RCPA Pathology Update Sydney 2017 Infective Endocarditis in the 21 st Century

Transcription

1 RCPA Pathology Update Sydney 2017 Infective Endocarditis in the 21 st Century Professor Eugene Athan Department of Infectious Disease Barwon Health Deakin University

2 Changes in IE Epidemiology Aging, IDU, HCA, devices Increased Staphylococci, candida Dental origin AB prophylaxis no longer recommended NICE controversial Antibiotic resistance Mortality remains high overall 20% (100% in pre-antibiotic era) despite advances in healthcare

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5 Streptococcal microbiology Viridans Streptococci hemolytic make up 40% total IE Oralis (Mitis) reduced pen MIC 25% each: sanguis, mutans (caries), salivarius, intermedius, anginosis/milleri Group B strep agalactiae underlying co-morbidities high mortality NVS 5% Gemella /hemolysans/abiotrophia rare pleomorphic on gram stain Indolent, underlying VHD, poor outcome

6 Clinical picture Streptococcal IE Dental origin Underlying valvulopathy, PVIE Subacute 20% Emboli, stroke, Heart failure Indications for surgery: uncontrolled sepsis, HF

7 Group D Streptococci Bovis/gallolyticus/infantarius in gut more common France Colonoscopy in all cases assoc d colon cancer Enterococci up to 18% IE increasing ageing population Sub-acute < 25% classic features, older males, urinary tract procedures Cure difficult intrinsic resistance to cephalosporins High mortality persists Bacteremia -?IE community acquisition, underlying VHD, cryptogenic source, mono-microbial

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9 Therapy principles in IE unique setting Vegetation fibrin mesh impairs host immune defense Inoculum effect high bacterial density with reduced metabolic rate/cell turnover Less susceptible to cell wall active therapy Increased lactamase, resistant sub-populations Penetration into vegetations correlates with serum concentration Weeks to eradicate, relapse common

10 Therapy principles in IE unique setting Bactericidal drugs In vitro killing reflected in vivo models Supported by clinical studies Combinations lactam and AG (synergy) Duration Prolonged high bacterial density, slow phase growth 2 weeks in uncomplicated NV VGS IE, Staph Right sided Drug penetration Variable into vegetation fibrin/plat Anti platelet/anticoagulant effect enhanced killing

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12 Therapy Empiric ID consultation Duration from negative BC, postop if valve culture positive Monitored for HB, HF Early surveillance cultures Anticoagulation controversial PVIE no change Cardiac surgery access 35-50% require surgery

13 Strep Therapy NV PV Bactericidal Combination lactam, aminoglycoside weeks HITH Cure > 90%

14 Viridans sensitive to pen. MIC < 0.12ug/ml Combination pen/ag 2-4 weeks excellent cure low relapse compared to pen alone for 2 weeks 50% relapse Uncomplicated NVIE pen sensitive Alter CTX 2g daily and AG for 2 weeks 4 weeks/2 week combination if complicated/pvie

15 Aminoglycoside synergy Gentamicin monitor nomogram Synergy low concentrations 1-3 ug/ml, daily total dose 3mg/kg at once/twice/ thrice Less nephrotoxicity excellent outcomes Ototoxicity Nephrotoxicity

16 NVS Treatment as per pen MIC highly susceptible Pen MIC < 0.12ug/ml, 98% cure 4 weeks pen, CTX, synergy AG 2 weeks daily dosing uncomplicated IE 4 weeks monotherapy avoids AG toxicity Alternative Vancomycin

17 Viridans Pen. intermediate 4 weeks including 2 weeks AG CTX or Vanc Pen >0.5ug/ml resistant CTX, Vanc, Amp, AG PVIE 6weeks 2 weeks AG Pen. allergy CTX or Vancomycin 30mg/kg/24 hrs for 4 weeks

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21 Staphylococcal IE Common, HCA Increased MRSA High Vanc MIC poorer outcome? Virulence factors L sided Mortality up to 40% R sided high cure rate > 85% CNS PVE, NVE, HCA, Meth Resist S lugdunensis increase virulence

22 Staphylococcal IE R sided > 2 weeks fluclox, dapto uncomplicated? Oral combinations L sided fluclox 6 weeks MRSA Vanc, Dapto >8mg/kg? Ceftaroline? Co-trimoxazole, not rifampicin Hypersensitivity cephazolin or Consider desensitisation?dapto 8-10mg/kg emergence of resistance 5%

23 Staph PVIE MRCNS Vanc, Rif, AG 6 weeks? FQ Abscess surgery S aureus Early surgery Combination fluclox, gent, rif? FQ

24 Enterococcal IE 10% IE mainly E fecalis Older, co-morbidities, CRF, HCA Highly resistant Relapse common Mortality 20% Ampicillin more active than pen E fecium more resistant then E fecalis

25 Enterococcal IE Test MIC pen, amp, HLAGR, Vanc Inhibited not killed without synergy AG increase permeability of cell wall to lactams Increasing HLAR No RCT on AG dosing 3mg/kg/d Individualised Wilson 4 weeks relapses 12.5% esp greater than 3 months sx, MV location, PVIE Reversible nephrotoxicity, 19% vestibular toxicity

26 Enterococcal IE NV/PVIE combination 4-6 weeks Pen million units divided, ampicillin 12g/24hrs, AG 3mg/kg divided doses Swedish observational study AG median 15 days Cure rate 81% (75/93) 5-10% mortality

27 Double lactam combination CTX/Amp Double lactam combination CTX/Amp? saturate PBPs encouraging 67% cure but 23% In-hosp mortality Fernández-Hidalgo et al CID centres Spain unblinded observational *Randomized comparative trial (A+G) vs (A+C) urgently needed

28 Enterococcal IE HLAR Increased AG toxicity HL Streptomycin resistance > 60% strains HL gent resistance increasing >35% strains Plasmid mediated AG modifying enzymes transferable Major challenge

29 Enterococcal IE HLAR Optimal therapy unknown Consider surgery Test all AG heterogeneous Consider daptomycin Longer term Amp 6-8 weeks Vancomycin bacteriostatic, synergistic with AG AG resistant? Streptomycin 15mg/kg/d Amp resistant Vanc 30mg/kg/day /gent 3mg/kg/d 4-6 weeks esp E fecium intrinsic or lactamase

30 VRE/MDR therapy 4 Options Test all potential agents MIC Daptomycin, teicoplanin, linezolid Linezolid (oxazolidinone static) some success toxicity, dapto (cyclic lipopeptide high dose) some cases success? Tigecycline, lactam amp, ceftaroline, combinations

31 Penicillin allergy Vancomycin 30mg/kg/daily combination AG Pen. desensitisation

32 Culture negative IE 10-20%, usually prior antibiotics Empiric Acute S aureus, haemolytic strep Subacute S aureus, VGS, HACEK, Enterococci? Vanc, CTX Bartonella, Chlamydia, Coxiella, Brucella, Legionella, Tropheryma whipplei, Fungal Serology, valve PCR Non infective antiphospholipid AB syndrome

33 HACEK Fastidious GNB 5-10% IE Hemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella Longer incubation all in 5 days Amp resistance common CTX 4-6 weeks?fq

34 Fungal PVE Endophthalmitis Surgical indications reduces mortality Ampho B, Echinocandins > 6 weeks? Lifelong azole suppression

35 Diagnosis of IE Echocardiography rapid and repeated in 1 week TOE preferred, high index suspicion, poor TTE quality, presence of prosthesis or device, positive TTE Vegetation, abscess, valvular perforation, or prosthetic valve dehiscence Other imaging 3D echo, Cardiac CT- PET infective focus

36 Surgery for IE 50% all cases IE Decreased embolic events small RCT early surgery 48 hours NVE, L sided, vege >10mm Indications/Considerations Micro, vege size, perivalvular infection, embolism, HF, age, comorbidities, surgical expertise Multidisciplinary model reduces mortality early same day referral to CT centres Timing early case by case MD Endocarditis team

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38 Surgery for IE Early NVE L sided Valve dysfunction causing HF Resistant organism CHB, aortic abscess Persistent sepsis >5-7 days Recurrent emboli Severe valve regurgitation, mobile veges >1 cm Mobile vege >1cm ant leaflet of MV

39 Early surgery PVIE HF, valve dehiscence, intra-cardiac fistula, severe prosthetic dysfunction Sepsis >5-7 days CHB, aortic root abscess Resistant organism Recurrent emboli Relapse Mobile vege >1cm

40 Surgery R sided Complications severe TR, RHF, persistent sepsis Vege >2cm Repair if possible

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42 Surgery post stroke Systematic MRI subclinical cerebrovascular complications in up to 50% cases Altered diagnosis and management esp. rate or timing of surgery Stroke RF for mortality Ischemic safe if not severe Wait > 4 weeks if hemorrhage

43 Embolisation Up to 50% cases Increased S aureus, ant. leaflet MV, Candida, HACEK, >1cm vege Decrease dramatically after therapy 2 weeks?cerebral MRI all cases for surgery With hold anticoagulation 2 weeks if CNS emboli in PVE

44 Perivalvular extension Increase mortality AV- AVnode, abscess, CHB 10-40% AVIE >60% PVE Intra-cardiac fistulae, abscess PET CT Urgent surgical treatment aortic homograft

45 Mycotic aneurysms Bifurcation intracranial 1-5% cases rupture 80% mortality Increase Strep? Neuro deficit Imaging angiography

46 Longer term HITH after 1-2weeks Low risk HF, emboli Echo end of therapy 1,3,6 12 months Dental review Poor oral hygiene, gingivitis main cause oral IE OPG Prevention: dental, IV devices, urinary, colorectal lesions Prophylaxis very limited Patient education regarding symptoms/signs of IE

47 Take home messages Incidence of IE is increasing worldwide HCA, elderly, Staph, devices Multidisciplinary approach to management Early TOE ID doc is your friend! Surgery improves outcome

48 References 1.Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. Athan E, Chu VH, Tattevin P, Selton-Suty C, Jones P, Naber C, Miró JM, Ninot S, Fernández-Hidalgo N, Durante- Mangoni E, Spelman D, Hoen B, Lejko-Zupanc T, Cecchi E, Thuny F, Hannan MM, Pappas P, Henry M, Fowler VG Jr, Crowley AL, Wang A; ICE-PCS Investigators.JAMA Apr 25;307(16): Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.Murdoch DR, Corey GR, Hoen B, Miró JM, Fowler VG Jr, Bayer AS, Karchmer AW, Olaison L, Pappas PA, Moreillon P, Chambers ST, Chu VH, Falcó V, Holland DJ, Jones P, Klein JL, Raymond NJ, Read KM, Tripodi MF, Utili R, Wang A, Woods CW, Cabell CH; International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) Investigators.Arch Intern Med Mar 9;169(5): Candida infective endocarditis.baddley JW, Benjamin DK Jr, Patel M, Miró J, Athan E, Barsic B, Bouza E, Clara L, Elliott T, Kanafani Z, Klein J, Lerakis S, Levine D, Spelman D, Rubinstein E, Tornos P, Morris AJ, Pappas P, Fowler VG Jr, Chu VH, Cabell C; International Collaboration on Endocarditis-Prospective Cohort Study Group (ICE-PCS).Eur J Clin Microbiol Infect Dis Jul;27(7): Emergence of coagulase-negative staphylococci as a cause of native valve endocarditis.chu VH, Woods CW, Miro JM, Hoen B, Cabell CH, Pappas PA, Federspiel J, Athan E, Stryjewski ME, Nacinovich F, Marco F, Levine DP, Elliott TS, Fortes CQ, Tornos P, Gordon DL, Utili R, Delahaye F, Corey GR, Fowler VG Jr; International Collaboration on Endocarditis-Prospective Cohort Study Group.Clin Infect Dis Jan 15;46(2): Contemporary clinical profile and outcome of prosthetic valve endocarditis.wang A, Athan E, Pappas PA, Fowler VG Jr, Olaison L, Paré C, Almirante B, Muñoz P, Rizzi M, Naber C, Logar M, Tattevin P, Iarussi DL, Selton-Suty C, Jones SB, Casabé J, Morris A, Corey GR, Cabell CH; International Collaboration on Endocarditis-Prospective Cohort Study Investigators.JAMA Mar 28;297(12): Staphylococcus aureus endocarditis: a consequence of medical progress.fowler VG Jr, Miro JM, Hoen B, Cabell CH, Abrutyn E, Rubinstein E, Corey GR, Spelman D, Bradley SF, Barsic B, Pappas PA, Anstrom KJ, Wray D, Fortes CQ, Anguera I, Athan E, Jones P, van der Meer JT, Elliott TS, Levine DP, Bayer AS; ICE Investigators.JAMA Jun 22;293(24):

49 References 7. Thuny F et al. Management of infective endocarditis: challenges and perspectives. Lancet 2012;379: Kang DH et al. Early surgery versus conventional treatment for infective endocarditis. NEJM 2012;366: Snugg-Martin U et al. Cerebrovascular complications in patients with left-sided infective endocarditis are common: a prospective study using MRI and neurochemical brain damage markers. CID 2008;47: Fowler VG et al. Daptomycin versus standard therapy for endocarditis caused by S. aureus. NEJM 2006;355: Infective endocarditis in adults: diagnosis, antimicrobial therapy and management of complications. Baddour LM, Wilson WR, Bayer AS et al. Circulation 2015;132: Outpatient parenteral antimicrobial therapy is safe and effective for the treatment of infective endocarditis: a retrospective cohort study. Htin AK, Friedman ND, Hughes A, O'Brien DP, Huffam S, Redden AM, Athan E. Intern Med J Jun;43(6): doi: /imj Enterococcal endocarditis in the beginning of the 21st century: analysis from the International Collaboration on Endocarditis- Prospective Cohort Study. Chirouze C, Athan E, Alla F, Chu VH, Ralph Corey G, Selton-Suty C, Erpelding ML, Miro JM, Olaison L, Hoen B; International Collaboration on Endocarditis Study Group. Clin Microbiol Infect Dec;19(12): doi: / Epub 2013 Mar 20.