Note: In the practice of veterinary medicine in the United States, two separate combinations with trimethoprim are used clinically. There are trimethoprim/sulfadiazine products approved for use in dogs, cats and horses in both parenteral and oral dosage forms. Many veterinarians also will use the human approved, trimethoprim/sulfamethoxazole oral products because of economic considerations. In Canada, sulfadoxine is available in combination with trimethoprim for veterinary use.
Chemistry - Trimethoprim occurs as odorless, bitter-tasting, white to cream-colored crystals or crystalline powder. It is very slightly soluble in water and slightly soluble in alcohol.
Sulfadiazine occurs as an odorless or nearly odorless, white to slightly yellow powder. It is practically insoluble in water and sparingly soluble in alcohol.
Sulfamethoxazole occurs as a practically odorless, white to off-white, crystalline powder. Approximately 0.29 mg is soluble in 1 ml of water and 20 mg are soluble in 1 ml of alcohol.
In combination, these products may be known as: Co-trimoxazole , SMX-TMP , TMP-SMX , trimethoprim-sulfamethoxazole , sulfamethoxazole-trimethoprim , sulfadiazine-trimethoprim , trimethoprim-sulfadiazine , TMP-SDZ , SDZ-TMP , Co-trimazine or by their various trade names.
Storage/Stability/Compatibility - Unless otherwise instructed by the manufacturer, trimethoprim/sulfadiazine and co-trimoxazole products should be stored at room temperature (15-30°C) in tight containers.
Pharmacology - Alone, sulfonamides are bacteriostatic agents and trimethoprim is bactericidal, but in combination, the potentiated sulfas are bactericidal. Potentiated sulfas sequentially inhibit enzymes in the folic acid pathway, thereby inhibiting bacterial thymidine synthesis. The sulfonamide blocks the conversion of para-aminobenzoic acid (PABA) to dihydrofolic acid (DFA), and trimethoprim blocks the conversion of DFA to tetrahydrofolic acid by inhibiting dihydrofolate reductase.
The in vitro optimal ratio for most susceptible bacteria is approximately 1:20 (trimethoprim:sulfa), but synergistic activity can reportedly occur with ratios of 1:1 - 1:40. The serum concentration of the trimethoprim component is considered to be more important than the sulfa concentration. For most susceptible bacteria, the MIC’s for TMP are generally above 0.5 micrograms/ml.
The potentiated sulfas have a fairly broad spectrum of activity. Gram positive bacteria that are generally susceptible include most streptococci, many strains of staphylococcus and Nocardia. Many gram negative organisms of the family Enterobacteriaceae are susceptible to the potentiated sulfas, but not Pseudomonas aeruginosa. Some protozoa (Pneumocystis carinii, Coccidia and Toxoplasma) are also inhibited by the combination. Potentiated sulfas reportedly have little activity against most anaerobes, but opinions on this vary.
Resistance will develop slower to the combination of drugs than to either one alone. In gram negative organisms, resistance is usually plasmid-mediated.
Uses/Indications - Although only approved for use in dogs and horses, trimethoprim/sulfadiazine et al is used in many species to treat infections caused by susceptible organisms. See Dosage section for more information.
Pharmacokinetics - Trimethoprim/sulfa is well absorbed after oral administration, with peak levels occurring about 1-4 hours after dosing. The drug is more slowly absorbed after subcutaneous absorption, however. In ruminants, the trimethoprim is apparently trapped in the ruminoreticulum after oral administration and undergoes some degradation.
Trimethoprim/sulfa is well distributed in the body. When meninges are inflamed, the drugs enter the CSF in levels of about 50% of those found in the serum. Both drugs cross the placenta and are distributed into milk. The volume of distribution for trimethoprim in various species are: 1.49 L/kg (dogs), and 0.59-1.51 L/kg (horses). The volume of distribution for sulfadiazine in dogs is 1.02 L/kg.
Trimethoprim/sulfa is both renally excreted unchanged via glomerular filtration and tubular secretion and metabolized by the liver. The sulfas are primarily acetylated and conjugated with glucuronic acid and trimethoprim is metabolized to oxide and hydroxylated metabolites. Trimethoprim may be more extensively metabolized by the liver in adult ruminants than in other species. The serum elimination half-lives for trimethoprim in various species are: 2.5 hours (dogs), 1.91-3 hours (horses), 1.5 hours (cattle). The serum elimination half-lives for sulfadiazine in various species are: 9.84 hours (dogs), 2.71 hours (horses), 2.5 hours (cattle). While trimethoprim is quite rapidly eliminated from the serum, the drug may persist for a longer period of time in tissues.
Because of the number of variables involved it is extremely difficult to apply pharmacokinetic values in making dosage recommendations with these combinations. Each drug (trimethoprim and the sulfa) has different pharmacokinetic parameters (absorption, distribution, elimination) in each species. Since different organisms have different MIC values and the optimal ratio of trimethoprim to sulfa also differs from organism to organism, this problem is exacerbated.
There is considerable controversy regarding the frequency of administration of these combinations. The veterinary product, trimethoprim/sulfadiazine is labeled for once daily administration in dogs and horses, but many clinicians believe that the drug is more efficacious if given twice daily, regardless of which sulfa is used.
Contraindications/Precautions/Reproductive Safety - The manufacturer states that trimethoprim/sulfadiazine should not be used in dogs or horses showing marked liver parenchymal damage, blood dyscrasias, or in those with a history of sulfonamide sensitivity. It is not for use in horses (or approved for other animals) intended for food.
This combination should be used with caution in patients with pre-existing hepatic disease.
Safety of trimethoprim/sulfa has not been clearly established in pregnant animals. Reports of teratogenicity (cleft palate) have been reported in some rat studies. Fetal mortality was also increased in rabbits receiving high doses of trimethoprim. Dog studies have not demonstrated any teratogenic effects. However, this combination should be used in pregnant females only when the benefits clearly outweigh the risks of use. Studies thus far in male animals have not demonstrated any decreases in reproductive performance.
Adverse Effects/Warnings - Adverse effects noted in dogs: keratoconjunctivitis sicca (which may be irreversible), acute neutrophilic hepatitis with icterus, vomiting, anorexia, diarrhea, fever, hemolytic anemia, urticaria, polyarthritis, facial swelling, polydipsia, polyuria and cholestasis. Potentiated sulfonamides may cause hypothyroidism in the dog, particularly with extended therapy. Acute hypersensitivity reactions manifesting as Type I (anaphylaxis) or Type III reaction (serum sickness) can also be seen. Hypersensitivity reactions appear to be more common in large breed dogs; Doberman Pinschers may possibly be more susceptible to this effect than other breeds. Other hematologic effects (anemias, agranulocytosis) are possible, but are fairly rare in dogs.
Adverse effects noted in cats may include anorexia, leukopenias and anemias.
In horses, transient pruritis has been noted after intravenous injection. Oral therapy has resulted in diarrhea development in some horses. If the 48% injectable product is injected IM, SQ, or extravasates after IV administration, swelling, pain and minor tissue damage may result. Hypersensitivity reactions and hematologic effects (anemias, thrombocytopenia, or leukopenias) may also be seen; long term therapy should include periodic hematologic monitoring.
Overdosage/Acute Toxicity - Manifestations of an acute overdosage can include symptoms of GI distress (nausea, vomiting, diarrhea), CNS toxicity (depression, headache, and confusion), facial swelling, bone marrow depression and increases in serum aminotransferases. Oral overdoses can be treated by emptying the stomach (following usual protocols) and initiating symptomatic and supportive therapy. Acidification of the urine may increase the renal elimination of trimethoprim, but could also cause sulfonamide crystalluria, particularly with sulfadiazine containing products. Complete blood counts (and other laboratory parameters) should be monitored as necessary. Bone marrow suppression associated with chronic overdoses may be treated with folinic acid (leucovorin) if severe. Peritoneal dialysis is not effective in removing TMP or sulfas from the circulation.
Drug Interactions - Trimethoprim/sulfa may prolong the clotting times in patients receiving coumarin (warfarin) anticoagulants. Sulfonamides may displace other highly bound drugs, such as methotrexate, phenylbutazone, thiazide diuretics, salicylates, probenicid and phenytoin. Although the clinical significance of these interactions is not entirely clear, patients should be monitored for enhanced effects of the displaced agents. Antacids may decrease the bioavailability of sulfonamides if administered concurrently. Trimethoprim may decrease the therapeutic effect of cyclosporine (systemic) and increase the risk of nephrotoxicity developing.
Drug/Laboratory Interactions - When using the Jaffe alkaline picrate reaction assay for creatinine determination, trimethoprim/sulfa may cause an overestimation of approximately 10%. Sulfonamides may give false-positive results for urine glucose determinations when using the Benedict’s method.
Note: There is significant controversy regarding the frequency of dosing these drugs. See the pharmacokinetic section above for more information. Unless otherwise noted, doses are for combined amounts of trimethoprim/sulfa.
For susceptible infections:
a) 15 mg/kg IV q8-12h (Brumbaugh 1987)
b) Foals: 15 mg/kg IV q12h (dose extrapolated from adult horses) (Caprile and Short 1987)
c) 22 mg/kg IV q24h or 30 mg/kg PO q24h (Upson 1988)
d) 30 mg/kg PO once daily or 21.3 mg/kg IV once daily (Package inserts; Tribrissen®—Coopers)
e) 24 mg/kg PO, IV or IM q12h (Baggot and Prescott 1987)
a) 22 mg/kg PO 4-6 times/day to maintain trough concentrations above the MIC in African elephants, however, the authors suggest favorable clinical response which is the basis for BID dosing in horses may also be effective in elephants (Page et.al. 1991).
a) Page,C.D., Mautino,M., Derendorf,H.D., and Anhalt,J.P. 1991. Comparative pharmacokinetics of trimethoprim-sulfamethoxazole administered intravenously and orally to captive elephants. Journal of Zoo and Wildlife Medicine 22:(4):409-416 Abstract: Three healthy captive female African elephants (Loxodonta africana) were used to determine the pharmacokinetics of trimethoprim-sulfamethoxazole (TMP-SMZ) after a single i.v. and a single oral dose of 3.7mg/kg TMP and 18.3mg/kg SMZ. A 2-mo wash-out period was allowed between the i.v. and oral trials. An adult female Asian elephant (Elephas maximus) was also used in this investigation; however, pharmacokinetic parameters calculated from data from this animal were not used to calculate mean pharmacokinetic parameters for TMP-SMZ in African elephants. Serum concentrations of TMP-SMZ were measured by high-performance liquid chromatography on blood samples collected via venous catheterization predose, over 12 hr after i.v. drug administration, and over 24 hr after oral drug administration. For African elephants, the mean terminal half-life (t1/2,z), clearance (CL), and volume distribution at steady state (Vdss) of TMP following i.v. administration were 1.4 + 0.7 hr, 856.0 + 114.0 ml/hr/kg, and 1.1 + 0.4 L/kg, respectively. For SMZ, these parameters were 1.83 + 0.06 hr, 93.6 + 10.8 ml/hr/kg, and 0.2 + 0.02 L/kg, respectively. Following oral administration, the mean t1/2,z was 3.0 + 1.1 hr, the maximum concentration (Cmax) was 0.43 + 0.07 micrograms/ml at time (tmax) 1.7 + 0.6 hr, and the bioavailability (F) was 61.2 + 21.3% for TMP. For SMZ, the mean t1/2,z was 2.0 + 0.3 hr, the Cmax was 30.7 + 2.5 micrograms/ml at tmax 3.0 + 1.0 hr, and F was 81.7 + 17.5%. Calculated pharmacokinetic parameters from this investigation were similar to values reported in horses. Based on these findings, metabolic scaling should not be employed to calculate the dose of TMP-SMZ in elephants.
Monitoring Parameters -
1) Clinical efficacy
2) Adverse effects; with chronic therapy, periodic complete blood counts should be considered.
3) Thyroid function tests should be considered (baseline and ongoing) particularly in dogs recieving long term treatment
Client Information - If using suspension, shake well before using. Does not need to be refrigerated. Animals must be allowed free access to water and must not become dehydrated while on therapy.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times -
Trimethoprim (TMP)/Sulfadiazine (SDZ) Oral Tablets:
30’s: 5 mg TMP/25 mg SDZ (coated tablets)
120’s: 20 mg TMP/100 mg SDZ (coated tablets)
480’s: 80 mg TMP/400 mg SDZ (uncoated, scored tablets)
960’s: 160 mg TMP/800 mg SDZ (uncoated, unscored tablets)
Tribrissen® (Schering), (Rx) Approved for use in dogs.
Trimethoprim (TMP)/Sulfadiazine (SDZ) Oral Paste. Each gram contains 67 mg trimethoprim and 333 mg sulfadiazine. Available in 37.5 gram (total weight) syringes.; Tribrissen® 400 Oral Paste (Schering) (Rx) Approved for use in horses.
In Canada, trimethoprim and sulfadoxine are available for use in cattle and swine (Trivetrin® —Wellcome; Borgal® —Hoechst). They have a slaughter withdrawal of 10 days and milk withdrawal of 96 hours.
Trimethoprim (alone) Tablets: 100 mg and 200 mg; Proloprim® (Glaxo Wellcome); Trimpex® (Roche); generic, (Rx)
Trimethoprim 80 mg and Sulfamethoxazole 400 mg Tablets; Trimethoprim 160 mg and Sulfamethoxazole 800 mg Tablets; Bactrim® , Bactrim-DS® (Roche); Septra® , Septra®; DS, (Glaxo Wellcome); Cotrim® , Cotrim-DS ® (Lemmon), generic; (Rx)
Trimethoprim 8 mg/ml and Sulfamethoxazole 40 mg/ml oral suspension in pint bottles; Bactrim Pediatric® (Roche); Septra® (Glaxo Wellcome); Cotrim Pediatric® (Lemmon) (Rx), Sulfatrim, generic (Rx); generic; (Rx)
Trimethoprim 16 mg/ml and Sulfamethoxazole 80 mg/ml for IV infusion in 5, 10, 20 and 30 ml vials ; Bactrim® IV(Roche); Septra® IV(Glaxo Wellcome); generic (Rx)
Because of the unavailability of veterinary trimethoprim/sulfadiazine injection in the USA, the human injectable product has been used. Before giving IV, the product must be diluted, generally at a rate of 1 ml of TMP/SMZ injection per 25 mls of dextrose 5% injection. Once diluted the injection should be used within 6 hours. Some reports of administering the drug SubQ to ruminants have also been received. To minimize potential local reactions, the injection should be diluted at a rate of about 1 ml TMP/SMZ injection to 5 ml dextrose 5%.
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