Dosing Regimen of Enrofloxacin Impacts Intestinal Pharmacokinetics and the Fecal Microbiota in Steers

Abstract

Objective: The intestinal concentrations of antimicrobial drugs that select for resistance in fecal bacteria of cattle are poorly understood. Our objective was to associate active drug concentrations in the intestine of steers with changes in the resistance profile and composition of the fecal microbiome.Methods: Steers were administered either a single dose (12.5 mg/kg) or 3 multiple doses (5 mg/kg) of enrofloxacin subcutaneously every 24 h. Enrofloxacin and ciprofloxacin concentrations in intestinal fluid were measured over 96 h, and the abundance and MIC of E. coli in culture and the composition of the fecal microbiota by 16S rRNA gene sequencing were assessed over 192 h after initial treatment.Results: Active drug concentrations in the ileum and colon exceeded plasma and interstitial fluid concentrations, but were largely eliminated by 48 h after the last dose. The concentration of E. coli in the feces significantly decreased during peak drug concentrations, but returned to baseline by 96 h in both groups. The median MIC of E. coli isolates increased for 24 h in the single dose group, and for 48 h in the multiple dose group. The median MIC was higher in the multiple dose group when compared to the single dose group starting 12 h after the initial dose. The diversity of the fecal microbiota did not change in either treatment group, and taxa-specific changes were primarily seen in phyla commonly associated with the rumen.Conclusions: Both dosing regimens of enrofloxacin achieve high concentrations in the intestinal lumen, and the rapid elimination mitigates long-term impacts on fecal E. coli resistance and the microbiota.

The effect of enrofloxacin on enteric Escherichia coli: Fitting a mathematical model to in vivo data

“…The experimental data have been previously described in [15] and was approved by the North Carolina State University Institutional Animal Care and Use Committee. Briefly, twelve healthy six-month-old steers were assigned to two dose regimes.…”

“…Following a subcutaneous administration, measurements of the enrofloxacin and ciprofloxacin concentrations were taken in the plasma, interstitial fluid, ileum, and colon. In addition to the antimicrobial drug concentrations, fecal samples were collected by hand and E. coli concentration was measured in colony forming units per milliliter (CFUs/ml) [15]. In the high dose treatment, fecal samples were taken every 12 hours for the first 48 hours, then 24 hours there after until hour 192.…”

“…We assumed all parameters had log-normal distributions. Furthermore, we assumed that the drug parameters could vary across the two cohorts as it has been previously shown that the transport mechanism in the colon may be concentration dependent [15]. Similarly, we let N max vary and σ vary across study groups to capture E. coli dynamics at the individual level.…”

“…To investigate what factors influence the effect of enrofloxacin on enterobacteriacea, we developed a mathematical model to represent the dynamics of enrofloxacin in steers following subcutaneous administration and its effects on E. coli population in the gut. The model was fit to data from twelve steers that were monitored following two dose regimens: a single high dose or three low doses [15]. These are currently the only two approved doses of fluoroquinolones in cattle.…”

Understanding and interpreting community sequencing measurements of the vaginal microbiome

“…Community sequencing measurements are less able to detect species with low relative abundance in the microbiome because genetic material from the other members of the microbiome (and possibly the host as well) compete for the limited sequencing reads from each sample. Multiple studies note that the detection of taxa by amplicon sequencing can have good positive predictive accuracy but poor negative predictive accuracy relative to culture‐based assays because of the lower sensitivity of community sequencing to minority members of the microbiome . Furthermore, even if a given taxon contributes to the pool of community sequencing reads, it is not guaranteed to be properly identified.…”