Clostridium difficile:Epidemiology, Management

and Focus on Fecal Bacteriotherapy/Fecal Microbiota Transplantation

Jayesh Patel, MD, DTM&HInfectious Disease ConsultantChair Infection Prevention and

Pharmacy/Therapeutics/Nutrition (Skyline)

C. difficile management :Financial disclosure

No financial conflict of interest

( Past speaker for Dificid)

Objectives: C. difficile

Learn current epidemiology of C. difficile infection

Understand clinical presentation of C. difficile disease

Understand testing methodology for C. difficile infection

Learn about prevention and treatment of C. difficile infection

Learn about rationale and methods of treatment by fecal microbiota transplantation

Clostridium difficile Gram positive anaerobic

bacillus Produces spores Commensal intestinal flora in

2-5 % of healthy adults, over 50%

of infants Fecal-oral transmission Colonizes 20-40 % hospitalized

patients Produces toxins A, B, and Binary

toxin

C. difficile: Epidemic Strain NAP1/BI/027strain of C. difficile  "North American Pulse-field type 1"

pattern (on gel electrophoresis) and a "BI" pattern (on restriction endonuclease analysis), and type "027" (on ribotyping)

Resistance to quinolone antibiotics Hypersporulation Binary toxin production High levels of toxin A,B (20 x greater) High morbidity and mortality

Epidemiology

USA 15,000 – 20,000 deaths annually, rising 20 % of all episodes of antibiotic associated

diarrhea are due to C. difficile

4-10 cases per 10,000 patient days

Relapse occurs in over 20 % of cases

Increase in average hospital cost : $ 27,000 Over 1 billion dollars in costs annually

Risk Factors

Current and prior antibiotics Elderly Immunocompromized Hospital stay, nursing home residence NG tube, tube feeding Recent Endoscopy, Gastrointestinal

surgery Proton pump inhibitors, H2 blockers,

Chemotherapy

Prevention of Transmission Private rooms Contact isolation: gloves, gowns Hand washing ( instead of alcohol

based ) Special entry signs EPA approved sporicidal agents,

diluted bleach for cleansing all environmental surfaces and reusable devices

Isolation till diarrhea resolved or discharged

Clinical Manifestations

Diarrhea, abdominal pain, N/V, fever, loss of appetite

Pseudomembranous colitis

Toxic megacolon Perforation of colon

Severe sepsis Death

Testing in C. difficile ? Smell WBC , creatinine, albumin Stool testing

Culture for C. difficile — slow— labor intensive, technical expertise— expensive— requires second test for toxin

detection

Stool Testing

Cell Cyto-toxicity Neutralization Assay— Toxin B detection only— Slow, Labor Intensive/technical

expertise— Moderate sensitive, High specificity

Stool Testing

Antigen detection ( Glutamate DeHydrogenase EIA)— Highly Sensitive— Rapid— Cheaper— Not specific

Stool Testing

Toxin Enzyme Immuno Assay— Detects toxin A and B— Quick, inexpensive— Less sensitive— Toxin is heat labile so testing must

be done within 2 hours or keep stool sample refrigerated

Stool Testing

PCR — Toxin B gene— Very sensitive and specific— Rapid if done in house— Expensive

Multistep Testing

Antigen negative: no further testing, not C. difficile

Antigen positive, Toxin positive: has C. difficile

Antigen positive, Toxin negative: send for PCR— PCR negative: not C. difficile— PCR positive: has C. difficile

C. Difficile treatment:Metronidazole Indication: mild to moderate CDI

Administration: 500 mg PO or IV tid for 10-14 days

First line therapy for mild to moderate CDI, but increasing rates of refractory infection are being observed

Vancomycin Indication: Moderate to severe CDI Administration: ~125-500 mg PO

qid for 10-14 d Oral, nasogastric, or rectal therapy

may be combined with IV metronidazole in critically ill patients.

Tapered/Pulse therapy for recurrent CDI

Nitazonxanide

Indication: index infection or recurrent CDI

Administration: 500 mg PO bid for 10 days

More studies are needed to clarify its role in CDI.

Rifaximin

Indication: recurrent CDI

Administration: 200 mg PO bid to 400 mg PO tid for 28 d. May be given as a “chaser” after completion of vancomycin therapy for recurrent CDI.

More controlled studies needed to decide best use of this drug.

Fidaxomicin

Indication: index infection of recurrent CDI

Administration: 200 mg PO bid for 10 d

Non-inferior to vancomycin and is associated with a significantly lower rate of recurrent infection

Expensive

Toxin Binders Indication: symptomatic adjunct to

antibiotic treatment

Administration: Cholestyramine 4 g PO tid or qid. ?? Duration

Toxin binders such as cholestyramine

should be used to control symptomatic diarrhea but not as the only treatment.

Immunoglobulins

Indication: refractory CDI

Administration: IV infusion at a dose of 400 mg/kg (IVIG) of body weight given with antibiotic therapy.

Enhances overall efficacy of treatment and reduces further recurrences.

Expensive

ProbioticsSaccharomyces boulardi Indication: prevention of recurrent CDI

Administration: 500 mg PO bid for 28 d. Usually started after 7 days of antibiotic treatment.

Avoid using in severely immunosuppressed patients; should not be given chronically.

(Lactobacillus not proven to help)

Other treatments

Bacitracin suspensionRifampinTeichoplaninTigecyclineSurgery: ColectomyFecal bacteriotherapy/FMT

Fecal Microbiota Transplantation Indication: recurrent/refractory CDI;

unclear role in severely ill CDI patients as first-line therapy.

Administration: stool suspension from a healthy donor administered by nasogastric/NJ tube, via colonoscopy or enema.

Excellent preliminary results in patients with severe and refractory disease. Best methodology is yet to be clarified.

Case Report

62 yr old white male Had URI ( ? Viral), got abx. and 3 days

later, develops diarrhea, becomes severe, Metronidazol started. Gets worse, abd cramping, weakness, mucousy stools, stools every ½ hour.

PMH: splenectomy, multiple sinus surgeries, fracture/laceration finger one month earlier, had pinning and got prophylactic antibiotic.

Case Report

Admitted to Hospital WBC 12.9k, Cr 1.2, C. diff Ag/Toxin

positive Oral vancomycin started Slow/poor response, Nitozoxanide

added Slow improvement, discharged on

oral Nitozoxanide. Nitozoxanide not covered by

insurance so changed to Metronidazol. Had 1-2 soft/loose stools daily.

Case Report

2 days after completing Metronidazol, develops explosive diarrhea

20 BM/day, nausea, chills, abdominal pain, weak

Readmitted Ill looking, T 100.1, HR 110, BP

100/52 Abdomen tender

Case report: CT Abdomen

Case Report

Treatment: IV fluids, Vanco PO, Metronidazol, Nitozoxanide

Poor response: ? Fidoxamicin ? FMT ?Colectomy

Patient elects to have FBT/FMT

Case Report

Approx. 70 grams donor stool instilled via Naso-duodenal tube, partial response, 2nd instillation of fresh 100 gram stool next day. Diarrhea resolves 3rd day.

Patient observed 2 more days than discharged home free of symptoms

Patient free of symptoms after 6 months

Procedure for FBT/FMT

Diagnosis will be confirmed by Gastroenterologist or Infectious Disease Specialist.

Gastroenterologist or Infectious Disease Specialist wishing to use(FBT) will notify designated departments to schedule the testing/procedure, and discuss the process with donor and recipient for Informed Consent.

Consents and Education

FBT/FMT Policy and ProcedurePatient ConsentPatient Education BrochureDonor ConsentDonor InstructionBowel Motion Record

Recipient testing

All recipients will have the following laboratory tests:— HIV antibody— Hepatitis A antibody— Hepatitis B surface antigen— Hepatitis C antibody

DONOR:

Ideally the stool transplant donors should be related to the recipient but not the spouse, significant other or a family household member. They should be healthy and have not received antimicrobial therapy in the last 2 months.

The donor should have normal bowel habits and be free of blood-borne or stool-borne pathogens.

Screening tests prior to the transplant Acute Hepatitis Panel, HIV antibody, and

CBC Donor stool testing for Clostridium difficile

toxin, Stool culture , Cryptosporidium stain, Stool O & P

Patient Prep

Obtain signed consent for Fecal Bacteriotherapy/FMT

Start Liquid diet the day prior to the scheduled FBT/FMT

Cleanse patients’ bowel using 3-4 liters of Golytely, the day before FBT/FMT

Give PPI agent day of procedure for upper GI administration

Stop antibiotics 24-48hr before FMT

Stool Specimen Preparation for Lower GI Administration Obtain 250-300 gms (approx one

cup) of fresh stool from donor as soon as possible prior to the transplantation procedure, never more than 4 hours prior.

Using a blender, add stool to 250ml of Normal Saline or Sterile Water. Mix until stool particles are dispersed throughout the liquid

Remove large particles by straining the stool/liquid mixture twice, utilizing strainer.

Stool Specimen Preparation for Lower GI Administration Mixture should be administered within 2

hours of preparation. No more than 6 hours should elapse between stool specimen collection and fecal administration.

Administer as Enema or by Colonoscopy into terminal ileum and colon.

Enema can be given by standard enema set or by Fecal Management System (ActiFlo). Retain enema for 1-2 hours.

Repeat enema with fresh stool next day if ordered.

Stool Preparation for Upper GI Administration On the day of the procedure, obtain 100 g

(approx 1/3 to 1/2 cup) of donor stool. Using a blender, add stool to 100 ml (or

necessary amount to facilitate installation) of Normal Saline or Sterile water. Mix until stool particles are dispersed throughout the solution.

Remove large particles by straining the stool/saline mixture twice, utilizing a strainer.

Transfer solution into catheter tip syringes for transport to patient.

FMT via Upper GI Tract

Place NG tube or Naso-duodenal tube morning of procedure in radiology department.

If NJ tube is used, it is inserted into Jejunum through endoscope.

Don gown, gloves, mask, and eye protection.

FMT Via Upper GI Tract

Using a syringe administer the freshly mixed stool via NJ/ Dobhoff tube.

After stool installation, flush with 50ml of normal saline. (DO NOT REMOVE NJ/DOBHOFF TUBE).

Repeat stool infusion procedure next day.

Do not remove NJ/Dobhoff tube until ordered by physician.

Naso-duodenal Tube Placement

FMT: Upper GI Tract Route

FMT: Upper GI Tract Route

Goodbye !

Listen to your mother:

Don’t forget to wash your hands after using

the restroom and before eating!