SULFADIMETHOXINE / ORMETOPRIM
Chemistry - A diaminopyrimidine structurally related to trimethoprim, ormetoprim occurs as awhite, almost tasteless powder. The chemistry of sulfadimethoxine is described in the previousmonograph.
Potentiated sulfas sequentially inhibit enzymes in the folic acid pathway, thereby inhibiting bacterialthymidine synthesis. The sulfonamide blocks the conversion of para-aminobenzoic acid (PABA) todihydrofolic acid (DFA) and ormetoprim blocks the conversion of DFA to tetrahydrofolic acid byinhibiting dihydrofolate reductase.
The potentiated sulfas have a fairly broad spectrum of activity. Gram positive bacteria that aregenerally susceptible include, most streptococci, many strains of staphylococcus, and Nocardia.
Many gram negative organisms of the family Enterobacteriaceae are susceptible to the potentiatedsulfas, but not Pseudomonas aeruginosa. Some protozoa (Pneumocystis carinii, Coccidia and Toxoplasma) are also inhibited by the combination. Potentiated sulfas reportedly have little activityagainst most anaerobes, but opinions on this vary.
Resistance will develop slower to the combination of drugs, than to either one alone. In gramnegative organisms, resistance is usually plasmid-mediated.
Uses, Indications - The present approved indications for this combination are for the treatment ofskin and soft tissue infections in dogs caused by susceptible strains of Staphylococcus aureus and E. coli. Because clinical experience with this drug is extremely limited at the time of this writing, further uses and indications may be forthcoming.
This combination should be used with caution in patients with pre-existing hepatic or thyroiddisease.
Safety of ormetoprim/sulfadimethoxine has not been established in pregnant animals. Reports ofteratogenicity (cleft palate) have been reported in some lab animals with trimethoprim/sulfa.
This combination would be expected to exhibit an adverse reaction profile in dogs similar to thatseen with trimethoprim/sulfa, including: keratoconjunctivitis sicca (which may be irreversible), acuteneutrophilic hepatitis with icterus, vomiting, anorexia, diarrhea, fever, hemolytic anemia, urticaria, polyarthritis, facial swelling, polydipsia, polyuria and cholestasis. Acute hypersensitivity reactionsmanifesting 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 Pinschersmay possibly be more susceptible to this effect than other breeds. Other hematologic effects(anemias, agranulocytosis) are possible, but fairly rare in dogs.
Long-term (8 weeks) therapy at recommended doses with ormetoprim/sulfadimethoxine (27.5mg/kg once daily) resulted in elevated serum cholesterol, thyroid and liver weights, mild follicularthyroid hyperplasia and enlarged basophilic cells in the pituitary. The manufacturer states that theprincipal treatment-related effect of extended or excessive usage is hypothyroidism.
It is suggested that very high oral overdoses be handled by emptying the gut using standard precautions and protocols and by treating symptoms supportively and symptomatically.
Drug Interactions; Drug/Laboratory Interactions - None have been noted for this combination, but it would be expected that the potential interactions outlined for the trimethoprim/sulfamonograph would also apply to this combination; refer to that monograph for more information.
Storage, Stability, Compatibility
Unless otherwise instructed by the manufacturer, store tabletsin tight, light resistant containers at room temperature.Pharmacology - SULFADIMETHOXINE/ORMETOPRIM
Sulfadimethoxine/ormetoprim shares mechanisms of action and probably thebacterial spectrum of activity with trimethoprim/sulfa. Alone, sulfonamides are bacteriostatic agents, but in combination with either ormetoprim or trimethoprim, the potentiated sulfas are bactericidal.Potentiated sulfas sequentially inhibit enzymes in the folic acid pathway, thereby inhibiting bacterialthymidine synthesis. The sulfonamide blocks the conversion of para-aminobenzoic acid (PABA) todihydrofolic acid (DFA) and ormetoprim blocks the conversion of DFA to tetrahydrofolic acid byinhibiting dihydrofolate reductase.
The potentiated sulfas have a fairly broad spectrum of activity. Gram positive bacteria that aregenerally susceptible include, most streptococci, many strains of staphylococcus, and Nocardia.
Many gram negative organisms of the family Enterobacteriaceae are susceptible to the potentiatedsulfas, but not Pseudomonas aeruginosa. Some protozoa (Pneumocystis carinii, Coccidia and Toxoplasma) are also inhibited by the combination. Potentiated sulfas reportedly have little activityagainst most anaerobes, but opinions on this vary.
Resistance will develop slower to the combination of drugs, than to either one alone. In gramnegative organisms, resistance is usually plasmid-mediated.
Uses, Indications - The present approved indications for this combination are for the treatment ofskin and soft tissue infections in dogs caused by susceptible strains of Staphylococcus aureus and E. coli. Because clinical experience with this drug is extremely limited at the time of this writing, further uses and indications may be forthcoming.
Pharmacokinetics - SULFADIMETHOXINE/ORMETOPRIM
The pharmacokinetics of sulfadimethoxine are outlined in the previousmonograph. Pharmacokinetic data for ormetoprim is not available at the time of this writing, but themanufacturer claims that therapeutic levels are maintained over 24 hours at recommended doses.Contraindications, Precautions, Reproductive Safety
The manufacturer states that ormetoprim/sulfadimethoxine should not be used in dogs or horses showing marked liver parenchymaldamage, blood dyscrasias, or in those with a history of sulfonamide sensitivity.This combination should be used with caution in patients with pre-existing hepatic or thyroiddisease.
Safety of ormetoprim/sulfadimethoxine has not been established in pregnant animals. Reports ofteratogenicity (cleft palate) have been reported in some lab animals with trimethoprim/sulfa.
Adverse Effects, Warnings
Adverse effects with this combination have not been reported atrecommended doses, but the number of evaluated patients is very small at the time of this writing.This combination would be expected to exhibit an adverse reaction profile in dogs similar to thatseen with trimethoprim/sulfa, including: keratoconjunctivitis sicca (which may be irreversible), acuteneutrophilic hepatitis with icterus, vomiting, anorexia, diarrhea, fever, hemolytic anemia, urticaria, polyarthritis, facial swelling, polydipsia, polyuria and cholestasis. Acute hypersensitivity reactionsmanifesting 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 Pinschersmay possibly be more susceptible to this effect than other breeds. Other hematologic effects(anemias, agranulocytosis) are possible, but fairly rare in dogs.
Long-term (8 weeks) therapy at recommended doses with ormetoprim/sulfadimethoxine (27.5mg/kg once daily) resulted in elevated serum cholesterol, thyroid and liver weights, mild follicularthyroid hyperplasia and enlarged basophilic cells in the pituitary. The manufacturer states that theprincipal treatment-related effect of extended or excessive usage is hypothyroidism.
Overdosage, Acute Toxicity
In experimental studies in dogs, doses greater than 80 mg/kg resulted in slight tremors and increased motor activity in some dogs. Higher doses may result indepression, anorexia or seizures.It is suggested that very high oral overdoses be handled by emptying the gut using standard precautions and protocols and by treating symptoms supportively and symptomatically.
Drug Interactions; Drug/Laboratory Interactions - None have been noted for this combination, but it would be expected that the potential interactions outlined for the trimethoprim/sulfamonograph would also apply to this combination; refer to that monograph for more information.