Sulfadiazine/Trimethoprim | Sulfamethoxazole/Trimethoprim
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 use the human approved, trimethoprim/sulfamethoxazole oral products. In Canada, sulfadoxine is available in combination with trimethoprim for veterinary use.
Prescriber Highlights
Potentiated sulfonamide antimicrobial agent
Contraindications: hypersensitive to sulfas, thiazides, or sulfonylurea agents; severe renal or hepatic impairment
Caution: diminished renal or hepatic function, or urinary obstruction or urolithiasis.
Adverse Effects: Dogs: keratoconjunctivitis sicca, hypersensitivity (type 1 or type 3) acute neutrophilic hepatitis with icterus, vomiting, anorexia, diarrhea, fever, hemolytic anemia, urticaria, polyarthritis, facial swelling, polydipsia, crystalluria, hematuria, polyuria, cholestasis, hypothyroidism, anemias, agranulocytosis, idiosyncratic hepatic necrosis in dogs. Cats: anorexia, crystalluria, hematuria, leukopenias and anemias. Horses: transient pruritic (after IV injection). Oral: diarrhea, hypersensitivity reactions and hematologic effects (anemias, thrombocytopenia, or leukopenias
Local injection effects possible (check label for product recommendation for injection technique)
Potentially teratogenic, weigh risk vs. benefit
Drug Interactions
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.
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.
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. Approximately 30% of strains tested of Streptococcus zooepidemicus are resistant to TMP/Sulfa in horses. 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.
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.
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. .
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
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.
Reproductive/Nursing Safety
Safety of trimethoprim/sulfa has not been clearly established in pregnant animals. Reports of teratogenicity (cleft palate) have been reported. Studies thus far in male animals have not demonstrated any decreases in reproductive performance. (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have uncovered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term.)
Use TMP/sulfa products in nursing animals with caution. TMP-SMZ is not recommended for human use in the nursing period as sulfonamides are excreted in milk and may cause kernicterus. Premature infants and infants with hyperbilirubinemia or G-6-PD deficiency are also at risk for adverse effects.
Adverse Effects/Warnings
Adverse effects noted in horses, transient pruritus has been noted after intravenous injection. Oral therapy has resulted in diarrhea development in some horses. Previous administration of potentiated sulfas has been implicated in increasing the mortality rate of equine diarrhea. If the 48% injectable product is injected IM, SC, 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, probenecid 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.
.
Doses
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.
Horses
For susceptible infections:
1. For respiratory tract infections: 15-30 mg/kg PO q12h. Give 30 minutes prior to feeding hay (grain is OK) (Foreman 1999)
2. Foals: 15 mg/kg IV q12h; 30 mg/kg PO q12h (Brumbaugh 1999)
3. 22 mg/kg IV q24h or 30 mg/kg, PO q24h (Upson 1988)
4. 30 mg/kg PO once daily or 21.3 mg/kg IV once daily (Package inserts; Tribrissen®--Coopers)
5. Foals: 15 mg/kg PO or IV twice daily (Furr 1999)
6. For EPM: Sulfadiazine 20 mg/kg (either alone or as a potentiated sulfa) PO once or twice a day with Pyrimethamine (1 mg/kg PO once a day) for 90-120 days (or longer). Monitor: CBC's (Moore 1999)
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 receiving long term treatment
Client Information
If using oral 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/Approval Status/Withholding Times
Veterinary-Approved Products:
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-Plough); (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-Plough); (Rx). Approved for use in horses not intended for food.
Trimethoprim/Sulfadiazine Sterile Injection: 48% in 100 ml vials. Approved for use in horses not intended for food. Di-Biotic 48%® (Phoenix Pharmaceutical), Tribrissen® 48% Injection (Schering-Plough); (Rx)
Trimethoprim/Sulfadiazine Powder: 67 mg trimethoprim and 333 mg sulfadiazine per gram. Approved for use in horses not intended for food. Tucoprim® Powder (Pfizer) in 200 g bottles and 2000 g pails, Uniprim® Powder (Macleod) in 37.5 g and 1,125 g packets; (Rx)
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.
Human-Approved Products:
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); generic; (Rx)
Trimethoprim 8 mg/ml and Sulfamethoxazole 40 mg/ml oral suspension in 20 ml, 100 ml, 150 ml, 200 ml, 473 ml, and 480 mls; Septra® (GlaxoWellcome); Cotrim Pediatric® (Lemmon), Sulfatrim®, (various); generic; (Rx)
Trimethoprim 16 mg and Sulfamethoxazole 80 mg per 5 ml for injection in 5 ml Carpuject; 80 mg trimethoprim and 400 mg sulfamethoxazole/5 ml in 10 ml, 20 ml, 30 ml multi-dose vials and 5 ml vials; Bactrim® IV (Roche); Septra® IV (Monarch); generic; (Rx)
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.
does not agree with the advice you want to give......
