Sulphonamides and potentiated sulphonamides

Sulphonamides

The sulphonamides form an extensive series of drugs that differ more in their physicochemical characteristics, and hence in mode of administration and pharmacokinetics, than they do in their antibacterial activity. They act by competing with tissue factors, notably p-aminobenzoic acid, and are therefore inactive in the presence of necrotic tissue. They are bacteriostatic to a range of Gram-positive and Gram-negative bacteria. They are active against aerobic Gram-positive cocci and some rods and many Gram-negative rods including Enterobacteriaceae. Leptospira and Pseudomonas spp. are resistant. Sulphonamides are also active against Chlamydophila, Toxoplasma, and coccidia. Acquired resistance to sulphonamides is widespread in the UK.

The sodium salts are alkaline and hence irritant by intramuscular injection and so are often given intravenously. However, there are safety concerns over intravenous administration of sulphonamides (see below). Sulphonamides are well absorbed following oral administration. They diffuse well into body tissues and are partly inactivated in the liver, mainly by acetylation. The acetylated derivatives are relatively insoluble in acidic urine and so may precipitate in the renal tubules of carnivores leading to crystalluria and renal failure. This problem may be reduced by increasing the urine volume or by increasing the urine pH. Prolonged administration of certain sulphonamides may cause keratoconjunctivitis sicca (dry eye) in dogs, and sulfadiazine-containing preparations may promote a reversible immune-mediated sterile polyarthritis in dogs. Sulphonamides may cause petechial haemorrhages in poultry as a result of vitamin K antagonism. Prolonged treatment with sulphonamides may lead to vitamin K deficiency causing agranulocytosis and haemolytic anaemia. Sulphonamides may inhibit thyroid hormone synthesis and, in some dogs can cause subclinical hypothyroidism with subnormal T4 concentrations and high concentrations of TSH detected in plasma in these cases. This effect is reversible when the therapy is stopped. Concurrent administration of sulphonamides and sedatives or anaesthetics is contra-indicated in horses because severe cardiac arrhythmias and collapse may result. Intravenous administration of sulphonamides to cattle and horses can result in sudden collapse. A relatively rare but severe idiosyncratic reaction to sulphonamides reported to occur in dogs is acute hepatopathy. It is likely that this occurs due to increased formation of toxic metabolites (hydroxylamine, nitroso metabolites, or both) in some individual animals although work on the pathogenesis is ongoing.

SULFADIMIDINE

(Sulphadimidine)

Indications. Sulfadimidine-sensitive infections; coccidiosis

Contra-indications. Sulphonamide hypersensitivity; severe hepatic impairment; blood dyscrasias

Side-effects. Agranulocytosis, haemolytic anaemia, avitaminosis-K with prolonged administration; cystalluria

Warnings. Care in renal impairment; ensure adequate water intake during treatment; avoid prolonged administration

Dose. Cattle, sheep, pigs: by subcutaneous or intravenous (preferred) injection, 200 mg/kg daily on day 1, then 100 mg/kg daily

Prescription-only medicine: Intradine (Norbrook) UK

Injection, sulfadimidine (as sodium salt) 308.9 mg/mL, for cattle, sheep, pigs

Withdrawal Periods.

Cattle: slaughter 18 days, milk 6.5 days.

Sheep: slaughter 18 days.

Pigs: slaughter 42 days

Potentiated sulphonamides

Sulphonamides may be combined with the dihydrofolate reductase inhibitors baquiloprim, ormetoprim, or trimethoprim. They inhibit the conversion of bacterial dihydrofolic acid to tetrahydrofolic acid which is necessary for the synthesis of certain amino acids, purines, and DNA synthesis. Potentiated sulphonamides block sequential stages in the synthesis of tetrahydrofolate and thus have a synergistic antibacterial action. This combination may be bactericidal and allows a smaller dose of sulphonamide to be used. The antibacterial spectrum of the combination is broad and includes a high proportion of anaerobic bacteria, Nocardia, CMamydophila, and Toxoplasma spp. Plasmid-mediated resistance to trimethoprim occurs. Side-effects seen with sulphonamides also occur with potentiated sulphonamide administration. In human medicine, the therapeutic activity of the combination has been found to be fully accounted for by the trimethoprim and the recommendations for combined therapy are rather restricted. Trimethoprim is cleared much more rapidly in animals than humans. There are no veterinary products containing only baquiloprim or ormetoprim.

Compound preparations usually contain 5 parts sulphonamide and one part trimethoprim, baquiloprim, or ormetoprim. The sulphonamides most commonly used in conjunction with trimethoprim are sulfadiazine (co-trimazine) and sulfadoxine, the latter acting for a longer period.

Trimethoprim, like the sulphonamides, diffuses well into body tissues and so the combination is the treatment of choice for disorders such as coliform meningitis. Unfortunately, in domesticated animals, trimethoprim is more rapidly inactivated than the sulphonamide component so that useful ratios are present in the body for a short time only. Trimethoprim is active against Gram-negative and Gram-positive bacteria. Trimethoprim is used alone in human medicine in the treatment of urinary tract, respiratory, and prostatic infections. The rapid clearance of trimethoprim from the plasma of domestic species makes its use as a sole agent less likely to be successful.

Baquiloprim is however more slowly inactivated and its prolonged half-life more closely matches the half-life of sulfadimidine in cattle and pigs or sulfadimethoxine in dogs and cats.

Ormetoprim has been less well studied in domestic animals. It appears to have similar pharmacokinetic properties to trimethoprim in those species in which it has been studied (horses and cattle) such that the drug is more rapidly cleared from the plasma than the sulphonamides with which it is combined.

Trimethoprim (and possibly baquiloprim) retain some slight activity on mammalian dihydrofolate reductase and so may predispose to a folate deficiency and hence to a reduction in bone marrow function. Intravenous administration of potentiated sulphonamides may precipitate collapse in horses and cattle.

SULFADIAZINE with TRIMETHOPRIM

(Co-trimazine: preparations of trimethoprim and sulfadiazine in the proportions, by weight, of 1 part to 5 parts)

Indications. Sulfadiazine/trimethoprim-sensitive infections

Contra-indications. Sulphonamide hypersensitivity; severe hepatic impairment; blood dyscrasias; horses with drug-induced cardiac arrhythmias; dogs with keratoconjunctivitis sicca; oral administration to calves with a functional rumen

Side-effects. Occasional transient polyarthritis and keratoconjunctivitis sicca in dogs, drowsiness in cats

Warnings. Care in renal impairment; care with concurrent chloramphenicol, detomidine, halothane, miconazole, phenylbutazone, procaine hydrochloride, romifidine, thiopental, warfarin; Drug Interactions.; the drug may cause salivation in cats and coated tablets should be fed whole, should not be halved, crushed, or chipped; ensure sufficient water intake to avoid crystalluria; safety of feeding milk from treated animals to young not established

Dose. Dosages vary. For guidance. Expressed as trimethoprim + sulfadiazine Horses, cattle: by mouth, 30 mg/kg daily (absorption may be better if food withheld for a few hours prior to treatment) by intramuscular or slow intravenous injection, 15-24 mg/ kg daily

Sheep: by intramuscular or slow intravenous injection, 15-24 mg/kg daily

Pigs: by mouth, 30 mg/kg body-weight daily by addition to feed, 300-450 g/tonne feed by intramuscular or slow intravenous injection, 15-24 mg/ kg daily

Dogs, cats: by mouth or by subcutaneous injection, 30 mg/ kg daily

Poultry: by addition to drinking water, 15 mg/kg body-weight daily

by addition to feed, 300 g/tonne feed

Fish: see Prescribing for fish for preparation details and dosage

Prescription-only medicine: Chanoprim 20/80 (Chanelle) UK

Tablets, scored, sulfadiazine 100 mg, trimethoprim 20 mg, for dogs, cats

Tablets, scored, sulfadiazine 400 mg, trimethoprim 80 mg, for dogs

Prescription-only medicine: Delvoprim Tablets (Intervet) UK

Tablets, s/c, sulfadiazine 100 mg, trimethoprim 20 mg, for dogs, cats

Tablets, scored, sulfadiazine 400 mg, trimethoprim 80 mg, for dogs

Prescription-only medicine: Duphatrim (Fort Dodge) UK

Tablets, s/c, sulfadiazine 100 mg, trimethoprim 20 mg, for dogs, cats

Tablets, scored, sulfadiazine 400 mg, trimethoprim 80 mg, for dogs

Tablets, or to prepare an oral solution, scored, sulfadiazine 1 g, trimethoprim 200 mg, for calves

Withdrawal Periods.

Calves: slaughter 28 days

Prescription-only medicine: Duphatrim Equine Formula (Fort Dodge) UK

Oral paste, sulfadiazine 1.3 g, trimethoprim 260 mg/division, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Duphatrim Granules for Horses (Fort Dodge) UK

Oral granules, for addition to feed, sulfadiazine 12.5 g, trimethoprim 2.5 g/sachet, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Duphatrim IS (Fort Dodge) UK

Injection, sulfadiazine 200 mg, trimethoprim 40 mg/mL, for horses, cattle, pigs, dogs, cats

Withdrawal Periods. Should not be used in horses intended for human consumption.

Cattle: slaughter 12 days, milk 2 days.

Pigs: slaughter 20 days

Prescription-only medicine: Equitrim Equine Paste (Boehringer Ingelheim) UK Oralpaste, sulfadiazine 1.25 g, trimethoprim 250 mg/division, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Equitrim Granules (Boehringer Ingelheim) UK

Oral granules, sulfadiazine 12.5 g, trimethoprim 2.5 g/sachet, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Norodine (Norbook) UK

Tablets, s/c, sulfadiazine 100 mg, trimethoprim 20 mg, for dogs, cats

Tablets, scored, sulfadiazine 400 mg, trimethoprim 80 mg, for dogs

Tablets, or to prepare an oral solution, scored, sulfadiazine 1 g, trimethoprim 200 mg, for calves

Withdrawal Periods.

Calves: slaughter 15 days

Prescription-only medicine: Norodine 24 (Norbook) UK

Injection, sulfadiazine 200 mg, trimethoprim 40 mg/mL, for horses, cattle, pigs, dogs, cats

Withdrawal Periods. Should not be used in horses intended for human consumption.

Cattle: slaughter 12 days, milk 2 days.

Pigs: slaughter 20 days

Prescription-only medicine: Norodine Equine Paste (Norbook) UK

Oralpaste, sulfadiazine 1.25 g, trimethoprim 250 mg/division, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Norodine Granules (Norbook) UK

Oral powder, for addition to feed, sulfadiazine 12.5 g, trimethoprim 2.5 g/sachet, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Strinacin II (Merial) UK

Tablets, or to prepare an oral solution, scored, suifadiazine 1 g, trimethoprim 200 mg, for calves

Withdrawal Periods.

Calves: slaughter 28 days

Prescription-only medicine: Synutrim Fortesol (Novartis) UK

Oral powder, for addition to drinking water, suifadiazine (as sodium salt) 625 g, trimethoprim 125 g/kg, for pigs, chickens

Withdrawal Periods.

Pigs: slaughter 14 days.

Chickens: slaughter 7 days, eggs from treated birds should not be used for human consumption

Medicated feedingstuff prescription: Synutrim Granular (Novartis) UK

Granules, suifadiazine 50 g, trimethoprim 250 mg/kg, for pigs, chickens, turkeys

Withdrawal Periods.

Pigs: slaughter 10 days.

Chickens: slaughter 5 days, should not be used in chickens producing eggs for human consumption.

Turkeys: slaughter 2 days, should not be used in turkeys producing eggs for human consumption

Prescription-only medicine: Tribrissen (Schering-Plough) UK

Tablets, scored, suifadiazine 400 mg, trimethoprim 80 mg, for dogs

Prescription-only medicine: Tribrissen 24 %/48% (Schering-Plough) UK

Injection, suifadiazine 200 mg, trimethoprim 40 mg/mL, for dogs, cats

Injection, suifadiazine 400 mg, trimethoprim 80 mg/mL, for horses, cattle, pigs

Withdrawal Periods. Should not be used in horses intended for human consumption.

Cattle: slaughter 43 days, milk 6.5 days.

Pigs: slaughter 28 days

Prescription-only medicine: Tribrissen Oral Paste (Schering-Plough) UK

Oral paste, suifadiazine 1.25 g, trimethoprim 250 mg/division, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Trimacare (Animalcare) UK

Tablets, suifadiazine 100 mg, trimethoprim 20 mg, for dogs, cats

Tablets, scored, suifadiazine 400 mg, trimethoprim 80 mg, for dogs

Tablets, or to prepare an oral solution, scored, suifadiazine 1 g, trimethoprim 200 mg,for calves

Withdrawal Periods.

Calves: slaughter 28 days

Prescription-only medicine: Trimacare 24% (Animalcare) UK

Injection, suifadiazine 200 mg, trimethoprim 40 mg/mL, for horses, cattle, sheep, pigs, dogs, cats

Withdrawal Periods. Should not be used in horses intended for human consumption.

Cattle: slaughter 10 days, milk 2.5 days.

Sheep: slaughter 18 days, should not be used in sheep producing milk for human consumption.

Pigs: slaughter 10 days

Medicated feedingstuff prescription: Trimediazine 15 (Vetoquinol) UK

Oral powder, suifadiazine 125 g, trimethoprim 25 g/kg, for pigs, chickens, turkeys

Withdrawal Periods.

Pigs: slaughter 5 days.

Chickens: slaughter 1 day, should not be used in chickens producing eggs for human consumption.

Turkeys: slaughter 3 days

Medicated feedingstuff prescription: Trimediazine BMP (Vetoquinol) UK

Oral powder, for addition to feed, suifadiazine 125 g, trimethoprim 25 g/kg, for pigs, chickens, turkeys

Withdrawal Periods.

Pigs: slaughter 7 days.

Chickens: slaughter 1 day, should not be used in chickens producing eggs for human consumption.

Turkeys: slaughter 3 days

Prescription-only medicine: Trimediazine Paste (Vetoquinol) UK

Oral paste, suifadiazine 1.3 g, trimethoprim 260 mg/division, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Trimediazine Plain (Vetoquinol) UK

Oral powder, for addition to feed, suifadiazine 250 mg, trimethoprim 50 mg/g, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Trimedoxine 4S (Vetoquinol) UK

Tablets, or to prepare an oral solution, suifadiazine, trimethoprim, for calves

Withdrawal Periods.

Calves: slaughter 15 days

Dose.

Calves: by mouth, 1 tablet/40 kg body-weight

Prescription-only medicine: Trimedoxine Tablets (Vetoquinol) UK

Tablets, scored, suifadiazine 400 mg, trimethoprim 80 mg, for dogs

Prescription-only medicine: Trinacol (Boehringer Ingelheim) UK

Injection, suifadiazine 200 mg, trimethoprim 40 mg/mL, for cattle, pigs, dogs

Withdrawal Periods.

Cattle: slaughter 12 days, milk 2 days.

Pigs: slaughter

20 days

Medicated feedingstuff prescription: Uniprim 150 (Pfizer) UK

Oral powder, for addition to feed, suifadiazine 125 g, trimethoprim 25 g/kg, for pigs, non-laying chickens

Withdrawal Periods.

Pigs: slaughter 5 days.

Chickens: slaughter 1 day, should not be used in birds producing eggs for human consumption

Prescription-only medicine: Uniprim for Horses (Pfizer) UK

Oral powder, for addition to feed, suifadiazine 12.5 g, trimethoprim 2.5 g/sachet, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Prescription-only medicine: Ventipulmin TMP/S (Boehringer Ingelheim) UK

Oral powder, for addition to feed, clenbuterol 21.44 micrograms, suifadiazine 335 mg, trimethoprim 67 mg/g, for horses

Withdrawal Periods. Should not be used in horses intended for human consumption

Dose.

Horses: 9 g (measure provided) of powder/250 kg body-weight twice daily

SULFADOXINE with TRIMETHOPRIM

Indications. Sulfadoxine/trimethoprim-sensitive infections

Contra-indications. Intraperitoneal administration; horses with cardiac arrhythmias; sulphonamide hypersensitivity; concurrent alpha2-adrenoceptor stimulants

Side-effects. Occasional transient swelling at site of injection; cardiac and respiratory shock in horses; anaphylactic or hypersensitivity reactions in horses; renal, hepatic, or haematopoietic system damage

Warnings. Drug Interactions.; safety in pregnant animals has not been established; use with caution in animals with renal or hepatic impairment or blood dys-crasias; ensure adequate water supply available

Dose. Expressed as sulfadoxine + trimethoprim

Horses: by intramuscular or slow intravenous (preferred) injection, 15 mg/kg

Cattle, pigs: by intramuscular (preferred) or intravenous injection, 15 mg/kg daily

Pigs: by subcutaneous or intramuscular injection, 15 mg/kg daily

Prescription-only medicine: Bimotrim Co (Bimeda) UK

Injection, sulfadoxine 200 mg, trimethoprim 40 mg/mL, for horses, cattle

Withdrawal Periods. Should not be used in horses intended for human consumption.

Cattle: slaughter 10 days, milk 2 days

Prescription-only medicine: Borgal 24% (Intervet) UK

Injection, sulfadoxine 200 mg, trimethoprim 40 mg/mL, for horses, cattle, pigs

Withdrawal Periods.

Horses: slaughter 8 days.

Cattle: slaughter 10 days, milk 2 days.

Pigs: slaughter 8 days

SULFAMETHOXAZOLE with TRIMETHOPRIM

(Co-trimoxazole: preparations of trimethoprim and sulfamethoxazole in the proportions, by weight, of 1 part to 5 parts)

Indications. Sulfamethoxazole/trimethoprim-sensitive infections

Contra-indications. Sulphonamide hypersensitivity; severe hepatic impairment; blood dyscrasias

Side-effects. Occasionally erythema and petechiae of the skin, internal haemorrhage, haematuria, keratoconjunctivitis sicca

Warnings. Drug Interactions.

Dose. Expressed as sulfamethoxazole + trimethoprim

Dogs, cats: by mouth, 30 mg/kg daily

Prescription-only medicine: Qj) Co-trimoxazole (Non-proprietary) UK

Tablets, sulfamethoxazole 400 mg, trimethoprim 80 mg

Paediatric oral suspension, sulfamethoxazole 40 mg, trimethoprim 8 mg/mL

Oral suspension, sulfamethoxazole 80 mg, trimethoprim 16 mg/mL

Strong sterile solution, sulfamethoxazole 80 mg, trimethoprim 16 mg/mL.

For dilution and use as an intravenous infusion

SULFAQUINOXALINE with TRIMETHOPRIM

Indications. Sulfadimidine/trimethoprim-sensitive infections; treatment of coccidiosis in chickens (see section 1.4)

Contra-indications. Use in water-proportioner systems

Dose. Expressed as sulfaquinoxaline + trimethoprim

Chickens, turkeys: bacterial infections, by addition to drinking water or feed, 30 mg/kg body-weight

Prescription-only medicine: Tribrissen (SQX) Poultry Formula (Schering-Plough) UK Granules, for addition to feed or drinking water, sulfaquinoxaline (as sodium) 500 mg/g, trimethoprim 165 mg/g, for chickens, turkeys more than 21 days of age

Withdrawal Periods. Broiler chickens: slaughter 7 days.

Turkeys: slaughter 9 days. Should not be used in layer or breeder flocks when birds are in lay