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Effects of Chlortetracycline and Copper Supplementation on Levels of Antimicrobial Resistance in the Feces of Weaned Pigs

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Effects of Chlortetracycline and Copper Supplementation on Levels of Antimicrobial Resistance in the Feces of Weaned Pigs EFFECTS OF CHLORTETRACYCLINE AND COPPER SUPPLEMENTATION ON LEVELS OF ANTIMICROBIAL RESISTANCE IN THE FECES OF WEANED PIGS by GETAHUN EJETA AGGA DVM, Addis Ababa University, 2003 MSc, Utrecht University, 2008 AN ABSTRACT OF A DISSERTATION submitted in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY Department of Diagnostic Medicine/Pathobiology College of Veterinary Medicine KANSAS STATE UNIVERSITY Manhattan, Kansas 2013 Abstract The use of antibiotics in food animals is of major concern as a purported cause of antimicrobial resistance (AMR) in human pathogens; as a result, alternatives to in-feed antibiotics such as heavy metals have been proposed. The effect of copper and CTC supplementation in weaned pigs on AMR in the gut microbiota was evaluated. Four treatment groups: control, copper, chlortetracycline (CTC), and copper plus CTC were randomly allocated to 32 pens with five pigs per pen. Fecal samples (n = 576) were collected weekly from three pigs per pen over six weeks and two Escherichia coli isolates per sample were tested phenotypically for antimicrobial and copper susceptibilities and genotypically for the presence of tetracycline (tet), copper (pcoD) and ceftiofur (blaCMY-2) resistance genes. CTC-supplementation significantly increased tetracycline resistance and susceptibility to copper when compared with the control group. Copper supplementation decreased resistance to most of the antibiotics, including cephalosporins, over all treatment periods. However, copper supplementation did not affect minimum inhibitory concentrations of copper or detection of pcoD. While tetA and blaCMY-2 genes were associated with a higher multi-drug resistance (MDR), tetB and pcoD were associated with lower MDR. Supplementations of CTC or copper alone were associated with increased tetB prevalence; however, their combination was paradoxically associated with reduced prevalence. These studies indicate that E. coli isolates from the weaned pigs studied exhibit high levels of antibiotic resistance with diverse multi-resistant phenotypic profiles. In a related study, total fecal community DNA (n = 569) was used to detect 14 tet genes and to quantify gene copies of tetA, tetB, pcoD and blaCMY-2. CTC and copper plus CTC supplementation increased both the prevalence and gene copies of tetA, while decreasing both the prevalence and gene copies of tetB, when compared with the control group. The diversity of tet genes were reduced over time in the gut bacterial community. The roles of copper supplementation in pig production and pco-mediated copper resistance in E. coli need to be further explored since a strong negative association of pcoD, with both tetA and blaCMY-2, suggests there exist opportunities to select for a more innocuous resistance profile. EFFECTS OF CHLORTETRACYCLINE AND COPPER SUPPLEMENTATION ON LEVELS OF ANTIMICROBIAL RESISTANCE IN THE FECES OF WEANED PIGS by GETAHUN EJETA AGGA DVM, Addis Ababa University, 2003 MSc, Utrecht University, 2008 A DISSERTATION submitted in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY Department of Diagnostic Medicine and Pathobiology College of Veterinary Medicine KANSAS STATE UNIVERSITY Manhattan, Kansas 2013 Approved by: Major Professor Dr. Harvey Morgan Scott Copyright GETAHUN EJETA AGGA 2013 Abstract The use of antibiotics in food animals is of major concern as a purported cause of antimicrobial resistance (AMR) in human pathogens; as a result, alternatives to in-feed antibiotics such as heavy metals have been proposed. The effect of copper and CTC supplementation in weaned pigs on AMR in the gut microbiota was evaluated. Four treatment groups: control, copper, chlortetracycline (CTC), and copper plus CTC were randomly allocated to 32 pens with five pigs per pen. Fecal samples (n = 576) were collected weekly from three pigs per pen over six weeks and two Escherichia coli isolates per sample were tested phenotypically for antimicrobial and copper susceptibilities and genotypically for the presence of tetracycline (tet), copper (pcoD) and ceftiofur (blaCMY-2) resistance genes. CTC-supplementation significantly increased tetracycline resistance and susceptibility to copper when compared with the control group. Copper supplementation decreased resistance to most of the antibiotics, including cephalosporins, over all treatment periods. However, copper supplementation did not affect minimum inhibitory concentrations of copper or detection of pcoD. While tetA and blaCMY-2 genes were associated with a higher multi-drug resistance (MDR), tetB and pcoD were associated with lower MDR. Supplementations of CTC or copper alone were associated with increased tetB prevalence; however, their combination was paradoxically associated with reduced prevalence. These studies indicate that E. coli isolates from the weaned pigs studied exhibit high levels of antibiotic resistance with diverse multi-resistant phenotypic profiles. In a related study, total fecal community DNA (n = 569) was used to detect 14 tet genes and to quantify gene copies of tetA, tetB, pcoD and blaCMY-2. CTC and copper plus CTC supplementation increased both the prevalence and gene copies of tetA, while decreasing both the prevalence and gene copies of tetB, when compared with the control group. The diversity of tet genes were reduced over time in the gut bacterial community. The roles of copper supplementation in pig production and pco-mediated copper resistance in E. coli need to be further explored since a strong negative association of pcoD, with both tetA and blaCMY-2, suggests there exist opportunities to select for a more innocuous resistance profile. Table of Contents List of Figures ................................................................................................................................ ix List of Tables ................................................................................................................................. xi Acknowledgements ...................................................................................................................... xiii Dedication ..................................................................................................................................... xv Chapter 1 - General introduction .................................................................................................... 1 Chapter 2 - Antimicrobial resistance: review of epidemiology and challenges ............................. 8 Introduction ................................................................................................................................. 8 Antimicrobial classes, mode of action and mechanism of resistance ....................................... 15 Aminoglycosides ................................................................................................................... 17 Beta-lactams .......................................................................................................................... 19 Folic acid biosynthesis inhibitors .......................................................................................... 22 Macrolides ............................................................................................................................. 23 Phenicols ............................................................................................................................... 24 Quinolones ............................................................................................................................ 25 Tetracyclines ......................................................................................................................... 26 Mechanisms of tetracycline resistance.............................................................................. 28 Efflux pumps ................................................................................................................. 30 Ribosomal protection .................................................................................................... 33 Enzymatic inactivation.................................................................................................. 34 Copper handling mechanisms in E. coli ................................................................................... 35 Copper homeostasis systems in E. coli ................................................................................. 37 Plasmid-borne copper resistance in E. coli ........................................................................... 40 Ecology of antimicrobial resistance: mechanism of dissemination and persistence ................ 43 Microbiological approaches for antimicrobial and copper susceptibility testing ..................... 50 Antibiotic susceptibility testing ............................................................................................ 50 Determination of copper resistance....................................................................................... 58 Statistical analysis of antimicrobial susceptibility data ............................................................ 59 Epidemiology of tetracycline, ceftiofur and copper resistance in E. coli from pigs ................. 67 vi Mitigating antimicrobial resistance .......................................................................................... 73 Summary ................................................................................................................................... 77 Chapter
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