Duodenal infusion of donor feces for recurrent Clostridium difficile infection A French experience

Transcription

1 Duodenal infusion of donor feces for recurrent Clostridium difficile infection A French experience Benoit Guery Unité des Maladies Infectieuses CHRU - Faculté de Médecine Lille

2 Conflicts of interest Conferences, Board, Research, Meeting, pencils. Pfizer Astellas Aromathérapie Creative antibiotics Sanofi Pasteur Glycomimetics Lesaffre

3 Almost poetry. «Re-establish the balance of nature» Eiseman 1958

4 CDI infection Microbiota Risks factors: Clindamycine, Cephalosporins, Fluoroquinolones Hospitalisation Age Spores Germination Multiplication vegetatives cells Colonisation Toxins Production Clinical symptoms

5 (1) Local production of toxins A and B leads to production of tumour necrosis factor-alpha and proinflammatory interleukins, increased vascular permeability, neutrophil and monocyte recruitment (2) opening of epithelial cell junctions (3) epithelial cell apoptosis (4) Local production of hydrolytic enzymes leads to connective tissue degradation, leading to colitis, pseudomembrane formation (5) and watery diarrhea.

6 Two large toxins, toxin A and toxin B (TcdA and TcdB), are encoded on the pathogenicity locus (PaLoc), which comprises five genes. A third toxin, the binary toxin or CDT, is encoded on a separate region of the chromosome (CdtLoc) and comprises three genes.

7 Vancomycin, Metronidazole, Fidaxomicin, Rifamixin, Nitazoxanide, SMT Tolevamer Ig, monoclonal Ab, Vaccine Probiotics, S boulardii,.

8 Quantitative pyrosequencing of the microbiota defined a core measurable microbiota (CMM) of 64 conserved taxonomic groups that varied quantitatively across most animals in the population by National Academy of Sciences Benson A K et al. PNAS 2010;107:

9 Microbiota

10 Ampicillin (1 g/l), vancomycin (500 mg/l), neomycin sulfate (1 g/l), and metronidazole (1 g/l) in drinking water for 4 wk before PR8 virus infection (10 pfu per mouse). Proc Natl Acad Sci USA 2011

11 Molasses flies preferred to mate with other molasses flies and starch flies preferred to mate with other starch flies Antibiotic treatment abolished mating preference, suggesting that the fly microbiota was responsible for the phenomenon. Analytical data suggest that symbiotic bacteria can influence mating preference by changing the levels of cuticular hydrocarbon sex pheromones

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13 (4) The 16S sequences of all patients in each group were pooled (3) (3) Compared with those from control subjects and patients with an initial episode, the fecal communities in patients with recurrent CDAD were highly variable in bacterial composition and were characterized by markedly decreased diversity.

14 So finally Infectious Diseases doctor can transplant..

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18 Debast SB, et al. Clin Microbiol Infect 2014;20(Suppl 2):1 26.

19 Study Population >18 years of age Relapse of C. difficile infection after at least one course of adequate antibiotic therapy C. difficile infection was defined as diarrhea ( 3 loose or watery stools per day for at least 2 consecutive days or 8 loose stools in 48 hours) and a positive stool test for C. difficile toxin.

20 Groups Vancomycin followed by bowel lavage and the infusion of a suspension of donor feces through a nasoduodenal tube the next day Vancomycin regimen Vancomycin regimen with bowel lavage on day 4 or 5. Second infusion with feces from a different donor if recurrence. Patients in whom antibiotic therapy failed were offered treatment with donor feces off protocol.

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23 Fecal samples were collected from 10 patients undergoing fecal bacteriotherapy Bacterial populations in patient fecal samples were followed from pretreatment to 24 weeks post-initial infusion At intervals of 4, 8, and 24 weeks after the procedure, the bacterial populations in the patients' fecal samples consisted predominantly of bacteria derived from the healthy donor samples. This study demonstrates a durable beneficial change in the patients' bacterial populations of the colon to represent those of the healthy donor's microbiota. J Clin Gastroenterol Sep 44(8):

24 A multicenter long-term follow-up study was performed on the use of FMT in hospitalized pts with severe or complicated CDI. CDI was defined as severe in the presence of abdominal tenderness, albumin < 3.0 g/dl or WBC >15,000 cells/μl and as complicated if there was admission to the intensive care unit (as a consequence of CDI); hypotension with or without the use of vasopressors; change in mental status; WBC>35,000 cells/μl or <2,000 cells/μl; serum lactate levels 2.2 mmol/l; end-organ failure; fever 38.5 C; ileus or significant abdominal tenderness. 13 eligible pts identified. Gastroenterology 2013;144: S-185.

25 All pts were hospitalized at the time of FMT and diagnosed with severe (84%) or complicated CDI (92%). After FMT, diarrhea resolved in 9 pts (75%) within 1-7 days (mean: 4.5 days) and improved in the remaining 3 pts (25%). Primary cure rate was 84%. Secondary cure rate was 92%. Late CDI recurrence ( 90 days) after FMT was seen in 1 of 13 pts (8%) in association with antibiotic treatment of diverticulitis. FMT is a successful treatment option in pts with severe or complicated CDI. Gastroenterology 2013;144: S-185.

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27 Adverse events Amsterdam 200 fecal transplantation procedures, Sydney more than 3000 without any serious adverse events diarrhea on the day of infusion, a small percentage report belching and/or abdominal cramping or constipation. In another case report, nasoduodenal FMT for Crohn s disease resulted in transient adverse effects, including fever and abdominal tenderness in 3 of 4 patients. Long-term follow-up studies have found that FMT is relatively free of adverse effects Am J Gastroenterol 2012;107:

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31 Let s do it!

32 Legal issues Microbiota transplantation=drug Under the pharmacist s responsability Authorization for clinical trials Screening of the donors March 2014

33 Perfect donor yo BMI<30 No chronic disease No current treatment No antibiotics within the last 3 months No foreign travel within the last 3 months No residency in tropical areas No admission in foreign hospitals within the last 12 months No diarrhea within the last 3 months No typhoid Normal aspect of the feces Negative tests for infectious pathogens

34 Parasites Virus Bacteria Screening Blood Treponema pallidum HIV HTLV Hepatitis A B C E CMV/EBV S stercoralis T gondii Trichinella sp Feces C difficile L monoctygenes V cholerae/parahemolyticus Salmonella Shigella MDR pathogens Adenovirus Astrovirus Cacivirus Picornavirus Rotavirus S stercoralis Cryptosporidium sp Cyclospora sp E histolytica G intestinalis Isospora sp Microsporidies

35 «A good movie is better than 25 lousy slides» late) (And time is running and I m probably already

36 This movie will not candidate for the oscars

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39 Fecal microbiome transplantation (FMT) via oral fecal microbial capsules for recurrent Clostridium difficile infection (rcdi) 27 patients >3 CDI treated with vanco Tablets from 100g of feces tb to swallow in 5-15 min Tolerance ok Efficacy No recurrence Microbiota modification persisting at 6 month T. Louie IDWeek 2013

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