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sulfonamides AND resistance

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Merck Manual sulfonamides pharmacokinetics antibacterial spectrum

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https://www.merckmanuals.com/professional/infectious-disease…

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Sulfonamides: explanation of the slides

Sulfonamides, or “sulfa drugs,” are synthetic antimicrobial drugs. They are folate antagonists, meaning they stop bacteria from making folic acid, which bacteria need to make DNA and multiply.

1. Classification

The slide groups them by where and how long they act:
GroupExamplesMain idea
Orally absorbableSulfadiazine, sulfamethoxazole, sulfadoxineEnter blood after oral intake and act systemically
Orally non-absorbableSulfasalazineRemains mainly in the gut, used for inflammatory bowel disease
TopicalSilver sulfadiazine, mafenide, sulfacetamideApplied locally, especially to burns or eyes
Historically, absorbable drugs were divided by half-life:
  • Short acting: 4-8 hours
  • Intermediate acting: 8-12 hours
  • Long acting: about 7 days
This classification is useful for exams, but in current practice the important agents are usually:
  • Sulfamethoxazole, almost always combined with trimethoprim as co-trimoxazole or TMP-SMX
  • Sulfadiazine, combined with pyrimethamine for toxoplasmosis
  • Sulfasalazine, for ulcerative colitis and other inflammatory bowel diseases
  • Silver sulfadiazine or mafenide, for burn wound care

2. Mechanism of action

Bacteria must synthesize their own folate. Humans mainly obtain folate from food, so this pathway provides selective toxicity.

Normal bacterial folate pathway

PABA → dihydrofolic acid → tetrahydrofolic acid → DNA synthesis
Sulfonamides resemble PABA structurally. They competitively block the bacterial enzyme dihydropteroate synthetase.
So:
Sulfonamide competes with PABA
→ inhibits dihydropteroate synthetase
→ decreases bacterial folate
→ decreases purine and DNA synthesis
→ bacteria cannot continue to multiply
They are generally bacteriostatic, meaning they inhibit bacterial growth rather than directly killing bacteria. Lippincott Illustrated Reviews: Pharmacology, p. 1029.

Why TMP-SMX is effective

Trimethoprim blocks the next step in the same pathway: it inhibits dihydrofolate reductase.
Therefore:
  • Sulfamethoxazole blocks early folate synthesis
  • Trimethoprim blocks later folate activation
This sequential blockade makes the combination much more effective, and it is often bactericidal in practice.

3. Pharmacokinetics

Absorption

Most systemic sulfonamides are well absorbed orally, mainly from the small intestine, with some gastric absorption. Peak blood levels are generally reached in about 2-6 hours.
Exception: sulfasalazine
  • It is poorly absorbed from the intestine.
  • Colonic bacteria split it into 5-aminosalicylic acid (5-ASA) and sulfapyridine.
  • The 5-ASA produces the local anti-inflammatory effect in inflammatory bowel disease.

Distribution

Systemic sulfonamides:
  • Are distributed widely in tissues and body fluids
  • May enter CSF, pleural fluid, synovial fluid, and ocular fluid
  • Cross the placenta and reach the fetus
  • Bind plasma albumin to variable degrees

Metabolism and excretion

  • Mainly metabolized in the liver, including acetylation
  • Mainly eliminated through the kidneys by glomerular filtration
  • Dose adjustment may be required in significant renal impairment
Good hydration is important because some sulfonamides can precipitate in urine, producing crystalluria or renal injury. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, p. 1124.

4. Antimicrobial spectrum

Sulfonamides have activity against a mixture of Gram-positive and Gram-negative organisms, including some:
  • E. coli
  • Klebsiella
  • Enterobacter
  • Haemophilus influenzae
  • Staphylococcus
  • Streptococcus
  • Nocardia
They also have roles against certain non-bacterial organisms:
  • Toxoplasma gondii: sulfadiazine + pyrimethamine
  • Plasmodium: sulfadoxine + pyrimethamine in selected malaria settings
  • Pneumocystis jirovecii: TMP-SMX
  • Cyclospora and Cystoisospora: TMP-SMX
However, the slide’s “broad spectrum” statement needs an important clinical qualification: resistance is now widespread, so susceptibility cannot be assumed. Current use should be based on local resistance patterns and culture results where possible. Merck’s sulfonamide review notes that resistance to one sulfonamide generally implies resistance to the others.

Important lack of activity

TMP-SMX is not reliably active against:
  • Pseudomonas aeruginosa
  • Anaerobes
  • Mycoplasma
  • Mycobacterium tuberculosis
  • Treponema pallidum
  • Group A streptococcal pharyngitis
So sulfonamides should not be used for streptococcal sore throat. Merck’s TMP-SMX guidance also emphasizes resistance among many urinary and respiratory pathogens.

5. Resistance mechanisms

Bacteria become resistant by:
  1. Altered dihydropteroate synthetase, so the drug no longer binds well
  2. Reduced drug entry or increased efflux from the bacterial cell
  3. Increased PABA production, which outcompetes the drug
  4. Using an alternate metabolic pathway
Resistance to one sulfonamide usually means resistance to the entire sulfonamide class. Lippincott Illustrated Reviews: Pharmacology, p. 1029.

6. Important adverse effects and precautions

High-yield adverse effects include:
  • Rash and photosensitivity
  • Severe hypersensitivity reactions, including Stevens-Johnson syndrome
  • Drug fever
  • Hemolytic anemia in G6PD deficiency
  • Crystalluria and renal injury
  • Bone marrow toxicity, such as leukopenia or thrombocytopenia
  • Bilirubin displacement from albumin

Avoid or use carefully in

  • Infants younger than 2 months
  • Late pregnancy and breastfeeding in some situations
  • Severe renal impairment
  • Sulfonamide allergy
  • G6PD deficiency
The bilirubin displacement issue can cause kernicterus in neonates, which is why sulfonamides are avoided near term and in very young infants.

One-line exam summary

Sulfonamides are bacteriostatic PABA analogues that inhibit bacterial dihydropteroate synthetase, blocking folate and DNA synthesis; their major modern use is usually in combination with trimethoprim as TMP-SMX.
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