CLOSTRIDIUM DIFFICILE INFECTION

UPDATE

Richard Siebert

Critical Care Fellow

Steve Biko Academic Hospital

WHAT’S NEW ?

• Reseach and therapy based on the gut microbiota has grown substantially and

evidence for bacteriotherapy and more tailored bacteriotherapy is growing.

• PCR testing has become widely avalaible with one step and two step protocols making

diagnostic testing more realiabe and faster.

• Community aquired ( >12 weeks since being in a health care facility) has emerged

• 453000 cases in the US in 2011

• 29000 deaths !

• Considered a public health emergency in

US., Canada and Europe

• >¼ of infections are community acquired

• Cost to US $1.5 Billion 2011 , projected

cost to Europe 3.7 euros in 2013

• South african data limited

N Engl J Med

Volume 372(9):825-834February 26, 2015

SOUTH AFRICAN DATA

• Single centre prospective trial : GSH 651 patients

• N Rajabally, G Watermeyer SouthAfr Med J 2013;103(3):168-172.

• Stools screened for toxin A if + further PCR testing

• Patient’s younger - 41

• Antibiotic exposure

• Inflamatory bowel disease

• Very low rate of HA-CDI compared to US/European studies

CLOSTRDIUM DIFFICILE

• First isolated in 1935 in healthy infants

• Highly prevelant in infants as the microbiota matures Clos. Diff disappears !

• Antibodies deveoped to toxin A and B give

• Non invasive gram positive , spore forming toxin producing bacillus which colonizes the colon

• Spores are heat , acid , alcohol and antibiotic resistant

• Diarrhoea is caused by Toxin A and B and

• The binary toxin emerging as a virulent factor in NAPI/027/B1 strain

• tcdA , tcdB and tcdC genes control the production of toxin A and B

• Virulence of the infecting strain ( BI/NAP1/027) and host immune response determine the

clinical expression of the disease

HOST RISK FACTORS

• Antibiotic use : Clindamycin – Ampicillin

– Amoxicillin – Cephalosporin's (3rd gen)

– Fluoroquinolones ( almost any other )

• Age ( 65+)

• Proton pump inhibitors

• CKD

• Immunodeficiency

• Inflammatory bowel disease

• Exposure to carriers

Leffler DA, Lamont JT. N Engl J Med 2015;372:1539-1548

GUT MICROBIOTA

• NIH human microbiome project and European Metgenomics of the human intestinal tract

consortium

• Healthy microbiota as certain features :

• Large number of micro-organisms

• Large number of species

• Increased number of certain bacterial phyla : ie Furmicutes and Bacteroidetes

• Decreased number of certain phyla : ie Proteobacteria

• A number of diseases' are associated with an abnormal microbiota including metabolic

disturbances i.e.#. obesity / IBD / Colon cancer

Robert et al : Gastroenterology, 2014-05-01, Volume 146, Issue

MICROBIOTA

Gastroenterology.

Shanahan, Fergus; Quigley, Eamonn M.M.. Published May 1, 2014. Volume

146, Issue 6. Pages 1554-1563.RUPNIK M. N ENGL J MED 2015;372:1566-1568.

DISEASE CYCLE

ROBERT ET AL : GASTROENTEROLOGY, 2014-05-01,

VOLUME 146, ISSUE

DIAGNOSIS

• > 3 unformed stools> 24h or

• Radiological evidence of ileus or toxic megacolon and

• Positive stool test or endoscopic or histopathologic evidence of pseudomembraneous

colitis

STOOL TEST

• Gold standard test : Toxigenic culture + Cell cytotoxicity assay

• Rapid test

• EIA –GDH

• EIA – Toxin A+B

• NAAT – ( Nuclear acid amplification testing)

• LAMP - ( Loop-mediated isothermal amplification)

LABORATORY DIAGNOSIS

GDH and

EIA

Single stool

Specimen that

‘takes shape of

container’

Both

+ve

Both -veTest

Positive

Test negativeNo further testing

required

GDA

+ve

EIA -ve

PCR for Toxin

gene+ve -ve

Test negativeNo further testing

required

Test Positive

P. Marik Evidence based critical care 3rd Rd.

MARKERS OF DISEASE SEVERITY

• ( BI/NAP1/027) strain ;3 x increased mortality 1

• WBC > 15000/mm3

• > CREATINE > 1.5 BASELINE

• HYPOTENSION , ILEUS , MEGAOLON

1. Loo VG NEJM 2005 ; 353 2442-9

2. ISDA CDI guideline 2010

DISEASE SEVERITY/TREATMENT

• Carrier asymptomatic None

• Mild (<5 loose stools No SIRS) None - metronidasol

• Moderate ( Loose stools + SIRS) Vancomycin 125mg QID x 14d

• Severe (Severe diarrhea+ AKI +SIRS) Vancomycin 500 qid/ivi metronidazole /

Fidoximicin

• Complicated ( Toxic megacolon / Shock) Surgical ( colon preserving ?)/ Vanco colonic

lavage/FMT

• First recurrence Vancomycin 125mg qid x 14d/Fidoxamicin

200mg bid x 10 d

• Second recurrence FMT/Vancomycin :pulsed/tapered regime – 125mg qid 1w, tds x

1w , bd x 1w , d x 1w , 48 x 1 w ,72h x 1 w

OTHER TREATMENTS OPTIONS

• Teicoplanin

• Tigecycline

• Ramoplanin

• Rifaximin

• Nitazoxanide

• Toxin binders – televomer

• Probiotics ? Kefir

• Vaccines

PROBIOTICS ?

• Inconclusive ?

• Probiotic associated bacteraemia and fungemia in critical ill and immune deficient

patients a concern

• Recent case series using kefir ( fermented milk) with staggered and tapered doses of

vancomycin/metronidasole showed less recurrences 1.

1. Bakken et al Clinical Infect Disease 2014;59)

RELAPSES

• 25%-30% of cases

• Second and 3rd relapses are problematic

• Standard treatment is Vancomycin Pulse/ tapered regime but what to do when it doesn’t

work ?

TREATMENT FOR RECURRENCE

Fidaxomicin versus Vancomycin for Clostridium difficile Infection

Treatment with Monoclonal

Antibodies against Clostridium

difficile Toxins

N Engl J Med

Volume 364(5):422-431February 3, 2011

N Engl J Med

Volume 362(3):197-205

January 21, 2010

FECAL MICROBIOTA TRANSPLANT

• First described by Chinese 4th century to treat severe diarrhea

• Coprophagia occurs in the animal kingdom

• Used by vetenarians

• First case published of FMT for CDI was in 1983

• Currently FMT is being used more frequently ( 500 cases published for CDI)with

guidelines recently set up for indications and preparation of FMT

Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile

Els van Nood, M.D., Anne Vrieze, M.D., Max Nieuwdorp, M.D., Ph.D., Susana Fuentes, Ph.D., Erwin G. Zoetendal,

Ph.D., Willem M. de Vos, Ph.D., Caroline E. Visser, M.D., Ph.D., Ed J. Kuijper, M.D., Ph.D., Joep F.W.M. Bartelsman, M.D., Jan G.P. Tijssen, Ph.D., Peter Speelman, M.D., Ph.D., Marcel G.W. Dijkgraaf, Ph.D., and

Josbert J. Keller, M.D., Ph.D.

N Engl J Med

Volume 368(5):407-415January 31, 2013

From Stool Transplants to Next-Generation Microbiota Therapeutics

Gastroenterology.

Petrof, Elaine O.; Khoruts, Alexander. Published May 1, 2014. Volume 146, Issue 6.

Pages 1573-1582.

Open bioma stool banks ?

Update on Fecal Microbiota

Transplantation 2015: Indications,

Methodologies, Mechanisms, and

Outlook

Gastroenterology, 2015-07-01, Volume 149, Issue 1, Pages 223-237

Contraindications

- AB in the last 3 months

- Metabolic syndrome

- GI illness / malignancy/surgery

- Autoimmune diseases

- Chronic pain syndroms

- Infectious diseases : numerous to be tested

Conclusions and Relevance Among patients with CDI

who clinically recovered following treatment with

metronidazole or vancomycin, oral administration of

spores of NTCD-M3 was well tolerated and appeared to

be safe. Nontoxigenic C difficile strain M3 colonized the

gastrointestinal tract and significantly reduced CDI

recurrence.

Administration of Spores of Nontoxigenic Clostridium difficile Strain M3 for Prevention of

Recurrent C difficile Infection: A Randomized Clinical Trial

JAMA. 2015;313(17):1719-1727.

PREVENTION

• Antibiotic use : antibiotic stewardship

• Decontamination and isolation

Vaccine development against toxoids of Tcd A and

TcD B