In vitro models

Ref ID: 19471

Author:

J. Meletiadis

Author address:

Attikon Hospital, Medical School, University of Athens, Greece

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Understanding the pharmacodynamics of antifungal drugs is impor-
tant in drug development, selection of the most effective drug and
dosing regimen, determination of susceptibility breakpoints and guid-
ance of therapeutic drug monitoring (TDM). Although antifungal
pharmacodynamics can be studied with animal experiments and in
human trials, in vitro models are good alternatives because they are
flexible, adaptable, and low cost with good correlation with animal
and human data without raising ethical concerns. Several models
have been developed for studying the pharmacodynamics of antifun-
gal drugs against Candida and Aspergillus species. These models can
be divided in static models where drug concentration remains con-
stant over time and in dynamic models where drug concentration
changes over time simulating in vivo pharmacokinetics. Dynamic
models are further differentiated to open and closed systems depend-
ing on whether or not fungal loss occurs, respectively, and to dilu-
tion or dialysis/diffusion models on the basis of the mechanism of
drug loss. In both static and dynamic models, fungi can be present in planktonic or biofilm forms together with tissue cell barriers in order
to simulate specific sites of infection and phagocytes in order to simu-
late the immune system. Different routes of drug administration such
as intravenous bolus or infusion and extra-vascular administration
can be simulated. Fungal burden is usually quantified with CFU
counts for Candida spp and galactomannan production for Aspergillus
spp. The nutrient medium and incubation conditions (temperature,
agitation, flow) are important factors in order to provide adequate
growth and a homogenous environment. Pharmacokinetics of two or
more drugs in combination can be simulated in order to assess the
efficacy of combination regimens.
Microdilution methods are static models that are commonly used
to describe the in vitro activity of antifungal drugs. These models
provide single-time-point information about inhibitory or fungicidal
effects of constant drug concentrations. Dynamic models that simu-
late bloodstream infections and pharmacokinetics of standard dosing
regimens of antifungal drugs have been developed for Candida spp.
In these models, the effect of continuous infusion regimens was
compared with rapid infusion regimens of conventional amphoteri-
cin B and the combination of standard dosing regimens of fluconaz-
ole (400 mg q24) and voriconazole (4 mg/kg q12) with
amphotericin B (1 mg/kg q24) was assessed after staggered and
simultaneous administration. A catheter related bloodstream infec-
tion model was used to study the effect of antifungal drugs in the
eradication of catheter colonization. Candida endocardial vegetations
were simulated in an in vitro dynamic model in order to assess the
effect of single or combination regimens of antifungal drugs. A lung
and brain infection static models have been developed for Aspergillus
species and the effect of antifungal drugs, delayed therapy, macro-
phages and cytokines were investigated. Both open and closed
dynamic models were applied to Aspergillus species in order to dis-
sect the pharmacodynamics of azoles and amphotericin B. Extrapo-
lation of in vitro data to animals and humans is a real challenge
that requires validation of the in vitro models with in vivo outcome
taking into account other factors like protein binding and immune
system. These models were used to determine susceptibility break-
points and target values for TDM of voriconazole and amphotericin
B for Aspergillus species.
Concluding, static models are extensively used, easy to handle, and
well investigated providing basic information of antifungal pharma-
codynamics. This information can then be used in dynamic models
in order to explore the pharmacokinetic/pharmacodynamic relation-
ships of antifungal drugs. Specific sites of infections can also be simu-
lated incorporating tissue cells and immune cells. Validated models
could be useful for a comprehensive understanding of the pharmaco-
dynamics of antifungal drugs, optimization of dosing regimens, and
guidance of in vivo and clinical studies.

Abstract Number: w19.1

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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