Sulfadiazine/Trimethoprim and Sulfamethoxazole/Trimethoprim
Trimethoprim/Sulfadiazine, Trimethoprim/Sulfamethoxazole
Also known as: Co-trimoxazole · Tribrissen · Bactrim · Septra · Tucoprim · Uniprim · Di-Biotic · Cotrim · Sulfatrim · Trivetrin · Borgal · SMX-TMP · trimethoprim-sulfamethoxazole · sulfadiazine-trimethoprim · TMP-SDZ · Co-trimazine
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
Audited v13 dosing evidence
Structured calculator evidenceCoccidiosis
- q12-24h
NA
Governing clinical context (3)
- NOTE: There is significant controversy regarding the frequency of administration of these drugs. See Pharmacokinetics for more information. Unless otherwise noted, doses are for combined sulfa-/trimethoprim. See Monitoring if treatment is expected to be longer than 7 days.
- Bacterial cystitis (extra-label): Potentiated sulfonamides (ie, sulfa-/ trimethoprim, sulfadimethoxine/ormetoprim) are first-tier drugs only if regional pathogen susceptibility patterns are known. 32
- Unless otherwise instructed by the manufacturer, sulfa-/trimethoprim products should be stored at room temperature of 20°C to 25°C (68°F-77°F) in tight containers and protected from freezing. Shake suspensions well before use.
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Potentiated sulfonamides (often referred to as TMS, SMZ-TMP, or co-trimoxazole) are broad-spectrum, bactericidal antimicrobial combinations used extensively in veterinary medicine.
Key Clinical Pearls:
- Excellent Tissue Penetration: Highly lipid-soluble, allowing therapeutic concentrations to be reached in difficult-to-penetrate tissues including the prostate, blood-brain barrier (CNS), and eye.
- Broad Spectrum: Effective against many Gram-positive and Gram-negative organisms, including many strains of methicillin-resistant Staphylococcus (MRSA/MRSP), Nocardia, and certain protozoa (Toxoplasma, Coccidia, Pneumocystis).
- Inactivation by Pus: The drug's efficacy is significantly inhibited by purulent debris and necrotic tissue (which are rich in PABA and thymidine). Abscesses must be drained for the drug to be effective.
- Breed Sensitivity: Doberman Pinschers have a known breed-specific susceptibility to sulfonamide-induced poly-systemic immune complex disease (hypersensitivity).
- Formulations: While veterinary-approved trimethoprim/sulfadiazine products exist, many practitioners utilize human-approved trimethoprim/sulfamethoxazole (Bactrim®, Septra®) off-label with similar efficacy.
Mechanism of action
Potentiated sulfas exhibit synergistic, bactericidal activity by sequentially blocking the bacterial folic acid synthesis pathway. Mammalian cells are largely unaffected because they utilize preformed dietary folate rather than synthesizing it.
- Sulfonamides (Bacteriostatic alone): Act as structural analogues of para-aminobenzoic acid (PABA). They competitively inhibit the bacterial enzyme dihydropteroate synthase → blocks the conversion of PABA to dihydrofolic acid (DFA).
- Trimethoprim (Bactericidal alone): Reversibly inhibits the bacterial enzyme dihydrofolate reductase → blocks the conversion of DFA to tetrahydrofolic acid (THFA).
- Synergy: The sequential blockade completely depletes THFA, an essential cofactor for bacterial DNA and RNA synthesis, leading to rapid bacterial cell death.
Pharmacologic Note: The optimal in vitro ratio for most susceptible bacteria is 1:20 (trimethoprim:sulfa), but synergistic activity occurs across a wide range (1:1 to 1:40). The serum concentration of the trimethoprim component is generally considered the primary driver of efficacy.
Safety & warnings
Contraindications
- Hypersensitivity to sulfonamides, thiazides, or sulfonylurea agents
- Severe renal or hepatic impairment
- Doberman pinschers (highly susceptible to immune complex disease)
- Marked blood dyscrasias
- Animals intended for food (in the USA/certain jurisdictions)
Adverse effects
- Dogs: Keratoconjunctivitis sicca (KCS/dry eye - potentially irreversible)
- Dogs: Hypersensitivity reactions (Type 1 anaphylaxis or Type 3 serum sickness, polyarthritis, urticaria, facial swelling)
- Dogs: Acute neutrophilic hepatitis with icterus, idiosyncratic hepatic necrosis
- Dogs: Vomiting, anorexia, diarrhea
- Dogs: Hemolytic anemia, agranulocytosis
- Dogs: Hypothyroidism (with extended therapy)
- Dogs: Crystalluria, hematuria, polyuria, polydipsia
- Cats: Anorexia, crystalluria, hematuria, leukopenias, anemias
- Horses: Transient pruritus (after IV injection), diarrhea, hypersensitivity, hematologic effects
- Injection site reactions: Swelling, pain, tissue damage (IM, SC, or extravasation)
Precautions
Use with caution in patients with pre-existing hepatic or renal disease. Because of its potential for crystallization in the urine, avoid use in dogs known to have uroliths, at increased risk for developing uroliths, or those with highly concentrated (dehydrated) or acidic urine. Potentially teratogenic (cleft palate reported); weigh risk vs. benefit in pregnant animals. Use with caution in nursing animals as sulfonamides are excreted in milk and may cause kernicterus in neonates.
Drug interactions
May cause toxic delirium (reported in humans)
May decrease the bioavailability of sulfonamides if administered concurrently
May increase the risk of nephrotoxicity
May increase digoxin levels
May increase risk for thrombocytopenia
May potentiate hypoglycemic effects
May displace from plasma proteins and increase risk for toxic effects; can also interfere with MTX assays
May increase half-life of phenytoin
May decrease efficacy of the antidepressant
May prolong INR/PT and increase bleeding risk
Monitoring
- Clinical efficacy
- Adverse effects (GI, hypersensitivity)
- Complete blood counts (CBC) periodically with chronic therapy
- Schirmer Tear Test (STT) in dogs to monitor tear production (e.g., at 5 days, then every 2-3 weeks)
- Thyroid function tests (baseline and ongoing) for dogs on long-term treatment
Pharmacokinetics
Half-life
Absorption
Well absorbed after oral administration, with peak levels occurring about 1-4 hours after dosing. More slowly absorbed after subcutaneous administration. In ruminants >8 weeks old, trimethoprim is trapped in the ruminoreticulum after oral administration and undergoes degradation.
Distribution
Well distributed in the body. Enters CSF at about 50% of serum levels when meninges are inflamed. Crosses the placenta and distributes into milk. Relatively well distributed into the prostate. Volume of distribution for trimethoprim: 1.49 L/kg (dogs), 0.59-1.51 L/kg (horses). Vd for sulfadiazine in dogs is 1.02 L/kg.
Metabolism
Metabolized by the liver. Sulfas are primarily acetylated and conjugated with glucuronic acid. Trimethoprim is metabolized to oxide and hydroxylated metabolites. Trimethoprim may be more extensively metabolized in the liver in adult ruminants.
Elimination
Renally excreted unchanged via glomerular filtration and tubular secretion, as well as hepatic metabolism. Trimethoprim is rapidly eliminated from serum but may persist longer in tissues.
Overdose
Manifestations of acute overdosage include GI distress (nausea, vomiting, diarrhea), CNS toxicity (depression, headache, confusion), facial swelling, bone marrow depression, and elevated serum aminotransferases.
Treatment:
- Oral Overdose: Empty the stomach following usual protocols and initiate symptomatic/supportive therapy.
- Fluid Therapy: Maintain hydration. Acidification of urine may increase renal elimination of trimethoprim but increases the risk of sulfonamide crystalluria (especially with sulfadiazine).
- Monitoring: Monitor complete blood counts and liver parameters.
- Bone Marrow Suppression: If severe and associated with chronic overdose, may be treated with folinic acid (leucovorin).
- Note: Peritoneal dialysis is not effective in removing TMP or sulfas from circulation.
Available products
Formulations
- Oral Paste
- Sterile Injection
- Oral Powder
- Oral Tablets
- Oral Suspension
Veterinary
- Trimethoprim/Sulfadiazine Oral Paste: 67 mg TMP / 333 mg SDZ per gram (Tribrissen 400 Oral Paste)
- Trimethoprim/Sulfadiazine Sterile Injection: 48% (Di-Biotic 48%, Tribrissen 48% Injection)
- Trimethoprim/Sulfadiazine Powder: 67 mg TMP / 333 mg SDZ per gram (Tucoprim, Uniprim)
- Trimethoprim/Sulfadoxine (Canada): Trivetrin, Borgal
Human-labeled
- Trimethoprim Tablets: 100 mg, 200 mg (Proloprim, Trimpex)
- Trimethoprim/Sulfamethoxazole (TMP-SMZ) Tablets: 80 mg TMP / 400 mg SMX (Bactrim, Septra)
- Trimethoprim/Sulfamethoxazole Double Strength (DS) Tablets: 160 mg TMP / 800 mg SMX (Bactrim DS, Septra DS)
- Trimethoprim/Sulfamethoxazole Oral Suspension: 8 mg TMP / 40 mg SMX per mL (Septra, Cotrim Pediatric, Sulfatrim)
- Trimethoprim/Sulfamethoxazole Injection: 16 mg TMP / 80 mg SMX per mL
Regulatory status
No regulatory data for: 🇺🇸 US · 🇪🇺 EU · 🇬🇧 UK · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Unless otherwise instructed by the manufacturer, trimethoprim/sulfadiazine and co-trimoxazole products should be stored at room temperature (15-30°C) in tight containers.
Client information
Important Guidance for Pet Owners:
- Hydration is Crucial: Ensure your pet has free access to plenty of fresh water at all times while on this medication. Dehydration can lead to drug crystals forming in the kidneys or urine.
- Watch the Eyes (Dogs): This medication can decrease tear production, leading to a condition called "dry eye" (keratoconjunctivitis sicca). Contact your veterinarian immediately if you notice your dog squinting, rubbing their eyes, redness, or thick yellow/green eye discharge.
- Allergic Reactions: Doberman Pinschers and some large breed dogs are more prone to allergic reactions. Stop the medication and call your vet if you notice facial swelling, hives, unexplained fever, joint stiffness/limping, or yellowing of the eyes/gums.
- Administration: Can be given with or without food. If using the liquid oral suspension, shake it thoroughly before drawing up each dose. The liquid does not need to be refrigerated.
- Finish the Course: Always complete the entire prescription as directed by your veterinarian, even if your pet seems completely better, to prevent antibiotic resistance.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.