Evaluation of Hepatotoxicity with Treatment Doses of Flucytosine and Amphotericin B for Invasive Fungal Infections.

Alexandra Folk,Anca Hermenean,Coralia Cotoraci,Aurel Ardelean,Lucian Paiusan,Maria Suciu,Hildegard Herman,Oana Maria Boldura,Sorina Dinescu,Cornel Balta

doi:10.1155/2016/5398730

Abstract

Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 μg/kg amphotericin B; 100 mg/kg flucytosine and 600 μg/kg amphotericin B; 150 mg/kg flucytosine and 900 μg/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-α, IL-6, and NF-κB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-α and IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-κB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-κB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.

Highlights

Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients, including those with transplantation, hematological malignancies, or corticosteroid therapy.Three classes of antifungal agents are extensively used for treatment of systemic fungal infections: polyenes, azoles, and echinocandins
Based on the well-established side-effect profiles for both monotherapies of flucytosine and amphotericin B, we aimed to evaluate the hepatotoxicity induced by combined therapy, at increasing doses
Flucytosine-amphotericin B cotreatment increased the number of cells labeled with IL-6 antibody in dose-dependent manner (Figure 2 A(b–d))

Summary

Introduction

Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients, including those with transplantation, hematological malignancies, or corticosteroid therapy. Three classes of antifungal agents are extensively used for treatment of systemic fungal infections: polyenes, azoles, and echinocandins. The polyene class of antifungal drugs is divided into conventional polyenes B-deoxycholate) and lipid-based formulations of amphotericin B. Polyenes are recommended in cases of intolerance to azoles or echinocandins, when the organism becomes resistant to other agents, or in the case of uncertainty infection due to non-Candida yeast [1]. Amphotericin B was the first antifungal drug available to treat systemic fungal infections, commonly used in cases of most yeasts and filamentous fungi, disseminated candidiasis, and invasive pulmonary aspergillosis [2]. Its primary mechanism of action acts via binding to ergosterol, located in the BioMed Research International

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