Pharmacokinetics and pharmacodynamics of enrofloxacin treatment of Escherichia coli in a murine thigh infection modeling.

BACKGROUND: Enrofloxacin is an antibacterial drug with broad-spectrum activity that is widely indicated for veterinary use. We aim to develop the clinical applications of Enrofloxacin against colibacillosis by using the neutropenic mice thigh infection model. RESULTS: The minimum inhibitory concentration (MIC) distribution of 67 isolated E. coli strains to ENR was calculated using CLSI guidelines. Whereas, the MIC50 value calculation was considered as the population PD parameter for ENR against E. coli strains. The MIC values of 15 E. coli strains were found to be nearest to the MIC50 i.e., 0.25 µg/mL. Of all the tested strains, the PK-PD and E. coli disease model was established via selected E. coli strain i.e., Heilong 15. We analyzed the PK characteristics of ENR and its metabolite ciprofloxacin (CIP) following a single subcutaneous (s.c.) injection of ENR (1.25, 2.5, 5, 10 mg/kg). The concentration-time profiling of ENR within the plasma specimens was determined by considering the non-compartmental analysis (NCA). The basic PK parameters of ENR for the peak drug concentration (Cmax) and the area under the concentration-time curve (AUC) values were found to be in the range of 0.27-1.97 µg/mL and 0.62-3.14 µg.h/mL, respectively. Multiple s.c. injection over 24 h (1.25, 2.5, 5, 10 mg/kg at various time points i.e., 6, 8, 12, and 24 h respectively) were administered to assess the targeted PD values. The Akaike Information Criterion (AIC) was used to choose PD models, and the model with the lowest AIC was chosen. The inhibitory Emax model was employed to calculate the related PK-PD parameters. The results of our study indicated that there was a strong correlation between the AUC/MIC and various antibacterial activities (R2 = 0.9928). The target values of dividing AUC/MIC by 24 h for bacteriostatic action were 1-log10 reduction, 2-log10 reduction, and 3-log10 reduction 0.325, 0.4375, 0.63, and 0.95 accordingly. CONCLUSION: The identified pharmacodynamics targets for various antibacterial effects will be crucial in enhancing ENR clinical applications and serving as a key step in reducing bacterial resistance.

The impact of therapeutic-dose induced intestinal enrofloxacin concentrations in healthy pigs on fecal Escherichia coli populations.

BACKGROUND: Knowledge of therapy-induced intestinal tract concentrations of antimicrobials allows for interpretation and prediction of antimicrobial resistance selection within the intestinal microbiota. This study describes the impact of three different doses of enrofloxacin (ENR) and two different administration routes on the intestinal concentration of ENR and on the fecal Escherichia coli populations in pigs. Enrofloxacin was administered on three consecutive days to four different treatment groups. The groups either received an oral bolus administration of ENR (conventional or half dose) or an intramuscular administration (conventional or double dose). RESULTS: Quantitative analysis of fecal samples showed high ENR concentrations in all groups, ranging from 5.114 ± 1.272 µg/g up to 39.54 ± 10.43 µg/g at the end of the treatment period. In addition, analysis of the luminal intestinal content revealed an increase of ENR concentration from the proximal to the distal intestinal tract segments, with no significant effect of administration route. Fecal samples were also screened for resistance in E. coli isolates against ENR. Wild-type (MIC≤0.125 µg/mL) and non-wild-type (0.125 < MIC≤2 µg/mL) E. coli isolates were found at time 0 h. At the end of treatment (3 days) only non-wild-type isolates (MIC≥32 µg/mL) were found. CONCLUSIONS: In conclusion, the observed intestinal ENR concentrations in all groups showed to be both theoretically (based on pharmacokinetic and pharmacodynamic principles) and effectively (in vivo measurement) capable of significantly reducing the intestinal E. coli wild-type population.

Diffusion of fluoroquinolones into equine fetal fluids did not induce fetal lesions after enrofloxacin treatment in early gestation.

While recent work demonstrated that enrofloxacin and ciprofloxacin reach the fetoplacental unit without causing obvious lesions in the 9-month-old equine fetus or resulting foal, many practitioners still hesitate to prescribe a fluoroquinolone during pregnancy. Since early gestation is a critical time for fetal skeletal development, if fluoroquinolones are chondrotoxic to the fetus at any point during gestation, this period would be important. The aim of this study was to assess the effects of 2 weeks' exposure to enrofloxacin on the equine fetus between 46 and 60 days gestation. Twelve pregnancies from nine healthy mares were allocated into two groups: untreated (n=7), or treatment (7.5mg/kg enrofloxacin, PO×14days, n=6). Abortion was induced with prostaglandin 24h after the last enrofloxacin dose, or on the equivalent day of gestation for untreated mares. Four of nine mares were rebred for a second cycle and were assigned to the opposite treatment to serve as their own controls. Fetal fluids from treated mares were analysed for enrofloxacin and ciprofloxacin concentrations. Fetal organs (heart, lungs, spleen, kidney, and liver) and limbs were examined histopathologically. Enrofloxacin and ciprofloxacin diffused to the fetal fluids during early gestation and did not result in detectable abnormalities in the fetus after 14 days of treatment. While current research does not determine long-term foal outcomes, enrofloxacin may be useful for select bacterial infections in pregnant mares.

Effects of lactic acid on drug-metabolizing enzymes in Chinese mitten crab (Eriocheir sisnensis) after oral enrofloxacin.

Enrofloxacin (ENR) is the most commonly used antibiotic in crustacean farming in China. Diet supplementation with lactic acid (LA) may, however, affect the efficacy and safety of ENR-based drugs. The aims of this study were to investigate the effects of LA on drug residues and elimination of oral ENR in Chinese mitten crab (Eriocheir sinensis) and to determine ENR and gene expression levels of drug-metabolizing enzymes in the hepatopancreas. To this end, ENR was orally administered to the crabs at a dose of 10.0 mg kg-1 body weight on the eighth day after feeding diets supplemented with 0.3%LA. The results showed that ENR levels in the hepatopancreas were significantly different at 1 and 12 h between the ENR and ENR + 0.3% LA groups (P < 0.05). Lactic acid did not significantly affect the expression of CYP2A (phase I). However, the expressions of CYP3 (phase I) and GST (phase II) were significantly up-regulated by LA during the elimination process of ENR (6-24 h). At Tmax (1 h), the expression of phosphoenolpyruvate carboxykinase (PEPCK) was induced and expression of succinate dehydrogenase (SDH) was inhibited by LA. Both of these enzymes were significantly inhibited during the elimination process of ENR. The results suggest that LA contributes to the elimination of ENR, and thus, enhances hepatopancreas biotransformation and anti-injury capacity in E. sinensis.

Pharmacokinetic and pharmacodynamic integration of enrofloxacin against Salmonella Enteritidis after administering to broiler chicken by per-oral and intravenous routes.

It is crucial to optimize the dose of fluoroquinolones to avoid antibiotic resistance and to attain clinical success. We undertook this study to optimize the dose of enrofloxacin against Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis) in chicken by assessing its pharmacokinetic/pharmacodynamic (PK/PD) indices. The antibacterial activities of enrofloxacin against S. Enteritidis were evaluated. After administering 10 mg/kg body weight (b.w.) of enrofloxacin to broiler chickens of both sexes by intravenous (IV) and peroral (PO) routes, blood samples were drawn at different intervals and enrofloxacin concentrations in plasma were determined. PK/PD indices were calculated by integrating the PK and PD data. The elimination half-lives (T1/2), time required to reach peak concentration (Tmax), peak concentration (Cmax), and area under curve (AUC) after administering enrofloxacin by PO and IV routes were 25.84 ± 1.40 h, 0.65 ± 0.12 h, 3.82 ± 0.59 µg/mL, and 20.84 ± 5.0 µg·h/mL, and 12.84 ± 1.4 h, 0.22 ± 0.1 h, 6.74 ± 0.03 µg/mL, and 21.13 ± 0.9 µg.h/mL, respectively. The bioavailability of enrofloxacin was 98.6% ± 8.9% after PO administration. The MICs of enrofloxacin were 0.0625-1 µg/mL against S. Enteritidis strains, and the MIC50 was 0.50 µg/mL. The Cmax/MIC50 were 7.64 ± 0.2 and 13.48 ± 0.7 and the 24 h AUC/MIC50 were 41.68 ± 0.1 and 42.26 ± 0.3 after administering the drug through PO and IV routes, respectively. The data in this study indicate that the application of 50 mg/kg b.w. of enrofloxacin to chicken through PO and IV routes with a dosing interval of 24 h can effectively cure S. Enteritidis infection, indicating the need for a 5-fold increase in the recommended dosage of enrofloxacin in chicken.