Clostridium difficile - a new Disease? Dr Mike Cooper Consultant Microbiologist and DIPC New Cross...

Clostridium difficile - a new Clostridium difficile - a new Disease?Disease?

Dr Mike CooperConsultant Microbiologist

and DIPCNew Cross Hospital

Wolverhampton

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 Prize:Royal Wolverhampton Hospitals NHS Trust, UK

2nd Prize:Cho Ray Hospital, Vietnam

Joint 3rd Prize:Southampton University Hospitals NHS Trust, UK and Aminu Kano Teaching Hospital, Nigeria.

C. difficileC. difficile

1935 - discovered Obligate anaerobe Motile Gram positive bacillus Oval, sub-terminal spores

Occasional case reports - infected wounds (1960s)

C. difficileC. difficile

1977 - C. difficile identified as cause Birmingham General Hospital

AAD - 20-30% AAC - 50-75% >90% - pseudomembranous colitis

C. difficileC. difficile Toxins Toxins

Toxigenic strains produce 2 major toxins: toxin A (enterotoxin) toxin B (cytotoxin)

Neutralised by C. sordellii antitoxin

Toxin AToxin A

Binds to specific CHO receptors on intestinal epithelium

Toxin induced inflammatory process: neutrophils inflammatory mediators fluid secretion altered membrane permeability haemorrhagic necrosis

Toxin BToxin B

Binding site not yet identified Depolymerization of filamentous actin

destruction of cell cytoskeleton rounding of cells

Clinical ManifestationsClinical 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

Clinical ManifestationsClinical 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

PathogenesisPathogenesis

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

PathogenesisPathogenesis

Microflora of gut: 1012 bacteria/gram 400-500 species colonisation resistance

Transmission - faecal/oral spores

Late log / early stationary phase toxin production

PathologyPathology

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

Inflamed mucosa

New C. difficile Toxin Positives in Wolverhampton - Quarterly Totals

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20

40

60

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100

120

140

160

180

2000

2001

2002

2003

2004

2005

2006

2007

Nu

mb

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Community

RWHT

MortalityMortality

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)

What Changed?What Changed?

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

What Changed?What Changed?

?Different organism

Independent 6-8Independent 6-8thth June 2005 June 2005

PCR Ribotype 027PCR Ribotype 027

In North America – PFGE Type NAP1 International = NAP1/027 Major problems in Montreal and several

states in the US


Montreal – 30/7 mortality increased 4.7% in 1991/2 8.6% in 2002 13.8% in 2003

Incidence per 100,000 individuals aged >65 102 (1991-2) 866 (2003)


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!!!


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”

RWHT Response

Also major problems with MRSA bacteraemias

MRSA Bacteraemias RWHT and West Midlands Region

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0.05

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0.15

0.2

0.25

0.3

0.35

0.4

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West Midlands

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Apr-June07

July-Sept07

Oct-Dec07

Jan-Mar08

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acte

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Total

Target

Upper WarningLimitUpper ActionLimit

RWHT MRSA Bacteraemia Statistical Process Control Chart

RWHT Response

DoH MRSA HCAI Improvement Programme

Disband ICC

Form IPB:chaired by Chief Executive

performance management for Divisions and Wards

SPCC - C. difficile D17

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C. difficiletoxin pos

UpperWarningLimitUpper ActionLimit

Target

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


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


‘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

C. difficileC. difficile – Antibiotic Risk – Antibiotic Risk

High Risk Antibiotics:

CefotaximeCeftriaxoneCefalexinCefuroximeCeftazidimeCiprofloxacinMoxifloxacinClindamycin (low dose)

Medium Risk Antibiotics:

MeropenemErtapenemClindamycin (high dose)Co-amoxiclavTazocinErythromycinClarithromycin

C. difficileC. difficile – Antibiotic Risk – Antibiotic Risk

Low Risk Antibiotics:

Benzyl penicillin Gentamicin

Amoxicillin Metronidazole

Flucloxacillin Vancomycin

Tetracyclines Teicoplanin

Trimethoprim Synercid

Nitrofurantoin Linezolid

Fusidic acid Tigecycline

Rifampicin Daptomycin

Symptomatic Proven or Suspected

C. diff infection

Assess Patient:AXR, CRP, U& E’s, FBCStool ChartStool for C. diff & culture (if not done)Consider Flexi Sig if diagnosis in doubtReview Antibiotics

Treatment Algorithm For New Cases of C. difficile Diarrhoea

Moderate DiseaseWellWCC < 20CRP <150Normal AXR

Severe Disease Unwell WC > 20 *CRP >150 *Abnormal AXR *Distended Abdomen *(* = severe if any of these features)

( If Deterioratesto Severe )

Start treatment without delay-Vancomycin 500mg QDS PO-Metronidazole 500mg TDS IV or 400mg TDS PO- IVI-Consider HDU / ITUColorectal Surgical Referral on day 1Daily 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

Moderate Severe

( If Deterioratesto Severe )

ResponseComplete 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

ResponseComplete 14 day course of metronidazole

No Response :-Add Vancomycin 500mg QDS PO for 5 daysComplete 14 day course of metronidazole

Can be discharged on metronidazole and vancomycin (125mg QDS)

Recurrence:Recurrence:??re-infection

Assess: if severe treat as above

Moderate: metronidazole 400mg TDS and PO vancomycin 500mg QDSIf 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.

Third Line Drug Regimes for Third Line Drug Regimes for Recurrent Disease:-Recurrent Disease:-

6 weeks Tapering Vancomycin:125mg every 6 hours for 1 week125mg every 12 hrs for 1 week125mg once daily for 1 week125mg every other day for 1 week125 mg every 3rd day for 2 weeks

IV Immunoglobulin400mg/kg single dose with a repeat at 21 days if necessary

YeastYeast 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

New C. difficile Toxin Positives in Wolverhampton - Quarterly Totals

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160

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RWHT

SPCC RWHT C. difficile Toxin Positives

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-06

Fe

b-0

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Ma

r-0

6

Ap

r-0

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y-0

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-06

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g-0

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v-0

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Upper ActionLimit

Upper WarningLimit

Target

RWHT

Mar-06 Apr-06 May-06 Jun-06 Jul-06 Aug-06 Sep-06 Oct-06 Nov-06 Dec-0646.73 46.73 46.73 46.73 46.73 46.73 46.73 46.73 46.73 46.7341.32 41.32 41.32 41.32 41.32 41.32 41.32 41.32 41.32 41.3230.5 30.5 30.5 30.5 30.5 30.5 30.5 30.5 30.5 30.5

54 57 55 25 46 27 18 18 35 14

SPCC RWHT C. difficile Toxin Positives

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Upper ActionLimit

Upper WarningLimit

Target

RWHT

Matrons lead Ward Declutter programme

Domestics training delivered by IPT

Bed space checklists introduced

Commode replacement

Mattress replacement

RCA for all c diff cases introduced

Antibiotic review commenced

Grand Round presentation

High Impact Intervention No 6 introduced

Medical division training

Commode Audit

Commode re-Audit &feedback

SPCC RWHT C. difficile

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Upper ActionLimitUpper WarningLimitTarget

RWHT

SPCC - C. difficile D17

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C. difficiletoxin pos

UpperWarningLimitUpper ActionLimit

Target

MortalityMortality


1.12.03 – 31.3.04 18/60 30.0% 1.12.05 – 31.3.06 71/183 38.8%

MortalityMortality


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)

MRSA Bacteraemias RWHT and West Midlands Region

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0.05

0.1

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West Midlands

MRSA Bacteraemias - Cumulative Numbers RWHT

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120A

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2005/6

2006/7 (actualtrajectory)

2006/7(projectedtrajectorybased on totalat 6 months)

Comparison: January 1st - April 23rd 2006 and 2007

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1.1.06-23.4.06

1.1.07-23.4.07

New ESBL Producers in Wolverhampton by Quarter

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70Ju

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02

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ep 0

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ep 0

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Hospital

ConclusionsConclusions

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!

Clostridium difficile - a new Disease? Dr Mike Cooper Consultant Microbiologist and DIPC New Cross...

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