Effective concentration-based serum pharmacodynamics for antifungal azoles in a murine model of disseminated Candida albicans infection

Katsuyuki Maki,Shuji Kaneko

doi:10.1007/s13318-013-0122-4

Abstract

An assessment of the effective in vivo concentrations of antifungal drugs is important in determining their pharmacodynamics, and therefore, their optimal dosage regimen. Here we establish the effective in vivo concentration-based pharmacodynamics of three azole antifungal drugs (fluconazole, itraconazole, and ketoconazole) in a murine model of disseminated Candida albicans infection. A key feature of this study was the use of a measure of mycelial (m) growth rather than of yeast growth, and pooled mouse sera rather than synthetic media as a growth medium, for determining the minimum inhibitory concentrations (MICs) of azoles for C. albicans (denoted serum mMICs). The serum mMIC assay was then used to measure antifungal concentrations and effects as serum antifungal titers in the serum of treated mice. Both serum mMIC and sub-mMIC values reflected the effective in vivo serum concentrations. Supra-mMIC and mMIC effects exhibited equivalent efficacies and were concentration-independent, while the sub-mMIC effect was concentration-dependent. Following administration of the minimum drug dosage that inhibited an increase in mouse kidney fungal burden, the duration periods of these effects were similar for all drugs tested. The average duration of either the mMIC effect including the supra-mMIC effect, the sub-mMIC effect, or the post-antifungal effect (PAFE) were 6.9, 6.5 and 10.6 h, respectively. Our study suggests that the area under the curve for serum drug concentration versus time, between the serum mMIC and the sub-mMIC, and exposure time above the serum sub-mMIC after the mMIC effect, are major pharmacodynamic parameters. These findings have important implications for effective concentration-based pharmacodynamics of fungal infections treated with azoles.

Highlights

Accurate determination of antifungal pharmacodynamics is important both for successful drug discovery in animal models (Maki et al 2008) and for improving clinical outcomes with current antifungals by optimizing drug dosage regimens
Serum mMIC values and sub-mMIC values of the drugs were as follows: fluconazole, 0.5 and 0.13 lg/ml; itraconazole, 1 and 0.25 lg/ml; and ketoconazole, 0.5 and 0.13 lg/ml. These mMIC and sub-mMIC values were included as the effective concentrations in the in vivo pharmacodynamic investigation for our study (Maki et al 2007)
Antifungal pharmacodynamics can determine the relationship between drug exposure and outcome (Andes 2003; Theuretzbacher et al 2006), with drug exposure being influenced by drug concentration and exposure time

Summary

Introduction

Accurate determination of antifungal pharmacodynamics is important both for successful drug discovery in animal models (Maki et al 2008) and for improving clinical outcomes with current antifungals by optimizing drug dosage regimens. Defined synthetic media were used in in vitro methods such as the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee for Clinical Laboratory Standards, NCCLS) microdilution reference method (CLSI 2008, NCCLS 2002) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) agar disk diffusion test (Lass-Florl et al 2008) for determining MICs. Defined synthetic media were used in in vitro methods such as the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee for Clinical Laboratory Standards, NCCLS) microdilution reference method (CLSI 2008, NCCLS 2002) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) agar disk diffusion test (Lass-Florl et al 2008) for determining MICs These dose-based investigations were used to indicate the optimal clinical dose regimen for improving efficacy and for prediction of the clinical outcome against susceptible and resistant pathogens (Lee et al 2000; Pai et al 2007; Clancy et al 2005). These MIC data contributed to progress in antifungal therapy, the values do not. There are no criteria for determining sub-MIC values using such methods, and the sub-MIC effect cannot be discriminated from the post-antifungal effect (PAFE)

Methods

Results

Conclusion