ENGLISH 7_Q4_LESSON 2_ Employing a Variety of Strategies for Effective Interp...
Fidaxomicin in cdiff
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.
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