Cardiac Toxicity of Azole Antifungals

John D. Cleary, Kayla R. Stover, Jerry Farley, William Daley, Patrick B. Kyle, Jon Hosler

Department of Biochemistry, Jackson, USA..
Department of Pathology, Jackson, USA.
Department of Pharmacology and Toxicology, Jackson, USA.
University of Mississippi Schools of Medicine & Pharmacy, Jackson, USA.

DOI: 10.4236/pp.2013.43052                

Abstract

Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED₂₅ (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.

Keywords

Mycology; Azole Antifungals; Itraconazole; Animal Model

Conflicts of Interest

The authors declare no conflicts of interest.

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