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

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.

Danofloxacin Treatment Alters the Diversity and Resistome Profile of Gut Microbiota in Calves.

Fluoroquinolones, such as danofloxacin, are used to control bovine respiratory disease complex in beef cattle; however, little is known about their effects on gut microbiota and resistome. The objectives were to evaluate the effect of subcutaneously administered danofloxacin on gut microbiota and resistome, and the composition of Campylobacter in calves. Twenty calves were injected with a single dose of danofloxacin, and ten calves were kept as a control. The effects of danofloxacin on microbiota and the resistome were assessed using 16S rRNA sequencing, quantitative real-time PCR, and metagenomic Hi-C ProxiMeta. Alpha and beta diversities were significantly different (p < 0.05) between pre-and post-treatment samples, and the compositions of several bacterial taxa shifted. The patterns of association between the compositions of Campylobacter and other genera were affected by danofloxacin. Antimicrobial resistance genes (ARGs) conferring resistance to five antibiotics were identified with their respective reservoirs. Following the treatment, some ARGs (e.g., ant9, tet40, tetW) increased in frequencies and host ranges, suggesting initiation of horizontal gene transfer, and new ARGs (aac6, ermF, tetL, tetX) were detected in the post-treatment samples. In conclusion, danofloxacin induced alterations of gut microbiota and selection and enrichment of resistance genes even against antibiotics that are unrelated to danofloxacin.

Pharmacokinetics of Ertapenem in Sheep (Ovis aries) with Experimentally Induced Urinary Tract Infection.

Sheep are commonly used as animal models for human biomedical research, but descriptions of their use for studying the pharmacokinetics of carbapenem antimicrobials, such as ertapenem, are unavailable. Ertapenem is a critical antimicrobial for human infections, and the description of the pharmacokinetics of this drug is of value for research using ovine as models for human diseases, such as urinary tract infections (UTI). There are currently no ovine models for comparative biomedical research of UTI. The objective of this study was to report the pharmacokinetics of ertapenem in sheep after single and multiple dosing. In addition, we explored the effects of an immunomodulatory drug (Zelnate) on the pharmacokinetics of ertapenem in sheep. Eight healthy ewes (weight, 64.4 ± 7.7 kg) were used in an ovine bacterial cystitis model of human cystitis with Pseudomonas aeruginosa. After disease confirmation, each ewe received 1 g of ertapenem intravenously once every 24 h for 5 administrations. Blood was collected intensively (14 samples) during 24 h after the first and last administration. After multiple-dose administration, the volume of distribution was 84.5 mL/kg, clearance was 116.3 mL/h/kg, T1/2(λz) was 1.1 h, and the extraction ratio was 0.02. No significant differences in pharmacokinetic parameters or time points were found between groups treated with the immunostimulant and controls or after the 1st or 5th administration of ertapenem. No accumulation was noted from previous administration. Our ovine pharmacokinetic findings can be used to evaluate therapeutic strategies for ertapenem use (varying drug dosing schedules and combinations with other antimicrobials or immune modulators) in the context of UTI.