Sulfonamides

Definition and Overview
Sulfonamides, commonly referred to as sulfa drugs, constitute a group of synthetic antimicrobial agents that contain the sulfonamide group (-SO2NH2) in their structure. They were among the first antibiotics developed and have played a pivotal role in the treatment of bacterial infections since the 1930s. While their usage has declined due to the development of newer, safer, and more effective antibiotics, sulfonamides remain clinically important in specific indications, especially in urinary tract infections (UTIs), Pneumocystis jirovecii pneumonia (PJP), toxoplasmosis, nocardiosis, and certain autoimmune skin disorders.

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Mechanism of Action

Sulfonamides are bacteriostatic antibiotics that work by:

• Inhibiting the enzyme dihydropteroate synthase (DHPS) in the folic acid synthesis pathway.

• This prevents bacteria from synthesizing tetrahydrofolic acid, which is essential for nucleic acid synthesis.

• Humans are unaffected since they obtain folic acid through diet and lack DHPS, providing selective toxicity.

When combined with trimethoprim, which inhibits dihydrofolate reductase, the combination becomes bactericidal (e.g., cotrimoxazole).

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Classification of Sulfonamides

Sulfonamides can be classified based on their route of administration and site of action:

1. Systemic Antibacterial Sulfonamides

• Used orally or intravenously for systemic infections

Generic Name	Brand Name(s)	Notes
Sulfamethoxazole	In combination only	Used in cotrimoxazole (with trimethoprim)
Sulfadiazine	—	Used in toxoplasmosis
Sulfisoxazole	Gantrisin (U.S.)	Mostly discontinued
Sulfadoxine	With pyrimethamine	Used in malaria (Fansidar)

2. Topical Sulfonamides

• Used in burns and wound infections

Generic Name	Brand Name(s)	Notes
Silver sulfadiazine	Flamazine, Silvadene	Topical burn treatment
Sulfacetamide sodium	Bleph-10, Klaron	Ophthalmic and dermatologic use

3. Non-antibacterial Sulfonamides

• Retain the sulfonamide structure but are not used as antimicrobials

Drug Class	Examples
Thiazide diuretics	Hydrochlorothiazide
Loop diuretics	Furosemide
Sulfonylureas	Glipizide, Glyburide
Carbonic anhydrase inhibitors	Acetazolamide
COX-2 inhibitors	Celecoxib

These are important due to potential cross-reactivity in sulfa-allergic individuals.

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Clinical Uses

Condition	Preferred Sulfonamide(s)
Urinary tract infections (UTIs)	Cotrimoxazole (SMX-TMP)
Pneumocystis jirovecii pneumonia	Cotrimoxazole (treatment & prophylaxis)
Toxoplasmosis	Sulfadiazine + Pyrimethamine
Malaria (chloroquine-resistant)	Sulfadoxine + Pyrimethamine (Fansidar)
Nocardiosis	Cotrimoxazole
Burn infections	Silver sulfadiazine
Seborrheic dermatitis, acne	Sulfacetamide sodium (topical)

Common Formulations and Dosing

1. Cotrimoxazole (Trimethoprim + Sulfamethoxazole)

• Standard ratio: 1:5 (e.g., 80 mg TMP + 400 mg SMX)

• Dosing:

  • Prophylaxis (PJP): 1 SS tablet daily

  • Treatment (UTI or PJP): 1 DS tablet every 12 hours for 7–14 days

2. Silver Sulfadiazine

• 1% cream applied topically once or twice daily to burn wounds

3. Sulfadiazine for Toxoplasmosis

• 1 gram orally 4 times daily, with pyrimethamine and leucovorin

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Adverse Effects

System Affected	Adverse Effects
Hypersensitivity	Rash, Stevens–Johnson syndrome, TEN
Hematologic	Agranulocytosis, hemolytic anemia (esp. in G6PD deficiency), aplastic anemia
Renal	Crystalluria, interstitial nephritis
Gastrointestinal	Nausea, vomiting
Hepatic	Hepatitis, elevated liver enzymes
Photosensitivity	Seen with sulfonamides like sulfamethoxazole
Neurological	Headache, depression, hallucinations (rare)

Contraindications

• Sulfonamide allergy

• Pregnancy (late term) – risk of kernicterus in neonates

• Neonates and infants <2 months

• Severe renal or hepatic insufficiency

• G6PD deficiency – high risk of hemolysis

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Drug Interactions

Interacting Drug	Interaction/Effect
Warfarin	Enhanced anticoagulant effect, ↑ INR
Methotrexate	Increased toxicity due to protein-binding competition
Phenytoin	Increased levels of phenytoin
Oral hypoglycemics	Potentiation of hypoglycemic effect
ACE inhibitors/ARBs	Increased risk of hyperkalemia with SMX-TMP
Cyclosporine	Increased nephrotoxicity
Digoxin	Levels may be increased with SMX-TMP

Precautions

• Hydration: Ensure adequate fluid intake to prevent crystalluria

• Monitor blood counts: Especially during long-term use

• Monitor liver and renal function during treatment

• Watch for early signs of hypersensitivity

• Use caution in elderly and those on multiple interacting drugs

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Resistance

• Resistance arises from:

  • Altered dihydropteroate synthase enzyme

  • Overproduction of PABA (competes with sulfonamide)

  • Decreased permeability or active efflux

• Resistance patterns vary by region; cotrimoxazole resistance in E. coli is increasing

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Pharmacokinetics

Parameter	Description
Absorption	Rapid and complete (oral agents)
Distribution	Widely distributed; crosses placenta and BBB
Protein binding	High for sulfamethoxazole
Metabolism	Hepatic acetylation
Excretion	Primarily renal
Half-life	Sulfamethoxazole: ~10 hours

Use in Special Populations

• Pregnancy: Avoid especially in 3rd trimester

• Breastfeeding: Avoid in newborns or if infant has jaundice

• Elderly: Higher risk of adverse effects, especially kidney injury and hyperkalemia

• G6PD-deficient patients: High risk for hemolysis; contraindicated

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Summary Table: Key Sulfonamides

Agent	Use	Route	Key Notes
Sulfamethoxazole	With trimethoprim (SMX-TMP)	Oral/IV	UTI, PJP, nocardiosis
Sulfadiazine	Toxoplasmosis	Oral	Used with pyrimethamine
Silver sulfadiazine	Burns	Topical	Not for facial use
Sulfacetamide sodium	Acne, eye infections	Topical	Ophthalmic, dermatologic use