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Giving the rafamycin antibiotic rifaximin (Xifaxan, Salix) after standard antibiotics may reduce the recurrence of Clostridium difficile infection (CDI) by as much as half, according to a meta-analysis of two randomized controlled trials. Writing online in British researchers led by Robin C. Spiller, MD, MSc, of the University of Nottingham, reported an approximately 50% decrease in CDI recurrence based on the two data sets.

Although the RAPID (RifAximin for the Prevention of recurrence following standard treatment of Infection with Clostridium Difficile) trial was able to recruit only 151 of its target of 180 patients, the investigators found rifaximin promising for the roughly 25% of patients who will relapse after initial CDI treatment.

"This provides some evidence for its efficacy, but larger trials are needed before the true effect size can be accurately estimated," the team said.

The 23-hospital parallel-group trial followed 151 patients ages ≥18 years immediately after resolution of CDI with metronidazole or vancomycin. The mean age of the patients overall was about 72, 56% were women, and 99% were of white ethnicity. For 78% of patients, this was their first episode of CDI, while 13% had had a previous diagnosis.

Over the the time period of 2012-2016, participants received either rifaximin (n=77) at 400 mg three times a day for 2 weeks, which was reduced to 200 mg three times a day for a further 2 weeks, or an identical placebo (n=74). The primary endpoint was CDI recurrence within 12 weeks of entry.

The rifaximin arm had a slightly higher proportion of men, as well as of participants taking a proton pump inhibitor (reported to raise CDI risk), having a previous episode of CDI, and recruited outside of hospital. Just over a third were inpatients at the start of the treatment.

At final analysis, 18 of 61 participants (29.5%) on placebo had a recurrence of CDI within 12 weeks, compared with 11 of 69 participants (15.9%) on rifaximin, for a risk difference of –13.7%, with wide 95% confidence intervals of –28.1 to 0.7% (P=0.06) and a risk ratio 0.54 (95% CI 0.28-1.05). Relapses in the placebo arm tended to occur earlier in the study.

At 6 months, the percentage of participants with CDI recurrence remained smaller in the rifaximin group, but the magnitude of the difference in risk between the groups had diminished: 21.2% versus 32.8%, for a risk ratio of 0.65.

Nine deaths occurred in each of the two arms. There were 15 participants (22%) with at least one serious adverse event on placebo and 12 (16%) on rifaximin in the 28 days after randomization. None of these were related to trial treatment, suggesting that this drug is safe in a frail elderly population, the researchers said.

Several studies have shown that while active against pathogens, rifaximin has the advantage of not altering the diversity of which is important for conferring resistance to CDI, whereas mainstay antibiotics can protective gut flora.

The investigators then factored in data from a from the U.S. by Kevin Garey and colleagues, which studied 78 elderly patients, where the rifaximin dose was not tapered in the treatment arm. This study reported that CDI recurrence occurred in 11 of 35 patients (31%) given placebo and five of 33 (15%) given rifaximin (P = 0.11), for a risk reduction of 16% and an overall absolute risk reduction of 14% (95% CI –28 to –3%), P=0.01).

The authors wrote that despite wide confidence intervals in both studies, "combining the data increased confidence in a true difference in outcome, favoring rifaximin treatment."

The main limitation of the trial, the researchers said, was its inability to recruit the full patient sample, resulting in reduced precision of the estimated treatment effect.

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