Antifolate Drugs and DNA Gyrase Inhibitors

Question 1

What type of drugs are sulfonamides?

Answer 1

Antifolate drugs

Question 2

What molecule are sulfonamides structural analogs of and what is the use of this molecule?

Answer 2

PABA, it is needed by organisms to form Dihydrofolic acid to produce purines

Question 3

What enzyme do sulfonamides inhibit and do they do it competitively or non-competitively?

Answer 3

Competitively inhibit dihydropteroate synthase (thus reversibly blocking folic acid synthesis)

Question 4

Are sulfonamides bacteriocidal or bacteriostatic?

Answer 4

Bacteriostatic

Question 5

Why are mammalian cells not affected by sulfonamides?

Answer 5

We lack the enzymes for folate synthesis (instead we use exogenous folate)

Question 6

Two gram-positive organisms that are susceptible to sulfonamides

Answer 6

Staphylococcus aureus, and Listeria

Question 7

5 gram-negative organisms that are susceptible to sulfonamides

Answer 7

Escherichia coli, Klebsiella, Salmonella, Shigella, Enterobacter

Question 8

Two protozoa that are susceptible to sulfonamides

Answer 8

Pneumocystis jiroveci (carinii), toxoplasma

Question 9

Two atypical bacteria that are suscpetible to sulfonamides

Answer 9

Nocardia, chlamydia

Question 10

Sulfonamides are not active against what type of bacteria?

Answer 10

Pseudomonas

Question 11

Three mechanisms of sulfonamide resistance

Answer 11

1) Overproduction of PABA, 2) Production of folic acid-synthesizing enzyme with low sulfonamide affinity, 3) Loss of permeability to sulfonamides

Question 12

Which sulfonamides are oral, absorbable (include the indication for each)

Answer 12

Sulfasoxazole and sulfamethoxazole (UTIs), Sulfadiazine (toxoplasmosis), sulfadoxine (malaria 2nd line)

Question 13

Which sulfonamides are oral, nonabsorbable (include the indication for each)

Answer 13

Sulfasalazine - ulcerative colitis, enteritis, other inflammatory bowel diseases

Question 14

Which sulfonamides are topical (include the indication for each)

Answer 14

Sodium sulfacetamide (ophthalmic) - conjuctivitis, Mafenide acetate - burn wounds, Silver sulfadiazine - burn wounds (less toxic than mafenide)

Question 15

Which sulfonamides are IV (include indications for each)

Answer 15

Sulfamethoxazole (in combination with trimethoprim) - pneumocystis pneumonia, shgellosis, salmonella, stenotrophomas, UTIs, prostatitis, tyhpoid

Question 16

How do sulfonamides cause hypoglycemia?

Answer 16

They can augment insulin release

Question 17

How do sulfonamides cause renal tubular acidosis?

Answer 17

They inhibit carbonic anhydrase

Question 18

Hematologic AEs of sulfonamides

Answer 18

Hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, hemolytic rxns in pts with G6PD deficiency

Question 19

Sulfonamides given in the third trimester might have what effect on the newborn?

Answer 19

Kernicterus

Question 20

Allergic rxns to sulfonamides

Answer 20

Type I (IgE), Serum sickness, Skin eruptions

Question 21

Idiosyncratic rxns to sulfonamides

Answer 21

Hepatitis, Stevens-Johnson, toxic epidermal necrolysis

Question 22

Sulfonamide antibiotics are cross-allergenic with what classes of drugs?

Answer 22

Carbonic anhydrase inhibitors, thiazides, furosemide, bumetanide, torsemide, diazoxide, sulfonylurea

Question 23

What enzyme does trimethoprim inhibit and what does this enzyme do?

Answer 23

Inhibits bacterial dihydrofolic acid reductase (converts dihydrofolic acid to tetrahydrofolic acid for folic acid synthesis)

Question 24

Indications for trimethoprim

Answer 24

UTIs

Question 25

What enzyme does pyrimethamine inhibit and what does this enzyme do

Answer 25

Inhibits dihydrofolic acid reductase in PROTOZOA. This is necessary for folic acid synthesis

Question 26

Indications for pyrimethamine

Answer 26

Toxoplasmosis, malaria, pneumocystis jiroveci pneumonia (2nd line)

Question 27

What is the effect of giving trimetoprim or pyrimethamine together with a sulfa drug?

Answer 27

Blocks sequential steps in purine synthesis, has bacteriCIDAL effect

Question 28

Mechanisms of trimethoprim/pyrimethamine resistance

Answer 28

1) Reduced cell wall permeability, 2) Overproduction of dihydrofolate reductase, 3) Production of altered dihydrofolate reductase (OFF: Resistance is often plasma encoded)

Question 29

AEs of trimethoprim and pyrimethamine

Answer 29

Megaoloblastic anemia, leukopenia, granulocytopenia (also nausea, vomiting, drug fever, vasculitis, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, hyponatremia) |S S p600

Question 30

What is used as prophylaxis to prevent hematologic side effects of trimethoprim and pyrimethamine?

Answer 30

Folinic acid (but dont use when treating pneumocystis pneumonia in AIDS pts)

Question 31

What is the trimethoprim-sulfamethoxazole combination not used much in URI or penumonia?

Answer 31

Increased resistance amongst pneumococci, also its not active against pseudomonas species

Question 32

In severe infections, the dosing of TMP-sulfametoxazole is based on which component?

Answer 32

The TMP component

Question 33

What is the mechanism of fluoroquinolones?

Answer 33

Inhibit bacterial topoisomerase II (DNA gyrase) and topoisomerase IV

Question 34

Which fluorquinolone is least affected by bacterial efflux pumps and why?

Answer 34

Moxifloxacin, has a bulky side chain

Question 35

Which tends to be more susceptible to fluoroquinolones, enterococci or staphylococci?

Answer 35

Staphylococci

Question 36

Which fluoroquinolones are active against atypical organisms (eg Chlamydia), intracellular pathogens (eg Legionella) and Tb and M. Avium complex?

Answer 36

All fluoroquinolones

Question 37

What type of drug is nalidixic acid and what is it used for?

Answer 37

A first generation fluoroquinolone, UTIs

Question 38

List second generation fluoroquinolones (six total, two important)

Answer 38

Cirpofloxacin (Cipro) and Levofloxacin (Levaquin). Also enoxacin, lomefloxacin, ofloxacin, pefloxacin

Question 39

Is ciprofloxacin most active against Gram-negative or Gram-positive organisms?

Answer 39

Gram-negative

Question 40

Which is better against Gram-positive organisms, ciprofloxacin or levofloxacin?

Answer 40

Levofloxacin

Question 41

List third generation fluoroquinolones (six total, two important)

Answer 41

Moxifloxacin (Avelox) and Gemifloxacin (Factive). Also clinafloxacin, gatifloxacin (tequin), sparfloxacin, and trovafloxacin (trovan)

Question 42

What is the main improvement from second to third generation fluoroquinolones?

Answer 42

Better activity against gram-positive organisms

Question 43

Which is better against gram-negative organisms, a 2nd or a 3rd generation fluoroquinolone?

Answer 43

Cipro (a 2nd gen) is better than the 3rd gens

Question 44

Which fluoroquinolone has the best anti-anaerobic activity?

Answer 44

Moxifloxacin (a 3rd generation)

Question 45

What type of medication should not be given within 2 hours of fluoroquinolone administration and why?

Answer 45

Antacids, they impair fluoroquinolone bioavailability

Question 46

Which fluoroquinolone does not require renal dose adjustment?

Answer 46

Moxifloxacin

Question 47

AEs of fluoroquinolones

Answer 47

Most minor. GI distress, headache, dizziness, insomnia, skin rash, abnormal LFTs, arthropathy, tendonitis, torsades de pointes, allergic rxns