Pharmacokinetics of a sulfadiazine and trimethoprim suspension in neonatal foals

Here are two studies of the use of TMP-SDZ in neonatal foals. Note the dosage of the oral study and it reaching therapeutic levels in the blood for susceptible organisms. The IV dose study showed that the much smaller dose given IV was insufficient to treat many susceptible organisms.
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J Vet Pharmacol Ther. 2020 Dec 1.
Pharmacokinetics of a sulfadiazine and trimethoprim suspension in neonatal foals
Elsbeth Swain O’Fallon 1, Patrick McCue 1, Sangeeta Rao 1, Daniel L Gustafson 1
Affiliations expand
PMID: 33289123 DOI: 10.1111/jvp.12930
Abstract
There is limited investigation of neonatal foal pharmacokinetic parameters for the antimicrobial combination of sulfadiazine (SDZ) and trimethoprim (TMP). Neonatal pharmacokinetic investigation of the sulfadiazine-trimethoprim combination is required to ensure safe and effective utilization in this population. The purpose of this study was to determine the pharmacokinetics of sulfadiazine-trimethoprim in five healthy neonatal foals with oral administration at 24 mg/kg every 12 hr (hrs) for 10 days. Blood samples were collected at serial time points at approximately 72 hr of age (steady-state) and at days 5 and 10 to monitor the influence of age within the neonatal period. Pharmacokinetic parameters were determined using a one-compartment model analysis, and mean ± SD was calculated. Cmax was 37.8 ± 13.4 μg/ml (SDZ) and 1.92 ± 0.25 μg/ml (TMP). Tmax was 1.4 ± 0.6 hr (SDZ) and 1.4 ± 0.4 hr (TMP). Cmin for SDZ and TMP was 16.84 ± 8.46 μg/ml and 0.46 ± 0.24 μg/ml, respectively. Elimination half-life was 10.8 ± 6.1 hr (SDZ) and 6.5 ± 2 hr (TMP). AUC0 → ∞ was 667 ± 424 μg × hr/ml (SDZ) and 21.1 ± 5.3 μg × hr/ml (TMP). Foals remained healthy, and the plasma concentration of sulfadiazine-trimethoprim reached levels above MIC(90) for Streptococcus equi ssp. (SDZ/TMP): 9.5/0.5 μg/ml).
Keywords: foal; horse; neonatal; pharmacokinetics; sulfadiazine; trimethoprim.

The disposition of trimethoprim and sulfadiazine in neonatal foals after intravenous administration
Vet Med Sci. 2022 Feb 13.
Carl Ekstrand 1 , Katarina Nostell 2 , Ronette Gehring 1 3 , Ulf Bondesson 4 , Johan Bröjer 2
Affiliations

1 Department of Biomedical Sciences and Veterinary Public Health, Division of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
2 Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
3 Department of Population Health Sciences, Division of Veterinary and Comparative Pharmacology, Utrecht University, Utrecht, The Netherlands.
4 Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute (SVA), Uppsala, Sweden.

PMID: 35152563
DOI: 10.1002/vms3.763

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.