Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits.

Clostridioides difficile is an important human pathogen, for which there are very limited treatment options, primarily the glycopeptide antibiotic vancomycin. In recent years, vancomycin resistance has emerged as a serious problem in several gram-positive pathogens, but high-level resistance has yet to be reported for C. difficile, although it is not known if this is due to constraints upon resistance evolution in this species. Here, we show that resistance to vancomycin can evolve rapidly under ramping selection but is accompanied by fitness costs and pleiotropic trade-offs, including sporulation defects that would be expected to severely impact transmission. We identified 2 distinct pathways to resistance, both of which are predicted to result in changes to the muropeptide terminal D-Ala-D-Ala that is the primary target of vancomycin. One of these pathways involves a previously uncharacterised D,D-carboxypeptidase, expression of which is controlled by a dedicated two-component signal transduction system. Our findings suggest that while C. difficile is capable of evolving high-level vancomycin resistance, this outcome may be limited clinically due to pleiotropic effects on key pathogenicity traits. Moreover, our data identify potential mutational routes to resistance that should be considered in genomic surveillance.

Learning from others: A low-cost-high-impact risk/opportunity identification technique.

News for risk/opportunity identification (NfROI) is a tool for practitioners to leverage the journey from a risk management mindset to an enterprise risk management approach. NfROI unleashes the power of storytelling and provides a standardized format to enhance the existing practice of gleaning information from sources such as JHRM, news outlets, social media, and the ASHRM Exchange. A series of 3 examples highlight the advantages of learning from others as a complement to retrospective internal data. The stories have implications across the ASHRM's ERM Framework domains and thereby provide bridges across the pillars in the organizational chart. Learning from others can reduce costs and reveal emerging risks before the direct impact on the organization.