1. PK/PD "PK/PD of quinolones: from basics (not too much) to registration and clinical implications.
Paul M. Tulkens
Françoise Van Bambeke
Unité de pharmacologie cellulaire et moléculaire
Université catholique de Louvain, Bruxelles
PK/PD - Budapest

2. PK/PD "PK/PD of quinolones: from basics (not too much) to registration and clinical implications.
Paul M. Tulkens
Françoise Van Bambeke
Unité de pharmacologie cellulaire et moléculaire
Université catholique de Louvain, Bruxelles
Don't be jealous, this is NOT our lab…
PK/PD - Budapest

3. at at a reasonable cost …
Why do we need quinolones for (and all antibiotics) in the first place ?
Efficacy ...
at at a reasonable cost …
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4. Cost is not too bad nowadays…
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5. May be, this is why …
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6. Efficacy of ciprofloxacin will not be too bad for Gram(-) bugs
If you get a AUC24h / MIC > 125
Forrest et al., AAC, 1993
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7. And that of levofloxacin for S. pneumoniae not bad either …
If you get a peak / MIC > 12
Preston et al., JAMA :125-9.
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8. To finish on this …
Modelling studies show that survival (= efficacy ...) for FQ
is linked mainly to Peak/MIC when > 10/1
is more linked to AUC/MIC when peak / MIC is < 10/1
Then, in the absence of a high peak ...
AUC/MIC ratio must be > 125 for all Gram (-)
AUC/MIC ratio can be 30 for Gram(+) if host is healthy
but with immunocompromised hosts , AUC/MIC for Gram(+) organisms is better >
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9. But is efficacy all we want from quinolones ?
We want eradication ...
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10. Which is the most basic pharmacological property of quinolones in comparison with most other antibiotics … ?
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11. They kill FAST and in a CONCENTRATION-dependent manner !
Which is the most basic pharmacological property of quinolones in comparison with most other antibiotics … ?
They kill FAST and in a CONCENTRATION-dependent manner !
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12. But what is their downside ?
Résistance …
S. pneumoniae
1.2
Levofloxacin
Gatifloxacin
1.0
0.8
Percent
0.6
0.4
0.2
0.0
1997
1998
1999
2000
2001
Year
From: Canadian Bacterial Surveillance Network.
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13. Resistance IS a problem for P. aeruginosa …
MIC distributions in Belgium …
J. van Eldere, 2003
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14. 1. Mutations (and this may be why …)
Why resistance ?
Persistent RecA-ssDNA filaments induce levels of LexA cleavage sufficient to de-repress the error prone polymerases, Pol IV and Pol V, which cooperate to induce mutations (pathway D).
1. Mutations (and this may be why …)
Cirz RT, Chin JK, Andes DR, de Crécy-Lagard V, Craig WA, et al. (2005) Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol 3(6):e176.
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15. Mutant Prevention Concentration …
Bactericidal effect of a FQ towards Mycobacterium bovis 1
MIC 99 = 0.8 10 -2
"Classic" bactericidal effect 10 -4
overlevenden 10 -6 10 -8
MPC 10 = 9
Elimination
of first mutants 10
-10
0.01
0.10
1.00
10.00
concentratie
Dong et al; AAC 43:
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16. Mutant Prevention Concentration …
Concentration which
will inhibit the majority
of the organisms 1
MIC 99 = 0.8 10 -2 10 -4
overlevenden
Concentratie necessary to prevent the selection of the first mutants 10 -6 10 -8
MPC 10 = 9 10
-10
0.01
0.10
1.00
10.00
concentratie
Dong et al; AAC 43:
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17. "Window" where the selection of mutants takes place …
Mutation selection window
MPC
concentratie
MSW
MIC
Tijd na toediening
concept overgenomen van Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80
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18. "Window" where the selection of mutants takes place …
Eradication of the first mutants
MPC
concentratie
MSW
Selection of the first mutantes
MIC
No therapeutic effect
Tijd na toediening
concept overgenomen van Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80
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19. Why resistance in Gram - ?
2. Decreased entry
susceptible bacteria
porin
periplasm
cytosol
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20. Why resistance in Gram - ?
2. Decreased entry
Less susceptible ...
porin
periplasm
cytosol
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21. 3. Efflux (and this an example of how it works in Gram (-)
Why resistance ?
3. Efflux (and this an example of how it works in Gram (-)
resistant bacteria
susceptible bacteria
pore
expressed in wild-type strains!
MexB
MexA
OprM
porin
periplasm
lipoprotein H+
pump
cytosol
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22. 2. Efflux (and this why it is dangerous …
Why resistance ?
2. Efflux (and this why it is dangerous …
-lac ML TET AG FQ Chl
MexAB-OprM
MexCD-OprJ
MexEF-OprN
MexHI-OprD
MexJK-OprM
MexXY-OprM
constitutive expression
inducible expression
Van Bambeke et al. JAC (2003) 51: ; Aeschlimann, Pharmacotherapy (2003) 23:916-24
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23. Efflux and mutations work together to bring the sensitivity of the organism above the berakpoint …
MIC
2e mut.
2e mut.
1e mut.
ciprofloxacin
Limiet voor gevoeligheid
1e mut.
wild
wild
w/o efflux
with
efflux
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24. Eradication is therefore less easy than you tought ...
Eradication must be geared towards
Sensitive bacteria (wild type)
Mutants
Efflux pumps overexpressers
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25. peak / MIC > 10 and/or > MPC
Let us do the exercise …
Prevention of resistance AND efficacy:
peak / MIC > 10 and/or > MPC
AUC / MIC > 100 (niet volledig immuuncompetente patiënt)
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26. Moxifloxacin Levofloxacin
Cumulative distribution van MIC for S. pneumoniae in Belgium
S.pneumoniae 2a
120,00%
Moxifloxacin
100,00%
80,00%
60,00%
40,00%
Levofloxacin
20,00%
,00%
0,002
0,004
0,008
0,015
0,03
0,06
0,12
0,25
0,5 1 2 4 8 16 32 64
128
256
Moxifloxacine
Levofloxacine
Ciprofloxacine
Clarithromycine
Doxycycline
J.Verhaegen et al. ECCMID 2003
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27. PK/PD in action … Levofloxacin 500 mg 1X / day AUC [(mg/l)xh] 47
Kritisch punt PK/PD 20 40 60 80
100
0.015
0.03
0.06
0.125
0.25
0.5 1 2 4
MIC
% gevoelige stammen
Levofloxacin 500 mg
1X / day
AUC [(mg/l)xh] 47
peak [mg/l]
MICmax < 0.5
moxi
levo
Moxifloxacin 400 mg
1X /day
AUC [(mg/l)xh] 48
peak [mg/l]
MICmax < 0.5
MIC data: J. Verhaegen et al., 2003
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28. Kunnen we de oefening maken voor P. aeruginosa?
Verdeling van de MIC-waarden van P. aeruginosa 50
100
150
0,02
0,06
0,19
PK/PD-limiet voor levo 500 mg: meer dan 60 % van de stammen die "gevoelig" genoemd worden ontsnappen… 4 12 32
0,5
1,5
J. van Eldere, 2003
oflox
levo
cipro
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29. Kunnen we de oefening maken in België?
Verdeling van de MIC-waarden van P. aeruginosa
Levo 1000 mg:
30 % van de stammen
die "gevoelig"
genoemd worden
ontsnappen nog steeds...
J. van Eldere, 2003
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30. Et pour la cipro … v-à-v de Pseudomonas …en Belgique ?
Distribution des CMI de Ps. aeruginosa
Cipro 1200 mg
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31. Therefore, new breakpoints …
Van Bambeke F, Michot JM, Van Eldere J, Tulkens PM. Quinolones in 2005: an update. Clin Microbiol Infect Apr;11(4): PMID:
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32. Rational principles for choosing a fluoroquinolone
Know your local epidemiology…
get MIC-distributions …
Compute (or have someone computing for you) the PK profile that will ensure > 90 % efficacy and prevention of resistance for the organims you are facing (in terms of peaks and AUC)
get some safety margin (MPC …)
Compare the offers …
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33. I hope you enjoyed… and we thank … The Belgian surrealism…
W.A. Craig, MD
MMM. Dudley, Pharm.
G.L. Drusano, MD
J.J. Schentag, Pharm.
A. McGowan, MD
X. Zao, PhD
V. Firsov, MD
S. Zinner, MD
A. Dalhoff, PhD
...
The Belgian peaks and troughs …
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