Clostridium difficile - a new
Disease?
Dr Mike Cooper
Consultant Microbiologist
and DIPC
New 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. difficile

1935 - discovered





Obligate anaerobe
Motile
Gram positive bacillus
Oval, sub-terminal spores
Occasional case reports - infected wounds
(1960s)
C. difficile

1977 - C. difficile identified as cause




Birmingham General Hospital
AAD - 20-30%
AAC - 50-75%
>90% - pseudomembranous colitis
C. difficile Toxins

Toxigenic strains produce 2 major toxins:



toxin A (enterotoxin)
toxin B (cytotoxin)
Neutralised by C. sordellii antitoxin
Toxin A


Binds to specific CHO receptors on intestinal
epithelium
Toxin induced inflammatory process:





neutrophils
inflammatory mediators
fluid secretion
altered membrane permeability
haemorrhagic necrosis
Toxin B


Binding site not yet identified
Depolymerization of filamentous actin


destruction of cell cytoskeleton
rounding of cells
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
Clinical Manifestations

Additional symptoms:


Acute toxic megacolon





abdominal pain, fever, nausea, malaise, anorexia,
hypoalbuminaemia, colonic bleeding, dehydration
acute dilatation of colon
systemic toxicity
signs of obstruction
high mortality (64%)
Colonic perforation
Pathogenesis




Disruption of normal colonic flora
Colonisation with C. difficile
Production of toxin A +/- B
Mucosal injury and inflammation
Pathogenesis

Microflora of gut:




Transmission - faecal/oral


1012 bacteria/gram
400-500 species
colonisation resistance
spores
Late log / early stationary phase

toxin production
Pathology

Colonic mucosa - raised yellow / white
plaques



initially small
enlarge and coalesce
Inflamed mucosa
New C. difficile Toxin Positives in Wolverhampton - Quarterly Totals
Community
180
RWHT
160
140
100
80
60
40
20
2007
2006
2005
2004
2003
2002
2001
0
2000
Number
120
New C. difficile Toxin Positives in Wolverhampton - Quarterly Totals
Community
180
RWHT
160
140
100
80
60
40
20
2007
2006
2005
2004
2003
2002
2001
0
2000
Number
120
New C. difficile Toxin Positives in Wolverhampton - Quarterly Totals
Community
180
RWHT
160
140
100
80
60
40
20
2007
2006
2005
2004
2003
2002
2001
0
2000
Number
120
Mortality

All cause 28/7 mortality for CDT positive:


1.12.03 – 31.3.04 18/60
1.12.05 – 31.3.06 71/183

RR 1.29 (CI 0.84 – 1.98)
30.0%
38.8%
What Changed?




Hand hygiene?
Environmental cleanliness?
Antimicrobial prescribing?
Other factors?
What Changed?

?Different organism
Independent 6-8th June 2005
PCR Ribotype 027



In North America – PFGE Type NAP1
International = NAP1/027
Major problems in Montreal and several
states in the US
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 >65


102 (1991-2)
866 (2003)
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!!!
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”
RWHT Response
Also major problems with MRSA bacteraemias
0.45
Apr-Jun 06
Oct-Dec 05
April-June 05
Oct-Dec 04
April-June 04
Oct-Dec 03
April-June 03
Oct-Dec 02
April-June 02
Oct-Dec 01
April-June 01
Rate per 1000 Bed Days
MRSA Bacteraemias RWHT and West Midlands Region
RWHT
West Midlands
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
RWHT MRSA Bacteraemia Statistical Process Control Chart
30
Number of Bacteraemias
25
Total
20
Target
15
Upper Warning
Limit
Upper Action
Limit
10
5
0
AprJune
05
JulySept
05
OctDec
05
JanMar
06
AprJune
06
JulySept
06
OctDec
06
JanMar
07
AprJune
07
JulySept
07
OctDec
07
JanMar
08
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
12
10
C. difficile
toxin pos
Upper
Warning
Limit
Upper Action
Limit
6
Target
4
2
Sep-06
Aug-06
Jul-06
Jun-06
May-06
Apr-06
Mar-06
Feb-06
Jan-06
Dec-05
Nov-05
0
Oct-05
Number
8
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
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
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
C. difficile – Antibiotic Risk
High Risk Antibiotics:
Medium Risk Antibiotics:
Cefotaxime
Ceftriaxone
Cefalexin
Cefuroxime
Ceftazidime
Ciprofloxacin
Moxifloxacin
Clindamycin (low dose)
Meropenem
Ertapenem
Clindamycin (high dose)
Co-amoxiclav
Tazocin
Erythromycin
Clarithromycin
C. difficile – Antibiotic Risk
Low Risk Antibiotics:
Benzyl penicillin
Amoxicillin
Flucloxacillin
Tetracyclines
Trimethoprim
Nitrofurantoin
Fusidic acid
Rifampicin
Gentamicin
Metronidazole
Vancomycin
Teicoplanin
Synercid
Linezolid
Tigecycline
Daptomycin
Treatment Algorithm For New Cases of C. difficile Diarrhoea
Symptomatic Proven or
Suspected
C. diff infection
Assess Patient:
AXR, CRP, U& E’s, FBC
Stool Chart
Stool for C. diff & culture (if not done)
Consider Flexi Sig if diagnosis in doubt
Review Antibiotics
Moderate Disease
Well
WCC < 20
CRP <150
Normal AXR
Severe Disease
Unwell
WC > 20 *
CRP >150 *
Abnormal AXR *
Distended Abdomen *
(* = severe if any of these
features)
Moderate
Start treatment without delay
-Metronidazole 400mg TDS for
5 days
-Daily Review including stool
chart
- FBC, CRP, AXR if deteriorates
( If Deteriorates
to Severe )
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
Response
Complete 14 day
course of
metronidazole
No Response :Add Vancomycin 500mg
QDS PO for 5 days
Complete 14 day course
of metronidazole
Response
Complete 14 day course
of Vancomycin
Complete course of
metronidazole
( If Deteriorates
to Severe )
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)
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.
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
New C. difficile Toxin Positives in Wolverhampton - Quarterly Totals
Community
180
RWHT
160
140
100
80
60
40
20
2007
2006
2005
2004
2003
2002
2001
0
2000
Number
120
New C. difficile Toxin Positives in Wolverhampton - Quarterly Totals
Community
180
RWHT
160
140
100
80
60
40
20
2007
2006
2005
2004
2003
2002
2001
0
2000
Number
120
SPCC RWHT C. difficile Toxin Positives
60
50
Upper Action
Limit
Upper Warning
Limit
Target
30
RWHT
20
10
Dec-06
Nov-06
Oct-06
Sep-06
Aug-06
Jul-06
Jun-06
May-06
Apr-06
Mar-06
Feb-06
0
Jan-06
Number
40
60
Mar-06
Apr-06
46.73
46.73
41.32
41.32
30.5
30.5
54
57
Commode
Audit
May-06
46.73
SPCC
41.32
30.5
55
Jun-06
Jul-06
Aug-06
Sep-06
Oct-06
46.73
46.73
46.73
46.73
46.73
RWHT
C.
difficile
Toxin
Positives
41.32
41.32
41.32
41.32
41.32
30.5
30.5
30.5
30.5
30.5
25
46
27
18
18
Commode
replacement
Mattress
replacement
Nov-06
46.73
41.32
30.5
35
Dec-06
46.73
41.32
30.5
14
Upper Action
Limit
50
Grand Round
presentation
Upper Warning
Limit
40
RCA for all c diff
cases introduced
High Impact
Intervention
No 6
introduced
30
Target
RWHT
Bed space checklists
introduced
20
Commode
re-Audit
&feedback
Matrons lead Ward
Declutter programme
Dec-06
Nov-06
Antibiotic review
commenced
Oct-06
Jul-06
Jun-06
May-06
Apr-06
Mar-06
Feb-06
Jan-06
0
Medical
division
training
Sep-06
Domestics training
delivered by IPT
Aug-06
10
Dec-07
Nov-07
Oct-07
Sep-07
Aug-07
Jul-07
Jun-07
May-07
Apr-07
Mar-07
Feb-07
Jan-07
Dec-06
Nov-06
Oct-06
Sep-06
Aug-06
Jul-06
Number
SPCC RWHT C. difficile
60
50
40
Upper Action
Limit
Upper Warning
Limit
Target
30
RWHT
20
10
0
SPCC - C. difficile D17
12
10
C. difficile
toxin pos
Upper
Warning
Limit
Upper Action
Limit
6
Target
4
2
Sep-06
Aug-06
Jul-06
Jun-06
May-06
Apr-06
Mar-06
Feb-06
Jan-06
Dec-05
Nov-05
0
Oct-05
Number
8
Mortality

All cause 28/7 mortality for CDT positive:

1.12.03 – 31.3.04 18/60
1.12.05 – 31.3.06 71/183

30.0%
38.8%
Mortality

All cause 28/7 mortality for CDT positive:


1.12.03 – 31.3.04 18/60
1.12.05 – 31.3.06 71/183
1.12.06 – 31.3.07 23/85

RR 0.70 (CI 0.47 – 1.03)

30.0%
38.8%
27.1%
0.45
Oct-Dec 06
Apr-Jun 06
Oct-Dec 05
April-June 05
Oct-Dec 04
April-June 04
Oct-Dec 03
April-June 03
Oct-Dec 02
April-June 02
Oct-Dec 01
April-June 01
Rate per 1000 Bed Days
MRSA Bacteraemias RWHT and West Midlands Region
RWHT
West Midlands
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
MRSA Bacteraemias - Cumulative Numbers RWHT
120
2004/5
100
2005/6
60
2006/7 (actual
trajectory)
40
2006/7
(projected
trajectory
based on total
at 6 months)
20
March
February
January
December
November
October
September
August
July
June
May
0
April
Number
80
Comparison: January 1st - April 23rd 2006 and 2007
250
150
1.1.06-23.4.06
1.1.07-23.4.07
100
MRSA PCT no screens
MRSA RWHT no screens
MRSA PCT
0
MRSA RWHT
50
New MRSAs
Number
200
Jan-Mar 07
70
Oct-Dec 06
Jul-Sep 06
Apr-Jun 06
Jan-Mar 06
Oct-Dec 05
Jul-Sep 05
Apr-Jun 05
Jan-Mar 05
Oct-Dec 04
Jul-Sep 04
Apr-Jun 04
Jan-Mar 04
Oct-Dec 03
Jul-Sep 03
Apr-Jun 03
Jan-Mar 03
Oct-Dec 02
Jul-Sep 02
Number
New ESBL Producers in Wolverhampton by Quarter
Community
Hospital
60
50
40
30
20
10
0
Conclusions

New strain(s) of C. difficile cause more
severe disease





Appear to spread more readily
More difficult to control
Multi-factorial approach to control needed
Requires involvement of entire Trust


??sub-strains
not just a medical / nursing solution
Not just antibiotics!