Clostridium difficile - a new Disease?

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Clostridium difficile - a new Disease?

• Dr Mike Cooper
• Consultant Microbiologist
• and DIPC
• New Cross Hospital
• Wolverhampton

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Oxoid Infection Control Team of the Year Awards
2006/2007 Winners Announced

• BASINGSTOKE, UK, 26 April 2007 - Oxoid, a world
  leader in microbiology, is pleased to announce
  the winners of the 2006/2007 Oxoid Infection
  Control Team of the Year Awards
• 1st PrizeRoyal Wolverhampton Hospitals NHS
  Trust, UK
• 2nd PrizeCho Ray Hospital, Vietnam
• Joint 3rd PrizeSouthampton University Hospitals
  NHS Trust, UK and Aminu Kano Teaching Hospital,
  Nigeria.

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C. difficile

• 1935 - discovered
• Obligate anaerobe
• Motile
• Gram positive bacillus
• Oval, sub-terminal spores
• Occasional case reports - infected wounds (1960s)

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C. difficile

• 1977 - C. difficile identified as cause
• Birmingham General Hospital
• AAD - 20-30
• AAC - 50-75
• gt90 - pseudomembranous colitis

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C. difficile Toxins

• Toxigenic strains produce 2 major toxins
• toxin A (enterotoxin)
• toxin B (cytotoxin)
• Neutralised by C. sordellii antitoxin

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Toxin A

• Binds to specific CHO receptors on intestinal
  epithelium
• Toxin induced inflammatory process
• neutrophils
• inflammatory mediators
• fluid secretion
• altered membrane permeability
• haemorrhagic necrosis

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Toxin B

• Binding site not yet identified
• Depolymerization of filamentous actin
• destruction of cell cytoskeleton
• rounding of cells

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Clinical Manifestations

• Asymptomatic carriage (neonates)
• Diarrhoea
• 5-10 days after starting antibiotics
• maybe be 1 day after starting
• may be up to 10 weeks after stopping
• may be after single dose
• spectrum of disease
• brief, self limiting
• cholera-like - 20X/day, watery stool

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Clinical Manifestations

• Additional symptoms
• abdominal pain, fever, nausea, malaise, anorexia,
  hypoalbuminaemia, colonic bleeding, dehydration
• Acute toxic megacolon
• acute dilatation of colon
• systemic toxicity
• signs of obstruction
• high mortality (64)
• Colonic perforation

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Pathogenesis

• Disruption of normal colonic flora
• Colonisation with C. difficile
• Production of toxin A /- B
• Mucosal injury and inflammation

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Pathogenesis

• Microflora of gut
• 1012 bacteria/gram
• 400-500 species
• colonisation resistance
• Transmission - faecal/oral
• spores
• Late log / early stationary phase
• toxin production

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Pathology

• Colonic mucosa - raised yellow / white plaques
• initially small
• enlarge and coalesce
• Inflamed mucosa

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Mortality

• All cause 28/7 mortality for CDT positive
• 1.12.03 31.3.04 18/60 30.0
• 1.12.05 31.3.06 71/183 38.8
• RR 1.29 (CI 0.84 1.98)

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What Changed?

• Hand hygiene?
• Environmental cleanliness?
• Antimicrobial prescribing?
• Other factors?

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What Changed?

• ?Different organism

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Independent 6-8th June 2005
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PCR Ribotype 027

• In North America PFGE Type NAP1
• International NAP1/027
• Major problems in Montreal and several states in
  the US

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PCR Ribotype 027

• Montreal 30/7 mortality increased
• 4.7 in 1991/2
• 8.6 in 2002
• 13.8 in 2003
• Incidence per 100,000 individuals aged gt65
• 102 (1991-2)
• 866 (2003)

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PCR Ribotype 027

• First UK isolate Preston 1999
• Second UK isolate Birmingham 2002
• Next seen March 2004 Stoke Mandeville
• Wolverhampton 8 isolates from Oct Dec 2005
  sent for typing
• all 027!!!

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PCR Ribotype 027

• North American outbreak strain
• 8 to 16 X production of toxins A and B in-vitro
• Hyper-toxin production
• 18bp deletion in the TcdC gene
• regulates toxin production
• Strong association with fluoroquinolone use
• The Lancet 24th Sept 2005
• Warny, Pepin, Fang, Killgore, Thompson, Brazier,
  Frost and McDonald Toxin production by an
  emerging strain of C. difficile associated with
  outbreaks of severe disease in North America and
  Europe

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RWHT Response

• Also major problems with MRSA bacteraemias

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RWHT Response

• DoH MRSA HCAI Improvement Programme
• Disband ICC
• Form IPB
• chaired by Chief Executive
• performance management for Divisions and Wards

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RWHT Response to C. difficile

• Regular commode auditing
• Replacement of 100 old/damaged commodes
• Replacement of 300 mattresses
• Introduction of Saving Lives HII Number 6
  following every case of CDAD
• Root cause analysis on every case
• Introduction of hotel style bed space check lists
  following discharge of every patient

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RWHT Response to C. difficile

• Matron led ward de-clutter programme
• Introduction of monthly clutter collection
• 200 domestics trained in CDAD and the role of the
  environment
• Medical division nurse training on CDAD, spread
  and role of equipment
• Grand Round presentation of case studies and
  action on CDAD. Mandatory attendance of at least
  one member of every clinical team. 250 attended

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RWHT Response to C. difficile

• Slide card for infection prevention for all
  staff
• C. difficile management / treatment guidelines
• New antimicrobial guidelines
• Antimicrobial prescribing policy
• Monitoring and antimicrobial prescribing
  performance management of Divisions
• Ward refurbishment programme

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C. difficile Antibiotic Risk

• High Risk Antibiotics
• Cefotaxime
• Ceftriaxone
• Cefalexin
• Cefuroxime
• Ceftazidime
• Ciprofloxacin
• Moxifloxacin
• Clindamycin (low dose)

• Medium Risk Antibiotics
• Meropenem
• Ertapenem
• Clindamycin (high dose)
• Co-amoxiclav
• Tazocin
• Erythromycin
• Clarithromycin

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C. difficile Antibiotic Risk

• Low Risk Antibiotics
• Benzyl penicillin Gentamicin
• Amoxicillin Metronidazole
• Flucloxacillin Vancomycin
• Tetracyclines Teicoplanin
• Trimethoprim Synercid
• Nitrofurantoin Linezolid
• Fusidic acid Tigecycline
• Rifampicin Daptomycin

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Treatment Algorithm For New Cases of C. difficile
Diarrhoea
Symptomatic Proven or Suspected C. diff infection
Assess Patient AXR, CRP, U Es, FBC Stool
Chart Stool for C. diff culture (if not
done) Consider Flexi Sig if diagnosis in
doubt Review Antibiotics
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Severe Disease Unwell WC gt 20 CRP gt150
Abnormal AXR Distended Abdomen ( severe
if any of these features)
Moderate Disease Well WCC lt 20 CRP lt150 Normal AXR
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Moderate
Severe

Start treatment without delay -Vancomycin 500mg
QDS PO -Metronidazole 500mg TDS IV or 400mg TDS
PO - IVI -Consider HDU / ITU Colorectal Surgical
Referral on day 1 Daily Surgical Review until
improving if fails to improve consider surgery
Start treatment without delay -Metronidazole
400mg TDS for 5 days -Daily Review including
stool chart - FBC, CRP, AXR if deteriorates
( If Deteriorates to Severe )
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Response Complete 14 day course of
metronidazole
No Response - Add Vancomycin 500mg QDS PO for 5
days Complete 14 day course of metronidazole
( If Deteriorates to Severe )

Response Complete 14 day course of Vancomycin
Complete course of metronidazole
No Response - Refer Gastroenterology for
flexible sigmoidoscopy advice. Continue Vanc
Met Treat as for severe if deteriorates
Can be discharged on metronidazole and vancomycin
(125mg QDS)
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Recurrence

• ??re-infection
• Assess if severe treat as above
• Moderate metronidazole 400mg TDS and PO
  vancomycin 500mg QDS
• If responds by day 5 14 days of metronidazole
  500mg QDS vancomycin, then 6 weeks tapering
  vancomycin
• If no response after 5 days of combined therapy
  refer to gastroenterology
• If remains symptomatic after 10 days and C. diff
  / PMC confirmed on flexible sigmoidoscopy then
  consider IV Immunoglobulin.
• If this is the third or more recurrence then
  consider immunoglobulin 2 weeks metronidazole
  400mg TDS PO / vancomycin 500mg QDS at the outset
  followed by 6 weeks of vancomycin.

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Third Line Drug Regimes for Recurrent Disease-

• 6 weeks Tapering Vancomycin
• 125mg every 6 hours for 1 week
• 125mg every 12 hrs for 1 week
• 125mg once daily for 1 week
• 125mg every other day for 1 week
• 125 mg every 3rd day for 2 weeks
• IV Immunoglobulin
• 400mg/kg single dose with a repeat at 21 days if
  necessary
• Yeast
• Yeast preparations are contraindicated.
• Prebiotic and Probiotics (live yoghurt)
• No proven benefit of prebiotics or probiotics.
• Cannot be prescribed and should not be advocated
  - no quality control over the agents that the
  patient will receive

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Commode replacement
Commode Audit
Mattress replacement
Grand Round presentation
RCA for all c diff cases introduced
High Impact Intervention No 6 introduced

Bed space checklists introduced
Commode re-Audit feedback
Matrons lead Ward Declutter programme
Antibiotic review commenced
Medical division training
Domestics training delivered by IPT
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Mortality

• All cause 28/7 mortality for CDT positive
• 1.12.03 31.3.04 18/60 30.0
• 1.12.05 31.3.06 71/183 38.8

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Mortality

• All cause 28/7 mortality for CDT positive
• 1.12.03 31.3.04 18/60 30.0
• 1.12.05 31.3.06 71/183 38.8
• 1.12.06 31.3.07 23/85 27.1
• RR 0.70 (CI 0.47 1.03)

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Conclusions

• New strain(s) of C. difficile cause more severe
  disease
• ??sub-strains
• Appear to spread more readily
• More difficult to control
• Multi-factorial approach to control needed
• Requires involvement of entire Trust
• not just a medical / nursing solution
• Not just antibiotics!

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