Ex vivo antibacterial activity of levofloxacin against Escherichia coli and its pharmacokinetic profile following intravenous and oral administrations in broilers

• Published in: Research in veterinary science 2017-06, Vol.112, p.26-33
• Main Authors: Lee, Hong Ki, DeVito, Virginia, Vercelli, Cristina, Tramuta, Clara, Nebbia, Patrizia, Re, Giovanni, Kovalenko, Kaspars, Giorgi, Mario
• Format: Article
• Language: English
• Subjects: Administration, Intravenous - veterinary; Administration, Oral; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antibiotics; Antimicrobial agents; Area Under Curve; Bacteria; Bacterial diseases; Bacterial infections; Bioavailability; Biological Availability; Broilers; Cellulose acetate; Chickens - blood; Chickens - metabolism; Design analysis; Diseases; Dosage; Drug dosages; E coli; Effectiveness; Escherichia coli; Escherichia coli - drug effects; Experiments; Half-Life; High-performance liquid chromatography; Incubation; Infectious diseases; Inhibition; Intravenous administration; Kidneys; Levofloxacin; Levofloxacin - administration & dosage; Levofloxacin - pharmacokinetics; Levofloxacin - pharmacology; Liquid chromatography; Liver; Lungs; Microbial Sensitivity Tests; Minimum inhibitory concentration; Optimization; Oral administration; Oral cavity; Pharmacodynamics; Pharmacokinetics; Pharmacology; Poultry; Residues; Risk assessment; Simulation; Streptococcus infections; Surveillance; Tissue Distribution; Tissues; Veterinarians; Veterinary medicine
• ISSN: 0034-5288; 1532-2661
• DOI: 10.1016/j.rvsc.2017.01.003

The use of antibiotics is necessary to treat bacterial diseases. Determination of optimal dosage in the target animals is increasingly being recognized as vital for maximizing efficacy and minimizing the risk of resistance, so this study aimed to evaluate the pharmacokinetics/pharmacodynamics (PK/PD) of levofloxacin in broilers. Using a parallel study design, each group of animals (n=20) received 5mg/kg of levofloxacin intravenously (IV) and orally (PO). Plasma, serum and tissues were collected for PK and PD studies. Plasma concentrations of levofloxacin were determined by HPLC. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined against E. coli, isolated in clinical broilers. Ex vivo antibacterial activity was evaluated using the time killing method. Mean values of terminal half-life for IV and PO groups were 6.93 and 8.09h, respectively. Following oral administration, the peak plasma concentration was achieved at 0.88h (Tmax). Mean value of oral bioavailability was 123.25%. Levofloxacin residues were found in all the tissues tested (muscle, liver, kidney and lung). Plasma concentration above 8× MIC lead to eradication of E. coli (incubation period of 24h). The results of ex vivo growth inhibition curves were consistent with the in vitro time-kill study. Levofloxacin showed dependent plasma concentration antibacterial activity against a clinical isolate of E. coli. According to the assessment of PK/PD relationship, administration of 5mg/kg of levofloxacin seems to be effective in killing E. coli. Also, simulated optimal dose based on the ex vivo PK/PD approach was 2.9mg/kg/day (bactericidal) to 4.3mg/kg/day (eradication) PO against E. coli (MIC=0.125μg/ml). •MIC of levofloxacin in wild E.coli is 0.03μg/ml and 0.06μg/ml in MHB and serum, while in MBC is 0.03 and 0.125μg/ml in MHB and serum, respectively.•Mean values of terminal half-life for IV and PO groups: 6.93 and 8.09h.•PO administration: the peak plasma concentration was achieved at 0.88h (Tmax) and the mean value of oral bioavailability was 123.25%. Levofloxacin was found in tissues up to 48h following PO administration at 5mg/kg. Levofloxacin was deposited in liver and kidney with high concentration.•PK/PD integrated results suggest that 5mg/kg is an effective dose to kill E. coli with a predicted maximum antibacterial effect (Emax): 10−6.65CFU/ml.