Clostridium difficile Research and Development; February/March 2014

February/March 2014

Here’s the latest from the Clostridium difficile research community:

C. difficile was first identified in the stool of neonates in 1935 by Hall and O’Toole. Approximately 30% of newborns are colonized with C. difficile, although by age 3, only 3-5% are asymptomatically colonized. CDI, historically not a pediatric disease, is now on the rise in this population. Pediatric patients with risk factors for CDI include that antibiotic therapy, immunodeficiency, poor diet, comorbidities should be tested for CDI if presented with persistent diarrhea.  Wendt et al looked at 944 pediatric cases of CDI and found that 71% of the cases were community-acquired and the incidence of CDI was highest among 1-year-olds, with 72% with diarrhea and 8% with severe disease.  With the increased severity of CDI, conscientious use of antimicrobials should be implemented in this patient population.

C.difficile is a spore forming anerobe. Although the vegetative form of the bacterium expresses the disease causing virulence factors, it is the highly-resistant spores that are the infectious units needed for fecal-oral transmission.  Spo0A is a master regulator of sporulation and has now been proven to positively regulate sporulation genes and also several virulence factors such as flagella, as well as factors involved in the metabolic pathway.

C.difficile expresses two major toxins, A and B. The toxins have a tripartite structure with an enzymatically active N-terminal domain, a central translocation section and a C-terminal receptor-binding domain (RBD) consisting of repeating units of 21, 30 or 50 amino acid residues.  The toxins function by internalization into endosomes followed by the release of the activation domain into the cytosol of the cell via the 1,050-aa translocation domain.  By systemic mutagenesis, Zhang et al have identified a region in toxin B between aa 1035 and 1107 that decrease cellular toxicity more than a 1000x due to impaired pore formation.

Given the importance of the role of the human microflora in preventing CDI, svereal groups have been studying the effects of various antibiotics on the microflora of the host. In one study, mice given tigecycline saw decreased Bacteroidetes and increased Proteobacteria and were at a higher risk of developing CDI.

In the second study, 16S rRNA was sequenced from healthy human controls (no antibiotic therapy); individuals receiving antibiotic therapy with subsequent CDI and individuals receiving antibiotic therapy without CDI.  The authors suggest that differential regulation of specific bacterial species may be involved in colonization resistance against CDI and this finding could lead to the identification of potential new therapies via the manipulation of the intestinal microbiome such as probiotic treatment.

Chandrabali Ghose-Paul,MS,PhD,  Chairperson of Research and Development