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REP3123 may be efficacious against C. difficile
Narrow spectrum antibacterial candidate REP3123 inhibited growth and prevented spore-forming of Clostridium difficile without inhibiting necessary intestinal organisms, according to a recent study.
REP3123 (Replidyne) was superior to vancomycin and metronidazole, two agents that are widely-used to treat C. difficile. REP3123 had greater potency in preventing spore formation than these two lead agents.
In another study, REP3123 was shown to inhibit the exotoxin production of C. difficile, which is key to relapse prevention and infection control. Exotoxin production is also of concern in the emergence of a hypervirulent C. difficile PCR ribotype 027epidemic. REP3123 destroys the toxinogenic phenotype, thereby reducing C. difficile’s pathogenicity.
The new agent could reduce the spore in the intestine, thus preventing further transmission in the environment and preventing outbreaks. It prevents growth in vitro by inhibiting the methionyl tRNA synthetase, the cell C. difficile uses to synthesize proteins. Methionyl tRNA is a novel target not previously used in antibiotics. It also showed no cross-resistance to other antibacterials.
Study results on spore growth were presented by Ian A. Critchley, PhD, executive director of microbiology at Replidyne, at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, held in September in Chicago.
Urs Ochsner, PhD, principal scientist in microbiology at Replidyne, presented the study on REP3123’s ability to inhibit C. difficile toxin production versus vancomycin and metronidazole.
REP3123 is not yet FDA approved.
Spores grown
Four clinical isolates, including two epidemic C. difficile strains from Quebec, were studied. The outbreak strains were selected because they produced greater toxin amounts, had increased sporulation capacity and caused severe disease with increased morbidity and mortality.
Strains were grown in the presence of minimum inhibitory concentrations (MICs) of either REP3123, vancomycin or metronidazole. Spore growth was examined 96 hours post drug exposure. Spores were quantified in parallel by treating cell suspensions with ethanol for one hour prior to staining.
In a second study, toxinogenic C. difficile strains, including a tcdC variant strain were grown anaerobically to determine REP123 and control agent’s effects on growth and toxin production.
Two potent exotoxins, TcdA (enterotoxin) and TcdB (cytotoxin) produced by C. difficile were detected in cultures using monoclonal antibodies and by cytotoxicity assays.
Agent decreased growth
REP3123 was the most effective agent at preventing the production of spores in all strains at 0.5 times the MIC. Sub-MICs of metronidazole promoted spore formation in three strains and vancomycin promoted sporulation in two strains.
No spores were detected at 0.05 times the MIC concentration with REP3123, which shows the agent’s ability to inhibit sporulation is concentration-dependent.
All four strains varied in their ability to produce spores under study conditions. Spores of two strains of C. difficile were detected in non-treated control cells and on media containing vancomycin and metronidazole at 0.5 times MIC; 96 hours post exposure, more than 90% of the recovered organisms were present as spores. On media containing REP3123, a significant reduction in spores was detected at 0.25 times MIC to 0.5 times MIC as less than 5% of organisms were recovered as spores post exposure.
In the second study, REP3123, vancomycin and metronidazole inhibited growth and toxin production in fresh C. difficile cultures with an inoculum of 105 CFU/mL. Stationary phase cultures of C. difficile grown for four to seven days without an antibacterial agent produced up to 25 mcg/mL of toxins.
In concentrations as low as 0.12 mcg/mL, REP3123 reduced de novo toxin production as much as 100-fold. Vancomycin and metronidazole did not reduce toxin production in stationary phase cells compared to drug-free control culture even when the concentration was above their MICs. – by Kirsten H. Ellis
For more information:
- Young CL, Hoang T, Critchley IA, Janjic N. REP3123: A narrow spectrum antibacterial agent that inhibits growth and prevents sporulation in Clostridium difficile. #229.
- Ochsner UA, Stone K, Hoang T, et al; REP3123 Inhibits toxin production in C. difficile. #229.
- Both presented at: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-20, 2007; Chicago.