Pharmacokinetics, pharmacodynamics, and local tolerance at injection site of penicillin and gentamicin administered by intravenous regional limb perfusion in standing horses: comparison between weightbearing and flexed limbs.

Research Overview

• This study investigates the pharmacokinetics, pharmacodynamics, and local tolerance of penicillin and gentamicin antibiotics administered via intravenous regional limb perfusion (IVRLP) in horses.
• It compares the effects and feasibility of IVRLP when performed on weightbearing versus flexed limbs to treat distal limb infections.

Background and Objectives

• Intravenous regional limb perfusion (IVRLP): A technique used to deliver high concentrations of antibiotics directly to the distal limbs of horses, targeting infections effectively.
• Antibiotics studied: Sodium benzylpenicillin (NaBP) and gentamicin.
• Main goals:
  • Determine the pharmacokinetics (drug behavior within the body) and local tolerance (side effects at the injection site) of NaBP via IVRLP.
  • Compare IVRLP performed on a weightbearing limb versus a flexed limb regarding ease, safety, and antibiotic delivery.
  • Predict the effectiveness of gentamicin and NaBP IVRLP based on pharmacodynamic parameters.

Methods

• Study design: Prospective crossover with six standing horses.
• Each horse underwent four IVRLP phases combining two antibiotics (gentamicin at 2.2 mg/kg and NaBP at 7,333 IU/kg) with two limb positions (weightbearing and flexed).
• After each antibiotic administration:
  • Synovial (joint fluid) and blood samples were collected at multiple time points to measure drug concentrations.
  • Local inflammation and sensitivity at the injection site and sampled joint were assessed.
• Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to estimate efficacy by calculating the area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio for different MIC values.

Key Results

• Antibiotic concentrations:
  • Both NaBP and gentamicin achieved high synovial fluid concentrations, though there was significant variability between horses.
  • Synovial antibiotic exposure was significantly higher when IVRLP was performed on weightbearing limbs compared to flexed limbs (p=0.04 for NaBP, p=0.02 for gentamicin).
• Local tolerance:
  • NaBP IVRLP was generally well tolerated but caused more cephalic vein inflammation than gentamicin (statistically significant difference).
  • Inflammation scores at the cephalic vein were significantly lower in weightbearing limbs than flexed limbs (p=2.5×10⁻³), indicating better local tolerance with the weightbearing method.
• Predicted efficacy based on PK/PD:
  • Gentamicin at 2.2 mg/kg is predicted to effectively treat synovial infections caused by bacteria such as Escherichia coli and Staphylococcus aureus, even some resistant strains (MIC ≤ 16 µg/mL).
  • NaBP at 7,333 IU/kg daily or every other day should be adequate against infections from Streptococcus equi and susceptible Staphylococcus aureus strains (MIC ≤ 2 µg/mL).

Conclusions and Clinical Implications

• IVRLP using NaBP and gentamicin achieves high drug concentrations in the distal limb joints, essential for treating infections effectively.
• Administering IVRLP with the horse’s limb weightbearing leads to:
  • Higher synovial concentrations of antibiotics.
  • Less local vein inflammation and better overall tolerance.
  • More feasible and potentially safer treatment compared to the flexed limb position.
• NaBP at 7,333 IU/kg is a practical option for treating infections by bacteria susceptible at an MIC ≤ 2 µg/mL with mild local side effects.
• Gentamicin at 2.2 mg/kg IVRLP may provide effective treatment for infections caused by more resistant bacterial strains with MICs up to 16 µg/mL.
• The research supports the clinical use of daily IVRLP antibiotic administration directly in the distal limbs of standing horses, favoring weightbearing limb positioning for better outcomes.