Pharmacodynamics of Antifungals

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Presentation transcript:

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

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

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

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

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

Relationship Between 5-FC PK/PD and Efficacy

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

Relationship Between Amphotericin B PK/PDP and Efficacy

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

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

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

Fluconazole vs Murine Candidiasis in Literature

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

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

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) 22 11 17 50% (28-72%) 16-32 (SDD) 6 1 1 8-4 7% (0-64%) > 32 (R) 6 0 2 0% (0-46%) Clancy & Nguyen, IDSA 1998, #98

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) 24 19 30 79 16-32 (SDD) 6 4 15-8 67 > 32 (R) 2 0 2 0 Lee et al. AAC 2000;44:2715-8

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

Comparative Efficacy of Ravuconazole Against 8 Strains of C. albicans Strains 24-h ED50 24-h AUC/MIC Free 24-h AUC/MIC* K-1 48.9 547 23.7 412 27.0 578 24.3 98-17 204 502 21.1 98-234 126 318 13.1 580 73.1 416 17.8 2512 34.2 390 16.4 2307 40.8 873 36.7 2183 41.8 238 10.0 MEAN  SD 20.3  8.2 * p-value = 0.43

Antifungal PK/PD Summary Drug Pattern PAE PK/PD Magnitude Fluconzole Static Long AUC/MIC 25 5-FC Static Modest T>MIC 25-50 AmB Cidal Long Peak/MIC 2 Echinocandin Cidal Long Peak/MIC 3-10 Sordarins ? ? AUC/MIC ?