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The Effect of Ceftiofur Treatment in Dairy Cattle on the Emergence of Ceftiofur-Resitance Salmonella


<li> Characterize the resistance genes and virulence factors present in Escherichia coli and Salmonella spp. isolates from dairy cattle. <li> Test for evidence of interspecific gene transfer of CMY-2 between Escherichia coli and Salmonella, as well as test for molecular sites under positive selection pressure in the CMY2 gene. <li> Determine if ceftiofur treatment of cows in early lactation increases the prevalence of Escherichia coli with resistance to extended spectrum cephalosporin antibiotics. </ol>

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NON-TECHNICAL SUMMARY: Salmonella is a high priority pathogen in the U.S. with an estimated 1.4 million human cases occurring annually. As antimicrobial resistance has increased, public health workers are concerned that agricultural drug use may select for resistance to antimicrobial agents important in human medicine. This study will enhance protection and safety of the nation's agriculture and food supply and reduce the incidence of foodborne illnesses and contaminants through science-based knowledge and education.
APPROACH: We will use Salmonella and Escherichia coli isolates from a previous field study of clinical salmonellosis in northeastern US dairy cattle for the first objective. Microarrays will be used to test for the presence of a large number of antimicrobial resistance and virulence genes. Data will be analyzed to determine if Escherichia coli and Salmonella isolates from the same herd are more likely to share resistance genes compared with isolates from different herds. The association between the presence of antimicrobial resistance genes and key virulence factors will also be analyzed. Objective 2 involves two separate comparative molecular evolution analyses, one designed to assess the role of lateral transfer of CMY-2 genes in spreading resistance and the other designed to assess which sites within the CMY-2 gene are under positive selection pressure and thus of greatest functional significance in conferring antimicrobial resistance. The isolates for this objective will be from the strain collection described for Objective 1. Approximately 100 Salmonella and 100 Escherichia coli isolates will be selected which exhibited ceftiofur resistance based on having an MIC of greater than or equal to 8 g/ml (over 400 isolates meet this criterion). Selection will be similar to that described for Objective 1 except that only isolates with a high likelihood of carrying the CMY-2 gene will be included. Objective 3 will evaluate the effect of ceftiofur treatment of post-partum dairy cows on the shedding of ceftiofur-resistant Escherichia coli. This will be done by randomizing post-partum cows with clinical metritis to treatment with either penicillin or ceftiofur. The reason for studying cows with clinical metritis is that this is a common indication for ceftiofur use, and study cows will therefore be more similar to cows normally receiving treatment in commercial herds than if only healthy cows were used for the study. Penicillin was chosen as the control drug because it is a frequently used alternative treatment to ceftiofur for common diseases of dairy cows; although it is also a beta-lactam antibiotic, Salmonella isolates are uniformly resistant to penicillin. The study will enroll relatively few cows but will screen a large number of Escherichia coli isolates from each study animal.
PROGRESS: 2006/10 TO 2007/09<BR>
OUTPUTS: The overall purpose of this project is to determine if ceftiofur treatment of dairy cattle results in selection of resistance factors in commensal Escherichia coli which are transmissible to highly virulent multi-drug resistant Salmonella. The activities of the project in its first year included a field study to describe the resistance profiles of E. coli isolated from adult dairy cattle, a comparison of third-generation cephalosporin resistance between ceftiofur-treated and control cows, and creating a database of existing Salmonella and E. coli isolates to be used for microarray and evolutionary analysis of antimicrobial resistant plasmids. One hundred fifty E. coli and 123 Salmonella isolates from previous studies were found to meet the criteria for inclusion in this project. Recovery of the isolates from storage is now underway. <BR> PARTICIPANTS: The project leaders were responsible for study design and evaluating existing bacterial isolate collections for use in this study. They provide oversight and supervision of microarray analysis of isolates to test for the presence of antimicrobial resistance and virulence genes and DNA-sequencing of plasmids to test for evidence of interspecific gene transfer of antimicrobial resistance genes between Escherichia coli and Salmonella. A laboratory technician working part time on the study performed bacterial culture and antimicrobial susceptibility measurements, storage and recovery of isolates and student training. The project served as a basis of a summer research project for a DVM student participating in the Cornell Leadership Program for Veterinary Students. She gained experience in field data and sample collection, laboratory procedures and presented an oral report on a preliminary study of ceftiofur use and resistance in dairy cows.
IMPACT: 2006/10 TO 2007/09<BR>
One of our three study objectives is to determine if ceftiofur treatment of cows in early lactation increases the prevalence of Escherichia coli with resistance to third-generation cephalosporin antibiotics. Three farms were enrolled in a preliminary study of E. coli antimicrobial resistance patterns to guide further study design of this question. One hundred twelve isolates from 56 cattle were tested for antimicrobial resistance using a disk diffusion assay. Ceftiofur resistance occurred only in 6 percent of isolates. While there was a numerical trend for ceftifur resistance to be more common in cows recently treated with ceftiofur, the difference was not statistically significant. The results of this study will be used to determine the sample size and methods for the next phase of the project.

Warnick, Lorin
Cornell University
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