Updated Evidence for Optimal Management of C. diff Infection

BY MARK H. WILCOX, MD, FRCPATH

Evidence continues to accumulate on the increased relative efficacy of some therapies for Clostridioides difficile infection (CDI), especially with respect to the prevention of recurrent infection.

There are 4 agents approved for managing CDI: 2 older antibiotics, metronidazole and vancomycin, and 2 newer options, the antibiotic fidaxomicin ( Dificid, Merck) and a newer monoclonal antibody against toxin B, 1 of the 2 major C. difficile toxins (bezlotoxumab [Zinplava, Merck]). Four additional agents are in phase 1 to 3 clinical trials.

Bezlotoxumab is given along with one of the standard-of-care antibiotics to reduce the risk for CDI recurrence by augmenting the host endogenous antibody response against C. difficile toxin B. The antibiotics aim to stop C. difficile growth and, thus, toxin production. However, the other crucial issues are whether C. difficile persists in the gut as spores, with the potential to germinate once antibiotic administration has stopped, and the extent of microbiome disturbance that the CDI therapeutic causes on top of the existing dysbiosis. Together, these issues determine the effectiveness of the therapeutic to achieve clinical cure and prevent infection recrudescence (recurrent CDI).

We know that metronidazole, until recently the most common option for treating CDI, is inferior to vancomycin (and almost certainly to fidaxomicin).1-3 Thus, guidelines increasingly advocate the use of vancomycin (or fidaxomicin) rather than metronidazole, especially for the treatment of non-mild cases of CDI.4 Notably, however, fidaxomicin and bezlotoxumab have been shown convincingly to reduce the risk for recurrent CDI by 40% to 50% compared with vancomycin alone.5-7 This review

focuses primarily on emerging evidence that under- particularly effective at reducing the risk for recurscores the efficacy of the newer CDI treatment rent CDI. First, in both fecal samples from human options, summarizes the new agents undergoing volunteers and gut model contents, fidaxomicin clinical trials (phase 2 or beyond), and highlights a can be detected well beyond the cessation of dosnew focused update of the recently published CDI ing (2-3 weeks), at levels well in excess of the minguideline from the Infectious Diseases Society of imum inhibitory concentration of fidaxomicin for America. C. difficile. 11,12 So, extended dosage regimens likely result in persistence of fidaxomicin for longer periods Emerging Evidence on Fidaxomicin Efficacy than standard dosing regimens, suppressing recruA recent randomized, controlled, open-label, descence of C. difficile spores but allowing recovsuperiority, phase 3b/4 clinical trial in hospital- ery of gut microbiota populations. Notably, no eviized adults aged ≥60 years demonstrated that an dence of the emergence of reduced susceptibility of extended-pulsed dosing regimen of fidaxomicin C. difficile has been associated with extended (200 mg twice daily on days 1-5, then once every dosage regimens. Second, in vitro studies show other day on days 7-25)—comprising the that fidaxomicin persists on C. difficile same total dose of antibiotic as a spores, whereas vancomycin does conventional course—can fur- not.13 Furthermore, persistence ther reduce the risk for recur- of fidaxomicin prevented C. difrent CDI compared with a ficile growth and toxin producstandard course of vanco- tion. Thus, it is possible that the mycin (125 mg 4 times daily on days continued presence of fidaxomi1-10).8 The primary end point was cin in the gut after cessation of dossustained clinical cure 30 days ing, coupled with the assoafter the end of treatment (day 55 ciation of antibiotic with for extended-pulsed fidaxomicin spores, explains why this antiand day 40 for vancomycin); 70% (124/177) of the extended-pulsed fidaxomicin recipients versus 59% Bezlotoxumab reduced CDI biotic reduced CDI recurrence. Such effects may be exploited by extended dosing of fidaxomicin.8 (106/179) of the vancomycin patients achieved sustained clinical cure 30 days after the end of recurrence risk in predefi ned In a follow-up report to the phase 3b/4 clinical trial, both prespecified and post hoc subgroup treatment (difference, 11%; 95% CI, 1.0%-20.7%; P=0.030; odds groups. analyses were presented to determine whether particular patient ratio, 1.62 [95% CI, 1.04-2.54]). Source: N Engl J Med. 2017;376:305-317. groups showed more benefit from Studies in an in vitro model that the extended fidaxomicin dossimulates conditions found in the human colon, and age regimen.14 Prespecified subgroup categories notably the gut microbiome in the context of CDI, included patient age (60-74 vs ≥75 years); canprovided a rationale for the above-mentioned novel cer diagnosis (presence vs absence); CDI severity; extended dosage of fidaxomicin.9 This gut model, and number of prior CDI episodes within 3 months which is primed with pooled fecal samples from before study participation. A post hoc subgroup elderly volunteers, has proven to be predictive of efficacy analysis also was performed in relation to antibiotic behavior in patients—both whether anti- presence of C. difficile ribotype 027 (vs other ribobiotics have high or low propensity to induce CDI types). The primary end point was sustained cliniand whether novel agents will treat CDI and pre- cal cure (initial cure and absence of recurrence) 30 vent recurrent infection successfully.10 Gut model days after end of treatment. Sustained clinical cure experiments showed that pulsed or tapered fidax- rates did not differ significantly between extended omicin regimens may enhance suppression of C. dosage fidaxomicin (124/177; 70.1%) and vancodifficile, while allowing microbiota recovery.9 Two mycin (106/179; 59.2%) according to age, canother key lines of evidence are pertinent to under- cer diagnosis, CDI severity, or history of CDI. Howstanding why an extended dosage of fidaxomicin is ever, in patients with CDI due to ribotype 027, the

Table. Patients Needed to Treat With Bezlotoxumab and Standard-of-Care Antibiotic To Prevent One Recurrence of CDIa

Subgroup NNT to Prevent a Recurrence

Patients aged ≥65 y 3.8

Patients who are immunocompromised 4.7

Patients who present with severe CDI 5.1

Patients aged ≥65 y who have had ≥1 previous episode in prior 6 mo

Patients who are immunocompromised and have had ≥1 previous episode in prior 6 mo

Patients who present with severe CDI and have had ≥1 previous episode in prior 6 mo

a Patients were stratified according to baseline risk factors for recurrence. CDI, Clostridioides difficile infection; NNT, number needed to treat 2.5

3.0

2.5

sustained clinical cure rate was significantly higher in extended fidaxomicin (20/25; 80%) than vancomycin (9/22; 40.9%) recipients (treatment difference, 39.1%; 95% CI, 13.2%-64.9%; P=0.006).14 Such data for a C. difficile type that is associated with poor outcomes, albeit from a post hoc analysis, provide added confidence about the efficacy of fidaxomicin in treating CDI.

In a prospective surveillance study spanning 5 years (2011-2016) across 28 European countries (40 sites) 3,499 isolates from cases of CDI were monitored for changes in antimicrobial susceptibility and ribotype distribution.15 Ribotype prevalence varied greatly among countries and among years, but the most common of the 264 ribotypes found was 027 (mean prevalence 11.4%). Metronidazole and vancomycin geometric mean MICs were 0.46 mg/L and 0.70 mg/L, respectively. Fidaxomicin susceptibility, including in ribotype 027, was maintained post-introduction; geometric mean MIC for years 1 to 5 was 0.04 mg/L, with only 1 fidaxomicin-resistant isolate (RT344) detected (MIC ≥4 mg/L).

Emerging Evidence for Bezlotoxumab

In phase 3 trials, bezlotoxumab significantly reduced the risk for CDI recurrence in predefined groups at high risk for recurrent disease and/or poor outcome (≥65 years, previous CDI, immunocompromised, or severe CDI, but not CDI due to ribotype 027).16 Bezlotoxumab also was associated with a significant reduction in the 30-day CDI-associated readmission rate (4.0% vs 9.6%; difference, –5.7%; 95% CI, –8.8% to –2.7%).17 Recent reports have added to our understanding of the efficacy of bezlotoxumab in preventing recurrent CDI. Higher host antitoxin B, but not antitoxin A, antibody titers were associated with protection against recurrent CDI, which is consistent with the MODIFY trial outcomes (bezlotoxumab, but not actoxumab, was efficacious).18 In addition, a post hoc analysis of the efficacy rates of bezlotoxumab according to the method used to diagnose CDI in the MODIFY clinical trials found that the magnitude of reduction in recurrent CDI was substantially larger in participants diagnosed by toxin tests (relative difference, –46.6%) than in subjects recruited on the basis of a (toxin gene) PCR test or toxigenic culture (–29.1%).19 Hence, bezlotoxumab recipients diagnosed by toxin testing had a lower rate of CDI recurrence than those recruited by indirect toxin tests (17.6% vs 23.6%). These data show the magnitude of reduction in recurrent CDI achieved by bezlotoxumab is probably greater than the headline rate reported in the primary publication of the MODIFY studies.6

A subsequent analysis of the modified intentto-treat population from the MODIFY studies who received bezlotoxumab or placebo (n=1,554) according to their baseline risk factors for recurrent CDI recently was published.20 These risk factors were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of placebo recipients who experienced

recurrent CDI exceeded 30% for each risk factor compared with 20.9% of those without a risk factor. Also, the rate of recurrent CDI increased with the number of risk factors (1 risk factor, 31.3%; ≥3 risk factors, 46.1%). In a separate analysis, the number of subjects needed to treat (NNT) to prevent a CDI recurrence was calculated (Table). This shows a very low NNT of 2 to 3 patients in those who have 2 risk factors for recurrent CDI, and provide a good basis for selecting patients to consider for bezlotoxumab treatment.21

In a real-world study of 46 patients receiving bezlotoxumab in 5 hospitals in Finland, 71% remained recurrence-free at 3 months.22 Of particular note, 8 patients were awaiting fecal microbiota transplantation (FMT). After stopping the antibiotics that were continued to prevent CDI recurrence (and receiving bezlotoxumab), all 8 patients remained free of recurrence and did not require FMT. Given that FMT is an experimental procedure, whereas bezlotoxumab has regulatory approval for the prevention of CDI recurrence, this (uncontrolled) observation is revealing. Similarly, in the 2 registrational phase 3 (MODIFY) clinical trials, 11% of patients in the placebo group went on to receive FMT, whereas only 3% of those receiving active treatment had FMT.23 Thus, these data are consistent with the recommendation in the IDSA CDI guideline that appropriate antibiotic treatments for at least 2 recurrences (ie, 3 CDI episodes) should be tried prior to offering FMT.4

Using pooled data from MODIFY I/II, a post hoc analysis examined CDI-related outcomes in participants with inflammatory bowel disease (IBD) and CDI.24 A total of 44 participants had IBD (ulcerative colitis, 23; Crohn’s disease, 18; and non-characterized IBD, 3). Given that overall recurrent CDI results were similar for the bezlotoxumab and the actoxumab plus bezlotoxumab groups, these groups were pooled (bezlotoxumab group); similarly, the actoxumab and placebo groups were pooled (no bezlotoxumab group). This meant that 28 IBD subjects received bezlotoxumab, while 16 were in the no-bezlotoxumab group (14 completed the study). There was a trend toward a reduced rate of initial clinical cure in IBD participants in the bezlotoxumab group versus the no-bezlotoxumab group (53.6% vs 81.3%). During a 12-week follow-up period, there was a trend toward less recurrent CDI in the bezlotoxumab group (26.7% vs 53.8%), representing a 27.2% absolute reduction (95% CI, –57.9% to 9.6%) in the incidence of recurrent CDI in participants with IBD. These data show promise for a subgroup of CDI patients for whom more evidence is needed about the efficacy of treatment options and justify the need for a prospective randomized study in this cohort with an unmet need.

A post hoc analysis of pooled MODIFY I/II data examined recurrent CDI rates according to the type of C. difficile strain.25 A technique known as restriction endonuclease analysis was used to categorize strains. Using this method, BI strains can be distinguished, and these are similar to the more frequently used term ribotype 027. It was shown that the recurrent CDI rate for BI strains treated with bezlotoxumab was lower than for those in the no-bezlotoxumab group (23.6% vs 43.9%); by comparison, recurrent CDI rates for cases due to non-BI strains were 21.4% versus 36.1%, respectively.

In a real-world study, 71% of 46 patients remained recurrence-free for 3 months after bezolotoxumab.

Source: Eur J ClinMicrobiol Infect Dis. 2019;38(10):1947-1952.

Pipeline Antibiotics for CDI

Noting the recent demise of surotomycin (Merck) and cadazolid (Actelion) after disappointing results in pivotal phase 3 clinical trials, there are now very few remaining novel agents in the investigational pipeline of CDI therapeutics.26-30

The only remaining late-stage (phase 3) antibiotic for CDI treatment is ridinilazole (SMT19969; Summit Therapeutics), a novel, nonabsorbable, very narrow-spectrum antimicrobial.31-35 The efficacy and safety of ridinilazole were established in healthy patients and in a recently reported phase 2, randomized, double-blind trial (CoDIFy) comparing 10 days of therapy with 200 mg of oral ridinilazole twice daily or 125 mg of oral vancomycin 4 times daily.33 Ridinilazole had a superior sustained clinical response rate (66.7%) compared with vancomycin (42.4%). The very narrow spectrum of activity and, therefore, relative avoidance of further gut microbiome dysbiosis associated with ridinilazole likely contributes significantly to its high efficacy.34,35 Phase 3 clinical trials of ridinilazole versus vancomycin have been in progress since early 2019.

Three other investigational agents to treat CDI have reached the phase 2 clinical trial stage: CRS3123 ( Crestone) is a novel diaryldiamine that targets methionyl-tRNA synthetase. A phase 2 randomized, double-blind trial of this agent is due to start shortly.36 DNV383714/DNV3681 (also known as MCB383714/MCB3681; Deinove) is an oxazolidinone–quinolone hybrid (similar to cadazolid). This intravenous (IV) prodrug of DNV3681 has completed a phase 1 trial,37 and has started a 2-part, phase 2, open-label trial (NCT03824795). Ibezapolstat (Acurx; formerly known as ACX-362E) is a poorly absorbed oral antibiotic that inhibits DNA polymerase IIIC (pol IIIC) of C. difficile. The results of a phase 1 trial were published recently,38 and a phase 2, open-label study has commenced ( NCT04247542). It remains too soon to know how effective these agents will be, but it is promising to have 3 candidate treatment options in the phase 2 stage, in addition to ridinilazole in phase 3.

In addition, it is likely that new options may soon become available for the management of patients with recurrent CDI that are based on FMT or substitute versions thereof. Notably, Seres recently announced very positive results from its phase 3 clinical trial of SER-109 (NCT03183128), an oral, biologically derived microbiome therapeutic, which met its primary end point in the treatment of patients with recurrent CDI. There was a highly statistically significant 30.2% absolute reduction in the rate of (further) CDI recurrence relative to placebo.39

Also, Rebiotix and Ferring Pharmaceuticals recently announced positive preliminary findings from their ongoing pivotal phase 3 trial of an investigational microbiome-based treatment, RBX2660.40 The ongoing RBX2660 pivotal phase 3 trial, PUNCH CD3, is a multicenter, randomized, double-blind, placebo-controlled study (NCT03244644). RBX2660 has been granted fast track, orphan drug, and breakthrough therapy designations from the FDA.

Updating IDSA Guidelines on CDI Treatment

A treatment-focused update of the 2017 IDSA CDI guideline is underway; the 2017 guideline (published in 2018) was limited to evidence published up to the end of 2016.4 Thus, evidence on CDI therapeutics published since 2016 will be reviewed for the update, which is hoped to be available in late 2020.

References

1. Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354.

2. Nelson RL, Suda KJ, Evans CT. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev. 2017;3:CD004610.

3. Vardakas KZ, Polyzos KA, Patouni K, et al. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob

Agents. 2012;40(1):1-8.

4. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017

Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.

5. Crook DW, Walker AS, Kean Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55(suppl 2):S93-S103.

6. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of Clostridium difficile infection recurrence. N Engl J Med. 2017; 376(4):305-317.

7. Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis. 2016;35(2):251-259.

8. Guery B, Menichetti F, Anttila VJ, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial.

Lancet Infect Dis. 2018;18(3):296-307.

9. Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated Clostridium difficile

infection in an in vitro human gut model. J Antimicrob Chemother. 2015;70(9):2598-2607.

10. Best EL, Freeman J, Wilcox MH. Models for the study of Clostridium difficile infection. Gut Microbes. 2012;3(2):145-167.

11. Chilton CH, Crowther GS, Freeman J, et al. Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure. J Antimicrob

Chemother. 2014;69(2):451-462.

12. European Medicines Agency. DIFICLIR Public Assessment Report. 22

September 2011. https://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002087/

WC500119707.pdf

13. Chilton CH, Crowther GS, Ashwin H, et al. Association of fidaxomicin with

C. difficile spores: effects of persistence on subsequent spore recovery, outgrowth and toxin production. PLoS One. 2016;11(8):e0161200.

14. Cornely OA, Vehreschild MJGT, Adomakoh N, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection:

EXTEND study subgroup analyses. Eur J Clin Microbiol Infect Dis. 2019;38(6):1187-1194.

15. Freeman J, Vernon J, Pilling S, et al. Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study. Eur J Clin Microbiol

Infect Dis 2020;39(1):169-177.

16. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II

Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-317.

17. Prabhu VS, Cornely OA, Golan Y, et al. Thirty-day readmissions in hospitalized patients who received bezlotoxumab with antibacterial drug treatment for Clostridium difficile infection.

Clin Infect Dis. 2017;65(7):1218-1221.

18. Kelly CP, Poxton IR, Shen J, et al. Effect of endogenous Clostridioides difficile toxin antibodies on recurrence of C. difficile infection.

Clin Infect Dis. 2019. pii: ciz809. doi: 10.1093/cid/ciz809

19. Wilcox MH, Rahav G, Dubberke ER, et al. Influence of diagnostic method on outcomes in phase 3 clinical trials of bezlotoxumab for the prevention of recurrent Clostridioides difficile infection: a post hoc analysis of MODIFY

I/II. Open Forum Infect Dis. 2019;6. pii: ofz293.

20. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence. Clin Infect Dis. 2018;67(5):649-656.

21. Prabhu VS, Dubberke ER, Dorr MB, et al. Cost-effectiveness of bezlotoxumab compared with placebo for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis. 2018;66(3):355-362.

22. Oksi J, Aalto A, Säilä P, et al. Real-world efficacy of bezlotoxumab for prevention of recurrent Clostridium difficile infection: a retrospective study of 46 patients in five university hospitals in Finland. Eur J Clin Microbiol

Infect Dis. 2019;38(10):1947-1952.

23. FDA. Minutes of the Antimicrobial Drugs Advisory Committee,

June 9, 2016. Acessed November 30, 2020. https://www.fda.gov/ media/99345/download

24. Kelly CP, Wilcox MH, Glerup H, et al. Bezlotoxumab for Clostridium difficile infection complicating inflammatory bowel disease. Gastroenterology. 2018;155(4):1270-1271.

25. Johnson S, Citron DM, Gerding DN, et al. Efficacy of bezlotoxumab in trial participants infected with Clostridioides difficile strain BI associated with poor outcomes. Clin Infect Dis. 2020. In press. doi: 10.1093/cid/ ciaa1035

26. Boix V, Fedorak RN, Mullane KM, et al. Primary outcomes from a phase 3, randomized, double-blind, active-controlled trial of surotomycin in subjects with Clostridium difficile infection. Open Forum Infect Dis. 2017;19(4):ofw275.

27. Deshpande A, Hurless K, Cadnum JL, et al. Effect of surotomycin, a novel cyclic lipopeptide antibiotic, on intestinal colonization with vancomycinresistant enterococci and Klebsiella pneumoniae in mice. Antimicrob

Agents Chemother. 2016;60(6):3333-3339. 28. Chilton CH, Crowther GS, Baines SD, et al. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J Antimicrob Chemother. 2014;69(3):697-705.

29. Gehin M, Desnica B, Dingemanse J. Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection.

Int J Antimicrob Agents. 2015;46(5):576-581.

30. Baldoni D, Gutierrez M, Timmer W, et al. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses.

J Antimicrob Chemother. 2014;69(3):706-714.

31. Goldstein EJ, Citron DM, Tyrrell KL, et al. Comparative in vitro activities of

SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates. Antimicrob Agents Chemother. 2013;57(10):4872-4876.

32. Vickers R, Robinson N, Best E, et al. A randomised phase 1 study to investigate safety, pharmacokinetics and impact on gut microbiota following single and multiple oral doses in healthy male subjects of SMT19969, a novel agent for Clostridium difficile infections. BMC Infect Dis. 2015;15:91.

33. Vickers RJ, Tillotson GS, Nathan R, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis. 2017;17(7):735-744.

34. Chang J, Kane A, McDermott L, et al. Ridinilazole preserves major components of the intestinal microbiota during treatment of Clostridium difficile infection. Presented at: ECCMID 2016; April 9-12, 2016;

Amsterdam, Netherlands. Abstract LB-116.

35. Chang J, Kane A, Snydman D. Ridinilazole preserves major components of the intestinal microbiota during treatment of Clostridium difficile infection. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston, MA.

Abstract LB-116.

36. Business wire. Crestone, Inc. (Boulder) secures BIH Funding for phase 2 clinical rial of novel antibiotic candidate. September 12, 2019. Accessed November 30, 2020. http://www.businesswire.com/news/home/20190912005834/ en/Crestone-Boulder-Secures-NIH-Funding-Phase-2

37. Dalhoff A, Rashid M-U, Kapsner T, et al. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clin Microbiol Infect. 2015;21(8):767.e1-767.e4.

38. Garey KW, Begum K, Lancaster C, et al. A randomized, double blind, placebo controlled, single and multiple ascending dose phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects.

J Antimicrob Chemother. 2020 Sep 6. [Epub ahead of print]. doi: 10.1093/jac/dkaa364

39. Businesswire. Seres Therapeutics announces positive topline results from SER-109 phase 3 ECOSPOR III study in recurrent C. difficile infection. August 10, 2020. Accessed September 21, 2020. http://www.businesswire.com/news/home/20200810005194/en/

Seres-Therapeutics-Announces-Positive-Topline-Results-from-SER109-Phase-3-ECOSPOR-III-Study-in Recurrent-C.-difficile-Infection

40. Rebiotix and Ferring announce world’s first with positive preliminary pivotal phase 3 data for investigational microbiome-based therapy RBX2660.

Accessed November 30, 2020. https://www.ferringusa.com/press/ rebiotix-and-ferring-announce-worlds-first-with-positive-preliminary-pivotalphase-3-data-for-investigational-microbiome-based-therapy-rbx2660/

About the Author Mark H. Wilcox, MD, FRCPath,

is the lead on CDI for Public Health England, and an expert advisor to National Health Service Improvement on infection prevention and control in the United Kingdom.