2/1/2017

Disclosures

Bacterial • Allergan – research grant • Genentech – research grant Henry F. Chambers, MD

Infective endocarditis: Outline

• Native valve endocarditis • Prosthetic valve endocarditis • Cardiac implantable device infections • Unusual causes of endocarditis • Prophylaxis (time permitting)

Circulation. 132:1435-86, 2015

1 2/1/2017

Which of the following is the most common bacterial etiology of worldwide?

1. Streptococcus mutans Native Valve Endocarditis 2. Streptococcus sanguis 3. Group A β-hemolytic streptococcus 4. Enterococcus faecalis 5. Staphylococcus aureus

When bacteremia is documented, which of the Which of the following is NOT a following is LEAST likely to be associated with endocarditis? HACEK Organism?

1. species 1.Streptococcus mutans 2. Acinetobacter species 2.Streptococcus gallolyticus 3. hominis 3.Streptococcus mitis 4. 4.Enterococcus faecalis 5. species 5.Group A β-hemolytic streptococcus 6. Who gives a flying #%&$ anyway?

2 2/1/2017

Etiology of Native Valve Endocarditis Etiology of Native Valve Endocarditis in Injection Drug Users

Organism Percent of cases Organism Right-sided Left-sided S. aureus 27-35 Streptococci 33-35 S. aureus 77% 23% Enterococci 8-10 Streptococci 5% 15% Enterococci 2% 24% Coagulase-negative staphylococci 4-9 Gram-negative bacilli 5% 12% HACEK/Gram-negative bacilli 3/4 Polymicrobial 2 Candida <1% 12% Candida 1 Culture-negative 3% 3% Culture-negative 6

Which of the following is NOT a major Definition of IE criterion in the Modified Duke Criteria for the Diagnosis of IE? • Definite IE 1. Typical organism consistent with IE from 2 – Pathological criteria: positive culture or histology separate blood culture in absence of a of vegetation, embolus, intracardiac focus primary focus – Clinical criteria: 2 major OR 1 major + 3 minor OR 2. Anti-phase 1 IgG antibody titer for Coxiella 5 minor burnetii > 1:800 • Possible IE: 1 major + 1 minor or 3 minor 3. Oscillating intracardiac mass on a valve or • Rejected: alternative diagnosis, does not supporting structure on TTE meet criteria for possible 4. Worsening or changing pre-existing regurgitation murmur

3 2/1/2017

Modified Duke Criteria for the Diagnosis of IE Major Criteria for Diagnosis of IE

1. Typical organism consistent with IE from 2 separate blood culture in absence of a • Blood cultures primary focus – At least 3 sets from different sites with first 2. Anti-phase 1 IgG antibody titer for Coxiella and last at least 1h apart burnetii > 1:800 • Echocardiography 3. Oscillating intracardiac mass on a valve or – Should be performed expeditiously in supporting structure on TTE, , PVE patients suspected of IE dehiscence 4. New valvular regurgitation

Typical Organisms in Blood Cultures Minor Criteria Consistent with IE

• Predisposing heart condition, IDU • Organisms* – Staphylococcus aureus o • Temperature > 38 C – Viridans group streptococci • Vascular/immunologic phenomena: GN, – Strep. gallolyticus (aka bovis) Osler node, Janeway lesion, Roth spot, +RF, – Enterococcus (community-acquired) septic pulmonary emboli, systemic emboli, – HACEK mycotic aneurysm • In absence of primary focus • Positive blood culture not meeting major • Or persistently positive blood cultures criterion, positive serologic test – 2 cultures drawn > 12h apart positive • ECHO minor criteria eliminated – All 3 or majority of > 4 separate cultures with first and last drawn > 1h apart

* Coag-negative staph in patients with prosthetic valve

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IE SUSPECTED What is High Risk?

High risk patient or moderate • High risk patients (examples) Low risk patient to high clinical suspicion, – Prosthetic valve & low clinical suspicion Initial TTE difficult imaging candidate – Congenital heart disease TEE after TTE asap – Previous endocarditis Neg Pos – New murmur, , , stigmata of IE Rx Neg Pos • High risk TTE (examples) Low High risk suspicion suspicion features on TTE – Large or mobile vegetations, anterior MV leaflet veg Look for Yes suspicion Rx – Valvular insufficiency, perivalular extension, valve No other TEE source perforation No – Ventricular dysfunction Look for other TEE source TEE

“Acute” Community-acquired Native Osler node Janeway lesions Valve Endocarditis

• A 63 y.o. man with no significant past medical history presents with a week of fever, rigors, and progressive dyspnea on exertion. •Exam – T 39.5, BP 160/40, P110 – Skin and conjunctiva (next slide) – JVD (+), rales ½ way up bilaterally. – Loud diastolic decrescendo murmur at the lower left sternal border. Conjunctival hemorrhage Roth spots

5 2/1/2017

Which of the following is the most appropriate empirical regimen for this patient?

1. + 2. Cefazolin + gentamicin 3. + gentamicin 4. Nafcillin + vancomycin 5. Vancomycin + gentamicin

Septic Pulmonary Emboli, Staph endocarditis

Definitive Therapy – Native Valve Endocarditis

Splinter Hemorrhage

6 2/1/2017

Native Valve S. aureus IE Treatment of Viridans Group Streptococci and Strep. gallolyticus IE Regimen Duration Comments MSSA • Pen MIC < 0.12 μg/ml Nafcillin or 6 wk 2 wk uncomplicated R- – , ceftriaxone, vancomycin x 4 weeks oxacillin sided IE (IDU) – Penicillin or ceftriaxone + gent x 2 weeks Cefazolin 6 wk Pen-allergic naf-intolerant • Pen MIC > 0.12 μg/ml, < 0.5 μg/ml patient (equivalent to naf) – Penicillin or ceftriaxone (4 wk) + gent (2 wk) MRSA – Ceftriaxone or vancomyin (4wk) Vancomycin 6 wk MSSA if beta-lactam hypersensitivity • Pen MIC > 0.5 μg/ml Daptomycin 6 wk > 8 mg/kg/day, vanco – Penicillin or ceftriaxone + gent alternative – Vancomycin – Duration not defined (4 wk?) No gentamicin, no rifampin – both III/B

Contraindications to Short Course Treatment of Endocarditis Caused by Penicillin-Susceptible Therapy of Endocarditis due to Viridans Streptococci/Strep gallolyticus “Nutritionally Variant Streptococci”

• Isolate with MIC Pen > • Prosthetic valve 0.1µg/ml – (short course not effective • Abiotrophia and Granulicatella species • High level resistance gent – ↑relapses) – Susceptibility tests unreliable • VIII nerve dysfunction • Native valve with cardiac – Often penicillin tolerant, tendancy to • Reduced renal function complications relapse – Intra or extra cardiac – Cr Cl < 20 mL/min abscess/focal infection • Visual impairment • Therapy • Native valve with CNS (severe) – Pen or amp 4 wks + gentamicin 2-4 wks complications • Non-viridans streptococci, (not β-lactam alone) • Yoyo Ma or Itzak Perlman Gemella, Abiotrophia, Granulicatella species – Or vancomycin alone (?)

7 2/1/2017

Enterococcal Endocarditis

Regimen Duration Comments HACEK Organisms (Strength of Rec) Pen or amp + gent 4-6 wk Pen S, Gent 1 mg/kg q8h, 6 • Haemophilus species wk for PVE, symptoms>3 mo Amp + Ceftriaxone 6 wk Pen S, • species susceptible or resistant • Pen or amp + strep 4-6 wk Gent resistant, Strep synergy, ClCr > 50 • Eikenella corrodens Vanco + gent 6 wk Pen resistant or beta-lactam • Kingella species intolerant (toxic!) Linezolid or dapto > 6 wk VRE: Dapto 10-12 mg/kg & combo with amp or ceftaroline

Regimens Recommended for Treatment of Culture-Negative Endocarditis IE Due to a HACEK organism • Prior antibiotics Regimen Comments • Fastidious organisms – HACEK Ampicillin Avoid: assume amp or pen resistant unless MIC test confirmed susceptible – Abiotrophia defectiva, et al – Brucella sp. Amp + gent NO GENT: nephrotoxic • “Non-cultivatable” organism – quintana Ceftriaxone Regimen of choice – , Chlamydophila psittaci, Ceftriaxone + gent NO GENT: nephrotoxic Trophyrema whipplei, Legionella sp, Mycoplasma • Fungi (molds) Ciprofloxacin Levo or FQ as single agent OK as • Not endocarditis alternative regimen – Libman-Sacks, myxoma, APLS, marantic, tumor

8 2/1/2017

Surgical Management NVE/PVE

• Optimal timing of surgery not known • Early surgery – Heart failure due to valvular dysfuntion Prosthetic Valve Endocarditis – IE from fungi or MDR organisms (i.e., VRE) – Presence of heart block, annular or aortic – Persistent bacteremia or fever > 5-7 days not attributable to another source – Emboli, large vegetations (> 10mm)

Prosthetic Valve Endocarditis While awaiting TEE, which of the following antimicrobial regimens is most appropriate • A 70 y.o. male with fever, chills, and low back in this setting? pain for 6 days. • Bioprosthetic AVR 9 months previously for critical . 1. Vancomycin •Exam 2. Daptomycin – T 38, BP 104/70, P 110 3. Vancomycin + rifampin – Left conjunctival petechiae. 4. Vancomycin + gentamicin + rifampin – Rales 1/3 way up bilaterally. 5. Daptomycin + linezolid + gentamicin – Grade II/VI SEM • Blood cultures: 3/3 positive at 18 hours for Gram-positive cocci

9 2/1/2017

PVE versus NVE Causes of Prosthetic valve endocarditis

• Similar presentations but ….. EARLY (≤ 2 mo post op) LATE (> 12 mo post op) • Different microbiology • Coag-neg Staph • Viridans streptococci • More invasive infection, higher rates of • S. aureus • S. aureus – Heart failure • Less common • Coag-neg Staph – Conduction disturbances – Gram Neg bacilli • Less comon – Enterococci – Enterococci – New or changing murmurs – Fungi (Candida) – Gram neg bacilli – Diphtheroids – CNS events – Fungi – Diphtheroids

JAMA 2007;297:13

Therapy for PVE due to viridans streptococci or S. gallolyticus Therapy for Staphylococcal PVE

24 h dosage Weeks Regimen 24 h dose Weeks Methicillin sensitive

Pen or ceftriaxone 24 mu/2g 6 nafcillin/oxacillin 12 g ≥ 6 plus rifampin 900 mg ≥ 6 +/- gentamicin* 3 mg/kg 2 plus gentamicin 3 mg/kg 2 Vancomycin 30 mg/kg 6 Methicillin resistant or major pen allergy vancomycin 30 mg/kg ≥ 6 *If pen MIC > 0.12 ug/ml add gent for 6 weeks plus rifampin 900 mg ≥ 6 or use ceftriaxone or vancomycin plus gentamicin 3 mg/kg 2

10 2/1/2017

Therapy for Enterococcal PVE

Same as for native valve endocarditis Cardiac Implantable Device Infections (permanent pacemakers, defibrillators)

J Am Coll Cardiol 2008;49:1851; Circulation 2010;121:458; NEJM 2012;367:842; JAMA 2012;307:1727

Pacemaker Infection Which of the following is the best • A 71 y.o. male, permanent pacemaker was management? implanted 2 months ago for sick sinus syndrome/syncope, presents subjective fever 1. Cefazolin + rif x 6 wks •Exam: – T37.8C, P78 (paced), R18, BP 122/80. 2. Remove generator, then cefazolin + rif x10 days – Generator pocket is slightly tender, swollen, with 3. Remove generator, then cefazolin + rif 6 wks moderate warmth and erythema; otherwise WNL. 4. Remove entire device, then cefazolin + rif 6 wks •Cultures 5. Remove entire device, then cefazolin x 10 days – Pus aspirated from the pocket: MSSA – Blood cultures: negative rif = rifampin

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Microbiology of Cardiac Cardiac Implantable Device Implantable Device Infections Infection Types Organism % of cases • Pocket site/generator only : ~ 60% Coag-neg staphylococci 42 – Blood culture positive <50% S. aureus 29 – Pocket infection or generator/lead erosion Gram-neg bacilli 9 Polymicrobial 7 • Occult bacteremia/fungemia: ~7-30% Culture-negative 7 • Lead infection +/- endocarditis: ~10-25% Fungal 2 Other 4

Survival with and without Survival with and without Device Removal Device Removal

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Algorithm for Management of an Infected Cardiac Implantable Algorithm for Management of an Infected Cardiac Implantable Device (CIED) Infection Device (CIED) Infection Suspected CIED Infection Blood Culture

Positive Remove Negative Entire Device

Baddour LM et al. N Engl J Med 2012;367:842-849 Baddour LM et al. N Engl J Med 2012;367:842-849

AHA Guidelines for Management of Cardiac Implantable Device Infections AHA Guidelines for Reimplantation

• Blood cultures before antibiotics – If positive, then TEE • Determine if reimplantation necessary • Gram stain, culture of pocket tissue, lead tips • New device on contralateral side • Device removal for all infections and occult • >72h negative BC before reimplantation staphylococcal bacteremia (consider for GNR • If IE: reimplant > 14d after original removal bacteremia) • Antibiotic prophylaxis: 1h before • Therapy (antibiotic based on susceptibility) implantation, none thereafter – Pocket infection: 10-14 days – Bloodstream infection: > 14 days – Lead or valve vegetations: 4-6 weeks

Circ 2010;121:458-77

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Case Presentation

• A 44 y.o man, subjective fever for 3 months, diarrhea x 1 year, 30 pound weight loss, intermittent Weird Causes of Endocarditis arthralgias, mainly in his hands. No travel or animal exposures • Vital signs: BP 172/52 P 92 R 24 T38C • Exam: diastolic murmur at the lower left sternal border, and rales halfway up bilaterally. • Blood cultures (6 sets) are drawn and remain negative after 21 days. • Valvular tissue obtained at valve replacement reveals foamy macrophages by PAS stain.

Which of the following is the most likely Tropheryma whipplei Infective Endocarditis etiologic agent?

• Indolent with arthralgia, CHF, murmur, emboli 1. A member of the HACEK group • Diarrhea and GI symptoms may be mild/absent 2. Coxiella burnetii • Fever: not prominent 3. Tropheryma whipplei • Modest laboratory abnormalities: ESR, anemia, CRP • Echocardiogram - vegetations, abscess, valve dysfunction 4. Chlamydia psittaci • Blood cultures negative, vegetations PCR positive 5. Bartonella sp. • Vegetations PAS positive foamy macrophages, on Warthin-Starry silver stain • Rx: Surgery plus ceftriaxone (pen/gent) followed by doxycycline-hydroxychloroquine (> 1 year)

Gubler, et al., Ann Intern Med 1999; 131:112.

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Tools for Diagnosis of Culture-Negative Endocarditis

Organism Clinical clues Serology Specific Universal PCR 16s/18s rRNA PCR Endocarditis Prophylaxis HACEK, strep, etc Prior antibiotics X Legionella Immunocompromise X X T. whipplei Chronic illness X X Brucella Travel X X Bartonella sp. Cats, homeless, lice X (>1:800) XX Mycoplasma X X Animal contact, lab X (>1:800) XX Chlamydia Bird exposure X X Circulation 2007; 116:1736-54

63 year old female, no significant PMH except calcified aortic sclerosis; no prior history of IE, Antimicrobial Prophylaxis for Endocarditis: no known drug allergies. Current AHA Recommendations The best recommendation for management prior to the extraction (all 30-60 minutes prior to the procedure) is: • List of cardiac conditions reduced 1. No prophylaxis • List of procedures greatly reduced 2. Amoxicillin 2 gm p.o. • Regimens simplified 3. Clindamycin 600 mg p.o. 4. Azithro 500 mg p.o. 5. Ampicillin 1 gm i.v.

J Am Dent Assoc 2008;139:suppl 35-24s

15 2/1/2017

Cardiac Conditions Associated with High Risk Rationale for Changes in Prophylaxis for Adverse Outcome: IE Guidelines Prophylaxis Advised with Dental Work • Bacteremia – Tooth brushing 154,000 times greater/yr than single extraction, daily activity possibly 5.6 x 10^6 greater/yr • Prosthetic cardiac valve • Antibiotics •Prior IE – do not eliminate bacteremia • Congenital heart disease (CHD) – not clear reduces IE – Unrepaired cyanotic CHD includes shunts/conduit • No prospective studies supporting efficacy – Repaired CHD with prosthetic material (within 6 mos) • Case-control study: dental event not increased in IE – Repaired CHD with residual defect • If 100% effective, antibiotics prevent rare cases of IE • Cardiac transplant with valvulopathy

AHA recommendations for Regimines Recommendations for prophylaxis of IE: Procedures Prophylaxis of Endocarditis

• Dental Preferred 30 – 60 min before – involving gingival crevice Oral Amoxicillin 2 gm • Surgery – inside oral cavity I.V. Amp 2 gm or ceftriaxone 1 gm – If bacterial infection present at the site Allergy to pcn-oral Clinda 600 mg •GU – with bacterial infection Allergy to pcn- I.V. Clinda 600 mg

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Questions?

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