Chemicals / Complex Chemical Agents/ Chemical:

Trimethoprim (with special reference to Hedgehogs, Elephants, Bears, Lagomorphs, Ferrets, Great Apes and Cranes)

INFORMATION AVAILABLE

GENERAL CHEMICAL INFORMATION THERAPEUTIC INFORMATION [DOSE, FREQUENCY & ROUTE]

NUTRITIONAL INFORMATION

TOXICITY INFORMATION ENVIRONMENTAL INFORMATION
Information in this page has been entered to support the current volumes of Wildpro and further information will be added as new volumes are completed. This page is not intended to substitute for the manufacturer's data sheet and the information is not yet complete for all species, or for all contra-indications etc.

CAUTION: Before any pharmaceutical product is used, the manufacturer's data sheet, containing information on uses, dosage and administration, contra-indications, warnings etc., should always be consulted. It is important to remember that licensing of pharmaceutical products for use in a particular species/condition, as well as mandatory meat and milk withdrawal times for food-producing animals, varies between countries and changes with time. Withdrawal times also may vary between different pharmaceutical formulations and depending on route of administration. In the EU, the prescription cascade must be followed (see LCofC1.2H and W564.Apr05.w1); note that specific restrictions apply for food-producing animals. In the USA, FARAD may be consulted regarding residues and meat and milk withdrawal times.

General Chemical Information

Summary 
A trimethoxybenzylpyrimidine antibiotic, used in conjunction with a sulphonamide

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Names and Formulae
Type A trimethoxybenzylpyrimidine. (B135.47.w47)
Alternative Names "Proloprim; Trimpex; 5-(3,4,5-Trimethoxybenzyl)-2,4-diaminopyrimidine; 5-((3,4,5-Trimethoxyphenyl)methyl)-2,4-pyrimidinediamine; Monotrim; Syraprim; Tiempe; Trimanyl; Trimopan; Wellcoprim; 2,4-Diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; Trimogal; Uretrim; Chemotrim; bw 56-72; Instalac; Abaprim; Alprim; Idotrim; Lidaprim; Methoprim; Primosept; Primsol; TMP-Ratiopharm; Trimexazole; Unitrim." (W324)
Chemical Formula C14H18N4O3. (W324)
Chemical Structure --
Molecular Weight 290.3212. (W324)
Related Chemicals Pyrimethamine (B135.47.w47)

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Physical Properties / Chemistry
Appearance
  • White to cream crystals/crystalline powder, odourless but bitter-tasting. (B263, W324)

Melting point
  • 199 - 203C. (W324)
Boiling point --
Density --
Water solubility
  • Very slightly soluble. (B263)
  • Less than 0.1 g/100 mL at 24C. (W324)
Other solubility
  • Sparingly soluble in alcohol. (B263)
Acid/Base
  • Weak base; pKa 7.2 (approx.). (B135.47.w47)

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Pharmacology & General Information
Pharmacology Inhibits dihydrofolate reductase (an enzyme in the folic acid pathway), thereby blocking the conversion of dihydrofolic acid (DFA) to tetrahydrofolic acid. (B263)
Storage / Stability --
Legal Category (In UK) --

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References

Associated Techniques

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ORGANISATIONS

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ELECTRONIC LIBRARY
(Further Reading)
Click image for full contents list of ELECTRONIC LIBRARY

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Authors Debra Bourne (V.w5); Gracia Vila-Garcia (V.w67)
Referees Suzanne I. Boardman (V.w6); Becki Lawson (V.w26); Susan Mikota (V.w72)

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Therapeutic Information

Uses/Indications
Activity
Appropriate Use  
Limitations
  • Not active against Leptospira, Pseudomonas spp. (B201.1.w1)
Notes
  • Inhibits bacterial dihydrofolic acid reductase approximately 50,000 times more effectively than it inhibits the same enzyme of mammalian cells. (B135.47.w47)
  • Trimethoprim is more lipid-soluble than the sulphonamides and therefore has a higher volume of distribution. (B135.47.w47)
  • Slower development of resistance if trimethoprim-sulphonamide combinations are used rather than trimethoprim alone or sulphonamides alone. (B263)

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Pharmacokinetics and Drug Interactions
Absorption /Bioavailability
  • Good absorption from the gut. (B135.47.w47)
  • Peak levels about one to four hours after oral administration. (B263)
    • In ruminants, orally administered trimethoprim is trapped in the rumino-reticulum and is partially degraded. (B263)
  • Slower absorption following subcutaneous administration. (B263)
Distribution
  • Widely distributed in body fluids and tissues, including CSF. (B135.47.w47)
  • Well distributed. (B263)
  • Cross the placenta. (B263)
  • Distributed into milk. (B263)
  • In CSF, in the presence of inflamed meninges, may reach about 50% of serum levels. (B263)

Volume of distribution:

  • Dogs: 1.49 L/kg. (B263)
  • Horses: 0.59-1.51 L/kg. (B263)
Plasma Protein binding / Storage
  • About 65-70% (human). (B135.47.w47)
Elimination Route
  • About 50-60% of the drug/its metabolites excreted in urine within 24 hours. (B135.47.w47)
  • Renal excretion unchanged, both glomerular filtration and tubular secretion. (B263)
  • Metabolised by the liver to both oxide and hydroxylated metabolites; this may occur more in adult ruminants. (B263)
Elimination half-life / Clearance Rate Rapid elimination from serum but may persist longer in the tissues. (B263)

Serum half life of trimethoprim:

  • Dogs: 2.5 hours. (B263)
  • Horses: 1.91-3.0 hours. (B263)
  • Cattle: 1.5 hours. (B263)
Drug Interactions
  • Trimethoprim/sulphonamide: clotting time may be increased if used in individuals receiving coumarin (warfarin) anticoagualants. (B263)
  • Trimethoprim: may decrease therapeutic effect of systemically administered cyclosporine and increase risk of nephrotoxicity. (B263)

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Administration
Formulations available --
Doses / Administration Routes / Frequencies

Use of Drugs (Medication):

  • Before administration of any pharmaceutical product the manufacturer's datasheet must be consulted regarding operator safety, relevant withdrawal times etc.
  • Many drugs are not registered for use in particular species and additional care should be taken in their use, with proper regard for possible toxic effects. 
  • Consideration should be given to relevant legislation regarding the use of drugs.
  • In the UK, guidelines regarding the use of drugs are set out in the Royal College of Veterinary Surgeons' Guide to Professional Conduct 2000: (See: LCofC1 - RCVS Guide to Professional Conduct 2000 - Choice of Medicinal Products).

General comments:

  • When used with sulphonamides, the minimum inhibitory concentration (MIC) of trimethoprim for most susceptible bacteria is generally greater than 0.5g/ml. (B263)
  • Dose is expressed in the UK as sulphonamide plus trimethoprim. (B201.1.w1)
Erinaceus europaeus - West European Hedgehog:
  • Trimethoprim 5mg/kg + sulfamethoxazole 25mg/kg intramuscularly or orally twice daily. Pulmonary infections, gram-negative bacteria. (B22.27.w3)
  • Sulphadoxine, trimethoprim, lidocaine (lignocaine) hydrochloride (Borgal 7.5% solution (Intervet UK Limited) 50 mg/kg intramuscularly or subcutaneously once daily. (D93)
  • Sulphadiazine/trimethoprim 30 mg/kg once daily for 5-8 days, intramuscularly or subcutaneously. (D107)
  • Sulphadoxine/trimethoprim/lidocaine (Borgal 7.5%, Intervet UK Limited) 75 mg/kg once daily for five days, subcutaneously. (D107)
Atelerix albiventris - Four-toed hedgehog:
  • Trimethoprim/sulphonamide 30mg/kg orally, subcutaneously or intramuscularly every 12 hours. For respiratory infections. (B267)

"Hedgehog" (species not distinguished between Atelerix albiventris - Four-toed hedgehog or Erinaceus europaeus - West European Hedgehog):

  • Trimethoprim/sulphonamide (SMZ/TMP) 30 mg/kg intramuscularly or orally every 12 hours. (B150.w1)

In Elephants:

Elephas maximus - Asian Elephant

  • Sulfamethoxazole-trimethoprim, 48 g orally twice daily was administered for four weeks to an adult elephant, after a regional digital intravenous perfusion (RDIP) of a sole abscess. (J2.34.w2)
  • Sulfamethoxazole- trimethoprim was given, 57 g orally for 21 days, to a 40-year-old 3,300 kg female in the treatment of a nail infection complicated by phalangeal osteomyelitis. (J2.28.w2, P9.1.w7)

Loxodonta africana - African Elephant

  • Trimethoprim-sulfadiazide 4.5 mg/kg orally for 12 days. (P30.1.w5)
  • Trimethoprim-sulfadiazide 60 g orally once daily for ten days for a 14 year-old female. (J3.152.w2)
  • Trimethoprim-sulphamethaxazole, 9,600 mg orally twice daily for 14 days was used in the treatment of a 1,136 kg eight-year-old male Loxodonta africana - African Elephant with a fractured and infected tusk, in addition to initial topical treatment with 0.9% sodium chloride followed by povidone iodine solution to flush the pulp cavity. (J4.185.w2)

The following information is taken with permission directly from the Elephant Care International website (W580.Aug2005.w30):

Elephants:

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).

Elephant References:

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.

Dogs:

  • Sulfadiazine-Trimethoprim, 30 mg/kg orally or subcutaneous injection, once daily (dose expressed as sulfadiazine + trimethoprim). (B373.1.w1)
  • Sulfamethoxazole-Trimethoprim, 30 mg/kg orally once daily (dose expressed as sulfamethoxazole + trimethoprim). (B373.1.w1)

Bears:

Lagomorphs - Oryctolagus cuniculus domesticus - Domestic rabbit:
  • Trimethoprim-sulfadiazine (Sulphonamides) 30 mg/kg orally or subcutaneously every 24 hours. (B546)
  • Trimethoprim-sulfamethoxazole (Sulphonamides) 40 mg/kg orally every 24 hours. (B546, B601.15.w15)
  • Trimethoprim-Sulphonamides 15 mg/kg orally every 12 hours. (B548.w8)
  • Trimethoprim-Sulphonamides 30 mg/kg orally, subcutaneously or intramuscularly every 12 hours. (B548.w8) Note: subcutaneous use may cause tissue necrosis. (B548.w8)
  • Trimethoprim-Sulphonamides 30 mg/kg subcutaneously every 24 hours. (B548.w8) Note: subcutaneous use may cause tissue necrosis. (B548.w8)
  • Trimethoprim-Sulphonamides 48 mg/kg subcutaneously every 12 hours. (B548.w8) Note: subcutaneous use may cause tissue necrosis. (B548.w8)
  • Trimethoprim-sulphadiazine (Sulphonamides) 30 mg/kg orally twice daily or 48 mg/kg subcutaneously. As an antibiotic. (B600.4.w4)
  • Trimethoprim-sulfamethoxazole (Sulphonamides) 40 mg/kg orally twice daily for seven days. As an antibiotic or as a coccidiostat. Note ""Co-trimoxazole" human formulation is available as a human paediatric syrup. (B600.4.w4)
  • Trimethoprim-sulphadiazine (Sulphonamides) 48 mg/kg subcutaneously every 24 hours. (B603.5.w5)
  • Trimethoprim-sulphamethoxazole (Sulphonamides) 30 mg/kg orally every 12 hours. (B603.5.w5)
  • Trimethoprim-sulphadiazine 30 mg/kg subcutaneously every 24 hours. (B601.15.w15)
  • Trimethoprim-sulphadiazine 30 mg/kg orally every 12 hours. (B601.15.w15)
  • Trimethoprim-sulfamethoxazole (Sulphonamides) 40 mg/kg orally every 12 hours. For the treatment of coccidiosis. (B601.15.w15)
  • Trimethoprim-sulphonamide 30 mg/kg orally or subcutaneously every 12 hours. (B602.41.w41)

Ferrets - Mustela putorius furo - Ferret:

  • Trimethoprim-Sulphonamide 20 - 30 mg/kg subcutaneously or orally twice daily. "Used for urinary and respiratory infections." May cause renal disease in geriatric ferrets. (B626.App.w22)
  • Trimethoprim-Sulphonamide 30 mg/kg subcutaneously or orally every 12 hours. "Renal disease possible." (B631.21.w21)
  • Trimethoprim-Sulphonamide 15 - 30 mg/kg orally or subcutaneously every 12 hours. (B602.41.w41)
  • Trimethoprim-Sulphonamide 30 mg/kg orally twice daily. This is concentrated in urine so may be the treatment of choice for urinary tract infections (broad-spectrum prior to culture and sensitivity test results). Note: in ferrets, ocassional idiopathic blood dyscrasias reported. (J213.3.w1)

Great Apes

  • Adult Pan troglodytes - Chimpanzee: Sulfamethoxazole (Sulphonamides)/Trimethoprim, 800 mg of the sulfamethoxazole orally twice daily or 15-20 mg/kg per day intravenously divided into two to four doses. (W768.Jun2012.w1)
  • Primates: trimethoprim/sulphonamide 30 - 50 mg/kg (total dose) intramuscularly, subcutaneously or orally once daily. Broad spectrum against Gram negative organisms with some activity against Gram-positive bacteria. In the treatment of gastrointestinal, respiratiry, skin and urinary tract infections. (D425.3.15.w3o)
  • Primates: Trimethoprim/Sulphonamides 20 mg/kg orally four times daily for 14 days. In the treatment of Pneumocystis carinii infection.

Cranes

  • Trimethoprim-sulfamethoxazole, 16-24 mg/kg (based on the trimethoprim) orally every 12 hours. (B336.20.w20)
  • 16-24 mg/kg orally every 8-12 hours. Regurgitation is common. (B115.8.w4)
  • 8 mg/kg intramuscularly every 12 hours. (B115.8.w4)
  • Used in the treatment of enteric and respiratory infections, and as an anticoccidial. (B115.8.w4)
Monitoring parameters --

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Withdrawal period / Withholding time
Notes Before the use of any pharmaceutical product in food-producing animals the label instructions for the product should be consulted regarding withdrawal requirements.

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Toxic Information

Toxic effects of Pharmaceutical Products
Contraindications / Precautions
  • Use with caution in individuals with pre-existing hepatic disease. (B263)
  • "The manufacturer states that trimethoprim/sulfadiazine should not be used in dogs or horses [the species in which it is licensed for use in the USA] showing marked liver parenchymal damage, blood dyscrasias, or in those with a history of sulfonamide sensitivity." (B263)
Adverse Effects / Side Effects / Warnings
  • In dogs: 
    • Keratoconjunctivitis sicca (sometimes irreversible). (B263)
    • Acute neutrophilic hepatitis (jaundice, vomiting, anorexia, diarrhoea, fever, haemolytic anaemia, urticaria, polyarthritis, facial swelling, polydipsia, polyuria, cholestasis). (B263)
    • Hypothyroidism (particularly with prolonged treatment. (B263)
    • Acute hypersensitivity reactions (Type I, i.e. anaphylaxis, or Type III, i.e. serum sickness. Commoner in larger breeds and perhaps especially in Doberman Pinschers. (B263)
    • Rarely other haematological disorders (anaemias, agranulocytosis). (B263)
    • Rarely idiosyncratic moderate to massive hepatic necrosis. (B263)
    • Possible risk factor for the development of acute pancreatitis (cause-and-effect have not been shown). (B263)
  • In cats:
  • In horses:
    • Intravenous administration may be followed by transient pruritis. (B263)
    • Oral administration may cause diarrhoea. (B263)
    • 48% injectable product: intramuscular or subcutaneous inoculation, or extravasation following intravenous inoculation, may result in swelling, pain and minor tissue damage. (B263)
    • Hypersensitivity reactions. (B263)
    • Haematological effects (anaemias, thrombocytopaenia, leucopaenias). (B263)
    • Periodic haematological monitoring is recommended during prolonged treatment. (B263)
  • Note: Safety of use of trimethoprim/sulphonamides in pregnant animals has not been clearly established. (B263)
Operator Warnings Before the use of any pharmaceutical product the label instructions for the product should be consulted regarding operator safety/warnings.
Overdose / Acute Toxicity
  • May cause: gastrointestinal distress (nausea, vomiting, diarrhoea), central nervous system toxicity (depression, headache, confusion), facial swelling, depression of bone marrow, increase in serum aminotransferases. (B263)
    • Oral overdose may be treated by emptying the stomach (normal protocols), plus supportive and symptomatic treatment. (B263)
    • Urinary acidification may increase renal elimination of trimethoprim but particularly with sulfadiazine may cause sulphonamide crystallisation in the urine. (B263)
    • Monitor e.g. complete blood count. For severe bone marrow suppression (chronic overdose), treat with folinic acid. (B263)

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Detailed Toxicological Information
Classification --
Acute Toxicity --
Chronic Toxicity --
Reproductive effects
  • In rabbits, increased fetal mortality following high doses of trimethoprim. (B263)
Teratogenic effects
  • In some studies on rats, reports of teratogenic effects: cleft palate. (B263)
  • In studies on dogs, no evidence of teratogenic effects. (B263)
Mutagenic effects --
Carcinogenic effects

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Organ toxicity --
Bird Toxicity --
Aquatic organism activity --
Other organism toxicity --

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Nutrient Information

Nutritional Data
Sources --
Biological Use --
Recommended Daily Allowance / Recommended level in food --
Stability in food (Storage time) --
Interactions --

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External / Environmental Information

External / Environmental Uses
Use --
Formulation --
Application method --
Application Concentration --
Persistence of Effect / Frequency of Application --

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Effects on the Environment
Effects in the aquatic environment

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Effects on land --

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Persistence in the Environment
Breakdown in soil and groundwater

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Breakdown in water --
Breakdown in vegetation --

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