Clostridium difficile
BATAM bijeenkomst
17 mei 2013
Dr DJ Bac, MDL-arts
Dr MA Schouten, arts-microbioloog
CDI
• Berucht vanwege ribotype 027
• Diverse uitbraken sinds 2000
• Toename morbiditeit + mortaliteit + kosten
CDI
Clostridium difficile
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Gram positieve anaerobe staaf
Produceert sporen
Produceert toxines
Nr 1 oorzaak nosocomiale diarree
Risk factors clostridium difficile
• Ziekenhuis opname
• Antibiotica:
• > 65 jaar
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IBD
PPI ??
sonde voeding
diverticulose
chemotherapie
(GI) chirurgie
dialyse
Epidemiologie clostridium difficile
Drager
• Gezonde personen
• Ziekenhuis
• Jonge kinderen
~3%
~20%
tot 80%
Diarree
• Hospital-acquired:
• Community-acquired:
~ 10 %
~ 1,5-2 %
1e lijns probleem?
• Clostridium difficile infection: it’s a family affair
UK 2007-2012: 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,
>10.000 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
1e lijns probleem?
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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
1e 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 ?
10.000 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
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
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
DJB: klinisch beeld
Diagnostiek
• Gold standard: cytotoxicity assay
• Kweek met toxine bepaling
• Elisa (toxin A and or B, or GDH)
– 72-92 % sensitiviteit
– 89-98 % specificiteit
• PCR
– Sensitiviteit 92%
– Specificiteit 96%
• Sigmoidoscopy
Behandeling
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De beste behandeling is nog steeds preventie!
Lokaal: antibioticum formularium ZGV
Gebaseerd op SWAB richtlijn
SWAB weer gebaseerd op ESCMID
“Infection control” strategie
Rigorous hand hygiene
Judicious use of antibacterial agents to preserve
patients’ microflora
Isolation of patients with faecal incontinence
Barrier protection (e.g. gowns and gloves)
Use of dedicated equipment for patients with CDI
Environmental 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
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.
Behandeling:
ESCMID recommendations:
First episode of CDI
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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
Diagnosis
ESCMID recommended treatment
Non-severe first episode
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Metronidazole 500 mg tid orally for 10 days*
Severe first episode
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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
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* Intravenous (IV ) if oral therapy is not possible
Bauer et al. Clin Microbiol Infect 2009;15:1067–79.
Behandeling (10-14 dgn)
• Metronidazol
3 dd 500
• Vancomycine
4 dd 125-500 mg
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eerste keus:
po en iv
geen selectie VRE
Goedkoop
vaak recidieven
tweede keus:
alleen po
selectie VRE
Duur
vaak recidieven
Ernstige colitis  vancomycin
Snapshot of current treatments for
initial episodes of CDI in Europe
Treatments used in an initial episode of CDI in a recent European survey
0.2%
18%
Oral metronidazole
IV metronidazole
11%
Oral vancomycin
Intracolonic vancomycin
71%
Bauer et al. Lancet 2011;377:63–73.
Cure rates:
Metronidazole & vancomycin
p=0.36
p=0.02
39/40
p=0.006
69/71
30/31
37/41
66/79
28/38
*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 <2.5 mg/dL, or peripheral white blood cell count >15,000 cells/mm3
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.
Zar et al. Clin Infect Dis 2007;45:302–7.
Recurrence of CDI
• Recurrence of CDI has been identified by ESCMID as the
most important problem in the treatment of CDI1
• CDI recurrence is common, occurring in up to 32% of
cases within 30 days following treatment2–4
• Rate of reported recurrences strongly depends on
definition applied1
• 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.
2.
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5.
Bauer et al. Clin Microbiol Infect 2009;15:1067–79;
Louie et al. N Engl J Med 2011;364:422–31;
Lowy et al. N Engl J Med 2010;362:197–205;
Bouza et al. Clin Microbiol Infect 2008;14:S103–4;
DuPont. N Engl J Med 2011;364:473–4.
Risk factors for a recurrence of CDI
• Immunocompromised patients1
• Exposure to other antibacterial agents that disrupt the normal
colonic microflora2–5
• Previous episode of CDI2,4–6
• Renal impairment7,8
• Aged 65 years or over2,4,9
• Impaired immune response to C. difficile toxin A2
• Severe underlying disease2
• Prolonged hospitalisation9
• Concomitant use of antacid medications (PPI)10 PPI, proton pump inhibitor
• Intensive care unit (ICU) stay5
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5.
Cohen. J Ped Gastroenterol Nutr 2009;48:63–5;
Kyne et al. Lancet 2001;357:189–93;
Bauer et al. Clin Microbiol Infect 2009;15:1067–79;
Bauer et al. Lancet 2011;377:63–73;
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.
Pharmacotherapy of CDI:
First recurrence
• ESCMID recommends treating a first recurrence as a first episode
unless the disease has progressed from non-severe to severe
Diagnosis
ESCMID recommended treatment
Non-severe first recurrence 
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Severe first recurrence
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Metronidazole 500 mg tid orally for 10 days*
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
Bauer et al. Clin Microbiol Infect 2009;15:1067–79.
ESCMID recommendations:
Second and later recurrences
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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
Diagnosis
Second and later
recurrences
ESCMID recommended treatment
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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
Bauer et al. Clin Microbiol Infect 2009;15:1067–79.
NTVG 2005; 149: 2081
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.
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 treatment2–4
– Risk of overgrowth of vancomycin-resistant enterococci (VRE) in
patients who are already colonised with VRE5
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.
Fidaxomicine
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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
Fidaxomicine
• Extramuraal vergoed via GVS mits
18 jaar of ouder
CDI
Recidief na metronidazol behandeling
Ernstige infectie
• 1620 euro per kuur
DJB: alternatieve therapie