EXTEND – Extended Fidaxomicin versus Vancomycin for C. difficile
Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial.
SuLouie TJ, Miller MA, Mullane KM, et al.; EXTEND Clinical Study Group.
Lancet Infect Dis. 2018 Mar;18(3):296-307. [Full text]
The frequency of community acquired and especially health care associated Clostridium difficile infection (CDI) seems to be declining; yet, when observed over a the same period, the rate of CDI recurrence did not change [1].
Fidaxomicin is a macrocyclic lactone antibiotic that inhibits RNA polymerase and is bactericidal against C difficile. It generally has a narrower spectrum of activity compared to vancomycin, which can deplete bacteroides and increase rates of VRE. Fidaxomicin also seems to have a prolonged postantibiotic effect (approximately 10 h). In 2012, Fidaxomicin had been shown non-inferior to vancomycin, with possibly decreased CDI recurrence [2]. It was postulated, in part, that the narrower spectrum (“microbiota-sparing”) of fidaxomicin leads to decreased recurrence .
The Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients aged ≥60 years (EXTEND) trial aimed to assess superiority of fidaxomicin compared to vancomycin. Age is a significant risk factor for recurrence (see, for example, the ATLAS score) and hence was the focus population for EXTEND.
Patient population and Design
This was a phase 3b/4, randomized, controlled, parallel, superiority, open-label trial was performed at 86 hospitals in 21 countries. Patients were eligible if they were ≥ 60 years old, with clinically confirmed CDI (defined by ≥3 unformed bowel movements or ≥200 mL unformed stool in 24 h before randomization plus the presence of C difficile toxin A or B in stool). Key exclusion criteria included CDI for ≥1 day within the past 48 h and ≥3 previous CDI episodes within 3 months of enrollment.
Patients were randomly assigned to receive extended-pulsed fidaxomicin (200 mg BID days 1–5, then Q48hr on days 7–25) or vancomycin 125 mg QID for 10 days. Patients was stratified by CDI severity (severe = WBC >15K, ↑SCr 50%, or albumin <3 g/dL; or non-severe); presence or cancer, age (≥75 years or <75 ), or number of previous CDI occurrences (0-2) in the 3 months before study entry.
Outcomes
The primary efficacy endpoint was sustained clinical cure of CDI at 30 days, defined as a clinical response (no recurrence) at confirmed negative test of cure after completing the study drug. Secondarily, the recurrence of CDI defined as return of diarrhea above that on the day of test of cure, with confirmatory lab testing, assessed on days 40, 55, and 90. Safety events were also monitored.
Results
Between Nov 6, 2014, and May 5, 2016, 362 patients were enrolled, randomly assigned to either extended-pulsed fidaxomicin or vancomycin (181 each). and received at least one dose of the study medication.
At day 12 and day 27 (2 days after end of each treatment, respectively), the clinical response to treatment did not differ between the extended-pulsed fidaxomicin and vancomycin. But the primary outcome of sustained clinical cure 30 days after completing each regiment was higher in the extended-pulsed fidaxomicin, 124 (70%) of 177 patients, compared with 106 (59%) of 179 patients receiving vancomycin (△11%, 95% CI 1.0-20.7, p=0.03; OR 1.62, 95% CI 1.04-2.54) using the modified full analysis patient set. Results were similar in the per-protocol analysis subset.
At each of the 40 , 55, and 90 days post enrollment follow up visits, the recurrence rate was lower in the extended-pulsed fidaxomicin compared to vancomycin (see table below). The hazard of CDI recurrence at any given time after day 10 for a vancomycin-treated patients was approximately 3.8-times that of an extended-pulsed fidaxomicin-treated patient.
Table 1. CDI Recurrences
| Follow up day | Fidaxomicin | Vancomycin | OR (95% CI) | P |
| 40 | 3 (2%) | 22 (18%) | 0.12 (0.04–0.41) | <0.0001 |
| 55 | 7 (6%) | 23 (18%) | 0.31 (0.13–0.73) | 0.0032 |
| 90 | 11 (9%) | 23 (18%) | 0.49 (0.23–1.04) | 0.048 |
Three (2%) patients receiving extended-pulsed fidaxomicin and six (3%) patients receiving vancomycin had drug-related serious adverse events. For fidaxomicin, this included one (1%) each of pruritus, biliary stone, and drug hypersensitivity; the latter two led to discontinuation of fidaxomicin. One death in the vancomycin arm from heart failure and sepsis, was considered a “probable” relation to vancomycin.
Discussion
In EXTEND, a multicenter, non-blinded, randomized trial showed that pulsed dosing fidaxomicin over 27 days, touted as “microbiota-sparing” strategy, was superior to standard 10 day vancomycin is sustained clinical cure of CDI at 30 days after the end of each respective treatment in patients aged 60 years and older. The authors estimate the corresponding NNT was 6.6.
The most obvious limitation to this study is no comparison to either standard 10-day fidaxomicin dosing as well as to an extended vancomycin regimen. The authors mainly cited the logistics of such a four arm trial as the major limitation, and the choice of standard dose 10-d vancomycin for comparison, as it was the standard regimen at the time of the study.
In 2021, the IDSA and SHEA released a focused update on the management of CDI in adults [3]. In that update, fidaxomicin at 200 mg BID for 10 days, is now the preferred regimen for initial CDI episode. This change was based on a better sustained clinical response (101 more responding with fidaxomicin per 1000), as well as a slight mortality benefit (9 fewer per 1000). The recommendation is given moderate quality evidence and is based on this EXTEND trial, as well as and three other similar randomized trials (see Table 2). Based on the IDSA/SHEA update, extended dosed fidaxomicin is reserved for the first recurrence. Also, it should be noted that they state that “vancomycin remains an acceptable alternative” for first CDI episode.
One reason using fidaxomicin may be limited is cost (GoodRx). It can generally be more costly than oral vancomycin; however, cost effectiveness analysis still seems to favor fidaxomicin based on decreased recurrence and readmission [4]. Perhaps for now, fidaxomicin could be reserved for those most likely to have recurrence, which could be based on available scoring systems (for example, the ATLAS score, the CDI calculator).
| F: Follow up | Every 2 weeks for 30 days; days 40, 55, and 90 for recurrence |
| R: Randomization | 1:1, stratified by severity, cancer, age ≥75 |
| I: Intention to treat | *Modified, only included if ≥1 dose of study drug received |
| S: Similar at baseline | Yes |
| B: Blinding | NO |
| E: Equal treatment | Extended duration fidaxomicin vs. standard dose vancomycin |
| S: Source (funding) | Astellas Pharma, Inc. |
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- Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422-31.
- Johnson S, Lavergne V, Skinner AM, Gonzales-Luna AJ, Garey KW, Kelly CP, Wilcox MH. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021 Sep 7;73(5):e1029-e1044.
- Burton HE, Mitchell SA, Watt M. A Systematic Literature Review of Economic Evaluations of Antibiotic Treatments for Clostridium difficile Infection. Pharmacoeconomics. 2017 Nov;35(11):1123-1140.
