LONDON – Fidaxomicin was noninferior to vancomycin in achieving clinical cure of Clostridium difficile infection after 10 days of treatment but was superior to vancomycin in attaining lower recurrence rates and higher sustained response rates at 4 weeks.
The findings come from a multicenter, randomized, controlled, double-blind study conducted in seven European countries, Canada, and the United States. It was funded by Optimer Pharmaceuticals, manufacturer of fidaxomicin, a novel macrocyclic antibiotic with a narrow spectrum of activity against gram-positive bacteria and minimal activity against normal gut flora. It was approved for treatment of C. difficile infection in the United States in May 2011 and in Europe in December 2011. A previous phase III trial in Canada and the United States showed fidaxomicin to be noninferior to vancomycin for clinical cure and superior for sustained response at 4 weeks after treatment completion (N. Engl. J. Med. 2011;364:422-31).
The current study, identical in design and procedures, compared the efficacy of fidaxomicin in Europe as well as in the United States and Canada, said Dr. Oliver A. Cornely of University Hospital, Cologne, Germany. The findings were published online prior to the ECCMID meeting (Lancet Infect. Dis. 2012;12:281-9).
The 509 patients included in the intent to treat analysis were all aged 16 years or older, had more than three unformed bowel movements per 24 hours, had C. diff infection confirmed by toxin A and/or B in stool, and had a first episode or recurrence within 90 days. They were randomized to either twice-daily 200-mg doses of fidaxomicin with twice-daily intervening placebo or the standard 125-mg doses of vancomycin four times daily.
The 198 patients from Europe were slightly older than those from the United States and Canada (66.9 vs. 61.2 years), and fewer were women (54.5% vs. 65%). More of the European group were inpatients at the time of study enrollment (84.3% vs. 57.9%), but fewer in Europe had had a previous episode of C. diff within the prior 90 days (10.1% vs. 18.0%). As expected, the hypervirulent, fluoroquinolone-resistant C. difficile strain NAP1/BI/027 was more common in the U.S./Canada (45.9% vs. 10.4%).
Use of concomitant antibiotics to treat other infections was more common in Europe than in the United States during both treatment and follow-up (34.8% vs. 26.7% for either time period), Dr. Cornely reported.
For the primary study end point ("resolution of diarrhea and no further need for treatment"), fidaxomicin was noninferior to vancomycin, 87.7% vs. 86.8%, well within the prespecified 10% margin. However, fidaxomicin was superior in recurrence, defined as return of diarrhea within 4 weeks of completing therapy plus a positive toxin test (12.7% vs. 26.9%). Fidaxomicin was also superior for sustained response, defined as clinical cure maintained for 4 weeks (76.6% vs. 63.4%). The median time to resolution of diarrhea did not differ between fidaxomicin and vancomycin (56 vs. 58 hours, respectively). (Time to resolution was defined as the number of hours from the first dose of the study drug to the last unformed bowel movement preceding 2 days of three or fewer unformed stools per day.)
Resolution of diarrhea was significantly delayed among patients who received antibiotics to treat other infections at the same time as they were being treated for CDI (median time to resolution 92 hours vs. 54 hours). Among the patients who were receiving concomitant antibiotics, fidaxomicin was superior to vancomycin in clinical cure rate (90.2% of 51 vs. 73.3% of 45), Dr. Cornely reported.
When Europe and the U.S./Canada were analyzed separately, fidaxomicin remained noninferior for clinical cure and superior for recurrence and sustained response. However, recurrence rates overall were slightly higher and sustained response slightly lower in the U.S./Canada, compared with Europe, although the confidence intervals were broad. Early resolution (in less than 72 hours) was more common in Europe (51 vs. 60 hours), but the overall trend was not significantly different for Europe and North America, he said.
There were no significant differences in cure rates between fidaxomicin and vancomycin for other subgroups, including those stratified by age, prior C. diff. infection, inpatient/outpatient, severity, strain, or location.
No fidaxomicin-resistant clones were isolated at baseline or at the end of treatment, although a single isolate recovered at recurrence in Canada has reduced susceptibility, Dr. Cornely noted.
The study was funded by Optimer Pharmaceuticals. Dr. Cornely disclosed that he has received research grants or lecture honoraria or is an adviser to Optimer and multiple other firms, including Actelion, Astellas, Basilea, Bayer, BioCryst, Celgene, F2G, Genzyme, Gilead, Merck, Miltenyi, Pfizer, Quintiles, and ViroPharma.