Synovial Concentration Of Trimethoprim-Sulphadiazine Following Regional Limb Perfusion In Standing Horses

Simple Summary Trimethoprim-sulphadiazine is a first line antimicrobial drug recommended for use in equine orthopedic infections such as deep wounds, ulcerative lymphangitis and septic arthritis. The pharmacokinetics of trimethoprim-sulphadiazine, when delivered through intravenous regional limb perfusion, has not been previously described. This study aimed at describing the pharmacokinetics and safety of the administration of trimethoprim-sulphadiazine through a single cephalic vein injection. Several horses in the study suffered from severe vasculitis, and the resulting synovial fluid concentration of trimethoprim-sulphadiazine over time was low. In light of these findings, the administration of trimethoprim-sulphadiazine to horses using regional limb perfusion via cephalic appears unwarranted. The aim of this study was to investigate the safety and pharmacokinetics of trimethoprim-sulphadiazine administered via intravenous regional limb perfusion (IVRLP) into the cephalic vein. According to the hypothesis, the drug could be administered without adverse effects and the synovial concentrations would remain above the minimum inhibitory concentration (MIC) for trimethoprim-sulphadiazine (0.5 and 9.5 mu g/mL) for 24 h. Ten (n = 10) horses underwent cephalic vein IVRLP with an Esmarch tourniquet applied for 30 min. Four grams (4 g) of trimethoprim-sulphadiazine (TMP-SDZ) were diluted at 0.9% NaCl for a total volume of 100 mL. Synovial fluid and blood samples were obtained immediately before IVRLP and at 0.25, 0.5, 2, 6, 12 and 24 h after the initiation of IVRLP. Trimethoprim and sulphadiazine concentrations were determined using a method based on liquid chromatography/tandem mass spectrometry. The C-max (peak drug concentration) values were 36 +/- 31.1 and 275.3 +/- 214.4 mu g/mL (TMP and SDZ). The respective t(max) (time to reach C-max) values were 20 +/- 7.8 and 26.4 +/- 7.2 min. The initial synovial fluid concentrations were high but decreased quickly. No horse had synovial concentrations of trimethoprim-sulphadiazine above the MIC at 12 h. Severe vasculitis and pain shortly after IVRLP, lasting up to one week post-injection, occurred in five out of 10 horses. In conclusion, IVRLP with trimethoprim-sulphadiazine cannot be recommended due to the low concentrations of synovial fluid over time and the frequent severe adverse effects causing pain and discomfort in treated horses. Thus, in cases of septic synovitis with bacteria sensitive to trimethoprim-sulphadiazine, other routes of administration should be considered.