Notes
Outline
Mechanism of action of fluoroquinolones:
the basics...
2 key enzymes in DNA replication:
Ternary complex
DNA - enzyme - fluoroquinolone
Ternary complex
DNA - enzyme - fluoroquinolone
Resistance to fluoroquinolones: the basics
Fluoroquinolones are the first entirely
man-made antibiotics:
do we understand our molecule ?
Chemistry and Activity
The pharmacophore common to all fluoroquinolones
From chloroquine to nalidixic acid...
Nalidixic acid *
From nalidixic acid to the
1st fluoroquinolone (1 of 4)
From nalidixic acid to the
1st fluoroquinolone (1 of 4)
From nalidixic acid to the
1st fluoroquinolone (1 of 4)
From nalidixic acid to the
1st fluoroquinolone (1 of 4)
From norfloxacin to the other 1st generation fluoroquinolones: pefloxacin
From norfloxacin to the other 1st generation fluoroquinolones: ofloxacin
From norfloxacin to the other 1st generation fluoroquinolones: ciprofloxacin
"1st generation" fluoroquinolones
The "first generation" of fluoroquinolones
From ofloxacin to levofloxacin...
The  present "first generation" of fluoroquinolones ...
How to improve the chemotherapeutic usefulness of
 the "first generation" fluoroquinolones
 The “second generation” fluoroquinolones
The “third generation” fluoroquinolones
Activity against S. pneumoniae
Resistance au fluoroquinolones :
les mécanismes de base ...
Resistance au fluoroquinolones :
rôle des mutations au niveau de la cible
Is there a SAR for emergence of resistance ?
Is there a SAR for emergence of resistance ?
Fluoroquinolones with a C8-methoxy
Toxicity
Frequent side effects of fluoroquinolones:
is there a SAR ?
SAR of frequent side effects
Fluoroquinolone with low or no drug interactions..
Rare side effects of fluoroquinolones:
Pharmacokinetics
 SAR of pharmacokinetic parameters
SAR of main pharmacokinetic parameters:
how to get a long half life
Resistance: do not forget the correct dosing...
Pharmacokinetic parameters in relation with efficacy
Optimizing dosage for fluoroquinolones
How to apply this ?
Take home” message
Dosage is key to success
Dosage should match bacterial sensitivity
peak, AUC/MIC are keys to success
use a single, appropriate dose for long-life fluoroquinolones (moxifloxacin), or
repeat the dose for short-lived fluoroquinolones (all others so far…)
for fluoroquinolones, the limit is an MIC of
0.5 µg/ml