Sulfonamides and Trimethoprim

The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. The primary indication for use is treatment of urinary tract infection (although significant resistance has emerged). In addition, the drugs are used to treat and prevent opportunistic infections such as toxoplasmosis encephalitis and pneumocystis pneumonia in immunosuppressed individuals. The most common adverse events are hypersensitivity reactions, fever, rash, GI upset, and hematologic reactions. The drugs are generally contraindicated in pregnancy, young/ill infants, and individuals with megaloblastic anemia or severe renal impairment.

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Sulfonamide antibiotics are antimicrobial drugs containing a sulfonamide functional group.

  • Sulfamethoxazole is the prototypical drug in the class.
  • Other sulfonamide antibiotics include:
    • Sulfadiazine
    • Sulfisoxazole
  • Many other sulfonamide drugs are not antimicrobial:
    • Sulfasalazine (treats Crohn’s disease)
    • Sulfonylureas (antidiabetic agents such as glipizide)
    • Some diuretics (e.g., acetazolamide, chlorthalidone, furosemide, and hydrochlorothiazide)
    • Some antiviral and antiretroviral medications
    • Some COX-2 inhibitors

Drugs with a mechanism of action similar to sulfonamide antibiotics (but not technically sulfonamides):

  • Trimethoprim
  • Dapsone
  • Pyrimethamine

Combination drugs (work synergistically):

  • Trimethoprim-sulfamethoxazole (TMP-SMX) (sold commercially as Septra and Bactrim)
  • Erythromycin-sulfisoxazole

Chemistry and Pharmacodynamics

Chemical structure

Sulfonamide antibiotics contain a sulfonamide functional group, which is a sulfur bonded to:

  • 2 separate oxygen molecules, each via a double bond
  • 1 nitrogen
  • 1 R-group side chain

Mechanism of action

Sulfonamides, trimethoprim, dapsone, and pyrimethamine disrupt folic acid synthesis in microbes. 

  • Folic acid synthesis:
    • Dihydropteroate synthase converts para-aminobenzoic acid (PABA) to dihydrofolate.
    • Dihydrofolate reductase converts dihydrofolate to tetrahydrofolate.
    • Tetrahydrofolate is used to synthesize purines, which are required for DNA synthesis.
    • Humans get tetrahydrofolate from the diet, however single-celled organisms must synthesize tetrahydrofolate.
  • Sulfonamides and dapsone: 
    • Structural analogs of PABA
    • Compete with PABA in binding to bacterial dihydropteroate synthase (competitive inhibition) → blocks the conversion of PABA to dihydrofolate
    • ↓ Dihydrofolate → ↓ tetrahydrofolate → bacteria cannot synthesize purines →  interrupts bacterial DNA synthesis
  • Trimethoprim and pyrimethamine:
    • Inhibit dihydrofolate reductase:
      • Trimethoprim: selectively binds bacterial dihydrofolate reductase
      • Pyrimethamine: selectively binds parasitic dihydrofolate reductase
    • Blocks the formation of tetrahydrofolate from dihydrofolate
    • ↓ Dihydrofolate → ↓ tetrahydrofolate → bacteria cannot synthesize purines →  interrupts bacterial DNA synthesis
  • Drugs are bacteriostatic when given independently, but bactericidal when given in combination:
    • TMP-SMX
    • Sulfadiazine + pyrimethamine
Mechanism of action of sulfonamides and trimethoprim in the folic acid pathway

Mechanism of action of sulfonamides and trimethoprim in the folic acid pathway

Image by Lecturio. License: CC BY-NC-SA 4.0

Mechanisms of resistance

  • Some bacteria use exogenous folate → not dependent on folate synthesis from PABA → no susceptibility to sulfonamides
  • Mutations leading to overproduction of substrates or enzymes:
    • ↑ PABA → sulfonamide resistance
    • ↑ Dihydrofolate reductase → trimethoprim resistance
  • Mutations and/or plasmids encode genes with an altered drug binding site → ↓ affinity:
    • Dihydropteroate synthetase with low sulfonamide affinity
    • Dihydrofolate reductase with low trimethoprim affinity
  • Impairs permeability to the drugs



  • TMP-SMX: 
    • Locations:
      • Middle ear
      • Sputum and bronchial secretions
      • Prostatic and vaginal fluid
      • CSF
      • Crosses the placenta (teratogenic)
    • TMP is more lipid soluble than SMX → formulated in a 1:5 ratio, resulting in optimal concentration for synergistic effect 
  • Pyrimethamine: 
    • Kidneys
    • Lung
    • Liver
    • Spleen

Absorption, metabolism, and elimination

  • Absorption: generally well absorbed by oral administration
  • Protein binding: All are protein bound (ranging from 40%–90%): 
    • SMX: 70%
    • TMP: 45%
    • Dapsone: 70%–90%
    • Pyrimethamine: 87% 
  • Metabolism:
    • Some hepatic metabolism
    • SMX undergoes hydroxylation via CYP2C9.
  • Elimination:
    • Renal: unchanged drug and metabolites
    • Half-life: intermediate to long (prolonged in renal failure):
      • TMP-SMX: 9–12 hours 
      • Dapsone: 28 hours
      • Pyrimethamine: 80–95 hours


Spectrum of activity: TMP-SMX

Due to significant resistance, especially against TMP-SMX, the agents are best used after antibiotic-susceptibility testing. Activity may be against:

  • Gram-positive bacteria:
    • Staphylococcus (including MRSA)
    • Streptococcus (unreliable coverage, significant resistance against S. pneumoniae
  • Gram-negative bacteria:
    • Enterobacteriaceae:
      • Escherichia coli (significant resistance)
      • Klebsiella
      • Enterobacter
      • Salmonella
      • Shigella
    • Haemophilus influenzae
    • Morganella
    • Chlamydia 
    • Neisseria
  • Opportunistic pathogens:
    • Pneumocystis jiroveci
    • Toxoplasma gondii
    • Nocardia
  • Organisms NOT covered by TMP-SMX:
    • Pseudomonas aeruginosa
    • Rickettsia

TMP-SMX indications

  • Urinary tract infections:
    • Primary indication for TMP-SMX
    • Increasing resistance to E. coli
  • Prostatitis
  • Chronic obstructive pulmonary disease (COPD) exacerbations
  • Acute otitis media
  • Travelers diarrhea caused by E. coli
  • Systemic salmonella
  • Shigellosis
  • Pneumocystis pneumonia (treatment and prophylaxis)
  • Off-label use:
    • Bite wounds
    • Cellulitis with high risk for MRSA
    • Meningitis and intracranial abscesses
    • Osteomyelitis and prosthetic joint infections

Dapsone indications

  • Leprosy
  • Prophylaxis and treatment in individuals with HIV against:
    • Toxoplasmic encephalitis
    • Pneumocystis pneumonia
  • Dermatologic conditions:
    • Dermatitis herpetiformis
    • Autoimmune bullous dermatoses (e.g., pemphigus vulgaris, bullous pemphigoid)
    • Relapsing polychondritis
    • Dermatologic manifestations of systemic lupus erythematosus (SLE)

Pyrimethamine indications

  • Prophylaxis and treatment in individuals with HIV against:
    • Toxoplasmic encephalitis (in combination with a sulfonamide (e.g., sulfadiazine))
    • Pneumocystis pneumonia
  • Cystoisosporiasis

Adverse Effects and Contraindications

Adverse effects

  • Hypersensitivity reactions
  • Fever
  • Dermatologic reactions:
    • Rashes
    • Exfoliative dermatitis
    • Photosensitivity
    • Stevens-Johnson syndrome
  • Nausea, vomiting, and/or diarrhea
  • Crystalluria (at neutral or acidic urinary pH)
  • Hematologic reactions:
    • Hemolytic anemia (especially in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency)
    • Megaloblastic anemia
    • Aplastic anemia
    • Granulocytopenia
    • Thrombocytopenia


  • Hypersensitivity to sulfa drugs
  • Megaloblastic anemia due to folate deficiency
  • G6PD deficiency
  • Infants < 2 months of age
  • Severe renal disease
  • Pregnancy (especially in the 1st trimester due to ↑ risk of neural tube defects)
  • Lactation if the infant is:
    • < 1 month of age
    • Jaundiced, premature, or ill
    • G6PD deficient

Comparison of Antibiotics

Comparison based on mechanism of action

Antibiotics can be classified in several ways. One way is to classify antibiotics by mechanism of action.

Table: Antibiotics classified by primary mechanism of action
MechanismClass of antibiotics
Bacterial cell wall synthesis inhibitors
  • Penicillins
  • Cephalosporins
  • Penems
  • Miscellaneous
Bacterial protein synthesis inhibitors
  • Tetracyclines
  • Macrolides
  • Ketolides
  • Lincosamides
  • Streptogramins
  • Linezolid
Agents acting against DNA and/or folate
  • Sulfonamides
  • Trimethoprim
  • Fluoroquinolones
Antimycobacterial agents
  • Tuberculosis agents
  • Leprosy agents
  • Atypical mycobacterium agents

Comparison based on coverage

Different antibiotics have varying degrees of activity against different bacteria. The table below outlines the antibiotics with activity against 3 important classes of bacteria: gram-positive cocci, gram-negative bacilli, and anaerobes.

Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0


  1. May, D. B. (2020). Trimethoprim-sulfamethoxazole: An overview. In Mitty, J. (Ed.), UpToDate, Retrieved July 19, 2021 from 
  2. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved July 19, 2021 from:
    1. Trimethoprim-sulfamethoxazole (co-trimoxazole): 
    2. Dapsone: 
    3. Pyrimethamine: 
    4. Sulfadiazine: 
  3. Kemnic, T. (2021). Trimethoprim sulfamethoxazole. In StatPearls. Retrieved July 19, 2021 from 
  4. Kurien, G. (2021). Dapsone. In StatPearls. Retrieved July 19, 2021 from

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