Summarized by Isabella Lai, MD; Laxmi Suthar, MD http://trialguru.org/

1. C. DIFF DIARRHEA:
FIDAXOMICIN VS. VANCOMYCIN
OVMC LANDMARK TRIALS SERIES
Louie TJ, et al. "Fidaxomicin versus Vancomycin for
Clostridium difficile Infection". The New England Journal of
Medicine. 2011. 365(5):422-431.

2. Fidaxomicin versus Vancomycin for Clostridium difficile Infection

3. BACKGROUND
 C. diff diarrhea is most common infectious entity in
nosocomial diarrhea
 Since 1990s>2x increase incidence of C.Diff
 Relapse rates are high
 New strains have emerged, including NAP1/BI/027
strain
 Fidaxomicin is a macrocylic antibiotic and has more
invitro activity against C.diff than Vancomycin
 Fidaxomicin has limited systemic absorption and
high fecal concentration

4. CLINICAL QUESTION
How does Fidaxomicin compare to Vancomycin in
terms of clinical cure for patients with Clostridium
difficile-associated diarrhea?

5. DESIGN
 Analysis: both modified intention-to-treat and per-protocol
 Trial Design: Prospective, multicenter, double-blind, randomized, parallel-group trial
 N=629
 Fidaxomicin (n=302)
 Vancomycin (n=327)
 Setting: 52 US sites and 15 Canadian sites
 Enrollment: May 2006 to August 2008

6. POPULATION
Inclusion Criteria
 Age ≥16 years
 Diarrhea positive for C. difficile toxin within 48h
prior to randomization
Exclusion Criteria
 Receiving other antibiotics effective against
CDAD (eg, rifaximin)
 Patients could receive ≤4 doses of
metronidazole/vancomycin within 24h prior to
randomization
 Likelihood of death within 72 hours from any
cause
 Toxic megacolon
 Past exposure to fidaxomicin
 Pregnancy/breastfeeding
 Inflammatory bowel disease
 >1 C.diff occurrence within 3 months of study

7. INTERVENTIONS
 Stratified according to whether current infection was FIRST EPISODE (primary occurrence) or SECOND
EPISODE (first recurrence) within 3 months before study start
 Received study medication orally each day for 10 days
 Fidaxomicin 200mg PO q12h with intervening matching doses of placebo
 Vancomycin 125mg PO q6h
 Assessed daily for clinical cure or failure during 10-day course of therapy

8. CRITICISMS/LIMITATIONS/FUNDING
 1st version of paper written by part-time employee of Optimer Pharmaceuticals
 Fidaxomicin is noninferior in rate of clinical cure and does have moderate recurrence reduction, but
is drastically more expensive (1 tab = $168, therapy course $3360)
 No report of PPI use, a risk factor for severe C.diff recurrence
 The treatment was mostly limited to the NAP1/BI/027 strain
 Unclear antibody levels to C. difficile toxin A, a value that may relate to risk of recurrence
 Excluded ill patients (eg patients with megacolon)
FUNDING:
Funded by Optimer Pharmaceuticals who manufactures Fidaxomicin

9. BOTTOM LINE
This Phase 3 trial showed that
Fidaxomicin was noninferior to
vancomycin in achieving rates of
clinical cure among patients
with Clostridium difficile-associated
diarrhea
Fidaxomicin was associated with a
significantly lower rate of
recurrence of C. difficile infection
associated with non-NAP1/BI/027
strain
Guidelines -- IDSA/SHE CDAD (2010)
Discontinue treatment with the antibiotic thought to be associated with CDAD
occurrence as soon as possible (A-II)
Start empirical treatment in severe or complicated CDAD as soon as suspected (C-III)
Avoid antiperistaltic agents (C-III)
Metronidazole 500 mg po TID for 10-14 days for initial episode of mild-to-moderate
CDAD (A-I)
Vancomycin 125 mg po QID for 10-14 days for initial episode of severe CDAD (B-I)
Vancomycin 500 mg PO QID +/- metronidazole 500 mg IV q8h for severe,
complicated CDAD (C-III)
--If ileus, vancomycin 500 mg in 100 mL NS PR q6h as a retention enema
≥2nd CDAD recurrence with taper or pulse of vancomycin (B-III)
Avoid metronidazole after the first recurrence of CDAD, including as a long-term
agent, beacause of the risk of neurotoxicity (B-II)

10. BOARD-LIKE QUESTION
A 41 yo woman is hospitalized for severe
cellulitis. She is treated with Vanc/Zosyn, and
discharged on PO Clindamycin. However, 5 days
later he develops a fever and diarrhea, described
as 5-8 liquid bowel movements over the last 24
hours. Medications include Metformin for DM2,
Amlodipine for HTN.
Physical exam:
T 38, HR 107, BP 148/71
Abdomen: B+, soft, mildly tender diffusely
Labs:
WBC 18K, Creatinine 1.7 (baseline 0.9)
Stool PCR shows C.diff
Which of the following is the most appropriate
treatment?
A. Oral Metronidazole
B. Oral Fidaxomicin
C. IV Vanc + IV Metronidazole
D. Oral Vanc + IV Vanc
E. Oral Vanc + Oral metronidazole

11. BOARD-LIKE QUESTION
ANSWER
Which of the following is the most appropriate
oral treatment?
A. Oral Metronidazole
B. Oral Fidaxomicin
C. IV Vanc + IV Metronidazole
D. Oral Vanc + IV Vanc
E. Oral Vanc + Oral metronidazole
Educational Objective:
Treat a severe case of Clostridium
difficile infection.
Key Point:
- Severe Clostridium difficile infection should be
treated with oral vancomycin.
- Oral Fidaxomicin non-inferior to oral
Vancomycin
- Severe CDI is defined by the Infectious
Diseases Society of America as a leukocyte
count of 15,000/µL (15 × 109/L) or greater and
a serum creatinine level greater than 1.5 times
the baseline level

12. REFERENCES
 Louie TJ, et al. "Fidaxomicin versus Vancomycin
for Clostridium difficile Infection". The New
England Journal of Medicine. 2011. 365(5):422-
431.
 Brain, L. P. (n.d.). Fidaxomicin in C. difficile
Diarrhea.
https://www.wikijournalclub.org/w/index.php?tit
le=Fidaxomicin_in_C._difficile_Diarrhea