Chemistry

The sulfonamide antimicrobials are derivatives of sulfanilamide, which contains the structural prerequisites for antibacterial activity. The sulfonamides differ in the radical (R) attached to the sulfonamido (‐SO₂NHR) group or occasionally in the substituent on the amino (‐NH₂) group (Figure 16.1). It should be noted that other drug classes can also contain a sulfonamido group (e.g., carbonic anhydrase inhibitors, loop diuretics, certain coxibs) and thus may be classified as sulfonamides. However, these drugs lack the arylamine ring that the antimicrobials contain, which has important implications for mechanism of action and potential for toxicity.

The various derivatives differ in physicochemical and pharmacokinetic properties as well as the degree of antimicrobial activity. As a group, sulfonamides are quite insoluble; they are more soluble at an alkaline pH than at an acidic pH and the degree of solubility is dependent on the individual drug moiety. Specifically, sulfamethoxazole and sulfadimethoxine are more soluble than older sulfonamides such as sulfadiazine (Cribb et al., 1996).

The sodium salts of sulfonamides are readily soluble in water, and parenteral preparations are available for IV injection. These solutions are highly alkaline in reaction, with the notable exception of sodium sulfacetamide, which is nearly neutral and is available as an ophthalmic preparation.

Mechanism of Action

Sulfonamides interfere with the biosynthesis of folic acid in bacterial cells by competitively preventing paraaminobenzoic acid (PABA) from incorporation into the folic (pteroylglutamic) acid molecule (Figure 16.2). Specifically, sulfonamides compete with PABA for the enzyme dihydropteroate synthetase. Their selective bacteriostatic action depends on the difference between bacterial and mammalian cells in the source of folic acid. Susceptible microorganisms must synthesize folic acid, whereas mammalian cells use preformed folic acid. The bacteriostatic action can be reversed by an excess of PABA, so that any tissue exudates and necrotic tissue should be removed if animals are to be treated with sulfonamides.

Antimicrobial Activity

Sulfonamides are antimicrobial agents with intrinsic activity against many bacteria, Toxoplasma, and other protozoal agents such as coccidia. However, their antibacterial activity as a single agent is significantly limited by the extensive resistance that has developed over 90 years of use. Different sulfonamides may show quantitative but not necessarily qualitative differences in activity.

The minimum inhibitory concentration (MIC) of sulfonamides is markedly affected by the composition of the medium and the bacterial inoculum concentration. Because of this, in vitro tests may sometimes falsely report a bacterium to be resistant. This will not be the case with proper quality controls employing a thymidine‐sensitive strain of Enterococcus faecalis. In agar diffusion tests, Mueller Hinton agar containing lyzed horse blood is the ideal medium because it contains thymidine phosphorylase that decreases the quantity of thymidine in the medium. Veterinary‐specific breakpoints for sulfonamide antimicrobials have not been established, so human breakpoints are commonly reported (CLSI Group C agent). An MIC of 8–32 μg/ml is a reasonable definition of susceptibility for short‐acting systemic sulfonamides; an MIC of ≥64–128 μg/ml can be interpreted as evidence of resistance, although the CLSI (or other standardizing organization) should be consulted for the most up‐to‐date recommendations.

Sulfonamide antimicrobials achieve high concentrations in the urine (≥100 μg/ml), so different breakpoints are used. The CLSI criteria for people describe susceptibility in bacteria for urinary tract infections as those having an MIC of ≤256 μg/ml and this breakpoint is sometimes used for urinary tract infections in dogs and cats. Therefore, it is important that susceptibility data be interpreted in light of the infection location.

Antimicrobial susceptibility categories given below are guidelines only; in vivo efficacy will vary with dosage, sites of infection, route of administration, and other variables (Chapter 2).

• Predictable susceptibility: Bacillus spp., Brucella spp., E. rhusiopathiae, L. monocytogenes, Nocardia spp., pyogenic Streptococcus spp., Chlamydia and Chlamydophila spp., coccidia, Pneumocystis spp., and Cryptosporidium spp.
  
• Variable susceptibility because of reasonable possibility for acquired resistance includes among Gram‐positive aerobes: staphylococci, some enterococci. Gram‐negative aerobes: Enterobacterales (including Enterobacter spp., E. coli, Klebsiella spp., Proteus spp.), Actinobacillus spp., Haemophilus and Histophilus spp., Pasteurella spp., Pseudomonas spp. Anaerobes such as Bacteroides spp. and Fusobacterium spp. are often susceptible in vitro if the medium is depleted of thymidine; however, this is often not the case in vivo. Clostridium spp. (other than C. perfringens) and anaerobic cocci are often resistant.
  
• Intrinsic resistance: Mycobacterium spp., Mycoplasma spp., most obligate intracellular pathogens (such as C. burnetii and Rickettsia spp.), P. aeruginosa, enterococci, and spirochetes are inherently resistant (Chapter 2).

Resistance

Resistance due to chromosomal mutation develops slowly and causes impaired drug penetration, production of an insensitive dihydropteroate enzyme, or hyperproduction of PABA. Plasmid‐ and integron‐mediated resistance is far more common and is the result of impaired drug penetration or the production of additional, sulfonamide‐resistant, dihydropteroate synthetase enzymes. Sulfonamide resistance genes include sul1, sul2, and sul3 and are sometimes linked to other resistance genes including trimethoprim (dfr) or streptomycin (strA, strB) (Maynard et al., 2003; Sheikh et al., 2012). Resistance to sulfonamides is extensively documented as widespread in bacteria isolated from animals, reflecting widespread use of the drug over many years. A restriction of the sul3 resistance gene to largely porcine E. coli has been noted (Kozak et al., 2009; Wu et al., 2010). There is complete cross‐resistance between the sulfonamides.

Pharmacokinetic Properties

The sulfonamides constitute a series of weak organic acids with pK_a values ranging from 10.4 for sulfanilamide to 5.0 for sulfisoxazole. They exist predominantly in the nonionized form in biological fluids of pH lower than their pK_a. It is the nonionized moiety that diffuses through cell membranes and penetrates cellular barriers.

Most sulfonamides are rapidly absorbed from the gastrointestinal tract. In horses, a biphasic absorption pattern may be observed; when administered with food, a portion of the drug may bind to ingesta, delaying absorption of that fraction until reaching the large intestine (Van Duikeren et al., 1996). Sulfonamides generally distribute widely to all tissues and body fluids, including synovial and cerebrospinal fluids. The sulfonamides are bound to plasma proteins to an extent varying from 15–90%. In addition, there is variation among species in binding of individual sulfonamides. Extensive (>80%) protein binding increases the elimination half‐life. In any one species, the extent of protein binding, apparent volume of distribution, and elimination half‐life vary widely among individual sulfonamides. This information, together with designating 100 μg/ml as the desired steady‐state plasma sulfonamide concentration, facilitates calculation of dosages.

Sulfonamides are eliminated by a combination of renal excretion and biotransformation. This combination contributes to species variations in the half‐lives of individual drugs. Sulfadimethoxine, for example, has elimination half‐lives of 12.5 hours in cattle, 8.6 hours in goats, 11.3 hours in horses, 15.5 hours in swine, 13.2 hours in dogs, and 10.2 hours in cats. These relatively long elimination half‐lives have been attributed to extensive binding to plasma albumin and pH‐dependent passive reabsorption of the drug from acidic distal renal tubule fluid.

Sulfonamides undergo metabolic alterations to a variable extent in the tissues, especially the liver. N4‐acetylation of the paraamino group is the principal metabolic pathway for most sulfonamides and takes place in humans and all domestic animals except the dog, which lacks functional genes for the N‐acetyltransferase enzymes (Trepanier, 2004). Acetylation takes place in the reticuloendothelial rather than the parenchymal cells of the liver and other tissues such as the lungs. Aromatic hydroxylation of the methyl group on the pyrimidine ring, which may be the principal metabolic pathway for sulfonamides in ruminants, and glucuronide conjugation are microsomal‐mediated metabolic reactions. The glucuronide conjugates are highly water soluble and are rapidly excreted.

Renal excretion mechanisms include glomerular filtration of free (unbound) drug in the plasma, active carrier‐mediated proximal tubular excretion of ionized unchanged drug and metabolites, and passive reabsorption of nonionized drug from distal tubular fluid. The extent of reabsorption is determined by the pK_a of the sulfonamide and the pH of the fluid in the distal tubules. Urinary alkalinization increases both the fraction of the dose that is eliminated by renal excretion (unchanged in urine) and the solubility of sulfonamides in the urine.

Drug Interactions

The important synergistic interaction of sulfonamides with antibacterial diaminopyrimidines such as trimethoprim and baquiloprim is discussed below under the Antibacterial Diaminopyrimidine–Sulfonamide Combinations section. The agents appear not to antagonize the bactericidal effect of penicillins, but the procaine of procaine penicillin is an analogue of PABA that will antagonize sulfonamides. Thus, sulfonamides should not be combined with procaine penicillin therapeutically.

Toxicity and Adverse Effects

The sulfonamides can produce a wide variety of usually reversible adverse effects, which may be divided into dose‐dependent (Type A) and idiosyncratic (Type B) reactions. Of the dose‐dependent reactions, gastrointestinal upset occurs fairly commonly. Sulfonamides have been associated with Clostridioides (Clostridium) difficile enterocolitis in horses, which may be fatal (Diab et al., 2013). Renal tubular necrosis can also occur as a result of drug precipitation and tubular crystalluria. However, newer sulfonamides such as sulfamethoxazole and sulfadimethoxine have higher solubility in normal urine pH and so are less likely to precipitate. Interestingly, acetylated sulfonamide metabolites have lower aqueous solubility so dogs, which lack the N‐acetyltransferase enzymes, may be at lower risk for nephrotoxicity. Sulfonamide antimicrobials also have dose‐dependent antithyroid effects via reversible inhibition of thyroid peroxidase. In dogs, sulfonamides reliably decrease circulating thyroid concentrations and can result in clinical hypothyroidism in a dose‐ and time‐dependent manner. In late gestational sows, ormetoprim‐sulfadimethoxine has been documented to cause goitrous disease, increasing the number of stillborn or weak piglets (Blackwell et al., 1989).

In a small proportion of animals (approximately 0.25% of dogs), sulfonamide therapy can produce idiosyncratic drug reactions, which are unpredictable and rare events occurring five days to several weeks after first exposure. These adverse events are thought to be due to a hypersensitivity reaction to the drug haptenized to endogenous proteins via its arylamine ring. The syndrome in dogs may include fever, polyarthropathy, blood dyscrasias, hepatopathy, epistaxis, skin eruptions, uveitis, retinitis, lymphadenopathy, proteinuria, edema, pneumonitis, pancreatitis, and neurological complications (Trepanier, 2003). Isolated cases of skin eruptions, uveitis, blood dyscrasias, and neurological signs have also been reported in horses. However, among the veterinary species, dogs appear to be at increased risk for sulfonamide hypersensitivity, possibly because they lack the ability to acetylate the arylamine ring, protecting it from oxidation and haptenization. Doberman Pinschers appear to be particularly susceptible, which may have a genetic basis (Reinhart et al., 2018).

In contrast to most other sulfonamide‐related morbidities, keratoconjunctivitis sicca (KCS) is a fairly common occurrence in dogs, with a reported incidence of 15% (Berger et al., 1995). Sulfonamide‐associated KCS also appears to be more common in small breeds and is delayed in onset relative to other manifestations, occurring months after initiation of antimicrobial therapy. There is also evidence that some sulfonamide antimicrobials may be directly toxic to the lacrimal gland mediated by a pyrimidine or pyridine ring in the R‐group structure. In these ways, sulfonamide‐associated KCS may be a separate reaction with a distinct pathogenesis, rather than part of the classic idiosyncratic hypersensitivity. However, KCS can occur in combination with other classic signs of sulfonamide hypersensitivity, so the classification of this adverse reaction remains unclear.

Accidental overdose of sulfaquinoxaline in a juvenile broiler flock resulted in hemorrhage and renal tubular injury (Fulton and Buchweitz, 2023). Unlike other sulfonamides, sulfaquinoxaline is an inhibitor of the dithiothreitol‐dependent reduction of both vitamin K epoxide and vitamin K quinone, similar to coumarins and hydroxyquinones.

Administration and Dosage

Dosages for sulfonamide antimicrobials used in veterinary medicine are presented in Table 16.1 Although it has previously been recommended to double the dosage on the first day and some veterinary‐approved product labels include this recommendation, loading doses of sulfonamide antimicrobials are no longer commonly used in veterinary practice.

Although a large number of sulfonamide preparations are available for use in veterinary medicine, many of these are different dosage forms of sulfamethazine. This sulfonamide is most widely used in food‐producing animals and can attain effective plasma concentrations when administered either orally or parenterally. Because of their alkalinity, most parenteral preparations should be administered only by IV injection. Rapid IV injection of high doses of sulfonamide preparations should be avoided due to concerns for hypotension. At least one prolonged‐release oral preparation of sulfamethazine is available for use in calves and could be administered to sheep and goats. This is a convenient form of maintenance therapy in that a single dose provides an effective level for 36–48 hours. Different oral forms have different systemic availability.

Sulfadimethoxine preparations are used in small animals in addition to cattle. In dogs and cats, sulfadimethoxine is administered as an oral tablet or suspension. A 40% parenteral solution as well as oral bolus forms are available for use in cattle. In these species, sulfadimethoxine is usually administered at a dosage of 27.5 mg/kg daily. Also, a sustained‐release oral formulation is available for cattle in some countries.

Unlike the sodium salts of other sulfonamides, sodium sulfacetamide is nearly neutral. It is the only sulfonamide available for topical ophthalmic use. When a 30% solution is applied to the conjunctivae, it penetrates well and attains high concentrations in ocular fluids and tissues.

Clinical Use

Widespread resistance greatly limits the effectiveness of sulfonamides in treating bacterial diseases of animals, so that indications for primary use are few. Trimethoprim– or other antibacterial diaminopyrimidine–sulfonamide combinations have largely replaced sulfonamides as therapeutic agents used in companion animals, although resistance also increasingly limits their use. Purulent material must always be removed, since free purines neutralize the effect of sulfonamides. Primary uses include treatment of toxoplasmosis (when combined with pyrimethamine), of chlamydiosis, of Pneumocystis spp., and possibly of nocardiosis (combined with minocycline), and the use of sulfasalazine in the treatment of chronic colitis.

Environmental Impact

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