Abstract
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 µg/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 Cmax (peak drug concentration) values were 36 ± 31.1 and 275.3 ± 214.4 µg/mL (TMP and SDZ). The respective tmax (time to reach Cmax) 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.
Highlights
Septic arthritis is a severe and potentially life-threatening infection of synovial structures in horses that has a poor prognosis regarding the return to athletic use or even survival if not treated successfully rapidly [1,2,3,4].Infection of synovial structures of the distal limb can be caused by trauma, iatrogenic intervention or via haematogenous spread [5]
During the course of the experimental protocol, five horses developed severe phlebitis of the cephalic vein, with associated cellulitis, which manifested in severe swelling, heat, pain upon palpation of the distal limb and lameness at walking
For the horses with phlebitis, local cryotherapy with ice bandages was applied for the first 24 h, and phenylbutazone (2.2 mg/kg, PO, q12h) administration was continued until the acute phlebitis resolved for 5–7 days, in addition to the standard two days
Summary
Infection of synovial structures of the distal limb can be caused by trauma, iatrogenic intervention (e.g., intra-articular injection or arthroscopic surgery) or via haematogenous spread [5]. Successful treatment is likely to be dependent on the achievement of high concentrations of antimicrobials within the affected synovial structure. Favorable results are seen when local delivery techniques to the affected synovial structure are used, such as intravenous regional limb perfusion (IVRLP), or antibioticimpregnated polymethyl methacrylate or plaster of Paris beads [6]. The use of intravenous or intraosseous routes for RLP is well described and provides high concentrations of selected antimicrobials to synovial structures, without the adverse effects associated with parental administration, such as colitis or nephrotoxicity [7,8,9,10]
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