Ridinilazole triggers sustained clinical response in CDI, inhibits infection recurrence

Tristan Manalac
27 Oct 2022
Ridinilazole triggers clinical response in CDI, inhibits recurrence

In patients with Clostridioides difficile infections (CDI), treatment with ridinilazole (RDZ) leads to high and sustained rates of clinical response, according to a study presented at the recently concluded Virtual ID Week 2022. Compared with vancomycin (VAN), RDZ also more strongly prevents recurrent CDI (rCDI).

Researchers conducted a global, double-blinded, and randomized phase III trial enrolling 759 patients, of whom 745 were included in the modified intention-to-treat analysis. RDZ was given as 200-mg twice-daily doses, while VAN was administered at 125 g every 6 hours.

The primary endpoint was sustained clinical response (SCR), defined as CR and the absence of rCDI through 30 days after the end of treatment.

Seventy-three percent of RDZ-treated patients achieved the primary outcome, while 70.7 percent did so in the VAN group. The difference was not statistically significant (p=0.4672). [IDWeek 2022, abstract 730]

However, looking at the individual components of SCR, the researchers found that RDZ was significantly protective against recurrence, yielding a rate that was less than half of that in VAN comparators (8.1 percent vs 17.3 percent; p=0.0002). This effect was more pronounced in the subgroup of patients not taking other antibiotics (6.7 percent in RDZ vs 16.5 percent in VAN; p=0.0005).

Easy on the gut microbiome

According to the researchers, VAN is a treatment proven to be effective for CDI, commonly reaching >80 percent clinical response. However, rate of infection recurrence remains high after VAN at around 20 percent to 30 percent. One potential reason for this is that VAN is a nonselective antibiotic, which also affects other organisms in the microbiome, leading to intestinal dysbiosis.

Several species of gut microbes convert primary bile acids to secondary bile acids, which in turn exert inhibiting effects against C. difficile germination. RDZ is being developed as a highly selective and DNA-binding antibiotic. To evaluate these properties, the researchers set key microbiome parameters, such as diversity, composition, and secondary bile acid levels, as secondary endpoints.

Their analysis showed that immediately at end of treatment RDZ-treated patients showed significantly higher alpha diversity than VAN comparators (p<0.0001). This effect remained significant until 30 days after treatment completion (p≤0.0007).

Relative abundances of major microbial phyla were also significantly better in the RDZ arm. At the end of treatment, VAN contributed to a strong disruption of microbial profile, leading to a larger relative abundance of Proteobacteria and Firmicutes, while nearly eliminating all Bacteroidetes species.

In the RDZ group, the Bacteroidetes phylum retained a 31-percent relative abundance at the end-of-treatment assessment.

Relative abundance rebounded in both groups by 40 days after the end of treatment but remained numerically better in the RDZ arm. The levels of secondary bile acids were also significantly higher in the RDZ arm both at end of treatment (p<0.0001) and 40 days later (p=0.0006).

The researchers also found that higher microbiome diversity was significantly correlated with higher SCR and lower rCDI. The same was true for higher concentrations of secondary bile acids.

In terms of safety, treatment-emergent adverse events arose in 36.4 percent of RDZ patients and 35.5 percent of VAN patients. Only 0.8 percent of the RDZ arm discontinued due to toxicities, as opposed to 2.9 percent in VAN comparators.

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