Sulfonamides and Sulfonamide Combinations Use in Animals

In most species, standard-use sulfonamides are administered every 6 to 24 hours, depending on the drug, to control systemic infections due to susceptible bacteria. In some instances, administration of the sulfonamide can be less frequent if the drug is eliminated slowly in the species being treated. Sulfonamides included in this class, depending on the species, are sulfamethazine (sulfadimidine), sulfamerazine, sulfadiazine, sulfabromomethazine, sulfaethoxypyridazine, and sulfadimethoxine.

A few very water-soluble sulfonamides (eg, sulfisoxazole [sulfafurazole] and sulfasomidine) are rapidly excreted via the urinary tract (>90% in 24 hours) mostly in an unchanged form; because of this, they are primarily used to treat urinary tract infections.

A group of diaminopyrimidines (trimethoprim, methoprim, ormetoprim, aditoprim, and pyrimethamine) inhibit dihydrofolate reductase in bacteria and protozoa far more efficiently than in mammalian cells. Used alone, these agents are not particularly effective against bacteria, and resistance develops rapidly. However, when combined with sulfonamides, a sequential blockade of microbial enzyme systems occurs with bactericidal consequences. Examples of such potentiated sulfonamide preparations include trimethoprim-sulfadiazine (co-trimazine), trimethoprim-sulfamethoxazole (co-trimoxazole), trimethoprim-sulfadoxine (co-trimoxine), and ormetoprim-sulfadimethoxine. Sulfonamides are used in combination with pyrimethamine to treat protozoal diseases such as leishmaniasis and toxoplasmosis. ( See also page Regulatory Considerations and Drug Withdrawal and Milk Discard Times.)

Several sulfonamides are used topically for specific purposes. Sulfacetamide is not highly efficacious but is occasionally used to treat ophthalmic infections. Mafenide and silver sulfadiazine are used on burn wounds to prevent invasion by many gram-negative and gram-positive organisms. Sulfathiazole is commonly included in wound powders for the same purpose.

The sulfonamides are structural analogues of para-aminobenzoic acid (PABA) and competitively inhibit dihydropterate synthetase (DPS), an enzyme that facilitates PABA as a substrate for the synthesis of dihydrofolic acid (folic acid). Dihydrofolate is a precursor for formation of tetrahydrofolate (folinic acid), an essential component of the coenzymes responsible for single-carbon metabolism in cells. Sulfonamides are antimetabolites that substitute for PABA, resulting in blockade of several enzymes needed for the biogenesis of purine bases and other metabolic reactions necessary for formation of RNA.

Protein synthesis, metabolic processes, and inhibition of growth and replication occur in organisms that cannot use preformed (eg, dietary) folate. The effect is bacteriostatic, although a bactericidal action is evident at the high concentrations that may be found in urine. Diaminopyrimidines such as trimethoprim inhibit dihydrofolate reductase, which is further into the folic acid synthesis pathway. The combination of a sulfonamide and a diaminopyrimidine results in synergistic bactericidal actions on susceptible organisms; as such, the combination is referred to as a potentiated sulfonamide.

The optimal ratio in vitro for the combination of trimethoprim or ormetoprim and a sulfonamide depends on the type of microorganism but is usually ~1:20. However, the commercially available preparations use a ratio of 1:5 because of pharmacokinetic considerations that presumably result in the optimal ratio at the site of infection.

Sulfonamides are most effective in the early stages of acute infections when organisms are rapidly multiplying. They are not active against quiescent bacteria. Typically, there is a latent period before the effects of sulfonamide treatment become evident. This lag period occurs because the bacteria use existing stores of folic acid, folinic acid, purines, thymidine, and amino acids. Once these stores are depleted, bacteriostasis occurs. Bacterial growth can resume when the concentration of PABA increases or when the level of sulfonamide decreases below an enzyme-inhibitory concentration.

Because of the bacteriostatic nature of sulfonamides, adequate cellular and humoral defense mechanisms are critical for successful sulfonamide treatment when used as sole agents. Even potentiated sulfonamides, which are bactericidal, are time dependent in their antibacterial efficacy.

Although all of the sulfonamides have the same mechanism of action, differences are evident with respect to activity, pharmacokinetic fate, and even antimicrobial spectrum at usual concentrations. The differences are due to the variety of physiochemical characteristics seen among the sulfonamides.

The efficacy of sulfonamides can be decreased radically by excess PABA, folic acid, thymine, purine, methionine, plasma, blood, albumin, tissue autolysates, and endogenous protein-degradation products.

Bacterial resistance to sulfonamides is both chromosomally and plasmid mediated. Altered proteins such that affinity is decreased appear to be the most common mechanism of resistance. For example, in staphylococci, chromosomally mediated resistance reflects mutations in genes encoding for dihydropterate synthetase, and plasmid-mediated resistance reflects mutations in dihydrofolate reductases, with the latter causing high-level resistance to trimethoprim. Staphylococci may have acquired some mechanisms of sulfonamide resistance from enterococci.

Because sulfonamides act in a competitive fashion, overproduction of PABA can also preclude inhibition of dihydropterate synthetase. Because PABA is released from decaying neutrophils in purulent debris, sulmonamides are less effective in purulent environments. Alternate pathways of folic acid synthesis may also contribute to low-level resistance. Cross-resistance between sulfonamides is common. Resistance emerges gradually and is widespread in many animal populations. Plasmid-mediated sulfonamide resistance in intestinal gram-negative bacteria is often linked with ampicillin and tetracycline resistance.

The spectrum of all sulfonamides is generally the same. Sulfonamides inhibit both gram-positive and gram-negative bacteria, Nocardia, Actinomyces spp, and some protozoa (eg, coccidia and Toxoplasma spp). More active or potentiated sulfonamides may have activity against several species of Streptococcus, Staphylococcus, Salmonella, Pasteurella, Corynebacterium, and even Escherichia coli in their spectra. Strains of Enterobacter, Klebsiella, Proteus, Clostridium, and Leptospira spp are susceptible but may become resistant. Rickettsiae, protozoa, coccidia, mycoplasmas, Pseudomonas, Bacteroides, and most Chlamydia are highly resistant.

Sulfonamides may be administered PO, IV, IP, IM, intrauterine, or topically, depending on the specific preparation. Most are rapidly and completely absorbed from the GI tract of monogastric animals. Absorption from the ruminoreticulum is delayed, especially if ruminal stasis is present. For sulfachlorpyridazine, bioavailability is greatly decreased via feeding. Therapeutic doses of sulfonamides are usually administered PO except in acute life-threatening infections when IV infusions are used to establish adequate blood concentrations as rapidly as possible.

Sulfonamides are frequently added to drinking water or feed either for therapeutic purposes or to improve feed efficiency. A few highly water-soluble preparations may be injected IM (eg, sodium sulfadimethoxine) or IP (some irritation of the peritoneum can occur). Absorption is rapid from these parenteral sites. Generally, sulfonamide solutions are too alkaline for routine parenteral use.

Trimethoprim is rapidly absorbed after administration PO (plasma concentrations peak in ~2–4 hours) except in ruminants, in which it tends to be trapped in the ruminoreticulum and appears to undergo a degree of microbial degradation.

Absorption occurs readily from parenteral injection sites; effective antibacterial concentrations are reached in < 1 hour, with peak concentrations in ~4 hours.

Sulfonamides are weak acids and hydrophilic, leading to distribution via the extracellular fluid. The distribution pattern depends on the ionization state of the sulfonamide, the vascularity of specific tissues, the presence of specific barriers to sulfonamide diffusion, and the fraction of the administered dose bound to plasma proteins. The unbound drug fraction is freely diffusible.

Sulfonamides are bound to plasma proteins to a greater or lesser extent, and concentrations in pleural, peritoneal, synovial, and ocular fluids may be 50%–90% of that in blood. Sulfadiazine is ≥90% bound to plasma proteins. Concentrations in the kidneys exceed plasma concentrations, and those in the skin, liver, and lungs are only slightly less than the corresponding plasma concentrations. Concentrations in muscle and bone are ~50% of those in the plasma, and those in the CSF may be 20%–80% of blood concentrations, depending on the particular sulfonamide.

Low concentrations are found in adipose tissue. After parenteral administration, sulfamethazine is found in jejunal and colonic contents at about the same concentration as in blood. Passive diffusion into milk also occurs; although the concentrations achieved are usually inadequate to control infections, sulfonamide residues may be detected in milk. Trimethoprim and ormetoprim are basic and tend to accumulate in more acidic environments such as acidic urine, milk, and ruminal fluid.

Trimethoprim diffuses extensively into tissues and body fluids. Tissue concentrations are often higher than the corresponding plasma concentrations, especially in lungs, liver, and kidneys. Approximately 30%–60% of trimethoprim is bound to plasma proteins. The extent of metabolic transformation of trimethoprim has not yet been established, although there is a suggestion that hepatic biotransformation can be extensive, at least in ruminants. This may not be the case in all species; >50% of a dose is excreted unchanged in many instances. Trimethoprim is largely excreted in the urine via glomerular filtration and tubular secretion. A substantial amount may also be found in the feces. Concentrations in milk are often 1–3.5 times as high as those in plasma.

Sulfonamides are usually extensively metabolized, mainly via several oxidative pathways, acetylation, and conjugation with sulfate or glucuronic acid. Species differences are marked in this regard. The acetylated, hydroxylated, and conjugated forms have little antibacterial activity. Acetylation (poorly developed in dogs) decreases the solubility of most sulfonamides except for the sulfapyrimidine group. The hydroxylated and conjugated forms are less likely to precipitate in urine.

Most sulfonamides are excreted primarily in the urine. Bile, feces, milk, tears, and sweat are excretory routes of lesser importance. Glomerular filtration, active tubular secretion, and tubular reabsorption are the main processes involved. The proportion reabsorbed is influenced by the inherent lipid solubility of individual sulfonamides and their metabolites and by urinary pH. Urinary pH, renal clearance, and the concentration and solubility of the respective sulfonamides and their metabolites determine whether solubilities are exceeded and crystals precipitate. This can be prevented by alkalinizing the urine, increasing fluid intake, reducing dose rates in renal insufficiency, and using triple-sulfonamide or sulfonamide-diaminopyrimidine combinations.

There are great differences between the pharmacokinetic values of various sulfonamides in animals, and extrapolation of these values is rarely appropriate; for example, the plasma half-life of sulfadiazine is 10.1 hours in cattle and 2.9 hours in pigs. The recommended dose rates and frequencies reflect this disparity in elimination kinetics.

The plasma half-life of trimethoprim is quite prolonged in most species; effective concentrations may be maintained for >12 hours, with the result that the frequency of administration is usually 12–24 hours. The elimination rates of trimethoprim in sheep seem to be much shorter than in monogastric species.

Adverse reactions to sulfonamides may be due to hypersensitivity or direct toxic effects. Possible hypersensitivity reactions include urticaria, angioedema, anaphylaxis, skin rashes, drug fever, polyarthritis, hemolytic anemia, and agranulocytosis. Keratitis sicca is a recognized adverse effect. The allergic response targets, in part, metabolites of the aryl amine of sulfonamides. Because dogs are deficient in acetylation, they may be at risk of increased formation of phase I metabolites associated with adverse effects.

Crystalluria with hematuria, and even tubular obstruction, is not common in veterinary medicine. Acute toxic manifestations may occur after too-rapid IV administration or if an excessive dose is injected. Clinical signs include thrombophlebitis, anaphylaxis, muscle weakness, ataxia, blindness, and collapse. Gastrointestinal disturbances, in addition to nausea and vomiting, may occur when sulfonamide concentrations are sufficiently high in the tract to disturb normal microfloral balance and vitamin B synthesis. Sulfonamides depress the cellulolytic function of ruminal microflora; however, the effect is usually transient (unless excessively high concentrations are reached).

Several adverse effects have been reported after prolonged treatment, including bone marrow depression (aplastic anemia, granulocytopenia, and thrombocytopenia), hepatitis and icterus, peripheral neuritis and myelin degeneration in the spinal cord and peripheral nerves, photosensitization, stomatitis, conjunctivitis, and keratitis sicca. Mild follicular thyroid hyperplasia may be associated with prolonged administration of sulfonamides in sensitive species such as dogs, and reversible hypothyroidism can be induced after treatment with high doses in dogs. Several sulfonamides can lead to decreased egg production and growth. Topically, the sulfonamides retard healing of uncontaminated wounds.

Up to 10 times the recommended dose of trimethoprim has been given with no adverse effects. Prolonged administration of trimethoprim at reasonably high concentrations leads to maturation defects in hematopoiesis due to impaired folinic acid synthesis. Clinical signs of folate deficiency include anemia, thrombocytopenia, and even pancytopenia. Supplementation with folic acid may be necessary in young or pregnant animals undergoing long-term high-dose treatment. Treatment with trimethoprim-sulfamethoxazole has been associated with immune-mediated hemolytic anemia in horses.

Sulfonamide solutions are incompatible with calcium- or other polyionic-containing fluids as well as many other preparations. Sulfonamides may be displaced from their plasma-protein binding sites by other acidic drugs with higher binding affinities. Antacids tend to inhibit the GI absorption of sulfonamides. Alkalinization of the urine promotes sulfonamide excretion, and urinary acidification increases the risk of crystalluria. Some sulfonamides act as microsomal enzyme inhibitors, which may lead to toxic manifestations of concurrently administered drugs such as phenytoin.

The IV administration of potentiated sulfonamides and detomidine sensitizes the myocardium and may result in potentially fatal cardiac dysrhythmias and hypotension. Procaine, found in procaine penicillin G, is a PABA analogue that may decrease efficacy of potentiated sulfonamides.

Sulfonamides may cause bilirubin concentration, BUN concentration, bromsulphthalein concentration, eosinophil count, methemoglobin concentration, AST activity, and ALT activity to increase. Platelet, RBC, and WBC counts are often decreased. Urinalysis may show a change in color, glucose, porphyrins, and urobilinogen. Sulfonamide crystals may also be found.

Sulfonamides are prohibited from extralabel use in lactating dairy cattle in the US; this definition therefore includes all dairy cattle >20 months of age. While not expressly prohibited, the extralabel use of sulfonamides in milking sheep and goats is discouraged. There are three sulfonamides approved for lactating dairy cattle: sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine, and these drugs must be used according to label directions.

In addition, sulfonamide residues, particularly in swine and poultry, continue to be a focus of detection. Because of adverse effects in people, including allergic reactions, attention must be paid to withdrawal times. Regulatory requirements for withdrawal times for food-producing animals and milk discard times vary among countries and may change. Withdrawal times can vary between products, even for the same drug. Therefore, when using products according to label recommendations, it is imperative to follow the label meat and milk withdrawal times for the particular product used.

For instances of extralabel drug use (ELDU), it is recommended to contact a country-specific advisory program to obtain evidence-based withdrawal recommendations extrapolated from known species pharmacokinetics. In the US, veterinarians may contact the Food Animal Residue Avoidance Databank (FARAD, www.farad.org) for withdrawal recommendations.