Novel Antimicrobials for the Treatment of Clostridium difficile Infection

Abstract

The current picture of Clostridium difficile infection (CDI) is alarming with a mortality rate ranging between 3% and 15% and a CDI recurrence rate ranging from 12% to 40%. Despite the great efforts made over the past 10 years to face the CDI burden, there are still gray areas in our knowledge on CDI management. The traditional anti-CDI antimicrobials are not always adequate in addressing the current needs in CDI management. The aim of our review is to give an update on novel antimicrobials for the treatment of CDI, considering the currently available evidences on their efficacy, safety, molecular mechanism of action, and their probability to be successfully introduced into the clinical practice in the near future. We identified, through a PubMed search, 16 novel antimicrobial molecules under study for CDI treatment: cadazolid, surotomycin, ridinilazole, LFF571, ramoplanin, CRS3123, fusidic acid, nitazoxanide, rifampin, rifaximin, tigecycline, auranofin, NVB302, thuricin CD, lacticin 3147, and acyldepsipeptide antimicrobials. In comparison with the traditional anti-CDI antimicrobial treatment, some of the novel antimicrobials reviewed in this study offer several advantages, i.e., the favorable pharmacokinetic and pharmacodynamic profile, the narrow-spectrum activity against CD that implicates a low impact on the gut microbiota composition, the inhibitory activity on CD sporulation and toxins production. Among these novel antimicrobials, the most active compounds in reducing spore production are cadazolid, ridinilazole, CRS3123, ramoplanin and, potentially, the acyldepsipeptide antimicrobials. These antimicrobials may potentially reduce CD environment spread and persistence, thus reducing CDI healthcare-associated acquisition. However, some of them, i.e., surotomycin, fusidic acid, etc., will not be available due to lack of superiority versus standard of treatment. The most CD narrow-spectrum novel antimicrobials that allow to preserve microbiota integrity are cadazolid, ridinilazole, auranofin, and thuricin CD. In conclusion, the novel antimicrobial molecules under development for CDI have promising key features and advancements in comparison to the traditional anti-CDI antimicrobials. In the near future, some of these new molecules might be effective alternatives to fight CDI.

A New Thiopeptide Antibiotic, Micrococcin P3, from a Marine-Derived Strain of the Bacterium Bacillus stratosphericus

“…A phase II trial, started in 2015, showed higher clinical response rates than vancomycin. However, higher recurrence rates than vancomycin were also reported [ 21 ]. Thus, LFF571 was unfortunately discontinued from clinical development for CDI in 2019.…”

Treatment Options for Colistin Resistant Klebsiella pneumoniae: Present and Future

“…In order to mitigate these risks, meticulous donor screening has been adopted so far, including the check for the absence of viruses and other pathogens in the donor microbiota. At present, live microbiota preparations are in development to obtain the beneficial effect of FMT with a more controlled and regulated product [150].…”

Current landscape in the discovery of novel antibacterial agents

“…Most of the AMPs that continue in clinical trials are for topical use. The following examples represent promising AMPs that have undergone clinical trials with different applications: OP-145 completed Phase II [40,[42][43][44], two AMPs targeting C. difficile, surotomycin which was discontinued after two Phase III studies [45][46][47] and NVB-302, has completed Phase I [40,[48][49][50].…”