Slide 1

Slide 2

Erythromycin: mode of action

Erythromycin: mode of action

Erythromycin: spectrum of activity

Slide 6

Erythromycin: the problems

Erythromycin: details of
acid the degradation

What have the chemists done to
avoid acid-instability ?

What have the chemists done to
avoid acid-instability ?

Did these modifications change
anything else in PK ?

Did these modifications change
anything else ?

Drug interactions with macrolides
The main problem due to interactions between some macrolides and the cytochrome P 450 system, especially the CYP3A subclass of enzymes
Finally results in lowered metabolism of CYP3A-dependent drugs
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drug azi clari diri ery josa mid roxi spira
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théophyllin 0 0 0 ++ + ND 0/+          0
ciclosporin ND ND ND +++ +++ +++ + 0
carbamazepin ND 0/+ ND +++ + + 0/+ 0/+
midazolam 0 ++ ND ++ ND ND + ND
warfarin 0 ND ND + ND ND 0 ND
terfenadin 0 ++ ND +++ 0/+ ND 0 ND
cisapride ND ++ ND ++ ++ ND ND 0
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From Petitjean et al. N=undocumented
Mainly considered as a class-effect, resulting from what is known for erythromycin, except for spira and azithromycin

Basic indications of (classical) macrolides
in a world of no resistance

Which is the best ?

But was has been the problem ?

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Inhibition of Protein Synthesis (1)
Inhibition of peptidyl transferase activity

Telithromycin

Resistance: a semi-rational answer ...

Inhibition of Protein Synthesis (2)
Inhibition of peptidyl transferase activity

MIC50 [µg/ml] of wild type and mutant strains

Telithromycin
Telithromycin, the first ketolide, was designed to overcome erythromycin A resistance within Gram (+) positive cocci and take advantage of PK improvements of clarithromycin

Pharmacokinetics of telithromycin
(as submitted to the FDA; april 2001)

Pharmacodynamics of telithromycin
(as based on FDA submission; april 2001)

Which are the sensivities of S. pneumoniae towards telithromycin in Belgium in 2000 ?

Macrolides: the 16 atoms family

Macrolides: the 16 atoms family

Properties of the 16 atoms family

Macrolides: the present family picture