A role for tetracycline selection in recent evolution of agriculture-associated Clostridium difficile PCR ribotype 078

Dingle, K. E. et al. (2019) A role for tetracycline selection in recent evolution of agriculture-associated Clostridium difficile PCR ribotype 078. mBio, 10(2), e02790-18. (doi: 10.1128/mBio.02790-18) (PMID:30862754) (PMCID:PMC6414706)

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The increasing clinical importance of human infections (frequently severe) caused by PCR ribotype 078 (RT078) was first reported in 2008. The severity of symptoms (mortality of ≤30%) and the higher proportion of infections among community and younger patients raised concerns. Farm animals, especially pigs, have been identified as RT078 reservoirs. We aimed to understand the recent changes in RT078 epidemiology by investigating a possible role for antimicrobial selection in its recent evolutionary history. Phylogenetic analysis of international RT078 genomes (isolates from 2006 to 2014,  = 400), using time-scaled, recombination-corrected, maximum likelihood phylogenies, revealed several recent clonal expansions. A common ancestor of each expansion had independently acquired a different allele of the tetracycline resistance gene Consequently, an unusually high proportion (76.5%) of RT078 genomes were positive. Multiple additional tetracycline resistance determinants were also identified (including efflux pump ), frequently sharing a high level of nucleotide sequence identity (up to 100%) with sequences found in the pig pathogen and in other zoonotic pathogens such as and Each RT078 clonal expansion lacked geographic structure, indicating rapid, recent international spread. Resistance determinants for infection-triggering antimicrobials, including fluoroquinolones and clindamycin, were comparatively rare in RT078. Tetracyclines are used intensively in agriculture; this selective pressure, plus rapid, international spread via the food chain, may explain the increased RT078 prevalence in humans. Our work indicates that the use of antimicrobials outside the health care environment has selected for resistant organisms, and in the case of RT078, has contributed to the emergence of a human pathogen. PCR ribotype 078 (RT078) has multiple reservoirs; many are agricultural. Since 2005, this genotype has been increasingly associated with human infections in both clinical settings and the community. Investigations of RT078 whole-genome sequences revealed that tetracycline resistance had been acquired on multiple independent occasions. Phylogenetic analysis revealed a rapid, recent increase in numbers of closely related tetracycline-resistant RT078 (clonal expansions), suggesting that tetracycline selection has strongly influenced its recent evolutionary history. We demonstrate recent international spread of emergent, tetracycline-resistant RT078. A similar tetracycline-positive clonal expansion was also identified in unrelated nontoxigenic , suggesting that this process may be widespread and may be independent of disease-causing ability. Resistance to typical infection-associated antimicrobials (e.g., fluoroquinolones, clindamycin) occurred only sporadically within RT078. Selective pressure from tetracycline appears to be a key factor in the emergence of this human pathogen and the rapid international dissemination that followed, plausibly via the food chain.

Item Type:Articles
Keywords:Clostridium difficile, PCR ribotype 078, emerging pathogen, phylogenetic analysis, tetracycline resistance, whole-genome sequencing.
Glasgow Author(s) Enlighten ID:Douce, Dr Gillian and Goswami, Dr Cosmika and Buchanan, Dr Sarah and Ijaz, Dr Umer
Authors: Dingle, K. E., Didelot, X., Quan, T. P., Eyre, D. W., Stoesser, N., Marwick, C. A., Coia, J., Brown, D., Buchanan, S., Ijaz, U. Z., Goswami, C., Douce, G., Fawley, W. N., Wilcox, M. H., Peto, T. E.A., Walker, A. S., and Crook, D. W.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Science and Engineering > School of Engineering > Infrastructure and Environment
Journal Name:mBio
Publisher:American Society for Microbiology
ISSN (Online):2150-7511
Published Online:12 March 2019
Copyright Holders:Copyright © 2019 Dingle et al.
First Published:First published in mBio 10(2): e02790-18
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
627401Molecular epidemiology of Clostridium difficile in Scotland - developing novel, clinically applicable research methods to combine genomic analysis with health informaticsGillian DouceScottish Government (SCOTGOV)SIRN/09III - BACTERIOLOGY
652772Understanding microbial community through in situ environmental 'omic data synthesisUmer Zeeshan IjazNatural Environment Research Council (NERC)NE/L011956/1ENG - ENGINEERING INFRASTRUCTURE & ENVIR