equally divided doses or vancomycin mg/kg IV
q8-12h (per renal function)
Baddour LM, et al. Circulation 2015; 32:1-40.

29. Streptococcus IE NO CHANGES !!! Native valve, Strep viridans/bovis
PCN MIC >0.25; <0.5 (Relatively PCN resistant)
Duration of therapy
PCN G 24 million units/day (in 4 or 6 divided doses) IV
(PCN G 4 million units IV q4h) OR
Ceftriaxone 2 g IV/IM q24h (PCN rash)
PLUS
Gentamicin 3 mg/kg q 24 hrs
4 weeks
2 weeks
Vancomycin for Beta-lactam allergic patients (IgE-mediated)
NO CHANGES !!!
Baddour LM, et al. Circulation 2015; 32:1-40.

30. Streptococcus IE NO CHANGES !!!
Prosthetic valve, penicillin (PNC) susceptible strep bovis and viridans
MIC ≤0.12mg/ml
Duration of Therapy
PCN G 24 million units/day (in 4 or 6 divided doses) IV
PCN G 4 million units IV q4h OR
Ceftriaxone 2 g IV/IM q24h
With or without
Gentamicin 3 mg/kg IV q24h or 1 mg/kg IV q8h
6 weeks
2 weeks
Vancomycin
Beta-lactam allergic patients (IgE-mediated)
NO CHANGES !!!
Baddour LM, et al. Circulation 2015; 32:1-40.

31. Prosthetic valve, penicillin (PNC) reristant strep bovis and viridans
Streptococcus IE
Prosthetic valve, penicillin (PNC) reristant strep bovis and viridans
MIC > 0.12mg/ml
Duration of Therapy
PCN G 24 million units/day (in 4 or 6 divided doses) IV
PCN G 4 million units IV q4h OR
Ceftriaxone 2 g IV/IM q24h
PLUS
Gentamicin 3 mg/kg IV q24h or 1 mg/kg IV q8h
6 weeks
Vancomycin
(Beta-lactam allergic patients (IgE-mediated))
NO CHANGES !!!
Baddour LM, et al. Circulation 2015; 32:1-40.

32. Staphylococcus IE UPDATE Native valve, S. aureus (MSSA)
Duration of Therapy
Nafcillin 2 g IV q4h (if no PCN allergy) 12g/24hrs OR
Cefazolin 2 g IV q8h (if PCN-allergic, non-IgE mediated) 6g/24
6 weeks
Vancomycin mg/kg IV
q8-12h (per renal function)
Beta-lactam allergic patients (IgE-mediated)
Gentamicin is no longer recommended
UPDATE
Baddour LM, et al. Circulation 2015; 32:1-40.

33. Staphylococcus IE UPDATE UPDATE Native valve, S. aureus (MRSA)
Duration of therapy
Vancomycin mg/kg IV q8-12h (per renal function)
Round to nearest 250 mg increment
Generally capped at 2 g/dose
≥ 6 weeks
Daptomycin ≥ 8mg/kg/dose
No gentamicin or rifampin recommended
UPDATE
UPDATE
Baddour LM, et al. Circulation 2015; 32:1-40.

34. Staphylococcus IE NO CHANGES !!! Prosthetic valve, S. aureus (MSSA)
Duration of Therapy
Nafcillin 2 g IV q4h (if no PCN allergy) /Oxacillin OR
Cefazolin 2 g IV q8h (if PCN-allergic, non-IgE mediated)
PLUS
Rifampin 300 mg IV/PO q8h
Gentamicin 1 mg/kg IV q8h
≥ 6 weeks
2 weeks
Vancomycin mg/kg IV
q8-12h (per renal function)
Beta-lactam allergic patients (IgE-mediated)
Gentamicin 1mg/kg q 8 hr
NO CHANGES !!!
Baddour LM, et al. Circulation 2015; 32:1-40.

35. Staphylococcus IE NO CHANGES !!! Prosthetic valve, S. aureus (MRSA)
Duration of Therapy
Vancomycin mg/kg IV q8-12h (per renal function)
PLUS
Rifampin 300 mg IV/PO q8h
Gentamicin 1 mg/kg IV q8h
≥ 6 weeks
2 weeks
NO CHANGES !!!
Baddour LM, et al. Circulation 2015; 32:1-40.

36. Staphylococcus IE UPDATE
In concurrent brain abscess and MSSA IE, nafcillin should be used over cefazolin (Level of Evidence C)
Vancomycin should be used in patients with nafcillin intolerance
Baddour LM, et al. Circulation 2015; 32:1-40.

37. Assessment Question #2
Which of the following is an appropriate therapy option for patients with prosthetic valves and S. aureus (MSSA)IE? Patient does not have any drug allergies.
Cefazolin
Nafcillin plus rifampin plus gentamicin
Vancomycin
Daptomycin
Lets do another question…
B. Both nafcillin and Cefazolin needs to be given with rifampin and gent

38. Assessment Question #2
Which of the following is an appropriate therapy option for patients with prosthetic valves and S. aureus (MSSA)IE? Patient does not have any drug allergies.
Cefazolin
Nafcillin plus rifampin plus gentamicin
Vancomycin
Daptomycin
HINT: its prosthetic valve therefore we need to do triple coverage, dapto is not first line and we need to give it with gent; gent needs to be given with gen

39. Enterococcus IE UPDATE
Enterococcus susceptible to amp/gent/vanco, prosthetic or native valve
Duration of Therapy
Ampicillin 2 g IV q4h
OR PNC G U/24 hrs in dived
PLUS
Gentamicin 1 mg/kg (IBW) IV q8h
Both total of 4 to 6 weeks
Native valve: 4 weeks for with symptoms ≤ 3 months; 6 weeks for symptoms > 3 months
Prosthetic valve: At least 6 weeks
Double B-lactam
Ampicillin 2g IV q4 hr
Ceftriaxone 2g IV q12 hr
6 weeks
For CrCl< 50 ml/min
UPDATE
Baddour LM, et al. Circulation 2015; 32:1-40.

40. Enterococcus IE UPDATE UPDATE
Enterococcus susceptible to PNC and resistant to aminoglycosides or streptomycin susceptible and gent resistant, native or prosthetic valve
Duration of Therapy
Double B-lactam
Ampicillin 2g IV q4 hr
PLUS
Ceftriaxone 2g IV q12 hr
Both for 6 weeks
Option for impaired renal function
Ampicillin 2 g IV q4 hr or PNC G
Streptomycin sulfate 15mg/kg (IBW) per 24 hrs divided into 2 doses
Both for 4 to 6 weeks
 Avoid streptomycin in crcl< 50 ml/min
UPDATE
UPDATE
Baddour LM, et al. Circulation 2015; 32:1-40.

41. Enterococcus IE NO CHANGES !!!
Enterococcus susceptible to gent/vanco and resistant to PCN, prosthetic or native valve
Duration of Therapy
No B-lactam allergy:
Ampicillin-sulbactam 3 g
IV q6h
PLUS
Gentamicin 1 mg/kg IV q8h
Both for 6 weeks
 B-lactam producing strains
B-lactam allergy:
Vancomycin mg/kg IV
q8-12h (per renal function)
Note: Duration of gentamicin is for the entire duration
NO CHANGES !!!
Baddour LM, et al. Circulation 2015; 32:1-40.

42. Enterococcus IE ID consult UPDATE
Enterococcus susceptible to amp/gent/vanco, either native valve or prosthetic valve
Duration of Therapy
Linezolid 600 mg IV/PO 12h OR
Daptomycin mg/kg IV per dose
Quinupristin/dalfropristin 7.5 mg IV q8h (off label)
>6 weeks
Alternative therapy:
Daptomycin + ampicillin
Daptomycin + ceftaroline
Considered for patients with persistent bacteremia and high MIC (3μg/ml)
ID consult
UPDATE
Baddour LM, et al. Circulation 2015; 32:1-40.

43. HACEK IE Therapy Duration of therapy 4 weeks for native valve
Considered ampicillin resistant
Avoid ampicillin and penicillin for empiric therapy
Ceftriaxone 2 g IV daily
Ampicillin 2 g IV q 4h ( if susceptibilities are known)
Ciprofloxacin 500 mg IV q12h ( if patient has true PNC allergy or can’t tolerate b-lactams)
Duration of therapy
4 weeks for native valve
6 weeks for prosthetic valve
Baddour LM, et al. Circulation 2015; 32:1-40.

44. Fungal IE Candida > aspergillus
Associated with high mortality rates
Survival rate <20%
Valve surgery is recommended in most cases of fungal IE (Level of Evidence B)
Fungicidal agent- drug of choice
Amphotericin B, Echinocandins
Duration of therapy >6 weeks
Life-long suppressive therapy is indicated
Oral azoles
Flucanozole
Baddour LM, et al. Circulation 2015; 32:1-40.

45. Culture Negative IE
Decision for treatment is based on patient’s past medical history and risk factors
Risk factors
Prior infections (cardiovascular infections)
Prior exposures to antimicrobials (duration of abx, severity of infections)
Infection of the extra-cardiac sites
Expert involvement (ID consult)
Baddour LM, et al. Circulation 2015; 32:1-40.

46. Culture Negative IE Empiric therapy Native Valve Prosthetic Valve
Coverage of S. aureus, B-hemolytic Streptococci and gram negative bacilli
Coverage for S. aureus, Viridans group streptococci, HACEK, and enterococci
Baddour LM, et al. Circulation 2015; 32:1-40.

47. Assessment Question #3 True/False
Gentamicin is one of the therapy options available to treat MSSA IE in patients with native valve?

48. Assessment Question #3
Gentamicin is one of the therapy options available to treat MSSA IE in patients with native valve?
False

49. Additional Updates

50. Surgical Management Valve surgery for left-sided IE
Early surgery is indicated in patients with valve dysfunction and symptoms of heart failure
Valve surgery for right-sided IE
Early surgery is indicated especially in patients with complications
Valve repair is recommended over replacement if feasible
Baddour LM, et al. Circulation 2015; 32:1-40.

51. Surgical Management Patient with stroke or cerebral emboli
Surgery may be considered in IE patients with stroke or cerebral emboli or residual vegetation once intracranial hemorrhage is excluded by imaging
In presence of ischemic stroke or intracranial hemorrhage surgery can be delayed for at least 4 weeks
Baddour LM, et al. Circulation 2015; 32:1-40.

52. Dental Management Current recommendations
Broad recommendations and very nonspecific
Oral hygiene and gingival disease (periodontal disease) is responsible for the majority of IE cases
Dental visits (minor)
Inpatients with IE should be evaluated by a dentist to identify and eliminate possible oral diseases
Baddour LM, et al. Circulation 2015; 32:1-40.

53. Who needs prophylaxis? Prosthetic heart valves History of IE
Congenital heart disease (CHD)
Unrepaired cyanotic CHD
Completely repaired congenital heart defect
Cardiac transplant recipients who develop valvular disease
Thanavaro KL. Heart & Lung 2014; 43:

54. Who needs prophylaxis?
Recommended for all dental procedures involving manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa
Procedures not requiring prophylaxis include
Routine anesthetic injections through non-infected tissue
Dental x-rays
Placement and adjustment of orthodontic appliances
Shedding of primary teeth
Bleeding from trauma to the lips or oral mucosa
Thanavaro KL. Heart & Lung 2014; 43:

55. Prophylaxis: Therapy Options
Amoxicillin 2 g po X 1 dose,
Azithromycin 500 mg po X1 dose,
Cephalexin 1 g po X1 dose
Clindamycin 600mg po X1 dose
Give the dose 30 to 60 mins prior to procedure
Thanavaro KL. Heart & Lung 2014; 43:

56. Assessment Question #4
AH is a 59 yo female with PMH of HTN, DM, and prosthetic heart valve surgery (2012) who is going to see her dentist for a root canal procedure. Does AH need to receive IE prophylaxis for her scheduled dental procedure.
Yes/no?
2. If yes, why does AH qualify for prophylaxis?

57. Summary of Updates
Gentamicin is no longer recommended for treatment of native valve staphylococcal IE
Daptomycin has been added as an alternative agent for treating IE caused by MSSA or MRSA
Use of double b-lactam therapy for treatment of enterococcal IE
Ampicillin+ high dose ceftriaxone
Use of high dose daptomycin alone or combination with a b-lactam for treatment of resistant enterococcal IE
We covered a lot of changes… lets summarize and recap on the main points…
Gent, for staph ( both MSSA/MRSA); yet is still reccomanded for MSSA/MRSA prosthetic valve
Dapto has been added as na alternative for staph IE both MSSA and MRSA 6 mg/kg dose
Dapro can also be used alone or combo in enteroccocal IE high dose here mg/kg

58. Summary of Updates Cont.
Recommendations to treat gram negative IE based on patients risk factors
Consult infectious diseases
The new guidelines have recommendations of treatment of staphylococcal IE in patients with concurrent brain abscess
A broader set of recommendations for prevention of IE (prophylaxis)
Treat high risk patients

59. Questions

60. References
Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications. Circulation 2015; 32:1-40.
Cahill TJ, Prendergast BD. Infective endocarditis. Lancet 2016; 387:
Thanavaro KL, Nixon JV. Endocarditis 2014: An update. Heart & Lung 2014; 43:
San Roman AJ, Vilacosta I, Castillo JC, et al. Comments on the 2015 guidelines for the management of infective endocarditis. Rev Esp Cardiol 2016; 69(1):7-10.