Encapsulated oral FMT for recurrent C. difficile Infection

Transcription

1 Encapsulated oral FMT for recurrent C. difficile Infection Elizabeth L. Hohmann MD Infectious Disease Division Massachusetts General Hospital Harvard Medical School Boston MA

2 DISCLOSURE Clinical Investigator and consultant for Seres Therapeutics, Cambridge MA

3 How much C. diff out there? CDC puts C difficile burden at 453,000 cases, 29,000 deaths Clostridium difficile was the most commonly reported pathogen (causing 12.1% of health care associated infections) CDI = C. difficile Infection Accuracy of ICD-10 Codes for Surveillance of C. difficile Infections, France G. Jones et al Emerg Infect Dis Jun; 18(6):

4 Medicare database USA, Million patients >65 36% with CDI died vs 25% of matched controls 11% attributable mortality CDI associated with: 2X risk of LTCF 3X risk of NH placement ECCMID 2016 Erik Dubberke MD et al

5 Pathogenesis of CDI Anaerobic, spore forming organism Risks for acquisition: healthcare, antacids, age, medical illness, low Abs, IS host, ANTIBIOTICS Dysbiotic state allows C.diff to flourish Toxin causes inflammation, colitis, diarrhea, leukocytosis, potentially sepsis, megacolon etc Hospitalization is common in older pts

6 Patient 65 yo man, working; Incidentally found to be Hep C seropositive Diagnosed with lung CA; resected. Surgery c/b pneumonia Abx C.difficile Rx Metronidazole, then Vancomycin, then Vanco taper, probiotics. Can t work anymore. Relapses again. Falls running to bathroom. Fractures ribs. More pneumonia, more Abx, more C.difficile. Referred for FMT by ID colleague.

7 Fecal Microbiota Transplant (FMT)! Restoration of normal flora from healthy person Restores normal diversity, colonization resistance It s microbiota, not matter or implant! Family member vs. healthy young donor*. Standard screening approaches published TIMING of FMT gotten better on vancomycin Rx 7-21 days; during taper is fine. *We use screening ala: Hamilton and Khoruts, Am J Gastroenterol 2012; 107: p761.

8 Consensus for use of FMT 3 Episodes of C. difficile OR: Two episodes requiring hospitalization Some feel it s reasonable to try and fail the vanco taper Cure = no relapse in 8 weeks, absent OTHER Abx Won t give FMT while getting other Abx!

9 Donors years Nl exam, history No Abx at least 6 mo ZERO GI history Normal BMI AAB Q. passed Routine Labs CBC w/ differential LFTs, complete Bun/Cr, Fasting glucose High Sensitivity CRP Fluorescent ANA Serum triglycerides LDL, HDL cholesterol Stool Testing Clostridium difficile toxin by ELISA, PCR Routine bacterial culture for enteric pathogens (with enrichment), including Vibrio and Listeria Fecal Giardia antigen Fecal Cryptosporidium antigen Acid-fast stain for Cyclospora, Isospora Ova and parasites (light microscopy) Helicobacter pylori fecal antigen (Mayo) Rotavirus ELISA Serology (pre- and post- ) HIV 1/2 (IgG) and E1A HAV (IgG and IgM) HBV HCV (IgG) Syphilis serology Recent adds. VRE, MRSA, CRE More carefully screened than blood donors... Only ~ 1/4 qualify. Optional; for IS pts CMV/EBV VL s

10 FMT Donor Read Fraction Genus Bilophila Blautia Clostridium Dialister Eubacterium Faecalibacterium Firmicutes Prevotella Roseburia Low Frequency 0.00 a b c d e f Timepoint Courtesy of: Ami Bhatt MD PhD Stanford Univ.

11 Routes of FMT Delivery/Efficacy Site of Infusion Efficacy Stomach 81% Duodenum/Jejunum 86% Cecum/Ascending Colon 93% Sum = 87%! Lower/Descending Colon 84% Systematic re-analysis of N=536, case series, reports, 1 randomized study. Cammarota et al; J. Clin. Gastro. 2014; 48 (8)

12 Self-reported Health Status COLO NGT 1 = worst 10 = best Youngster, Hohmann et al CID 2014

13 MGH series with capsules Capsugel vegan hypromellose caps Double capsules N=20 capsule patients - published To date we have treated 233 patients with caps Ages 7-95! Libby Hoh FMT Youngster, Sauk et al Clin Infect Dis Jun;58(11):1515 Youngster, Russell et al JAMA Nov 5;312(17):1772

14 MGH Caps Protocol 15 capsules on each of 2 successive days NPO x 4 h before and 1 h after Standard phone follow-up only unless they relapse by Sx AND testing. Transport capsules on dry ice. Offered as billed care at MGH for rcdi GI/ID physicians Mostly outpatients!

15 Efficacy 8 weeks, 1-3 doses; N = 209 Overall cure rate 93% 194 Cures 1 dose 82% 15 Fails 2 dose 91% 3 dose 93%

16 Failure details, N = 15 Failure Details Number Failed 1st dose 10 Refused 2nd treatment 2 More other antibiotics 2 Unable to receive 4 Awaiting 2nd treatment 2 Failed 2nd dose 4 Failed 3rd dose 1 Options thereafter: Slow taper Vanco Suppressive Vanco Come back later!

17 EVENT #(%) Related Serious Adverse Events Fever (>102.4) 1 (0.4%) Ulcerative colitis dx 2 (1%) Hospitalized relapsed CDI/diarrhea 8 (3.8%) N= 209 All out to 8 weeks 195 to 6 months Updated Sept 2016 Unrelated Serious Adverse Events Hospitalized (unrelated conditions) Death (unrelated to FMT) 30 (14%) 20 (9.6%)

18 All Mild and Moderate N= 209 Adverse Events Fever 5 (2%) Diarrhea 131 (63%) Vomiting 7 (3%) Nausea/Bloating 68 (33%) Abdominal Pain 50 (24%) Fatigue/Malaise/Headache 75 (36%) Other complaints* 15 (7%) * e.g. dizziness, UTI, URI

19 Course of Recovery Generally rapid (d4, d7-10 calls) Rare spontaneous relapses late 2-3 mo IBS can be long-lasting Setting expectations is important I encourage fermented foods Stop omeprazole?* *K. Weiss et al BMJ 2015 Open Gastro PPI s H2RA s not associated with worse outcome when TREATING CDI ; FDA warning about increased risk for acquisition

20 FMT recipients YES On Chemo dep upon timing Steroids up to 40 mg/day HIV -positive CD4 > 200 Post-partum/nursing Solid organ transplant s/p Bone marrow Tx Inflammatory bowel ds Severe, Refractory CDI NO Pregnant Neutropenic <500 ANC < 2 years old > 40 mg/day prednisone

21 Recipients increase diversity - close to donor levels. PRE FMT POST FMT DONOR Shannon Diversity Index = Measure of microbial diversity!

22 Are some organisms more broadly transferrable than others? 1 Donor 15 Recipients Donor core organisms Eric Alm PhD and Colleagues, MIT 15% Number of recipients that retain the donor organism Only a small fraction is engrafting in all patients

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25 Universal Dynamics Universality of human microbial dynamics Amir Bashan, Travis E. Gibson, Jonathan Friedman, Vincent J. Carey, Scott T. Weiss, Elizabeth L. Hohmann & Yang-Yu Liu Nature, June 2016 DOC = Dissimilarity Overlap Curve Host-specific Dynamics Your personal flora? Someone else s? Whose is better? For CDI -- any healthy will do!

26 Future Fun with FMT Obesity Metabolic Syndrome Placebo-controlled Elaine Yu MD Open Label after Bone Marrow Transplant Feasibility, safety and GVHD (enrolled 7/13) HIV positive with virological suppression Markers of immune activation/inflammation

27 Ilan Youngster MD Jenny Sauk MD Jess Kaplan MD Joanne Levin MD Hamed Khalili MD Yi-Bin Chen MD A shipload of thanks to: Lab techs extraordinaire! Christina Pindar Hannah Systrom 14 Jasmin Mahabamunuge 15 USS FMT

28 Questions?