By Richard R. Watkins, MD, MS, FACP, FIDSA
Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH
Dr. Watkins reports that he has received research support from Allergan.
SYNOPSIS: A randomized, controlled, open-label clinical trial conducted at 86 European hospitals that included adults aged 60 years or older found that extended-pulsed dosing of fidaxomicin was superior to standard-dose vancomycin for sustained cure of Clostridium difficile infection and resulted in fewer disease recurrences.
SOURCE: Guery B, Menichetti F, Anttila VJ, et al. 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. Lancet Infect Dis 2018;18:296-307.
Clostridium difficile infection (CDI) recurs in approximately 25% of patients treated with a standard 10- to 14-day course of oral vancomycin. Previous studies have shown that a 10-day course of fidaxomicin is non-inferior to vancomycin in achieving initial clinical cure.
Fidaxomicin is thought to cause less collateral damage to the gut microbiota than vancomycin, and extending the dosing of fidaxomicin may cause sustained suppression of C. difficile, leading to better microbiota recovery. Therefore, Guery and colleagues sought to assess whether extended-pulsed fidaxomicin would lead to more sustained clinical cures of CDI compared to vancomycin.
The study was a phase 3b/4, randomized, controlled, superiority, open-label trial conducted at 86 hospitals in 21 European countries (the EXTEND study). Patients eligible for the study were hospitalized, 60 years of age or older, and with clinically confirmed CDI, defined as having three or more unformed bowel movements in the 24 hours before randomization with a positive test for C. difficile toxin A or B.
Patients were excluded who received therapy for CDI for more than one day within the past 48 hours or who had three or more episodes of CDI within three months of enrollment. The participants were randomized in a 1:1 fashion to receive either fidaxomicin 200 mg twice daily for five days, followed by 200 mg every other day for 20 days, or vancomycin 125 mg four times a day for 10 days. The primary outcome was sustained clinical cure of CDI at 30 days at the end of treatment (day 40 for vancomycin and day 55 for fidaxomicin).
There were 177 patients randomized to the extended-pulsed fidaxomicin group and 179 to the vancomycin group. For the primary endpoint, 124 of 177 (70%) patients in the group that received extended-pulsed fidaxomicin had sustained clinical cure at 30 days compared to 106 of 179 (59%) patients in the vancomycin group (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.04-2.54; P = 0.030). For the patients who demonstrated clinical response to treatment at the test of cure visit (day 12 for vancomycin and day 27 for fidaxomicin), fewer who received fidaxomicin had a recurrence of CDI at days 40, 55, and 90 compared to those who received vancomycin.
At day 90, only 11 (6%) of the patients who received fidaxomicin had a recurrence of CDI, compared with 34 (19%) who received vancomycin. Furthermore, bacterial diversity increased in stool samples to a higher extent in the fidaxomicin-treated patients compared to the vancomycin group. The rate of serious drug-related adverse events was low in both groups.
The EXTEND study demonstrated the superiority of extended-pulsed fidaxomicin compared to standard-dose vancomycin for sustained clinical cure of CDI in patients 60 years of age and older. It also had the lowest rate of recurrent CDI at day 90 (6%) of any reported randomized clinical trial using metronidazole, vancomycin, or fidaxomicin.
Previously, studies with fidaxomicin showed a recurrence rate of 8-26%, depending on the number of recurrent CDIs. Thus, it seems probable that the dosing regimen in the present study accounted for the observed improved outcomes. As the authors hypothesized, this likely is due to the less harmful effects on the gut microbiota with the extended-pulsed fidaxomicin than oral vancomycin, the latter of which is known to deplete many beneficial types of gut bacteria, such as the Bacteroidetes.
One limitation of the study was the lack of an arm that used a tapering dosage of vancomycin, which the authors attributed to cost. Another was the exclusion of patients with three or more episodes of CDI. These patients are challenging to manage in clinical practice, and it needs to be determined how extended-pulsed fidaxomicin compares to fecal microbiota transplant in this patient population.
EXTEND is unusual because of its robust study design: a superiority antibiotic randomized clinical trial. Yet, one of the downsides of fidaxomicin has been its high cost, especially compared to generic vancomycin. The authors argued that because the extended-pulsed fidaxomicin uses the same number of tablets as the standard regimen, there is no additional increase in treatment cost with this approach. Additional studies of pulsed dosing of fidaxomicin for CDI in other scenarios, for example in patients with multiple disease recurrences or in those receiving antibiotics for another concurrent infection, along with more pharmacoeconomic analyses, are especially warranted.