Presence of multiple Clostridium difficile strains at primary infection is associated with development of recurrent disease

Abstract

Recurrence of Clostridium difficile infection (CDI) places a major burden on the healthcare system. Previous studies have suggested that specific C. difficile strains, or ribotypes, are associated with severe disease and/or recurrence. However, in some patients a new strain is detected in subsequent infections, complicating longitudinal studies focused on strain differences that may contribute to disease outcome. We examined ribotype composition over time in patients who did or did not develop recurrence to examine infection with multiple C. difficile ribotypes (mixed infection), during the course of infection. Using a retrospective patient cohort, we isolated and ribotyped a median of 36 C. difficile colonies from 61 patients (105 total samples) at initial infection, recurrence (a second case of CDI within 15-56 days of initial infection), and reinfection (a second case of CDI after 56 days of initial infection). We observed mixed infection in 78.6% of samples at initial infection in patients who went on to develop recurrence compared to 18.1% of patients who did not, and mixed infection remained associated with subsequent recurrence after adjusting for gender and prior antibiotic exposure (OR 3.5, 95% CI 1.3-9.4, P = .015). In patients who were sampled longitudinally (44 consecutive events in 32 patients), the dominant ribotype changed in 31.8% of consecutive samples and the newly dominant ribotype was not detected in prior samples from that patient. Our results suggest that mixed C. difficile infection is more prevalent than previously demonstrated and potentially a marker of susceptibility to recurrence.

Protection from lethalClostridioides difficileinfection via intraspecies competition for co-germinant

“…Reports of patients infected with multiple strains of C. difficile suggest that despite our results, infection with multiple strains can occur (21, 22). When we infected mice with different ratios of spores from each of the two strains simultaneously, we found that both strains were capable of colonizing despite starting with over a 1000x less str.…”

“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted February 27, 2021. ; https://doi.org/10.1101/2021.02.26.433146 doi: bioRxiv preprint Reports of patients infected with multiple strains of C. difficile suggest that despite our results, infection with multiple strains can occur (21,22). When we infected mice with different ratios of spores from each of the two strains simultaneously, we found that both strains were capable of colonizing despite starting with over a 1000x less str.…”

Antimicrobial Susceptibility and Molecular Characterization Using Whole-Genome Sequencing of Clostridioides difficile Collected in 82 Hospitals in Japan between 2014 and 2016

“…In a previous report, the same C. difficile ribotypes isolated at baseline were also isolated over a long period of time (14 to 56 days) in recurrent CDI cases (31). Therefore, the differences in the timing of sampling for analysis of C.…”

Clostridioides difficile Whole-Genome Sequencing Reveals Limited Within-Host Genetic Diversity in a Pediatric Cohort

“…It is possible that we would have detected more frequent within-host genetic diversity if we had sampled more than 8 colonies per culture. In a previous study in adults (15), 36 colonies per culture were isolated from adults with CDI, and half of the cultures had more than 1 (median of 2) unique ribotype; the presence of multiple ribotypes at the time of initial CDI was associated with subsequent CDI recurrence.…”