Fidaxomicin in cdiff
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Transcript of Fidaxomicin in cdiff
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