Sulfonamides: What are they? Clinical Uses, Mechanism of Action and Adverse Effects

People get folic acid from their diet, but bacteria need to synthesize it.

Sulfonamides are a group of synthetic drugs that contain the chemical group sulfonamide.

Sulfonamide-based antimicrobials work by interfering with the synthesis of folic acid in bacteria, which is essential for the formation of nucleic acids and ultimately DNA and RNA.

When used alone, sulfonamide antibiotics are bacteriostatic (the bacteria reproduce, but do not necessarily kill them); however, in combination with trimethoprim (cotrimoxazole), which acts on a different enzyme in the pathway of folic acid synthesis, sulfonamides become bactericidal (kill bacteria).

Many sulfonamides are rapidly excreted and highly soluble in urine, which is why they are used to treat urinary tract infections. Not all sulfonamides have antibacterial activity. Thiazide, furosemide, acetazolamide, sulfonylureas, and some COX-2 inhibitors are also sulfonamides.

Clinical use

Sulfonamides were previously widely used, alone or in combination with trimethoprim, for the treatment of urinary tract infection, but are no longer recommended due to possible adverse reactions.

The use in the treatment of respiratory infections is now limited to a few special problems, notably nocardiasis (and also for brain nocardiasis) and, in combination with trimethoprim in the prevention and treatment of pneumonia due to Pneumocystis jiroveci.

The value of sulfonamides in the prophylaxis and treatment of meningococcal infection is now greatly reduced by bacterial resistance.

Sulfonamides are sometimes used for chlamydia and chancroid infections but are not reliable. Some formulations are used topically for eye infections and bacterial vaginosis.

Combination preparations with pyrimethamine are used in the treatment of drug-resistant malaria and for toxoplasmosis.

Mechanism of action

Sulfonamides are structural analogs of amino benzoic acid (PABA) and therefore act as competitive antagonists in microbial cells.

Microbes need PABA to form dihydrofolic acid, a precursor to folic acid.

Folic acid is necessary for the synthesis of purines and pyrimidines and therefore the synthesis of nucleic acids.
Sulfonamides not only block the formation of folic acid: they are incorporated into the precursors, forming a pseudometabolite that is reactive and antibacterial.

Mammalian cells are not susceptible to sulfonamides as they absorb and use preformed folic acid, resulting in a broad therapeutic index.

The combination of sulfonamides with trimethoprim or other diaminopyrimidines enhances their activity.

Trimethoprim enters bacteria and inhibits bacterial dihydrofolic acid reductase, thus acting on the same metabolic pathway as sulfonamides.

Therefore, the combination has synergistic activity. The binding affinity of trimethoprim is much higher for the bacterial enzyme than for the mammalian enzyme; therefore, selective bacterial toxicity occurs.

Sulfonamides do not appear to antagonize the bactericidal effects of penicillins, but should not be used with procaine benzylpenicillin (procaine penicillin), as procaine is a PABA analog and will antagonize the antibacterial action of sulfonamide.


Sulfonamides have a bacteriostatic effect by inhibiting the synthesis of bacterial folic acid.

Important representatives of this group are sulfadiazine, sulfadoxine, sulphalene, sulfamerazine, sulfamethizole, and sulfamethoxazole.

For local applications, silver sulfadiazine is used for burns and sulfacetamide for eye infections.

Sulfonamides reach 50-90% of the maternal concentration in the fetus and compete with bilirubin for binding sites on albumin.

Currently, sulfonamides are rarely used as monotherapy because their spectrum is limited and resistance develops rapidly.

In combination with a folate antagonist such as trimethoprim or pyrimethamine), sulfonamides are indicated, among others, in the treatment of toxoplasmosis and malaria.

The fixed combination of sulfonamide sulfamethoxazole and trimethoprim is available as cotrimoxazole.

Both agents in this combination are not subject to pregnancy-induced clearance variation that would require dose modifications.

Trimethoprim is effective as monotherapy in uncomplicated urinary tract infections with sensitive pathogens.


Sulfonamides are highly protein bound, so drug interactions can occur if sulfonamides displace other drugs from plasma protein binding sites.

This can lead to adverse effects when used with medications such as warfarin , non-steroidal anti-inflammatory drugs, and sulfonylureas.

Sulfonamides are contraindicated in short-term pregnant women and infants younger than 2 months because these drugs displace bilirubin from protein-binding sites in newborns.

Hyperbilirubinemia in newborns can cause kernicterus (central nervous system disorders caused by high levels of bilirubin).


Bacteria develop resistance to sulfonamides in the following ways:

  • Reduction of bacterial absorption of drugs.
  • Development of alternative metabolic pathways to synthesize folic acid.
  • Production of excessive amounts of para-amino benzoic acid (up to 70 times normal) to compete with sulfonamides for the synthesis of folic acid.
  • Alterations or mutations in dihydropteroate synthase, the enzyme that catalyzes the rate-limiting step of folate synthesis.

Adverse effects

Sulfonamides predispose patients to photosensitivity. Bone marrow suppression may occur, including hemolytic anemia, leukopenia, and thrombocytopenia .

There is an increased risk of adverse haematological effects in patients who are genetically deficient in G6PD. Sulfonamides can precipitate in the kidneys, causing kidney stones; good hydration prevents this.

Other miscellaneous effects include hepatotoxicity, pseudomembranous colitis, and hypersensitivity reactions, including Stevens-Johnson syndrome .

Due to chemical similarities, patients who are allergic to sulfonamides may also be hypersensitive to sulfonylureas, thiazide diuretics, and sunscreens that contain para-amino benzoic acid.