Infective Endocarditis Clinical Practice Guideline

St. Paul’s Hospital

Committee Members

Chair: Dr. Peter Phillips

Cardiology: Dr. Brad Munt Dr. Chris Thompson

Cardiac Surgery: Dr. Jim Abel Dr. Sam Lichtenstein

Neurology: Dr. Alistair Prout Dr. Dean Johnson

Infectious Diseases: Dr. Val Montessori

Internal Medicine: Dr. Barry Kassen

Additions: Rosemarie Riddell, CNS Dr. Stan Devlaming

Pharmacy: Dr. Glen Brown

Emergency: Dr. Eric Grafstein

May 13, 2002Revised June 3, 2003

Introduction

Infective endocarditis (IE) is an uncommon infection occurring predominantly in patients with

valvular disease and among those using injection drugs. However, at St. Paul’s Hospital

endocarditis is common, accounting for the discharge diagnosis of approximately 80 patients

annually in recent years (1994-2000). The high incidence is related to the large cardiology/

cardiac surgery service and IDU population served. Among the 542 hospitalizations for IE

during the seven year period from 1994 to 2000, 63% (302 of 478 where IDU status was

available) were IDUs and 33% (174 of 542) were HIV positive. The average length of stay was

27 days, and the average total bed utilization for endocarditis was 2,090 bed-days/year.

Although most cases were managed on medical wards, critical care requirements averaged 249

bed-days/year. Valve replacement surgery was required in 15% of cases. The overall in-hospital

mortality rate was approximately 11%.

The impetus for development of this clinical guideline was to try to standardize as much as

possible the approach to diagnosis and management, based upon published evidence. IN

addition, the recent modifications to the Duke criteria for the diagnosis of IE and the increasingly

limited access to hospital beds at SPH make it timely of the development of a clinical practice

guideline. The potential benefits may include better utilization of diagnostic techniques,

improved patient outcomes, and possibly reduced length of stay related to adoption of short

course regimens where appropriate. The clinical guideline is directed to Internists, Cardiologists,

Cardiac Surgeons, Neurologist, and Infectious Diseases specialists. The Committee welcomes

your critical feedback regarding the content, format, implementation, and usefulness of this

document.

Peter Phillips, MD, FRCP(C)

Head, Infectious Diseases

St. Paul’s Hospital

May 31, 2002Revised June 3, 2003

SPH Encocarditis Clinical Pathway Committee March 2002

Investigations: (Appendix 2a)•Blood cultures x 3 (different times)•CBC, diff., creatinine, urea, urinalysis, Rheumatoid factor, CXR, EKG•echocardiography (Appendix 3) i) TTE - initial echo procedure in all patients ii) TEE- may be indicated if TTE non-diagnostic plus one of the following: a) prosthetic valve; or b)

suspected complications (e.g. perivalvular abscess); or c) S. aureus bacteremia in a non-IDU; or d) intermediate risk of IE; or e) TTE was technically unsatisfactory

Monitor therapy (Appendix 6a). If on anticoagulants, reassess risks of anticoagulation (Appendix 6b). Observe for neurologic complications (Appendix 6c)

ENDOCARDITIS (IE) CLINICAL GUIDELINE ALGORITHMSee reverse side of this page for instructions

Consult Cardiac surgery (cardiology and ID if not already involved) +/- repeat echocardiogram

Clinical Suspicion for IE (Appendix 1)

Diagnosis: Apply Modified Duke Criteria: (Appendix 4)i) definite IE treatmentii) possible IE consider treatmentiii) rejected consider other diagnoses

Treatment:i) Organism known therapy (Appendix 2b); [if streptococcus, order MIC for penicillin,

ceftriaxone ; if Staphylococcus, consider rifampin, gentamicin susceptibility]ii) Organism unknown consider other microbiologic tests (Appendix 5), ID consult

and treatment for culture-negative IE ( <5% of all cases)

Cardiac surgery indications: CHF, cardiac abscess, vegetation complication, or other (Appendix 7)

Yes

Continue medical therapy

No

+/- Valve replacement

Persistent positive BC’s or

Home IV antibiotic candidate (Appendix 8)

YesHome IV antibiotic referral No Medical therapy as inpatient

Endocarditis Clinical Practice Guideline Instructions

1. See Endocarditis Clinical Practice Algorithm for overview of management plan. Details of each section of the algorithm are outlined in the appendices.

2. If strong suspicion (see Appendix 1) or confirmed diagnosis of endocarditis then complete relevant sections of Endocarditis Standing Orders Form (√ boxes)

3. While awaiting test results (e.g. blood cultures, echo) either give no antibiotic therapy (stable, non-toxic patients) or initiate empiric antibiotics for sicker patients (see Endocarditis Empiric Therapy Antibiotic Form).

4. When the organism has been identified, complete either the Native Valve Endocarditis Antibiotic Form or the Prosthetic Valve Endocarditis Antibiotic Form. At this point complete sections II to V as needed on a new Endocarditis Standing Orders Form. If culture-negative endocarditis suspected then consult Infectious Diseases.

5. During the course of treatment refer back to the algorithm for management of complications, reassessment of anticoagulation, and consideration of home IV antibiotic therapy.

Endocarditis Clinical Practice Guidelines

Appendices_______________________________________________________________________

Page1. Clinical features

a) Clinical presentation suggestive of IE 2b) Clinical manifestations of IE 2

2. Ordersa) Standing orders 3b) Antibiotic forms 4

3. Echocardiography: indications, sensitivity and specificity for IE 8

4. Diagnosis of IE: Modified Duke Criteria 9

5. Investigations to consider in suspected culture-negative IE 11

6. Monitoring therapya) Blood tests, EKGs, audiograms 12b) Anticoagulant therapy 12c) Neurologic complications 13

7. Cardiac surgerya) Indications 14b) Contraindications 14c) Post-operative antibiotic duration 15

8. Home IV antibiotic therapy: eligibility criteria 15

9. References 16

Page 1 of 18

Appendix 1a: Clinical presentation suggestive of IE:

Usually fever (or history of fever) plus > 1 of following:1) Predisposing factor: prosthetic valve, known valvular lesion, IDU, or previous IE [Echocardiogram and other investigations for endocarditis may not be necessary in febrile

patients with predisposing factors if blood cultures are negative and other possible reasons for fever seem probable (i.e. culture negative endocarditis not suspected)]

2) Cardiac sign: new valvular regurgitation3) Extracardiac signs: i) CNS – mycotic aneurysm/intracranial hemorrhage, or “febrile stroke” ii) Chest – septic pulmonary emboli (right sided IE) iii) Cutaneous: Janeway lesions, Osler’ s nodes, conjunctival hemorrhages iv) Other vascular: major arterial emboli v) Renal: glomerulonephritis

Appendix 1b. Clinical Manifestations of IE*:

Symptoms % of Patients Affected

Signs % of Patients Affected

Fever 80 Fever 90Chills 40 Heart Murmur 85Weakness 40 Changing murmur 5 – 10Dyspnea 40 New murmur 3 – 5Sweats 25 Embolic phenomenon >50Anorexia 25 Skin manifestations 18 – 50Weight loss 25 Osler nodes 10 – 23Malaise 25 Splinter hemorrhages 15Cough 25 Petechiae 20 - 40Skin lesions 20 Janeway lesion <10Stroke 20 Splenomegaly 20 – 57Nausea/vomiting 20 Septic complications (pneumonia,

meningitis, etc.)20

Headache 20 Mycotic aneurysms 20Myalgia/arthralgia 15 Clubbing 12 – 52Edema 15 Retinal lesion 2 – 10Chest pain 15 Signs of renal failure 10Abdominal pain 15Delirium/coma 10 - 15Hemoptysis 10Back pain 10

* from Bayer et al. Endocarditis and Intravascular Infections. In: Principles and Practice of Infectious Diseases. Eds: Mandell GL, Bennett JE, Dolin R. 5th Ed. 2000. Churchill Livingstone. P886.

Page 2 of 18

Appendix 2 a

Endocarditis Standing Orders [suspected or confirmed] (√ boxes)I Investigations (if not already done): Blood cultures X 2, at least 1 hour apart Rheumatoid factor, Repeat blood cultures > 12 hrs later CXR, - PA & lateral (or > 1 hr later if antibiotics being started) EKG

If blood culture already positive, other susceptibility tests (call 62522)

strep viridans: MIC for penicillin, ceftriaxone Staph. aureus: gentamicin, rifampin

CBC, diff, creat, urea, ALT, alk. phos., u/a Echocardiography

TTE (transthoracic)- initial echo procedure in all patients TEE (transesophageal) (echocardiographer or ID consult required) – may be indicated if

TTE non-diagnostic plus one of the following: a) prosthetic valve; or b) suspected complications (e.g. perivalvular abscess); or c) S. aureus bacteremia in a non-IDU; or d) intermediate risk of IE; or e) TTE was technically unsatisfactory

II Consult (consider) Infectious Diseases Cardiac Surgery (appendix 7*) Cardiology Neurology (appendix 6c*) other____________

III Endocarditis Diagnosis (Modified Duke Criteria, see reverse side of this form) definite (2 major; or 1 major + 3 minor; or 5 minor) possible (1 major + 1 minor; or 3 minor) investigations pending, diagnosis not yet “definite” or “possible”

IV See Endocarditis Antibiotic order form: native valve; or prosthetic valve or empiric therapyV Monitoring therapy

CBC, diff., weekly for duration of hospital stay (FDHS) Vancomycin levels on 3rd dose (target peak 30-45 mg/L, trough 10-15 mg/L) blood cultures X 2 on 2 nd day of antibiotic therapy EKG- repeat weekly in aortic or mitral valve IE

creatinine/BUN, ALT/alk phos.- weekly (FDHS)If gentamicin therapy:

creatinine/BUN- Mon/Wed/Fri FDHS Gentamicin levels on 3rd dose (target peak 3 – 5 mg/L, trough < 1 mg/L) audiograms: baseline ASAP, then weekly while on gentamicin

Name Signature____________ Pager_________

Page 3 of 18

• See Sunrise Clinical Manager for Endocarditis Clinical Guideline and instructions (go to “Start” menu, then “Programs”, then “Specialty Documents”)

• Tick boxes not checked will be considered not ordered

Appendix 2b-i Antibiotic Form only for [Check boxes (√) for organism, antibiotic regimen, & duration if variable]NATIVE VALVE ENDOCARDITIS: Creatinine:_________ Creat. Clearance _________(ml/min) Weight:_____kgOrganism •••••••••••Regimens•••••••••••••••••••••••••••••Duration•••••••••••••••••2) 1. Viridans streptococci or Streptococcus bovis Penicillin MIC < 0.1 ml/L 1) Penicillin G 3 million U IV q4h1,2,3 4 weeks

or 2) Ceftriaxone 2 gm q24h3 4 weeks or 3) Ceftriaxone 2 gm q24h3 2 weeks4

plus Gentamicin ________(3 mg/kg) q24h1 2 weeks4

or 4) other regimen Penicillin MIC > 0.1 to <0.5 mg/L or result pending (if MIC≥0.5 mg/L, see enterococci) 1) Penicillin G 3 million U IV q4h1,2,3 4 weeks

plus Gentamicin ________(1 mg/kg) IV q8h1 2 weeks or 2) other regimen 2. Enterococci (susceptible to Penicillin, Gentamicin, and Vancomycin); viridans streptococci

(includes nutritionally variant) or Streptococcus bovis (Penicillin MIC ≥0.5mg/L) Check () duration (see footnote5)

1) Penicillin G 4 million U IV q4h1,2,3 4 wks , or 6 wks 5

plus Gentamicin ________(1 mg/kg) IV q8h1,6 2 wks , 4 wks , or 6 wks 5

or 2) Ampicillin 2 gm IV q4h12,3 4 wks , or 6 wks 5

plus Gentamicin ________(1 mg/kg) IV q8h1,6 2 wks , 4 wks , or 6 wks 5

or 3) other regimen 3. Staphylococcus aureus Methicillin-susceptible (MSSA)

a) aortic or mitral Check () duration 1) Cloxacillin 2 gm IV q4h3,7,8 4 wks , or 6 wks

or 2) other regimen b) tricuspid 1) Cloxacillin 2 gm IV q4h3,7,8 2 weeks9

plus Gentamicin ________(1 mg/kg) IV q8h1 2 weeks9

or 2) Cloxacillin 2 gm IV q4h3,7 4 weeks or 3) other regimen

Methicillin-resistant (MRSA) 1) Vancomycin _____(15 mg/kg) IV q12h1,8 4 wks , or 6 wks or 2) other regimen

4. Other organism other regimen

Name Signature Pager_________

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• See Sunrise Clinical Manager for Endocarditis Clinical Guideline and instructions (go to “Start” menu, then “Programs”, then “Specialty Documents”)

• Tick boxes not checked will be considered not ordered

• Footnotes 1-12, see back of this form

Appendix 2b-ii

Antibiotic Form only for [Check boxes (√) for organism, antibiotic regimen, & duration if variable]PROSTHETIC VALVE ENDOCARDITIS: Creatinine:_______ Creat. Clearance ________ (ml/min) Weight:_____kgOrganism •••••••••••Regimens•••••••••••••••••••••••••••••••••••Duration•••••••••••••••••••••••1. Viridans streptococci or Streptococcus bovis

Penicillin MIC < 0.1 mg/L 1) Penicillin G 3 million U IV q4h1,2,3 6 weeks plus Gentamicin ________(1 mg/kg) IV q8h1 2 weeks

or 2) Ceftriaxone 2 gm IV q24h3 6 weeks plus Gentamicin ________(1 mg/kg) IV q8h1 2 weeks

or 3) other regimen Penicillin MIC > 0.1 to <0.5 mg/L or result pending (if MIC ≥0.5 mg/L, see enterococci)or 1) Penicillin G 4 million U IV q4h1,2 ,3 6 weeks

plus Gentamicin ________(1 mg/kg) IV q8h1 4 weeksor 2) other regimen

2. Enterococci (susceptible to Penicillin, Gentamicin, and Vancomycin); viridans streptococci (includes nutritionally variant) or Streptococcus bovis (Penicillin MIC ≥ 0.5 mg/L),

or 1) Penicillin G 4 million U IV q4h1,2,3 6 weeks plus Gentamicin ________(1 mg/kg) IV q8h1,6 6 weeksor 2) Ampicillin 2 gm IV q4h1,2,3 6 weeks plus Gentamicin ________(1 mg/kg) IV q8h1,6 6 weeksor 3) other regimen

3. Staphylococci (S. aureus or coagulase-negative staphylococci) Methicillin-susceptible Check (√) duration

1) Cloxacillin 2 gm IV q4h3,7 6 wks , or 8 wks plus Gentamicin ________(1 mg/kg) IV q8h1 2 weeks plus Rifampin 300 mg PO TID10 6 wks , or 8 wks

(start 3 days after Cloxacillin, Gentamicin)10

or 2) other regimen Methicillin-resistant11 Check (√) duration

1) Vancomycin ________(15 mg/kg) IV q12h1 6 wks , or 8 wks plus Gentamicin ________(1 mg/kg) IV q8h1, 11 2 weeks plus Rifampin 300 mg PO TID10 6 wks , or 8 wks (start 3 days after Vancomycin, Gentamicin)10

or 2) other regimen 4. Other organism

other regimen

Name Signature_____________Pager________

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• See Sunrise Clinical Manager for Endocarditis Clinical Guideline and instructions (go to “Start” menu, then “Programs”, then “Specialty Documents”)

• Tick boxes not checked will be considered not ordered

• Footnotes 1-12, see back of this form

Appendix 2b-iii

Antibiotic Form only for [Check boxes (√) for patient category, and antibiotic regimen]ENDOCARDITIS EMPIRICAL THERAPY12

Creatinine:_______ Creat. Clearance ________ (ml/min) Weight:_____kg

DurationI. Native Valvea) a) non-IDU

1) Cloxacillin 2 g IV every 4 h3 3 days plus Ampicillin 2 g IV every 4 h1,2,3 3 days plus Gentamicin ________(1 mg/kg) IV q8h1 3 days

or 2) other regimen

b) b) IDU 1) Cloxacillin 2 g IV every 4 h3,12 3 days

plus Gentamicin ________(1 mg/kg) IV q8h1 3 daysor 2) other regimen

II. Prosthetic valve 1) Vancomycin ________(15 mg/kg) IV q12h1 3 days plus Gentamicin ________(1 mg/kg) IV q8h1 3 days plus Rifampin 300 mg PO TID10 3 days (start Rifampin 3 days after Vancomycin and Gentamicin)10

or 2) other regimen

Name Signature_____________Pager________

Footnotes: 1. Dose adjustment needed for renal impairment. Gentamicin and Vancomycin dosing should be rounded to the

nearest 20 mg and 250 mg increment respectively; and based on ideal body weight in obese patients. For enterococcal IE, once daily aminoglycoside therapy should be avoided (2 or 3 doses are required each day).

2. Continuous 24 hr/day infusion can be given for Penicillin or Ampicillin using the same total daily dose.3. For β–lactam allergy history, allergy consult and possibly skin testing and desensitization are recommended.

Avoid cephalosporins in patients with major allergy (immediate hypersensitivity) to β-lactams. • Ceftriaxone is an alternative to penicillin for IE due to Viridans streptococci with penicillin MIC ≤

0.1μg/mL.• Cefazolin (2 gm IV q8h) is an alternative to Penicillin/Cloxacillin in methicillin-susceptible Staph.

aureus (MSSA), Strep. bovis or viridans streptococcal (penicillin MIC > 0.1 to < 0.5 mg/L) IE. • Vancomycin (15 mg/kg IV q12h) is indicated only for patients with allergy to β-lactams. Vancomycin

(+/- gentamicin) is less effective than Cloxacillin for MSSA IE (up to 40% failure rate) and likely less effective than Penicillin/Ampicillin (plus Gentamicin) for enterococcal IE. Due to additive nephrotoxicity, the combination of Vancomycin plus Gentamicin should only be used for IE due to enterococcus, relatively Penicillin-resistant streptococci (Penicillin MIC > 0.5 mg/L), and prosthetic valve endocarditis due to methicillin resistant staphylococci.

4. 2-week regimen for viridans streptococci may be appropriate for uncomplicated IE, but it is not recommended if any of the following are present:

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• See Sunrise Clinical Manager for Endocarditis Clinical Guideline and instructions (go to “Start” menu, then “Programs”, then “Specialty Documents”)

• Tick boxes not checked will be considered not ordered• Footnotes 1-12, see back of this form

1) extracardiac foci of infection; 2) perivalvular extension/abscess; 3) prosthetic valve; 4) duration of symptoms > 2 months; 5) relative/absolute contraindications to gentamicin; or 6) age > 65 yrs.

5. 6 week combination regimen ([Penicillin or Ampicillin] plus Gentamicin) for enterococcal IE recommended if any of the following are present:

1) patients with duration of symptoms > 3 months; or 2) mitral valve involvement; or3) prosthetic valve; or

4) relapsed infection. Other patients with enterococcal IE may be treated with the “Swedish regimen” which consists of Penicillin or

Ampicillin for 6 weeks plus aminoglycoside for the initial 2-3 weeks (reference C-16). Another alternative is 4 weeks with the combination regimen as above. Reported experience with the “Swedish regimen” for Penicillin resistant viridans streptococci is lacking.

6. Enterococcus high level Gentamicin resistance (ie MIC > 500ug/ml) should be excluded by microbiology lab. If Gentamicin and Streptomycin not adequate, then consider substituting a fluoroquinolone to which the enterococcus is susceptible. For enterococcal IE, the Penicillin dose can be up to 30 million units/day (5 million units IV q4h) if renal function is normal.

7. If Staph. aureus is susceptible to Penicillin, then Penicillin G 4 million units IV q4h is the drug of choice rather than Cloxacillin.

8. Benefit of Gentamicin in Staph. aureus native valve IE is limited to earlier defervescence and sterilization of blood cultures, but no survival benefit. Consider adding Gentamicin 1 mg/kg IV q8h for 3-5 days in patients with severe infection.

9. 2 week regimen for tricuspid valve IE due to MSSA not recommended if : 1) confirmed or suspected left-sided IE (e.g. left-sided murmurs, systemic emboli, cutaneous stigmata); 2) metastatic sites of infection or empyema (excluding septic pulmonary emboli);3) cardiac or extracardiac complications; 4) MRSA; 5) any prosthetic valve; 6) vegetation size >10 mm; 7) incomplete response to therapy (e.g. fevers > 1 week or evidence of ongoing septic pulmonary emboli

after 2 weeks of starting appropriate therapy). 8) HIV positive and CD4 count < 200/mm3

If relative/absolute contraindication to Gentamicin, then consider Cloxacillin alone for 2 weeks (similar success rate [76%] as for Cloxacillin 14d plus Gentamicin 7d [69%] in one study) (reference C-17). Patients who elect to leave hospital AMA before completion of the 2 week regimen can be considered for a 28 day oral regimen with Ciprofloxacin 750 mg bid plus Rifampin 300 mg bid (reference C-12), which is best suited for a supervised setting (e.g. drug-treatment facility).

10. Staphylococcal prosthetic valve endocarditis it is recommended that 2 drugs active against the organism (or 1 drug for a few days) be started before the addition of Rifampin in order to reduce the likelihood of Rifampin resistance developing. Caution re: Rifampin drug-drug interactions.

11. Methicillin- and Gentamicin-resistant staphylococcal prosthetic valve endocarditis. If an alternative aminoglycoside to which the Staphylococcus is susceptible cannot be identified, then a quinolone with activity (e.g. Levofloxacin 500 mg q12h) should be used in place of the aminoglycoside (ref. C-14).

12. Empiric Therapy. If patient not acutely ill or in heart failure, then wait for blood culture (BC) results before starting antibiotics. If initial 3 sets of BCs are negative, then draw 2-3 more sets, consider causes of culture-negative IE and consider starting empiric therapy. For seriously ill IDU with suspected endocarditis, consider empiric Vancomycin plus Cloxacillin plus Gentamicin.

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Appendix 3: Echocardiography

A. Echocardiography Sensitivity and Specificity

Method Lesion Sensitivity Specificity

TTE1 vegetations < 60% 98% abscess 28% 99%

TEE2 vegetations (native valve)3 94-97% 91-100% vegetations (prosthetic valve) 86-94% 88-100%

abscess 87% 95%perivalvular extension 76-100% 94%

1TTE, Transthoracic echocardiogram2TEE, Transesophageal echocardiogram3 for right-sided endocarditis, sensitivity of TEE is not superior to TTE

B. Choice of Echocardiography Method in Suspected Endocarditis:

1) TTE as the initial echocardiography procedure in all patients. This approach is recommended by the St Paul’s hospital echocardiographers. Although the results of some studies have prompted recommendations for TEE as the initial echocardiography procedure in selected patients (i.e. prosthetic valve, or a patient with an intermediate probability of IE), several reasons support a role for initial TTE in all patients. These include: the considerably lower cost of TTE in British Columbia (vs USA); and information provided by the TTE which may prompt additional considerations to be addressed at the time of TEE. The current TTE technology used at SPH is superior to TEE for assessment of chamber size and function as well as the presence of right-sided endocarditis.

In a study of 134 patients with suspected native valve endocarditis who had technically adequate TTE, the incremental diagnostic yield of TEE was mainly limited to those 47 patients (35%) who had abnormal but non-diagnostic TTE examinations (defined as valve thickening or calcification, or more than trace valvular regurgitation, but no definite vegetation of abscess) [reference B-5]. TEE showed an abscess or vegetation in 17 of the 47 (36%) with a non-diagnostic TTE, but in only 2 or 46 patients with a normal TTE (defined as no valvular abnormality).

2) Possible indications for TEE following a non-diagnostic TTE (Echocardiographer or Infectious Diseases consult recommended): a) prosthetic valve b) known or suspected complications: e.g. perivalvular extension (persistent fevers,

or positive blood cultures, conduction disturbance, development of pericarditis); CHF.

d) S. aureus bacteremia in a non-IDU (or in an IDU if left-sided endocarditis suspected and repeat TTE negative 1 week later)

e) intermediate probability of endocarditis (e.g. high risk patient or moderate to high clinical suspicion)

f) TTE was technically unsatisfactory

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Appendix 4: Diagnosis of Infective Endocarditis (IE): Modified Duke Criteria (CID 2000;30:633)‡ Appendix 4a. Case Definition (Check appropriate boxes √; see Appendix 4 b)

Definite:

Pathologic criteria: vegetation (on valve or embolized) or cardiac abscess specimen

(histologic evidence or organisms demonstrated by culture or histology)

orClinical Criteria: 2 major, or

1 major plus 3 minor, or 5 minor

Possible*:

Clinical criteria: 1 major plus 1 minor or 3 minor

Rejected: 1) firm alternate diagnosis explaining evidence of

IE, or 2) resolution of IE syndrome with antibiotic

treatment for < 4 days, or 3) no pathologic evidence of IE at surgery with < 4

days of antibiotic treatment, or 4) does not meet criteria for possible IE (as above).

‡ Appendix 4b (Definition of Terms used in the Modified Duke Criteria for the Diagnosis of IE) will appear on the reverse side of the Suspected IE Standing Orders (Appendix 2a).* In one study, 24% of pathologically proven IE cases (mainly culture-negative or Q-fever) were misclassified as “possible” IE according to the Duke criteria.

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Appendix 4 b. Definition of Terms used in the Modified Duke Criteria for the Diagnosis of IE (Check appropriate boxes √)

Major criteria

1. Blood culture positive for IE a) typical organisms consistent with IE from 2 separate blood cultures (BC) - viridans streptococci - Streptococcus bovis - HACEK group §

- Staphylococcus aureus (hospital or community acquired) - enterococci (community-acquired in the absence of a primary focus)

or b) organisms consistent with IE from persistently positive BCs defined as follows: i) > 2 BCs positive which were drawn > 12 hr apart, or ii) 3/3 or a majority of > 4 separate BCs positive (with 1st and last BC drawn at least 1

hr apart)

or c) Coxiella burnetii: single positive BC or antiphase I IgG antibody titer >1:800

2. Evidence of Endocardial Involvement a) echocardiogram positive for IE, defined as follows: 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 of pre-existing murmur not sufficient)

Minor criteria

1. Predisposition: a) predisposing heart condition ‡ or b) injection drug use

2. Fever, temperature >38° C3. Vascular phenomena:

a) major arterial emboli, or d) intracranial hemorrhage, or b) septic pulmonary infarcts, or e) conjunctival hemorrhages, or c) mycotic aneurysm, or f) Janeway’s lesions

4. Immunologic phenomena: a) glomerulonephritis, or c) Roth’s spots, or b) Osler’s nodes, or d) rheumatoid factor

5. Microbiological evidence: a) positive blood culture but does not meet a major criterion as noted above *, or b) serological evidence of active infection with organism consistent with IE

*Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.‡ Predisposing heart conditions include: a) high risk: previous IE; aortic valve disease; rheumatic heart disease; prosthetic valve; aortic coarctation; complex cyanotic congenital heart diseases; and b) moderate risk: mitral valve prolapse with valvular regurgitation or leaflet thickening; mitral stenosis; tricuspid valve disease; pulmonary stenosis; or hypertrophic cardiomyopathy§ HACEK (see appendix 5 footnote)

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Appendix 5: Investigations to Consider in Suspected Culture-Negative Endocarditis_______________________________________________________________________Etiology/reason Investigations

_______________________________________________________________________• Abiotrophia species routine BCs are adequate (BacT/Alert (nutritionally deficient system at SPH)streptococci), or HACEK*organisms

• fungi (e.g. Candida) “fungal BC” (routine BacT/Alert FAN™ bottle is incubated longer , i.e.3 weeks), and lysis-centrifugation BC; serum cryptococcal antigen; occassionally urine for histoplasma antigen (reference lab); valve or embolus silver stain

• Bartonella lysis-centrifugation BC (indicate for Bartonella on requisition); serology; valve or embolus for Warthin-Starry stain, PCR, and special culture

• Legionella notify microbiology lab for blind subculture of routine BCs on BCYE (buffered charcoal-yeast extract) agar; Legionella serology; valve or embolus for immunohistochemistry

• Brucella notify microbiology lab and routine BCs will be incubated longer (3 weeks); serology

• Q fever (Coxiella burnetii) serology (IgG titer > 1:800); valve or embolus for PCR, Giemsa stain, and immunohistochemistry

• Chlamydia (psittaci) species serology; valve or embolus for immunohistochemistry

• Whipple’s disease heart valve PAS or silver stain; vegetation, (Tropheryma whipplei) embolus or blood for PCR

________________________________________________________________________Setting Investigations_____________________ ________________________________________________________________________• recent antibiotic use hold antibiotics for 2-4 days if clinically stable and

not toxic, then repeat BCs, +/- using resin bottles.

• valve tissue or embolus special stains, immunhistochemistry, PCR, and special cultures as outlined for organisms above

________________________________________________________________________

HACEK*, slow growing fastidious gram negative bacilli: Hemophilus species, Actinobacillus, Cardiobacterium hominis, Eikenella corrodens, Kingella.

BC, blood culture

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Appendix 6 : Monitoring Treatment of Endocarditis

Appendix 6a: Blood tests, EKGs, and audiograms

Test Frequency Comment• CBC, differential WBC weekly watch for drug-induced cytopenias

(neutropenia*)• Creatinine - 3x/week (gentamicin)

- weekly (other antibiotics)

watch for renal toxicity (e.g. aminoglycoside, interstitial nephritis)

• ALT, alkaline phosphatase weekly if receiving rifampin or cloxacillin• Drug levels: - gentamicin weekly target 1 hr post dose peak 3-5 mg/L, and

trough < 1.0 mg/L for q8h dosing - vancomycin weekly target peak 30-45 mg/L (extrapolated 1 hr

post dose), target trough 10-15 mg/L • Audiograms (gentamicin) weekly obtain at baseline, and document that risks/

benefits were discussed• EKG weekly watch for heart block (may be 1st sign of

perivalvular abscess in left-sided endocarditis). EKG weekly in left sided IE; as clinically indicated for tricuspid valve IE

• follow-up blood cultures- during 1st few days after starting treatment to document clearance of bacteremia. Repeat q2 days or with fevers until sterile.repeat 2 weeks after end of treatment.

Appendix 6b : Anticoagulants during Endocarditis Therapy

i) not indicated for infective endocarditisii) indicated only if other conditions are present which warrant anticoagulant therapy (e.g.

mechanical prosthetic valve)iii) should be discontinued if the patient develops an intracranial hemorrhage or mycotic

aneurysm; for ischemic stroke (embolic or thrombotic), discontinue anticoagulation until CT scan and neurology evaluation performed

iv) consider discontinuation in the patient who develops Staph. aureus prosthetic valve endocarditis

v) prior to cardiac surgery, discuss with the surgeon the risks/benefits of peri-operative and post-operative anticoagulant therapy and choice of prosthetic valve (bioprosthesis vs. mechanical)

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Appendix 6c: Neurologic Complications in Infective Endocarditis

I. Guidelines for Neurologic Investigation

A) Brain Imaging:i) Non contrast CT scan indicated if: 1. Severe headache 2. Focal neurologic symptoms 3. Focal neurologic signs 4. Encephalopathy or seizure ii) Contrast CT or MRI if non-contrast CT scan is negative

B) Lumbar punctureIndicated if the CT scan is negative in the setting of either:

1. Headache or2. Encephalopathy

C) i) Cerebral angiographyIndicated if:

1. CT head reveals hemorrhage2. LP reveals pleocytosis

Possibly indicated if:1. CT reveals infarct2. Persistent focal headache or deficit unexplained after imaging

and LP.3. Equivocal imaging studies by CT or MRI4. If anticipating full anticoagulation during valve replacement

surgery or for other indicationRepeat angiography every 2-3 weeks if positive for aneurysm.

ii) MR angiography or CT angiographyNot yet generally accepted as a replacement for contrast angiography but may be used to follow a known aneurysm or as initial imaging in an attempt to avoid contrast angiography.

II. Management of Mycotic Aneurysms A) Surgical management is indicated for:

i) single, distal (peripheral) aneurysms, particularly if enlarging on serial angiography; orii) ruptured aneurysms if surgically accessible

B) Endovascular therapy. Consider radiologic endovascular therapy for proximal inoperable lesions.

C) Medical management (antibiotic only) is indicated for:

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i) unruptured proximal aneurysms, orii) multiple aneurysms

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Appendix 7: Cardiac Surgery in Endocarditis

A. Cardiac Surgery Indications: Definite* and Possible (consultation recommended for all cases with perivalvular abscess, new aortic regurgitation, or CHF)

1) Valve *a) Dysfunction: acute aortic or mitral regurgitation plus CHF, particularly if

unresponsive to medical therapyb) Prosthetic valve: often require replacement in setting of endocarditis,

particularly if early onset or due to Staph. aureus. 2) *Perivalvular extension (abscess). Suspect if:

a) new heart block (particularly 2° or 3°); orb) pericarditis; orc) continued fevers despite appropriate antibiotic therapy

3) Vegetationa) persistent vegetation after major systemic embolization‡

b) mitral valve, anterior leaflet > 10 mmc) > 1 embolus‡ during 1st or 2nd week of therapyd) > 2 emboli‡ during or after antibiotic therapy (benefit of surgery for prevention of more emboli is greatest early on, since antibiotic therapy rapidly reduces the risk)e) vegetation size increasing after 4 wk antibiotic therapy‡ excluding pulmonary emboli in right-sided endocarditis unless hemodynamically significant

4) Organism for which medical therapy alone is usually unsuccessful *a) fungal endocarditis*b) enterococci, if no synergistic antibiotic regimenc) Pseudomonas aeruginosad) brucellae) Q-fever (Coxiella burnetti)

5) Uncontrolled infection: persistent positive blood cultures drawn > 7 days after initiation of appropriate antimicrobial therapy

B. Relative Contraindications to Cardiac Surgery: 1) Neurologic (Management decisions depend upon the size of the infarct/

hemorrhage and the degree of hemodynamic instability): a) non-hemorrhagic embolic infarct in the central nervous system within the

preceding 2-3 weeksb) intracerebral hemorrhage within the preceding 4 weeksc) patients with mycotic aneurysms who require urgent valve replacement should receive bioprosthetic rather than mechanical valves

2) Other: Ongoing injection drug use during the past month and no expectation of adherence to a drug rehabilitation program.

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Appendix 7: Cardiac Surgery in Endocarditis (continued)

C. Antibiotic Duration Post Cardiac Surgery

1) Pre-operative plus post-operative duration should be at least equal to or greater than the usual duration (as per standing orders)

2) Full course of post-operative antibiotic therapy if: a) myocardial abscess; b) positive intra-operative culture; c) positive Gram’s stain for organisms on a prosthetic valve in a patient with prosthetic valve IE.

Appendix 8: Home IV Antibiotic Therapy for Endocarditis

Eligibility Criteria

1. Good clinical response and antibiotic tolerance during 1st week of in-patient therapy

2. Organism fully susceptible and associated with a good prognosis (eg. viridans streptococcus, penicillin MIC < 0.1 µg/L)

3. Stable hemodynamics4. No complications: cardiac or extracardiac5. Able to comply with home IV antibiotic logistics, teaching, and 1 – 2 x/week out

patient ID physician follow-up.6. Stable/safe home environment accessible for 3 x weekly home care nurse visits.7. Not suspected to be actively or recently using injection drugs.8. Patient is in agreement with home IV therapy, and is aware of the possible

complications, and that the risk is likely the same at home as in hospital.9. Patient has been instructed to report any new or worsening symptoms and has

prompt access to medical care.

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Appendix 9: Endocarditis Clinical Practice Guideline References

A. Diagnosis 1. Bayer et al. Diagnosis and management of infective endocarditis and its complications. Circulation

1998;98:2936-48.2. Fang et al. Prosthetic valve endocarditis resulting from nosocomial bacteremia. A prospective,

multicenter study. Annals of Internal Medicine 1993;119:560-7.3. Habib et al. Value and limitations of the Duke criteria for the diagnosis of infective endocarditis.

Journal of the American College of Cardiology 1999;33:2023-9.4. Hoen et al. The Duke criteria for diagnosing infective endocarditis are specific: Analysis of 100

patients with acute fever or fever of unknown origin. Clinical Infectious Diseases 1996;23:298-302.5. Kupferwasser et al. Diagnosis of culture-negative endocarditis: The role of the Duke criteria and the

impact of transesophageal echocardiography. American Heart Journal 2001;142:146-52.6. Lamas et al. Suggested modifications to the Duke criteria for the clinical diagnosis of native valve and

prosthetic valve endocarditis: Analysis of 118 pathologically proven cases. Clinical Infectious Diseases 1997;25:713-9.

7. Li et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clinical Infectious Diseases 2000;30:633-8.

8. Martos-Perez et al. Comparable sensitivity of the Duke criteria and the modified Beth Israel criteria for diagnosing infective endocarditis. Clinical Infectious Diseases 1996;23:410.

9. Mylotte et al. Staphylococcus aureus bacteremia: Predictors of 30 – day mortality in a large cohort. CID 2000;31:1170-4.

B. Echocardiography1. Bach D.S. Transesophageal echocardiographic (TEE) evaluation of prosthetic valves. Cardiology

Clinics 2000;18:751-71.2. Daniel et al. Improvement in the diagnosis of abscesses associated with endocarditis by

transesophageal echocardiography. NEJM 1986;324:795-843.3. Daniel et al. Transesophageal echocardiography. NEJM 1995;332:1268-78.4. Fowler et al. Role of echocardiography in evaluation of patients with Staphylococcus aureus

bacteremia: Experience in 103 patients. J Am Coll Cardiol 1997;30:1072-8.5. Irani et al. A negative transthoracic echocardiogram obviates the need for transesophageal

echocardiography in patients with suspected native valve active infective endocarditis. Am J Cardiol 1996;78:101-103.

6. Lengyel. The impact of TEE on the management of PVE: Experience of 31 cases and review of the literature. The Journal of Heart Valve Disease 1997;6:204-11.

7. Lindner et al. Diagnostic value of echocardiography in suspected endocarditis. An evaluation based on the pretest probability of disease. Circulation 1996;93:730-6.

8. Rosen et al. Cost-effectiveness of transesophageal echocardiography to determine the duration of therapy for intravascular catheter-associated Staphylococcus aureus bacteremia. Annals of Internal Medicine 1999;130:810-20.

9. Ryan et al. Transesophageal echocardiography (TEE) in the evaluation of infective endocarditis. Cardiology Clinics 2000;18:773-87.

10. San Roman et al. Transesophageal echocardiography in right-sided endocarditis. JACC 1993;21:1226-1230.

11. Shively et al. Diagnostic value of transesophageal compared with transthoracic echocardiography in infective endocarditis. JACC 1991;18(2):391-7.

12. Shapiro et al. Transesophageal echocardiography in diagnosis of infective endocarditis. Chest 1994;105(2):377-82.

C. Treatment1. Ackerman. Clinical value of monitoring serum vancomycin concentrations. Clinical Infectious

Diseases 1994;19:1180-2.2. Bayer et al. Diagnosis and management of infective endocarditis and its complications. Circulation

1998;98:2936-48.3. Cantu et al. Serum vancomycin concentrations: Reappraisal of their clinical value. Clinical Infectious

Diseases 1994;18:533-43.4. Chambers H.F. Short-course combination and oral therapies of Staphylococcus aureus endocarditis.

Infectious Diseases Clinics of North America 1993;7:69-80.5. Chambers et al. Right-sided Staphylococcus aureus endocarditis in intravenous drug abusers: Two-

week combination therapy. Annals of Internal Medicine 1988;109:619-24.6. Cook et al. Vancomycin revisited. Annals of Internal Medicine 1978;88:813-8.

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7. DiNubile M.J. Short-course antibiotic therapy for right-sided endocarditis caused by Staphylococcus aureus in injection drug users. Annals of Internal Med. 1994;121:873-6.

8. Ellis et al. Fungal endocarditis: Evidence in the world literature, 1965-1995. Clinical Infectious Diseases 2001;32:50-62.

9. Fortun et al. Right-sided endocarditis caused by Staphylococcus aureus in drug abusers. Antimicrobial Agents and Chemotherapy 1995;39:525-8.

10. Fortun et al. Short-course therapy for right-side endocarditis due to Staphylococcus aureus in drug abusers: Cloxacillin versus glycopeptides in combination with gentamicin. Clinical Infectious Diseases 2001;33:120-5.

11. Geraci et al. Vancomycin therapy for infective endocarditis. Reviews of Infectious Diseases 1981;3:S250-8.

12. Heldman et al. Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: Prospective randomized comparison with parental therapy. The American Journal of Medicine 1996;101:68-76.

13. Jorgensen et al. Antimicrobial susceptibility testing: Special needs for fastidious organisms and difficult-to-detect resistance mechanisms. Clinical Infectious Diseases 2000;30:799-808.

14. Karchmer AW. Infections of prosthetic valves and intravascular devices. In: Principles and Practice of Infectious Diseases. Eds Mandell, Douglas, and Bennett. 5th edition 2000, p903.

15. Levine et al. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Annals of Internal Medicine 1991;115:674-80.

16. Olaison et al. Enterococcal endocarditis in Sweden, 1995-1999: Can shorter course therapy with aminoglycosides be used? Clinical Infectious Diseases 2002;34:159.

17. Ribera et al. Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial. Annals of Internal Medicine 1996;125:969-74.

18. Saunders. Why monitor peak vancomycin concentrations? Lancet 1994;344:1748-50.19. Sexton et al. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once

daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Clinical Infectious Diseases 1998;27:1470-4.

20. Shanson. New guidelines for the antibiotic treatment of streptococcal, enterococcal and staphylococcal endocarditis. Journal of Antimicrobial Chemotherapy 1998;42:292-6.

21. Wilson WR, Karchmer AW, Dajani AS, Taubert KA, Bayer A, Kaye D et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA 1995;274(21):1706-1713.

D. IDU or HIV1. Brau et al. Cardiac valve replacement in patients infected with the human immunodeficiency virus.

Ann Thorac Surg 1992;54:552-4.2. Chambers et al. Staphylococcus aureus endocarditis: Clinical manifestations in addicts and

nonaddicts. Medicine 1983;62:170-7.3. Hecht SR et al. Right-sided endocarditis in intravenous drug users. Ann Intern Med

1992;117:560-566.4. Nahass et al. Infective endocarditis in intravenous drug users: A comparison of human

immunodeficiency virus type 1-negative and –positive patients. J Infect Dis. 1990;162:967-70.5. Pulvirenti et al. Infective endocarditis in injection drug users: Importance of human immunodeficiency

virus serostatus and degree of immunosuppression. Clinical Infectious Diseases 1996;22:40-5.6. Ribera et al. Influence of human immunodeficiency virus 1 infection and degree of

immunosuppression in the clinical characteristics and outcome of infective endocarditis in intravenous drug users. Arch Intern Med. 1998;158:2043-50.

E. Complications1. Bingham. Treatment of mycotic intracranial aneurysms. J. Neurosurg 1977;46:428-37.2. Bullock et al. Intracranial mycotic aneurysms: A review of 9 cases. SA Medical Journal 1981:970-3.3. Cabell et al. The risk of stroke and death in patients with aortic and mitral valve endocarditis.

American Heart Journal 2001;142:75-80.4. Clare et al. Infectious intracranial aneurysms. Neurosurgery Clinics of North America 1992;3:551-66.5. De Castro et al. Role of transthoracic and transesophageal echocardiography in predicting embolic

events in patients with active infective endocarditis involving the native cardiac valves. Am J Cardiol 1997;80:1030-4.

6. Di Salvo et al. Echocardiography predicts embolic events in infective endocarditis. Journal of the American College of Cardiology 2001;37:1069-76.

7. Fraszee et al. Bacterial intracranial aneurysms. J Neurosurg 1980;53:633-41.

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8. Harris et al. Cardiac, cerebral, and vascular complications of infective endocarditis. Cardiology Clinics 1996;14:437-50.

9. Kumar et al. Infective and traumatic aneurysms. Neurosurgery Clinics of North America 1998;9:577-86.

10. Millaire et al. Incidence and prognosis of embolic events and metastatic infections in infective endocarditis. European Heart Journal 1997;18:677-84.

11. Olmsted et al. The pathogenesis of peripheral aneurysms of the central nervous system: A subject review from the AFIP1. Radiology 1977;123:661-6.

12. Shapiro et al. Echocardiography predicts embolic events in infective endocarditis. Editorial Comment. Journal of the American College of Cardiology 2001;37:1077-9.

13. Steckelberg et al. Emboli in infective endocarditis: The prognostic value of echocardiography. Annals of Internal Medicine 1991;114:635-40.

14. Tischler et al. The ability of vegetation size on echocardiography to predict clinical complications: A meta-analysis. J Am Society of Echocardiography 1997;10:562-8.

F. Cardiac Surgery1. Brau et al. Cardiac valve replacement in patients infected with the human immunodeficiency virus.

Ann Thorac Surg 1992;54:552-4.2. Carrel et al. Endocarditis in intravenous drug addicts and HIV infected patients: Possibilities and

limitations of surgical treatment. The Journal of Heart Valve Disease 1993;2:140-7.3. DiNubile. Surgery in active endocarditis. Annals of Internal Medicine 1982;96:650-9.4. John et al. Staphylococcus aureus prosthetic valve endocarditis: Optimal management and risk factors

for death. Clinical Infectious Diseases 1998;26:1302-9.5. Pomar et al. Tricuspid valve replacement using a mitral homograft. Surgical technique and initial

results. The Journal of Heart Valve Disease 1993;2:125-8.6. Wilson et al. Valve replacement in patients with active infective endocarditis. Circulation

1978;58:585-8.

G. Home IV antibiotic therapy1. Choudhrie SH et al. Consensus guidelines for the treatment of infectious endocarditis with outpatient

parenteral antibiotic therapy. Can J Infect Dis 2000; 11 (Supp D): 4D-10D.2. Francioli P. et al. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone

sodium for 4 weeks: efficacy and outpatient treatment feasibility. JAMA 1992; 267:264-7.3. Stamboulian D et al. Antibiotic management of outpatinets with endocarditis due to penicillin-

susceptible streptococci. Rev Infect Dis 1991;13(suppl2):S160-34. Williams DN et al. Practive Guidelines for Community-Based Parenteral Anti-Infective Therapy.

Clin Infect Dis 1997;25:787-801

H. Review1. Mylonakis E et al. Infective endocarditis in adults. N Engl J Med 2001;345:1318-1330 (Letters and

reply: NEJM 2002;346:782-3).

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