Clostridium difficile: Emergence of Hypervirulence and Fluoroquinolone Resistance

Abstract

Clostridium difficile is a well-known cause of sporadic and healthcare-associated diarrhea. Multihospital outbreaks due to a single strain and outbreaks associated with antibiotic selective pressure, especially clindamycin, have been well documented. Severe cases and fatalities from C. difficile are uncommon. The recent global emergence of a hypervirulent strain containing binary toxin (Toxinotype III ribotype 027), with or without deletion in a regulatory gene (tcdC gene), together with high-level resistance to third generation fluoroquinolones, has been associated with increased morbidity and mortality. Although the defective regulatory gene locus is associated with increased toxin production in vitro, the in vivo significance of this mutation and of the binary toxin remains undefined. To date, treatment strategies have not evolved in response to the emergence of this hypervirulaent strain. We provide a critical, quantitative summary of the evolving clinical and molecular epidemiology of C. difficile along with implications relevant to future treatment strategies.

Antivirulence Genes: Insights into Pathogen Evolution through Gene Loss

“…The term "hypervirulent" is often used to describe a strain that exhibits a significant increase in virulence compared to either the parental wild-type strain or related strains within the same species. Such an increase in virulence may be due to the functional loss of one or more genes, and this phenomenon has been documented in wild-type strains or discovered through genetic manipulation of strains within the laboratory (3,26,44). However, such genes are still functional in either the majority of wild-type strains within the same species or, in the case of labinduced hypervirulence, in the parent wild-type strain and therefore do not fit our criteria for AVGs.…”

Clostridium difficileinfection

“…Fluoroquinolone (FQ) resistance has increased in C. difficile 80 and NAP1/027/BI isolates are typically FQ resistant, though this is not always the case. 81 Resistance is primarily mediated by mutations in the DNA gyrase-encoding genes gyrA/B, leading to subnormal weaning weights and, ultimately, reduced slaughter weights.…”

Multilocus Sequence Typing of Clostridium difficile

“…The rate and severity of nosocomial infections increased between the years 2000 and 2008 (27,46,47), coincident with the emergence of a hypervirulent fluoroquinolone-resistant clone, designated PCR ribotype 027 (31,34). Outbreaks of C. difficile infection (CDI) caused by the 027 clone have been reported in North America and throughout Europe (15,18,23,31,32).…”