La terapia delle infezioni da C difficile Nicola Petrosillo Istituto Nazionale per le Malattie Infettive “Lazzaro Spallanzani”, IRCCS Roma

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:

Burning issues: Metro vs Vanco Mono vs Combo

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

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

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

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

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

Bagdasarian N et al. JAMA 2015; 313:

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

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

Microbiological approach The microbiological supplementation approach (FMT and Rebiotix oral preparation) addresses the high rates of recurrence, and particularly the debilitating impact of multiple recurrences following treatment with either vanco or metro by attempting to restore the «normal» gut flora. With the exception of VP20621, none of these approaches are aimed at preventing the initial episode of CDI.

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<0.001 p=0.008 p=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.

Stollman N et al. Am J Gastroenter 2015

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

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: /S (13)

No. at risk Antibody Placebo 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– Recurrence of infection (%) 1020 Days after infusion Placebo Antibody p<

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.

Novel and old anti CDI treatment options

46 pts  26 teico, 20 vanco

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.

Gerding GR et al. J Antimicrob Chemother 2015 October 3 For all cadazolid doses, the faecal concentration was in excess of several thousand-fold the MIC90 for C. difficile. The MIC of cadazolid for all C. difficile isolates, including epidemic strains, was low and in the same narrow range regardless of treatment outcome.

Louie T et al. Antimicrob Agents Chemother 2015; 59:

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: