1. 9/28/2016
Megan Patch MS, PharmD, BCPS
Antimicrobial Stewardship Pharmacist
Don’t Go Veggin’ my Heart: Updates to the Infective Endocarditis Diagnosis and Treatment Guidelines

2. Objectives
Describe updated diagnosis criteria for infective endocarditis (IE)
Discuss changes to treatment recommendations within the updated guidelines
Apply new treatment recommendations for IE from various microbial sources
Evaluate the role of the pharmacist in management of IE

3. Infective Endocarditis
Annual incidence: 3-7/100,000 person-years
Remained stable
4th most common life-threatening infectious process
High morbidity and mortality
Staphylococcus aureus is the most common causative organism
Contemporary surveys – sepsis, PNA, intra-abdom abscess
Baddour LM et al. Circulation 2015

4. Infective Endocarditis
Shift in causative organism to S. aureus dominance
Also increase in mean age of patient
Higher portion of prosthetic valve IE
Increase in other cardiac devices
Decrease in rheumatic heart disease as cause
Outcomes have not improved despite advances in care
Product of increase in Staphylococcal origin
Viridans group step
Streptococcus gallolyticus (bovis)
HACEK organisms
Enterococci
--Original Duke criteria for major criteria
Baddour LM et al. Circulation 2015

5. American Heart Association - IDSA
2015 Update
Last guidelines in 2005
Baddour LM et al. Circulation 2015

6. Duke Criteria Have been modified over the years
Used to aid in determining diagnosis
Endocarditis is heterogenous and these criteria should be paired with a complete clinical workup for a diagnosis
Major and minor criteria
1994 Durack and colleagues at Duke University Medical Center came up with these
They have been verified with 12 major studies and over 1,700 patients to confirm specificity and sensitivity
IE is a heterogenous disease with highly variable clinical presentations, and therefore the use of the Duke criteria alone will not suffice
Baddour LM et al. Circulation 2015

7. Duke Criteria
Baddour LM et al. Circulation 2015

8. Diagnosis Early identification is key Reliable history of patient
High risk patients who can benefit from surgery
Reliable history of patient
Risk factor profile
Valve replacement
Intravenous drug use (IVDU)
Clinical picture
Duke Criteria
Baddour LM et al. Circulation 2015

9. Diagnostic Testing At least 3 sets of cultures should be obtained
1st and last drawn at least 1 hour apart
Different venipuncture sites
Commonly, only 2 sets of cultures will be drawn
Imaging
Transthoracic echocardiogram (TTE)
Transesophageal echocardiogram (TEE)
More cultures drawn – increased chance of growing organism
Baddour LM et al. Circulation 2015

10. Antibiotic Therapy - Goals
Eradicate infection
Sterilize vegetation
Prevent sequelae
Challenges of treatment
High bacterial density
Penetration into vegetation
Slow rate of bacterial growth in biofilms
Goal + Challenges = prolonged IV antibiotics
Slow rate of growth – harder to target with agents that work on replicating bacteria
Need bactericidal therapy
Stationary growth phase – those that work on bacterial cell wall and are
Baddour LM et al. Circulation 2015

11. Inoculum Effect High bacterial density at vegetation
Higher minimum inhibitory concentration (MIC) at vegetation site
Antimicrobials can be less effective with a high inoculum
β-lactams (ceftriaxone) and glycopeptides (vancomycin)
Require higher antimicrobial doses to overcome higher MIC
More β-lactamase produced
In large densities, some organisms can become resistant to bactericidal effects of some antibiotics
Resistant subpopulations with higher inoculum
Lesser extent lipopeptides such as daptomycin
Penicillin vs streptococci – demonstrated this. Curative dose of PCN for strep in animal models increased with the number of organisms inoculated and the duration of the infection
Stationary growth phase organisms have been associated with loss of penicillin binding protein that are active target sites of beta-lactam antibiotics. This may be responsible for the inoculum
B-lactamase – enterococci, staph aureus, gram negative bacilli
Baddour LM et al. Circulation 2015

12. Antimicrobial Therapy
Drug penetration
Mechanical barrier to drug target
Bactericidal drugs
May need combination to achieve bactericidal activity
β-lactam + aminoglycoside
Duration of therapy
2-6 weeks
Right-sided vegetations tend to have lower bacterial densities
Baddour LM et al. Circulation 2015

13. Antimicrobial Therapy
Pharmacokinetic and pharmacodynamic properties
Penicillins and cephalosporins require free drug to exceed the MIC for % of the dosing interval for bactericidal action
Less than 60% only achieves bacteriostatic effects
When administering antibiotics to achieve synergy, administration together or as close as possible can maximize synergistic effect
We will revisit the antibiotics
Baddour LM et al. Circulation 2015

14. Other Treatment Considerations
Broad empiric therapy based on most likely organisms
Complete and thorough history should be obtained
Infectious Diseases consultation should be obtained when IE is suspected
Duration of treatment should start with the first negative culture
Keep in mind some organisms involved in IE are hard to culture
Two sets of blood cultures should be drawn every hours while still positive
Native valve IE with prosthetic valve replacement, no consensus on how to treat
If valve resection (with culture positive valve)– it is reasonable to start the course of antibiotics after the removal of the valve
If negative, reasonable to include treatment duration from prior to surgery
Gram staining of valve tissue can actually reveal killed organism and should not be a factor in the duration of treatment
Baddour LM et al. Circulation 2015

15. Viridans Group Streptococcus Streptococcus gallolyticus Abiotrophia defectiva Granulicatella species
Treatment
Strep gallolyticus previously Strep bovis

16. NVE: Highly PCN-susceptible S. gallolyticus
Red box: outpatient use
Ampicillin is reasonable alternative to PCN (12g/day or 2g every 4 hours)
Vancomycin in patients with severe PCN allergy TROUGH 10-15, dosing is not going to be the same as guidelines
If giving gentamicin – give at the same time as beta-lactam.
Baddour LM et al. Circulation 2015

17. NVE: Relatively PCN-resistant S. gallolyticus and VGS
Daily dosing of gentamicin for the first two weeks
Baddour LM et al. Circulation 2015

18. NVE: Highly PCN-resistant S. gallolyticus and VGS
Ampicillin 12g/day (2g every 4 hours)
-OR-
Penicillin million units/day divided or continuous infusion
-PLUS-
Gentamicin 3 mg/kg/day in 2-3 divided doses
Treatment is the same for Abiotrophia defectiva and Granulicatella spp
Baddour LM et al. Circulation 2015

19. PVE: Penicillin-susceptible S. gallolyticus and VGS
Difference in treatment duration of gentamicin, longer synergy
Any time you see prosthetic valve, treatment is going to be 6 weeks
Baddour LM et al. Circulation 2015

20. PVE: Penicillin-resistant S. gallolyticus and VGS
Difference in treatment duration of gentamicin, longer synergy
Any time you see prosthetic valve, treatment is going to be 6 weeks
Baddour LM et al. Circulation 2015

21. Streptococcus pneumoniae, Streptococcus pyogenes, and Groups B, C, F, and G β-Hemolytic Streptococci
Treatment

22. Highly PCN-susceptible Streptococcus pneumoniae
Penicillin MIC < 0.1 µg/mL
NVE
4 weeks of antibiotic therapy
Penicillin, cefazolin, or ceftriaxone
Vancomycin therapy recommended with β-lactam allergy
PVE
6 weeks of antibiotic therapy
Difference is 4-6 weeks
Baddour LM et al. Circulation 2015

23. PCN-resistant Streptococcus pneumoniae
Penicillin MIC > 0.1 µg/mL
If no meningitis present
High-dose penicillin or 3rd generation cephalosporin
If meningitis present
High-dose cefotaxime or ceftriaxone
Uncommonly isolated
All treated the same
Did not have a worse prognosis
Baddour LM et al. Circulation 2015

24. Other Streptococci Streptococcus pyogenes (group A Streptococci)
Penicillin for 4-6 weeks
Groups B, C, F, and G Streptococci
Slightly more PCN resistance
Penicillin
-OR-
Ceftriaxone for 4-6 weeks
-PLUS-
Gentamicin for at least 2 weeks
Early cardiac surgical intervention
Early surgery has improved overall survival rates in patients with beta-hemolytic strep IE compared with patients treated decades ago…
Baddour LM et al. Circulation 2015

25. Patient Case #1
QR is a 46 year old male with a past history of gout, depression, and hypertension. He presented to the ER with weakness and fatigue. He was hospitalized 2 months prior with pneumonia.
Blood cultures were positive 2/2 for Streptococcus pneumoniae.
Vancomycin was initiated until sensitivity results are known. A TTE and TEE were performed and showed a large vegetation on his mitral valve. He has no history of endocarditis or valve replacement. Culture results show highly susceptible penicillin sensitivity.
What therapy should be used for QR?
PCN, cefazolin, or ceftriaxone.
4 weeks
Possible surgical intervention.
Mitral valve -

26. Patient Case #1 continued
What is the appropriate treatment duration for QR?
2 weeks
4 weeks
6 weeks
8 weeks
B. 4 weeks

27. Patient Case #1 continued
What is the appropriate treatment duration for QR?
2 weeks
4 weeks
6 weeks
8 weeks
B. 4 weeks

28. Staphylococci
Treatment

29. History and Current State
Staphylococcal species (specifically S. aureus) are the most common cause of IE
Previously, S. aureus was traditionally associated with NVE and coagulase-negative Staphylococci (CoNS) was associated with PVE
S. aureus becoming a larger cause of PVE
Prevalence of CoNS NVE is increasing
Increase in the incidence of S. aureus IE due to healthcare contact
Treatment is complicated with increasing resistance
This is no longer the case and there is considerable overlap
Healthcare contact: intravascular catheters, surgical wounds, indwelling prosthetic devices, hemodialysis
Baddour LM et al. Circulation 2015

30. Staphylococcus aureus IE
Intravenous drug users (IVDU)
Mainly right-sided (tricuspid)
Non-intravenous drug users (non-IDUs)
Mainly left-sided (mitral/bicuspid valve)

31. Coagulase-Negative Staphylococci (CoNS)
Similar risk factors and outcomes as S. aureus IE
High methicillin resistance rate
These organisms are also resistant to cephalosporins and carbapenems
Staphylococcus lugdunensis
More virulent form of IE
Clinically resistant. May not be reflected in in vitro testing
S lugdenensis: High rate of perivalvular extension (extra-cardiac spread) and metastatic manifestations
Baddour LM et al. Circulation 2015

32. Staphylococcal IE in IDUs
Gentamicin has previously been standard treatment for right-sided IE in patients with NVE
β-lactam + gentamicin for 2 weeks for uncomplicated IE
Increasing risk of nephrotoxicity without added benefit
Vancomycin + gentamicin (short-course) less effective
Difficult to penetrate vegetation
Slowly bactericidal
Increased drug clearance in this patient population
Longer duration of therapy with vancomycin treatment in MRSA IE is warranted
Uncomplicated: no evidence of renal failure, extrapulmonary metastatic infections, aortic or mitral valve involvement, meningitis, or infection by MRSA
Baddour LM et al. Circulation 2015

33. Staphylococcal IE in non-IDUs
MSSA
Treatment with nafcillin + gentamicin shortened duration of bacteremia by roughly one day
No effect on clinical outcomes
Increase in nephrotoxicity with dual therapy
MRSA
Increased risk of nephrotoxicity when vancomycin + gentamicin are given concomitantly
Baddour LM et al. Circulation 2015

34. NVE: Staphylococci Baddour LM et al. Circulation 2015
Uncomplicated right sided IE can be treated for 2-4 weeks
Vancomycin is often included with nafcillin for initial treatment until MSSA/MRSA can be determined
Baddour LM et al. Circulation 2015

35. PVE: Staphylococci MSSA MRSA Baddour LM et al. Circulation 2015
Rifampin seems to be the addition that allows for sterilization in patients with MRSA PVE
MRSA
Baddour LM et al. Circulation 2015

36. Abscess with Staphylococcal IE
Brain abscess with MSSA
Nafcillin is preferred over cefazolin due to increased penetration at the blood brain barrier
If allergy prohibits nafcillin use, vancomycin should be substituted
Septic pulmonary emboli
Daptoymcin can be used for MRSA
Baddour LM et al. Circulation 2015

37. Oral Therapy for MSSA IE in IDU
Two studies
Right-sided MSSA IE in IDU
Ciprofloxacin + rifampin
4 weeks treatment
Many patients HIV+
Cure rate >90%
Increasing rates of resistance of MSSA to fluoroquinolones
Effective absorption – must be taken correctly
IV therapy in IDU is problematic. Usually keep at hospital or an extended care facility
Baddour LM et al. Circulation 2015

38. Enterococcus
Treatment

39. NVE and PVE: Enterococcus
Double beta-lactam: saturation of penicillin binding proteins, enhanced activity of ampicillin
Meningitis dosing of ceftriaxone
Double beta-lactam therapy recommended in patients with CrCl <50 mL/min or those whose CrCl drops below 50 during treatment with gent-containning therapy.
Baddour LM et al. Circulation 2015

40. NVE and PVE: Enterococcus
Cut off the part of table with streptomycin recommendation
Baddour LM et al. Circulation 2015

41. NVE and PVE: Resistant Enterococcus
Or quinupristin-dalfopristin (Synercid) – needs central line and only active against E. faecium
Baddour LM et al. Circulation 2015

42. Linezolid Not FDA approved for treatment of IE (off-label use)
Not often used
Dosing 600 mg IV every 12 hours
Bacteriostatic
Problematic for patients with immunosuppression
Side effects with long-term use
Myelosuppression including thrombocytopenia
Baddour LM et al. Circulation 2015

43. Daptomycin Approved for treatment of right-sided IE
Often used off label for left-sided endocarditis
Dosing (with CrCl >30 mL/min)
Package insert: 6 mg/kg daily
Some experts: 8-10 mg/kg daily
Other experts: mg/kg daily
Monitor weekly CPK
May need to monitor more frequently with higher doses or concomitant statin therapy
Generic projected for Summer 2016 (hopefully by early 2017)
Waiting for generic to become available. May see more use as easier transition to outpatient
Issues with renal dysfunction as well as obesity
Smith JR, et al. Journal of Antimicrobial Chemo. 2015
Baddour LM et al. Circulation 2015

44. Daptoymcin/Beta-lactam Synergy
Enterococcus species with daptomycin resistance are increasing nationally
The rate of daptomycin resistance for E. faecalis and E. faecium have been measured around 0.5% and 4.7%, respectively
Addition of ceftaroline, ertapenem, cefepime, ceftraixone, and ampicillin have shown to provide synergy to daptomycin and decrease time to blood clearance compared to monotherapy
Ceftaroline has been shown to restore daptomycin susceptibility in non- susceptible strains
MIC of 4 or greater for enterococcus
Even strains with MIC 2 to 4 have shown to develop mutations and can be resistant
Cefazolin and cefotaxime did not show synergy with daptomycin
Smith JR, et al. Journal of Antimicrobial Chemo. 2015

45. Patient Case #2
MP is a 64 year old male who has been experiencing fever and chills for the past 3.5 months. The patient has positive blood cultures for Gram-positive cocci in pairs. The patient has a history of hypertension, hyperlipidemia, chronic kidney disease (CrCl ~40 mL/min), and mitral valve replacement.
What is the likely causative organism in this patient based on the Gram-stain?
What treatment should be recommended and how long should this patient receive antibiotic therapy?
GPC in pairs: Enterococcus
CKD : amp + ceftriaxone for 6 weeks
6 weeks for both previous valve replacement as well as duration of symptoms.

46. HACEK Organisms Haemophilius species Aggregatibacter species
Cardiobacterium hominis
Eikenella corrodens
Kingella species
Historically, all strains were susceptible to ampicillin
Increased β-lactamase production
Most all susceptible to ceftriaxone
4-6 weeks of treatment
Account for 5-10% of community-acquired NVE in patients who are not IDUs
These organisms grow SLOWLY and may require prolonged incubation
Bacteremia with these organisms even without a focus of infection is highly suggestive of IE
Resistance to ampicillin can also occur in strains without beta-lactamase production
If susceptibility results are unknown- assume amp resistance and do not use amp or penicillin
Baddour LM et al. Circulation 2015

47. NVE or PVE: HACEK Organisms
Ceftriaxone dosing is daily, not BID as with synergy dosing
Baddour LM et al. Circulation 2015

48. Culture-negative IE
Failure to isolate an organism in IE patients can lead to problematic treatment regimens
Risk of not covering organism
Risk of treating with extra agents
Most studies estimate around 5-10% of IE is culture negative
Study of 820 patients with confirmed IE showed around 20% of patients were culture negative
Fastidious organisms
Fungi
Low bacterial concentration in blood
Antibiotics prior to blood cultures
Account for 5-10% of community-acquired NVE in patients who are not IDUs
These organisms grow SLOWLY and may require prolonged incubation
Bacteremia with these organisms even without a focus of infection is highly suggestive of IE
Resistance to ampicillin can also occur in strains without beta-lactamase production
If susceptibility results are unknown- assume amp resistance and do not use amp or penicillin
Baddour LM et al. Circulation 2015

49. Patient Case #3
MR is a 30 year old intravenous drug user with a history of hypertension. She presents to the emergency department 1 day ago with fatigue over the past 3 days, a fever of 102oF, and chills. The patient was empirically started on vancomycin and piperacillin/tazobactam.
Blood cultures were positive for Gram-positive cocci in clusters still awaiting sensitivities.
How would you adjust antimicrobial therapy in this patient?
Either wait until sensitivities to narrow
What test are we waiting for?
Could change to nafcillin + vanc until we know MRSA vs MSSA

50. Pharmacist’s Role in Management of Endocarditis
Follow culture and sensitivity results – communication with microbiology lab
Recommend appropriate antimicrobial therapy
Provide pharmacokinetic services
Vancomycin, aminoglycosides
Optimize dosing of antibiotics
Analyze overall medication regimen and screen for drug-drug interactions
Patient education of antibiotics
List is not all-enclusive

51. Self-assessment Question
A patient with suspected endocarditis reveals blood cultures positive for Streptococcus gallolyticus (S. bovis). Which additional testing is recommended for this patient?
CT of the chest with contrast
MRI of the head
Colonoscopy
Endoscopy

52. Self-assessment Question
A patient with suspected endocarditis reveals blood cultures positive for Streptococcus gallolyticus (S. bovis). Which additional testing is recommended for this patient?
CT of the chest with contrast
MRI of the head
Colonoscopy
Endoscopy

53. 9/28/2016
Megan Patch MS, PharmD, BCPS
Antimicrobial Stewardship Pharmacist
Don’t Go Veggin’ my Heart: Updates to the Infective Endocarditis Diagnosis and Treatment Guidelines