About Plasma and intestinal concentrations of sulfadiazine-trimethoprim in pigs after (non)conventional oral and intramuscular treatment, within the context of antimicrobial resistance Department of Pharmacology, Toxicology and Biochemistry Faculty of Veterinary Medicine, Ghent University, Belgium Pharm. Joren De Smet Joren.DeSmet@UGent.be

Context Impact on GIT exposure? Dosage and administration route Dosing discrepancies of antimicrobials are observed in the Belgian field1 Oral therapy: often under dosed Intramuscular therapy: often over dosed 1.Callens, B., et al., Prophylactic and metaphylactic antimicrobial use in Belgian fattening pig herds. Prev Vet Med, 2012. 106(1): p. 53-62.

Experimental setup 36 pigs, 6 pigs/ group Uniform feeding strategy Allows for assessment Dosing discrepancy Administration route Five-day treatment period Daily collection blood and manure End: collection GIT contents

Results – Plasma 1.1. Plasma concentrations SULFADIAZINE (0-108h) Group 1 – Oral bolus 25 mg SDZ/ kg BW Group 2 – Oral bolus 12.5 mg SDZ/ kg BW Group 3 – IM injection 12.5 mg SDZ/ kg BW Group 4 – IM injection 25 mg SDZ/ kg BW Group 5 – Feed 25 mg SDZ/ kg BW Group 6 – Feed 12.5 mg SDZ/ kg BW

Results – Plasma 1.2. Plasma concentrations TRIMETHOPRIM (0-108h) Group 1 – Oral bolus 5mg TRIM/ kg BW Group 2 – Oral bolus 2.5 mg TRIM/ kg BW Group 3 – IM injection 2.5 mg TRIM/ kg BW Group 4 – IM injection 5 mg TRIM/ kg BW Group 5 – Feed 5 mg TRIM/ kg BW Group 6 – Feed 2.5 mg TRIM/ kg BW

Results – Plasma Conclusions IM administration results in highest Cpmax values for SDZ and TRIM Oral gavage same magnitude Medicated feed: lower plasma concentrations Dosing discrepancy = difference in systemic exposure Indicating linear pharmacokinetics

Results – Intestinal content 2. Intestinal concentrations SDZ-TRIM End of therapy after 5 consecutive days Intestinal concentrations of SDZ-TRIM were measured Duodenum Jejunum Ileum Cecum Colon Rectum

Dosage of 30 mg SDZ-TRIM/ kg bodyweight Sulfadiazine Trimethoprim

Dosage of 15 mg SDZ-TRIM/ kg bodyweight Sulfadiazine Trimethoprim

Results intestinal content Conclusions High oral bioavailabilities for SDZ-TRIM Extensive absorption from proximal segments Sulfadiazine Literature: mainly renal excretion for SDZ Our study: high levels of SDZ in GIT segments (~ Cpmax) Accumulation in distal segments Mechanism of gastro-intestinal secretion after absorption Next, accumulation SDZ distal segments due to ion-trapping With pKa 6.5, partly ionized at gut pH Selection pressure for microbiota in GIT due to high SDZ levels

Results intestinal content Conclusions Trimethoprim TRIM decreases towards distal segments Full resorption and no intestinal secretion is assumed Less selection pressure for microbiota in GIT

Future perspectives Project “DOSERESIST” (contract RF 14/6287). New insights intestinal concentrations of antimicrobials By evaluating different treatment strategies Assess impact of these concentrations on resistance selection By use of E.coli as indicator bacteria In vitro model mimicking porcine gut

Acknowledgements Department of Pharmacology, Toxicology and Biochemistry Prof. Dr. P. De Backer Prof. Dr. S. Croubels Prof. Dr. M. Devreese