Table 3.

Novel therapies: usage, availability, and effectiveness

Agent #		Class	Administration	USA Availability	Effectiveness
	NEW ANTIMICROBIALS
1	Rifaximin	Rifamycin	400 mg orally twice daily for 14 days or three times daily for 20 days following standard therapy	Xifaxan (Salix) Additional clinical trials needed	A retrospective study showed effectiveness 126. Chaser treatment after vancomycin could be effective for recurrence123–125.
2	Nitazoxanide	Thiazolide	500 mg orally twice daily for 10 days	Alinia (Romark) Additional clinical trials needed	A randomized clinical trial in PCDI patients showed similar symptomatic cure and recurrence rates versus vancomycin 138.
3	Cadazolid	Oxazolidone	N/A	Former ACT-179811 (Actelion) RCT phase 3 NCT01983683 RCT phase 3 NCT01987895	A phase 2 study has shown efficacy and tolerability in CDI patients; rates of recurrence were numerically lower versus vancomycin 140.
4	CB-183,315	Cyclic lipopeptide	N/A	Surotomycin (Cubist) RCT phase 3 NCT01597505 RCT phase 3 NCT01598311	A small phase 2 clinical trial showed similar efficacy to vancomycin but also showed lower relapse rates 145.
5	Tigecycline	Glycylcycline	50 mg IV twice daily after a loading dose of 100 mg	Tygacil (Pfizer-Wyeth) No active clinical trials	Some success in severe or refractory cases 146, 147. A phase 3 study was recently completed; data pending (NCT01401023). FDA warning regarding increased risk of mortality associated with tigecycline.
6	Teicoplanin	Glycopeptide	100 mg orally twice daily	Limited use in US	Cochrane review found that oral teicoplanin was superior to vancomycin for bacteriologic cure following PCDI 110. Data regarding efficacy in treating recurrences is lacking.
7	Ramoplanin	Lipoglycodepsipeptide	N/A	(Nanotherapeutics) No active clinical trials	Showed efficacy against CDI in phase 2 studies 151.
8	LFF571	Thiopeptide	N/A	(Novartis) No active clinical trials	A randomized, double-blind, placebo- controlled study showed that the drug is well tolerated 154. A phase 2 safety and efficacy study was recently completed; results pending (NCT01232595).
	BIOTHERAPY
9	S. Boulardii	Probiotic	3 x 1010 colony- forming units orally once per day	Multiple products, alone or in combination	Effective at preventing second recurrences as an adjunctive therapy to standard vancomycin or metronidazole therapy 19.
10	Lactobacilus GG	Probiotic	2.8x1011 colony- forming units orally once per day	Multiple products, alone or in combination	No statistically significant clinical benefit; not effective at preventing recurrences 157, 158.
11	L. plantarum	Probiotic	5x1010 colony- forming units orally once per day	Multiple products, alone or in combination	Apparently not effective at preventing recurrence; sample size too small for statistical comparisons 158, 159.
12	VP20621	Non-toxigenic C. difficile	N/A	VP20621 (Shire) No active clinical trials	A recent phase 2 trial demonstrated favorable tolerability and lower rates of recurrence versus placebo (NCT01259726) 160.
13	Fecal Microbiota Transplant	Microbiota	Duodenal infusion Retention enema Colonoscopy	Local compounding Fecal banks Several active studies	A small randomized clinical trial 131 and meta-analyses 161 show benefit in the treatment of recurrent CDI.
14	Microbiota Suspension	Microbiota	Retention enema	RBX2660 (Rebiotix) No active clinical trials	A phase 2 trial was recently completed demonstrating 87.1% efficacy; the retention enema was well-tolerated (NCT01925417).
15	Rectal Bacteriotherapy	Microbiota	Variable	Local research compounding (University of Copenhagen, Copenhagen, Denmark/Skaraborgs Hospital Skövde, Sweden) Additional clinical trials needed	Two small studies using a mixture of 10 intestinal bacterial species via enema demonstrated success 162, 163.
16	Bacterial Sediment	Microbiota	Oral fecal microbial capsules	Local research compounding (University of Calgary, AB, Canada) Additional clinical trials needed	A case-series of 27 patients administered the oral fecal microbial capsules observed arrested RCDI in all 27 patients 164.
17	Frozen Fecal Microbiota Transplant	Microbiota	Oral capsulized frozen fecal microbiota	Local research compounding (Openbiome) Additional clinical trials needed	A small open-label single-group study observed diarrhea resolution among 18/20 (90%) patients treated with frozen FMT. No serious adverse events were observed 165.
18	Bacterial spore therapy	Microbiota	Oral capsulized fecal bacterial spores	SER-109 (Seres Health) No active clinical trials; a phase 3 trial is upcoming	A small single-arm open label phase 1/2 study saw clinical cure among 29/30 (96.7%) RCDI patients treated with SER-109. No serious adverse events were observed 166.
	IMMUNOTHERAPY
19	Anti-toxin A and anti-toxin B human monoclonal antibodies	Intravenous anti-toxin	N/A	Actoxumab/bezlotoxumab (Merck) RCT phase 3 NCT01513239 RCT phase 3 NCT01241552	A phase 2 randomized, double-blind, placebo-controlled study showed lower recurrences among patients treated with these antibodies plus standard-of-care treatment, including infections due to BI/NAP/027 strain 167. Two phase 3 studies are ongoing.
20	C. difficile immune whey	Oral immunoglobulin	200 ml orally three times daily	(Novatreat) No new studies done	An open-label study showed efficacy 168. A randomized, double-blind study showed similar efficacy between CDIW and oral metronidazole 169.
21	Highly purified toxoid A and B	Toxoid vaccine	N/A	ACAM-Cdiff (Acambis/Sanofi Pasteur) RCT phase 3 NCT01887912	Purified toxoid A and B were tolerated and elicited good response among healthy adults 170. An open-label study 171 and a phase 1 randomized clinical trial 172 with highly purified toxoid showed good seroconversion rates.
22	Genetically modified full-length TcdA and B	Toxoid vaccine	N/A	(Pfizer) RCT phase 1 NCT02052726 RCT phase 2 NCT02117570	Genetically modified toxins in non- sporulating C. difficile strains 173. A phase 1 study (NCT01706367) has been completed but results are not yet available.
23	IC84 recombinant fusion protein	Recombinant vaccine	N/A	(Valneva) No active clinical trials	C-terminal receptor binding domains of TcdA and TcdB incorporated into a recombinant fusion protein 174 have shown to be safe and tolerable, and induced antibodies against TcdA and B in a phase 1 study (NCT01296386).
	OTHER APPROACHES
24	Cholestyramine/Colestipol	Toxin binding polymer	4 g orally once daily started during the last 2 weeks of tapered- pulsed vancomycin regimen	No new studies done	A small uncontrolled case series found colestipol successful in treating RCDI when used as an adjunctive therapy following tapered/pulsed vancomycin 175.
25	Synsorb 90	Toxin binding polymer	N/A	(Synsorb Biotech) Development halted	No clear benefit in phase 2 studies 176.
26	Tolevamer	Toxin binding polymer	9 g (loading dose) followed by 3 g every 8 hours for 14 days	Exodif, GT267-004 (Genzyme) Development halted	Two randomized phase 3 trials showed that tolevamer was inferior to metronidazole or vancomycin 113, 176.