Sulfonamides

Question 1

What is a sulfonamide group?

Answer 1

SO₂-N

Question 2

What is a “sulfa” drug?

Answer 2

Contains a sulfonamide group

Question 3

Describe bacterial folate synthesis

Answer 3

Question 4

Sulfonamide antibiotics MOA

Answer 4

Competively Inhibit the enzyme Dihydropteroate Synthase preventing PABA from becoming Dihydropteroic acid and thereby inhibiting DNA synthesis

Question 5

Trimethoprim MOA

Answer 5

Inhibits Dihydrofolate Reductase thereby preventing dihydrofolic acid from forming tetrahydrofolate thus inhibiting DNA synthesis

Question 6

Pyrimethamine MOA

Answer 6

Inhibits Dihydrofolate Reductase thereby preventing dihydrofolic acid from forming tetrahydrofolate thus inhibiting DNA synthesis

Question 7

List of Sulfonamide antibiotics

Answer 7

• Sulfamethoxazole (SMX)
• Sulfisoxazole
• Sulfadiazine

Question 8

What are Sulfonamide antibiotics?

Answer 8

mimics of PABA that Competitively inhibit dihydropteroate synthase

Question 9

Mechanisms of Resistance to sulfonamide antibiotics

Answer 9

• increase amount of PABA inside the cell
• Altered dihydropteroate synthase
• Decreased uptake of the drug

Question 10

Another drug that competes with PABA for dihydropteroate Synthase that is not a sulfonamide?

Answer 10

Dapsone

Question 11

What is Dapsone?

Answer 11

NOT a sulfonamide

Competitively inhibits dihydropteroate synthase

Question 12

Clinical uses of Dapsone?

Answer 12

• Mycobacterium leprae (leprosy)
• Pneumocystitis jiroveci

Question 13

Clinical applications of sulfonamide antibiotics

Answer 13

Sulfamethoxazole is usually given with trimethoprim

• TMP-SMX (Bactrim)
  
  • Sequential block of THF synthesis

Sulfadiazine

• Silver-sulfadiazine (cream) for burns

Sulfadiazine and Pyrimethamine

• sequential block of THF synthesis
  
  • used in toxoplasmosis (HIV)

Question 14

Adverse effects of sulfonamide antibiotics

Answer 14

• Hypersensitivity reaction 3% of pts
• reactions linked to
  
  • Arylamine (NH2) at N4 position
  • Nitrogen ring attached to N1 nitrogen
  • Only sulfonamide antibiotics contain both features
• Hypersensitivity reactions include like PCN
  
  • anaphylaxis
  • delayed maculopapular rash
  • serum sickness
  • interstitial nephritis
  • Stevens-Johnson Syndrome or TEN
• Photosensitivity
  
  • drug interaction with UV light
  • Caused by many drugs such as tetracycline, sulfonamides and amiodarone
• Hemolysis in G6PD deficient patients
  
  • sulfonamides are oxidants so act as a trigger
  • Dapsone is also a trigger
• binds to albumin and displace other bound substances such as bilirubin or warfarin
  
  • Kernicterus in infants (sulfonamides increase free bilirubin levels) unconjugated bilirubin is neurotoxic (basal ganglia, brainstem nuclei)
    
    • Permanent neurologic impairment
    • movement disorders (chorea, tremor)
    • Hearing loss
    • Limited gaze
  • Raise warfarin levels so the INR may raise if Sulfonamides are taken, also because GI bacteria may be disrupted (any antibiotic can do this) from making Vitamin K2 leading to increased INR.

Question 15

Which antibiotics inhibit dihydrofolate reductase?

Answer 15

• Trimethoprim
• Pyrimethamine

Question 16

Trimethoprim and Pyrimethamine chemical structure

Answer 16

similar to dihydrofolate

Question 17

Trimethoprim and Pyrimethamine adverse effects

Answer 17

Trimethoprim and Pyrimethamine retain some activty against human DHF reductase so this inhibits the folate pathway in rapidly dividing human cells

• Bone marrow suppression
  
  • pancytopenia, megaloblastic anemia, leukopenia, decreased platelets

Can be alleviated with Leucovorin (folinic acid)

• converted to THF
• does not require dihydrofolate reductase
• “Leucovorin rescue”

Question 18

TMP-SMX bacterial effect

Answer 18

Each by themself are bacteriostatic but the Combination is bactericidal

Question 19

TMP-SMX coverage

Answer 19

• Covers many Gpos and Gneg
• Does NOT cover Pseudomonas
• Does NOT cover B. fragilis (and most anaerobes)
• Covers some fungi and parasites

Question 20

Common uses of TMP-SMX

Answer 20

• Urinary tract infections
• Pneumocystitis pneumonia in HIV (treatment/prophylaxis)

Question 21

TMP-SMX contraindications

Answer 21

• Pregnancy
  
  • Risk of Kernicterus w/ sulfonamides antibiotics
  • also trimethoprim can disrupt human folic acid metabolism

Question 22

PCP AKA

Answer 22

Pneumocystis Pneumonia

Question 23

What is Pneumocystis jirovecii?

Answer 23

an opportunitic fungal infection which occurs in end stage HIV/AIDS

Question 24

Treatment of choice for Pneumocystis jirovecii

Answer 24

TMP-SMX

Question 25

Considerations of TMP-SMX in Pneumocystis jirovecii infection

Answer 25

hypersensitivity reactions are 6-25x more likely in HIV alternative therapies may be needed

Question 26

Alternative therapies for Pneumocystis jirovecii

Answer 26

* Dapsone * Pentamidine * Atovaquone (malaria drug)