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Our main objective is to promote an increased understanding of the mechanisms and dynamics of antimicrobial resistance transmission between humans, animals, and the environment. The overall goal of our research is to identify modifiable factors associated with the development and spread of antimicrobial resistance in bacteria from humans, domestic animals, and wildlife, and to apply this information to the development of strategies designed to reduce and control the spread of drug resistance in Michigan ecosystems.
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To complete this long-term goal, the following objectives will be pursued: <OL> <LI> Determine if reducing on-farm use of subtherapeutic levels of antimicrobial agents results in increased susceptibility to select antimicrobial agents in enteric bacteria isolated from cattle and cattle environments. <BR>a) Conduct long-term studies of changes in antimicrobial resistance patterns of enteric bacteria on cattle farms under different management approaches to reducing the development of drug resistance; <BR> b) Identify the costs and benefits associated with reducing antimicrobial use in food animal production. <LI> Compare antimicrobial resistance patterns found in wildlife, livestock, and humans. <BR> a) Determine if terrestrial wildlife can serve as a reservoir of antimicrobial resistance for human and livestock pathogens by demonstrating resistance in these hosts; <BR> b) Describe antimicrobial resistance patterns of fish in different watersheds throughout the state of Michigan, and determine the risk of humans acquiring resistant bacteria through sport fishing and the consumption of these fish. <LI> Use molecular tools and spatio-temporal analytic approaches in a long-term study to identify and track surface water contamination in watersheds with different sources of fecal contamination (e.g., rural areas versus highly urbanized areas). <LI> Describe the transmission of antimicrobial resistance between dogs and cats and their human caregiver: <BR> Describe this process in a veterinary teaching hospital; <BR> Expand this research to encompass humans and their pets in the home. <LI> Develop decontamination methods that will eliminate drug-resistant bacteria and resistance factors (e.g. plasmids) from the environment, for use on farms and in homes.
NON-TECHNICAL SUMMARY: Antimicrobial drug resistance, or the failure of a drug to treat an infectious disease for which the drug was previously effective, was recognized soon after the widespread use of antibiotics. The use of antimicrobial drugs has been associated with the emergence of antimicrobial resistance in bacteria in humans and animals, by creating selective pressure that allows resistant bacteria to survive while susceptible bacteria are killed. The development of resistance to many drugs currently used for disease treatment increases the risk for treatment failures in both animals and humans. The maintenance of antimicrobial-resistant bacteria in the gastrointestinal tracts of human and animals hosts makes fecal transmission of resistant bacteria a serious health threat: exposure to resistant bacteria can occur through consuming contaminated food or water, or through physical contact with humans or animals infected with drug-resistant bacteria. Manure contaminated with drug-resistant bacteria poses a threat to humans and animals that come into contact with it, and runoff contaminated with manure can introduce drug-resistant bacteria to surface waters that are used by wildlife, livestock, and humans. Unfortunately, several studies have shown that drug resistance will persist even after the selective pressure of antimicrobial drug use has been discontinued. Furthermore, if resistance develops in one species of bacteria, it can be transferred to other species, thereby allowing drug resistance to spread easily across a wide range of bacterial species. Because of the interdependence of drug resistance observed between veterinary medicine, human medicine, and the environment, potential sources of antimicrobial resistance must be eliminated to slow this trend. The main goal of our research is to identify factors associated with the development and spread of drug resistance in bacteria from humans, domestic animals, and wildlife, and to apply this information to develop measures to reduce and control the spread of drug resistance. To meet this goal, our research will: 1) Determine if reducing on-farm use of antimicrobial drugs will reduce drug resistance in bacteria isolated from cattle and cattle farms over time, and identify the most cost-effective drug usage and disinfection programs for eliminating drug-resistant bacteria on the farm and in homes. 2) Compare drug resistance patterns in wildlife, livestock, and humans to describe how antimicrobial resistance is transmitted between these groups. 3) Use drug resistance and genetic analysis to identify and track surface water contamination by different sources of fecal contamination (e.g., manure, sewage) 4) Describe the transmission of drug resistance between pets (dogs, cats) and their human caregivers in a veterinary hospital and at home.
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APPROACH: A prospective study will track long-term changes in antimicrobial resistance patterns in enteric bacteria on cattle farms using different resistance reduction strategies. Herds feeding medicated milk replacer will be recruited and randomly assigned to 1 of 3 groups: no change; stop medicated milk replacers only; stop all medicated feeds. Herds will be visited monthly over a 3-year period to collect samples (calf & cow feces, housing, maternity pens, manure storage, water) and herd inventory and health, management, housing, and antimicrobial use data. Bacteria will be cultured and susceptibility testing on 3 isolates from each sample will be done using automated microbroth dilution. Differences in patterns of susceptibility between groups and multivariable analyses will be used to identify factors associated with long-term changes in susceptibility. Health and management data will be used in a cost-benefit analysis to determine if different resistance-reducing practices are economically feasible. Long-term changes in genetic and antimicrobial resistance patterns of enteric bacteria in wildlife and surface waters near study herds, and other sources of fecal contamination and sites along the main waterways within the watershed will be sampled and tested. Associations between changes in susceptibility and genetic patterns of wildlife, livestock, and human bacterial isolates will be measured. Discriminant function and spatial analyses will be applied to susceptibility and genetic profiles of contamination sources to determine sources of bacterial contamination and the effects of distance from sources of fecal contamination, geology, hydrology, and land cover. A cross-sectional study will describe patterns of antimicrobial resistance in bacteria from freshwater fish in these watersheds, by testing bacteria from mucous scrapings and gill plates from several fish species. A prospective study will determine if pets and their caregivers acquire antimicrobial resistance from each other. Pets admitted to a veterinary teaching hospital (VTH) and VTH staff will be asked to give fecal and nasal swabs to be tested for resistant bacteria, and environmental swabs will be taken in the VTH. Susceptibility testing will be conducted using microbroth dilution. Multivariable models will be used to describe the relationships between risk factors and susceptibility patterns, and the associations between resistance patterns from caregivers, pets, and environmental samples. Clients bringing pets to the VTH for routine visits will be asked to collect uncontaminated fecal samples and nasal swabs from themselves and their pets at recruitment and 6 weeks later. Experimental studies will determine the best decontamination methods for eliminating drug resistant bacteria and resistance factors. Substrates will be sterilized and inoculated with resistant E. coli, and different decontamination methods will be used. Samples will be collected before and after treatment, and molecular tools will be used to determine the presence of any E. coli or major resistance factors. The best methods will be taken to farms, VTH, and private homes, where sampling and testing will be repeated.