Intravenous tigecycline has been reported as an effective treatment for severe CDI in one small series (4 patients) and one case report. Tigecycline was used as adjunctive treatment for these patients who had failed to respond to metronidazole and vancomycin, or, in one case, tigecycline was used as primary treatment. Fecal concentrations of tigecycline may be higher than those of metronidazole when given intravenously, and establishment of tigecycline efficacy in well‐designed trials would be a welcome advance in treatment of severe CDI.
Among the experimental agents being developed for treatment of CDI, fidaxomicin has the most clinical data. It is a member of a new class of macrocycle antibiotics that targets bacterial RNA polymerase, shows no cross‐resistance with other antibiotics, and is highly active against C. difficile and other clostridia. A phase 2 dose‐ranging study of fidaxomicin for treatment of CDI showed low plasma concentrations but fecal concentrations that exceeded the MIC90 by 2000–10,000‐fold. Sequential, semiquantitative stool cultures for a cohort of patients treated with fidaxomicin, compared with a control group treated with vancomycin, showed that both drugs decreased C. difficile counts from a mean (± standard deviation) of log10 colony‐forming units (cfu)/g at the start of treatment to <102 cfu/g in the majority of patients after 10 days of treatment. In contrast, there was no decrease in Bacteroides group counts with fidaxomicin treatment, whereas the Bacteroides group counts decreased by almost 3 logs in patients treated with vancomycin. These data demonstrate that fidaxomicin is less active against one element of the normal microbiota and may help to explain the lower CDI recurrence rates after fidaxomicin treatment. Two large, phase 3, randomized, placebo‐controlled, double‐blinded trials comparing fidaxomicin with vancomycin have been completed, including >1000 patients with CDI from North America and Europe. Interim analysis of the phase 3 studies showed that fidaxomicin is not inferior to vancomycin for the primary end point of response to therapy and has a significantly lower recurrence rate. Other preliminary findings suggest that concomitant antibiotic administration for systemic infection increases the recurrence rate and that infection with the epidemic BI /NAP1/027 strain significantly lowers the initial cure rates regardless of treatment agent. Lower cure rates were also predicted by advanced patient age, low serum albumin level, and elevated white blood cell count or fever.
Ramoplanin is a glycolipodepsipeptide that is active against vancomycin‐resistant enterococci as well as C. difficile. Ramoplanin was shown to inhibit C. difficile spore formation in vitro in a chemostat model of the human gut and in vivo in clindamycin‐treated hamsters, compared with vancomycin. Preliminary results of a phase 2 clinical study that compared ramoplanin at 2 doses and oral vancomycin showed comparable cure rates for ramoplanin at 200 mg twice a day, ramoplanin at 400 mg twice a day, and vancomycin at 125 mg 4 times a day (79%, 86%, and 86%, respectively), although the study was small (<30 patients per group). At the end of treatment, ramoplanin‐treated patients were less likely to have enterococci recovered from their stools, and those with positive cultures had enterococci counts that were several logs lower than those of the vancomycin‐treated patients. Recurrence rates were similar for the 3 treatment groups (22.7%, 20%, and 20%, respectively).