Repeated administration of trimethoprim/sulfadiazine in the horse –pharmacokinetics, plasma protein binding and influence on the intestinal microflora

Abstract

Six healthy adult horses were given repeated administrations of trimethoprim/ sulfadiazine (TMP/SDZ) intravenously (i.v.) (2.5 mg/kg TMP and 12.5 mg/kg SDZ) and orally (p.o.) as a paste (5 mg/kg TMP and 25 mg/kg SDZ). Both formulations were given twice daily for 5 days, with a 3-week interval between i.v. and oral administration. The influence of the drug combination on the intestinal microflora was examined and the plasma concentrations, pharmacokinetic parameters and plasma protein binding were determined. There were no major changes in the bacterial intestinal flora and no clinical evidence of gastrointestinal disturbances following the i.v. and oral TMP/SDZ administration. An initial reduction in the number of coliform bacteria during the treatment was notable, though with no evident difference between i.v. and oral treatment. The minimum concentration during a dose interval at steady state (Cminss), the elimination half-life (t1/2beta) and the mean residence time (MRT) were significantly greater after oral administration compared to i.v. for both TMP and SDZ. The plasma protein binding was measured to be 20% for SDZ and 35% for TMP. Oral administration of TMP/SDZ in a dose of 30 mg/kg given twice daily in the form of paste appeared as a satisfactory method for obtaining plasma levels above MIC (minimum inhibitory concentration in vitro) values during the interdosing interval.

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

“…However, in the latter study, a very high dose of SDZ (100 mg/kg bw) was used and this could have led to a capacity-limited elimination process (Van Gogh, 1980). Shorter terminal half-lives, relatively closer to the ¢ndings of the present study in sheep, have been reported in other animal species: *3.5^4.5 h in cattle (Clarke et al, 1989;Shoaf et al, 1989;Kaartinen et al, 1999), *4.6 h in horses (Van Duijkeren et al, 1994a, Gustafsson et al, 1999, and *3 h in chickens (Batzias et al, 2000;Baert et al, 2003). The bioavailability (+SD) of 69.00%+10.51% was found to be lower than that reported by Shoaf and colleagues (1987), who studied the bioavailability of SDZ after s.c. administration of a SZD/TMP combination in calves, as well as by Kaartinen and colleagues (1999), after either i.m.…”

“…Studies in other species, such as swine (Nielsen and Rasmussen, 1975a,b;Garwacki et al, 1996), dogs and cats (Craig and White, 1976;Sigel et al, 1981), horses (Brown et al, 1983;Bogan et al, 1984;Van Duijkeren et al, 1994a, Gustafsson et al, 1999, poultry (Lo« scher et al, 1990;Batzias et al, 2000;Baert et al, 2003), rabbits (Ladefoged, 1977) and ¢sh (Nouws et al, 1993), have also been performed. All investigators clearly reported higher values of volume of distribution (V) and clearance (Cl), together with a substantially shorter elimination half-life for TMP, compared to SDZ.…”

Comparison of Fecal Microbiota of Mongolian and Thoroughbred Horses by High-throughput Sequencing of the V4 Region of the 16S rRNA Gene

“…Studies using direct sequencing methods have revealed a greater diversity of horse microbiota than previously estimated by culture-dependent methods (Gustafsson et al, 1999). Previous were insufficient to fully understand the horse microbial communities.…”

“…Previous were insufficient to fully understand the horse microbial communities. Direct sequencing analysis was used to study the gut microbiota of Irish Thoroughbred race horses in a recent study (O’Donnell et al, 2013), Ponies (Gustafsson et al, 1999) and so on. We examined and compared the composition and variation in the fecal microbiota of two horse breeds, Mongolian horses and Thoroughbred horses, using the high-throughput sequencing.…”

Evaluation of Veterinary-Specific Interpretive Criteria for Susceptibility Testing of Streptococcus equi Subspecies with Trimethoprim-Sulfamethoxazole and Trimethoprim-Sulfadiazine

“…It has been shown in equine practice that potentiated sulfonamides achieve the 1:20 plasma ratio and can be regarded to as therapeutically effective for susceptible S. equi when administered at 5 mg of TMP/kg of body weight and 25 mg of SDZ/kg (1:5 ratio) with a dosing interval of 12 h (15–19). The results support the available literature, since the FIC indices showed synergy at a wide range of TMP-to-sulfonamide ratios and concentrations.…”