Ceftiofur formulation differentially affects the intestinal drug concentration, resistance of fecal Escherichia coli, and the microbiome of steers

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.

Impact of Ceftiofur Administration in Steers on the Prevalence and Antimicrobial Resistance of Campylobacter spp.

“…The steers for this study and their treatment have been previously described [17]. They consisted of 12 healthy Holstein steers (six months old and weighing 186-288 kg) and were obtained from the Dairy Educational Unit at North Carolina State University (NCSU) in Raleigh, NC, USA.…”

“…They consisted of 12 healthy Holstein steers (six months old and weighing 186-288 kg) and were obtained from the Dairy Educational Unit at North Carolina State University (NCSU) in Raleigh, NC, USA. They were housed in pairs in stalls at the College of Veterinary Medicine (CVM), NCSU, from May 2016 to July 2016, as described in [17]. The steers for the CCFA treatment (n = 6) were here designated D1-D6 while those for CHCL (n = 6) were designated N1-N6.…”

“…The CHCL treatment was from 24 June through 12 July 2016 for steers N1, N2, N3, and N4 and from June 29 through 12 July 2016 for steers N5 and N6. As previously described [17], the sample size was determined based on previous pharmacokinetic-pharmacodynamic studies in cattle [25,40,41]. All steers received lidocaine and flunixin meglumine for disbudding within the first month of life, while steer D6 received flunixin and CHCL for four days due to diarrhea and fever, several months prior to the CCFA treatment.…”

“…The ceftiofur treatments of the steers were previously described [17]. Briefly, ultrafiltration probes for drug level determination were placed in the ileum and spiral colon as described [17].…”

“…The ceftiofur treatments of the steers were previously described [17]. Briefly, ultrafiltration probes for drug level determination were placed in the ileum and spiral colon as described [17]. Within 24-48 h after placement of the probes, the steers were administered either CCFA (6.6 mg/kg, one dose; Zoetis, Parsippany, NJ, USA) or CHCL (2.2 mg/kg, three daily doses; Zoetis).…”