Cardiac toxicity of some echinocandin antifungals

Stover, Kayla R.; Farley, Jerry M.; Kyle, Patrick B.; Cleary, John D.

doi:10.1517/14740338.2013.829036

Cited by 27 publications

(40 citation statements)

References 25 publications

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“…Arrhythmias were not described after antifungal drug administration in the Langendorff studies or in our ICU patients (12,13). The effects of echinocandin treatment observed in our in vivo and in vitro studies, in the Langendorff heart studies, and in the published case reports were rapid.…”

Section: Discussionmentioning

confidence: 55%

“…In agreement with the data on cardiac side effects seen in our ICU patients after echinocandin administration (12) and case reports of hemodynamic instability (19) and pulmonary edema (20) during anidulafungin administration, we found decreased cardiac function after treatment with anidulafungin and caspofungin. Ex vivo cardiotoxicity studies in rats performed with a Langendorff heart model revealed similar findings (13). We searched the FDA Adverse Events Reporting System (FAERS) database and found four cases of arrhythmias and cardiac failure which may also reflect cardiac events after echinocandin administration (21).…”

Section: Discussionmentioning

confidence: 85%

“…Otherwise, cardiovascular decompensation in critically ill patients is common, so echinocandin-related side effects may have been considered a result of the primary disease. Stover et al (13,15) suggest that there are different possible mechanisms of drug-induced cardiotoxicity, including direct toxic effects, alterations in mitochondrial oxidative function, modulation of cardiac gene expression, alterations in myocyte protein synthesis/function, apoptosis, oxidative stress/free-radical generation, neurohormonal activation, and arrhythmia (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Following these approaches, we performed hemodynamic measurements after central venous administration of anidulafungin, caspofungin, and micafungin in clinically relevant concentrations in adult male rats to assess echinocandin-induced cardiotoxicity. Previous studies claimed that mitochondrial toxicity is the underlying mechanism behind echinocandin-induced cardiac failure (13,15). To test this hypothesis in our model, we also determined left ventricular mitochondrial enzyme activity.…”

mentioning

confidence: 94%

“…Development of septic cardiomyopathy reflects a crucial pathogenic part of hemodynamic instability in septic shock that aggravates tissue hypoperfusion and organ failure (11). Cardiac effects following echinocandin administration were seen in our ICU patients (12), in isolated rat hearts (Langendorff model) (13), and in isolated cardiomyocytes of rats (14). Following these approaches, we performed hemodynamic measurements after central venous administration of anidulafungin, caspofungin, and micafungin in clinically relevant concentrations in adult male rats to assess echinocandin-induced cardiotoxicity.…”

mentioning

confidence: 99%

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Cardiac Effects of Echinocandins after Central Venous Administration in Adult Rats

Koch

Uhle

Wolff

et al. 2015

Antimicrob Agents Chemother

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Echinocandins have become the agents of choice for early and specific antifungal treatment in critically ill patients. In vitro studies and clinical case reports revealed a possible impact of echinocandin treatment on cardiac function. The aim of our study was to evaluate echinocandin-induced cardiac failure. Using an in vivo rat model, we assessed hemodynamic parameters and time to hemodynamic failure after central venous application (vena jugularis interna) of anidulafungin (lowdose group, 2.5 mg/kg body weight [BW]; high-dose group, 25 mg/kg BW), caspofungin (low-dose group, 0.875 mg/kg BW; high-dose group, 8.75 mg/kg BW), micafungin (low-dose group, 3 mg/kg BW; high-dose group, 30 mg/kg BW), and placebo (0.9% sodium chloride). Left ventricular heart tissue was collected to determine mitochondrial enzyme activity via spectrophotometric measurements. mRNA expression of transcriptional regulators and primary mitochondrial transcripts, mitochondrial DNA (mtDNA) content, and citrate synthase activity were also explored. Animals receiving high-dose anidulafungin or caspofungin showed an immediate decrease in hemodynamic function. All of the subjects in these groups died during the observation period. Every animal in the untreated control group survived (P < 0.001). Hemodynamic failure was not noticed in the anidulafungin and caspofungin low-dose groups. Micafungin had no impact on cardiac function. In analyzing mitochondrial enzyme activity and mitochondrial transcripts, we found no association between echinocandin administration and the risk for hemodynamic failure. Further experimental studies are needed to elucidate the underlying mechanisms involved in cardiotoxic echinocandin effects. In addition, randomized controlled clinical trials are needed to explore the clinical impact of echinocandin treatment in critically ill patients.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

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Cardiac Effects of Echinocandins after Central Venous Administration in Adult Rats

Koch

Uhle

Wolff

et al. 2015

Antimicrob Agents Chemother

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Anidulafungin liposome nanoparticles exhibit antifungal activity against planktonic and biofilm Candida albicans

Vera‐González

Bailey‐Hytholt

Langlois

et al. 2020

J Biomedical Materials Res

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Fungal infections can cause significant patient morbidity and mortality. Nanoparticle therapeutics have the potential to improve treatment of these infections. Here we report the development of liposomal nanoparticles incorporating anidulafungin, a potent antifungal, with the goal of increasing its solubility and aiding in localization to fungi. Liposomes were fabricated with three concentrations of anidulafungin yielding monodisperse ~100 nm unilamellar vesicles. All three formulations inhibited planktonic Candida albicans growth at a minimum inhibitory concentration equivalent to free drug. All three formulations also disrupted preformed C. albicans biofilms, reducing fungal burden by as much as 99%, exhibiting superior biofilm disruption compared with free drug. Liposome formulations tested in vivo in C. albicans infected Galleria mellonella wax moth larvae demonstrated increased survival compared to free drug equivalents, leading to a survival of 33 to 67% of larvae over 7 days depending on the liposome utilized compared with only 25% survival of larvae administered free drug. Liposomal formulations along with free anidulafungin did not cause red blood cell lysis. Ultimately, the liposome formulations reported here increased anidulafungin solubility, displayed promising efficacy against planktonic and biofilm C. albicans, and improved the survival of C. albicans–infected G. mellonella compared to free anidulafungin.

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Effects of echinocandin preparations on adult rat ventricular cardiomyocytes

et al. 2014

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BackgroundCandida infections represent a relevant risk for patients in intensive care units resulting in increased mortality. Echinocandins have become the agents of choice for early and specific antifungal treatment in critically ill patients. Due to cardiac effects following echinocandin administration seen in intensive care unit (ICU) patients the in vitro effects of echinocandins and fluconazole on isolated cardiomyocytes of the rat were examined.AimThe study was designed to investigate a possible impact of echinocandins and fluconazole in clinically relevant concentrations on the in vitro contractile responsiveness and shape of isolated rat cardiomyocytes.Material and methodsVentricular cardiomyocytes were isolated from Lewis rats. Cardiomyocytes were cultured in the presence of all licensed echinocandin preparations and fluconazol at concentrations of 0 (control), 0.1, 1, 3.3, 10, 33 and 100 μg/ml for 90 min. Cells were stimulated by biphasic electrical stimuli and contractile responsiveness was measured as shortening amplitude. Additionally, the ratio of rod-shaped to round cells was determined.ResultsAnidulafungin concentrations of 3.3 and 10 μg/ml caused a significant increase in contractile responsiveness, caspofungin showed a significant decrease at 10 μg/ml and micafungin concentrations of 3.3–33 μg/ml led to a significant increase in cell shortening. Measurement was not possible at 33 μg/ml for anidulafungin and caspofungin and at 100 μg/ml for all echinocandins due to a majority of round-shaped, non-contracting cardiomyocytes. Fluconazole showed no significant effect on cell shortening at all concentrations tested. For the three echinocandins the ratio of round-shaped, non-contracting versus rod-shaped normal contracting cardiomyocytes increased in a dose-dependent manner.ConclusionsEchinocandins impact the in vitro contractility of isolated cardiomyocytes of rats. This observation could be of great interest in the context of antifungal treatment.

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Cardiac toxicity of some echinocandin antifungals

Cited by 27 publications

References 25 publications

Cardiac Effects of Echinocandins after Central Venous Administration in Adult Rats

Cardiac Effects of Echinocandins after Central Venous Administration in Adult Rats

Anidulafungin liposome nanoparticles exhibit antifungal activity against planktonic and biofilm Candida albicans

Effects of echinocandin preparations on adult rat ventricular cardiomyocytes

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