Quinolones & Fluoroquinolones

Question 1

enrofloxacin is what type of drug

Answer 1

fluoroquinolone

Question 2

fluoroquinolone drug examples

Answer 2

ciprofloxacin, enrofloxacin, marbofloxacin, pradofloxacin

Question 3

fluoroquinolones MOA

Answer 3

inhibition of bacterial DNA gyrase and/or topoisomerase IV = inhibition of DNA supercoiling and replication

Question 4

how do fluoroquinolones enter cells

Answer 4

via porins and accumulate rapidly inside susceptible bacteria

Question 5

are fluoroquinolones concentration or time dependent

Answer 5

concentration

Question 6

how can you measure efficacy of fluoroquinolones?

Answer 6

• concentration dependent
• Cmax : MIC
• AUC:MIC; AUIC

Question 7

what effect has been demonstrated for enrofloxacin and orbifloxacin in some bacteria?

Answer 7

post-antibiotic effect (PAE)

Question 8

what PK properties do fluoroquinolones share?

Answer 8

1. good oral absorption
2. large volume of distribution
3. good intracellular drug penetration
4. extended elimination half-lives that allow for every 24-48 hour dosing

Question 9

what factors could decrease absorption of fluoroquinolones?

Answer 9

high concentrations of divalent/trivalent cations: ex thru interactions with antacids, nursing young: milk has a lot of Ca2+

Question 10

oral absorption of fluoroquinolones is low in what species?

Answer 10

adult ruminants: can be as low as 10-20%
pre-ruminant calves appear to be like monogastrics with regard to oral absorption of fluoroquinolones

Question 11

absorption of fluoroquinolones in horses

Answer 11

variable: enrofloxacin is well absorbed, cipro poorly

Question 12

distribution of fluoroquinolones

Answer 12

• concentrations as high as plasma in a wide range of tissues
• therapeutic concentrations for Gram - organisms maybe reached in CNS and eye!
• rapidly accumulate in macrophages and neutrophils = higher drug concentrations in infected tissues

Question 13

where might there be higher concentrations of fluoroquinolones?

Answer 13

• therapeutic concentrations for Gram - organisms may be reached in the CNS
• rapidly accumulate in macrophages and neutrophils = high concentrations in infected tissues

Question 14

where do fluoroquinolones rapidly accumulate?

Answer 14

macrophages and neutrophils

Question 15

how are fluoroquinolones eliminated?

Answer 15

urinary accumulation: often occurs due to renal elimination and prostate concentrations can equal or exceed plasma concentrations

Question 16

enrofloxacin is metabolized to form what?

Answer 16

ciprofloxacin

Question 17

what is an important contributor to the activity of enrofloxacin?

Answer 17

ciprofloxacin: enro is metabolized to form cipro: up to 40% of a dose of enro is converted to cipro in dogs

Question 18

classification of fluoroquinolones

Answer 18

3 groups/generations

Question 19

1st generation fluoroquinolones

Answer 19

older drugs like nalidixic acid, flumequine
activity if restricted to enterobacteriaceae

Question 20

2nd generation fluoroquinolones

Answer 20

all but 1 vet product in this group
extended spectrum of activity, but limited against Strep and obligate anaerobes

Question 21

3rd generation fluoroquinolones

Answer 21

pradofloxacin is only vet drug. better activity for strep in vitro and obligate anaerobes

Question 22

off-label use of fluoroquinolones in food producing animals

Answer 22

ILLEGAL

Question 23

what bacterias are resistant to fluoroquinolones?

Answer 23

most anaerobic bacteria

Question 23

fluoroquinolone spectrum of activity

Answer 23

• good: gram - aerobes (ecoli, kleb, proteus, salmonella)
• moderate: gram + aerobes (Strep, rhodococcus, mycobacteria)
• resistant: MOST anaerobic bacteria (except pradofloxacin)

Question 24

what adverse effects do fluoroquinolones have in cats?

Answer 24

retinal degeneration with enrofloxacin at doses higher than 5mg/kg/day
temporary or permanent blindness with mydriasis

Question 25

what drug causes retinal degeneration in cats?

Answer 25

enrofloxacin

Question 26

you see a cat who has recently been treated with antibiotics, but is experiencing visual issues. you notice dilation of the eye even while the cat is calm. what might you suspect the cat was recently treated with?

Answer 26

enrofloxacin

Question 27

MOA of retinal degeneration in cats

Answer 27

reduced function of ABCG2/BCRP efflux transporter in cat retina leading to drug accumulation; fluoroquinolones are reactive

Question 28

what should you do with a cat who is exhibiting symptoms after being treated with enrofloxacin?

Answer 28

keep them in the dark to prevent photo-activation; these drugs are photoreactive

Question 29

fluoroquinolones in young animals

Answer 29

contraindicated in immature animals in some species
- administration during rapid growth associated with arthropathies and cartilage erosions in immature cats, dogs, horses

Question 30

when should you avoid use of fluoroquinolones in dogs?

Answer 30

small and medium dogs during rapid growth (2-8 months) and large or giant breeds (up to 18 months)

Question 31

fluoroquinolones adverse effects

Answer 31

neurotoxic effects! horses, dogs, cats treated with enrofloxacin
- high doses IV more likely to cause CNS

Question 32

what is the likely cause of CNS effects of fluoroquinolones?

Answer 32

GABA receptor inhibition
because of greater BBB penetration of enro, enro can cause hallucinations in people

Question 33

fluoroquinolones in horses

Answer 33

although generally well-tolerated, use in horses (like most antimicrobial agents) has been associated with occasional cases of enterocolitis

Question 34

what are drugs that could have potential antagonism of fluoroquinolones?

Answer 34

chloramphenicol, rifampin

Question 35

what are the 4 categories of resistance that has been identified for fluoroquinolones?

Answer 35

1. target modification
2. decreased permeability
3. efflux
4. target protection
   each mechanism can occur within the same bacterial cell simultaneously = high level resistance!!

Question 36

target modification of fluoroquinolones

Answer 36

• mutation in DNA gyrase with 2ndary mutations in topoisomerase IV
• gyrA mutations lead to reduced binding to DNA gyrase
• parC mutations lead to reduced binding to Topoisomerase IV

Question 37

what bacteria has higher incidence of resistance against fluoroquinolones?

Answer 37

Campylobacter: doesn’t have topoisomerase IV and thus a single mutation can lead to high level resistance

Question 38

why are fluoroquinolones banned in poultry production?

Answer 38

Campylobacter does not have Topoisomerase IV and thus a single mutation can lead to high level resistance: this may explain the higher incidence of fluoroquinolone resistant Campylobacter compared to E. Coli from food animals exposed to fluoroquinolones

Question 39

fluoroquinolone reduced intracellular drug levels

Answer 39

• altered outer membrane porins can decrease permeability of cell wall to drugs
• induced membrane efflux pumps can remove drug before it interacts with targets: gyrase and Topo IV

Question 40

fluoroquinolones target production

Answer 40

quinolone resistance gene qnr functions to protect DNA gyrase (not Topo IV) from inhibition by fluoroquinolones
results in a small decrease in drug susceptibility

Question 41

resistance of fluoroquinolones

Answer 41

“achilles’ heel” : targeting the dosage to the MIC of the pathogen will not only increase clinical resolution of infx, but will reduce emergence of resistance :)))))

Question 42

class of microorganisms that fluoroquinolones work at

Answer 42

1. bacteria
2. mycoplasma
3. rickettsia
4. chlamydia

Question 43

abx spectrum of activity of fluoroquinolones

Answer 43

• gram - aerobes
• gram + aerobes

Question 44

are fluoroquinolones bacteriostatic or bactericidal?

Answer 44

bacteriostatic at or near MIC
bactericidal at 2-4x MIC

Question 45

are fluoroquinolones time or concentration dependent?

Answer 45

concentration dependent