Tome Miha, Zupan Jure, Tomičić Zorica, Matos Tadeja, Raspor Peter
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Biotechnology, Microbiology, and Food Safety, Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
PeerJ. 2018 Jun 13;6:e4999. doi: 10.7717/peerj.4999. eCollection 2018.
Candidemia and other forms of invasive fungal infections caused by and to a lesser extent are a serious health problem, especially if their steadily rising resistance to the limited range of antifungal drugs is taken into consideration. Various drug combinations are an attractive solution to the resistance problem, and some drug combinations are already common in the clinical environment due to the nature of diseases or therapies. We tested a few of the common antifungal-immunomodulatory drug combinations and evaluated their effect on selected strains of and . The combinations were performed using the checkerboard microdilution assay and interpreted using the Loewe additivity model and a model based on the Bliss independence criterion. A synergistic interaction was confirmed between calcineurin inhibitors (Fk506 and cyclosporine A) and antifungals (fluconazole, itraconazole, and amphotericin B). A new antagonistic interaction between mycophenolic acid (MPA) and azole antifungals was discovered in non-resistant strains. A possible mechanism that explains this is induction of the Cdr1 efflux pump by MPA in ATCC 2001. The Pdr1 regulatory cascade plays a role in overall resistance to fluconazole, but it is not essential for the antagonistic interaction. This was confirmed by the CgΔ mutant still displaying the antagonistic interaction between the drugs, although at lower concentrations of fluconazole. This antagonism calls into question the use of simultaneous therapy with MPA and azoles in the clinical environment.
念珠菌血症以及由白色念珠菌引起的其他形式的侵袭性真菌感染，在较小程度上也包括热带念珠菌引起的感染，是一个严重的健康问题，尤其是考虑到它们对有限种类抗真菌药物的耐药性在稳步上升。各种药物组合是解决耐药问题的一个有吸引力的方案，并且由于疾病或治疗的性质，一些药物组合在临床环境中已经很常见。我们测试了一些常见的抗真菌 - 免疫调节药物组合，并评估了它们对选定的白色念珠菌和热带念珠菌菌株的作用。这些组合通过棋盘微量稀释法进行，并使用洛氏加和模型以及基于布利斯独立性标准的模型进行解释。证实了钙调神经磷酸酶抑制剂（FK506和环孢素A）与抗真菌药物（氟康唑、伊曲康唑和两性霉素B）之间存在协同相互作用。在非耐药菌株中发现了霉酚酸（MPA）与唑类抗真菌药物之间一种新的拮抗相互作用。对此一种可能的解释机制是，MPA在白色念珠菌ATCC 2001中诱导了Cdr1外排泵。Pdr1调节级联在对氟康唑总的耐药性中起作用，但对于这种拮抗相互作用并非必不可少。这通过CgΔ突变体仍显示出药物之间的拮抗相互作用得到证实，尽管氟康唑浓度较低。这种拮抗作用对临床环境中MPA与唑类药物联合治疗的使用提出了质疑。
