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Examining Antibiotic Resistance in the Feedlot Cattle Industry Using Real-Time, Quantitative PCR (Qpcr) and Enterococci As an In

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Examining Antibiotic Resistance in the Feedlot Cattle Industry Using Real-Time, Quantitative PCR (Qpcr) and Enterococci As an In Examining antibiotic resistance in the feedlot cattle industry using real-time, quantitative PCR (qPCR) and enterococci as an indicator bacterium Alicia Grace Beukers A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Faculty of Veterinary Science The University of Sydney 2016 Abstract Antibiotics are administered to livestock at subtherapeutic levels to maintain animal health. Many of the antibiotics used are analogues or the same as those used in human medicine, raising the possibility that genes conferring resistance arise within agricultural production systems with implications for human health. In beef cattle, macrolides are administered for the control of bovine respiratory disease and liver abscesses and have been identified by the World Health Organization as critically important antibiotics for which management strategies are required to prevent resistance development. Enterococci are present in the gastrointestinal tract of humans and cattle and are also associated with nosocomial infections in humans. They are an indicator bacterium that can be used to monitor macrolide resistance. This thesis examined antibiotic resistance in the Canadian beef feedlot industry. Real-time, quantitative PCR was used to examine differences in the relative abundance of eighteen resistance genes across five antibiotic families including sulfonamides [sul1 and sul2], tetracyclines [tet(A), tet(B), tet(M), tet(O), tet(Q) and tet(W)], macrolides [erm(A), erm(B), erm(C), erm(F) and mef(A)], fluoroquinolones [qnrS and oqxB] and β-lactams [blaSHV, blaTEM1 and blaCTX-M] from feedlot cattle faeces and urban environments. The effect of in-feed administration and withdrawal of tylosin phosphate on macrolide resistance was examined using enterococci as an indicator bacterium. Resistant enterococci (n=21) were selected for whole-genome sequencing and comparative genomics. Results presented here show that the relative abundance of resistance genes differs between cattle feedlots and urban environments, likely a reflection of differences in antibiotic use. Sulfonamide, fluoroquinolone and β-lactam resistance genes predominated in urban wastewater, whilst tetracycline resistance genes were more prevalent in cattle faeces. The inclusion of tylosin in the diet of cattle at subtherapeutic levels increased the proportion of erythromycin- and ii tylosin-resistant enterococci. However, withdrawal of tylosin from the diet appeared to contribute to a reduction in macrolide resistant enterococci. Comparative genomics revealed resistance to macrolides was present on mobile genetic elements, specifically the Tn917 transposon harbouring erm(B). This transposon was identified in both Enterococcus hirae and Enterococcus faecium, suggesting inter-species transfer of resistance genes may occur in the bovine gastrointestinal tract. Furthermore, the integrative conjugative elements (ICEs) Tn916 and Tn5801, both conferring tetracycline resistance, were identified in E. faecium. As the cost of genomic sequencing continues to decrease, further investigation of ICEs using whole genome sequencing will help determine if there are linkages between enterococci isolates from bovine environmental and human clinical sources and whether bovine enterococci represent a source of dissemination and spread of antibiotic resistance. Although macrolide resistance in enterococci decreased following the withdrawal of macrolides from cattle feed, this is not a reason to become complacent with the use of macrolides in cattle production. Investigating alternatives to macrolides for the control of bovine respiratory disease and liver abscesses, such as vaccines and plant bioactives, is becoming increasingly important. Furthermore, implementation of management practices by cattle producers that reduce the likelihood of disease spread is also essential to reduce the need to use antibiotics to control infectious diseases. iii Declaration The work described in this thesis was conducted under the supervision of Associate Professor Alexandre V. Chaves, Faculty of Veterinary Science, The University of Sydney, Australia and under the co-supervision of Professor Michael P. Ward, Faculty of Veterinary Science, The University of Sydney, Australia and Dr. Tim A. McAllister, Lethbridge Research Centre, Agriculture and Agri-Food Canada, Canada. I declare that this thesis is the result of my own work, original and is not currently being submitted for any other degree or qualification. Full acknowledgement has been made where the work of others has been cited or used. Alicia Grace Beukers iv Acknowledgements First of all I would like to thank my supervisors Associate Professor Alex V. Chaves and Professor Michael Ward from the University of Sydney and Dr. Tim A. McAllister from Agriculture and Agri-Food Canada for your continued support, encouragement and guidance. I especially would like to thank Associate Professor Alex V. Chaves and Dr. Tim A. McAllister for giving me the opportunity to conduct my research at Agriculture and Agri-Food Canada. It was a truly invaluable experience and one that I will never forget. Thank you to Dr. Rahat Zaheer for your unwavering support and assistance. I cannot express how grateful I am for your patience and the knowledge you have shared with me. Thank you to Shaun Cook for showing me the ‘ropes’, your technical assistance and always being there to discuss ideas. To the staff at Agriculture and Agri-Food Canada, thank you for making me feel so welcome when I was so far from home. A special thanks to Krysty Munns for being my first Canadian friend. Thank you for organising the many social events and introducing me to so many wonderful people. I have made so many lifelong friends and I have you to thank for that. To Cassidy and Pam, I cannot thank you enough for all your support and friendship. I’m not sure what I would have done without ‘Soup Sundays’. To Steph, my fellow Aussie, thank you for always being there, for our many Costco visits and cooking endeavours. To Brie, thank you for your encouragement and support, for being my ‘Pen Pal’, escorting me back to Australia and being an overall great friend. To the many other beautiful people (my Canadian family) I met along the way, my sincere thanks for your friendship and sharing so many wonderful experiences with me. v Lastly I would like to thank my family for their love, support and encouragement to follow my dreams, even if those dreams took me halfway across the world. To my parents, Leanne and Tony, none of this would have been possible if it wasn’t for you. Thank you for always being there through the good and the bad times, putting up with my mood swings and providing me with the love and the support I needed to complete my PhD. To my sisters, Maddy and Shonai, I cannot thank you enough for being there when I needed you. You are truly my best friends and I am so blessed to have you in my life. vi Table of Contents Abstract .......................................................................................................................................... ii Declaration ................................................................................................................................... iv Acknowledgements ...................................................................................................................... v Table of Contents ....................................................................................................................... vii List of Figures .............................................................................................................................. ix List of Tables ............................................................................................................................. xiii List of Abbreviations ................................................................................................................ xiv List of Publications and Presentations .................................................................................... xix Chapter 1 – General Introduction ................................................................................................. 1 Chapter 2 – Literature Review ..................................................................................................... 5 Chapter 3 – Objectives ............................................................................................................... 88 Chapter 4 – Antimicrobial resistance genes within feedlots and urban wastewater ................... 89 Chapter 5 – Effect of in-feed administration and withdrawal of tylosin phosphate on antibiotic resistance in enterococci isolated from feedlot steers ..................... 116 Chapter 6 – Draft genome sequence of an Enterococcus thailandicus strain isolated from bovine faeces .................................................................................. 156 Chapter 7 – Comparative genomic analysis of Enterococcus spp. isolated from bovine faeces ........................................................................................................ 163 Chapter 8 – General Discussion ............................................................................................... 217 Appendices ................................................................................................................................ 241 Appendix 1 ....................................................................................................................
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