Treatment with high-dose VE303, a defined bacterial consortium composed of eight strains of commensal Clostridia, was associated with a significant reduction in antibiotic resistance genes (ARGs) among individuals with Clostridioides difficile infection(CDI), according to the phase II CONSORTIUM* study presented at IDWeek 2024.

“Repeated antibiotic treatment for recurrent CDI may promote colonization of antimicrobial resistant microbes, which can worsen CDI outcomes and increase the risk of drug-resistant infections,” said lead author Dr Rajita Menon from Vedanta Biosciences, Inc., Cambridge, Massachusetts, US.

Hence, the researchers conducted a double-blind, phase II trial to assess the presence of ARGs, after completion of standard-of-care antibiotic therapy, in 79 individuals (median age, 63.5 years, 70.5 percent female) diagnosed with laboratory-confirmed CDI. Participants were then randomized to receive oral VE303 (high dose [8 x 10⁹ CFUs**] or low dose [1.6 x 10⁹ CFUs]) once daily or placebo for 14 days.

The researchers found that the number of ARGs was significantly reduced in the high-dose VE303 group by day 14 (p<0.005), which was maintained through day 28 (p<0.0005). [IDWeek 2024, abstract 377]

However, no significant differences in ARG levels were observed between the low-dose VE303 and placebo groups.

Of note, there was a subset of ARGs that were strongly correlated with the phylum Pseudomonadota, previously known as proteobacteria, according to Menon. “This phylum includes a number of disease-causing pathobiont such as Klebsiella pneumoniae and E. coli, which are known to have mechanisms for antibiotic resistance,” she noted.

Interestingly, the relative abundance of the phylum Pseudomonadota decreased more rapidly in the high-dose VE303 group than in the low-dose VE303 or placebo groups,” said Menon.

In addition, the number of Pseudomonadota-related ARGs reduced significantly as early as day 7 among high-dose VE303 recipients and remained low throughout the first month after dosing. No significant differences were observed between low-dose VE303 and placebo recipients.

With regard to ARGs by colonization status, a high VE303 colonization (5?8 strains) was associated with reduced ARG levels compared with a low VE303 colonization (0?4 strains; p=0.003).

“VE303 strain colonization was negatively correlated with recurrence-associated Pseudomonadota, … and we also saw superior VE303 colonization and expedited microbiome recovery in the high-dose group,” Menon noted.

“Receipt of a higher dose significantly increased total VE303 strain colonization and participants with high VE303 colonization had a lower probability of CDI recurrence than those with low colonization, suggesting a positive-exposure relationship,” the researchers noted in a published paper. [JAMA 2023;329:1356-1366]

“[Overall, high-dose VE303 resulted in] significantly improved clinical response compared with placebo … This suggests that treatment with high-dose VE303 protects against recurrence in the context of CDI and may also reduce the pool of ARGs as well as the abundance and prevalence of antibiotic-resistant pathogens,” Menon concluded.

Furthermore, a global phase III study of VE303, RESTORATiVE303, is already underway, she highlighted.

*CONSORTIUM: Clinical research study for rCDI

**CFUs: Colony-forming units