Clostridium Difficile

I.  Diagnostic assays for C.diff:

1) Toxin A/B EIA - variable sensitivity (depending on assay and if they test for both A/B) 60-95%, fairly specific (up to 95% or greater).  Advantages: rapid, fairly cheap.  This is used at the VA (although we may soon be moving to PCR).  Due to the relatively low sensitivity, multiple EIA's are often required (this is where the "C.diff x 3" comes from).

2) Cytotoxin assay - highly sensitive (>90%) and 99% specific.  Considered the "gold standard."  Essentially, stool sample is poured onto a plate of fibroblast cells, and is examined for rounding of fibroblasts (for cytopathic effect from c.diff toxin), with neutralizing Ab added for specificity.  Main problem is turnaround time (48-72 hours) and high labor/cost.  This was used at Stanford up until about 2 years ago.

3) C.diff toxin PCR - relatively new, was instituted at Stanford 2 years ago to replace the cytotoxin assay.  Equally or more sensitive (>90-95%), 99% specific.  Advantages: faster turnaround time, cheaper than cytotoxin assay, less labor intensive. Not yet formally recommended by IDSA although that may change in the future.
                   ** With PCR and Cytoxin assay, multiple serial tests are NOT necessary unlike for the EIA**

4)  Anaerobic culture – important for epidemiological purposes, but practically it is not very useful as it does not distinguish between asymptomatic carriage, vs toxin-producing strains that cause disease.

5) Sigmoidoscopy or colonoscopy – looking for pseudomembranous colitis.  Done mainly if high suspicion with negative lab assay, or if need prompt diagnosis before lab results come back.  Beware risk of perforation if ileus/toxic megacolon.

II. Classification of C.diff severity and management (2010 IDSA guidelines)

1) Mild-moderate disease = WBC< 15 k and Cr < 1.5x baseline (i.e. no acute renal failure) --> Metronidazole 500 mg po q8 hrs x  10-14 days

2) Severe disease = WBC >15 k OR Cr > 1.5x baseline --> PO Vancomycin 125 mg q6 hrs x 10-14 days

3) Severe complicated = Hypotension/Shock, Ileus, or Megacolon --> PO Vancomycin 500 mg q6 hrs AND IV Metronidazole 500 mg q8 hrs +/- Rectal Vancomycin (if ileus present), and consider colectemy if progressive/septic disease

As you can see, the guidelines are based on the evidence that PO Vancomycin is superior to Metronidazole for severe C.diff infection (mainly from the RCT published in CID 2007, where patients classified as severe C.diff according to a point system involving age, WBC, albumin, temperature, ICU status, and presence of pseudomembranes did better with Vancomycin). 

Recurrent Disease:

• For 1st recurrence, treatment is same as for the initial episode.
• For the second recurrence, recommendation is for Vancomycin either pulsed or tapered over several weeks.  (Avoid Metronidazole due to cumulative, dose-dependent peripheral neuropathy).
• Some experts recommend a course of Rifaximin following Vancomycin for recurrent disease (see below for more about Rifaxmin).

III.  Potential Alternative Therapies for Refractory C.diff
1) Probiotics – idea is to repopulate colonic flora with healthy, non-C.diff bacteria.  Benefit has been suggested by case reports and case series, but no good RCTs to support this.  In addition, there are case reports of fungemia (mostly from Saccharomyces) and bacteremia (mostly from Lactobacillus); this has happened mostly in sick patients who are immunocompromised, with prolonged hospitalizations, and/or with recent surgery.  Because of the lack of great supportive data and the small possibility of harm, currently the 2010 IDSA guidelines do NOT recommend probiotics as a general rule.  However, it can be considered in non-severe, recurrent C.diff in patients without significant comorbidities that would place them at risk for invasive bloodstream infection.

2) IVIG and Monoclonal Antibodies

• IVIG - idea is to give the patient serum from patients with Abs against C.diff toxin.  Benefit suggested in animal studies and in case reports although there is conflicting data including a retrospective study of 18 patients which showed no benefit (2007 Am J Infect Control).  
• Monoclonal Ab vs C.diff toxin A and B – newer therapy, and the focus of an RCT of ~200 patients published in 2009 NEJM which showed that when added to conventional antibiotics vs. C.diff, patients had significantly lower recurrence rates (~7% vs 25%) after 84 days.  This has not yet become a mainstream treatment, however.

3) Antibiotics other than PO Vancomycin or Flagyl

• Rifaximin – used sometimes in recurrent C.diff as part of sequential therapy followed a course of Vancomycin.  Resistance to rifaximin is a problem, however.
• Nitazoxanide – antiprotozoal agent usually used for Cryptosporidium or Giardia, but unlabeled use for C.diff.  Small RCT of 50 patients published in CID 2009 showing similar efficacy as PO vancomycin.  
• Tigecycline – small case series published in CID 2009 showing efficacy, including 4 patients with refractory C.diff who were treated successfully. However, subsequent reports of both success and failure.
• Fidaxomicin – new macrocyclic antibiotic with great promise because of its narrow spectrum of activity against C.diff (and not other gut flora) and favorable pharmacokinetics (stays in the colon and minimally absorbed).  Phase 3 RCT results published in NEJM 2010 showed equal efficacy as PO Vancomycin in achieving clinical cure, but more efficacious in preventing recurrence. 

4) Stool transplant (aka Fecal Bacteriotherapy)

• Idea is to repopulate patient’s colon with healthy stool and microbiota.  This is typically reserved for patients with chronic, recurrent C.diff refractory to conventional therapy. 
• Different methods of administration – via NG tube, enema, or infusion via colonoscopy. 
• Usually, the donor is someone close to the patient and is screened for HIV, hepatitis, stool pathogens, etc.  The patient should also be on antibiotics to reduce the burden of C.diff as much as possible, and often receive a GoLytely prep to cleanse the colon as much as possible prior to transplant.  Then, the stool, which should be filitered and suspended in saline (to a “milkshake” type of consistency) is administered via one of the 3 above methods.
• Efficacy has been demonstrated in multiple case reports and case series with an overall success rate of >90% in pooling all the data.  Often, symptoms resolve almost immediately. 
• See attached article from Manny for more information about stool transplant.

(Chanu Rhee MD, 4/18/11)