Clostridioides difficile Pharmacologic Treatment Insights: An Expert Interview With Kevin W Gary, PharmD

Contagion, October 2020 Supplement,

Editors from Contagion® spoke with Kevin W. Garey, PharmD, MS, chair of the Department of Pharmacy Practice and Translational Research and professor of pharmacy practice at the University of Houston in Houston, Texas, about the latest and upcoming pharmacologic treatments for Clostridioides difficile (C difficile).

Contagion®: How has pharmacologic treatment of CDI evolved in the past 10 years?Garey: For the past 2 decades, we have been living in a world with high rates of CDI. In the early 2000s, an outbreak of C difficile caused the rate of infection to increase by at least twofold, and in many places tenfold.1,2 This massive increase in infections was caused by the virulent strain called ribotype 027.1 It was associated with higher rates of colectomy and death, and longer hospital admissions.1,2 Antibiotic use increased to fight the ongoing epidemic, which, in turn, increased the antibiotic selection pressure on C difficile. As the epidemic was waning, ribotype 027 became endemic [in the United States], along with other strains, such as ribotype 106 and ribotype 014-020.1-3 Furthermore, diagnostic methods switched to the polymerase chain reaction diagnostic, which is more sensitive to capture C difficile and meant that more infections were detected.

With the changing landscape of C difficile, treatment also changed. During this 20-year time period, the effectiveness of metronidazole has dramatically decreased. Metronidazole used to be as good as vancomycin for the treatment of CDI. However, vancomycin has been shown to have a lower failure rate and improved clinical success, and so guidelines from the Infectious Diseases Society of America and the Society of Healthcare Epidemiology of America recommend it as a first-line option.4-6

What is the biggest misconception that you would like to correct about pharmacologic treatment of CDI?

The biggest misconception in CDI is that when the major signs and symptoms of the disease (eg, diarrhea) stop around day 10, the patient is cured. However, about 18% to 35% of previously treated patients will have CDI recurrence within 2 to 8 weeks of treatment.7 No one would say an 18% to 35% relapse rate is a cure; however, [this high relapse rate] has led to a move toward prevention of recurrence in drug discovery.

Two drugs, specifically designed as an antirecurrent strategy, are in the market. The first is fidaxomicin, which is a macrocyclic antibiotic that is recommended a first-line option.6 Fidaxomicin is highly selective for C difficile and does not have the same effect on the gut microbiome as vancomycin.6,8 In patients treated with fidaxomicin, symptoms resolve and initial clinical cure is achieved, while the recurrence rate decreases to 14%.9

The second drug is the monoclonal antibody bezlotoxumab, which is an immunologic specifically directed against one of the toxins of C difficile, toxin b. The treatment is given as an adjunct to standard therapy with an antibiotic, such as vancomycin or fidaxomicin.8,10 Once again, with the use of bezlotoxumab, recurrence rates decrease.11

How else can clinicians fight CDI, outside of pharmacologic treatment?

The best way to treat CDI is to ensure that the patient does not become infected in the first place. We know what causes CDI. We need to use antibiotics to treat infections, but antibiotic use almost always has a negative effect on the gut microbiome.7,12 This negative effect on the host gut microbiome allows C difficile to germinate and cause infection. Therefore, anything we can do to optimize antibiotic use by ensuring that we are not only appropriately using antibiotics, but also reviewing the dosing and duration of treatment, will ensure that we are doing our best to avoid CDI in the first place.

The second aspect we need to consider is the pathophysiology of CDI. It is a gut microbiome disease that occurs more often in older adults because they do not mount a good antibody response.13 There exist treatments that complement each other better than others. For example, treatment with a highly effective antibiotic such as fidaxomicin or vancomycin may be enough. However, if that treatment is not enough and there is recurrence, there may be a need to augment the immune response, by adding a treatment such as bezlotoxumab. And, to get the host microbiota back to a healthy state and out of dysbiosis, another option is fecal microbiota transplantation and/or the introduction of probiotics. Clinicians should approach treatment of CDI in 3 ways: kill the bug, replenish the microbiota, and augment the immune response. Those 3 aspects of treatment complement each other to help improve outcomes for CDI.

What are your biggest concerns regarding pharmacologic treatment of CDI?

In terms of pharmacological treatment, and antibiotic treatment specifically, as discussed previously, the C difficile epidemic and changing diagnostic patterns have increased the [known] rates of CDI tremendously. Increased resistance in metronidazole—so much so that it’s no longer guideline-recommended—mean there are really only 2 antibiotics to treat a large disease state: vancomycin and fidaxomicin. That is putting a lot of antibiotic selection pressure on those 2 antibiotics, and I am [therefore] worried that we will start to see resistance to them as well. The history of antibiotic use back to penicillin and Fleming has shown that as soon as someone says, “This antibiotic will never get resistance,” that changes quickly. Sometime in the future, there will be resistance. And there is already tolerance to vancomycin.14 In the clinical trials, there was 1 case of nonsusceptibility in fidaxomicin.9 I am worried that this selection pressure with only a few antibiotics is going to lead to more resistance.

Are you excited about any newer treatments in the pipeline for CDI?

The higher rate of infections has generated interest in the pharmaceutical development world to target agents for the treatment of CDI and I am most excited about that. In the antibiotic pipeline are agents that augment the immune response and others that repopulate the microbiota. For example, an antibiotic called ridinilazole is an exquisitely narrowed-spectrum antibiotic.15 It kills only C difficile and a small handful of other species of organisms, and considering that there are thousands of species of organisms in the gut, to get down to a handful, it redefines narrow spectrum to “targeted spectrum.” It’s currently in phase 3, and the phase 2 study results were encouraging.16 That treatment is probably the closest to coming out in the market.

Another treatment, called ibezapolstat, is just going into phase 2 right now (NCT04247542).17 Results from a phase 1 study were encouraging with good safety and pharmacokinetic results.18 Ibezapolstat is interesting because it kills one type of phylum called the Firmicutes (the phylum that contains C difficile) but does not kill Bacteroidetes or Actinobacteria, which are commonly found in the healthy gut.

In terms of treatments aimed at augmenting the immune response, there are vaccines in phase 3 trials right now, such as the Clostridium Difficile Vaccine Efficacy Trial (Clover) (NCT03090191).19 The development of a vaccine for C difficile is a bit difficult, because although the risks are known, infection usually involves an acute event, such as a hospital stay or a course of antibiotics. The months after that acute event are when individuals are at greater risk of infection; however, it is difficult to time when to administer the vaccine to patients in that population to confer protection. And so, it has been difficult to obtain a high enough control population to prove the benefit of a vaccine.

C difficile is ubiquitous; every hospital has it, and anyone who is admitted to a hospital or long-term care facility and receives antibiotics is at risk of infection. Therefore, it is much harder to target a vaccine and to prove its benefit in clinical trials; however, there is certainly a need for it.

Looking to the microbiota replenishment pipeline, the microbiota world is booming. It has been said that the Human Microbiome Project20 is the next big leap forward in science. C difficile is kind of a poster child for a microbiome-related disease and so a lot of advancing technology is being put into C difficile microbiome discovery. There is research on the use of C difficile isolates that are not toxigenic (ie, the toxin genes of C difficile are not present).21 Each of these treatments is [extremely] novel.

In your opinion, what is needed to improve pharmacologic treatment of CDI?

There needs to be a greater focus on the 3 facets of treatment: kill the bug, replenish the microbiota, and augment the immune response. Do not simply add on another antibiotic if current therapy is failing. One [effective] antibiotic will generally kill the bug and adding more antibiotic will only further disrupt the microbiome. We need to consider all facets of the disease and treatment approaches to optimize our likelihood of successful treatment. A greater appreciation of those 3 facets of treatment will prevent someone from adding on more antibiotics or increasing dosing when a patient is not responding.

References

1. Guh AY, Kutty PK. Clostridioides difficile infection. Ann Intern Med. 2018;169(7):ITC49-ITC64. doi:10.7326/AITC201810020

2. Aitken SL, Alam MJ, Khaleduzzaman M, et al. In the endemic setting, Clostridium difficile ribotype 027 is virulent but not hypervirulent. Infect Control Hosp Epidemiol. 2015;36(11):1318-1323. doi:10.1017/ice.2015.187

3. Tickler IA, Obradovich AE, Goering RV, Fang FC, Tenover FC; HAI Consortium. Changes in molecular epidemiology and antimicrobial resistance profiles of Clostridioides (Clostridium) difficile strains in the United States between 2011 and 2017. Anaerobe. 2019;60:102050. doi:10.1016/j.anaerobe.2019.06.003

4. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307. doi:10.1086/519265

5. Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) Investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354. doi:10.1093/cid/ciu313

6. 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. doi:10.1093/cid/cix1085

7. De Roo AC, Regenbogen SE. Clostridium difficile infection: an epidemiology update. Clin Colon Rectal Surg. 2020;33(2):49-57. doi: 10.1055/s-0040-1701229

8. Mendo-Lopez R, Villafuerte-Gálvez J, White N, Mahoney MV, Kelly CP, Alonso CD. Recent developments in the management of recurrent Clostridioides difficile infection. Anaerobe. 2020;62:102108. doi:10.1016/j.anaerobe.2019.102108

9. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431. doi:10.1056/NEJMoa0910812

10. Khanna S, Gerding DN. Current and future trends in clostridioides (clostridium) difficile infection management. Anaerobe. 2019;58:95-102. doi:10.1016/j.anaerobe.2019.04.010

11. 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(4):305-317. doi:10.1056/NEJMoa1602615

12. Czepiel J, Dróżdż M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019;38(7):1211-1221. doi:10.1007/s10096-019-03539-6

13. Jump RLP, Donskey CJ. Clostridium difficile in the long-term care facility: prevention and management. Curr Geriatr Rep. 2015;4(1):60-69. doi:10.1007/s13670-014-0108-3

14. Shen W-J, Deshpande A, Hevener KE, et al. Constitutive expression of the cryptic vanGCd operon promotes vancomycin resistance in Clostridioides difficile clinical isolates. J Antimicrob Chemother. 2020;75(4):859-867. doi:10.1093/jac/dkz513

15. Cho JC, Crotty MP, Pardo J. Ridinilazole: a novel antimicrobial for Clostridium difficile infection. Ann Gastroenterol. 2019;32(2):134-140. doi:10.20524/aog.2018.0336

16. Summit Therapeutics reports new data from phase 2 clinical trial connecting ridinilazole’s microbiome preservation to improved clinical outcomes for patients with C. difficile infection. News release. Biospace; October 7, 2019. Accessed September 17, 2020. https://www.biospace.com/article/summit-therapeutics-reports-new-data-from-phase-2-clinical-trial-connecting-ridinilazole-s-microbiome-preservation-to-improved-clinical-outcomes-for-patients-with-c-difficile-infection/

17. ACX-362E [ibezapolstat] for oral treatment of Clostridioides difficile infection. ClinicalTrials.gov. Updated March 24, 2020. Accessed September 18, 2020. https://clinicaltrials.gov/ct2/show/NCT04247542

18. 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. Published online September 6, 2020. doi:10.1093/jac/dkaa364

19. Clostridium difficile vaccine efficacy trial (Clover). ClinicalTrials.gov. Updated February 21, 2020. Accessed September 16, 2020. https://clinicaltrials.gov/ct2/show/NCT03090191.

20. NIH Human Microbiome Project. Human Microbiome Project Data Analysis and Coordination Center. Accessed September 16, 2020. https://www.hmpdacc.org/hmp/

21. Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA. 2015;313(17):1719-1727. doi:10.1001/jama.2015.3725