Abstract
In the past decade Clostridium difficile has become a bacterial pathogen of global significance. Epidemic strains have spread throughout hospitals, while community acquired infections and other sources ensure a constant inoculation of spores into hospitals. In response to the increasing medical burden, a new C. difficile antibiotic, fidaxomicin, was approved in 2011 for the treatment of C. difficile-associated diarrhea. Rudimentary fecal transplants are also being trialed as effective treatments. Despite these advances, therapies that are more effective against C. difficile spores and less damaging to the resident gastrointestinal microbiome and that reduce recurrent disease are still desperately needed. However, bringing a new treatment for C. difficile infection to market involves particular challenges. This review covers the current drug discovery pipeline, including both small molecule and biologic therapies, and highlights the challenges associated with in vitro and in vivo models of C. difficile infection for drug screening and lead optimization.
Highlights
Stable to passage through the stomach and small intestine, are desirable to maintain high concentrations of antibiotic at the site of infection, minimizing systemic toxicity and reducing the possibility of treatment failure due to minimal inhibition concentration (MIC) creep associated with antimicrobial resistance
Other nonantibiotic treatment approaches such as vaccines and monoclonal antibiotics in clinical trials offer hope for another strategy to combat C. dif f icile infection (CDI) and if successful could change the landscape of C. dif f icile research and development
The growing understanding of the complex gut microbe interactions and identification of which bacterial populations need to be maintained for good health will influence the development of new drugs
Summary
The first line treatment for C. dif f icile infection is antibiotics, either metronidazole 1 for mild to moderate infection or oral vancomycin 2 for moderate to severe infection (Figure 1) Both of these drugs are generic and have been on the market for over 40 years.[11,12] in 14−27% of cases they do not effectively treat the infection or prevent relapsing infection.[13] Rifaximin 3 is sometimes used as a “chaser therapy”, following initial treatment.[14] Fidaxomicin 4 (Figure 1) is the first new drug on the market designed to treat C. dif f icile and has been available since 2011. Continued investment into the development of new antimicrobials is important to mitigate the potential for development and spread of resistance to the current arsenal of antibiotics
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