C. DIFF DIARRHEA: FIDAXOMICIN VS. VANCOMYCINOVMC 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.

Fidaxomicin versus Vancomycin for Clostridium difficile Infection

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

CLINICAL QUESTION

How does Fidaxomicin compare to Vancomycin in terms of clinical cure for patients

with Clostridium difficile-associated diarrhea?

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

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 start

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

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

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)

BOARD-LIKE QUESTIONA 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 148/71Abdomen: B+, soft, mildly tender diffuselyLabs: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 MetronidazoleD. Oral Vanc + IV VancE. Oral Vanc + Oral metronidazole

BOARD-LIKE QUESTION

ANSWERWhich of the following is the most appropriate oral treatment?A. Oral Metronidazole B. Oral Fidaxomicin C. IV Vanc + IV MetronidazoleD. Oral Vanc + IV VancE. 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

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?title=Fidaxomicin_in_C._difficile_Diarrhea