The disposition of trimethoprim and sulfadiazine in neonatal foals after intravenous administration

Abstract

Background: Septicaemia in the neonatal foal is caused by both Gram positive and Gram negative bacteria. The life-threatening nature of this condition requires treatment to be initiated with broad spectrum antimicrobial drugs pending antimicrobial susceptibility testing. Potentiated sulphonamides, for example, trimethoprim combined with sulfadiazine, could be clinically relevant options but their pharmacokinetics in the neonatal foal are unknown.

Objectives: To describe the plasma disposition of trimethoprim and sulfadiazine in neonatal foals and to relate the results to patterns in the minimum inhibitory concentration (MIC) for Escherichia coli, a recognized pathogen in neonatal foal sepsis.

Method: A total of five doses of trimethoprim (2.5 mg/kg) and sulfadiazine (12.5 mg/kg) were administered intravenously every 12 h to eight neonatal foals that were 3 days old at inclusion. A non-linear mixed effects model was fitted to the trimethoprim and sulfadiazine experimental data. The 24 h area under the free plasma trimethoprim and sulfadiazine concentration-time curves (fAUC) and the pharmacokinetic/pharmacodynamik (PK/PD)-index fAUC/MIC was calculated to evaluate the potential clinical benefits of the administered dose.

Results: For trimethoprim, the typical values were 1.99 L/kg, 0.33 L/h·kg and 4.2 h for the apparent volume of distribution, clearance and terminal half-life, respectively. The 24 h fAUC for trimethoprim was 11.3 μg·h/ml (7.2-15.2) and the fAUC/MIC ratio for E. coli was 23 (16.4-29.2) (population mean (range)). For sulfadiazine, the typical values were 0.61 L/kg, 0.09 L/h·kg and 5.3 h for the apparent volume of distribution, clearance and terminal half-life, respectively. The 24 h fAUC for sulfadiazine was 246.8 μg·h/ml (175.6-335.4).

Conclusion: For trimethoprim, the plasma exposure is insufficient in some foals to successfully treat bacterial infections with an MIC-value of 0.5 μg/ml using the studied dosing regimen.

Keywords: antibiotics; horse; pharmacokinetics; potentiated sulphonamides; sepsis.

FIGURE 1

Spaghetti plot of observed (circles) and model predicted (lines) trimethoprim total concentration‐time courses (upper plot) and sulfadiazine total concentration‐time courses (lower plot) following the last of five intravenous 2.5 mg/kg trimethoprim and 12.5 mg/kg sulfadiazine administrations every 12 h to eight neonatal foals. The trimethoprim/sulfadiazine combination was administered at –48, –36, –24, –12 and 0 h. Insets show mean ± SD observed total trimethoprim and sulfadiazine concentrations