A Controlled Safety Study of Elevated Dosages of Trimethoprim Plus Sulfadiazine in Mature Horses (original) (raw)
Related papers
Trimethoprim/sulfonamide combinations in the horse: a review
Journal of Veterinary Pharmacology and Therapeutics, 1994
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.
Journal of Veterinary Pharmacology and Therapeutics, 1994
The biopharmaceutical properties of four fixed trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 +/- 0.48 h for a commercial paste (1), and at 1.84 +/- 0.66 h and 1.95 +/- 0.61 h for the two self-made formulations (2 and 3). Mean peak plasma TMP concentrations (+/- SD) were 1.72 +/- 0.36 micrograms/ml, 1.42 +/- 0.37 micrograms/ml and 1.31 +/- 0.36 micrograms/ml, and mean peak plasma SDZ concentrations 12.11 +/- 4.55 micrograms/ml, 12.72 +/- 3.47 micrograms/ml and 15.45 +/- 4.74 micrograms/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 +/- 20.3%, 57.7 +/- 21.6% and 60.9 +/- 18.9% and of SDZ 57.6 +/- 14.8%, 59.3 +/- 19.5% and 65.9 +/- 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (+/- 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time-span.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Veterinary Pharmacology and Therapeutics, 1995
In the present study, the pharmacokinetic parameters of a trimethoprim/sulphachlorpyridazine preparation following intravenous administration, administration by nasogastric tube and administration with concentrate were determined in the horse. Eight adult horses were dosed at 1 week intervals in a sequentially designed study at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulphachlorpyridazine (SCP) on all occasions. Plasma concentrations of both drugs were measured serially for 48 h. Pharmacokinetic parameters of clinical importance (distribution and elimination half-lives, clearance, bioavailability, volume of distribution) were determined both for TMP and SCP. Following intravenous administration, the volume of distribution at steady-state (Vd(ss)) was significantly larger for TMP (1.51 +/- 0.25 L/kg than for SCP (0.26 +/- 0.05 L/kg. The clearance was 7.73 +/- 2.26 mL/min.kg for TMP and 2.64 +/- 0.48 mL/min.kg for SCP. For both TMP and SCP, mean peak plasma concentrations (Cmax) and the bioavailabilities (F) were reduced significantly when the drugs were mixed with concentrate (ct) as compared with those after nasogastric administration (ngt) (Fct = 44.3 +/- 10.7% vs. Fngt = 68.3 +/- 12.5% for TMP; Fct = 46.3 +/- 8.9% vs. Fngt = 67.3 +/- 13.7% for SCP). Following the administration of TMP and SCP mixed with concentrate, the plasma concentration-time curves showed a biphasic absorption pattern in all horses. The first peak occurred 1-2 h and the second peak 8-10 h after administration of the combination preparation.(ABSTRACT TRUNCATED AT 250 WORDS)
The disposition of trimethoprim and sulfadiazine in neonatal foals after intravenous administration
Veterinary Medicine and Science, 2022
Background: Septicaemia in the neonatal foal is caused by both Gram positive and Gram negative bacteria. The life-threatening nature of this condition requires treatment to be initiated with broad spectrum antimicrobial drugs pending antimicrobial susceptibility testing. Potentiated sulphonamides, for example, trimethoprim combined with sulfadiazine, could be clinically relevant options but their pharmacokinetics in the neonatal foal are unknown. Objectives: To describe the plasma disposition of trimethoprim and sulfadiazine in neonatal foals and to relate the results to patterns in the minimum inhibitory concentration (MIC) for Escherichia coli, a recognized pathogen in neonatal foal sepsis. Method: A total of five doses of trimethoprim (2.5 mg/kg) and sulfadiazine (12.5 mg/kg) were administered intravenously every 12 h to eight neonatal foals that were 3 days old at inclusion. A non-linear mixed effects model was fitted to the trimethoprim and sulfadiazine experimental data. The 24 h area under the free plasma trimethoprim and sulfadiazine concentration-time curves (fAUC) and the pharmacokinetic/pharmacodynamik (PK/PD)-index fAUC/MIC was calculated to evaluate the potential clinical benefits of the administered dose. Results: For trimethoprim, the typical values were 1.99 L/kg, 0.33 L/h⋅kg and 4.2 h for the apparent volume of distribution, clearance and terminal half-life, respectively. The 24 h fAUC for trimethoprim was 11.3 μg⋅h/ml (7.2-15.2) and the fAUC/MIC ratio for E. coli was 23 (16.4-29.2) (population mean (range)). For sulfadiazine, the typical values were 0.61 L/kg, 0.09 L/h⋅kg and 5.3 h for the apparent volume of distribution, clearance and terminal half-life, respectively. The 24 h fAUC for sulfadiazine was 246.8 μg⋅h/ml (175.6-335.4). Conclusion: For trimethoprim, the plasma exposure is insufficient in some foals to successfully treat bacterial infections with an MIC-value of 0.5 μg/ml using the studied dosing regimen.
Veterinary research communications, 2001
The pharmacokinetics were studied of sulfadimethoxine (SDM) or sulfamethoxazole (SMX) in combination with trimethoprim (TMP) administered as a single oral dose (25 mg + 5 mg per kg body weight) to two groups of 6 healthy pigs. The elimination half-lives of SMX and TMP were quite similar (2-3 h); SDM had a relatively long half-life of 13 h. Both sulfonamides (S) were exclusively metabolized to N4-acetyl derivatives but to different extents. The main metabolic pathway for TMP was O-demethylation and subsequent conjugation. In addition, the plasma concentrations of these drugs and their main metabolites after medication with different in-feed concentrations were determined. The drug (S:TMP) concentrations in the feed were 250:50, 500:100, and 1000:200 mg per kg. Steady-state concentrations were achieved within 48 h of feed medication, twice daily (SDM+TMP) or three times a day (SMX+TMP). Protein binding of SDM and its metabolite was high (>93%), whereas SMX, TMP and their metabolite...
Journal of Equine Veterinary Science, 2018
The objective of this experiment was to assess the concentrations of sulfadiazine and trimethoprim in the blood and endometrium of nonpregnant mares after oral treatment. We hypothesized that the potentiated sulfonamide would reach tissue concentrations greater than the minimum inhibitory concentration (MIC) reported for common pathogens. Over two breeding seasons, mares in estrus were treated with sulfadiazine-trimethoprim (Equisul-SDT Aurora Pharmaceutical, LLC, Northfield, MN), 333 mg/67 mg combination per mL, at a dosage of 24 mg/kg, orally, every 12 hours for five treatments. Blood was obtained at 0, 12, 36, and 60 hours. An endometrial biopsy was also performed at 60 hours. In year 1, the mean concentrations of sulfadiazine and trimethoprim at 60 hours were 12.14 mg/mL and 0.25 mg/mL in the blood and 3.19 mg/g and 0.69 mg/g in the endometrium, respectively. In year 2, the mean concentrations of sulfadiazine in the blood were 5.17, 10.22, and 13.39 mg/mL and 0.04, 0.15, and 0.27 mg/mL for trimethoprim at 12, 36, and 60 hours, respectively. Mean concentrations of sulfadiazine and trimethoprim in the endometrium at 60 hours were 7.96 mg/g and 0.23 mg/g, respectively. Concentrations of sulfadiazine and trimethoprim in the endometrium after five consecutive treatments with the oral suspension were above the in vitro MIC reported for common pathogens known to cause bacterial endometritis, for example, Streptococcus equi subsp. zooepidemicus (MIC ¼ 0.25e4 mg/mL) and Escherichia coli (>0.25e4 mg/mL). The oral suspension of sulfadiazine-trimethoprim should be an efficacious and viable treatment for bacterial endometritis.
Veterinary Clinical Pathology, 1993
Trimethoprim-sulfadiazine (TMP-SDZ) (Tribressin tablets 120-700 mg sulfadiazine, 20-mg trimethoprim [Coopers Animal Health, Inc., A Pitman-Moore Company, Mundelein, Ill.]) is a broad spectrum antibiotic combination effective in the treatment of bacterial pneumonia, urinary tract infections, pyoderma, meningitis, and prostatitis.' In clinical trials in puppies and adult dogs, TMP-SDZ was considered safe at both the manufacturer's recommended dose (15 mglkg, b.i.d., or 30 mglkg, u.i.d., per 0s for < 14 days2) and at 10 times that dose for 20 days3 Many infections, however, require prolonged high-dose therapy for resolution. The following study describes two cases of aplastic anemia and sepsis associated with intermittent, chronic (1 7-25 days), high-dose (25-30 mglkg, b.i.d., per 0s) TMP-SDZ therapy recommended for the treatment of py~derma.~"