Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2021; 27(42): 7210-7232
Published online Nov 14, 2021. doi: 10.3748/wjg.v27.i42.7210
Frontiers in antibiotic alternatives for Clostridioides difficile infection
Matthew Phanchana, Phurt Harnvoravongchai, Supapit Wongkuna, Tanaporn Phetruen, Wichuda Phothichaisri, Supakan Panturat, Methinee Pipatthana, Sitthivut Charoensutthivarakul, Surang Chankhamhaengdecha, Tavan Janvilisri
Matthew Phanchana, Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
Phurt Harnvoravongchai, Surang Chankhamhaengdecha, Department of Biology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Supapit Wongkuna, Tanaporn Phetruen, Wichuda Phothichaisri, Supakan Panturat, Methinee Pipatthana, Tavan Janvilisri, Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Sitthivut Charoensutthivarakul, School of Bioinnovation and Bio-based Product Intelligence, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Author contributions: Phanchana M and Janvilisri T conceptualized and conceived the idea; all authors have been involved equally and have read and approved the final manuscript; Janvilisri T supervised the project.
Supported by Research Cluster (Multi-generation Researchers) Grant, Mahidol University, No. MRC-MGR 02/2563.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Tavan Janvilisri, PhD, Professor, Department of Biochemistry, Faculty of Science, Mahidol University, 272 Rama VI Road, Thung Phayathai, Ratchathewi, Bangkok 10400, Thailand.
Received: March 21, 2021
Peer-review started: March 21, 2021
First decision: April 30, 2021
Revised: May 12, 2021
Accepted: October 25, 2021
Article in press: October 25, 2021
Published online: November 14, 2021

Clostridioides difficile (C. difficile) is a gram-positive, anaerobic spore-forming bacterium and a major cause of antibiotic-associated diarrhea. Humans are naturally resistant to C. difficile infection (CDI) owing to the protection provided by healthy gut microbiota. When the gut microbiota is disturbed, C. difficile can colonize, produce toxins, and manifest clinical symptoms, ranging from asymptomatic diarrhea and colitis to death. Despite the steady-if not rising-prevalence of CDI, it will certainly become more problematic in a world of antibiotic overuse and the post-antibiotic era. C. difficile is naturally resistant to most of the currently used antibiotics as it uses multiple resistance mechanisms. Therefore, current CDI treatment regimens are extremely limited to only a few antibiotics, which include vancomycin, fidaxomicin, and metronidazole. Therefore, one of the main challenges experienced by the scientific community is the development of alternative approaches to control and treat CDI. In this Frontier article, we collectively summarize recent advances in alternative treatment approaches for CDI. Over the past few years, several studies have reported on natural product-derived compounds, drug repurposing, high-throughput library screening, phage therapy, and fecal microbiota transplantation. We also include an update on vaccine development, pre- and pro-biotics for CDI, and toxin antidote approaches. These measures tackle CDI at every stage of disease pathology via multiple mechanisms. We also discuss the gaps and concerns in these developments. The next epidemic of CDI is not a matter of if but a matter of when. Therefore, being well-equipped with a collection of alternative therapeutics is necessary and should be prioritized.

Keywords: Bacteriophage, Pharmaceutical, Clostridioides difficile, Alternative therapy, Drug resistance, Fecal microbiota

Core Tip: Clostridioides difficile is considered a threat to public health owing to increases in treatment failure over the past few years. Current antibiotic treatment options are highly limited. Therefore, alternative strategies are critical. Herein, we review recent advances in alternative therapeutics, including the development of new chemical entities, fecal microbiota transplantation, pre- and pro-biotic, antitoxin antibodies, use of bacteriophages, and vaccines. We also highlight the concerns, limitations, and directions for each of these developments.