Antibiotics II - inhibitors of nucleic acid synthesis

Question 1

Targets of inhibitors of nucleic acid synthesis?

Answer 1

Targets of nucleic acid synthesis inhibitors:

a. Topoisomerases: regulate supercoiling of DNA and mediate segregation of replicated strands. [a] Type II = DNA gyrase [b] = Type IV
b. Folates
c. RNA polymerase - transcribe DNA to RNA: initiation, elongation, and termination

Question 2

Inhibitors of topoisomerases/replication:

Class?

2nd gen drugs?

3rd gen drugs?

4th gen drugs?

Answer 2

Inhibitors of topoisomerases/replication:

Quinolones

2nd Gen: Ciprofloxacin

3rd Gen: Levofloxacin

4th Gen: Moxifloxacin

Question 3

Quinolones:

1. Target in G+?
2. Target in G-?
3. Bacteri_____.

Answer 3

Quinolones:

1. G+: Topoisomerase IV: blocks decatenation (unlinking) of daughter chromosomes
2. G-: Topoisomerase II (DNA gyrase); inhibits gyrase-mediated negative supercoiling and impacts DNA replication, repair, and transcription
3. Bactericidal: although we have topoisomerases they have a greater affinity for bacteria especially because they are more actively growing

Question 4

Quinolones:

General uses?

Answer 4

Quinolones

General use: broad spectrum that will treat G-/+ and atypical. Overuse drives resistance (generally G-). UTI/prostatis (not Moxifloxacin) and GI tract infections caused by GNR (pseudomonas, E.coli, campylobacter jejuni, salmonella, and shigella)

Question 5

Quinolones:

Ciprofloxacin uses?

Answer 5

Quinolones:

Ciprofloxacin:

a. complicated UTI
b. Bacillis anthracis (G+) infection/exposure
c. Pneumonia and bronchitis due to G- aerobes
d. Legionella pneumoniae G-
e. Mycoplasma pneumoniae (no cell wall)

Question 6

Quinolones:

Levofloxacin uses?

Answer 6

Quinolones:

Levofloxacin:

a. complicated UTI
b. Pneumonia and bronchitis due to G- aerobes
c. CAP
d. Strep pneumoniae G+ with high PCN resistance

Question 7

Quinolones:

Moxifloxacin use?

Answer 7

Quinolones:

Moxifloxacin:

a. CAP
b. Strep pneumoniae G+ with high PCN resistance

Question 8

Quinolones:

1. Moxifloxacin kinetics?
2. Antagonism?
3. Additive?

Answer 8

Quinolones:

1. Moxifloxacin - hepatic elimination, not for UTI
2. Antagonism: metals chelate and block absorption (antacids/supplements); also quinolones slow metabolism of theophylline/caffiene - build up of theophylline causes N/V and CNS effects (tremor, agitation)
3. Additive: Contraindicated: Antiarrhythmics - patients taking drugs prolonging QTc interval

Question 9

Quinolones:

Adverse effects?

Answer 9

Quinolones:

Adverse effects:

a. GI: anorexia, pain, and N/V
b. CNS: HA, nervousness, insomnia, peripheral neuropathy, and increased risk of seizures with NSAIDs and theophylline
c. Cardio: QTc prolongation: DONT USE CLASS 3Antiarrhyth.
d. Tendinitis: and risk of spontaneous tendon rupture - especially those on corticosteroids. Most commone with ciprofloxacin. FDA black box warning.

Question 10

Quinolones:

Resistance?

Contraindications?

Answer 10

Quinolones:

Resistance:

a. Mutation of target - the drug wont bind
b. Efflux pump in G-
c. NO chemical modifications of quinolones

Contra: kids, pregnant, or nursing women (except kids with CF)

Question 11

Inhibitors of folate metabolism:

Drugs/classes?

Answer 11

Inhibitors of folate metabolism:

a. Sulfonamides - sulfamethoxazole
b. Trimethoprim
c. Combination trimethoprim/sulfamethoxazole (TMP-SMX)

Question 12

Sulfonamides/Sulfamethoxazole:

1. MOA?
2. Use?
3. Interactions?

Answer 12

Sulfonamides/Sulfamethoxazole:

1. MOA: PABA analog: reversibly inhibits dihydropteroate synthetase (DHPS) conversion of dihydropteroate diphosphate to dihydrofolic acid. Bacteriostatic
2. Use: UTI
3. Interactions: [a] potentiates anticoagulants [b] increased risk of crystalluria with methenamine (another UTI drug)

Question 13

Sulfonamides/Sulfamethoxazole:

1. Adverse effects?
2. Contraindications?
3. Resistance?

Answer 13

Sulfonamides/Sulfamethoxazole:

1. AE: hypersensitivity (fever, rash, photosensitivity, stomatitis), hemolytic anemia if G6P dehydrogenase deficient, and GI distress/anorexia
2. Contraindications: pregnant/lactating women and infants due to risk of bilirumin displacement, jaundice, and kernicterus
3. Resistance: common and thus rarely used alone

Question 14

Trimethoprim:

1. MOA?
2. Use?
3. Resistance?

Answer 14

Trimethoprim:

1. MOA: selectivly inhibits bacterial DHFR conversion of dihydrofolic acid to THF acid. Bacteriostatic
2. Use: uncomplicated UTI
3. Resistance: rapidly increasing due to decreased permeability, overexpression of DHFR, mutated DHFR, and overproduction of PABA

Question 15

Trimethoprim/Sulfamethoxazole Combination:

1. MOA?
2. Uses?
3. Interactions?

Answer 15

Trimethoprim/Sulfamethoxazole Combination:

1. MOA: inhibits both steps. Becomes BACTERIOCIDAL
2. Uses: almost exclusively UTI, acute exacerbation of chronic bronchitis, GI infections (salmonella, shigella), beta-lactam resistant ear infections, and opportunistic infections in AIDS (nocardia)
3. Interactions: other antifolates (methotrexate/trimetrexate) - additive antifolate activity in humans

Question 16

Trimethoprim/Sulfamethoxazole Combination:

Adverse effects?

Answer 16

Trimethoprim/Sulfamethoxazole Combination:

Adverse effects:

a. Adverse effects of sulfamethoxazole (hypersensitivity/anemia/GI distress)
b. Antifolates - megaloblastic anemia, leukocytopenia, granulocytopenia, HA (if G6PD deficient) - offset with supplemental folinic acid.
c. Nephrotoxicity - avoid in renal impaired
d. Both can cause steven-johnson syndrome
e. Avoid warfarin