Decoding the clinical impact of the recent evolution of metronidazole resistance on Clostridium difficile infection.

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PROJECT SUMMARY/ABSTRACT Clostridium difficile infection (CDI) is a major hospital-acquired illness that causes severe morbidity and mortality. In 2011, the CDC reported that there were 453,000 cases of CDI in the United States, with 29,000 deaths. The emergence of epidemic strains, notably NAP1/027, has considerably increased the prevalence and severity of the disease. This clade of C. difficile developed resistance to both metronidazole (a CDI medication) and fluoroquinolones (commonly used antibiotics). As a result, two selection forces drove the worldwide spread of epidemic strains. Now the strains are increasingly becoming resistant to vancomycin, the antibiotic of choice for CDI. Vancomycin is an important first-line treatment for CDI, and increased prescribing of this antibiotic has raised selection pressures. Vancomycin resistance is increasingly more prevalent in epidemic strains, especially NAP1/027, and our study revealed that these strains are spreading internationally. This is concerning since this lineage is associated with severe illness and rapid transmission in hospitals. Preliminary findings indicate that patients infected with vancomycin resistant strains are twice as likely to have poor clinical outcomes. Genome analyses indicate these strains are developing primary and secondary resistance mechanisms that allow them to persist in drug concentrations predicted to occur in the colons of patients. Critical questions remain to understand this emerging form of C. difficile, which address in three cohesive aims. In one goal, we perform clinical studies and epidemiological research using biobanked samples and patient metadata to understand how these emerging pathogens affect clinical outcomes and disease characteristics, during vancomycin therapy. It is supported by clinical reflective in vitro and animas models of CDI. In the second goal, the strains will be genetically characterized to delineate genetic variations that promote treatment failures in patients. These genetic signatures will be molecularly validated in the lab and used in population-based analyses of public genomes to understand global patterns of resistance among patient isolates. Lastly, given there are few treatment options for CDI, other antibiotic strategies will be investigated to provide additional coverage of organisms prone to vancomycin to fail. The outcome of this research will be delineation of genetic variations that evolve in C. difficile that cause therapeutic failure. This will lay the foundation for molecular and genomic diagnostics to rapidly detect these strains to improve prescribing approaches for CDI patients. Public health. This study has significant implications for the diagnosis and treatment of CDI, a disease that imposes a major public health and economic burden in the United States.