Quinolones

Question 1

List the quinolones (4 of them)

Answer 1

Norfloxacin, Ciprofloxacin, levo, and moxi

Question 2

What is the MOA of quinolones?

Answer 2

Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV.

Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. * Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.

Question 3

Which is more important to gram +ve organisms with regards to MOA of quinolones - Inhibition of Topoisomerase 4, or inhibition of DNA gyrase?

Answer 3

Inhibition of topoisomerase 4 is more important to gram positive, while inhibition of DNA gyrase is more important to gram negative.

Question 4

What does the addition of a fluoride group to the quinolone molecule do?

Answer 4

It increases its penetration through the cell wall (makes it a fluoroquinolone)

Question 5

What does the addition of groups to the R side chain beside the blue R side chain do?

Answer 5

Additions of groups to the R side chain beside the blue R side chain increases its bioavailability but also affect photosensitivity.
- Placing a methoxy group at this side decreases photosensitivity (i.e. Moxifloxacin)

Question 6

What does the addition of groups at the R side chain beside the red fluoride side chain do?

Answer 6

It increases activity against gram -ve organisms, but also can cause sedation as it binds to GABA receptors in the CNS.

Question 7

What does additions to the N group do?

Answer 7

Increases activity against “atypical” organisms.

Question 8

What are the three mechanisms by which resistance occurs in quinolones?

Answer 8

1. Alterations in Topoisomerase, making it difficult for quinolone to bind
2. Changes in outer membrane which interfere with antibiotic penetraction
3. Development of efflux pumps which reduce intracellularly concentrations of quinolones

Question 9

How does the inappropriate and overuse of cipro and levo do?

Answer 9

Alterations in topoisomerase (TP), making it difficult for quinolone to bind o gyrA or gyrB are subunits where FQs bind to DNA gyrase (TP I) and parC or parE for TP IV. Binding to these sites, fluoroquinolones block enzymatic activity such that bacterial replication cannot take place.
o Moxifloxacin binds in a site that preferentially selects for mutations in gyrA whereas levofloxacin and ciprofloxacin bind in sites that select for mutations in parC.
o Isolates with mutations in parC only are resistant to ciprofloxacin but not to the other quinolones, whereas isolates with mutations in gyrA only and isolates with mutations in both parC and gyrA tend to be resistant to all fluoroquinolones.
o If the “first-step” mutation occurs with parC, there is an increased risk for subsequent mutation in gyrA.
o Overuse of cipro and standard dose levo (500 mg daily) can increase the probability of a mutation occurring via parC, which increases the risk of a gyrA with further FQ exposure.
**o Thus, inappropriate and overuse of Cipro/Levo can lead to moxi resistance. **

Question 10

Describe generally the difference in spectrum of activity between lower generations vs. later generations of fluoroquinolones.

Answer 10

Lower generations typically lacked activity vs. gram positive bacteria. * Later generations have gained activity vs. gram positive bacteria; also known as respiratory quinolones.

Question 11

List the second, Third and 4th gen fluoroquinolones

Answer 11

1. Second - Ciprofloxacin, and norfloxacin
2. Third - Levofloxacin
3. 4th - Moxifloxacin

Question 12

What are common Toxicities for quinolones?

Answer 12

1. GI - C.diff, Taste disturbance (metallic taste)
2. Derm - photosensitivity, hypersensitivity reactions
3. Liver - Increased LFTs
4. Kidney - hematuria, cystalluria, interstitial nephritis, crystalluria should be uncommon due to the acidic pH of the urine (normally around 6, but can range from 4.5 to 8)
5. CNS - Headache, dizziness, confusion, seizures (possibly due to Gaba inhibition)
6. MS - Arthropathy, tendinitis, tendon rupture. Tendon toxicity is rare (FQ tendon rupture occurs in about 1 in 10,000 patients)
7. Endocrine - Disturbances in glucose homeostasis, hypoglycemia may be due to the inhibition of ATP-sensitive potassium channels in pancreatic beta cells resulting in insulin release.,
8. CV - QTc interval prolongation (class effect)

Question 13

Describe the risk of tendon rupture likelihood?

Answer 13

1 in 10,000

Question 14

Are specific fluoroquinolones implicated in tendon rupture?

Answer 14

Nope.

Question 15

What are know risk factures for achilles tendon rupture (ATR)

Answer 15

Corticosteroids, renal failure, advanced age, male gender, rheumatologic disease, diabetes, hyperparathyroidism, hyperlipidemia, physical activity or trauma and transplant patients.
RISK IS HIGH IN ELDERLY and those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of steroids is present in almost 1/3 quinolone associated tendon rupture

Mechanism of tendon toxicity: poorly understood. Chelation of key cations such as Mg2+ may weaken the tendon (already subject to immense forces from walking or running).
▪ Free radical damage may play a role. There is some evidence that tendon toxicity is dose-related.

Question 16

What are risk factors for dysglycemia with FQs?

Answer 16

Type 2 diabetes treated with oral hypoglycemic drugs, mild-moderate renal insufficiency.

Question 17

What is the mechanism of QT prolongation with FQs?

Answer 17

** interference with potassium efflux from the myocardial cell, prolonging repolarization.** Accumulation of multiple risk factors is necessary for a person to develop TdP from an FQ. Known risk factors: inherited long QT syndrome, bradycardia, CHF, hypokalemia, hypomagnesemia, older age, female gender, drugs that delay repolarization (e.g. class 1a/III antiarrhythmics).

Question 18

Describe the PK of Cipro, levo and moxi (% absorbed, elimination, and product availability)

Answer 18

Question 19

Describe the two different main drug interactions with FQs?

Answer 19

As object drugs:
o Products containing multivalent cations (calcium, aluminum, magnesium, iron, zinc) ingested within two to four hours of an orally administered fluoroquinolone may result in a 25-90% reduction in fluoroquinolone Cmax.
o These products include antacids, sucralfate, nutritional supplements, vitamins, and mineral supplements.

o There are no meaningful differences among the fluoroquinolones with respect to this interaction.

o Can interact with various CYP enzymes and used caustioulsy in places where medication ADRs overlap (eg. Photosensitivity, QT prolongation)

Question 20

What is the spectrum of activity 2nd and 3rd gen FQs?

Answer 20

Spectrum of Activity: (NOTE: this does not include norfloxacin)
Gram +ve
* Penicillin-susceptible and penicillin-resistant Strep. pneumoniae (3rd Generations)
* Some strains of Staph aureus and Staph epi, probably not MRSA (2nd, 3rd, generations)
* Can cover Enterococcus faecalis (in urine) but not would not be considered drug of choice
* Cipro is not a reliable drug for most gram+ve organisms and should not be used. It can also induce resistance in other quinolones when overused.

Gram –ve
* Very good activity against gram negative bacteria, including H. influenzae, Moraxella catarrhalis, and harder-to-kill gram negative pathogens
* Check sensitivities of Cipro to N. gonorrhoeae

• Interestingly enough, may not be effective against ESBL producing E. coli and Klebsiella spp. check susceptibilities.
• Variable activity vs. Pseudomonas aeruginosa; ciprofloxacin is best, high dose levofloxacin can also be used

Anaerobes
* Limited anaerobic activity; moxifloxacin has moderate activity including some strains of Bacteroides fragilis

Organisms without Cell Walls (Atypicals)
* 2nd, 3rd, generations are active against atypicals including Chlamydia spp. Legionella pneumonia