Nicola Petrosillo

Istituto Nazionale per le Malattie Infettive

«lazzaro Spallanzani», IRCCS-Roma

Le infezioni da Clostridium difficile, gravi,

ricorrenti e complicate

The infectious cycle of transmission and recurrence of CDI

1. Ingestion of spores transmitted from

other patients, via

hands of healthcare

personnel and

the environment

2. Germination

into growing

(vegetative) cells

5. Transmission

of spores via the

3. Disruption of normal

colonic microflora

allows colonisation

and overgrowth of

C. difficile in the colon

C. difficile

4. Toxin production

leads to

inflammation

and damage to

intestinal cells

Toxins

faecal-oral route

Adapted from Sunenshine RH, et al. Cleve Clin J Med 2006;73:187-97. SJ101

Bagdasarian N et al. JAMA 2015; 313: 398-408

Mizumura N et al. Intern Med 2015; 54: 1559-62

Bagdasarian N et al. JAMA 2015; 313: 398-408

Surgical evaluation in CDI

• Prompt surgical evaluation should be

obtained in patients with complicated CDI

• Early intervention can reduce mortality

• Subtotal or total colectomy with end

ileostomy is often performed when surgery

is required, although there are newer colon-

preserving techniques.

Stewart DB et al. Colorectal Dis 2013;15:798-804

Fulminant CDC is defined as disease of such severity

as to require any one of the following:

1.Admission to the ICU;

2.Consideration for surgery, or

3.Death due to CDC

• Recurrence of symptomatic disease following initial

resolution of symptoms is a frequent complication, with

rCDI occurring in 20-30% of CDI patients.

• In hospitalised patients, rCDI is responsible for

increased mortality and decreased quality of life.

• The risk of subsequent recurrences after a first one

doubles after 2 or more recurrent episodes.

• Finally the patient could be trapped in a ‘recurrent CDI

cycle’, which is problematic to resolve, and further

increases the burden to healthcare facilities.

Epidemiology of Recurrent CDI (rCDI)

Louie TJ et al. N Engl J Med 2011;364: 422-31

Johnson S et al J Infect 2009;58: 403-410

Kelly C et al Clin Microb Infect 2012; 18: 21-27

How much a rCDI costs?

• 540 hospitalized patients (62±17 years) with

primary CDI 95 patients (18%) experienced 101

rCDI episodes.

• CDI-attributable median LOS and costs

increased from 7 days and $13,168 for patients

with primary CDI only versus 15 days and

$28,218 for patients with rCDI (P<0.0001, each).

Shah DN et al. J Hosp Infect 2016 ;93:286-9

How much a rCDI costs?

•Total hospital median LOS and costs increased

from 11 days and $20,693 for patients with primary

CDI only versus 24 days and $45,148 for patients

with rCDI (P<0.0001, each).

•The median cost of pharmacological treatment

while hospitalized was $60 for patients with

primary CDI only (N=445) and $140 for patients

with rCDI (P=0.0013).

Shah DN et al. J Hosp Infect 2016 ;93:286-9

Recurrence: when is Reinfection and when is Relapse?

Recurrence of Clostridium difficile infection can occur within

two contexts

•the recrudescence of C. difficile spores persisting in the gut

(relapse), or

•reinfection with spores obtained from the environment.

Distinguishing between the two, however, is challenging.

Molecular assays could be helpful, but not often feasible.

A temporal criterium could be helpful.

• The greatest risk of recurrence due to relapse is

during the first 14 days after successful treatment.

• Greater time periods between initial and recurrent

episodes tend to be associated with.

• One study reported that the median time to a

recurrent episode of CDI was 26 days for relapse vs

67.5 days for reinfection.

Relapse or reinfection?

Wilcox M et al J Hosp Infect 1998; 38:93-100.

Marsh JW et al. J Clin Microb 2012; 50: 4078-4082.

Kim J et al. Clin Microb Infect 2014; 20: 1198-1204.

modifiable

rCDI: a matter of severity, morbidity and mortality

Elderly more than 90% of CDI-related deaths occur in

people aged over 65 years (Garey KW et al. J Hosp Infect 2008;70:298-304)

Immunocompromised patients mortality associated

with CDAD 11.9% (Magee G et al. Am J Infect Control 2015; 43:1148-53)

Abou Chakra CN et al. Plos One 2014: 9; e98400

• Advanced age, additional antibiotic therapy during

follow up and PPI therapy are the most frequent

independent risk factors for rCDI.

• However, meta-analysis and systematic reviews have

shown that the risk factors for recurrent CDI are similar

to those of initial CDI.

• Moreover, patients with chronic renal insufficiency and

those previously receiving fluoroquinolones have

higher risks for rCDI.

• Finally, also CDI strain has been reported as a risk

factor.

Are risk factors for rCDI different from primary CDI?

Deshpande A et al. Infect Control Hosp Epidemiol 2015; 36: 452-460.

Garey KW et al. J Hosp Infect 2008;70:298-304.

Abou Chakra CN et al. Plos One 2014: 9; e98400.

Deshpande A et al. Infect Control Hosp Epidemiol 2015; 36: 452-460

Age

Additional antibiotics during follow up

Proton-Pump Inhibitors during follow up

Renal insufficiency

Tube feeding

Immunity and recurrence

• It is well known that humoral immunity plays a

crucial role in protecting from severe and/or

recurrent CDI

• Patients that acquire CD and become

asymptomatic carriers have higher serum IgG

antibody levels against TcdA vs symptomatic CDI.

• Low anti-TcdA IgG has been reported to be

associated with higher mortality rates among CDI

patients.

Di Bella S et al. Toxins 2016; 8:134

Kyne L et al. NEJM 2000; 342:390-7

Warny M et al. Infect Immun 1994; 62: 384-9

Courtesy

M. Bassetti

C difficile is not invasive. Toxins’ production is the key to pathogenesis

Di Bella S et al. Toxins 2016; 8: 134

Bagdasarian N et al. JAMA 2015; 313: 398-408.

Antibiotic stewardship and CDI

• CDI is usually an adverse effect of

antibiotic use – Cannot be completely prevented

– However, good antibiotic stewardship may help reduce it

• Includes1,2

– Antibiotics used according to guidelines

– Avoiding the use of multiple antibiotics and prolonged therapy

– Reducing the use of agents most frequently implicated in CDI

– Stopping the use of antibiotics (other than those used to treat

CDI) as soon as possible in CDI-infected patients1

1. Vonberg RP, et al. Clin Micro Infect 2008;14 Suppl 5:2–20.

2. UK Department of Health, England. High impact intervention. Care bundle to reduce the risk from Clostridium difficile, 2010

25

Aldeyab MA et al. JAC 2012

Feazel LM et al.

Feazel LM et al.

Take home messages

• Recurrence of symptomatic disease following initial resolution

of symptoms is a frequent complication, with rCDI occurring in

20-30% of CDI patients.

• The risk of subsequent recurrences after a first one doubles

after 2 or more recurrent episodes.

• The patient is trapped in a ‘recurrent CDI cycle’, which is

problematic to resolve

• Advanced age, additional antibiotic therapy during follow up

and PPI therapy are the most frequent independent risk factors

for rCDI.

• Antimicrobial stewardship programs can reduce the

occurrence of CDI cases in the healthcare settings