Nicola Petrosillo Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, IRCCS Roma. L infezione da C difficile grave o complicata

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1 Nicola Petrosillo Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, IRCCS Roma L infezione da C difficile grave o complicata

2 Bagdasarian N et al. JAMA 2015; 313:

3 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

4 Bagdasarian N et al. JAMA 2015; 313:

5 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 colonpreserving techniques.

6 Stewart DB et al. Colorectal Dis 2013;15: 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

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8 Burning issues: Metro vs Vanco Mono vs Combo

9 Metronidazole vs vancomycin for mild CDI Li R et al. PLoS ONE 2015;10(10): e

10 Metronidazole vs vancomycin for severe CDI Li R et al. PLoS ONE 2015;10(10): e

11 Metronidazole vs combination therapy Li R et al. PLoS ONE 2015;10(10): e

12 Metro vs vanco for CDI recurrence Li R et al. PLoS ONE 2015;10(10): e

13 Vanco 125x4 os (82%) Metro 500x3 IV (72%) Rokas KEE et al. Clin Infect Dis 2015; 61:934-41

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

15 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

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

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

18 Bagdasarian N et al. JAMA 2015; 313:

19 All disease begins in the gut Hippocrates 460 BC c. 370 BC

20 Gerding DN et al. Clin Infect Dis 2010 ;51:

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22 Probiotics

23 Probiotics for prevention of CDI in older inpatients A multicentre, randomised, double-blind, placebo-controlled trial ~3,000 patients aged 65 years who were receiving antibiotics Probiotic capsule 21 days 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: /s (13)

24 Faecal microbiota transplantation (FMT) Image reproduced with permission from Syates21, via Wikimedia Commons

25 Duodenal FMT vs vancomycin plus lavage Study stopped after interim analysis No significant differences in AEs between groups, except for mild diarrhoea and abdominal cramping in the infusion group p<0.001 p<0.001 p=0.008 p=0.003 van Nood E, et al. N Engl J Med 2013;368:

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. Agrawal M et al. J Clin Gastroenterol 2015 Aug 26

27 Orenstein R et al.

28 Stollman N et al. Am J Gastroenter 2015

29 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):

30 Gerding DN et al. JAMA 2015;313(17):

31 Gerding DN et al. JAMA 2015;313(17):

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33 Recurrence of infection (%) Monoclonal antibodies against C. difficile Relative risk of recurrence significantly lower in the antibody group 0.23 (95% CI: 0.08, 0.54; p=0.01) Placebo 20 p<0.001 Antibody No. at risk Antibody Days after infusion Placebo Lowy I, et al. N Engl J Med 2010;362:

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35 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.

36 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. Gerding GR et al. J Antimicrob Chemother 2015 October 3

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

38 Ursodeoxycholic Acid Inhibits Clostridium difficile Spore Germination and Vegetative Growth, and Prevents the Recurrence of Ileal Pouchitis Associated With the Infection. 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. Weingarden AR et al. J Clin Gastroenterol 2015 Oct 17

39 Mizumura N et al. Intern Med 2015; 54: