1. eccmid 2003 Aminoglycosiden bij neonaten Canisius-Wilhelmina Hospital Nijmegen, The Netherlands Johan W Mouton Relationship between bacterial killing, MIC and antibacterial effect

2. eccmid 2003 Killing by Beta-lactams are time-dependent. It is often assumed that concentrations need to be above the MIC, and if concentrations decline below the MIC regrowth occurs. There is no PAE. Is this true? And Why?

3. eccmid 2003 Aminoglycosides have a PAE in vivo: bacteria do not regrow immediately when concentrations decline below the MIC. Why? In vivo time kill curve

4. eccmid 2003 Patterns of activity: Kill curves of P. aeruginosa ceftazidimetobramycin

5. eccmid 2003 Figure 5 1a 1b 3.59 h -1 13.4 h -1 Steep Shallow

6. eccmid 2003 Antibiotics showing increasing effect (killing) over a wide range of concentrations are called ‘concentration dependent’. In vivo effects are usually AUC and/or Peak related. Those with a limited range of increasing effect are called (wrongly) ‘concentration- independent’. In vivo effects are usually Time >MIC related.

7. eccmid 2003 Pk/Pd models Emax model

8. eccmid 2003 Effect of Hill coefficient  EC 50 Emax  =10  =1

9. eccmid 2003 Figure 9 1a 1b 3.59 h -1 13.4 h -1 Steep Shallow  high :steep slope 'concentration independent'  low: shallow slope 'concentration dependent'

10. Since results from killing curves are growth + kill the killing rate has to be corrected for growth

11. eccmid 2003 P.aeruginosa cfu over time simulation

12. eccmid 2003 Effect Modelling The number of bacteria at a certain point of time is the result of the initial inoculum + growth + kill Function of bacterial growth over time Function of bacterial kill over time

13. eccmid 2003 Function of bacterial growth Function of bacterial growth with Nmax Growth rate

14. eccmid 2003 Function of Bacterial Kill Function of bacterial kill over time

15. eccmid 2003 (1) GrowthKill Mouton et al 1997 Growth rateMax kill rate

16. eccmid 2003 (2)

17. eccmid 2003 We are not so much interested in number of bacteria / the change of bacteria over time as a function of concentration We ARE interested in the CONCENTRATIONS at which certain events occur (static effects, max effects etc) The equations therefore have to be rewritten with C as the ‘dependent’ variable Effects vs concentration : chickens and eggs

18. eccmid 2003 (4)ln(5)

19. eccmid 2003 Static concentrations :N(t)=N(0)

20. eccmid 2003 Static Concentration (SC)= (7) The static concentration If concentrations are higher, bacteria are killed. If concentrations are lower, they grow

21. eccmid 2003 The MIC is read after 18h incubation And thus is a result of growth and killing over time rather than a parameter for a specific moment in time (such as the SC is) The big question : Now, what about the MIC ??

22. eccmid 2003 MIC = SC ??

23. eccmid 2003 (8) N(0) is beginning inoculum = 5. 10 5 t = 18h N(t) = 0 - 10 8

24. eccmid 2003 =

25. Thus, bacteria do NOT regrow when concentrations decline below the MIC but DO when below the SC What is the quantitative relationship between MIC and SC? Growthrate in vitro vs growth in vivo Max kill rate  equal Hill slope  equal Time t 18h vs 0 h

26. eccmid 2003 Figure 26 Conc independent Conc dependent tobramycin meropenem

27. eccmid 2003 Figure 27

28. eccmid 2003 If  is high, the MIC more or less equals the SC Decreasing  results is an increase of the MIC/SC ratio Relationship MIC and SC

29. eccmid 2003 For concentration independent drugs the MIC ~ SC. This explains why regrowth occurs when concentrations decline below the MIC For most concentration dependent drugs, the MIC = SC. The SC is lower. This may, in part, explain the PAE of some drugs and the relation with AUC rather than T>MIC Conclusions