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Epidemiology of Β-Lactamase-Producing Enterobacteriaceae in Humans and Livestock

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Epidemiology of Β-Lactamase-Producing Enterobacteriaceae in Humans and Livestock Epidemiology of β-lactamase-producing Enterobacteriaceae in Humans and Livestock DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Dixie Francis Mollenkopf, M.S. Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2017 Dissertation Committee: Joshua Daniels Gregory Habing Armando Hoet Thomas Wittum, Advisor Copyrighted by Dixie Francis Mollenkopf 2017 Abstract Carbapenems have the broadest spectrum of the large β-lactam antimicrobials and have been reserved as a “drug of last resort” against invasive Gram-positive and Gram-negative human infections. The increasing prevalence of complicated MDR infections involving extended spectrum (ESβL) and AmpC β-lactamases has triggered the increasing need for carbapenem use. The emergence of carbapenemase-producing Enterobactericeae was described as “the end of the antibiotic era” as these potential pathogens harbor highly-mobile genetic elements that confer resistance to our most critically important drugs. In the US, nontyphoidal Salmonella are a common foodborne zoonotic pathogen causing gastroenteritis. MDR invasive Salmonella infections mediated by ESβL or AmpC genotypes are more likely to require carbapenem therapy compared to susceptible infections. Of 571 isolates, we characterized 44 blaCMY-2-bearing Salmonella that resulted from 5,050 individual cattle fecal samples from 68 large (1,000+ head capacity) US feedlots participating in the NAHMS Beef Feedlot 2011 study, and assessed risk factors for blaCMY-2 carriage. Cultured without antimicrobial selection, the isolates represented eight serotypes and carried the blaCMY-2/IncA/C gene/plasmid combination with most expressing the penta-resistance (ACSSuT) phenotype. Cattle fed chlortetracycline in their diet and heavier weight cattle were less likely to carry Salmonella with i blaCMY-2. In contrast, cattle fed the macrolide feed additive tylosin and cattle in pens with increasing numbers of dairy cattle were more likely to harbor blaCMY-bearing Salmonella. To determine the prevalence of foodborne resistance mechanisms, we screened human diarrheic stool samples submitted for Clostridium difficle culture from patients of The Ohio State University Wexner Medical Center (OSUWMC) to estimate the frequency of carriage of ESβL- and AmpC- as well as carbapenemase-producing enteric bacteria. The 692 deidentified samples received between July and December 2013 were cultured using selective media to detect the resistant phenotypes. Our selective culture yielded 184 isolates (26.6 %) with reduced susceptibility to cefotaxime. Of these, 46 (6.7%) samples harbored commensal isolates carrying the AmpC blaCMY. Another 21 (3.0%) samples produced isolates harboring the ESBL blaCTX-M: 19 carrying CTX-M-15 and 2 with CTX-M-27. Additionally, 13 samples (1.9 %) produced Enterobacteriaceae or Pseudomonas spp. resistant to carbapenems. Of these, whole genome sequencing identified a prominent CRE strain, sequence type ST258, K. pneumoniae harboring blaKPC-3 and a second K. pneumoniae carrying blaNDM-1 ST1602 which had not been previously reported. Reporting the first mobile carbapenemase, blaIMP-64 on an IncQ1 plasmid, in US livestock, we followed a cohort of 350+ pigs from late sow gestation to the final finishing phase in order to better understand the maintenance of this rare resistance genotype in a large farrow-to-finish swine operation. Environmental and fecal samples were collected during 8 visits over 5 months in 2016 and screened for CPE using selective media. The frequency of IMP-64-positive environmental (n=32), sow fecal (n=30), and piglet fecal swab (120) samples was highest for all groups when the market pig cohort was between 1 and 10 d, with observed prevalence of 97%, ii 28%, and 18%, respectively. After weaning, blaIMP-64 was detected in a single environmental sample from a nursery pen, with no CPE recovered in the finishing phase. iii For Mom and Dad. Love, Dixie iv Acknowledgments Credit and thanks must be given to my graduate committee members, Dr. Gregory Habing, Dr. Joshua Daniels, and Dr. Armando Hoet, and especially to my advisor, Dr. Tom Wittum. Without their knowledge, support and guidance, this character-building experience would have never been possible. v Vita 1997 ..................................................................... B.S. Food, Agriculture, and Environmental Science, The Ohio State University 2012 ..................................................................... M.S. Comparative and Veterinary Medicine, The Ohio State University Publications Mollenkopf, DF, Mathys, DA, Dargatz, DA, Erdman, MM, Habing, GG, Daniels, JB, Wittum, TE. 2017. Genotypic and epidemiologic characterization of extended-spectrum cephalosporin resistant Salmonella enterica from US beef feedlots. Prev. Vet. Med. doi: https://doi.org/10.1016/j.prevetmed.2017.08.006. Haywood, L, Spike-Pierce, D, Barr, B, Mathys, D, Mollenkopf, D. 2017. Gestation length and racing performance in 115 Thoroughbred foals with incomplete tarsal ossification. Equine Vet. J. doi: 10.1111/evj.12712. Mathys, DA, Mollenkopf, DF, Nolting, J, Bowman, AS, Daniels, JB, Wittum, TE. 2017. Extended- Spectrum Cephalosporin-Resistant Enterobacteriaceae in Enteric Microflora of Wild Ducks. J. Wildl. Dis. 53(3):690-694. Adams, RJ, Mathys, DA, Mollenkopf, DF, Whittle, A, Daniels, JB, Wittum, TE. 2017. Carbapenemase-Producing Aeromonas veronii Disseminated in the Environment of an Equine Specialty Hospital. Vector Borne Zoonotic Dis. 17(6):439-442. Mathys, D, Mollenkopf, D, Bremer, C, Daniels, J, Wittum, T. 2017. Prevalence of AmpC-and Extended-Spectrum β-Lactamase-Harbouring Enterobacteriaceae in Faecal Flora of a Healthy Domestic Canine Population. Zoonoses Public Hlth. doi: 10.1111/zph.12341. Mathys, DA, Mathys, BA, Mollenkopf, DF, Daniels, JB, Wittum, TE. 2017. Enterobacteriaceae Harboring AmpC (blaCMY) and ESBL (blaCTX-M) in Migratory and Nonmigratory Wild Songbird Populations on Ohio Dairies. Vector Borne Zoonotic Dis. 17:254-259. vi Landers, T, Mollenkopf, D, Faubel, R, Dent, A, Pancholi, P, Daniels, J, Wittum, T. 2017. Extended- Spectrum β-lactam Resistance in the Enteric Flora of Patients at a Tertiary Care Medical Centre. Zoonoses and Public Health. 64:161-164. Mollenkopf, DF, Stull, JW, Mathys, DA, Bowman, AS, Feicht, SM, Grooters, SV, Daniels, JB, Wittum, TE. 2016. Carbapenemase-producing Enterobacteriaceae recovered from the environment of a swine farrow-to-finish operation in the United States. Antimicrob. Agents Chemother. 61:e01298- 16 Habing, GG, Kessler, SE, Mollenkopf, DF, Wittum, TE, Anderson, TC, Barton Behravesh, C, Joseph, LA, Erdman, MM. 2015. Distribution and Diversity of Salmonella Strains in Shipments of Hatchling Poultry, United States, 2013. Zoonoses Public Hlth. 62:375-380. Mollenkopf, DF, Faubel, RL, Pancholi, P, Landers, TF, Erdman, MM, Daniels, JB, Wittum, TE. 2015. Surveillance and Characterization of Carbapenemase-Producing Klebsiella pneumoniae Recovered from Patient Stool Samples at a Tertiary Care Medical Center. Antimicrob Agents Chemother. 59:5857-5859. Mollenkopf, DF, Cenera, JK, Bryant, EM, King, CA, Kashoma, I, Kumar, A, Funk, JA, Rajashekara, G, Wittum, TE. 2014. Organic or Antibiotic-Free Labeling Does Not Impact the Recovery of Enteric Pathogens and Antimicrobial-Resistant Escherichia coli from Fresh Retail Chicken. Foodborne Pathog Dis. 11:920-929. Mollenkopf, DF, Mirecki, JM, Daniels, JB, Funk, JA, Henry, SC, Hansen, GE, Davies, PR, Donovan, TS, Wittum, TE. 2013. Escherichia coli and Klebsiella pneumoniae producing CTX-M cephalosporinase from swine finishing barns and their association with antimicrobial use. Appl. Environ. Microbiol. 79:1052-1054. Mollenkopf, DF, Weeman, MF, Daniels, JB, Abley, MJ, Mathews, JL, Gebreyes, WA, Wittum, TE. 2012. Variable within- and between-herd diversity of CTX-M cephalosporinase-bearing Escherichia coli isolates from dairy cattle. Appl. Environ. Microbiol. 78:4552-4560. doi: 10.1128/AEM.00373-12. Wittum, TE, Mollenkopf, DF, Erdman, MM. 2012. Detection of Salmonella enterica Isolates Producing CTX-M Cephalosporinase in US Livestock Populations. Appl. Environ. Microbiol. 78:7487-7491. Mollenkopf, DF, Kleinhenz, KE, Funk, JA, Gebreyes, WA, Wittum, TE. 2011. Salmonella enterica and Escherichia coli Harboring blaCMY in Retail Beef and Pork Products. Foodborne Pathog Dis. 8:333-336. doi: 10.1089/fpd.2010.0701. Lutz, EA, McCarty, MJ, Mollenkopf, DF, Funk, JA, Gebreyes, WA, Wittum, TE. 2011. Ceftiofur use in finishing swine barns and the recovery of fecal Escherichia coli or Salmonella spp. resistant to ceftriaxone. Foodborne Pathog Dis. 8:1229-1234. Wittum, TE, Mollenkopf, DF, Daniels, JB, Parkinson, AE, Mathews, JL, Fry, PR, Abley, MJ, Gebreyes, WA. 2010. CTX-M-Type Extended-Spectrum β-Lactamases Present in Escherichia coli from the Feces of Cattle in Ohio, United States. Foodborne Pathog Dis. 7:1575-1579. vii Mollenkopf, DF, Glendening, C, Wittum, TE, Funk, JA, Tragesser, LA, Morley, PS. 2010. Association of dry cow therapy with the antimicrobial susceptibility of fecal coliform bacteria in dairy cows. Prev. Vet. Med. 96:30-35. Fields of Study Major Field: Comparative and Veterinary Medicine viii Table of Contents Abstract ............................................................................................................................................. i Acknowledgments...........................................................................................................................
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