Update: Clostridium difficile Colitis David H. Kerman, MD Assistant Professor of Clinical Medicine Director, Fellowship Program Division of Gastroenterology University of Miami Miller School of Medicine 64 yo man Patient presentation History of HIV HCV cirrhosis s/p recent successful completion with ledipasvir/sofosbuvir Also with history of chronic kidney disease 3 documented occurrences of c difficile colitis April 2015 PCR positive August 2015 PCR positive October 2015 PCR positive Page 1 of 24
Complex RCDI case contd First two episodes were treated with Flagyl 500 mg orally TID x 2 weeks Last episode treated with Vancomycin 125 mg orally QID x 2 weeks He reports never responding to any of the antibiotic regimens Currently has 3 4 muddy bowel movements daily Lost 15 lbs since April 2015 Questions What are the risk factors for his recurrence? What can be done to prevent recurrence? What are his treatment options? What are the indications for FMT? Page 2 of 24
C difficile in the United States 14,000 deaths annually Leading cause of hospital associated gastrointestinal illness Costs upwards of $3 billion dollars annually PQRS measure in IBD Hospital discharge rates of CDI Lessa et al. C difficile epidemiology. Clin Inf Dis 2012 Page 3 of 24
Pediatric hospitalization for CDI Lessa et al. C difficile epidemiology. Clin Inf Dis 2012 Hospital related infections Magill et al. NEJM March 2016 Page 4 of 24
C difficile History A difficult bug 1935 Initially detected in fecal flora of healthy infants 1978 First case of reported c difficile infection Pseudomembranous colitis was a known entity related to antibiotic use 1984 commercial availability of ELISA testing 2000 2008 hypervirulent strain emerged The bug Spore forming Gram POSITIVE Fecal oral spread Non invasive Virulent forms produce the exotoxins a/b Toxin negative strains are non pathogenic B1/NAP1/027 has emerged as a more virulent strain Increased toxin production 20 30% of cases in North America High level of resistance Page 5 of 24
US prevalence of B1/NAP1/027 strain Martin et al, Nat Rev Gastro Hep 2016 Natural History Hospitalized/Nur sing home patient Altered gut flora (antibiotics) Elderly Exposure to C difficile Immunocompromised Asymptomatic carrier state 25 50% CDAD mild diarrhea Colitis Pseudomembranous colitis Page 6 of 24
Carrier state 80% of infants are carriers Has also been found on shoe swabs, soil, and household surfaces Rate of colonization 5 15% Non hospitalized, healthy adults 25 55% amongst hospitalized or nursing home patients Environmental surface contamination Asymptomatic carriage of the organism confers protection against future infection Asymptomatic carriers can spread toxigenic strains and infect others Transmission Transmission via ingestion of spores from Other patients Health care workers Spores are resistant to gastric acidity Increased risk of infection if on ppi Vegetative form in the small intestine Disruption of normal gut flora Antibiotics Immune suppression Tleyjeh et al. PLoS One July 2012 Kwok et al. Am J Gastro July 2012 Page 7 of 24
Risk factors Who gets infected Recent antibiotic use Elderly INPATIENT Alcohol based gels do NOT confer protection Immunocompromised Inflammatory Bowel Disease organ transplant Peri partum Normal healthy individuals with no antibiotic exposure Disinfection of environmental surfaces is recommended using an Environmental Protective Agency (EPA) registered disinfectant with C. difficile sporicidal label claim or 5000 ppm chlorine containing cleaning agents in areas of potential contamination by C. difficile IBD and C difficile Patients with IBD are at increased risk of acquiring infection Should be the first test done during a flare Is now included in quality assurance guidelines C difficile infection is a risk factor for development of IBD Higher rate of colectomy in UC Patients with j pouches can get the infection Page 8 of 24
Diagnosis labs Clinical suspicion initial infection Recurrent infection Often times do not test positive for toxin or gdh Reference on test positivity If there is formed stool likelihood of infection decreases dramatically, thus no need to test Most hospital labs will not accept formed stool Exception is patient with an ileus must inform the lab Bloodwork Leukocytosis What are the currently available laboratory tests? GDH antigen Tests for the clostridium antigen (produced by toxigenic and non toxigenic strains) Very cheap Sensitive, but not very specific for disease (good for a screen) Toxin assays EIA (enzyme immunoassays) A only will miss those that are B positive/a negative strains A + B specific, but not sensitive PCR (polymerase chain reaction) Nucleic acid amplification test Tests for the gene for toxin B PCR real time is expensive, but very quick and accurate Can utilize rectal swab for patients with ileus Page 9 of 24
University of Miami/Jackson Memorial Hospital algorithm JMH Antimicrobial Stewardship Program: ugotabug.med.miami.edu Are we overdiagnosing? Many centers today use the PCR as a standalone test HOWEVER, recent data suggest PCR testing may be overdiagnosing infection leading to inappropriate use of antibiotics Polage et al. JAMA Int Med Sept 2015 Page 10 of 24
It s the toxin that matters Polage et al. JAMA Int Med Nov 2015 Traditional antibiotics Metronidazole Vancomycin Fidaxomicin Biological therapies FMT Spore therapy Non toxigenic c difficile Immune based therapies Antibodies against toxin A/B IVIG Treatment Page 11 of 24
ACG Recommendations 2013 Severity Criteria Treatment Mild moderate diarrhea Flagyl 500 mg TID x 10 days Severe Severe complicated Albumin < 3 g/dl WBC > 15k or Abdominal tenderness ICU setting hypotension fever > 38.5 ileus mental status changes WBC > 35k serum lactate > 2.2 mmol/l end organ failure Vanco 125 mg orally 4 x daily Vanco 500 mg orally 4 x daily and flagyl 500 mg IV every 8 hrs, and vanco enemas Surawicz et al. Am J Gastro April 2013 Cost of therapy Treatment 10 day cost Metronidazole (oral) $15 30 Vancomycin (oral formulation) $1,100 Vancomycin (IV formulation given orally) $40 300 fidaxomycin $2,700 Page 12 of 24
Other treatment considerations Vancomycin pulse taper With kefir 5 ounces tid increases the effectiveness of vancomycin (Bakken JS, Minn Med 2009) Rifaximin chaser Nitazoxanide IV immunoglobulin Cholestyramine Probiotics S boulardii mixed results in prevention Recurrent Infection Defined as recurrence of CDI within 8 weeks of completion of therapy from a prior CDI One recurrence 10 20% After first recurrence 40 60% Page 13 of 24
Why do patients get recurrent infection? Prior episodes of CDI Immune compromised status Recurrent antibiotic exposure Older age (> 64) PPI use? Dysbiosis Pepin, J Clin Infect Dis. 2005 Rodrigo Pardo et al. J Clin Microbiol, 2013 Evidence against Retesting Toxin can stay positive up to 6 weeks following infection and therapy NO evidence favoring confirmation of eradication Based more on symptom complex and clinical context Recurrent diarrhea Leukocytosis Repeat antibiotic use McFarland et al, Am J Gastro 2002 Page 14 of 24
IBS D following c difficile Gutierrez et al. Gastro 2015 Retrospective cohort study of ~ 900 military personnel who developed c difficile 1998 2010 C difficile was associated with independent increased risk ratio for IBS development Jackson, M and Kelly, C J Clin Gastro 2015 Retrospective review of 117 patients referred to Brown for RCDI 25% of patients had diagnosis of IBS Only 54% underwent FMT FMT History Fecal Microbiota Transplantation Initially performed in 4 th century in China Used human feces to treat severe diarrhea Initially reported in medical literature in 1958 Eiseman (a surgeon) Fecal enemas in 4 patients with pseudomembranous colitis Page 15 of 24
Recent History of FMT 1983 first confirmed, documented case of CDI treated with FMT 2000 2010 increasing use in RCDI, IBD, IBS Scattered case reports without any regulation Thomas Borody (Australia) ~1000 of cases Pay for poop clinics AGA workgroup May 2013 FDA requires IND for FMT 2013 FDA public workshop Exercise enforcement discretion for FMT without an IND in RCDI only All other indications require IND March 2016 FDA Draft Guidance Definition of a stool bank Stool bank sponsor may request IND waiver Know the donor? FMT indications 2010 workgroup (not the the FDA) Relapsing CDI >3 episodes and failure to respond to a 6 8 week taper of antibiotics 2 episodes requiring hospitalization (Moderate CDI with no response to standard therapy for at least one week) Severe (even fulminant) CDI with no response to standard therapy for 48 hours Page 16 of 24
Donor selection Preferably not a household member No antibiotics in last 6 months Normal formed stools No GI illnesses IBD constipation Donor considerations Other medical history Screen for transmissible diseases HIV RPR Hepatitis serologies Stool testing History of atopy or allergies (in both donor and recipient) Metabolic syndrome Chronic pain syndrome Page 17 of 24
Other considerations Family history What about future polyps or cancers? Other transmissible infections? Third Party Vendors Page 18 of 24
FMT protocols Colonoscopic route Most practitioners use this Anecdotally ~ 92% success rate NGT had to be stopped early due to high success rate ~ 88% success rate Enema Can be done at home (discouraged) Frozen capsules Dysbiosis Harmony PRE FMT microbial diversity and richness urobilinogen fecal tryptic activity all fatty acids microbial function (metabalome) INCREASE in Proteobacteria POST FMT Firmicutes and Bacteroidetes butyrate producing organisms secondary bile acids DECREASE in Proteobacteria Kelly et al. FMT Update 2015, Gastroenterology July 2015 Page 19 of 24
Van Nood trial NEJM 2013 Durability in RCDI 73 patients >3 months post FMT Average 17 month follow up Cure rate 91% Brandt et al. Am J Gastro 2012 Page 20 of 24
Risks of FMT Observed Abdominal discomfort Bloating Flare of ulcerative colitis Fever Worse diarrhea Increased CrP Orthostasis Pancreatitis Potential Hepatitis HIV Autoimmune diseases Obesity Rubin DT Amer J Gastro 2013. 108: 1631 2 Smith MB et al. Nature 2014: 506: 290 1 FMT in Immunocompromised patients Multicenter retrospective series Pre and post FMT questionnaire 99 patients from 16 centers 80 eligible patients included (75 adult, 5 pediatric) Outcomes rates of CDI cure after FMT serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT infection within 12 weeks of FMT AEs (related and unrelated) to FMT. Kelly et al. Am J Gastro July 2014 Page 21 of 24
FMT in Immunocompromised patients Mean follow up period 11 months (3 46 months) 36 patients with IBD on IS 3 UC patients underwent colectomy > 100 days post FMT Cure rate after single FMT 78% 62 without recurrence at 12 weeks post FMT 12 that did recur underwent repeat FMT and 8 were cured Overall cure rate 89% 2 deaths (both unrelated to FMT) Kelly et al. Am J Gastro July 2014 The Scientific Value of FMT FMT and the Treatment of Type 2 Diabetes The success of FMT in the treatment of CDI is proof of principle that the dysbiotic human microbiota can be modified to treat disease. Emphasizes the importance of using a resilient microbial community to modify dysbiosis. FMT is a window into the biology of the gut microbiome in humans: Translation of findings in animal models into human biology. Understand the long term consequences of manipulating the gut microbiota in humans Page 22 of 24
Ongoing Clinical trials ~ 90 trials Efficacy/Safety of newer formulations Most for C difficile and IBD Irritable Bowel Syndrome Both pediatric and adult Diabetes and obesity HIV NASH, hepatic encephalopthy, PSC Antibiotic resistant bacteria Parkinson s clinicaltrials.gov Questions What are the risk factors for his recurrence? What can be done to prevent recurrence? What are his treatment options? What are the indications for FMT? Page 23 of 24
It is interesting where we find the solutions to life s problems Page 24 of 24