Cardiac Safety of High-dose Micafungin

Pharmacotherapy in patients with systemic fungal infections continues to challenge the heartiest clinicians. The inability of the antimycotic to discriminate the infected eukaryotic host from the pathogen often leads to treatment‑limiting adverse events. In our continued efforts to improve the safety of antifungal therapy, we initiated studies to evaluate the dose, onset, peak, and duration of echinocandin‑induced cardiomyopathy. Over the past 5–6 years, a plethora of animal data and case reports has been published that describes this phenomenon. First, we performed ex vivo studies in an attempt to elucidate the toxicity of the echinocandin antifungals. Clear decreases in cardiac contractility were observed in adult male Sprague‑Dawley rat hearts after infusion of caspofungin and anidulafungin. To determine whether these displayed effects would translate to a live model, we performed in vivo studies in live, adult male Sprague‑Dawley rats. Blood pressure and echocardiography were evaluated before, during, and after a 10‑minute central infusion of caspofungin, anidulafungin, or micafungin. At doses known to replicate human pharmacologic exposures, caspofungin and anidulafungin were associated with significant decreases in cardiac output (CO). No changes were seen with micafungin. In a similar in vivo rat model, investigators evaluated the effect of high (8.75–30 mg/kg)‑ and low‑dose (0.875–3 mg/kg) echinocandin administration on cardiac function. Their results were similar to those described above: high‑dose anidulafungin and caspofungin showed immediate hemodynamic decreases, while animals treated with micafungin had no impact on cardiac function. Finally, several clinical reports of toxicity associated with these agents, ranging from pulmonary edema to cardiac decompensation, have substantiated this previous research. The purpose of this study was to expand assessments of cardiac toxicity to include a wider array of doses of micafungin to define dose and onset of this adverse event.