A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078
ABSTRACT The increasing clinical importance of human infections (frequently severe) caused by Clostridium difficile 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 co...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-04-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.02790-18 |
| _version_ | 1818997444477714432 |
|---|---|
| author | Kate E. Dingle Xavier Didelot T. Phuong Quan David W. Eyre Nicole Stoesser Charis A. Marwick John Coia Derek Brown Sarah Buchanan Umer Z. Ijaz Cosmika Goswami Gill Douce Warren N. Fawley Mark H. Wilcox Timothy E. A. Peto A. Sarah Walker Derrick W. Crook |
| author_facet | Kate E. Dingle Xavier Didelot T. Phuong Quan David W. Eyre Nicole Stoesser Charis A. Marwick John Coia Derek Brown Sarah Buchanan Umer Z. Ijaz Cosmika Goswami Gill Douce Warren N. Fawley Mark H. Wilcox Timothy E. A. Peto A. Sarah Walker Derrick W. Crook |
| author_sort | Kate E. Dingle |
| collection | DOAJ |
| description | ABSTRACT The increasing clinical importance of human infections (frequently severe) caused by Clostridium difficile 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, n = 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 tetM. Consequently, an unusually high proportion (76.5%) of RT078 genomes were tetM positive. Multiple additional tetracycline resistance determinants were also identified (including efflux pump tet40), frequently sharing a high level of nucleotide sequence identity (up to 100%) with sequences found in the pig pathogen Streptococcus suis and in other zoonotic pathogens such as Campylobacter jejuni and Campylobacter coli. Each RT078 tetM clonal expansion lacked geographic structure, indicating rapid, recent international spread. Resistance determinants for C. difficile 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. IMPORTANCE Clostridium difficile 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 C. difficile, suggesting that this process may be widespread and may be independent of disease-causing ability. Resistance to typical C. difficile 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. |
| first_indexed | 2024-12-20T21:45:44Z |
| format | Article |
| id | doaj.art-752316b0b3094d6aa6a828efa7146167 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-20T21:45:44Z |
| publishDate | 2019-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-752316b0b3094d6aa6a828efa71461672022-12-21T19:25:41ZengAmerican Society for MicrobiologymBio2150-75112019-04-0110210.1128/mBio.02790-18A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078Kate E. Dingle0Xavier Didelot1T. Phuong Quan2David W. Eyre3Nicole Stoesser4Charis A. Marwick5John Coia6Derek Brown7Sarah Buchanan8Umer Z. Ijaz9Cosmika Goswami10Gill Douce11Warren N. Fawley12Mark H. Wilcox13Timothy E. A. Peto14A. Sarah Walker15Derrick W. Crook16Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomSchool of Life Sciences and Department of Statistics, University of Warwick, Coventry, United KingdomNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomPopulation Health Sciences, School of Medicine, University of Dundee, Scotland, United KingdomScottish Microbiology Reference Laboratories, Glasgow, United KingdomScottish Microbiology Reference Laboratories, Glasgow, United KingdomUniversity of Glasgow, Scotland, United KingdomUniversity of Glasgow, Scotland, United KingdomUniversity of Glasgow, Scotland, United KingdomUniversity of Glasgow, Scotland, United KingdomDepartment of Microbiology, Leeds General Infirmary, Leeds Teaching Hospitals, University of Leeds, Leeds, United KingdomDepartment of Microbiology, Leeds General Infirmary, Leeds Teaching Hospitals, University of Leeds, Leeds, United KingdomNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomABSTRACT The increasing clinical importance of human infections (frequently severe) caused by Clostridium difficile 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, n = 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 tetM. Consequently, an unusually high proportion (76.5%) of RT078 genomes were tetM positive. Multiple additional tetracycline resistance determinants were also identified (including efflux pump tet40), frequently sharing a high level of nucleotide sequence identity (up to 100%) with sequences found in the pig pathogen Streptococcus suis and in other zoonotic pathogens such as Campylobacter jejuni and Campylobacter coli. Each RT078 tetM clonal expansion lacked geographic structure, indicating rapid, recent international spread. Resistance determinants for C. difficile 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. IMPORTANCE Clostridium difficile 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 C. difficile, suggesting that this process may be widespread and may be independent of disease-causing ability. Resistance to typical C. difficile 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.https://journals.asm.org/doi/10.1128/mBio.02790-18Clostridium difficiletetracycline resistancewhole-genome sequencingphylogenetic analysisemerging pathogenPCR ribotype 078 |
| spellingShingle | Kate E. Dingle Xavier Didelot T. Phuong Quan David W. Eyre Nicole Stoesser Charis A. Marwick John Coia Derek Brown Sarah Buchanan Umer Z. Ijaz Cosmika Goswami Gill Douce Warren N. Fawley Mark H. Wilcox Timothy E. A. Peto A. Sarah Walker Derrick W. Crook A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078 mBio Clostridium difficile tetracycline resistance whole-genome sequencing phylogenetic analysis emerging pathogen PCR ribotype 078 |
| title | A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078 |
| title_full | A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078 |
| title_fullStr | A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078 |
| title_full_unstemmed | A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078 |
| title_short | A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated <italic toggle="yes">Clostridium difficile</italic> PCR Ribotype 078 |
| title_sort | role for tetracycline selection in recent evolution of agriculture associated italic toggle yes clostridium difficile italic pcr ribotype 078 |
| topic | Clostridium difficile tetracycline resistance whole-genome sequencing phylogenetic analysis emerging pathogen PCR ribotype 078 |
| url | https://journals.asm.org/doi/10.1128/mBio.02790-18 |
| work_keys_str_mv | AT kateedingle arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT xavierdidelot arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT tphuongquan arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT davidweyre arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT nicolestoesser arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT charisamarwick arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT johncoia arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT derekbrown arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT sarahbuchanan arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT umerzijaz arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT cosmikagoswami arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT gilldouce arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT warrennfawley arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT markhwilcox arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT timothyeapeto arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT asarahwalker arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT derrickwcrook arolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT kateedingle rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT xavierdidelot rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT tphuongquan rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT davidweyre rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT nicolestoesser rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT charisamarwick rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT johncoia rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT derekbrown rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT sarahbuchanan rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT umerzijaz rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT cosmikagoswami rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT gilldouce rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT warrennfawley rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT markhwilcox rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT timothyeapeto rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT asarahwalker rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 AT derrickwcrook rolefortetracyclineselectioninrecentevolutionofagricultureassociateditalictoggleyesclostridiumdifficileitalicpcrribotype078 |