Harmful combination therapy with rifampicin and metronidazole for diarrhea caused by Clostridium difficile

To date, the results of randomized trials evaluating the efficacy of the treatment of diarrhea caused by Clostridium difficile, rifampicin in combination with metronidazole have not been published. Rifampicin has excellent activity in vitro against C. difficile and enters cells where microorganisms can persist. In this regard, a prospective randomized blind study was conducted in 39 patients, who compared metronidazole treatment and metronidazole treatment in combination with rifampicin for 10 days with a first confirmed episode of diarrhea caused by C. difficult. An analysis was carried out in a population of patients to be treated.

Metronidazole monotherapy received 12 patients and the combined treatment - 19. The 10-day combination therapy and the 10-day metronidazole monotherapy were characterized at the same time until symptoms improved (9.0 vs 6.5 days; p = 0.74), the time to the first relapse (26 vs 16 days; p = 0.23), the rate relapse on day 40 of the study (42% vs 38%; p = 1.0) and the incidence of non-fatal adverse events (37% vs 40 %; p = 0.55). During the 10-day therapy, 2 out of 19 patients in the combination therapy group and not a single patient in the comparison group died. A significantly higher number of deaths were observed in the combination treatment group with metronidazole and rifampicin compared to the monotherapy group with metronidazole (6 patients out of 19 vs 1 patient out of 20; p = 0.04), but fewer laboratory-confirmed results relapse on day 40 of the study (2 vs 4; p = 0.66).

The study was terminated prematurely because an interim analysis showed a very low probability of success and the potential harmful effects of a combination therapy, including rifampicin.

Therefore, in the treatment of hospital patients with diarrhea caused by C.difficile, metronidazole and rifampicin should not be combined. The recovery rate during treatment with metronidazole and a combination of metronidazole and rifampicin remains unacceptably low, and mortality with this combination is higher than with monotherapy.