Can resistance be dependent on spesific pharmacokinetic properties? - - PowerPoint PPT Presentation

Can resistance be dependent on spesific pharmacokinetic properties?

Kjetil K. Melby Dpt of Microbiology Ullevaal University Hospital, OSLO

• Macrolides attaining low

serum serum levels but are efficient ON SITE of the infection.

–Do they induce resistance and do pharmacokinetics matter?

• Erythromycin

S

• Roxitromycin

S

• Clarithromycin

L

• Azithromycin

L

• Dirithromycin

S

• Spiramycin etc.

L

• ”Linked” to pharmacokinetics

–Relation to low serum/high tissue levels

• Key points

–T1/2 (S= short L=Long) –AUC/MIC – low level resistance ?

• ”Unlinked” to pharmacokinetics

–Volume of antibiotic use –Various areas (vet/human etc) of antibiotic application –Mode of resistance »Mef »Point mutation 23S rRNA

nov 01 KKM 2

Areas of resistance developement

Residing flora? Infecting

• rganism

TARGET Macrolide M (M) MMM

Site of infection vrs NORMAL FLORA

Residing flora Potential pathogens

Developement of resistance??

Drug Serum level Saliva levels(fraction) Tissue ”PDAC” #

Ery 3 0,1-1.0 x3(?) short Clar 2 0,1 -1.0 x3(?) short Azithro 1 0,1 -1,0 x10 (?) long # Post Dosage Antibiotic Challenge (Drug elimination)

nov 01 KKM 3

Macrolide resistance developement

Relation to type of macrolide

Conclusion:

Increase in Erythromycin resistance Increase in azithromycin

use

Comments:

• Low level exposure to

antibiotic implies: Induction

• f low level resistance.
• Related to type of antibiotic
• Beta-lactams
• Macrolides
• Consequences
• Global: Gradual

increase in bacterial resistance.

• Practical
• Revision of

indication(s) ?

Approaches In vitro studies: Nagai et al: JAC 2000 46: 909-915 In vivo results: Adapted from Baquero, J. Chemother 11: 35-43, 1999

nov 01 KKM 4

Resistance developement

Relation to macrolide use

Conclusion: NO increase in resistance in Norway but low increase in azithromycin usage

Data from Norway

nov 01 KKM 5

Final comments - macrolides

Q: Can resistance be dependent on specific pharmacokinetic properties? A: Probably – Yes; if their different actions on local (normal) flora are considered a consequence of pharmacokinetics of the compound (”PDAC”). Thus to consider:

• Longacting macrolides (Azithromycin) should

be used in infections due to obligatory pathogens (not potential partner(s) of the local ”normal flora”)

• Regulatory board should ask for data on low

level resistance development for new compounds

INFEC TED AREA

nov 01 KKM 6

Pharmacokinetic prophiles - macrolides

• Erytromycin (Er)
• Clarithromycin
• Roxitromycin
• Azitromycin(Az)
• Spiramycin
• Dirythromycin
• Other

Note: MICs and serum levels differences Az vrs Er

0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 2 1 2 3 4 5 6 7