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Pharmacological particulars
Pharmacotherapeutic group: Combinations of sulphonamides and trimethoprim
ATCvet code: QJ01EW10
Pharmacodynamic properties
Sulfadiazine (SDZ) inhibits the incorporation of para-aminobenzoic acid into folic acid and trimethoprim (TMP) inhibits the enzyme dihydrofolate reductase (DHFR) which converts dihydrofolic acid into tetrahydrofolic acid. TMP and SDZ act together synergistically with a double-blockade mode of action. The combination is bactericidal, inhibiting sequential steps in the synthesis of purines which are required for DNA synthesis. TMP/SDZ combinations have a broad bactericidal action against many gram-positive and gram-negative aerobic bacteria and a large proportion of anaerobic bacteria.
Bacterial resistance to trimethoprim and to sulphonamides can be mediated via 5 main mechanisms: (1) changes in the permeability barrier and/or efflux pumps, (2) naturally insensitive target enzymes, (3) changes in the target enzymes, (4) mutational or recombinational changes in the target enzymes, and (5) acquired resistance by drug-resistant target enzymes.
Pharmacokinetic properties
Sulfadiazine is protein bound only to a limited extent and is well distributed. Metabolism occurs in the liver and the major by-products are acetylated derivatives which are excreted mainly by glomerular filtration. The plasma half-lives in cattle, pigs and dogs are 2, 3 and 4 hours respectively. Trimethoprim is a weak base with low water solubility. Trimethoprim is about 65% protein bound but, being lipid soluble, readily penetrates cellular barriers to become widely distributed. It is partly oxidised and conjugated in the liver and the metabolites, plus unchanged trimethoprim are excreted in the urine.
The degree of metabolism varies: 80% in the dog and almost 100% in the cow. The half-life is also variable: 2 hours in the pig and 1 hour in the cow.
Given the wide interspecies variability in the half-life of both active substances, it is not possible to attain pharmacokinetic matching of the two compounds, but there is evidence that synergism occurs over a wide range of dose ratios. The combination of 1:5 trimethoprim:sulfadiazine is well documented for veterinary use.
Environmental properties
Trimethoprim is persistent in soils.