Frozen, Thawed Fecal Microbiota Effective for C difficile

Laird Harrison

January 13, 2016

Fecal microbiota can successfully treat Clostridium difficile infections after being frozen and thawed, a new study shows.

The finding may lead to ways of overcoming logistical challenges presented by the use of fresh fecal microbiota, according to Christine H. Lee, MD, from McMaster University, Hamilton, Ontario, Canada, and colleagues.

The researchers published their study in the January 12 issue of JAMA.

C difficile infections resist conventional treatments, and more than 60% of patients experience further episodes after a first recurrence, the researchers report.

The organism apparently profits from the destruction of protective gut flora by antibiotics used to treat other infections.

Previous studies have shown that transplantation of fecal microbiota by enema from a healthy donor can cure these infections, apparently by restoring protective flora.

The use of frozen, thawed fecal microbiota could reduce costs by cutting down the number and frequency of donor screenings. In addition, the material could be available immediately and could be provided to centers that do not have on-site laboratories.

Although previous studies have supported the use of frozen fecal material, they have not directly compared frozen with fresh material, the researchers report. To fill that gap, Dr Lee and colleagues randomly divided adult patients with recurrent or refractory C difficile infections into two groups. They administered frozen, thawed fecal microbiota to 108 of these patients and fresh fecal microbiota to 111.

The patients had a mean age of 73.0 years. The median duration of their C difficile infections was about 3 months, and they had been receiving antibiotic treatments for these infections for a median of about 7 weeks. The two groups were not significantly different in age, sex, or severity of infection.

The study took place at six academic medical centers in Canada. The researchers diluted 100 g of stool samples from healthy donors with 300 mL of commercially bottled water and emulsified it using a sterile wooden spatula.

Most of the samples came from three donors, who were prospectively screened and rescreened every 6 months.

The researchers strained out the solids through gauze and aspirated the remaining suspension into 60-mL syringes, which they used to administer the enemas. The researchers administered the fresh suspensions within 24 hours of collection. They kept the frozen suspensions at −20°C for up to 30 days and then thawed them overnight at 25°C.

The researchers defined resolution as no C difficile-related diarrhea for 13 weeks.

The C difficile infections resolved in 75% of those who received the frozen suspension and 70.3% of those who received the fresh material (difference, 4.7% [95% one-sided confidence interval, −5.2% to ∞]; P < .001 for noninferiority).

Some patients received multiple enemas, and the rate of rate of resolution increased with the number of enemas.

The researchers performed a second analysis in which they eliminated patients who received antibiotics, received both fresh and frozen suspensions, or did not complete the study because of death, withdrawal, or loss to follow-up.

In this per protocol population, 91 patients received the thawed material and 87 received the fresh material. Of these, the infections resolved in 83.5% in the group receiving frozen suspension and 85.1% receiving fresh suspensions (difference, −1.6% [95% one-sided confidence interval, −10.5% to ∞]; P = .01 for noninferiority).

Because the lower confidence limits were above the noninferiority margin of −15% in both populations, the researchers determined the thawed fecal microbiota to be noninferior to fresh.

There were no differences in the proportion of adverse or serious adverse events between the treatment groups. The most common adverse events considered to be possibly related to the treatments were transient diarrhea, abdominal cramps, or nausea during the 24 hours after a treatment, and constipation and excessive flatulence during the follow-up period. All were mild to moderate.

The researchers acknowledged limitations to their study: its short follow-up, a lower rate of clinical response than some previous studies, and the low number of donors.

"In this clinical trial, the use of frozen [fecal macrobiota transplants (FMT)] compared with fresh FMT for the treatment of recurrent or refractory [C difficile infections] was noninferior in terms of efficacy; findings for frozen FMT and fresh FMT were similar in terms of safety," the authors conclude.

"Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting."

The researchers plan to continue following these patients to study the long-term effects of the treatment.

The study will probably result in fecal microbiota being available to more patients with C difficile, as — if the microbiota can be frozen — "stool collection and processing need not be tied to the procedure date and time," write Preeti N. Malani, MD, MSJ, and Krishna Rao, MD, in an accompanying editorial. "This study also provides greater support for the practice of using centralized stool banks," write the editorialists, from the Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor.

However, they note that many hurdles remain. For example, draft guidelines by the US Food and Drug Administration could stop stool banks from operating, Dr Malani and Dr Rao write. "Specifically, language in the draft guidance states the donor must be personally known to either the patient or treating physician, a criterion not met by most stool banks."

In addition, the number of patients with refractory C difficile infections in this study was too small to determine the safety and efficacy in this population. And more studies are needed to see whether this type of treatment could benefit patients with other conditions related to gut microbiota, such as obesity, inflammatory bowel disease, diabetes, and colon cancer.

The study was funded by Physicians Services Incorporated, Natural Sciences and Engineering Council, National Science Foundation, and Gastrointestinal Diseases Research Unit, Kingston General Hospital, Ontario. Dr Lee reported relationships with ViroPharma, Actelion, Cubist, Merck and Rebiotix. Various coauthors reported relationships with Cubist, Merck Canada, Sanofi Pasteur, the Heart and Stroke Foundation of Ontario, Leo Pharma, Bayer Alexion, Ortho Clinical Diagnostics, BMS-Pfizer Alliance, Celgene, Shire, and CSL Behring. Dr Rao reported that his work was partially supported by a grant from the Claude D. Pepper Older Americans Independence Center.

JAMA. Published online January 12, 2015. Article abstract, Editorial extract


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