Notes
Outline
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 ?
Slide 17
Slide 18
Slide 19
Slide 20
Slide 21
Slide 22
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