Repurposing a Veterinary Antiprotozoal to Replace Metronidazole for C difficile

A veterinary antiprotozoal, ronidazole, has demonstrated promise for being repurposed to treat Clostridioides difficile in humans, in a study that suggests it could serve as a more potent and less toxic alternative to metronidazole, which is no longer recommended in treatment guidelines from the Infectious Diseases Society of America (IDSA).

The need for better treatments of C difficile is urgent, according to Mohamed Seleem, DVM, PhD and Ahmed AbdelKhalek, PhD, Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue Universiity, West Lafayette, IN.The co-authors of the study on the potential repurposing of ronidazole for this purpose note that C difficile infection (CDI) has been declared as an urgent threat requiring rapid action, by the U.S. Centers for Disease Control and Prevention (CDC).

"The recent escalation in the severity of CDI is mainly due to the emergence of hypervirulent C difficile strains," Seleem and AbdeKhalek observed."Hypervirulent strains produce more robust amounts of toxins at all growth phases."

Metronidazole was one of 3 antibiotics recommended for CDI by the IDSA, with vancomycin and fidaxomicin, but was removed from the IDSA guidelines for its inferiority to vancomycin. Seleem and AbdelKhalek note, however, that vancomycin is associated with an approximate 22% rate of failure and recurrence of infection.Although fidaxomicin has improved on that overall rate, they suggest that the improvement has not been demonstrated with hypervirulent strains.

The possibility of repurposing an existing drug has many advantages over developing a new compound, including the potential shorter time from identification to clinical trials.The investigators also note that possible candidates from veterinary medicine are often overlooked.

"There is so much potential in veterinary drugs for treatment of human diseases, that we encourage researchers to explore," Seleem commented to ContagionLive®.

Seleem and AbdelKhalek identified a number of nitroimidazole compounds which inhibited the growth of C difficile in vitro, and found that several, including ronidazole, were more potent than metronidazole.

"After the initial screening of almost all FDA approved drugs and veterinary drugs, we had several candidates to pursue further—and are still pursuing—but the interest in ronidazole was due to two things: potent activity and because it is a veterinary drug," Seleem commented.

The investigators reported that ronidazole inhibited the growth of clinical C difficile isolates at low concentration (0.125μg/mL) and showed superior killing kinetics compared to metrondiazole.In addition, ronidazole did not inhibit growth of several commensal organisms that, Seleem and AbdelKhalek point out, naturally present in the human intestine to play a protective role in preventing CDI.Further, they determined that ronidazole was non-toxic to human gut cells, and permeated a monolayer of colonic epithelial cells at a slower rate than metronidazole.

With the promising performance in vitro, they then evaluated ronidazole in vivo, in a mouse model with CDI at a test doses of 1mg and 10mg/kg/ day, compared to 1mg and 10mg/kg/day of metronidazole, and 10mg/kg/day of vancomycin.

"In our mouse study, ronidazole at 1mg/kg protected 60% of the mice, which was equivalent to the effect of metronidazole at 10mg/kg," Seleem recounted. "In contrast, all mice treated with 1mg/kg metronidazole died only 2 days post-infection.Also, ronidazole is less absorbed from the intestine and has faster bactericidal activity than metronidazole.All these features can contribute to efficacy at lower dose."

These promising results warrant further study, Seleem indicated."Since this is not an FDA approved drug, an extensive toxicity study needs to be performed to identify safety and maximum tolerated dose for this drug before moving to potential human application," he said.