Can the use of older-generation beta-lactam antibiotics in livestock production over-select for beta-lactamases of greatest consequence for human medicine? An in vitro experimental model.

Though carbapenems are not licensed for use in food animals in the U.S., carbapenem resistance among Enterobacteriaceae has been identified in farm animals and their environments. The objective of our study was to determine the extent to which older-generation ß-lactam antibiotics approved for use in food animals in the U.S. might differentially select for resistance to antibiotics of critical importance to human health, such as carbapenems. Escherichia coli (E. coli) strains from humans, food animals, or the environment bearing a single ß-lactamase gene (n = 20 each) for blaTEM-1, blaCMY-2, and blaCTX-M-* or else blaKPC/IMP/NDM (due to limited availability, often in combination with other bla genes), were identified, along with 20 E. coli strains lacking any known beta-lactamase genes. Baseline estimates of intrinsic bacterial fitness were derived from the population growth curves. Effects of ampicillin (32 µg/mL), ceftriaxone (4 µg/mL) and meropenem (4 µg/mL) on each strain and resistance-group also were assessed. Further, in vitro batch cultures were prepared by mixing equal concentrations of 10 representative E. coli strains (two from each resistance gene group), and each mixture was incubated at 37°C for 24 hours in non-antibiotic cation-adjusted Mueller-Hinton II (CAMH-2) broth, ampicillin + CAMH-2 broth (at 2, 4, 8, 16, and 32 µg/mL) and ceftiofur + CAMH-2 broth (at 0.5, 1, 2, 4, and 8µg/mL). Relative and absolute abundance of resistance-groups were estimated phenotypically. Line plots of the raw data were generated, and non-linear Gompertz models and multilevel mixed-effect linear regression models were fitted to the data. The observed strain growth rate distributions were significantly different across the groups. AmpC strains (i.e., blaCMY-2) had distinctly less robust (p < 0.05) growth in ceftriaxone (4 µg/mL) compared to extended-spectrum beta-lactamase (ESBL) producers harboring blaCTX-M-*variants. With increasing beta-lactam antibiotic concentrations, relative proportions of ESBLs and CREs were over-represented in the mixed bacterial communities; importantly, this was more pronounced with ceftiofur than with ampicillin. These results indicate that aminopenicillins and extended-spectrum cephalosporins would be expected to propagate carbapenemase-producing Enterobacteriaceae in food animals if and when Enterobacteriaceae from human health care settings enter the food animal environment.

Effects of intermittent feeding of tylosin phosphate during the finishing period on feedlot performance, carcass characteristics, antimicrobial resistance, and incidence and severity of liver abscesses in steers.

Liver abscesses (LA) are a source of economic loss for feedlot cattle feedlots, and the 2017 veterinary feed directive has restricted further use of tylosin phosphate to prevention and control of LA. Our objective was to evaluate effects of intermittent tylosin phosphate feeding on incidence and severity of LA in feedlot cattle and presence of total antimicrobial-resistant Enterococcus spp. Steers (n = 312, 411.4 ± 6.71 kg) were blocked by initial BW and randomly assigned to a treatment group. Treatments included a negative control group (no tylosin phosphate throughout the finishing period), a positive control group (tylosin phosphate fed continuously throughout the finishing period), and a group that received tylosin phosphate off-label by feeding the drug on a repeated intermittent basis (1 wk on, 2 wk off). Steers were housed in 24 soil-surfaced pens with 13 steers per pen. Body weights of cattle were obtained every 28 d and at the end of 119 d the steers were weighed and harvested at a commercial abattoir. Fecal samples were collected on days 0, 21, and 118 to characterize antimicrobial-resistant Enterococcus spp. Total LA percentage was greater (P = 0.012) for the no tylosin phosphate treatment compared with the other treatments, but did not differ between the continuous tylosin phosphate treatment and the intermittently fed tylosin phosphate treatment (P = 0.716). No difference was observed among treatments for ADG (P = 0.21), DMI (P = 0.28), or G:F (P = 0.75). Marbling score was lower (P = 0.022) for tylosin phosphate treatment when compared with both intermittent treatment and continuous tylosin phosphate treatment. Enterococcus spp. bacterial counts did not differ by treatment group over time (P > 0.05); however, there was a strong period effect for macrolide resistance among all groups (P < 0.01), suggesting an important environmental component as cattle were first placed in pens and then progressed through the feeding period. We conclude that feeding tylosin phosphate intermittently during the finishing phase decreases the total percentage of LA and maintains feedlot performance and carcass characteristics to the same extent as feeding tylosin phosphate throughout the finishing phase; furthermore, we hypothesize that enteric antimicrobial resistance is a result of longer term antibiotic usage in a particular environment rather than a direct short-term result of the treatment during any given feeding period.