Promising New Treatment Emerges For Deadly C. difficile Colitis

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A new Phase 2 pilot study shows that giving spores of a non-toxic C. difficile bacteria by mouth is effective in stopping repeated bouts of C. diff infection, a major complication of hospitalization.

While C. diff infections used to cause an unpleasant but generally benign illness with repeated bouts of diarrhea, there has been a remarkable change over the last 10 years of my practice. The infection became more common, patients were generally more severely ill, and the infection became increasingly difficult to treat. C. diff colitis (bowel inflammation) went from responding to a brief course of Flagyl (metronidazole), to requiring more prolonged and very expensive courses of oral Vancomycin, to now being often refractory to therapy. I’ve seen patients require emergency colectomy, surgery to remove the bowel, or occasionally die.

C. difficile fluorescence - CDC

Epidemiology of C. difficile infections

Most cases of C. diff are associated with healthcare—being hospitalized and receiving broad-spectrum antibiotics, in particular, as well as in nursing home or clinic patients. About half the infections occur in those older than 65, but they account for 90% of the deaths. Use of proton pump inhibitors (e.g. Nexium, Prilosec, Prevacid, or Protonix) also predisposes to this infection.
From 2000-2010, hospitalizations for C. diff doubled, along with emergence of a more virulent strain, North American pulsed-field gel electrophoresis type 1 (NAP1, aka BI or 027)), which produces more toxins. During that period, deaths related to C. difficile increased 400%, now reaching 29,000 deaths each year in the U.S., up from 14,000 in 2013 CDC report.

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Treatment

C. diff, especially the NAP1 strains, don’t respond well to oral metronidazole, which is inexpensive. Oral Vancomycin is expensive ($1161 for a 10 day course), and is often given for 2-3 weeks. If patients relapse, which happens in 25-30% of patients, treatment is resumed, followed by a gradually tapering course of that antibiotic. A new antibiotic, Fidoxamicin (Optimer Pharmaceuticals), approved in 2011, is now sometimes used, but again is prohibitively expensive to many, at $2800/course. It has the advantage of not altering the GI flora as much as vancomycin and flagyl do. More recently, some favor stool transplants, euphemistically known as fecal microbiota therapy (FMT), for patients with recurrent infections. While unaesthetic and of limited use due to the “ick” factor, FMT is dramatically effective, with a 90% cure rate. Unfortunately, current recommendations are that the stool donor be tested for a variety of infectious diseases at a cost of $1500-2000. There might be a week’s delay, while the donor is tested for hepatitis and other infections, particularly if at a community hospital that relies on sending out specimens for lab testing. Other than the burdensome testing, I haven’t entirely understood why FMT has not been more widely recommended as first-line treatment.

In this just released Phase 2 study report in Journal of the American Medical Association (JAMA), Dale Gerding’s team at the Hines VA hospital and 44 other sites used a novel approach to therapy—a sort of biological warfare, in which they fed some of the patients spores of a specific strain of C. difficile, NTCD-M3, in an attempt to repopulate their bowel with a nontoxigenic strain. By recolonizing the bowel, this way, they hypothesized that recurrent infections would be reduced.

The researchers randomized 173 patients with either their first infection or first recurrence to one of four treatment groups: oral liquid formulation of the nontoxigenic strain of C. difficile, NTCD-M3, at a dose of 104 spores/day for 7 days, 107 spores/day for 7 days or 14 days, or placebo. The researchers found they were able to recolonize 71% of the patients with the higher dose of the spores compared to 63% with the lower dose. Recurrent C. diff infection occurred in 30% of placebo patients vs. 11% of the treated patients, with the lowest recurrence (5%) in those who received the higher dose. Only 2% of patients who were successfully colonized became recurrently ill, vs. 31% of those who were not colonized. Also, the need for repeated antibiotic courses reduced from 33% in the placebo group to 14% in patients who were treated with the NTCD-M3 strain. No significant adverse events were seen in this small trial.

This is a well-done study in that it was randomized, double-blind, and placebo-controlled. This means that the researchers did not know which treatment each patient received until all the evaluations were completed, eliminating bias or manipulation of data. The primary limitation is that there were small numbers of patients in each of the treatment groups, to be expected in a pilot study. Hopefully, the findings will be replicated in Phase 3 clinical trials. The trial was sponsored by ViroPharma/Shire.

The study is important for markedly reducing recurrent infections as well as limiting the use of oral vancomycin, which contributes to the emergence of antibiotic resistant organisms. Recolonization of a patient’s GI tract with a seemingly benign organism would be an important treatment option.

Prevention

Of course, the best option would be to prevent nosocomial (healthcare acquired) infections to begin with. For C. diff, it is important to limit exposure to antibiotics, as they wipe out normal bowel flora, predisposing to infection with toxigenic strains of C. diff. Thorough cleaning of patient rooms is important, and patients should be carefully isolated from others. Gloves should be used for additional protection. One important difference is that hands must be washed with soap and water—not an alcohol hand sanitizer—as alcohol is ineffective in killing the spores. So for Hand Hygiene Day, remember to wash your hands.

Source: Forbes