1. Endocarditis & Endovascular Infections
Thomas Hawn, July 2010
Vegetation
Tricuspid
valve
Medic.med.uth.tmc.edu

2. Case 45 yo female S/P MVA ARDS in the ICU x 15 d with new onset fever.PE
IJ central line along with 2 peripheral ivs.
Question:
How do you diagnose a CVC infection?

3. Central Venous Catheter Infections
Criteria for positivity
Paired quantitative: catheter:vein cfu ratio >3
Unpaired quantitative: catheter cx >100 cfu/ml
Differential time: >120 minutes
Sens Spec
Paired quantitative Siegman-Igra, meta-analysis (cath:vein ratio>3-10:1)
Unpaired quantitative Siegman-Igra, meta-analysis (CFU/ml>15-100)
Differential time to positivity Gaur et al, n=33 (time>120 minutes)
Blot et al (1998), n=64, (time > 120 minutes)
Blot et al (1999), n=28, (time > 120 minutes)

4. Central Venous Catheter Infections
Diagnostic Recommendations
If CVC infection is suspected,
1. Draw 2 sets of bld cxs (one percutaneously)
2. Check paired quantitative or qualitative with time to positivity monitoring
3. If catheter is removed, send tip for culture.
Criteria for positivity:
>15 CFU by semi-quantitative method (roll-plate)
>100 CFU by quantitative method (sonication)

5. Central Venous Catheter Infections
Case:
Blood culture grow Staphylococcus aureus in 2 out of 2 sets (4 bottles).
Catheter 100 CFU/ml
Vein 15 CFU/ml
Question:
What is your management recommendation?
Should the line be removed?
Duration of Rx?
Should a TTE or TEE be obtained?

6. Short Term CVC Management
Mermel et al CID 2009 IDSA Catheter Rx Recs

7. Long Term CVC Management
Mermel et al CID 2009 IDSA Catheter Rx Recs

8. Uncomplicated CVC Bacteremia
1) No septic emboli
2) Negative surveillance cultures 2-4 d after starting therapy
3) Removable focus of infection
4) Not immunocompromised
5) Rapid clinical resolutions of sxs within 72h of starting abx and removing focus of infection
6) No indwelling prosthetic devices or underlying heart disease

9. Should the line be removed in S. aureus bacteremia?
S. aureus bacteremia, n=244
Management recommended: remove focus of infection, check surveillance cultures, TEE, start therapy (decide duration based on whether endocarditis present)
Cure rate:
Recommendations followed: 79.5%
Recommendations not followed: %
Foreign body removed: %
Foreign body not removed: 43.5%
Fowler et al (1998) CID 27:

10. Case 50 yo F in ICU with fever Bld Culture with Candida in 4/4 bottles
Questions
What anti-fungal treatment do you start?
When do you change Rx after species known?
When do you get MICs for fluconazole?

11. IDSA Candida 2009 Guidelines
Pappas et al (2009) CID 48:
Candidemia in non-neutropenic host
Initial Rx:
Fluconazole 800 mg load, then 400 mg qday
OR Echinocandin qday (A-I)
Echinocandin preferred if higher illness severity or recent azole exposure (A-III)
Remove catheter (A-II)
Search for metastatic foci
Rx duration: 2 wks if uncomplicated (A-III)

12. Anidulafungin non-inferior to fluconazole,
Reboliet al (2007) NEJM 356: 2472
Anidulafungin non-inferior to fluconazole,
But, … possibly more efficacious

13. Micafungin versus Caspofungin for Treatment
of Candidemia and Other Forms of Invasive
Candidiasis
Pappas et al (2007) CID 45:
Rx Success associated with Catheter Removal
RDBPCT, n=595 candidemic pts
Treatment Success
Catheter removed %
Catheter not removed 63.2%
P=0.001

14. IDSA Candida 2009 Guidelines
Drug choice & need to check sensitivities
C. albicans: sensis not routine, based on risks
C. glabrata: echinocandin preferred (B-III) or check fluc sensi
C. krusei: no fluc
C. parapsilosis: fluc preferred (B-III)

15. Case 40 yo M with mitral valve prolapse.
Dentist plans to place orthodontic brackets.
50 yo F with a history of endocarditis will undergo cystoscopy
What do you recommend for IE prophylaxis?

16. What is the highest risk of bacteremia exposure?
Cumulative exposure measures CFU per minute per ml per year of bacteria
Tooth extraction
Dental Exam
Mucoperiosteal surgery
Daily life
Flossing
Brushing teeth
Chewing
NT tube
Risk
(Relative to tooth extraction) 1
222
5,555
1,693,556
365,000
702,556
136,778
166
2007 guidelines: Emphasize that daily activities incur highest risk, rather than procedures.

17. Case
Lockhart et al Circulation 117: 3118 (2008)

18. What are risk factors for IE?
IE incidence
#/100,000 person years
General population
Prior endocarditis
Rheumatic heart disease
Congenital heart disease:
overall
VSD with medical Rx
VSD with surgical Rx
Aortic stenosis
Pulmonic stenosis
Prosthetic valve
MVP with murmur
MVP without murmer
Steckelberg & Wilson 1999
740
440
120
220 60
180 20 52
4.6

19. 2007 AHA Guidelines Cardiac Conditions with recommended prophylaxis:
1. Prosthetic cardiac valve
2. Previous IE
3. Congenital Heart Disease:
A. Unrepaired cyanotic CHD, including palliative shunts & conduits
B. Completely repaired CHD with prosthetic material or device, during the first 6 months after the procedure
C. Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or device
4. Cardiac transplant recipients who develop cardiac valvulopathy
Compared to 1997: Simplified list with emphasis on risk of adverse outcome from IE rather than risk of acquisition.
(no longer recommended for MVP or RHD)

20. 2007 AHA Guidelines
Procedures for which endocarditis is recommended for the above categories of patients:
1. All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa.
2. Respiratory tract or infected skin/soft tissue procedures
3. NOT recommended for GU or GI procedures solely to prevent IE
Compared to 1997:
Simplified list of which procedures qualify
(no GU/GI, criteria for dental procedure straightforward)

21. Cases HPI: 14 yo M 2 m h/o of fever, HA, myalgias.
RLQ pain led to appendectomy
w/ necrotizing lymphadenitis.
Left calf pain resolved with Abx.
After Abx, fever returned
Then, R wrist swollen & tender
R thigh pain developed.
PE: T 39.3, P 108, BP 128/35
II/VI systolic murmur
splinter hemorrhages in 3 nails
petechial rash on legs
Labs:
Bld Cx 6/6 bottles Viridans strep
45 yo M h/o ESLD, HCV, EtOH
Fever x 3d.
Also with SOB and abdominal pain.
PE: Tm 38.5
Gingivitis
CV III/VI SEM over LUSB,
?splinter hemorrhages 2 nails
Labs:
Bld Cx: 1/6 bottles with Viridans strep

22. Questions: What is your DDx?
How many modified Duke criteria does this patient have?
How useful are the modified Duke criteria?
What work-up is needed?

23. DDx of Endocarditis
A. associated with neoplasms: atrial myxoma, marantic (adenoCa), carcinoid
B. associated with autoimmune: rheumatic heart disease, SLE (Libman-Sacks endocarditis), anti-phospholipid syndrome, polyarteritis nodosa, Behcet’s disease
C. Postvalvular operation: thrombus, sutures
D. Other: eosinophilic heart disease, ruptured mitral chordae, myxomatous degeneration

24. Modified Duke Clinical Criteria
Definite IE
Pathological criteria:
Microorganisms: demonstrated by culture or histology in a vegetation, in a vegetation that has embolized, or in an intracardiac abscess, or
Pathologic lesions: vegetation or intracardiac abscess present, confirmed by histology showing active endocarditis.
Clinical criteria
2 major criteria, or
1 major and 3 minor criteria
5 minor criteria

25. Modified Duke Clinical Criteria
Possible IE
1 major and 1 minor
3 minor
Rejected
Firm alternate diagnosis for manifestations of endocarditis
Resolution of manifestations of endocarditis with antibiotic therapy for ≤ 4 days, or
No pathological evidence of IE at surgery or autopsy, after antibiotic therapy for ≤ 4 days.

26. Major Criteria 1. Positive blood culture for IE
A. Typical microorganism consistent with IE from 2 separate blood cultures as noted below:
viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus, or community-acquired enterococci,
in the absence of a primary focus
B. Microorganisms consistent with IE from persistently positive blood cultures as defined as
(i) ≥2 positive cultures of blood samples drawn >12 hours apart
(ii) all of 3 or a majority of ≥4 separate cultures of blood
(with the first and last samples drawn ≥1 hour apart)
iii. Coxiella: + Bld cx or anti-phase I Ab titer>1:800

27. Bacteremia & IE Likelihood
Pathogen IE:non IE Ratio
S. mutans
S. bovis
S. sanguis
S. mitior
E. faecalis
S. anginosus
Grp G Streptococcus
Grp B Streptococcus
Grp A Streptococcus
14.2 : 1
5.9 : 1
3.0 : 1
1.8 : 1
1.0 : 1.2
1.0 : 2.6
1.0 : 2.9
1.0 : 7.4
1.0 : 32.0

28. Major Criteria 2. Evidence of endocardial involvement
A. Positive echocardiogram for IE defined as
(i) 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
(ii) abscess, or
(iii) new partial dehiscence of prosthetic valve, or
B. New valvular regurgitation (worsening or changing or pre-existing murmur not sufficient)

29. Minor Criteria
1. Predisposition: predisposing heart condition or intravenous drug use
2. Fever: temperature ≥ 38.0 C
3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, and Janeway lesions
4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth spots, and rheumatoid factor
5. Microbiological evidence: positive blood culture but does not meet a major criteria as noted above or serologic evidence of active infection with organism consistent with IE (excludes single positive cultures for coagulase-negative Staphylococci and organisms that do not cause endocarditis).

30. Clinical Manifestations
Osler’s nodes
Splinter hemorrhages
Janeway’s lesions
Conjunctival
hemorrhages
Mylonakis, NEJM, 2001

31. Clinical Manifestations
Septic pulmonary emboli

32. Clinical Manifestations: Complications
Mycotic aneurysm

33. Duval et al Ann Int Med 152: 497 (2010)
High rate of lesions in neurologically asymptomatic cases

34. Does it change management?

35. Assessment of Duke Criteria
Sensitivity: 80% for definite IE
100% for definite + possible IE
Negative predictive value >98% for rejected category
Adopted modifications from Li et al (2000)
a. S. aureus bacteremia should be a major criteria regardless of the source (community or nosocomial)
b. Eliminate the ECHO minor criteria since TEE’s are more widely used now
c. Add Coxiella to list of major criteria (a single positive blood culture or antiphase I IgG antibody titer > 1:800).
d. To increase specificity, change the category “possible IE” to cases with 1 major and 1 minor criteria or 3 minor criteria.

36. Questions: When do you recommend a TEE?
Should all pts with CVC-associated S. aureus bacteremia get a TEE?

37. Role of Transesophageal ECHO in diagnosing IE
1. Prosthetic valves
2. Suspected complication
(such as perivalvular abscess)
3. Those in “Possible Endocarditis” category
4. ? Negative TTE & S. aureus bacteremia

38. Should all patients with S. aureus bacteremia have a TEE?
Arguing in favor:
1) Increased sensitivity leads to more diagnoses & better Rx
TTE sensitivity=32%
TEE sensitivity=100%
2) ? Cost effective (save costs of lengthy treatment)
Arguing against:
3) TEE more labour intensive
4) Small vegetations may be adequately treated with short course treatment.

39. Case: Rx ?s
yo female with 4 weeks of fever, myalgias, nausea and decreased appetitie.
ECHO: MV vegetation with severe MR.
year old male with h/o IVDU and dental caries with fever for 1 day after recent injection.
ECHO: AV vegetation with severe AI.
Question:
What empiric treatment do you recommend before the results of blood cultures are known?
What antibiotics do you recommend for viridans strep?
Who can be treated for 2 wks?

40. Empiric Antibiotic Selection
Empiric Therapy for IE
Main goal is to treat acute IE, most often caused by S. aureus
Acute IE:
Vancomycin +/- gentamicin
Subacute IE:
more difficult and less important to Rx empirically.
Vancomycin + ceftriaxone covers many of the important organisms.

41. AHA: Rx of Viridans Strep IE
Viridans streptococci & S. bovis,
PCN susceptible (MIC ≤0.12 mg/ml)
i. PCN G mU iv/day x 4 wks,
ii. ceftriaxone 2g iv or im qd x 4 wks,
iii. PCN G mU iv qd + x 2 wks,
gentamicin 1 mg/kg iv q8h
iv. vancomycin 1g iv bid x 4 wks (for b-lactam allergic pts)

42. AHA: Rx of Viridans Strep IE
Viridans streptococci & S. bovis,
relatively resistant to PCN (MIC > 0.12 mg/ml & < 0.5 mg/ml)
i. PCN G 24 mU iv/day x 4 wks
+ gentamicin 3 mg/kg iv qd x 2 wks
Ceftriaxone 2g iv qd x 4 wks
iii. vancomycin 1g iv bid x 4 wks (for b-lactam allergic pts)

43. AHA: Rx of Enterococcus, Abiotrophia, & Grunulicatella IE
i. PCN G mU iv/day x 4-6 wks
+ gentamicin 1 mg/kg iv q8h x 4-6 wks
ii. ampicillin 12 g/day iv x 4-6 wks
iii. vancomycin 1g iv bid x wks
+ gentamicin 1 mg/kg iv q8h x wks
(for b-lactam allergic pts)

44. AHA: Rx of HACEK IE i. ceftriaxone 2g iv/im qd x 4 wks
(or other 3rd or 4th gen. cephalosporin)
ii. Ampicillin-sulbactam 12g iv/day x 4 wks
iii. Ciprofloxacin 500 mg po bid or 400 mg iv bid x 4 wks
(less experience with quinolones & HACEK)

45. Case 30 yo M with h/o IDU with fever Diagnosed with MV IE 2° MRSA
Started on vancomycin/gentamicin
Daily cultures positive x 8 d
Questions:
Should a vancomycin MIC be obtained?
Should vancomycin troughs be obtained?
Should a different drug be used?
Does this patient need cardiac surgery?

46. Randomized trial
Inclusion: positive SA blood cx
Randomize to: daptomcyin (n=124)
vs. standard therapy ( b-lactam or vancomycin/gentamicin 1 mg/kg x 4d)
Results:
Overall success ITT: daptomycin 42.7%
standard Rx: 39.3%
Conclusion: Daptomycin is non-inferior to standard Rx
Median duration of bacteremia:
Dapto Std Rx P
MRSA 8d 9d 0.28
MSSA 4d 3d 0.25
Fowler et al NEJM 2006

47. Vancomycin Dose & MICs Do high troughs help?
Hidayat et al Arch Int Med 2008
Are high MICs associated with poor outcomes?
Soriano et al CID 2008
Prospective observational study
Inclusion: MRSA bacteremia, n=414
If vancomycin MIC = 2
OR for mortality: 6.39 ( )
Prospective cohort study
Inclusion: MRSA sputum, blood, wound
Measure vancomycin MIC
Compare high (≥2) vs low (<2) MIC
Compare achievement of trough goal target of 15 ucg/ml

48. Case 16 yo male with a 1 week history of fever to 103 F.
Developed confusion, blurrred vision and abdominal pain. Head CT showed hypodense lesions bilaterally in the parietal lobe, abdominal CT showed a 2 cm splenic infarct, and an ophthalmologic exam showed bilateral emboli.
4 out of 4 cultures grew MRSA. ECHO showed mild MR and a vegetation on the anterior leaflet.
Does this patient need cardiac surgery?

49. Indications for Cardiac Surgery
Valvular dysfunction
-Acute aortic or mitral insufficiency with signs of ventricular failure
-Heart failure unresponsive to medical therapy
-Valve perforation or rupture
Perivalvular extension
-Valvular dehiscence, rupture, or fistula
-New heart block
-Large abscess, or extension of abscess despite appropriate antimicrobial therapy.

50. Indications for Cardiac Surgery
Vegetation
Persistent vegetation after systemic embolization:
-Anterior mitral leaflet vegetation, particularly >1 cm
-One or more embolic events during the 1st 2 wks of therapy
-2 or more embolic events during or after antimicrobial therapy
Increase in vegetation size after 4 weeks of antimicrobial therapy

51. Complications from IE
1. Embolization: Difficult to predict who will embolize
 emboli with: AV & MV anterior leaflet,
S. aureus, Candida, HACEK, & Abiotrophia organisms,
? Size > 1 cm
2. CHF: Poor prognosis with medical Rx alone
Delaying surgery until decompensation will  mortality
3. Extracranial Mycotic Aneurysms
Surgical intervention advised
4. Intracranial Mycotic Aneurysms
merits of screening & surgery.
Very little data to guide decision.

52. Case
CC: fever and rash
HPI: 45 year old male from St. Paul Island in Alaska
R thumb stung by the barb of a yellow-fin Irish Lord fish.
Pain, swelling, and erythema of the thumb x 2d, spread to R arm.
Prescribed TMP-SMX for cellulitis.
Erythema progressed
After 1 week, annular, flat, erythematous macules developed on all extremities.
Pt developed fever, chills, sweats, nausea, vomiting, and myalgias over the next month.

53. Culture Negative Endocarditis
Exposure Common pathogens Diagnostic methods
Birds C. psittaci Complement fixation, ELISA
EtOHism, Bartonella quintana “Fastidious” organism bld cx,
homeless subCx to chocolate agar
Animals Coxiella burnetti CFA titers to phase I & II Ags
Brucella species “Fastidious” organism bld cx Serology
Nosocomial, Fungi Extended incubation of blood immuosuppression cultures
STD, Neisseria gonorrhea Bld cx. Commercial systems sexually active may inhibit Neisseria.
Epidemic Legionella Special culture for fastidious pneumophilia organisms, consider urinary antigen for Legionella

54. Culture Negative Endocarditis
Houpikian & Raoult Medicine 84: (2005)
n=348 subjects, France
blood culture negative IE
Pathogen N (%)
C. burnetti (48)
Bartonella (28)
Rare fastidious (1)
Tropheryma whipplei
Abiotrophia elegans
Mycoplasma hominis
Legionella pneumophila
No etiology: on abx (16.7)
not on abx (4.3)

55. Guidelines
Baddour et al Infective Endocarditis: Treatment, Diagnosis, & Management. Circulation 111: e (2005).
Mermel et al Guidelines for the Management of Intravascular Catheter-Related Infections. CID 49: 1-45 (2009).
Pappas et al Guidelines for the management of Candidiasis CID 48: (2009).
Wilson et al Prevention of Infective Endocarditis. Circulation 115: (2007).