Wiederhold Nathan P
University of Texas at Austin College of Pharmacy, Austin, Texas 78229, USA.
Med Mycol. 2009;47 Suppl 1:S369-75. doi: 10.1080/13693780802428542. Epub 2009 Feb 28.
The echinocandins have been a welcome addition for the treatment of invasive fungal infections. Despite their excellent safety profile and clinical efficacy, concerns exist regarding an attenuation of activity at higher concentrations, known as the paradoxical effect. In vitro studies have reported this phenomenon against both Candida and Aspergillus species. Recent data have also demonstrated this effect to be species-related and echinocandin specific. Although not completely understood, studies have pointed towards involvement of the protein kinase C cell wall integrity pathway as well as increases in cell wall chitin content as potential mechanisms responsible for this phenomenon. Increases in galactomannan have been reported in vitro and in vivo following echinocandin exposure. Although some in vivo studies of invasive aspergillosis have also reported a paradoxical increase in other markers of invasive disease and fungal burden with echinocandin therapy, these observations are inconsistent. The paradoxical effect has also not been demonstrated clinically. Thus, the clinical implications of the paradoxical attenuation of echinocandin activity at elevated concentrations remain unknown. A complete understanding of this effect may further our knowledge of fungal responses to echinocandin cell wall damage and potentially improve treatment strategies.
棘白菌素类药物已成为治疗侵袭性真菌感染的一项受欢迎的补充药物。尽管其具有出色的安全性和临床疗效，但对于较高浓度下活性减弱的情况仍存在担忧，这种现象被称为矛盾效应。体外研究已报道了针对念珠菌属和曲霉属的这一现象。近期数据也表明这种效应与菌种相关且具有棘白菌素特异性。尽管尚未完全了解，但研究指出蛋白激酶C细胞壁完整性途径的参与以及细胞壁几丁质含量的增加是导致这一现象的潜在机制。在棘白菌素暴露后，体外和体内均已报道半乳甘露聚糖增加。尽管一些侵袭性曲霉病的体内研究也报道了棘白菌素治疗后侵袭性疾病和真菌负荷的其他标志物出现矛盾性增加，但这些观察结果并不一致。矛盾效应在临床上也未得到证实。因此，棘白菌素在高浓度下活性出现矛盾性减弱的临床意义仍不明确。对这一效应的全面了解可能会增进我们对真菌对棘白菌素细胞壁损伤反应的认识，并有可能改善治疗策略。
