Sulfonamides

Question 1

Bacterial Folate Synthesis

Answer 1

Question 2

3 Sulfonamides

mimic:

competitively inhibit:

Answer 2

Sulfamethoxazole (SMX), sulfisoxazole, sulfadiazine

Mimics of PABA • Competitively inhibit dihydropteroate synthase

Question 3

3 Sulfonamides Resistance mechanism:

Answer 3

• Increased PABA • Altered dihydropteroate synthase • Decreased uptake

Question 4

Dapsone

sulfonamide?

competes with:

two main uses:

Answer 4

Not a sulfonamide

Competes with PABA for dihydropteroate synthase

Two main uses: • Mycobacterium leprae (leprosy) • Pneumocystis jiroveci

Question 5

Sulfonamides

usually given with:

sulfadiazine:

sulfadiazine + pyrimethamine:

Answer 5

Usually given with trimethoprim • TMP-SMX (Bactrim) • Sequential block of THF synthesis

Sulfadiazine • Silver-sulfadiazine (cream) for burns

Sulfadiazine and pyrimethamine • Also sequential block of THF synthesis • Used in toxoplasmosis (HIV)

Question 6

Sulfonamides Toxicity

Answer 6

Hypersensitivity reactions ~3% of patients

Reactions linked to: • Arylamine (NH2 ) at N4 position • Nitrogen ring attached to N1 nitrogen

Only sulfonamide antibiotics contain both features

Question 7

Sulfonamides Hypersensitivity (allergic) reactions

Answer 7

• Similar to penicillin allergic reactions • Anaphylaxis • Maculopapular rash • Serum sickness (fever, rash, arthritis) • Interstitial nephritis • Stevens-Johnson Syndrome • Toxic epidermal necrolysis, Photosensitivity**

Question 8

Sulfonamides Toxicity • Hemolysis in G6PD deficient patients

Answer 8

RBC susceptible to oxidative stress

Sulfonamides are oxidants - classic trigger for hemolysis

Other triggers: Dapsone

Question 9

Sulfonamides Toxicity

binds to:

_ in infants:

Answer 9

• Binds to albumin • Displaces other bound substances • Bilirubin • Warfarin (Raise warfarin levels)
• Kernicterus in infants • Sulfonamides → increased free bilirubin levels • Unconjugated bilirubin: neurotoxic to Basal ganglia& brainstem nuclei

Permanent neurologic impairment • Movement disorder (chorea, tremor) • Hearing loss • Limited gaze

Question 10

Trimethoprim/Pyrimethamine Mechanism of Action

Answer 10

• Inhibit dihydrofolate reductase • Similar structure to dihydrofolate

Question 11

Trimethoprim/Pyrimethamine Toxicity

Answer 11

• Preferentially inhibits bacterial DHF reductase • Some inhibition of human enzyme can occur • Inhibits DNA synthesis of rapidly dividing cells

Bone marrow suppression • Pancytopenia: megaloblastic anemia, leukopenia, ↓platelets

Can alleviate with leucovorin (folinic acid) • Converted to THF • Does not require dihydrofolate reductase • “Leucovorin rescue”

Question 12

TMP-SMX Bactrim

static or cidal?

coverage: does not cover:

common uses:

Answer 12

Combination is bactericidal

Covers many gram (+) and gram (-) • Does not cover pseudomonas • Does not cover B. fragilis (and most anaerobes) • Covers some fungi and parasites

Common uses: • UTI (covers E. Coli well) • Pneumocystis pneumonia in HIV (treatment/prophylaxis)

Question 13

TMP-SMX Pregnancy:

Answer 13

Risk of kernicterus • Disrupts folic acid metabolism

Question 14

Treatment of choice for Pneumocystis jirovecii:

Answer 14

• Treatment of choice: TMP-SMX but Hypersensitivity reactions: 6-25x higher in HIV • Alternative therapy often needed • Dapsone • Pentamidine • Atovaquone (malaria drug)