Commentary

Fighting in a passive manner active against Clostridium difficile


 

Infections resulting from Clostridium difficile are a major clinical challenge. In hematology and oncology, the widespread use of broad-spectrum antibiotics is essential for patients with profound neutropenia and infectious complications, which are a high-risk factor for C. difficile enteritis.

C. difficile enteritis occurs in 5%-20% of cancer patients.1 With standard of care antibiotics, oral metronidazole or oral vancomycin, high C. difficile cure rates are possible, but up to 25% of these infections recur. Recently, oral fidaxomicin was approved for treatment of C. difficile enteritis and was associated with high cure rates and, more importantly, with significantly lower recurrence rates.2

Dr. Thomas Fischer
Dr. Thomas Fischer
About 40 years ago, the pathogenesis of C. difficile enteritis was described when toxin A (enterotoxin) and toxin B (cytotoxin) were identified.3 There is good evidence that, among both toxins, toxin B plays the essential role in virulence of C. difficile.4C. difficile toxin B uses eukaryotic signals for induced autoproteolysis to deliver its toxic products into the cytosol of target cells. Toxin B binds to the surface of intestinal epithelial cells, where it is internalized and catalyzes the glucosylation of cytoplasmic-rho proteins, leading to disaggregation of the cytoskeleton and cell death.5 Toxin B must be neutralized to protect against recurrent infection.6

Bezlotoxumab, a fully humanized monoclonal antibody against C. difficile toxin B, has been shown by x-ray crystallography to neutralize toxin B by blocking its ability to bind to host cells.7 Most recently, this new therapeutic approach was investigated in humans.8

Wilcox et al. used pooled data of 2655 adults treated in two double-blind, randomized, placebo-controlled phase III clinical trials (MODIFY I and MODIFY II) for primary or recurrent C. difficile enteritis. This industry-sponsored trial was conducted at 322 sites in 30 countries.

In one treatment group, patients received a single infusion of bezlotoxumab (781 patients) or placebo (773 patients) and one of the three oral standard-of-care C. difficile antibiotics. Importantly, the primary end point of this trial was recurrent infection within 12 weeks. About 28% of the patients in both the bezlotoxumab group and the placebo group previously had at least one episode of C. difficile enteritis. About 20% of the patients in both groups were immunocompromised.

Pooled data showed that recurrent infection was significantly lower (P less than 0.001) in the bezlotoxumab group (17%), compared with the placebo group (27%). The difference in recurrence rate (25% vs. 41%) was even more pronounced in patients with one or more episodes of recurrent C. difficile enteritis in the past 6 months. Furthermore, a benefit for bezlotoxumab was seen in immunocompromised patients, whose recurrence rates were 15% with bezlotoxumab, vs. 28% with placebo. After the 12 weeks of follow-up, the absolute difference in the Kaplan-Meier rates of recurrent infection was 13% (absolute rate, 21% in bezlotoxumab group vs. 34% in placebo group; P less than 0.001).

The results indicate that bezlotoxumab, which was approved in 2016 by the U.S. Food and Drug Administration, might improve the outcome of patients with C. difficile enteritis. However, bezlotoxumab is not a “magic bullet.” The number needed to treat to prevent one episode of C. difficile enteritis is 10.

It is conceivable that bezlotoxumab may find its role in high-risk patients – those older than 65 years or patients with recurrent C. difficile enteritis – since the number needed to treat is only 6 in these subgroups.8

This new agent could be an important treatment option for our high-risk patients in hematology. However, more studies concerning costs and real-life efficacy are needed.

The new approach of passive immunization for prevention of recurrent C. difficile enteritis shows the importance and the role of toxin B – not only the bacterium per se – in pathogenesis and virulence of C. difficile. This could mean that we have to renew our view on the role of antibiotics against C. difficile. However, in contrast, bezlotoxumab does not affect the efficacy of standard of care antibiotics since the initial cure rates were 80% for both the antibody and the placebo groups.8 Toxin B levels are not detectable in stool samples between days 4 and 10 of standard of care antibiotic treatment. Afterward, however, they increase again.9 Most of the patients had received bezlotoxumab 3 or more days after they began standard-of-care antibiotic treatment – in the time period when toxin B is undetectable in stool – which underlines the importance of toxin B in the pathogenesis of recurrent C. difficile enteritis.8

In summary, the introduction of bezlotoxumab in clinical care gives new and important insights and solutions not only for treatment options but also for our understanding of C. difficile pathogenesis.

Dr. Schalk is consultant of internal medicine at the department of hematology and oncology, Magdeburg University Hospital, Germany, with clinical and research focus on infectious diseases in hematology and oncology.

Dr. Fischer is professor of internal medicine, hematology and oncology, at the Otto-von-Guericke University Hospital Magdeburg, Germany. He is head of the department of hematology and oncology and a clinical/molecular researcher in myeloid neoplasms. He is a member of the editorial advisory board of Hematology News.

Contact Dr. Schalk at enrico.schalk@med.ovgu.de.

References

1. Vehreschild, MJ et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: Wvidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol. 2013;24:1189-202

2. Cornely, OA. Current and emerging management options for Clostridium difficile infection: What is the role of fidaxomicin? Clin Microbiol Infect. 2012;18(Suppl 6):28-35.

3. Bartlett, JG et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298(10):531-4.

4. Lyras, D et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458:1176-9.

5. Reineke, J et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature. 2007;446:415-9.

6. Leav, BA et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965-9.

7. Orth, P et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289:18008-21.

8. Wilcox, MH et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-17.

9. Louie, TJ et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012;5(Suppl 2):S132-42.

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