Department of Medicine, Division of Infectious Diseases, Wayne State University, Detroit, MI, USA.
J Antimicrob Chemother. 2010 Apr;65(4):701-3. doi: 10.1093/jac/dkq020. Epub 2010 Feb 3.
Zygomycosis is an uncommon but devastating disease with few therapeutic options. Calcineurin inhibitors and sirolimus (mTOR inhibitor), commonly used in transplant patients as immunosuppressives, have antifungal activity. They are known to demonstrate synergy with triazoles against certain fungi, though limited data exist about their activity against zygomycetes. Our aim was to study the in vitro interaction of posaconazole with calcineurin inhibitors and sirolimus against zygomycetes.
Drug interactions were assessed with chequerboard dilution for posaconazole with calcineurin inhibitors and sirolimus according to the CLSI M38-A2 method for filamentous fungi. Twenty-eight clinical isolates were studied, including Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, Mucor sp., Cunninghamella bertholletiae, Myocladus corymbifera and Apophysomyces elegans. Combinations of posaconazole with tacrolimus, cyclosporin A or sirolimus were used. Experiments were performed in duplicate. Mean fractional inhibitory concentration indices were calculated.
Posaconazole with calcineurin inhibitors demonstrated consistent synergy against C. bertholletiae, M. corymbifera and A. elegans, whereas synergy or no interaction was primarily observed against R. arrhizus, R. microsporus, R. pusillus and Mucor. Antagonism was seen with the combination of posaconazole and sirolimus. Strain variability was noted among the same species.
The clinical significance of these findings is unclear, but further studies are warranted given the potential for concomitant use of these agents in transplant patients treated for zygomycosis.
接合菌病是一种罕见但具有破坏性的疾病，治疗选择有限。钙调神经磷酸酶抑制剂和西罗莫司（mTOR 抑制剂）通常作为免疫抑制剂用于移植患者，具有抗真菌活性。已知它们与唑类药物对某些真菌具有协同作用，但关于它们对接合菌的活性的数据有限。我们的目的是研究泊沙康唑与钙调神经磷酸酶抑制剂和西罗莫司联合应用于接合菌的体外相互作用。
根据 CLSI M38-A2 方法对丝状真菌进行棋盘稀释，评估泊沙康唑与钙调神经磷酸酶抑制剂和西罗莫司的药物相互作用。研究了 28 株临床分离株，包括根毛霉、微小根毛霉、少根根毛霉、毛霉、毛霉、冠状弯孢霉和拟外瓶霉。使用泊沙康唑与他克莫司、环孢素 A 或西罗莫司联合。实验重复进行。计算平均部分抑菌浓度指数。
钙调神经磷酸酶抑制剂与泊沙康唑联合使用对 C. bertholletiae、M. corymbifera 和 A. elegans 表现出一致的协同作用，而对 R. arrhizus、R. microsporus、R. pusillus 和毛霉则主要表现为协同作用或无相互作用。泊沙康唑与西罗莫司联合使用则表现出拮抗作用。同一物种的菌株变异性也有观察到。
这些发现的临床意义尚不清楚，但鉴于这些药物在移植患者中同时用于治疗接合菌病的潜在可能性，需要进一步研究。
