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No evidence of plasmid-mediated antibiotic resistance in North American Yersinia pestis

No evidence of plasmid-mediated antibiotic resistance in North American Yersinia pestis. David M. Wagner 1 , Janelle Runberg 1 , Amy J. Vogler 1 , Judy Lee 1 , Lance B. Price 2 , David M. Engelthaler 2 , Jacques Ravel 3 , & Paul Keim 1

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No evidence of plasmid-mediated antibiotic resistance in North American Yersinia pestis

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  1. No evidence of plasmid-mediated antibiotic resistance in North American Yersinia pestis David M. Wagner1, Janelle Runberg1, Amy J. Vogler1, Judy Lee1, Lance B. Price2, David M. Engelthaler2, Jacques Ravel3, & Paul Keim1 1Northern Arizona University, Flagstaff, AZ; 2Translational Genomics Research Institute (TGen), Flagstaff, AZ; 3University of Maryland School of Medicine, Baltimore, MD

  2. Bubonic or Septicemic plague Plague Transmission Cycle Secondary Wild Rodent Cycle plague pneumonia Wild Rodent Direct contact Primary pneumonic plague cases Infective Infective Flea Direct contact Flea contaminated soil contact Direct Infective Flea Domestic Rodent Wild Rodent Pathways Infective usual Flea Domestic occasional Rodent Commensal Rat Cycle rare or theoretical Slide courtesy of Ken Gage

  3. Three Plague Pandemics – 200 Million Deaths Perry & Fetherston 1997 Achtman et al. 1999

  4. Control of Plague – Hygiene & Antibiotics • Kill or eliminate habitat for rat hosts – very important in urban areas • Control flea vectors using insecticides • Rapid diagnosis, followed by • Standard treatment with antibiotics • Streptomycin • Tetracyclines • Sulfonamides

  5. Plague Today – Global Distribution Stenseth et al. 2008. PLoS Medicine

  6. Plague Today – Increases in Africa Stenseth et al. 2008. PLoS Medicine

  7. Plague Today – Increases in Africa Stenseth et al. 2008. PLoS Medicine

  8. Plague Vaccines – Little Success to Date • Killed vaccine no longer available in the US • Live attenuated vaccine not licensed for humans • Injected subunit vaccines show promise for future • As a result, efforts to save human lives are still focused on rapid diagnosis followed by treatment with antibiotics • Resistance to antibiotics could represent a serious threat to human health given high pathogenicity and ability to rapidly spread under optimal conditions

  9. Antimicrobial Resistance in Y. pestis Galimand et al. 1997. New England Journal of Medicine

  10. Typical and Atypical Plasmids in Y. pestis • Three main plasmids, all associated w/ virulence: • pCD1 (found in all pathogenic Yersinia) • pPCP1 • pMT1 • pMT1 very similar to plasmid in Salmonella enterica Serovar Typhi • Several different studies have documented atypical plasmids present in Y. pestis strains • Indicates that this species readily acquires plasmids Filippov et al. 1990; Parkhill et al. 2001 ; Prentice et al. 2001

  11. Plasmid Acquisition Likely Occurs in Fleas • In co-infected fleas, E. coli donated pIP1202 to Y. pestis at frequency of 10-3 after three days • After four weeks, 95% of co-infected fleas contained MDR Y. pestis (Hinnebusch et al. 2002) • Y. pestis infected fleas can harbor diverse bacterial communities (Wagner et al. unpubl.) • Y. pestis infected fleas commonly co-infected with Salmonella spp. (Eskey et al. 1951) • What do we know about MDR plasmids in Y. pestis?

  12. Plasmid pIP1202 from Y. pestis • Similar to MDR plasmids from Y. ruckeri and S. enterica Newport • All share the same plasmid backbone (IncA/C) • Backbone contains gene conferring resistance to sulfonamides (sul2) • Other resistance genes vary Welch et al. 2007. PLoS One

  13. Similar MDR Plasmids in US Meat Products • Plasmids with similar IncA/C backbones and varying MDR profiles found in bacteria recovered from meat • Sources: turkey, chicken, beef, pork • States: CA, CO, CT, GA, IA, MD, MN, ND, NM, NY, TN, and OR • Hosts: S. enterica Typhimurium, Newport, Kentucky, Heidelberg, Dublin, Bredeney, Klebsiella spp., E. coli • Most resistant to tetracycline and many resistant to streptomycin and others, in addition to sulfonamides • Many strains readily transferred plasmids to Y. ruckeri Welch et al. 2007. PLoS One

  14. No Evidence in North American Y. pestis

  15. Discussion/Conclusions • No IncA/C plasmid-mediated MDR in North American Y. pestis – why? • Our isolates mostly from human plague investigations • MDR resistant plasmids in meats probably arose in Concentrated Animal Feeding Operations (CAFOs) • Plague limited to 17 westernmost states, whereas most CAFOs in the eastern states • Plausible that MDR Y. pestis could arise in fleas co-infected with MDR enteric pathogens and Y. pestis • However, no obvious selection pressure to maintain these MDR plasmids in Y. pestis

  16. Acknowledgements • Funding: NIH-NIAID, NIH Pacific-Southwest Regional Center of Excellence, Arizona Game & Fish, NAU-Cowden Endowment • CDC-Ft. Collins: Ken Gage, Becky Eisen, Jeannine Petersen, Marty Schriefer, Michael Kosoy • Arizona Department of Health Services: Craig Levy • Coconino County Health Department: Marlene Gaither • NAU Y. pestis Group: Amy Vogler, Becky Colman, Joe Busch, Judy Lee, Adina Doyle, Roxanne Nera

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