Chapter 9 Notes

Question 1

difference btw quinoline and quinolone

Answer 1

quinolone has ketone at 4 position (G - effective)

Question 2

microbiologic rationale for development of FQ

Answer 2

inc activity, enhance biodisposition, and dec ADR

Question 3

R 1 position in FQ

Answer 3

potency/gyrase affinity
spectrum of activity
drug interaction: theo

Question 4

R 2 position in FQ

Answer 4

DNA Gyrase Affinity

Question 5

carbonyl in FQ

Answer 5

DNA gyrase affinity
intrinsic activity: bacterial penetration
Drug interactions: metals, NSAID
ADR: GI, CNS

Question 6

R 5 position in FQ

Answer 6

Potency and Activity:G+ Activity!

Question 7

F position in FQ

Answer 7

potency and spectrum

(Affinity/Penetration)and disposition!

Question 8

R 7 position in FQ

Answer 8

G + and G - potency and spectrum
oral
drug interaction: theo
metabolism
ADR: CNS, rash, kidney

Question 9

X 8 position in FQ

Answer 9

anaerobic activity
oral
ADR: photoreactivity

Question 10

FQ are zwitterions which means

They are also amphoteric (ion trapping) and lipophilic

Answer 10

no net charge –> inc log P –> better distribution than beta lactams –> penetrate cytoplasmic membrane of bacteria and human cells

They can cross OM of G - by porin diffusion or simple diffusion

Question 11

FQ bind polyvalent

Answer 11

metals (calcium, magnesium, iron, zinc, copper, aluminum) and form insoluble chelates
avoid this by separating FQ by 2 hours or more.
If binding monovalent metal, it forms a salt

Question 12

Nitrogen at R 1 position and R 7 position are

Answer 12

not basic b/c of resonance

Question 13

FQ MOA

Answer 13

bind DNA processing enzymes (gyrase and topoisomerase) in the cytoplasm

Question 14

sites of FQ resistance

These are chromosomal, not on the plasmid

Answer 14

targets, uptake, and efflux pumps (inner membrane)

Bugs with efflux pump resistance: P. aeruginosa, E. Coli, S. aureus, S. pneumonia
Bugs with membrane fusion protein resistance:P. aeruginosa, E. Coli
Bugs with OM protein resistance and regulatory gene resistance: P. aeruginosa, E. Coli

Question 15

supercoiling

Answer 15

DNA packing: a tertiary structural conformation of DNA that involves the formation of twists opposite the direction of the right-handed DNA double helix.

Question 16

strand unwinding

Answer 16

required for transcription, repair, or recombinational events.

Question 17

topoisomerase II (DNA gyrase)

Answer 17

catalyzes reactions that increase or decrease the negative supercoil density. These reactions involve highly site-specific breakage and reunion of double-stranded DNA.

Question 18

topoisomerase IV

Answer 18

catalyzes decatenation (separation) of linked daughter DNA molecules.

Question 19

FQ work in pH of

Answer 19

< 7

Question 20

FQ induce

Answer 20

resistance

Question 21

FQ MIC ranges are large

Answer 21

because of resistance

Resistant bugs: pseudomonas, acinetobacter, gonorrhea, E coli, Campylobacter, Klebsiella

Question 22

1st gen FQ effective against

Answer 22

acinetobacter (but treat with combo of drugs), M. Catarrhalis, H. Influ, pasturella, eikenella, E. Coli, Salmonella, Shigella, Proteus Mirabilis, Proteus Vulgaris, Klebsiella, providencia stuartii, citrobacter, enterobacter, P. aeruginosa

Question 23

2nd gen FQ effective against

Answer 23

acinetobacter (but treat with combo of drugs), M. Catarrhalis, H. Influ, pasturella, eikenella, E. Coli, Salmonella, Shigella, Proteus Mirabilis, Proteus Vulgaris, providencia stuartii, citrobacter, enterobacter, P. aeruginosa (cipro works best), serratia (cipro works best), legionella, chlamydia, rickettsia, mycoplasma, ureaplasma, mycobacteria

anthrax, plague, tularemia

Question 24

2.5 gen FQ effective against

Answer 24

MSSA/MSSE (not best choice drug to use)
PSSP, PRSP, other strep, acinetobacter (but treat with combo of drugs), M. Catarrhalis, H. Influ, pasturella, eikenella, E. Coli, Salmonella, Shigella, Proteus Mirabilis, Proteus Vulgaris, Klebsiella, providencia stuartii, citrobacter, enterobacter, P. aeruginosa, serratia, legionella, chlamydia, rickettsia, mycoplasma, ureaplasma, mycobacteria

Question 25

3rd gen FQ effective against

Answer 25

MSSA/MSSE (not best choice drug to use) PSSP, PRSP, other strep, listeria, acinetobacter (but treat with combo of drugs), M. Catarrhalis, H. Influ, pasturella, eikenella, E. Coli, Salmonella, Shigella, Proteus Mirabilis, Proteus Vulgaris, Klebsiella, providencia stuartii, citrobacter, enterobacter, P. aeruginosa, serratia, legionella, chlamydia, rickettsia, mycoplasma, ureaplasma, mycobacteria

Question 26

4th gen FQ effective against | ***have highest affinity for range of Gyr and Par topoisomerase subunit in which mutation occurs

Answer 26

MSSA/MSSE (not best choice drug to use) PSSP, PRSP, other strep, listeria, acinetobacter (but treat with combo of drugs), M. Catarrhalis, H. Influ, pasturella, eikenella, E. Coli, Salmonella, Shigella, Proteus Mirabilis, Proteus Vulgaris, Klebsiella, providencia stuartii, citrobacter, enterobacter, P. aeruginosa, serratia, legionella (moxi works best), campylobacter, B. Fragilis, Prevotella, Clostridium, peptostrep, propionibacterium chlamydia, rickettsia, mycoplasma, ureaplasma, mycobacteria (moxi works best)

Question 27

bugs with increasing resistance to FQ

Answer 27

pseudomonas, acinetobacter, S. aureus (only a single mutation required, relatively high mutation rate) gonorrhea, E coli, campylobacter (multiple mutations required, relatively low mutation rate) klebsiella

Question 28

Qnr

Answer 28

quinolone resistance protein that bind gyrase on plasmid which prevent FQ from binding. It increases MIC values - toxic enterococci and enterobacteriacaea has this resistance bugs that survive using these mech of resistance, accumulate resistance determinants on their plasmids

Question 29

GyrA is mostly in

Answer 29

G - bugs Gyr is most likely to be FQ resistant alkyl non-polar amino acids are used in resistance, so there is loss of binding for FQ.

Question 30

SOS gene system

Answer 30

arrest DNA replication by binding repressor gene that turns on SOS gene system ---> new gyrase made ---> hopefully won't bind FQ This system induces Qnr production this is least likely to occur with S. pneumonia

Question 31

FQ are not to be used in

Answer 31

``` kids pregnant women (cross placenta and enter breast milk) ```

Question 32

FQ don't distribute well to

Answer 32

CSF, eye, or bone, but they do distribute well in tissues (unlike Pens)

Question 33

FQ ADR

Answer 33

``` GI upset N/V CDAD seizure (affinity for GABA, NMDA receptors) - ofloxacin HSR type 1 phototoxicity (free radical rxn) - NSAID, phenol, PABA irreversible ocular toxicity hepatoxicity (trova) dysglycemia musculoskeletal QTc prolongation peripheral neuropathy ```

Question 34

FQ DDI

Answer 34

antacid, vitamin, sucralfate, didanosine, probenecid, NSAID, warfarin, anti-arrhythmic