Quinolone Antimicrobial Agents

Question 1

first generation quiolones

Answer 1

first generation quinolones were developed because of their activity against Gram-(–) bacteria. They have limited activity vs. Gram-(+) bacteria. They do not achieve useful systemic concentrations and are only useful for treatment of lower urinary tract infections

Question 2

second generation quiolones

Answer 2

• have a fluorine substituent at C-6 and a heterocyclic ring (usually piperazine) at C-7.
• broader spectrum of bactericidal activity and are more potent

Question 3

second generation quiolones

Answer 3

Norfloxacin
levofloxacin
Ciprofloxacin

Question 4

third and forth generation quiolones

Answer 4

multiple fluorine atoms

improved activity against Gram-(+) organisms, particularly Streptococcus pneumoniae

Question 5

third and forth generation quiolones: drug of last resort

Answer 5

Moxifloxacin

Question 6

most potent fluoroquinolone

Answer 6

Ciprofloxacin

Question 7

quinolone MOA

Answer 7

Steps in DNA unwinding:
1) Binding of dsDNA that 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 a
tyrosine (protein)-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 induce a conformational change.
4) The phosphodiester backbone is rejoined (ligated) by nucleophilic displacement of the
protein tyrosine residue by the 3’-OH of the cleaved strand.
5) To repeat the cycle, the ATP has to be hydrolyzed.

-quinolones bind to the cleavage complex that exists after step 2

Question 8

quiolone MOA part 2

Answer 8

drug molecules are assumed to be stacked between the base pairs at the cleavage site so that the cleavage complex is stabilized and the religation reaction is inhibited (see below). This blocks the progression of the replication fork and the double-strand breaks eventually lead to apoptosis
(bacterial cell death)
-DNA religation is blocked by the quinolones
-drug basically takes place of base pair, can’t re-ligate

Question 9

therapeutic uses of quinolones

Answer 9

1.) Urinary tract infections.
2.) Prostatitis.
3.) STD’s
4.) Gastrointestinal infections: traveler’s diarrhea
5.) Respiratory tract infections
6.) Bone, joint, and soft tissue infections
7.) norfloxacin and ciprofloxacin: intracellular bacteria (requiring high blood levels for treatments) like Chlamydia,
Mycoplasma, Legionella, Brucella, and Mycobacterium

Question 10

UTI quinolone drugs

Answer 10

Norfloxacin, ciprofloxacin, ofloxacin and nalidixic acid

Question 11

Prostatitis drugs

Answer 11

Norfloxacin, ciprofloxacin, ofloxacin

Question 12

STD drugs

Answer 12

Neisseria gonorrhoeae: ciprofloxacin
Chlamydia trachomatis: ofloxacin or sparfloxacin, and Haemophilus ducreyi: ciprofloxacin
(N. gonorrhea ceftriaxone used)

Question 13

GI drugs

Answer 13

Norfloxacin, ciprofloxacin, and ofloxacin

Question 14

RTI drugs

Answer 14

newer fluoroquinolones: moxifloxacin

-Streptococcus pneumoniae. Respiratory tract exacerbations in cystic fibrosis patients

Question 15

Bone, joint, and soft tissue infections drugs

Answer 15

Fluoroquinolones

Question 16

resistance

Answer 16

resistance in Fluoroquinolones is correlated with use
-also decreased cellular permeability, efflux pumps (in G- bacteria),
and mutation of the target enzymes.
-spontaneously occurring point mutations in the A-subunit of DNA gyrase which leads to an enzyme with altered binding affinity for the drug that translates into
a 16-fold higher MBC for fluoroquinolone drugs
-also mutation of B-subunit of DNA gyrase (less commone)

Question 17

fluoroquinolones pharmacokinetics

Answer 17

-readily absorbed orally and have a high degree of
bioavailability
-widely distributed
-Renal and hepatic clearance are important in all cases (except oxafloxacin (95% renal))

Question 18

interstitial concentrations of quinolones

Answer 18

range from 50-100% of serum concentrations after 2 hours
and exceed serum concentrations from 4 to 24 hours. CSF levels of drug range from 40-90%
of serum levels.

Question 19

what do quinolones form?

Answer 19

form insoluble chelates with heavy metals and should therefore not be administered with foods and drugs that contain heavy metals

Question 20

metabolism of quinolones

Answer 20

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

Question 21

adverse reactions from quinolones

Answer 21

-fluoroquinolones are very well tolerated
-most common: nausea, vomiting and diarrhea
-CNS adverse reactions include headache and
dizziness
-rare: hallucinations, delirium and seizures
-Skin rash and abnormal liver function
-tests have been reported.
- peripheral neuropathy

Question 22

rare side effects occur when patients also take what?

Answer 22

theophylline and nonsteroidal antiinflammatory drugs

Question 23

why aren’t fluoroquinolones recommended for those under 18 years old?

Answer 23

may damage growing cartilage and cause arthropathy (reversible)

Question 24

lomefloxacin adverse side effects

Answer 24

photosensitivity

Question 25

Gatifloxacin side effects

Answer 25

hyperglycemia and hypoglycemia in diabetic patients