SULFADIAZINE / TRIMETHOPRIM, SULFAMETHOXAZOLE / TRIMETHOPRIM
Note: In the practice of veterinary medicine in the United States, two separate combinations withtrimethoprim are used clinically. There are trimethoprim/sulfadiazine products approved for use indogs, cats and horses in both parenteral and oral dosage forms. Many veterinarians also will use thehuman approved, trimethoprim/sulfamethoxazole oral products because of economicconsiderations. In Canada, sulfadoxine is available in combination with trimethoprim for veterinary use.
Chemistry - Trimethoprim occurs as odorless, bitter-tasting, white to cream-colored crystals orcrystalline 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 ispractically 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.
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.
The in vitro optimal ratio for most susceptible bacteria is approximately 1:20 (trimethoprim:sulfa), but synergistic activity can reportedly occur with ratios of 1:1 - 1:40. The serum concentration ofthe trimethoprim component is considered to be more important than the sulfa concentration. Formost susceptible bacteria, the MIC's for TMP are generally above 0.5 micrograms/ml.
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 - Although only approved for use in dogs and horses, trimethoprim/sulfadiazineet al is used in many species to treat infections caused by susceptible organisms. See Dosagesection for more information.
Trimethoprim/sulfa is well distributed in the body. When meninges are inflamed, the drugs enterthe CSF in levels of about 50% of those found in the serum. Both drugs cross the placenta and aredistributed into milk. The volume of distribution for trimethoprim in various species are: 1.49 L/kg(dogs), and 0.59-1.51 L/kg (horses). The volume of distribution for sulfadiazine in dogs is 1.02
L/kg.
Trimethoprim/sulfa is both renally excreted unchanged via glomerular filtration and tubular secretion and metabolized by the liver. The sulfas are primarily acetylated and conjugated withglucuronic acid and trimethoprim is metabolized to oxide and hydroxylated metabolites.
Trimethoprim may be more extensively metabolized by the liver in adult ruminants than in otherspecies. The serum elimination half-lives for trimethoprim in various species are: 2.5 hours (dogs), 1.91-3 hours (horses), 1.5 hours (cattle). The serum elimination half-lives for sulfadiazine invarious species are: 9.84 hours (dogs), 2.71 hours (horses), 2.5 hours (cattle). While trimethoprimis quite rapidly eliminated from the serum, the drug may persist for a longer period of time intissues.
Because of the number of variables involved it is extremely difficult to apply pharmacokineticvalues in making dosage recommendations with these combinations. Each drug (trimethoprim andthe sulfa) has different pharmacokinetic parameters (absorption, distribution, elimination) in eachspecies. Since different organisms have different MIC values and the optimal ratio of trimethoprimto sulfa also differs from organism to organism, this problem is exacerbated.
There is considerable controversy regarding the frequency of administration of these combinations. The veterinary product, trimethoprim/sulfadiazine is labeled for once daily administration indogs and horses, but many clinicians believe that the drug is more efficacious if given twice daily, regardless of which sulfa is used.
This combination should be used with caution in patients with pre-existing hepatic disease.
Safety of trimethoprim/sulfa has not been clearly established in pregnant animals. Reports ofteratogenicity (cleft palate) have been reported in some rat studies. Fetal mortality was also increased in rabbits receiving high doses of trimethoprim. Dog studies have not demonstrated anyteratogenic effects. However, this combination should be used in pregnant females only when thebenefits clearly outweigh the risks of use. Studies thus far in male animals have not demonstratedany decreases in reproductive performance.
Potentiated sulfonamides may cause hypothyroidism in the dog, particularly with extended therapy.
Acute hypersensitivity reactions manifesting as Type I (anaphylaxis) or Type III reaction (serumsickness) can also be seen. Hypersensitivity reactions appear to be more common in large breeddogs; Doberman Pinschers may possibly be more susceptible to this effect than other breeds. Otherhematologic effects (anemias, agranulocytosis) are possible, but are fairly rare in dogs.
Adverse effects noted in cats may include anorexia, leukopenias and anemias.
In horses, transient pruritis has been noted after intravenous injection. Oral therapy has resulted indiarrhea development in some horses. If the 48% injectable product is injected IM, SQ, 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.
Complete blood counts (and other laboratory parameters) should be monitored as necessary. Bonemarrow 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/Laboratory Interactions - When using the Jaffe alkaline picrate reaction assay for creatinine determination, trimethoprim/sulfa may cause an overestimation of approximately 10%.
Sulfonamides may give false-positive results for urine glucose determinations when using the
Benedict's method.
Chemistry - Trimethoprim occurs as odorless, bitter-tasting, white to cream-colored crystals orcrystalline 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 ispractically 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.
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.
Storage, Stability, Compatibility
Unless otherwise instructed by the manufacturer, trimethoprim/sulfadiazine and co-trimoxazole products should be stored at room temperature (15-30°C) intight containers.Pharmacology - SULFADIAZINE/TRIMETHOPRIM, SULFAMETHOXAZOLE/TRIMETHOPRIM
Alone, sulfonamides are bacteriostatic agents and trimethoprim is bactericidal, butin combination, the potentiated sulfas are bactericidal. Potentiated sulfas sequentially inhibitenzymes in the folic acid pathway, thereby inhibiting bacterial thymidine synthesis. The sulfonamide blocks the conversion of para-aminobenzoic acid (PABA) to dihydrofolic acid (DFA), andtrimethoprim blocks the conversion of DFA to tetrahydrofolic acid by inhibiting dihydrofolatereductase.The in vitro optimal ratio for most susceptible bacteria is approximately 1:20 (trimethoprim:sulfa), but synergistic activity can reportedly occur with ratios of 1:1 - 1:40. The serum concentration ofthe trimethoprim component is considered to be more important than the sulfa concentration. Formost susceptible bacteria, the MIC's for TMP are generally above 0.5 micrograms/ml.
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 - Although only approved for use in dogs and horses, trimethoprim/sulfadiazineet al is used in many species to treat infections caused by susceptible organisms. See Dosagesection for more information.
Pharmacokinetics - SULFADIAZINE/TRIMETHOPRIM, SULFAMETHOXAZOLE/TRIMETHOPRIM
Trimethoprim/sulfa is well absorbed after oral administration, with peak levelsoccurring about 1-4 hours after dosing. The drug is more slowly absorbed after subcutaneousabsorption, however. In ruminants, the trimethoprim is apparently trapped in the ruminoreticulumafter oral administration and undergoes some degradation.Trimethoprim/sulfa is well distributed in the body. When meninges are inflamed, the drugs enterthe CSF in levels of about 50% of those found in the serum. Both drugs cross the placenta and aredistributed into milk. The volume of distribution for trimethoprim in various species are: 1.49 L/kg(dogs), and 0.59-1.51 L/kg (horses). The volume of distribution for sulfadiazine in dogs is 1.02
L/kg.
Trimethoprim/sulfa is both renally excreted unchanged via glomerular filtration and tubular secretion and metabolized by the liver. The sulfas are primarily acetylated and conjugated withglucuronic acid and trimethoprim is metabolized to oxide and hydroxylated metabolites.
Trimethoprim may be more extensively metabolized by the liver in adult ruminants than in otherspecies. The serum elimination half-lives for trimethoprim in various species are: 2.5 hours (dogs), 1.91-3 hours (horses), 1.5 hours (cattle). The serum elimination half-lives for sulfadiazine invarious species are: 9.84 hours (dogs), 2.71 hours (horses), 2.5 hours (cattle). While trimethoprimis quite rapidly eliminated from the serum, the drug may persist for a longer period of time intissues.
Because of the number of variables involved it is extremely difficult to apply pharmacokineticvalues in making dosage recommendations with these combinations. Each drug (trimethoprim andthe sulfa) has different pharmacokinetic parameters (absorption, distribution, elimination) in eachspecies. Since different organisms have different MIC values and the optimal ratio of trimethoprimto sulfa also differs from organism to organism, this problem is exacerbated.
There is considerable controversy regarding the frequency of administration of these combinations. The veterinary product, trimethoprim/sulfadiazine is labeled for once daily administration indogs and horses, but many clinicians believe that the drug is more efficacious if given twice daily, regardless of which sulfa is used.
Contraindications, Precautions, Reproductive Safety
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 (orapproved for other animals) intended for food.This combination should be used with caution in patients with pre-existing hepatic disease.
Safety of trimethoprim/sulfa has not been clearly established in pregnant animals. Reports ofteratogenicity (cleft palate) have been reported in some rat studies. Fetal mortality was also increased in rabbits receiving high doses of trimethoprim. Dog studies have not demonstrated anyteratogenic effects. However, this combination should be used in pregnant females only when thebenefits clearly outweigh the risks of use. Studies thus far in male animals have not demonstratedany decreases in reproductive performance.
Adverse Effects, Warnings
Adverse effects noted in dogs: keratoconjunctivitis sicca (which maybe irreversible), acute neutrophilic hepatitis with icterus, vomiting, anorexia, diarrhea, fever, hemolytic anemia, urticaria, polyarthritis, facial swelling, polydipsia, polyuria and cholestasis.Potentiated sulfonamides may cause hypothyroidism in the dog, particularly with extended therapy.
Acute hypersensitivity reactions manifesting as Type I (anaphylaxis) or Type III reaction (serumsickness) can also be seen. Hypersensitivity reactions appear to be more common in large breeddogs; Doberman Pinschers may possibly be more susceptible to this effect than other breeds. Otherhematologic effects (anemias, agranulocytosis) are possible, but are fairly rare in dogs.
Adverse effects noted in cats may include anorexia, leukopenias and anemias.
In horses, transient pruritis has been noted after intravenous injection. Oral therapy has resulted indiarrhea development in some horses. If the 48% injectable product is injected IM, SQ, 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 GIdistress (nausea, vomiting, diarrhea), CNS toxicity (depression, headache, and confusion), facialswelling, bone marrow depression and increases in serum aminotransferases. Oral overdoses can betreated by emptying the stomach (following usual protocols) and initiating symptomatic andsupportive 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. Bonemarrow 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 receivingcoumarin (warfarin) anticoagulants. Sulfonamides may displace other highly bound drugs, suchas methotrexate, phenylbutazone, thiazide diuretics, salicylates, probenicid andphenytoin. Although the clinical significance of these interactions is not entirely clear, patientsshould be monitored for enhanced effects of the displaced agents. Antacids may decrease thebioavailability of sulfonamides if administered concurrently. Trimethoprim may decrease thetherapeutic effect of cyclosporine (systemic) and increase the risk of nephrotoxicity developing.Drug/Laboratory Interactions - When using the Jaffe alkaline picrate reaction assay for creatinine determination, trimethoprim/sulfa may cause an overestimation of approximately 10%.
Sulfonamides may give false-positive results for urine glucose determinations when using the
Benedict's method.