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

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.

Antioxidant and Antifungal Activity of Naphthoquinones Dimeric Derived from Lawsone

“…The secretion of extracellular phospholipases is considered a key attribute that aids in the invasion of the host mucosal epithelia. In general, phospholipases catalyse the hydrolysis of phospholipids, which are the major components of all cell membranes [11] [12]. So the amount of these enzymes is important as well as their presence [8].…”

Postantifungal Effect of Antifungal Drugs against Candida: What Do We Know and How Can We Apply This Knowledge in the Clinical Setting?

“…The in vivo models most commonly used to study the properties of antimicrobials are mice [ 46 ]. In fact, in all in vivo studies in which the PAFE was analyzed, murine models of infection were employed to determinate the PD characteristics of the antifungal drugs against Candida [ 47 , 48 , 49 , 50 , 51 , 52 ].…”

“…The in vivo PAFE of anidulafungin, posaconazole and ravuconazole on C. albicans , Candida glabrata and Candida tropicalis has been reported in different studies [ 47 , 49 , 50 ]. The studied animals were ICR/Swiss specific-pathogen-free female, CD1 male [ 51 ] and DBA/2 male mice [ 52 ].…”

“…The Candida inoculum to create the infection in the neutropenic mice was 10 4 –10 6 CFU/mL. Disseminated infection was achieved injecting a determinate inoculum via the lateral tail vein from 2–5 h prior to the start of drug therapy [ 47 , 49 , 50 , 51 , 52 ].…”

“…From 1–2 h after infection with Candida , mice were treated with intraperitoneal doses of anidulafungin, posaconazole, ravuconazole [ 47 , 49 , 50 ], isavuconazole, [ 51 ], fluconazole, itraconazole or ketoconazole [ 52 ]. Groups of three or four treated and control mice were sacrificed at determinate sampling intervals over a total period of between 3 and 4 days.…”