Trimethoprim/sulfonamide combinations in the horse: a review

Abstract

The indications for use, side-effects, and pharmacokinetic parameters of trimethoprim, sulfonamides and their combinations in the horse are reviewed. Trimethoprim/sulfonamide (TMPS) combinations are used for the treatment of various diseases caused by gram-positive and gram-negative bacteria, including infections of the respiratory tract, urogenital tract, alimentary tract, skin joints and wounds. TMPS combinations can be administered orally, since absorption from the gastrointestinal tract is relatively good. However, peak serum concentrations can vary significantly between individual horses. Feed intake affects serum concentrations after oral administration. Concentrations of non-bound trimethoprim (TMP) and sulfadiazine (SDZ) in synovial fluid and peritoneal fluid are equal to serum concentrations after intravenous (i.v.) administration, and high concentrations are found in urine. Concentrations of TMP and sulfamethoxazole (SMX) in cerebrospinal fluid after i.v. administration exceed the minimum inhibitory concentration for common equine pathogens. The volume of distribution is 1.5-2.7 l/kg for TMP and 0.3-0.7 l/kg for various sulfonamides. The plasma half-life of TMP is 1.9-4.3 h, whereas the plasma half-lives of the different sulfonamides vary between 2.7 and 14.0 h. About 50% of total TMP is bound to plasma proteins. The binding of sulfadoxine to plasma proteins depends on total plasma concentration and varies between 14% and 72%. The binding of other sulfonamides to plasma proteins may range from 33% for sulfaphenazole (SPZ) to 93% for sulfadimethoxine (SDM). Sulfonamides are metabolized by acetylation of the para-amino (N4) group and by hydroxylation of the methyl group and the pyrimidine ring. The metabolic pathways of TMP in the horse are not fully known. Bacterial resistance to TMPS combinations is still relatively low. The sensitivity of different micro-organisms may vary with the relative activity of the sulfonamide used in the combination. The advised oral and i.v. dose rate is 15-30 mg/kg (in a 1:5 TMP/S ratio) with a dose interval of 12 h. The acute toxicity of TMPS is low, but there have been several reports of death after i.v. administration, probably due to vagal stimulation and subsequent bradycardia and vasodilatation caused by the pharmaceutical formulation (excipients, solvents) used. Future research should concentrate on establishing the optimum pyrimidine/sulfonamide combination and its dosing regimen for antimicrobial therapy in horses.

Comparison of Hydrolytic and Conjugative Biotransformation Pathways in Horse, Cattle, Pig, Broiler Chick, Rabbit and Rat Liver Subcellullar Fractions

“…Pigs also appeared to be good acetylators, and lower but measurable activities towards either substrate were observed in equine preparations. Interestingly, the acetylating capacity of horses has been questioned (Schmid and Schmid, 1994), although the N 4 -acetylation of several sulfonamides has been reported in this species (Van Duijkeren et al, 1994). Acetylation defects have been documented in other species: the domestic dog and other canids lack cytosolic NAT owing to the absence of NAT genes (Trepanier et al, 1997), whereas in domestic and wild felids only NAT1 appears to be expressed.…”

Silver sulfadoxinate: Synthesis, structural and spectroscopic characterizations, and preliminary antibacterial assays in vitro

“…Besides the antimalarial activity, the sulfadoxine-pyrimethamine hybrid is also active against the parasite Toxoplasma gondii [15] and is considered as primary prophylaxis of pneumonia caused by Pneumocyctis carinii [16][17][18] and toxoplasmatic encephalitis in patients infected with HIV [17,18]. Sulfadoxine is also used in combination with trimethoprim to treat different bacterial infections in animals as horses and calves, being active against Gram-negative and Gram-positive bacteria [19][20][21].…”

Bioavailability and Pharmacokinetics of Sulphadiazine, N4-acetylsulphadiazine and Trimethoprim following Intravenous and Intramuscular Administration of a Sulphadiazine/Trimethoprim Combination in Sheep

“…Considerable tissue irritation or damage occurs after i.m. or s.c. administration of SA/TMP combinations (Van Duijkeren et al, 1994b;Kaartinen et al, 1999Kaartinen et al, , 2000. Causative factors are the presence of organic solvents in the injectable formulations, the high drug concentrations (24% or even 48%) and the high pH (10^12) of the formulations (Van Duijkeren et al, 1994b).…”