Cardiac Effects of Echinocandins in Endotoxemic Rats

Abstract

cEchinocandins are known as effective and safe agents for the prophylaxis and treatment of different cohorts of patients with fungal infections. Recent studies revealed that certain pharmacokinetics of echinocandin antifungals might impact clinical efficacy and safety in special patient populations. The aim of our study was to evaluate echinocandin-induced aggravation of cardiac impairment in septic shock. Using an in vivo endotoxemic shock model in rats, we assessed hemodynamic parameters and time to hemodynamic failure (THF) after additional central-venous application of anidulafungin (2.5 mg/kg of body weight [BW]), caspofungin (0.875 mg/kg BW), micafungin (3 mg/kg BW), and control (0.9% sodium chloride). In addition, echinocandin-induced cytotoxicity was evaluated in isolated rat cardiac myocytes. THF of the animals in the caspofungin group (n ‫؍‬ 7) was significantly reduced compared to that in the control (n ‫؍‬ 6) (136 min versus 180 min; P ‫؍‬ 0.0209). The anidulafungin group (n ‫؍‬ 7) also showed a trend of reduced THF (136 min versus 180 min; log-rank test P ‫؍‬ 0.0578). Animals in the micafungin group (n ‫؍‬ 7) did not show significant differences in THF compared to those in the control. Control group animals and also micafungin group animals did not show altered cardiac output (CO) during our experiments. In contrast, administration of anidulafungin or caspofungin induced a decrease in CO. We also revealed a dose-dependent increase of cytotoxicity in anidulafungin-and caspofungin-treated cardiac myocytes. Treatment with micafungin did not cause significantly increased cytotoxicity. Further studies are needed to explore the underlying mechanism.

Caspofungin Modulates Ryanodine Receptor-Mediated Calcium Release in Human Cardiac Myocytes

“…However, critically ill patients suffering from multiple organ failure might be at high risk for excessive plasma levels, especially if CAS is infused rapidly via a central venous catheter. This might explain previous observations of sustained cardiac impairment following standard-dose administration of echinocandins in endotoxemic rats (10).…”

“…Mitochondrial damage was suspected as a result of analysis of isolated rat hearts in transmission electron microscopy following echinocandin infusion (7). In contrast to these findings, we were not able to identify mitochondrial damage in spectrophotometric measurements of rat left ventricular cardiac tissue or altered mitochondrial enzyme activity after echinocandin treatment (8,10). Therefore, we hypothesized that the mechanism behind CAS-induced cardiac alterations was not yet fully identified.…”

“…Since adverse effects of echinocandins have been observed especially in septic patients, endotoxemic rats were examined subsequently. While control and micafungin-treated animals did not show hemodynamic alterations, administration of anidulafungin or CAS in clinically used dosages led to a significant and dose-dependent decrease in cardiac output (10). Mitochondrial damage was suspected as a result of analysis of isolated rat hearts in transmission electron microscopy following echinocandin infusion (7).…”

“…Therefore, we hypothesized that the mechanism behind CAS-induced cardiac alterations was not yet fully identified. With respect to the hemodynamic impairment of endotoxemic rat hearts following echinocandin infusion and studies supporting an endotoxin-induced suppression of the L-channel-dependent calcium flow, we hypothesized that alterations in Ca 2ϩ homeostasis induced by echinocandins might be one potential harmful mechanism (10,(17)(18)(19).…”

The impact of real life treatment strategies for Candida peritonitis—A retrospective analysis

“…Thus, we cannot conclude that early treatment in these patients would have proven to be beneficial. It should also be considered that unnecessary antifungals may be associated with liver toxicity or haemodynamic impairment, and thus may contribute to additional morbidity or mortality in severely ill ICU patients. The overall outcome in severely ill patients does not only relate to the antifungal treatment, but also to operative procedure (eg source control).…”