Investigational Treatment Agents for Recurrent Clostridioides difficile Infection (rCDI)

Abstract

Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea that is deemed a global health threat. C. difficile strain BI/NAP1/027 has contributed to the increase in the mortality, severity of CDI outbreaks and recurrence rates (rCDI). Updated CDI treatment guidelines suggest vancomycin and fidaxomicin as initial first-line therapies that have initial clinical cure rates of over 80%. Unacceptably high recurrence rates of 15–30% in patients for the first episode and 40% for the second recurrent episode are reported. Alternative treatments for rCDI include fecal microbiota transplant and a human monoclonal antibody, bezlotoxumab, that can be used in patients with high risk of rCDI. Various emerging potential therapies with narrow spectrum of activity and little systemic absorption that are in development include 1) Ibezapolstat (formerly ACX-362E), MGB-BP-3, and DS-2969b-targeting bacterial DNA replication, 2) CRS3213 (REP3123)-inhibiting toxin production and spore formation, 3) ramizol and ramoplanin-affecting bacterial cell wall, 4) LFF-571-blocking protein synthesis, 5) Alanyl-L-Glutamine (alanylglutamine)-inhibiting damage caused by C. difficile by protecting intestinal mucosa, and 6) DNV3837 (MCB3681)-prodrug consisting of an oxazolidinone–quinolone combination that converts to the active form DNV3681 that has activity in vitro against C. difficile. This review article provides an overview of these developing drugs that can have potential role in the treatment of rCDI and in lowering recurrence rates.

Keywords:

• Clostridioides difficile
• CDI
• C. difficile
• C. difficile infection
• investigational drugs

Disclosure

RK serves on the Advisory Board for BioK+. EJCG has served on Advisory boards for Acuryx Inc, Merck & Co, Bayer Pharmaceuticals, BioK+, Sanofi-Adventis, Summit Corp. plc, Cutis Pharmaceuticals, Kindred Healthcare Corp., Novartis, Sankyo-Daichi, Paratek Pharma, and Shionogi Inc. EJCG has also been on the Speakers’ bureau for Bayer Inc., Merck & Co, Medicines Co., Allergan Inc and has received research grants from Bayer Inc., Cutis Pharmaceuticals, Entasis Therapeutics, Merck & Co., Micromyx LLC, Parateck Pharmaceuticals, Spero Therapeutics, Tetraphase Inc. The authors report no other conflicts of interest in this work.