Abstract
Antimicrobial agents are used extensively off-label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30mg/kg, i.e. 5mg/kg TMP and 25mg/kg SDZ). fAUC/MIC with a target value of 24hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30mg/kg, PO, once daily) therefore appears adequate for treatment of wild-type E.coli and S.delphini infections in mink.
Highlights
Potentiated sulfonamides are combinations of a sulfonamide and a diaminopyrimidine (typically trimethoprim (TMP)), which exhibit synergistic bactericidal effects by interfering at two different stages in the process of bacterial folic acid biosynthesis
Three experiments with a total of 22 minks were conducted: In the first two studies, we investigated the disposition of SDZ and TMP after IV administration, and the third study was an evaluation of PK parameters of these drugs after oral administration
SXD is used off-label to manage various infections in mink caused by pathogens such as E. coli, P. aeruginosa, and S. delphini
Summary
Potentiated sulfonamides are combinations of a sulfonamide and a diaminopyrimidine (typically trimethoprim (TMP)), which exhibit synergistic bactericidal effects by interfering at two different stages in the process of bacterial folic acid biosynthesis. PKPD modeling and simulation have been investigated extensively as an alternative approach for conventional antimicrobial dose titration studies (Lees & Aliabadi, 2004; Toutain, Del Castillo, & Bousquet-Mélou, 2002) Using this approach, drug disposition (PK) is explored experimentally in the target animal species. The objectives of this study were to (a) establish PK data for SDZ and TMP in mink after intravenous (IV) and oral administration of SXD, (b) investigate the effect of blood sampling site (vein versus nail) and feeding status (fed versus fasted) on PK parameters in mink, (c) evaluate the current empirical dosage regimen of SXD for mink bacterial infections after oral administration in feed, and (d) to provide data for development of CBPs for target pathogens in mink
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