Abstract
Antimicrobial drug concentrations in the gastrointestinal tract likely drive antimicrobial resistance in enteric bacteria. Our objective was to determine the concentration of ceftiofur and its metabolites in the gastrointestinal tract of steers treated with ceftiofur crystalline-free acid (CCFA) or ceftiofur hydrochloride (CHCL), determine the effect of these drugs on the minimum inhibitory concentration (MIC) of fecal Escherichia coli, and evaluate shifts in the microbiome. Steers were administered either a single dose (6.6 mg/kg) of CCFA or 2.2 mg/kg of CHCL every 24 hours for 3 days. Ceftiofur and its metabolites were measured in the plasma, interstitium, ileum and colon. The concentration and MIC of fecal E. coli and the fecal microbiota composition were assessed after treatment. The maximum concentration of ceftiofur was higher in all sampled locations of steers treated with CHCL. Measurable drug persisted longer in the intestine of CCFA-treated steers. There was a significant decrease in E. coli concentration (P = 0.002) within 24 hours that persisted for 2 weeks after CCFA treatment. In CHCL-treated steers, the mean MIC of ceftiofur in E. coli peaked at 48 hours (mean MIC = 20.45 ug/ml, 95% CI = 10.29-40.63 ug/ml), and in CCFA-treated steers, mean MIC peaked at 96 hours (mean MIC = 10.68 ug/ml, 95% CI = 5.47-20.85 ug/ml). Shifts in the microbiome of steers in both groups were due to reductions in Firmicutes and increases in Bacteroidetes. CCFA leads to prolonged, low intestinal drug concentrations, and is associated with decreased E. coli concentration, an increased MIC of ceftiofur in E. coli at specific time points, and shifts in the fecal microbiota. CHCL led to higher intestinal drug concentrations over a shorter duration. Effects on E. coli concentration and the microbiome were smaller in this group, but the increase in the MIC of ceftiofur in fecal E. coli was similar.
Highlights
Ceftiofur, a third generation cephalosporin, is one of the most common antimicrobials administered to feedlot cattle and lactating dairy cows in the United States for treatment of respiratory disease, [1,2] metritis, [3] and is used in an extralabel manner to treat enteric disease [4]
This use has led to widespread concern over selection for bacteria with antimicrobial resistance (AMR) in the feces of treated cattle that could be transferred to humans through the food chain [5]
Low drug concentrations in the gastrointestinal tract (GIT) were noted over a longer time as the half-life of ceftiofur and metabolites were 2–3 times greater in the ileum and colon for Ceftiofur crystalline-free acid (CCFA) than for ceftiofur hydrochloride (CHCL), but due to the variability between animals this difference was not statistically significant
Summary
A third generation cephalosporin, is one of the most common antimicrobials administered to feedlot cattle and lactating dairy cows in the United States for treatment of respiratory disease, [1,2] metritis, [3] and is used in an extralabel manner to treat enteric disease [4] This use has led to widespread concern over selection for bacteria with antimicrobial resistance (AMR) in the feces of treated cattle that could be transferred to humans through the food chain [5]. Some producers may use CHCL because of the shorter withdrawal time and easier route of administration, while others may prefer CCFA due to the ease of singledose therapy Both products are FDA-approved for similar conditions in cattle and used somewhat interchangeably, they produce different exposure profiles, which could affect selection of antibiotic-resistant bacteria. A comparison of the effect of these formulations on AMR in fecal bacteria of treated cattle has not been performed
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