Population pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in clinically diseased or injured Eastern box turtles (Terrapene carolina carolina), yellow-bellied sliders (Trachemys scripta scripta), and river cooters (Pseudemys concinna).

Enrofloxacin is frequently administered to turtles in wildlife clinics during rehabilitation due to its wide spectrum of antibacterial activity and availability of injectable formulations. However, sufficient pharmacokinetic data to guide dosing are lacking. The objective of this study was to determine pharmacokinetic parameters of enrofloxacin and its active metabolite, ciprofloxacin, in chelonians presenting injured to a wildlife clinic. Thirty-six Eastern box turtles (EBT, Terrapene carolina carolina), 23 yellow-bellied sliders (YBS, Trachemys scripta scripta), and 13 river cooters (RC, Pseudemys concinna) received a single subcutaneous injection of enrofloxacin at 10 mg/kg. Blood samples were collected between 0 and 240 hr postinjection. Pharmacokinetic parameters were determined using nonlinear mixed-effects modeling (NMLE). Overall elimination half-life (T½) was over 75 hr, and varied among species. T½ was 63 hr in EBT and 79 hr in YBS, which is longer than in previous reports. The volume of distribution (steady-state) was 1.4 L/kg across turtle species, but highly variable-ranging from 0.4 L/kg in RC to 1.9 L/kg in YBS. Antibiotic concentrations were above a minimum inhibitory concentration value of 0.5 µg/ml for over 200 hr. These results indicate variable pharmacokinetic parameters for enrofloxacin among turtle species, which will help guide appropriate dosing protocols in injured turtles.

Pharmacokinetics of enrofloxacin and danofloxacin in premature calves.

The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramuscular (IM) administrations in premature calves. The study was performed on twenty-four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six premature calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR-IV (10 mg/kg, IV), ENR-IM (10 mg/kg, IM), DNX-IV (8 mg/kg, IV), and DNX-IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high-pressure liquid chromatography with UV detector and analyzed by noncompartmental methods. Mean PK parameters of ENR and DNX following IV administration were as follows: elimination half-life (t1/2λz ) 11.16 and 17.47 hr, area under the plasma concentration-time curve (AUC0-48 ) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady-state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr-1  kg-1 , respectively. The PK parameters of ENR and DNX following IM injection were t1/2λz 21.10 and 28.41 hr, AUC0-48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was determined to be 118% and 124%, respectively. The mean AUC0-48CPR /AUC0-48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC0-24 /minimum inhibitory concentration (MIC) and maximum concentration (Cmax )/MIC ratios for susceptible bacteria, with the MIC90 of 0.5 and 0.03 µg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.

Pharmacokinetics of an intravenous and oral dose of enrofloxacin in white rhinoceros (Ceratotherium simum).

South Africa currently loses over 1000 white rhinoceros (Ceratotherium simum) each year to poaching incidents, and numbers of severely injured victims found alive have increased dramatically. However, little is known about the antimicrobial treatment of wounds in rhinoceros. This study explores the applicability of enrofloxacin for rhinoceros through the use of pharmacokinetic-pharmacodynamic modelling. The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin were evaluated in five white rhinoceros after intravenous (i.v.) and after successive i.v. and oral administration of 12.5 mg/kg enrofloxacin. After i.v. administration, the half-life, area under the curve (AUCtot ), clearance and the volume of distribution were 12.41 ± 2.62 hr, 64.5 ± 14.44 µg ml-1  hr-1 , 0.19 ± 0.04 L h-1  kg-1 , and 2.09 ± 0.48 L/kg, respectively. Ciprofloxacin reached 26.42 ± 0.05% of the enrofloxacin plasma concentration. After combined i.v. and oral enrofloxacin administration oral bioavailability was 33.30 ± 38.33%. After i.v. enrofloxacin administration, the efficacy marker AUC24 : MIC exceeded the recommended ratio of 125 against bacteria with an MIC of 0.5 µg/mL. Subsequent intravenous and oral enrofloxacin administration resulted in a low Cmax: MIC ratio of 3.1. The results suggest that intravenous administration of injectable enrofloxacin could be a useful drug with bactericidal properties in rhinoceros. However, the maintenance of the drug plasma concentration at a bactericidal level through additional per os administration of 10% oral solution of enrofloxacin indicated for the use in chickens, turkeys and rabbits does not seem feasible.

Pharmacokinetics of enrofloxacin HCl-2H2 O (ENRO-C), PK/PD, and Monte Carlo modeling vs. Leptospira spp. in cows.

The pharmacokinetics, PK/PD ratios, and Monte Carlo modeling of enrofloxacin HCl-2H2 O (Enro-C) and its reference preparation (Enro-R) were determined in cows. Fifty-four Jersey cows were randomly assigned to six groups receiving a single IM dose of 10, 15, or 20 mg/kg of Enro-C (Enro-C10 , Enro-C15 , Enro-C20 ) or Enro-R. Serial serum samples were collected and enrofloxacin concentrations quantified. A composite set of minimum inhibitory concentrations (MIC) of Leptospira spp. was utilized to calculate PK/PD ratios: maximum serum concentration/MIC (Cmax /MIC90 ) and area under the serum vs. time concentration of enrofloxacin/MIC (AUC0-24 /MIC90 ). Monte Carlo simulations targeted Cmax /MIC = 10 and AUC0-24 /MIC = 125. Mean Cmax obtained were 6.17 and 2.46 µg/ml; 8.75 and 3.54 µg/ml; and 13.89 and 4.25 µg/ml, respectively for Enro-C and Enro-R. Cmax /MIC90 ratios were 6.17 and 2.46, 8.75 and 3.54, and 13.89 and 4.25 for Enro-C and Enro-R, respectively. Monte Carlo simulations based on Cmax /MIC90  = 10 indicate that only Enro-C15 and Enro-C20 may be useful to treat leptospirosis in cows, predicting a success rate ≥95% when MIC50  = 0.5 µg/ml, and ≥80% when MIC90  = 1.0 µg/ml. Although Enro-C15 and Enro-C20 may be useful to treat leptospirosis in cattle, clinical trials are necessary to confirm this proposal.

Pharmacokinetic/pharmacodynamic relationship of enrofloxacin against Aeromonas hydrophila in crucian carp (Carassius auratus gibelio).

The pharmacokinetic (PK) properties of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated in crucian carp following oral administration at different dose levels (5, 10, 20, 40 mg/kg body weight). The disposition kinetics of ENR was found to be linear over the dose range studied. Serum half-lives ranged from 64.56 to 72.68 hr. The in vitro and ex vivo activities of ENR in serum against a pathogenic strain of Aeromonas hydrophila were determined. In vitro and ex vivo bactericidal activity of ENR was concentration dependent. Dosing of 10 mg/kg resulted in an AUC/minimum inhibitory concentration (MIC) ratio of 368.92 hr and a Cmax /MIC ratio of 7.23, respectively, against A. hydrophila 147 (MIC = 0.48 µg/ml), indicating a likely high level of effectiveness in clinical infections caused by A. hydrophila with MIC value ≤ 0.48 µg/ml. Modeling of ex vivo growth inhibition data to the sigmoid Emax equation provided the values of AUC24 hr /MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria, these values were 21.70, 53.01, and 125.21 hr, respectively. These findings in conjunction with MIC90 data suggested that ENR at the dose of 7.81 mg/kg predicted a positive clinical outcome and minimize the risk of emergence of resistance.

Pentacenequinone-Modulated 2D GdSn-PQ Nanosheets as a Fluorescent Probe for the Detection of Enrofloxacin in Biological and Environmental Samples.

The fate and effects of fluoroquinolone antibacterial (FQ) on the environment are important since there appears to be a surge in FQ resistance like enrofloxacin (ENR) in both environmental and clinical organisms. Numerous reports indicate that the sensing capabilities of these antibiotics need to be improved. Here, we have investigated the interaction of ENR with our synthesized pentacenequinone-modulated gadolinium-tin (GdSn-PQ) nanosheets and the formation of intermolecular interactions that caused the occurrence of aggregation-induced emission enhancement. The concept for designing hybrid metallic nanosheets comes from the unique features inherited from the parent organic precursor. Due to the distinct interaction between ENR and GdSn-PQ, the interstate conversion (ISC) between GdSn-PQ and ENR induces a significant wavelength shift in photoluminescence (PL), improving reliability, selectivity, and visibility compared to quenching- or AIEE-based methods without peak shifts, allowing for highly sensitive and visually detectable analyses. The fluorescence signal of GdSn-PQ exhibited a linear relationship (R2 = 0.9911), with the added ENR concentrations ranging from 5 to 90 nM, with a detection limit of 0.10 nM. We have demonstrated its potential and wide use in the detection of ENR in biological samples (human urine and blood serum) and environmental samples (tap water and seawater) with a recovery rate of 98- 108%. The current approach has demonstrated that the 2D GdSn-PQ nanosheet is a novel and powerful platform for future biological and environmental studies.

Pharmacokinetics in plasma and alveolar regions of healthy calves subcutaneously administered a single dose of enrofloxacin.

This study aimed to analyze the pharmacokinetics of enrofloxacin (ERFX) and its metabolite ciprofloxacin (CPFX) in plasma, as well as their migration to, and retention in, the epithelial lining fluid (ELF) and alveolar cells within the bronchoalveolar fluid (BALF). Four healthy calves were subcutaneously administered a single dose of ERFX (5 mg/kg). ERFX and CPFX dynamics post-administration were analyzed via a non-compartment model, including the absorption phase. The Cmax of plasma ERFX was 1.6 ± 0.4 µg/ml at 2.3 ± 0.5 hr post-administration and gradually decreased to 0.14 ± 0.03 µg/ml at 24 hr following administration. The mean residence time between 0 and 24 hr (MRT0-24) in plasma was 6.9 ± 1.0 hr. ERFX concentrations in ELF and alveolar cells peaked at 3.0 ± 2.0 hr and 4.0 ± 2.3 hr following administration, respectively, and gradually decreased to 0.9 ± 0.8 µg/ml and 0.8 ± 0.5 µg/ml thereafter. The plasma half-life (t1/2) of ERFX was 6.5 ± 0.7 hr, while that in ELF and alveolar cells was 6.5 ± 3.6 and 7.4 ± 4.3 hr, respectively. The Cmax and the area under the concentration-time curve for 0-24 hr for ERFX were significantly higher in alveolar cells than in plasma (P<0.05). These results suggest that ERFX is distributed at high concentrations in ELF and is retained at high concentrations in alveolar cells after 24 hr in the BALF region; hence, ERFX may be an effective therapeutic agent against pneumonia.

Solid lipid nanoparticles with enteric coating for improving stability, palatability, and oral bioavailability of enrofloxacin.

BACKGROUND: The poor palatability, variable oral bioavailability, stimulation to gastric mucosa, and light instability limited the application of enrofloxacin (ENR). The enteric granules combining solid lipid nanoparticles (SLNs) with enteric coating were explored to overcome these disadvantages. MATERIALS AND METHODS: ENR-loaded SLNs were produced by a hot homogenization and ultrasonic emulsification method and the enteric granules with SLNs as inner core were prepared by wet granulation followed by coating using polyacrylic resin II (PRII). The formulation was optimized by using orthogonal or single factor test screening. RESULTS: The optimal SLNs with loading capacity (LC) and price as inspection indexes were consisted of 10 mL 3% polyvinyl alcohol per 0.8 g ENR and 2.4 g octadecanoic acid. The sizes, LC, polydispersion index, and zeta potential of the SLNs were 308.5±6.3 nm, 15.73%±0.31%, 0.352±0.015, and -22.3 mv, respectively. The best enteric granules were used 15% PRII as coating materials. The release of the enteric granules in simulated intestine fluid (SIF, pH=8) was significantly faster than in simulated gastric fluid (SGF, pH=2) and simultaneously slower than those of SLNs and native ENR. The granules showed good stability in influencing factor experiment. The granules displayed a similar daily feed intake as the control group and higher daily feed intake than ENR powder and single-coating granules. Compared to the ENR soluble powder, the area under the plasma concentration-time curve and mean retention time of the enteric granules after intragastric administration were increased from 4.26±0.85 µg h/mL and 6.80±2.28 hours to 11.24±3.33 µg h/mL and 17.97±4.01 hours, respectively. CONCLUSION: The enteric granules combination SLNs with enteric coating significantly improved the stability, palatability, sustained-release performance and oral bioavailability of ENR. The novel technology will be a potential measure to overcome the similar disadvantages of other drugs.

Covalent organic framework-based electrochemical aptasensors for the ultrasensitive detection of antibiotics.

We designed and synthesized a novel covalent organic framework (COF) by condensation polymerization of 1,3,6,8-tetrakis(4-formylphenyl)pyrene and melamine through imine bonds (represented by Py-M-COF). The basic characterizations revealed that the Py-M-COF not only exhibited an extended π-conjugation framework, a large specific surface area (495.5 m2 g-1), big pore cavities, and nanosheet-like structure but also possessed rich functional groups, such as CË­C, CË­N, CË­O, and NH2. These features endowed the Py-M-COF with high charge carrier mobility, further improving the strong immobilization of DNA aptamer strands via π-π stacking interaction and electrostatic interaction. As such, the Py-M-COF-based electrochemical aptasensors are ultrasensitive in detecting different antibiotics, including enrofloxacin (ENR) and ampicillin (AMP), yielding extremely low detection limits of 6.07 and 0.04 fg mL-1 (S/N = 3) toward ENR and AMP, respectively, along with other excellent sensing performances. This biosensing platform based on Py-M-COF has potential applications for the sensitive detection of antibiotics or other analytes by replacing the corresponding aptamers.

Diffusion of enrofloxacin to pregnancy fluids and effects on fetal cartilage after intravenous administration to late pregnant mares.

BACKGROUND: In selective cases, enrofloxacin may be an alternative antibacterial agent to treat unresponsive infections in pregnant mares. Supratherapeutic doses of enrofloxacin are toxic to adult horses and also to newborn foals, however, it is unknown if enrofloxacin crosses the equine placenta or if it is toxic to the fetus. OBJECTIVES: To assess the diffusion of enrofloxacin and its metabolite to fetal fluids and its effects on fetal cartilage when administered to pregnant mares. STUDY DESIGN: In vivo and terminal controlled experiment. METHODS: Healthy mares at 260 days of gestation were allocated into three groups: untreated (n = 3), therapeutic treatment (5 mg/kg enrofloxacin, i.v., n = 7) or supratherapeutic treatment (10 mg/kg, i.v., n = 6) for 11 days. Fetal fluids were collected on days 1, 5 and 11 of treatment. Premature delivery was induced on day 11 with oxytocin and fetal fluids and plasma were collected during delivery. Plasma and fetal fluid enrofloxacin and ciprofloxacin concentrations were measured by liquid chromatography-mass spectrometry. Fetal articular cartilage was examined macroscopically and histologically for lesions. RESULTS: Enrofloxacin and ciprofloxacin reached the minimum inhibitory concentrations for common pathogens in all fluids. Ciprofloxacin did not increase with the double enrofloxacin dose in maternal plasma, but allantoic fluid showed a 10-fold increase relative to fetal trough plasma concentrations. Administration of enrofloxacin at recommended doses did not result in cartilaginous lesions in fetuses. MAIN LIMITATIONS: Only one time point in gestation was evaluated and mares treated in the study were healthy at the time of treatment. It remains to be determined if enrofloxacin shows toxicity at other stages of pregnancy, after a longer duration of treatment, or once the foals are delivered and articular surfaces are weightbearing. CONCLUSIONS: Short-term administration of enrofloxacin to late gestation mares resulted in detectable enrofloxacin and ciprofloxacin concentrations in fetal fluids and did not result in macroscopic or microscopic lesions in the fetus. While further research is needed to address long-term foal outcomes, enrofloxacin may be useful for select bacterial infections in pregnant mares.