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C. difficile : The Role of Colonization and Phages

Dominik Mertz, MD, MSc & David Speicher, PhD

 

Dr. David Speicher (left) is a Post-doctoral Fellow from St. Joseph’s Healthcare Hamilton. Dr. Dominik Mertz (right) is an Associate Professor within McMaster University’s Department of Medicine and is the Hamilton Health Sciences Medical Director of Infection Control.

In this month’s ID/IIDR Combined Rounds, infectious disease experts Dr. Dominik Mertz and Dr. David Speicher presented their most recent research findings regarding C. difficile colonization and phages, respectively.

Dr. Mertz began the presentation with a discussion of C. diff colonization prevalence, which remains widely variable depending on the patient population of interest, the screening strategy applied, and the detection method used, amongst other factors. Screening methods for C. diff are primarily limited to small-scale routine admission screenings, as it is currently unclear how to sufficiently screen for C. diff on a larger scale. One small study of interest found that screening patients with risk factors for MRSA/VRE could identify approximately 75 percent of C. diff carriers.

Dr. Mertz further presented our present knowledge of C. diff transmission, particularly as it pertains to acquisition within health-care settings. He introduced one study in which clinicians screened and isolated asymptomatic C. diff carriers upon hospital admission, which led to a significant reduction in healthcare-associated C. diff infection (CDI) incidence rates in the months to follow. These results suggested this approach as a reasonable method for reducing C. diff prevalence in health-care settings; however, study limitations and Whole Genome Sequencing (WGS) data from other studies suggest a much lower potential. As such, although it is known that colonization plays an important role in hospital-acquired C. diff transmission, it is unclear whether the rate of transmission from colonized patients is closer to 10% or 60%.

In an effort to better determine C. diff colonization and transmission rates, Dr. Mertz’s research team developed the novel DECEnCy (Detection of C. difficile Colonization) research program. Along with a pilot randomized control trial, this program consists of four main projects, which Dr. Mertz proceeded to discuss in detail. The objective of the first project is to identify high-risk Hamilton in-patient populations that may benefit from active screening, with the second project intending to identify the most optimal screening strategy for C. diff carriers. In project three, the team is analyzing WGS data to determine what proportion of C. diff infections results from asymptomatic carriers. Finally, the fourth DECEnCy project aims to develop the most effective and cost-efficient method for the large-scale testing of C. diff samples.

Dr. Speicher followed Dr. Mertz with an introduction to C. diff-associated bacteriophages. To date, there are about twenty well-known phages associated with C. diff. Of the six most abundant phages, the majority are found to increase C. diff toxicity by affecting one or more bacterial functions. To better highlight this ability, Dr. Speicher discussed the concept of fecal filtrate transfer (FFT) as an alternative to fecal microbiota transplantation (FMT) for the treatment of CDI. Although FMT is highly effective in treating recurrent CDI, it may be possible to treat patients using only the sterile filtrate, which eliminates the risk of exposing the patient to disease-causing bacteria. He presented one study in which investigators performed FFT with five patients experiencing symptomatic chronic-relapsing CDI, and found that FFT restored normal stool habits and eliminated the infection in all five. Although no bacteria were found within the filtrate, tons of phage was identified – evidence suggesting that phages alone may be sufficient to restore normal stool habits.

Based on these findings, Dr. Speicher’s main research objective was to identify which phages associate with clinical CDI. In his first research project, Dr. Speicher screened both C. diff positive and C. diff negative fecal samples for associated myoviruses. Amongst the several phage types identified within the samples, three were found to have a substantial effect on C. diff toxicity. However, ambiguous results from his study questioned if phage was truly being amplified, suggested the need for greater quality control for the extraction of phage in fecal samples.

Clostridium difficile or “C. diff” infection can cause debilitating gastrointestinal symptoms that range from diarrhea to life-threatening colon inflammation.

This brought Dr. Speicher to the design of his second project, CrAssphage. CrAssphage – short for “Cross Assembly” – is a highly abundant bacteriophage found in approximately 75 percent of normal feces. Because of its abundance, Dr. Speicher selected CrAssphage as a quality control marker for the extraction of phage DNA from fecal samples. He found that in the presence of C. diff, CrAssphage is low, implying an inverse correlation between C. diff and CrAssphage abundance. However, upon further analysis, no clear-cut correlation was determined, suggesting that other bacteria could be contributing to this profile. Dr. Speicher suggested that the change in positivity and abundance might be due to the change in abundance and/or diversity of Bacteroides spp; however, further work must be done to confirm this.

Finally, Dr. Speicher presented his third project, looking at prophages found within previous WGS data. In this study, Dr. Speicher’s team screened 69 isolates from St. Joseph’s Healthcare Hamilton for intact, whole prophages. His team found 71 intact prophages, identified within 28 distinguishing clusters. Of particular interest, one cluster contained 34 phages that were incomparable with any other identified phage. This is likely a new phage species, discovered at St. Joes.

In conclusion, Dr. Mertz’s and Dr. Speicher’s presentation on C. diff colonization and associated bacteriophages highlight the importance of taking multi-disciplinary approaches towards understanding and managing infectious diseases.

ID/IDR Combined Joint Rounds are presented on the first Wednesday of every month at the McMaster University Medical Centre and are open to all IIDR members and trainees. Check out October’s IIDR/ID Rounds, in which IIDR principal investigators Dr. Marek Smieja and Dr. Andrew McArthur describe how they are applying clinical and molecular research to prevent CDI.