Becky McCall

April 05, 2012

April 4, 2012 (London, United Kingdom) — Fidaxomicin (Dificid, Optimer Pharmaceuticals) treatment was superior to vancomycin for initial cure, recurrence, and sustained response, according to a subanalysis of patients with cancer and Clostridium difficile–associated diarrhea (CDAD).

In addition, concomitant antibiotics had less effect on clinical cure rate with fidaxomicin than with vancomycin, according to data from a phase 3 clinical trial conducted in Europe and North America. Both studies were presented here at the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Oliver A. Cornely, MD, oncologist/hematologist and infectious diseases physician from the University Hospital Cologne in Germany, led the European/North American phase 3 study (OPT-80-004). He presented the results of a subanalysis of data from both studies.

The European/North American multicenter, randomized, controlled, double-blind, noninferiority study was published in February (Lancet Infect Dis. 2012;12:281-289). An earlier phase 3 study of fidaxomicin conducted in the United States and Canada was published last year (N Engl J Med. 2011;364:422-431).

The subanalysis of cancer patients with CDAD was presented here at ECCMID for the first time.

Fidaxomicin is a novel macrocyclic antibiotic with a narrow spectrum of activity against Gram-positive bacteria and minimal activity against normal gut flora. "Fidaxomicin is not absorbed, which makes it like a magic bullet because it stays where it is needed in extremely high concentrations," Dr. Cornely told Medscape Medical News.

Further to the North American study, results of the second phase 3 trial in 509 patients from Europe and North America also demonstrated that clinical cure for fidaxomicin was noninferior to vancomycin in the modified intent-to-treat population (87.7% vs 86.8%).

Dr. Cornely emphasized the recurrence rates with fidaxomicin. "This is the first point at which we see a difference in the 2 antibiotics, and it is a large difference," he said. "We see double the incidence of recurrence with vancomycin over fidaxomicin [26.9% vs 12.7%; difference, 14.2%; 95% confidence interval [CI], –21.4% to –6.8%; P < .001]. It cuts the recurrence rate in half. A high recurrence rate is expected with vancomycin in a very sick population, but this is still an extreme."

These findings were also reflected in the sustained response rates, which showed fidaxomicin was superior to vancomycin (76.6% vs 63.4%; difference, 13.2%; 95% CI, 5.2% to 20.9%; P = .001).

Cancer Patients a Special Population

The subanalysis in cancer patients was drawn from data derived from the 2 phase 3 trials. "Patients with cancer are a population of special interest because of their lower response rates, and they are very prone to recurrent disease," Dr. Cornely told Medscape Medical News.

Cancer patients with CDAD were given fidaxomicin 200 mg twice daily (539 patients) or vancomycin 125 mg 4 times daily (566 patients) for 10 days. They were analyzed for response to each drug in terms of initial clinical cure (resolution of diarrhea, measured by 3 or fewer unformed bowel movements per day, maintained until the end of treatment and 2 days after), recurrence (after clinical cure, the return of diarrhea within 4 weeks of completing therapy, confirmed by a positive stool toxin test), and sustained response (clinical cure maintained for 4 weeks after completing therapy with no recurrence).

In the combined population on either drug, a comparison was drawn in response to treatment for CDAD in patients with and without cancer.

Dr. Cornely found that overall, patients with cancer had a lower clinical cure rate and prolonged episodes of diarrhea.

Patients without cancer who received at least 8 days of either fidaxomicin or vancomycin had a clinical cure rate of 96.5%, whereas those with cancer and who had been on at least 8 days of treatment (n = 153) had a clinical cure rate of 92.2% (P = .0130).

Time to resolution of diarrhea was also prolonged in cancer patients, compared with those without cancer (55 vs 100 hours; = .0004). Recurrence rate was 19.9% in those without cancer and 22.0% in those with cancer (P = .57). Sustained response rates were 77.3% and 71.9%, respectively (P = .147).

However, there was a clear difference in clinical response between the 2 antibiotics in cancer patients. Those treated with fidaxomicin had significantly higher clinical cure and sustained clinical cure rates and significantly lower rates of recurrence than patients treated with vancomycin.

Analysis by odds ratios showed that fidaxomicin is 5 times more likely than vancomycin to produce a clinical response (odds ratio [OR], 5.07; 95% CI, 1.07 to 23.98; = .041) and 3 times more likely to lead to a sustained response (OR, 3.22; 95% CI, 1.50 to 6.91; = .003).

There was a 2.6-fold greater odds of recurrence with vancomycin (OR, 0.38; 95% CI, 0.16 to 0.89; = .025) than with fidaxomicin.

"It works in cancer patients — 97.3% of patients on fidaxomicin achieved clinical cure, compared with 87.5% on vancomycin [P = .041]. Regarding recurrence, 14.1% of patients on fidaxomicin, compared with 30.0% on vancomycin, experienced recurrence [P = .025]. Sustained response showed 83.6% and 61.3% [P = .03], respectively," Dr. Cornely reported.

Consider Effect of Concomitant Antibiotics

According to Dr. Cornely, another significant finding from the European/North American trial was the effect of concomitant antibiotics on clinical outcomes of the drugs.

"For the first time, we have evidence of the effect of concomitant antibiotics. If patients received antibiotics during the 10-day period when they received fidaxomicin or vancomycin, then we see a statistically significant difference in outcome," reported Dr. Cornely.

Resolution of diarrhea was more readily achieved in those who did not receive additional antibiotics, and varied with type of antibiotic. The time to resolution of diarrhea doubled from a median of 54 hours for those without concomitant antibiotics to 92 hours for those with concomitant antibiotics.

"The patients in this study were receiving a lot of different antibiotics. We can't do anything about the age risk factor, but we can modify the number of antibiotics they receive," Dr. Cornely noted.

Notably, fidaxomicin was superior to vancomycin in clinical cure rate among patients who were receiving concomitant antibiotics to treat other infections. For patients on fidaxomicin, 90.2% receiving concomitant antibiotics and 87.1% not receiving concomitant antibiotics achieved clinical cure. In contrast, for patients on vancomycin, 73.3% receiving concomitant antibiotics and 89.6% not receiving concomitant antibiotics achieved clinical cure.

Arno Lechner, MD, consultant for the Department of Internal Medicine and Infectious Diseases at the University Hospital, Salzburg, Austria, commented on the findings presented at the congress.

"As far as I know, the price is relatively high, so in our institution there will be some discussion about cost/benefit," he said. The price of a 10-day course of fidaxomicin is $2800.

"It should be cost effective because of the high cost of recurrences, but this topic needs discussion. Fidaxomicin will probably become a standard alternative to vancomycin," Dr. Lechner said.

"Fidaxomicin might be reserved for a group of patients who are at high risk for recurrences. But I would also like to see the longer-term outcome regarding recurrences after 30 days. What happens, if anything? Recurrences between 1 and 2 months would make a difference," he added.

Uwe Lodes, MD, an intensive care physician at the University Hospital in Magdeburg, Germany, said he sees the problem related to recurrent C difficile on the intensive care unit often. "This is a problem we see in around 100 patients per year in our unit. I think it would be good to have this drug, which will benefit these patients."

"We also have an issue with stopping other antibiotics," he added. "Many of our patients need concomitant antibiotics because they are surgical patients who have abdominal sepsis, pneumonia, organ distress, multiple organ distress syndrome, or other infections — so they need other treatments. In fact, we have more cases in which we cannot stop concomitant antibiotics than cases in which we can."

This phase 3 trial was funded by Optimer Pharmaceuticals Inc. Dr. Cornely reports receiving funding from the Federal Ministry of Research and Education (BMBF 01KN1106, 01KN0706, 01GH1001E, 01EZ0931), the German Research Foundation, the German Center for Infectious Disease Research, the German José Carreras Leukaemia Foundation, and the European Organization for Research and Treatment of Cancer; and receiving research grants or being a speaker for Actelion, Astellas, Basilea, Bayer, F2G, Gilead, Menarini, MSD, Miltenyi, Novartis, Optimer, Pfizer, Quintiles, Viropharma. Dr. Lechner has disclosed no relevant financial relationships. Dr. Lodes reports receiving a travel grant from Astellas.

22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID): Poster 2289 and abstract O670. Presented April 3, 2012.