1. Pharmacodynamics of Antifungals
D. Andes
University of Wisconsin, Madison, WI

2. Value of Animal Models
Time course of drug concentrations at sites of infection
Time course of antimicrobial activity at sites of infection
Dose-response relationships
Correlation of PK/PD parameters with efficacy
Magnitude of PK/PD parameter required for efficacy

3. Fungal Densities in Kidneys of Mice Treated with Various Fluconazole Total Doses Administered in 1, 2, or 4 Divided Doses

5. We started with the azole, fluconazole.
Here is a graph of the single dose in vivo PAEs- where we determine the amount of time that organism growth is suppressed after serum drug levels have fallen below the MIC
Both doses were essentially static, with no reduction in counts from our zero time points
However, both doses significantly flattened the candida growth curves, keeping organisms in the kidneys from reaching the target 1 log growth for more a prolonged period.
We feel this long period of time represents a sub-mic effect as opposed to an actual PAE in the strictest sense
This has actually been demonstrated in-vitro by John Turnidge with Dr Craig more than 10 years ago
It took around 9 hours for candida to increase 1 log and grew nearly 3 log in 24 hours
The lower and higher fluconazole doses were calculated to remain above the MIC for around 9 and 14 hrs respectively

7. Patterns of Antimicrobial Activity
Time-dependent killing and prolonged persistent effects (duration related to AUC)
Seen with triazoles
Goal of dosing regimen: optimize amount of drug
AUC/MIC major parameter correlating with efficacy

8. Relationship Between 5-FC PK/PD and Efficacy

9. Patterns of Antimicrobial Activity
Time-dependent killing and minimal to moderate persistent effects
Seen with flucytosine
Goal of dosing regimen: optimize duration of exposure
Time above MIC major parameter correlating with efficacy

10. Relationship Between Amphotericin B PK/PDP and Efficacy

12. Patterns of Antimicrobial Activity
Concentration-dependent killing and prolonged persistent effects
Seen with amphotericin B, echinocandins,
Goal of dosing regimen: maximize concentrations
AUC/MIC and Peak/MIC major parameters correlating with efficacy

13. Relationship Between Fluconazole 24 h AUC/MIC and Outcome Against C
Relationship Between Fluconazole 24 h AUC/MIC and Outcome Against C. albicans with Varying MICs

14. Relationship Between Fluconazole Data Sets: AUC/MIC and Outcome Against C. albicans with Varying MICs

15. Fluconazole vs Murine Candidiasis in Literature

16. Fluconazole dose-response with 9 C
Fluconazole dose-response with 9 C. albicans strains with a >2000-fold susceptibility
Sorensen et. al. ICAAC 1999

17. Correlation of Animal Fluconazole PK/PD to Clinical Trials and Susceptibility Breakpoints

18. Fluconazole/Candidemia Correlation
34 patients, all species
Mean and median dose of 200 mg/day Success rates varied with MIC
MIC N Cure AUC/MIC Cure (95% )
< 8 (S) % (28-72%)
16-32 (SDD) % (0-64%)
> 32 (R) % (0-46%)
Clancy & Nguyen, IDSA 1998, #98

19. Fluconazole/Candidemia Correlation
32 patients, all species
Non-HIV (41% underlying malignancy)
Deep-seated infection (66% Blood stream infection)
Dose of 400 mg/day
Success rates varied with MIC
MIC N Cure AUC/MIC %Cure
< 8 (S)
16-32 (SDD)
> 32 (R)
Lee et al. AAC 2000;44:2715-8

20. PD for fluconazole and Candida
Translation to humans
If we use a target of 25, then
Loosely:1x above MIC for 24 hr = required dose
100 mg/day should treat up to  4 mg/l
400 mg/day should treat up to  16 mg/l
800 mg/day should treat up to  32 mg/l

21. Comparative Efficacy of Ravuconazole Against 8 Strains of C. albicans
Strains 24-h ED h AUC/MIC Free 24-h AUC/MIC* K
MEAN  SD  8.2
* p-value = 0.43

24. Antifungal PK/PD Summary
Drug Pattern PAE PK/PD Magnitude
Fluconzole Static Long AUC/MIC
5-FC Static Modest T>MIC
AmB Cidal Long Peak/MIC
Echinocandin Cidal Long Peak/MIC
Sordarins ? ? AUC/MIC ?