Because fecal transplant was always too gross for mainstream use: Bezlotoxumab for prevention of recurrent Clostridium difficile infection

Hi friends! We at IM HEAT are happy to have another piece from our resident ID specialist, Risa Fuller. Yes, she’s also my wife. No, she’s not blind. Why does everyone always ask me that? She’s tracked down a really exciting development in the treatment of a very common disease to go over with us today, so let’s get started!

What CAN’T we use monoclonal antibodies for anymore? Bezlotoxumab for prevention of recurrent C. diff

When it comes to hot topics in infectious diseases, one of the hottest is hospital-acquired infections (HAIs). These infections tend to affect our sickest patients and are a tremendous source of morbidity and mortality. HAIs tend to be caused by some of the scariest and most resistant bugs. The CDC counted 721,800 of these infections in 2014, and that number will continue to grow as our patients get older and sicker. But the main reason HAIs are such a hot topic is because they are thought to be preventable. And the smelliest, most isolation-gown causing HAI of all is definitely C. diff.

Clostridium difficile is the most common cause of infectious diarrhea in high-income countries. After patients with C. diff complete a course of antibiotics for the infection, up to 35% of them will have recurrence. These recurrent infections tend to be more difficult to treat and are associated with worse outcomes and higher cost than the first episode. C. diff causes infection through the production of two toxins, A and B. In humans, both toxins seem to be important, and antibodies against toxin A or toxin B have been correlated with protection against both primary and recurrent infection. Actoxumab and bezlotoxumab are two human monoclonal antibodies that bind to and neutralize C. diff toxins A and B (Actoxumab for A and Bezlotoxumab for B, duh). Today we’re going to take a look at a recently-published pair of randomized controlled trials by M.H. Wilcox and colleagues comparing these two drugs to placebo for preventing recurrent C. diff infection.

If You’re Only Going to Read One Paragraph

In a pair of double-blind RCTs, addition of bezlotoxumab to usual care in patients with either primary or recurrent C. diff infection resulted in similar initial cure rates but a huge 38% relative risk reduction and 9.9% absolute risk reduction for recurrent infection. There was no incremental benefit to adding actoxumab, and actoxumab did not have any benefit as monotherapy. There are no comparative effectiveness data comparing this therapy to fecal transplant, and no cost effectiveness data as of yet for this promising novel therapy.

The Trials

The MODIFY I and MODIFY II trials are randomized, double-blind, placebo-controlled trials. As the names imply, MODIFY II was designed and carried out after MODIFY I and designed with knowledge of the interim analysis from that trial. Investigators recruited adults with either primary or recurrent C. diff who were receiving oral standard-of-care antibiotics (either metronidazole, vancomycin, or fidaxomicin) for 10 to 14 days. Those receiving oral vancomycin or fidaxomicin could also receive IV metronidazole. Patients were randomly assigned to one of four groups: bezlotoxumab alone, bezlotoxumab plus actoxumab, placebo (normal saline), or actoxumab alone (only in MODIFY I), all in addition to the standard antibiotics. 68% of the patients were treated as inpatients, and almost all of them received either metronidazole or oral vanc as the standard of care antibiotic (only 4% got fidaxomicin, pretty representative of common practice).

The primary outcome was recurrence of C. diff infection in patients who had initial cure. Secondary outcomes included initial cure rate, as well as sustained cure (i.e. satisfying both initial cure and having no recurrence by 12 weeks).

The Results

Neither trial demonstrated a difference in initial cure rate between the bezlotoxumab group and the placebo group, with rates of initial cure 77-83% across the board. However, in both trials, the rate of recurrent infection was significantly lower in the bezlotoxumab group than in the placebo group — in MODIFY II, there was an absolute risk reduction of 9.9 percentage points (95% CI, −15.5 to −4.3; P<0.001). This risk was also significantly lower in the actoxumab-bezlotoxumab group than the placebo group, but not between the bezlotoxumab alone group and the actoxumab-bezlotoxumab groups or between the actoxumab group alone and the placebo group in MODIFY I (hence why it was left out in MODIFY II). These names are exhausting. (“Try proofreading them!” – Bill).

When there was recurrence, most cases (71%) occurred within 4 weeks after the infusion. Differences in recurrence rates were observed as early as two weeks after infusion.

bezlotux

Wilcox et al., N Engl J Med 2017; 376:305-317

In MODIFY I, sustained cure (defined as initial cure plus lack of recurrence at 12 weeks) was achieved in 60% of patients in the bezlotoxumab group and in 59% of patients in the actoxumab-bezlotoxumab group, compared to 55% of patients in the placebo group. In MODIFY II, sustained cure was achieved in 64% of patients in the bezlotoxumab group and in 58% of the combined group, compared to 54% of patients in the placebo group. The only significant difference here was between bezlotoxumab and placebo in MODIFY II, so not really a consistent signal of superiority. Rates of adverse effects were similar between all groups.

Overall, the authors concluded that administration of bezlotoxumab was associated with a significantly lower rate of recurrence compared to placebo. In fact, bezlotoxumab was associated with a 38% lower rate of recurrent infection compared to placebo/standard-of-care antibiotics alone. Actoxumab was not efficacious alone and did not add anything when given with bezlotoxumab (last time typing that, phew), perhaps suggesting that toxin B is more important in pathogenesis of C. diff infection in humans. Number needed to treat to prevent one episode of recurrence was 10, and in patients over 65 or those with previous C. diff infection it was 6.

However, it seems that bezlotoxumab does not help in initial cure rates, and because of this does not increase rate of sustained cure in all patients. The patients who do have initial cure with antibiotics are less likely to get recurrence if they get bezlotoxumab, but because patients needed to have initial cure to have sustained cure, bezlotoxumab did not increase the rates of this outcome.

No head-to-head evidence here on how this compares to fecal transplant. Though the monoclonals are definitely less gross, they are almost certainly more expensive, and significantly more difficult to pronounce. So, stay tuned for cost effectiveness analyses — bezlotoxumab may be coming to an infectious disease service near you!

Read the original study here.

Tomorrow on IM HEAT

Heard of the obesity paradox? It’s the fact that despite all of the medical illness that we know is caused by obesity, patients who are obese tend to die at lower rates than their normal BMI counterparts in cohort studies. This has confused people for a very long time, but it’s starting to become less confusing. We’ll take a look at why being obese is a bad thing, right up until it isn’t.

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