Fidaxomicin in C. difficile Diarrhea

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Louie TJ, et al. "Fidaxomicin versus Vancomycin for Clostridium difficile Infection". The New England Journal of Medicine. 2011. 365(5):422-431.
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Clinical Question

In patients with Clostridium difficile-associated diarrhea, is treatment with fidaxomicin non-inferior to vancomycin in terms of clinical cure?

Bottom Line

Fidaxomicin was noninferior to vancomycin in achieving rates of clinical cure among patients with Clostridium difficile-associated diarrhea and resulted in fewer recurrent infections.

Major Points

Clostridium difficile-associated diarrhea (CDAD) is a major adverse effect of antibiotic usage and its incidence is on the rise, particularly among hospitalized patients receiving broad-spectrum antibiotics. While the Vancomycin vs. Metronidazole in C. difficile Diarrhea trial (2007) demonstrated superiority of vancomycin for severe disease, there have remained unacceptably high recurrence rates even among patients appropriately treated.

This study sought to investigate whether fidaxomicin was non-inferior to vancomycin for the treatment of CDAD. The study randomized 629 patients with characteristics similar to most hospitalized patients with either non-severe or severe CDAD, with average age 62 years and recent exposure to antibiotics. Clinical cure was achieved in 86-92% in each group, demonstrating the non-inferiority of fidaxomicin compared to vancomycin. Fidaxomicin was, however, associated with only 13% recurrences compared to 24% with vancomycin, yielding 45% fewer recurrences in the fidaxomicin group. Nevertheless, its prohibitive cost and lack of sufficient superiority data have yet to establish fidaxomicin as a first-line agent for the treatment of CDAD.

The 2012 Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile publication demonstrated a more than a 60% absolute increase in the rate of cure of recurrent CDAD over vancomycin. A comparison between this therapy and fidaxomicin has yet to be published.

Guidelines

Published before the 2011 fidaxomicin and 2012 fecal transplant trials.
IDSA/SHEA CDAD (2010):[1]

  • 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)

Design

  • Prospective, multicenter, double-blind, randomized, parallel-group trial
  • N=629
    • Fidaxomicin (n=302)
    • Vancomycin (n=327)
  • Setting: 52 sites in the US and 15 sites in Canada
  • Enrollment: May 2006 to August 2008
  • Analysis: both modified intention-to-treat and per-protocol

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
  • Life-threatening or fulminant CDAD
  • Toxic megacolon
  • Prior exposure to fidaxomicin
  • History of inflammatory bowel disease
  • Recurrent CDAD (>1 episode in 3 months prior to study)

Baseline Characteristics

  • Age: 61.5 years
  • Female: 56%
  • Unformed stools per day: 8.3
  • Inpatient: 58%
  • Lack of response to metronidazole: 5.1%
  • Treatment for C. difficile infection in previous 24 hours: 16.9%
  • BI/NAP1/027 strain: 37%

Interventions

  • Stratified according to whether current infection was first episode (primary occurrence) or second episode (first recurrence) within 3 months before start of study
  • 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
    • If criteria for clinical cure were met, patient followed for recurrence, by means of weekly assessment, for 28 days after last dose of study medication had been administered
  • Fecal samples for toxin assays obtained at time of screening or enrollment, at time of early termination or end-of-therapy visit in case of patients with clinical failure, and at visits for diagnosis and treatment of recurrent infection in case of patients in whom disease recurred

Outcomes

Comparisons are fidaxomicin vs. vancomycin.

Primary Outcome

Clinical cure
88.2% vs. 85.8% (modified intention-to-treat analysis)
92.1% vs. 89.8% (per-protocol analysis)

Secondary Outcome

Recurrence
15.4% vs. 25.3% (P=0.005, intention-to-treat analysis)
13.3% vs. 24.0% (P=0.004, per-protocol analysis)

Subgroup Analysis

No difference in rates of clinical cure or recurrence within subgroups defined by age, inpatient/outpatient status, history of CDAD, treatment vs. no treatment for CDAD within 24h prior to randomization, baseline severity of disease, C. difficile strain, prior response to metronidazole, or concomitant use of systemic antibiotics.

Criticisms

  • No report of PPI use, a risk factor for CDAD recurrence[2]
  • The treatment was mostly limited to the NAP1/BI/027 strain[2]
  • Unclear antibody levels to C. difficile toxin A, a value that may relate to risk of recurrence[2]

Funding

Sponsored by Optimer Pharmaceuticals

Further Reading

  1. Cohen SH et al. "Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)." Infection Control and Hospital Epidemiology. 2010;31(5):431-455.
  2. 2.0 2.1 2.2 Multiple authors. "Correspondence: Fidaxomicin for Clostridium difficile infection." The New England Journal of Medicine. 2011;364:1875-1876.