Frontiers in antibiotic alternatives for Clostridioides difficile infection

Table 1 Representatives of anti-Clostridioides difficile chemical clusters from reported literature

Cluster No.	Compound class
21	Antifungal imidazoles
42	Metronidazole and its derivatives
61	Benzalkonium cationic surfactants
88–97	β-lactams
98–99	Tetracycline and its derivatives
123	Aminoglycosides

Table 2 Recent clinical trials examining potential fecal microbiota transplantation for treatment of Clostridioides difficile infection

Current phase	Title	ClinicalTrials.gov Identifier	First posted
NA	Fecal microbiota transplantation for C. difficile infection	NCT01905709	July 23, 2013
	Immune response to FMT for C. difficile	NCT02797288	June 13, 2016
	Outcomes and data collection for fecal microbiota transplantation for the treatment of recurrent C. difficile	NCT03562741	June 19, 2018
	Fecal microbiota transplantation (FMT) for C. difficile (CEFTA)	NCT03712722	October 1, 2018
	Rescue fecal microbiota transplantation for national refractory intestinal infection	NCT03895593	March 29, 2019
	Safety and efficacy of fecal microbiota transplantation	NCT04014413	July 10, 2019
1	Fecal transplant for pediatric patients who have recurrent C. difficile infection (FMT)	NCT02134392	May 9, 2014
2	Stool transplants to treat refractory C. difficile	NCT02127398	April 30, 2014
	FMT versus antimicrobials for initial treatment of recurrent CDI	NCT02255305	October 2, 2014
	Fecal microbiota therapy for recurrent C. difficile infection	NCT02686645	February 19, 2016
	Phase II trial of fecal microbiota transplant (FMT) for VRE and CRE patients	NCT03643887	August 23, 2018
	Fecal microbiota transplantation (FMT) plus fidaxomicin for severe of fulminant C. difficile	NCT03760484	November 30, 2018
	Multicentre blinded comparison of lyophilized sterile fecal filtrate to lyophilized fecal microbiota transplant in recurrent C. difficile infection	NCT03806803	January 16, 2019
	FMT and bezltoxumab compared to FMT and placebo for patients with IBD and CDI (ICON-2)	NCT03829475	February 4, 2019
	PMT for severe-CDI	NCT03970200	May 31, 2019
	Penn microbiome therapy (PMT) for recurrent C. difficile infection	NCT03973697	June 4, 2019
3	Fecal transplantation for primary C. difficile infection (COLONIZE)	NCT03796650	January 8, 2019
	Microbiota restoration therapy for recurrent C. difficile infection (PUNCH CD3-OLS) (CD3-OLS)	NCT03931941	April 30, 2019
	Fecal microbiota transplantation for primary C. difficile diarrhea	NCT02801656	June 16, 2016

FMT: Fecal microbiota transplantation; C. difficile: Clostridioides difficile; PMT: Penn microbiome therapy.

Table 3 Key experiments in bacteriophage for Clostridioides difficile infection treatment

Phage	Experiment	Finding	Ref.
phiCD140	A single dose of phage treatment for C. difficile infection in hamsters	Surviving of phage treated hamster	[135]
phiCD27	Phage treatment of CDI in an in vitro batch fermentation and human colon model	(1) Reduction of both vegetative cell and toxin A and toxin B productions from C. difficile; and (2) No impact on others gut microbes	[135]
phiCDHM1 to phiCDHM6, and phiCDHS1	(1) Investigation for an effective phage combination; and (2) Phage delivered orally in hamster model every 8 h after C. difficile challenge	(1) Discovery of phage-resistant colonies after a single phage treatment; and (2) Reduction of C. difficile amount and colonization using phage combination in vivo	[124]
phiCDHM1, 2, 5, and 6	(1) Phage treatment before and after the biofilm formation; (2) First time using Galleria mellonella (wax moth) model for C. difficile phage; and (3) Using phage in combination with antibiotics (vancomycin)	(1) Reduction and prevention of the biofilm establishment in vitro; and (2) Disease prevention in the prophylaxis group and increasing the wax moth survival rates	[130]
phiCDHM1, 2, 5, and 6	(1) Optimized temperate phage cocktail to treat in batch fermentation model; and (2) First metagenomic analysis of phage treatment on gut microbiome	(1) C. difficile elimination after 24 h in prophylactic condition while maintain other microbiota components; and (2) No significant impact on other bacterial groups in human gut	[127]
phiCDHS1	Measurement of planktonic and adhered C. difficile cells and free phage to human colon tumorigenic cell line HT-29	(1) Reduction of planktonic and adhered C. difficile; and (2) No cytotoxicity to human cells	[129]
phiCD24-2	(1) Using engineered phage delivered Type 1-B CRISPR system as antimicrobial agent in vitro and in vivo; and (2) Mutation of phage lysogenic gene by the cI repressor and integrase gene deletion	(1) C. difficile eradication effectively in engineered phage comparing with wild-type phage; and (2) Detection of lysogen due to potentially functional complements from C. difficile prophage	[125]

C. difficile: Clostridioides difficile.