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