Voriconazole efficacy against Candida glabrata and Candida krusei: Preclinical data using a validated in vitro pharmacokinetic/pharmacodynamic model

Abstract

Background: Voriconazole exhibits in vitro activity against Candida glabrata and Candida krusei (EUCAST/CLSI epidemiological cut-off values 1/0.25 and 1/0.5 mg/L, respectively). Yet, EUCAST found insufficient evidence to set breakpoints for these species. We explored voriconazole pharmacodynamics (PD) in an in vitro dynamic model simulating human pharmacokinetics (PK). Methods: Four C. glabrata and three C. krusei isolates (voriconazole EUCAST and CLSI MICs of 0.03-2 mg/L) were tested in the PK/PD model simulating voriconazole exposures (t½ ∼6 h q12h dosing for 3 days). PK/PD breakpoints were determined calculating the PTA for exposure indices fAUC0-24/MIC associated with half-maximal activity (EI50) using Monte Carlo simulation analysis. Results: Fungal load increased from 3.60±0.35 to 8.41±0.24 log10 cfu/mL in the drug-free control, with a maximum effect of ∼1 log10 kill of C. glabrata and C. krusei isolates with MICs of 0.06 and 0.25 mg/L, respectively, at high drug exposures. The 72 h log10 cfu/mL change versus fAUC0-24/MIC relationship followed a sigmoid curve for C. glabrata (R2=0.85-0.87) and C. krusei (R2=0.56-0.76) with EI50 of 49 (32-76) and 52 (33-78) fAUC/MIC for EUCAST and 55 (31-96) and 80 (42-152) fAUC/MIC for CLSI, respectively. The PTAs for C. glabrata and C. krusei isolates with EUCAST/CLSI MICs ≤0.125/≤0.06 mg/L were >95%. Isolates with EUCAST/CLSI MICs of 0.25-1/0.125-0.5 would require trough levels 1-4 mg/L; isolates with higher MICs would not attain the corresponding PK/PD targets without reaching toxicity. Conclusions: The in vitro PK/PD breakpoints for C. glabrata and C. krusei for EUCAST (0.125 mg/L) and CLSI (0.06 mg/L) bisected the WT populations. Trough levels of >4 mg/L, which are not clinically feasible, are necessary for efficacy against WT isolates.