Comparisons of plasma and fecal pharmacokinetics of danofloxacin and enrofloxacin in healthy and Mannheimia haemolytica infected calves

Abstract

Danofloxacin and enrofloxacin are fluoroquinolones (FQs) used to treat and control bovine respiratory disease (BRD) complex. While low toxicity, high bactericidal activity, and availability in single and multiple dosing regimens make them preferable, the increasing incidence of FQ-resistance in foodborne pathogens and effects on gut microbiota necessitate evaluating their pharmacokinetics (PKs). The objective of this study was to determine the exposure level of gut microbiota to subcutaneously administered FQs and compare their PKs between plasma and feces in healthy and Mannheimia haemolytica infected calves. A single dose of danofloxacin (8 mg/kg), low dose (7.5 mg/kg), or high dose (12.5 mg/kg) of enrofloxacin was administered to calves. Blood and feces were collected from calves under experimental conditions over 48 h, and FQ concentrations were measured using Ultra High-Pressure Liquid Chromatography. While moderate BRD signs were exhibited in most calves in the infected cohorts, the plasma PKs were similar between healthy and sick calves. However, the fecal danofloxacin concentration was lower in the BRD group (area under concentration–time curve [AUCinf], BRD median = 2627, healthy median = 2941 h*μg/mL, adj.P = 0.005). The dose normalized plasma and fecal danofloxacin concentrations were higher than those of enrofloxacin and its metabolite ciprofloxacin. Further, FQs had several fold higher overall concentrations in feces than in plasma in both groups. In conclusion, parenterally administered FQs expose gut microbiota to high concentrations of the antibiotics.

Influence of Single Dose Enrofloxacin Injection on Development of Fluoroquinolone Resistance in Campylobacter jejuni in Calves

“…However, on DPI 19 (i.e., 72 h after the enrofloxacin injection), both the number of colonized calves and the magnitude of colonization (CFU/g feces) returned to the levels comparable to the pre-injection values and remained as such for the next 4 days until the end of the experiment. In line with these observations, fecal concentrations of enrofloxacin and its active metabolite ciprofloxacin were found to be at the peak levels (~20–40 µg/g) during the 12–24 h period after the antibiotic injection, and almost totally eliminated 48 h after the injection in all four treatment groups regardless of the dose administered or BRD status of the calves [ 43 ]. Interestingly and importantly, as shown by differential plating and MIC determination ( Figure 1 and Figure 2 ), the re-establishment of the colonization observed soon after the enrofloxacin injection (DPI 19 and beyond) in all of the calves in all four treatment groups was by FQ-susceptible C. jejuni .…”

“…The results from those studies suggested that the successful development of FQ resistance in C. jejuni during antibiotic exposure required an initial cell density of at least 6 log10 CFU/mL and a FQ antibiotic concentration of at least 0.625 µg/mL (or 5X MIC of the strain used). Given that the highest level of C. jejuni detected in pre-treatment rectal feces of this study was around 6–7 log10 CFU/g (likely higher in the intestine) in a few calves prior to the enrofloxacin injection in each of the four treatments groups ( Figure 1 c,e,g,i) and that the concentrations of enrofloxacin (and its metabolite ciprofloxacin) were far above 4 µg/g feces for at least 24 h following the antibiotic injection [ 43 ], it is reasonable to assume that spontaneous FQ-resistant mutants would have been selected if they existed in the calves. Obviously, this was not the case as development of FQ-resistant C. jejuni was not detected in this study.…”

“…The pharmacokinetic data provide important information about the localized FQ concentrations in the intestines of calves, which could explain why no FQ-resistant mutants were detected in this study [ 43 ]. As reported in previous publications, the typical MICs of ciprofloxacin in FQ-resistant C. jejuni is between 4–16 µg/mL [ 22 , 46 , 47 , 53 , 54 ].…”

“…The peak concentration of enrofloxacin was found to be around 2–4 µg/mL in the intestines of broiler chickens during a standard multi-dose enrofloxacin water treatment in a previous study, in which FQ-resistant C. jejuni developed soon after the start of enrofloxacin treatment [ 54 ]. However, the drug concentration in the rectal feces of calves examined in the current study is much higher (median: 38–54 µg/g feces for enrofloxacin and 18–21 µg/g feces for ciprofloxacin within 12 h of the enrofloxacin injection and remaining at comparable levels by 24 h post-injection) [ 43 ]. Such a high level of antibiotic selection pressure may have reached above the mutant selection window [ 55 ] and thus prevented the emergence of FQ-resistant mutants in the intestines of calves.…”

Impacts of Gut Microbiota on the Immune System and Fecal Microbiota Transplantation as a Re-Emerging Therapy for Autoimmune Diseases

“…However, studies have demonstrated that parenteral delivery of antibiotics also has an impact on the gastrointestinal microbiota [ 55 , 56 ]. In our recent animal study, we observed that the concentrations of subcutaneously administered fluoroquinolones found in feces were several folds higher than that of plasma [ 57 ].…”