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Clostridium difficile BATAM bijeenkomst 17 mei 2013 Dr DJ Bac, MDL-arts Dr MA Schouten, arts-microbioloog.

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Presentatie over: "Clostridium difficile BATAM bijeenkomst 17 mei 2013 Dr DJ Bac, MDL-arts Dr MA Schouten, arts-microbioloog."— Transcript van de presentatie:

1 Clostridium difficile BATAM bijeenkomst 17 mei 2013 Dr DJ Bac, MDL-arts Dr MA Schouten, arts-microbioloog

2 CDI Berucht vanwege ribotype 027 Diverse uitbraken sinds 2000 Toename morbiditeit + mortaliteit + kosten

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4 CDI

5 Clostridium difficile Gram positieve anaerobe staaf Produceert sporen Produceert toxines Nr 1 oorzaak nosocomiale diarree

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9 Risk factors clostridium difficile Ziekenhuis opname Antibiotica: > 65 jaar IBD PPI ?? sonde voeding diverticulose chemotherapie (GI) chirurgie dialyse

10 Epidemiologie clostridium difficile Drager Gezonde personen~3% Ziekenhuis~20% Jonge kinderentot 80% Diarree Hospital-acquired:~ 10 % Community-acquired:~ 1,5-2 %

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12 1 e lijns probleem? Clostridium difficile infection: it’s a family affair UK : 238 patiënten met CDI; verspreiding na ontslag? slechts in 3 gevallen verspreiding thuis (1) Community-associated Clostridium difficile infection: How real is it? (2) Studie CDC: CA= diarree niet voorafgegaan door ziekenhuis bezoek afgelopen 3 maanden, > gevallen; 32% CA: hiervan 25% opgenomen na vaststellen CDI, recurrence rate 9%, PFGE type NAP1, NAP11, NAP4 Risicofactoren CA CDI: AB gebruik, protonpomp remmers literatuur: vlees, huisgenoten met CDI, kinderen < 2 jaar. 1: ICHE 2013, 2: Anaerobe 2013

13 1 e lijns probleem? Clostridium difficile carriage in healthy infants in the community asymptomatisch dragerschap volwassenen 1-7% Kinderen tot 2 jaar 2-75% drager maar zelf zelden ziek Studie: 10 gezonde kinderen van 1 jaar gevolgd + screening 2 dagopvangcentra Alle 10 verwerven CD en bleven maanden POS Dagverblijf 45% van de 85 kinderen CD POS Risicofactoren: ab gebruik, gebruik ab moeder zwangerschap, verandering voeding (met name bij verdwijnen Bifidobacterium cave melk / BV minder CD, flesvoeding meer CD) Geen relatie met aantal siblings of dieren Recente ziekenhuis opname enige risicofactor voor kolonisatie pathogene stam CID 2012

14 1 e lijns probleem? Clostridium difficile contamination of public tap water distribution system during a waterborne outbreak in Finland Nov-dec 2007 drinkwater Nokia gecontamineerd met rioolwater Grote uitbraak gastro-enteritis; Rol Clostridium difficile ? inwoners, 8000 ziek, 1000 behandeld, 17 CD POS (65 getest) 12 CD isolaten gevonden in water (5 kraanwater, 7 riool) Aantal malen zelfde stam in water en patiënt SAGE 2013

15 Dieren Clostridium difficile infection in the community: a zoonotic disease? (1) Review LUMC; CD komt zowel bij mensen als dieren voor; verschillende biotypes Bij vinden nieuwe types als verwekker humane infecties dan zoeken naar dierlijk reservoir Clostridium difficile in faeces from healthy dogs and dogs with diarrhea (2) Stockholm; 50 gezonde honden: 2 met CD; niet toxine producerend 20 honden met diarree: 2 met CD; toxine producerend, humane types 1: CMID 2012, 2: AVS 2013

16 Voeding Detection of Clostridium difficile in retail ground meat products in Manitoba 48 porties vlees (rund en varken); 6,3% CD POS Verschillende types; wel allemaal bekend humane toxine producerende stamen JIDM 2012

17 DJB: klinisch beeld

18 Diagnostiek Gold standard: cytotoxicity assay Kweek met toxine bepaling Elisa (toxin A and or B, or GDH) – % sensitiviteit – % specificiteit PCR – Sensitiviteit 92% – Specificiteit 96% Sigmoidoscopy

19 Behandeling De beste behandeling is nog steeds preventie! Lokaal: antibioticum formularium ZGV Gebaseerd op SWAB richtlijn SWAB weer gebaseerd op ESCMID

20 “Infection control” strategie Rigorous hand hygiene Judicious use of antibacterial agents to preserve patients’ microflora Isolation of patients with faecal incontinenceBarrier protection (e.g. gowns and gloves)Use of dedicated equipment for patients with CDIEnvironmental cleaning and disinfection Education of healthcare workers and visitors about CDI transmission Kelly & Lamont. NEJM 2008;359:1932–40 Vonberg et al Clin Microbiol Infect 2008;14(Suppl. 5):2–20

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22 Behandeling: ESCMID recommendations: An initial mild episode of CDI Discontinuation of the antibacterial treatment that induced CDI, if possible Avoidance of treatments that reduce gut transit – e.g. opioids, including those used in diarrhoea relief (loperamide etc) Provision of supportive care – e.g. fluid and electrolyte replacement Observation for signs of clinical deterioration Bauer et al. Clin Microbiol Infect 2009;15:1067–79.

23 Behandeling: ESCMID recommendations: First episode of CDI Aim of treatment is to eradicate C. difficile from the intestines and promote restoration of the normal colonic microflora Cessation of antibacterial therapy, if possible, is usually the first step DiagnosisESCMID recommended treatment Non-severe first episode  Metronidazole 500 mg tid orally for 10 days* Severe first episode  Vancomycin 125 mg qid orally for 10 days (or teicoplanin 100 mg bid)  IV metronidazole 500 mg tid for 10 days plus intracolonic vancomycin 500 mg in 100 mL saline every 4–12 hours and/or vancomycin 500 mg qid by nasogastric tube if oral therapy impossible * Intravenous (IV ) if oral therapy is not possible Bauer et al. Clin Microbiol Infect 2009;15:1067–79.

24 Behandeling (10-14 dgn) Metronidazol 3 dd 500 eerste keus: po en iv geen selectie VRE Goedkoop vaak recidieven Vancomycine 4 dd mg tweede keus: alleen po selectie VRE Duur vaak recidieven Ernstige colitis  vancomycin

25 Snapshot of current treatments for initial episodes of CDI in Europe Bauer et al. Lancet 2011;377:63–73. Treatments used in an initial episode of CDI in a recent European survey

26 Cure rates: Metronidazole & vancomycin p=0.006p=0.36 p= /41 39/40 28/38 30/31 66/79 69/71 Zar et al. Clin Infect Dis 2007;45:302–7. *Patients were stratified by mild or severe disease based on severity assessment score developed for this study. Patients received one point each for age >60 years, temperature >38.3°C, albumin level 15,000 cells/mm 3 within 48 hours of enrolment. Two points were given for endoscopic evidence of pseudomembranous colitis or treatment in an intensive care unit. Patients with ≥2 points were considered to have severe CDI.

27 Recurrence of CDI Recurrence of CDI has been identified by ESCMID as the most important problem in the treatment of CDI 1 CDI recurrence is common, occurring in up to 32% of cases within 30 days following treatment 2–4 Rate of reported recurrences strongly depends on definition applied 1 Recurrence appears to be related to a combination of: 5 – A failure to re-establish the colonic microflora – The presence in the intestines of spores of C. difficile – A sub-optimal host immune response to the infecting organism and its toxins 1.Bauer et al. Clin Microbiol Infect 2009;15:1067–79; 2.Louie et al. N Engl J Med 2011;364:422–31; 3.Lowy et al. N Engl J Med 2010;362:197–205; 4.Bouza et al. Clin Microbiol Infect 2008;14:S103–4; 5.DuPont. N Engl J Med 2011;364:473–4.

28 Risk factors for a recurrence of CDI Immunocompromised patients 1 Exposure to other antibacterial agents that disrupt the normal colonic microflora 2–5 Previous episode of CDI 2,4–6 Renal impairment 7,8 Aged 65 years or over 2,4,9 Impaired immune response to C. difficile toxin A 2 Severe underlying disease 2 Prolonged hospitalisation 9 Concomitant use of antacid medications (PPI) 10 Intensive care unit (ICU) stay 5 1.Cohen. J Ped Gastroenterol Nutr 2009;48:63–5; 2.Kyne et al. Lancet 2001;357:189–93; 3.Bauer et al. Clin Microbiol Infect 2009;15:1067–79; 4.Bauer et al. Lancet 2011;377:63–73; 5.Hu et al. Gastroenterology 2009;136:1206–14; 6.McFarland et al. Am J Gastroenterol 2002;97:1769–75; 7.Do et al. Clin Infect Dis 1998;26:954–9; 8.Bauer et al. Clin Microbiol Infect 2011;17(Suppl 4):A1–A4; 9.Pépin et al. Clin Infect Dis 2005;40:1591–7; 10.Kwok et al. Am J Gastroenterol 2012;107:1011–9. PPI, proton pump inhibitor

29 ESCMID recommends treating a first recurrence as a first episode unless the disease has progressed from non-severe to severe Pharmacotherapy of CDI: First recurrence Bauer et al. Clin Microbiol Infect 2009;15:1067–79. DiagnosisESCMID recommended treatment Non-severe first recurrence  Metronidazole 500 mg tid orally for 10 days* Severe first recurrence  Vancomycin 125 mg qid orally for 10 days  IV metronidazole 500 mg tid for 10 days plus intracolonic vancomycin 500 mg in 100 mL saline every 4–12 hours and/or vancomycin 500 mg qid by nasogastric tube if oral therapy impossible *Intravenous (IV ) if oral therapy is not possible; tid, three times daily; qid, four times daily

30 DiagnosisESCMID recommended treatment Second and later recurrences  Vancomycin 125 mg qid orally for at least 10 days  Consider tapering vancomycin dose by decreasing daily dose with 125 mg every 3 days  Consider pulse dosing with vancomycin 125 mg every 3 days for 3 weeks  IV metronidazole 500 mg tid for 10–14 days plus retention enema of vancomycin 500 mg in 100 mL saline every 4–12 hours and/or vancomycin 500 mg qid by nasogastric tube if oral therapy impossible ESCMID recommendations: Second and later recurrences ESCMID recommends treating second or later recurrences in the same way as severe first recurrence – With the option of using tapered or pulsed dosing regimens Bauer et al. Clin Microbiol Infect 2009;15:1067–79.

31 NTVG 2005; 149: 2081

32 ESCMID recommendations: Surgical intervention In the minority (<5%) of patients who develop fulminant colitis, surgical intervention (colectomy) may be needed Surgical intervention carries a high rate of mortality Optimal timing for colectomy has not been established Current guidelines recommend intervention before: – The disease becomes too severe – Serum lactate levels exceed 5 mmol/L Bauer et al. Clin Microbiol Infect 2009;15:1067–79.

33 Clinical limitations associated with current treatments for CDI Although metronidazole and vancomycin are effective in a first episode of CDI, therapy remains suboptimal Among the most significant drawbacks of current therapy for CDI are: – Rates of treatment failure with metronidazole of up to 18% 1 – Rates of recurrent infection following treatment with metronidazole and vancomycin of up to 32% within 30 days following treatment 2–4 – Risk of overgrowth of vancomycin-resistant enterococci (VRE) in patients who are already colonised with VRE 5 1.Aslam et al. Lancet Infect Dis 2005;5:549–57; 2.Louie et al. N Engl J Med 2011;364:422–31; 3.Lowy et al. N Engl J Med 2010;362:197–205; 4.Bouza et al. Clin Microbiol Infect 2008;14:S103–4; 5.Al-Nassir et al. Antimicrob Agents Chemother 2008;52:2403–6.

34 Fidaxomicine Macrocyclisch antibioticum Remt bacteriële RNA polymerase Smal spectrum; Gram negatieve bacteriën resistent Remt sporenvorming Remt toxine productie Wordt beperkt geresorbeerd: lokaal werkzaam Zwangerschap / lactatie: onbekend Bijwerkingen: misselijkheid, braken, obstipatie... Dosering 2 dd 200mg 10 dagen

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38 Fidaxomicine Extramuraal vergoed via GVS mits 18 jaar of ouder CDI Recidief na metronidazol behandeling Ernstige infectie 1620 euro per kuur

39 DJB: alternatieve therapie

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