rep-3123 and Enterocolitis--Pseudomembranous

Clostridium difficile infection (CDI) is associated with consumption of antibiotics which disrupt the normal microbial flora of the gut, allowing C. difficile to establish itself and produce disease. Currently, only vancomycin or metronidazole are recommended for treatment and many patients suffer from relapse on infection. Hence, there is a need for new treatment options.. This review evaluates five agents in development where the focus is on treatment of CDI.. This review gives up-to-date information on fidaxomicin, REP3123, oritavancin, NVB302 and nitazoxanide and their likelihood of being licensed for the treatment of CDI.. One agent, fidaxomicin, has undergone Phase III clinical trials which show it to be a promising new agent for the treatment of CDI with a low rate of relapse. Nitazoxanide is licensed for the treatment of parasitic intestinal infections but is not licensed for CDI. However, in small scale clinical trials it has been shown to have activity comparable to that of vancomycin and metronidazole. The other agents are all at early stages of development and clinical trials to evaluate their therapeutic potential for CDI have not yet been undertaken.

Topics: Aminoglycosides; Anti-Bacterial Agents; Benzopyrans; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Glycopeptides; Humans; Lipoglycopeptides; Nitro Compounds; Thiazoles; Thiophenes

REP3123 is a fully synthetic methionyl-tRNA synthetase inhibitor in pre-clinical development as a novel agent to treat Clostridium difficile infection (CDI). This novel agent was investigated for its ability to block the production of toxins and spores, and was tested for efficacy in vivo in a hamster model.. Clostridial toxin levels were determined qualitatively using monoclonal antibodies and by cytotoxicity assays. Spores were detected by staining and by quantitative dilution plating after ethanol treatment. Efficacy of REP3123 was tested in a clindamycin-induced C. difficile hamster gastrointestinal (GI) infection model.. REP3123 at concentrations as low as 1 mg/L inhibited de novo toxin production in high cell density, stationary phase cultures of C. difficile. Among comparator agents currently used for CDI therapy, vancomycin required much higher levels of 20 mg/L, and metronidazole had no effect on toxin levels. REP3123 caused a >10-fold reduction of the sporulation rate in vitro. Vancomycin and, in particular, metronidazole appeared to promote the formation of spores. REP3123, at concentrations as low as 0.5 mg/kg, demonstrated efficacy in the hamster model of CDI and was superior to vancomycin in the overall survival of the animals at the end of the study (33 days).. REP3123 inhibited growth of C. difficile, affected the production of toxins and spores and demonstrated superior efficacy compared with vancomycin in the hamster GI infection model. This agent may be a promising candidate for CDI treatment; in particular, the inhibition of toxin production and spore formation may reduce the severity and spread of the disease, respectively.

Topics: Animals; Anti-Bacterial Agents; Bacterial Toxins; Benzopyrans; Cell Line; Clostridioides difficile; Cricetinae; Enterocolitis, Pseudomembranous; Enzyme Inhibitors; Male; Spores, Bacterial; Survival Analysis; Thiophenes; Vancomycin