L’infezione da

C difficile grave o

complicata

Nicola PetrosilloIstituto Nazionale per le Malattie Infettive

“Lazzaro Spallanzani”, IRCCS

Roma

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

European Society of Clinical Microbiology and Infectious Diseases

(ESCMID): update of the treatment guidance document for Clostridium

difficile infection (CDI)

Debast SB et al. Clin Microb Infect 2013

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

Burning issues:

Metro vs Vanco

Mono vs Combo

Li R et al. PLoS ONE 2015;10(10): e0137252

Metronidazole vs vancomycin for mild CDI

Li R et al. PLoS ONE 2015;10(10): e0137252

Metronidazole vs vancomycin for severe CDI

Li R et al. PLoS ONE 2015;10(10): e0137252

Metronidazole vs combination therapy

Li R et al. PLoS ONE 2015;10(10): e0137252

Metro vs vanco for

CDI recurrence

Rokas KEE et al. Clin Infect Dis 2015; 61:934-41

Vanco 125x4 os (82%)

Metro 500x3 IV (72%)

Rokas KEE et al. Clin Infect Dis 2015; 61:934-41

Louie TJ et al. Clin Infect Dis 2015;60:S91–7

Tolevamer C difficile persisted in high counts during treatment

Both vancomycin and metronidazole suppressed microbiome

components during treatment of CDI

Louie TJ et al. Clin Infect Dis 2015;60:S91–7

Louie TJ et al. Antimicrob Agents Chemother 2009; 53: 261-3

Bagdasarian N et al.

JAMA 2015; 313:

398-408.

“All disease begins in the gut”Hippocrates 460 BC – c. 370 BC

Gerding DN et al. Clin Infect Dis 2010 ;51:1306-13

Probiotics

• ~3,000 patients aged ≥65 years who were receiving antibiotics

• Probiotic capsule × 21 days

Probiotics for prevention of CDI in older inpatients

A multicentre, randomised, double-blind, placebo-controlled trial

• “No evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective” in prevention of antibiotic associated diarrhoea or CDI

Allen SJ, et al. Lancet 2013; doi:10.1016/S0140-6736(13)61218-0.

Faecal microbiota transplantation (FMT)

Image reproduced with permission from Syates21, via Wikimedia Commons

• Study stopped after interim analysis

• No significant differences in AEs between groups, except for mild diarrhoea and abdominal cramping in the infusion group

Duodenal FMT vs vancomycin plus lavage

p<0.001p<0.001p=0.008p=0.003

van Nood E, et al. N Engl J Med 2013;368:407–15.

Agrawal M et al. J Clin Gastroenterol 2015 Aug 26

The Long-term Efficacy and Safety of Fecal Microbiota

Transplant for Recurrent, Severe, and Complicated

Clostridium difficile Infection in 146 Elderly Individuals.

• A multicenter, long-term follow-up study was performed

with demographic, pre-FMT, and post-FMT data collected

from elderly patients with RCDI, SCDI, and CCDI, through

a 47-item questionnaire.

• 146 patients

• FMT was performed for RCDI in 89 (61%), SCDI in 45

(30.8%), and CCDI in 12 (8.2%) patients.

• The primary and secondary cure rates were 82.9% and

95.9%, respectively.

• Early and late recurrences occurred in 25 and 6 patients,

respectively.

Orenstein R et al.

Stollman N et al. Am J Gastroenter 2015

Gerding DN et al. JAMA 2015;313(17):1719-1727

OBJECTIVE To determine the safety, fecal colonization,

recurrence rate, and optimal dosing schedule of

nontoxigenic C difficile strain M3 (VP20621; NTCD-M3)

for prevention of recurrent C difficile infection (CDI).

Gerding DN et al. JAMA 2015;313(17):1719-1727

Gerding DN et al. JAMA 2015;313(17):1719-1727

No. at riskAntibody 101 93 89 85Placebo 99 77 66 62

• Relative risk of recurrence significantly lower in the antibody group

– 0.23 (95% CI: 0.08, 0.54; p=0.01)

Monoclonal antibodies against C. difficile

Lowy I, et al. N Engl J Med 2010;362:197–205.

80

60

40

20

0Rec

urr

ence

of

infe

ctio

n (

%)

10 20Days after infusion

100

0

Placebo

40 50 60 70 80 90

Antibodyp<0.001

30

• Antibiotic inactivation is targeted at

eliminating the collateral damage associated

with the initial antibiotic exposure, thereby

potentially reducing the risk of CDI.

• As antibiotic are often necessary, the

coadministration of an agent such as SYN-

004 can inactivate the antibiotic in the large

intestine

• This approach minimize the risk of CDI and

allows the continued use of antibiotic for

prevention an treatment.

Gerding GR et al. J Antimicrob Chemother 2015 October 3

The aim of this study was to evaluate the susceptibilities of

Clostridium difficile isolates to cadazolid, a novel antibiotic

for the treatment of C. difficile infection

Patients were randomized to receive 250, 500 or 1000 mg of

cadazolid twice daily or 125 mg of vancomycin four times

daily, for 10 days.

MICs of cadazolid, vancomycin, fidaxomicin, linezolid and

moxifloxacin were determined at baseline for all patients and

post-baseline for patients with clinical failure or recurrence,

using the agar dilution method.

Bender KO et al. Sci Transl Med 2015;7:306ra148

• Cysteine protease domain (CPD) within C difficile

major virulence factor toxin B (TcdB) is a target for

experimental therapies.

• One potent CPD inhibitor, ebselen, showed a

therapeutic benefit in a mouse model of CDI

Ursodeoxycholic Acid Inhibits Clostridium difficile

Spore Germination and Vegetative Growth, and

Prevents the Recurrence of Ileal Pouchitis Associated

With the Infection.

Weingarden AR et al. J Clin Gastroenterol 2015 Oct 17

• To test whether ursodeoxycholic acid (UDCA) is

inhibitory to Clostridium difficile and can be used in the

treatment of C. difficile-associated ileal pouchitis.

• The restoration of secondary bile metabolism may be the key

mechanism for FMT in treating RCDI.

• Therefore, it is possible that exogenous administration of

inhibitory bile acids may be used directly as nonantibiotic

therapeutics for this indication.

• The need for such a treatment alternative is especially

significant in patients with refractory C. difficile-associated

pouchitis, where the efficacy of FMT may be limited.

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