Pharmacodynamics of antifungal combinations

J. Meletiadis

Author address: 

National Cancer Institute, Bethesda, USA

Abstract: 

Combination antifungal therapy is often employed to manage difficultto- treat fungal infections with the premise to increase the antifungal activity, decrease toxicity, broaden antifungal spectrum, and decrease emergence of resistant strains. However, antifungal combinations may be disadvantageous particularly when a negative pharmacodynamic interaction occurs. In order to assess in vitro pharmacodynamics of antifungal combinations, different methodologies have been employed such as the checkerboard broth dilution, agar diffusion and time-kill assays where drug effects on growth, metabolism and fungal killing are assessed turbidimertrically, colorimetrically or with viability assays. In vivo pharmacodynamics can be assessed in animal models based on tissue fungal burden, survival and other biomarkers, taking into account pharmacokinetic, toxicological and immunological factors. A central role in the analysis of the results obtained from in vitro and in vivo combination studies has the zero interaction theory, based on which a drug combination will be classified synergistic or antagonistic when its effect is greater or less, respectively, than the expected noninteractive effect determined from a zero interaction theory such as the Loewe additivity (LA) or Bliss independence (BI). The LA-based fractional inhibitory concentration index is the most commonly used model to assess antifungal combinations. Various other models have been developed in order to assess statistically departures from LA and BI such as the isobolographic analysis of LA and the three-dimensional response-surface analysis of BI. Response-surface modeling is an attractive approach because a mathematical equation is fitted to the entire data and interactions can be assessed statistically based on model parameters. Although different methodologies and analytical tools have been employed to assess antifungal combinations against Candida spp., Cryptococcus neoformans, Aspergillus spp. and other filamentous fungi, additive/independent to synergistic interactions were found for the combination of amphotericin B plus 5-fluctytosine or echinocandins and azoles plus echinocandins, terbinafine or 5-flucytosine whereas a more complicate pattern of interaction may exist for amphotericin B plus azoles with antagonism being the most potent interaction. However, the nature and magnitude of pharmacodynamic interactions may be strain dependent and different at different concentrations of antifungal drugs. Finally, pharmacodynamic synergy does not always correspond to therapeutic synergy and pharmacodynamic antagonism is not necessarily correlated with therapeutic failure. Therefore, pharmacodynamics of antifungal combinations should be properly analyzed and carefully translated in clinical settings.
2005

abstract No: 

S01.3

Full conference title: 

2nd Trends in Medical Mycology
    • TIMM 2nd (2010)