INTRODUCTION TO CLOSTRIDIUM DIFFICILE INFECTIONSLIDE RESOURCE SET

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Introduction to Clostridium difficile

• C. difficile is a Gram-positive, spore-forming, anaerobic bacillus that was first identified in 19351

• C. difficile is the leading cause of infective nosocomial diarrhoea in industrialised countries2

• C. difficile passes through a life cycle where it exists in two forms; as vegetative cells and as spores3

1. Hall IC, O’Toole E. Am J Dis Child 1935;49:390–402;2. Crobach MJT, et al. Clin Microbiol Infect 2009;15:1053–66;3. Poutanen S, Simor AE. CMAJ 2004;171:51–8.

Vegetative form Spores surrounding a vegetative cell

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Clinical presentation of C. difficile infection (CDI)

• Asymptomatic colonisation

• Diarrhoea without colitis

– Watery

– Mucus but no blood

• Colitis without pseudomembrane formation

• Pseudomembranous colitis

• Fulminant colitis

Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79;Bartlett JD, Gerding DN. Clin Infect Dis 2008;46:S12–8.

Increasin

g severity

Normal, healthy colon

Pseudomembranous colitis

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Other signs and symptoms of CDI, including severe colitis

• Vomiting

• Abdominal tenderness

• Fever (rigors)

• Dehydration

• Leucocytosis

• Hypoalbuminaemia

• Exhaustion

Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79.AI/12/0055/EUg | DM104

Risk factors for CDI

1. Cohen SH, et al. Infect Control Hosp Epidemiol 2010;31:431–55;2. Bignardi GE. J Hosp Infect 1998;40:1–15.

There are numerous reported risk factors

for CDI

Broad-spectrum

antibacterials1

Immuno-compromised2

Older age2

Severity of underlying diseases2Prolonged

stay in hospital/

care home2

ICU stay2

Nasogastric tube/

GI surgery2

PPIs2

GI, gastrointestinal;ICU, intensive care unit;

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Key steps in the pathogenesis of CDI

Kelly CP, LaMont JT. Annu Rev Med 1998;49:375–90.

Antibacterial therapy

Alteration of colonic microflora

C. difficile exposure and colonisation

Release of toxins A and B

Colonic mucosal injury and inflammation

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The infectious cycle of transmission and recurrence of CDI

Adapted from Sunenshine RH, et al. Cleve Clin J Med 2006;73:187–97.

1. Ingestion of spores transmitted from other patients, via hands of healthcare personnel and the environment

2. Germination into growing (vegetative) cells

3. Disruption of normal colonic microflora allows colonisation and overgrowth of C. difficile in the colon

4.Toxin production leads to inflammation and damage to intestinal cells

5. Transmission of spores via the faecal–oral route

C. difficile

Toxins

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Cycle of infection with C. difficile

Adapted from Poutanen SM, Simor AE. CMAJ 2004;171:51–8.

C. difficilespores andvegetative cellsare ingested

Most vegetative cells are killed in the stomach,but spores can survivethe acid environment

C. difficile spores germinate in the small bowel uponexposure to bile acids

Flagellae facilitateC. difficile movement

C. difficile multiplies inthe colon

Gut mucosafacilitatesadherenceto thecolonicepithelium

ColonStomach

Small bowel

Spores Vegetative cells

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CDI is toxin mediated

• Toxin A*1

– Referred to as the ‘enterotoxin’ because of the easily demonstrated

effects of purified toxin in animal intestinal models

– Likely to be intimately involved in CDI pathogenesis

• Toxin B*1

– Potent cytotoxin

– Structurally similar to toxin A but effects in animal intestinal models have

not been easy to demonstrate

– Likely to be intimately involved in CDI pathogenesis

• Binary toxin– Unrelated to toxins A and B1

– Present in the epidemic BI/NAP1/027 strain2

– Role in pathogenesis uncertain21. Rupnik M, et al. Nat Rev Microbiol 2009;7:526–36;2. Warny M, et al. Lancet 2005;366:1079–84.

*Large, single-unit, glucosylating toxins;BI/NAP1, characterised as group BI by restriction

endonuclease analysis and North American pulse-field type 1 by gel electrophoresis

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Role of host antibody-mediated responses in CDI pathogenesis

Adapted from Rupnik M, et al. Nat Rev Microbiol 2009;7:526–36.

Patients with risk factors for CDI,

including antibacterialuse in hospital setting

Exposure to toxigenicC. difficile accompanied by

IgG response to toxin A

C. difficile negative

Asymptomatically colonised

Asymptomatically colonised

Symptomatic CDI

Exposure to toxigenicC. difficile without an IgG response

to toxin A

Exposure to non-toxigenic C. difficile

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Impact of CDI on short- and long-term patient management

• CDI may necessitate treatments for underlying diseases to be reduced in intensity or suspended

– Alterations to treatment plans may irreversibly affect long-term outcomes1

• Episodes of CDI arising in the ICU may prolong ICU stay and overall hospitalisation2

– Excess ICU length of stay: 2.2 days (p=0.069)

– Excess hospital length of stay: 4.5 days (p=0.030)

1. Hautmann MG, et al. Radiat Oncol 2011;6:89; 2. Kenneally C, et al. Chest 2007;132:418–24.

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Length of hospital stay among patients with CDI by country

Wiegand PN, et al. J Hosp Infect 2012;81:1–14.FDX/12/0076/EUd | DN139

EU, European Union

45

40

35

20

10

0

Leng

th o

f sta

y (d

ays)

Belgium

25

30

15

5

France

Germany

Ireland

Spain

Switzerland

Netherlands UK

16 17 17

1215

50

EU

27

2118

37

Association of CDI with hospital readmissions

Dubberke ER, et al. Emerg Infect Dis 2008;14:1031–8.

• In this study, CDI patients were significantly more likely to be readmitted to hospital than controls; the readmission rate attributable to CDI was 19.3%

Kaplan–Meier estimates of time until hospital readmission for matched pairs (N=580) in patients with and without CDI

1.0

0.8

0.6

0.4

0.2

0.00 30 60 90 120 150 180

Time since hospital discharge (days)

Pro

por

tion

with

out

read

mis

sion

No CDI

CDI

Log-rank p<0.001

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Association of CDI with mortality

Dubberke ER, et al. Emerg Infect Dis 2008;14:1031–8.

• 38% of patients with CDI died within 180 days after hospital admission vs 12% of patients without CDI

Kaplan–Meier survival estimates for cohort (N=18,050) in patients with and without CDI

1.0

0.8

0.6

0.4

0.2

0.0

Time since hospital discharge (days)

Cum

ula

tive

sur

viva

l No CDI

CDI

Log-rank p<0.001

0 30 60 90 120 150 180

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Mortality rates in studies of CDI

• In a recent pan-European hospital-based survey:1

– ~2% of patients with CDI died as a result of the infection

– CDI contributed to mortality in a further 7% of cases

• In a case-control study in Canada:2

– ~7% of patients with CDI died as a result of the infection

– CDI contributed to mortality in a further 8% of cases

1. Bauer MP, et al. Lancet 2011;377:63–73;2. Loo VG, et al. N Engl J Med 2005;353:2442–9.

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Mortality rates associated with CDI across Europe

Wiegand PN, et al. J Hosp Infect 2012;81:1–14.

• Data from a systematic review found the weighted average 30-day mortality from CDI ranged from 3–30%

Weighted average 30-day mortality in patients with healthcare facility-acquired CDI by country

45

40

35

20

10

0

30-d

ay m

orta

lity

(%)

Austria

25

30

15

5

DenmarkFinland

France

Germany

Ireland

LuxembourgSpain

Switzerland

The Netherlands UK

14%16% 14%

3%

16%

7%

15%

22%

9%

20%

30%

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Age-specific incidence of CDI and attributable mortality

Loo VG, et al. N Engl J Med 2005;353:442–9.

<40 41–50 51–60 61–70 71–80 81–90 >900

10

20

30

40

50

60

70

80

CDI rate per 1,000 ad-missions

Attributable 30-day mortal-ity rate

Age (years)

Rat

e (%

)

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Factors contributing to risk of mortality from CDI

• Advancing age1,2

• Older age and severity associated with the epidemic 027/NAP1 strain3

• Use of metronidazole for severe disease4

• Haematological malignancy and severe disease5

• Comorbidity– Renal disease4

– Ischaemic heart disease4

– Inflammatory bowel disease6

– Liver disease (cirrhosis)7

1. Loo VG, et al. N Engl J Med 2005;353:2442–9;2. Bauer MP, et al. Lancet 2011;377:63–73;3. Miller M, et al. Clin Infect Dis 2010;50:194–201;4. Wilson V, et al. Clin Infect Dis 2010;50:e77–81;

5. Dubberke ER, et al. Infect Con Hosp Epidemiol 2007;28:208–11;6. Ananthakrishnan AN, et al. Gut 2008;57:205–10;7. Bajaj JS, et al. Am J Gastroenterol 2010;105:106–13.

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Toxic megacolon

Increased mortality: a result ofCDI severity

1. Jaber MR, et al. Am J Gastroenterol 2008;103:3195–203;2. Longo WE, et al. Dis Colon Rectum 2004;47:1620–6;3. Berman L, et al. J Clin Gastroenterol 2008;42:476–80;4. Dallal RM, et al. Ann Surg 2002;235:363–72.

• Up to 8% of patients develop fulminant CDI1

• Fulminant colitis accounts for serious complications including toxic megacolon2

• Many patients with toxic megacolon require emergency surgery (colectomy) to remove dead sections of the colon2–4

– Approximately half of all patients who undergo colectomy die3,4

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Recurrence of CDI

• Recurrence of CDI has been identified by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) as the most important problem in the treatment of CDI1

• CDI recurrence is common, occurring in up to 25% of cases within 30 days following treatment2–4

• 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 MP, et al. Clin Microbiol Infect 2009;15:1067–79;2. Louie TJ, et al. N Engl J Med 2011;364:422–31;3. Lowy I, et al. N Engl J Med 2010;362:197–205;4. Bouza E, et al. Clin Microbiol Infect 2008;14(Suppl 7):S103–4;5. DuPont HL. N Engl J Med 2011;364:473–4.

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The incidence of recurrent CDI

1. Louie TJ, et al. N Engl J Med 2011;364:422–31;2. Lowy I, et al. N Engl J Med 2010;362:197–205;3. Bouza E, et al. Clin Microbiol Infect 2008;4(Suppl 7):S103–4;4. McFarland LV, et al. Am J Gastroenterol 2002;97:1969–75;5. McFarland LV, et al. JAMA 1994;271:1913–8.

1st recurrence of CDI

Recurrence(s) of CDI

~45–65% of patients have further

recurrences4,5

Up to 25% of patients have recurrent CDI1–3

Initial episode of CDI

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Risk factors for a recurrence of CDI

• Immunocompromised state1

• Exposure to other antibacterial agents that disrupt the normal colonic microflora2–5

• Renal impairment6,7

• Aged 65 years or over2,4,8

• Impaired immune response to C. difficile toxin A2

• Severe underlying disease2

• Prolonged hospitalisation8

• ICU stay5

1. Cohen MB. J Pediatr Gastroenterol Nutr 2009;48(Suppl 2):S63–5;

2. Kyne L, et al. Lancet 2001;357:189–93;3. Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79;4. Bauer MP, et al. Lancet 2011;377:63–73;

5. Hu MY, et al. Gastroenterology 2009;136:1206–14;6. Do AN, et al. Clin Infect Dis 1998;26:954–9;7. Bauer MP, et al. Clin Microbiol Infect 2011;17(Suppl 4):A1–4;8. Pépin J, et al. Clin Infect Dis 2005;40:1591–7.

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Laboratory detection of CDI

The recommended approach is to demonstrate:1,2

• Organism in stool– GDH or culture: do not distinguish toxigenic vs non-toxigenic

– Need confirmatory test for toxigenicity

• Toxin in stool– Cell culture toxin cytotoxicity

– EIA to detect toxins A and/or B

• Toxin from organism– Culture cytotoxicity

• Toxin genes in organism – PCR for toxin B gene1. Crobach MJT, et al. Clin Microbiol Infect 2009;15:1053–66;

2. Kelly CP, LaMont JT. Annu Rev Med 1998;49:375–90.FDX/12/0087/EUu | slide 018

EIA, enzyme immunoassay; GDH, glutamate dehydrogenase;PCR, polymerase chain reaction

−+ − +

ESCMID recommended diagnostic algorithm for CDI

Adapted from Crobach MJT, et al. Clin Microbiol Infect 2009;15:1053–66.

EIA to detectTcdA and TcdB

EIA to detect GDH, or real-time PCR to detect TcdB

EIA to detect GDH,or real-time PCR to detect TcdB, or

cytotoxicity assay

High clinical suspicion:

toxigenic culture

No CDI

CDI isdiagnosed

No CDICDI is

diagnosed

C. difficile toxins are not detectable in faeces

but C. difficile is present; CDI cannot be excluded

+ − − +

Toxin detection or bacterial detection

EIA, enzyme immunoassay; GDH, glutamate dehydrogenase;PCR, polymerase chain reaction

EIA to detect TcdA,and TcdB,

or cytotoxicity assay

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CDI imposes a significant burden on hospitals

• Infection control and environmental decontamination1

• Patient isolation and ward closures1

• Monitoring and surveillance2

• Laboratory tests3

• Surgical costs1,3

• ICU length of stay4

• Hospital length of stay2,4,5

1. Kuijper EJ, et al. Clin Microbiol Infect 2006;12:2–18;2. Wiegand PN, et al. J Hosp Infect 2012;81:1–14;3. Ghantoji SS, et al. J Hosp Infect 2010;74:309–18;4. Kenneally C, et al. Chest 2007;132:418–24;5. Vonberg RP, et al. J Hosp Infect 2008;70:15–20.

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CDI: a public health challenge

• The recorded incidence and severity of CDI have increased in many settings in recent years, including in people previously thought to be at lower risk1–6

• Clusters/outbreaks of CDI cause ward closures and disruption of hospital activity7

• There is a considerable burden of morbidity and mortality due to CDI7

• The resultant effect is an erosion of public confidence concerning the risk of healthcare-associated infection

• Also, the financial burden of disease is high8

1. Bauer MP, et al. Lancet 2011;377:63–73; 2. Vonberg RP, et al. Emerg Infect Dis 2007;13:179–80;3. Soler P, et al. Infect Control Hosp Epidemiol 2008;29:887–9;4. Lyytikäinen O, et al. Emerg Infect Dis 2009;15:761–5;

5. Søes L, et al. Euro Surveill 2009;14:1–4;6. CDC. MMWR Morb Mortal Wkly Rep 2005;54:1201–5;7. Kuijper EJ, et al. Clin Microbiol Infect 2006;12:2–18;8. Wilcox M, et al. J Hosp Infect 1996;34:23–30.

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