Koch Christian, Uhle Florian, Wolff Matthias, Arens Christoph, Schulte Astrid, Li Ling, Niemann Bernd, Henrich Michael, Rohrbach Susanne, Weigand Markus A, Lichtenstern Christoph
Department of Anesthesiology and Intensive Care Medicine, University Hospital of Giessen and Marburg, Giessen, Germany
Department of Anesthesiology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany.
Antimicrob Agents Chemother. 2015 Mar;59(3):1612-9. doi: 10.1128/AAC.04446-14. Epub 2014 Dec 29.
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 (low-dose 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.
棘白菌素已成为重症患者早期特异性抗真菌治疗的首选药物。体外研究和临床病例报告显示，棘白菌素治疗可能对心脏功能产生影响。我们研究的目的是评估棘白菌素诱导的心力衰竭。使用体内大鼠模型，我们评估了在经颈内静脉中心静脉应用阿尼芬净（低剂量组，2.5mg/kg体重[BW]；高剂量组，25mg/kg BW）、卡泊芬净（低剂量组，0.875mg/kg BW；高剂量组，8.75mg/kg BW）、米卡芬净（低剂量组，3mg/kg BW；高剂量组，30mg/kg BW）和安慰剂（0.9%氯化钠）后血流动力学参数及发生血流动力学衰竭的时间。收集左心室心脏组织，通过分光光度法测量来确定线粒体酶活性。还探讨了转录调节因子和线粒体初级转录本的mRNA表达、线粒体DNA（mtDNA）含量以及柠檬酸合酶活性。接受高剂量阿尼芬净或卡泊芬净的动物血流动力学功能立即下降。这些组中的所有受试者在观察期内死亡。未治疗的对照组中的每只动物均存活（P<0.001）。阿尼芬净和卡泊芬净低剂量组未观察到血流动力学衰竭。米卡芬净对心脏功能无影响。在分析线粒体酶活性和线粒体转录本时，我们发现棘白菌素给药与血流动力学衰竭风险之间无关联。需要进一步的实验研究来阐明棘白菌素心脏毒性作用的潜在机制。此外，需要进行随机对照临床试验来探索棘白菌素治疗对重症患者的临床影响。
