Recently, the New England Journal of Medicine published a paper by Wilcox and colleagues outlining the efficacy of a novel monoclonal antibody against toxin B of C.difficile, the bacterial organism most infamously known to cause relentless diarrhea in the setting of antibiotic use .  The antibody, known as bezlotoxumab, is creating a stir after 2 randomized double-blinded, placebo-controlled phase 3 clinical trials (MODIFY I and II) were conducted to compare the efficacy of bezlotoxumab against actoxumab (another monoclonal antibody targeting toxin A of C. difficile), as well as placebo—all patients also received standard of care treatment for C. difficile colitis along with one of the above interventions.  Interestingly enough, in both trials, bezlotoxumab, combined with standard-of-care therapy significantly lowered the rate of recurrent C. difficile colitis when compared to placebo (by 38%), and was similar in efficacy to combined actoxumab plus bezlotoxumab therapy, suggesting that the addition of the former did not provide any significant benefit. With regards to initial clinical cure of acute C.difficile infection, cure rates were again highest in the bezlotoxumab group, followed by combination actoxumab/bezlotoxumab therapy and then placebo. Actoxumab alone did not result in significant benefits as monotherapy, both for acute and recurrent infection.

Based on these results, the FDA has now approved the use of bezlotoxumab (market name Zinplava) for the use of C. difficile infection, however its precise role amidst the various number of other therapeutic options for both acute and recurrent C. difficile infection remains to be clarified.  With potentially cheaper options such as fecal microbiota transplantation, and oral drugs such as metronidazole, vancomycin and even fidoxamicin, when should the use of bezlotoxumab be considered in the management of acute and recurrent C.difficile infection?

Safety profile analysis, along with cost effectiveness will both play a major role in deciding this question among individual hospitals. In addition, other novel drugs are currently in the pipeline (surotomycin, cadazolid, ridinilazole, etc) and even vaccine development is currently underway as a potentially preventative measure against acquiring C. difficile infection in the first place. How these will play a role in overall management of C. difficile infection still remains to be seen.

At our fellow’s journal club on 2/6, Palash Samanta prevented this article and there was lively discussion regarding role of therapy in hospitalized and non-hospitalized patients.  Much of the discussed centered on the absolute risk reduction (ARR) which was  about 10%, and was lower than prior smaller studies (ARR ~20%).  Looking at the pre-specified subgroups, some populations of patients had a larger effect of the drug ~(15% ARR) including those with multiple episodes and then over 65.   Identifying and addressing the highest risk groups make make this drug more effective in an implementation strategy.

These findings, of course have be placed in the context of fecal microbiota transplantion. In the 2013 NEJM study by van Nood and colleagues, the ARR was 50% for initial infusion.   Obviously there are difference between therapies and in terms of cost, availability, safety etc., so choosing which therapy is correct for each patient remains a challenge. Looking at the inverse of ARR, the number needed to treat , puts these figures in better context.

Approximate number of patients needed to treat to prevent 1 recurrence of C. difficile:

Bezlotoxumab: 10

Bezlotoxumab (older patients or prior recurrence): 6-7

Fecal microbiota transplantation: 2

In an age where more and more antibiotics are being given to patients, often inappropriately, the topic of antibiotic associated colitis and C. difficile infection is becoming more and more significant, both among clinicians and the patients who develop this unfortunate complication. A combination of responsible antibiotic administration, patient education and appropriate therapy for those individuals who do develop C. difficile infection will be critical in managing this problem long term.

PUBMED References

Wilcox MH et al NEJM 2017 Jan 26;376(4):305-317

van Nood E et al  NEJM 2013 Jan 31;368(5):407-15.