Cushman Quinolones

Question 1

Quinolone MOA

Answer 1

Inhibition of DNA relegation in the topoisomerase-II DNA complex

Question 2

First generation Quinolones

Answer 2

Oxolinic and Nalidixic acid

Gram (-) activity

Do not achieve useful systemic concentrations and are only useful to treat lower UTI

DICONTINUED

Question 3

Second generation Quinolones

Answer 3

Ciprofloxacin: most potent fluoroquinolone showing MIC=0.01 to 1 ug/mL for Gram (-) organisms

Contain a fluorine substituent at C-6 and heterocyclic ring at C-7

Question 4

Third and Fourth generation Quinolones

Answer 4

Improved activity against gram (+) organisms, specifically streptococcus pneumoniae

Levofloxacin shows a 40-100 fold increase in potency over Nalidixic acid against most gram (-) organisms

MIC= 0.06-4 ug/mL

Moxifloxacin is considered last resort due to side effects

Question 5

Ozenoxacin

Answer 5

Ozenoxacin is used topically to treat impetigo due to staphylococcus aureus or streptococcus pyogenes in adults or pediatrics

Question 6

Delafloxacin

Answer 6

Oral or IV for treatment of skin infections caused by a wide variety of Gram (+) and Gram (-) bacteria, including MRSA

Question 7

Delafloxacin SE

Answer 7

Tendonitis, tendon rupture, peripheral neuropathy, CNS effects, exacerbation of myasthenia gravis

N/V/D have an incidence of greater than 2%

Question 8

Function of gyrases and topoisomerase

Answer 8

During DNA replication, strand separation of the double helix causes the DNA to twist, tangling and kinking the DNA

Gyrases and topoisomerase have evolved that untangle the DNA by cutting one strand (topo I) or two (topo II) strands, then allowing the DNA to twist

Topoisomerases and gyrases cleave DNA by carrying out a nucleophilic attack on a phosphodiester linkage, so one part of the strand becomes “free” and the other becomes enzyme-linked

Question 9

What are the mechanism features of gyrase, bacterial DNA topoisomerase IV, and mammalian topoisomerase II?

Answer 9

1. The dimeric enzyme binds duplex DNA and cleaves both opposing strands with a 4-base stagger.
2. Cleavage involves covalent attachment of each subunit of the dimer through a phosphotyrosine to the 5’ end of the DNA.
3. The two DNA ends at the cleavage site are pulled apart by a conformation change of the enzyme to create an opening in the gated DNA. The transported DNA duplex is then passed through the opening.
4. The transported DNA can be from the same molecule or from a different molecule.
5. All of the type II enzymes can be distinguished by their relative abilities to relax DNA vs. decatenate DNA.
6. The catalysis Mg, and ATP hydrolysis is involved

Question 10

DNA unwinding by the passage mechanism catalyzed by DNA gyrase, topoisomerase IV, and topoisomerase II

Answer 10

1. Binding of dsDNA covers up to 140 bases and wraps around the two A-subunits in the dimeric protein
2. Cleavage of a phosphodiester bond on each strand of DNA by the nucleophilic attack of tyrosine OH group to form two covalent bonds between protein and DNA
3. The dsDNA is “passed through” the cleavage site and this is dependent upon ATP hydrolysis in the B-subunits to cause a conformational change
4. The phosphodiester backbone is rejoined by nucleophilic displacement of the protein tyrosine residue by the 3’ OH cleaved strand
5. To repeat cycle, ATP is hydrolyzed

Question 11

Quinolone indications

Answer 11

UTI’s
Prostatitis
STI (gonorrhorea, chlamydia)
GI infections
RTI
Bone, joint, and soft tissue infections
Chlamydia, mycoplasma, legionella, brucella, mycobacterium

Question 12

Fluoroquinolone resistance mechanism

Answer 12

Decreased cellular permeability

Efflux pumps

Mutation of target enzymes

Question 13

Mutation of target enzymes

Answer 13

Point mutations in the A-subunit of DNA gyrase

Point mutation in the B-subunit of the DNA gyrase (less frequently)

Question 14

Efflux pumps

Answer 14

Resistance mutations that increase expression of genes encoding efflux pumps occur in E. coli and pseudomonas aeuroginosa

Question 15

Pharmacokinetics

Answer 15

High degree of oral bioavailability

Renal and hepatic clearance

Interstitial fluid concentrations range from 50-100% of serum concentrations after 2 hours and exceed serum concentrations from 4-24 hours. CSF levels of drug range from 40-90% when meninges are inflamed

Form insoluble chelates with heavy metals, so should not be administered with foods and drugs that contain heavy metals

Question 16

Metabolism

Answer 16

The major inactive metabolite glucuronide at the 3-carboxyl position and this is excreted in the urine

Question 17

Adverse effects

Answer 17

Nausea
Vomiting
Diarrhea
Headache
Dizziness
Hallucinations, delirium (rare)
Rash
Abnormal LFTs
Peripheral neuropathy

May damage growing cartilage

Tendonitis in adults is rare but serious because of tendon rupture

Question 18

Gatifloxacin adverse effects

Answer 18

Hyperglycemia and hypoglycemia in diabetic patients