Fluoroquinolone Antimicrobial Agent Levofloxacin in Veterinary Medicine and its Pharmacokinetic-Pharmacodynamic Studies. Doctoral Thesis

Abstract

In medicine, antibacterial agents represent one of the most important classes of drugs. Fluoroquinolones are among the most widely used antimicrobials. Levofloxacin is a third-generation fluoroquinolone for the use in human medicine, but it has certain applications in veterinary medicine worldwide. This Thesis is a compilation of four scientific publications aimed at investigating the suitability of levofloxacin as an antimicrobial agent in the veterinary field, and to evaluate its properties and activity in animal species, where it has not been previously comprehensively studied. Narratively, the first publication was a scientific literature review assessing the role of levofloxacin in veterinary medicine, covering the status of levofloxacin use in veterinary medicine worldwide, its antimicrobial activity, resistance problems, pharmacokinetics, tissue residues, adverse effects and drug interactions. The second publication was an experimental evaluation of the levofloxacin pharmacokinetic profiles in 6 clinically healthy rabbits after the 5 mg/kg intravenous, intramuscular and subcutaneous administration using the crossover study design. Additionally, the effects of single levofloxacin administration on tear production and osmolarity were measured. In this study levofloxacin showed high clearance (0.60 mL/g/h) and complete bioavailability after extravascular administration. The third publication assessed the pharmacokinetic profiles of levofloxacin in healthy geese (2 groups of 8 animals, which received 2 mg/kg intravenously and 5 mg/kg orally, respectively) and its depletion profiles in goose muscle, heart, liver, kidney and lung after a single oral dose of 5 mg/kg. In this study levofloxacin clearance was also high (0.28 mL/g/h) and oral bioavailability was also complete. The highest levofloxacin concentrations were found in the liver and kidneys. The fourth publication was aimed to assess the activity of levofloxacin against the two of the most common bacterial species associated with infections in rabbits. Minimum inhibitory and minimum bactericidal concentrations were determined for 10 isolates of Pasteurella multocida and 5 isolates of Escherichia coli. A time-killing curve study was performed in vitro and ex vivo in order to calculate proposed levofloxacin daily doses against P. multocida (MIC = 0.015 μg/mL) and E. coli (MIC = 0.03 μg/mL) isolates. Doses were calculated as ≤ 0.91 and ≤ 1.43 mg/kg, respectively. Levofloxacin was well tolerated in most of the study animals, had favourable pharmacokinetic profiles for extravascular administration and was active against bacteria isolated from animals. Despite being used in veterinary medicine in countries outside the EU, as it is categorised by the WHO as the highest priority critically important antimicrobial it is not registered for veterinary use and is not currently allowed to be used in veterinary medicine in the EU. The selection of levofloxacin as a research topic was based on its global ubiquity, distinct usage status, and broad antimicrobial activity. This makes it a compelling subject for scientific investigation.