School of Pharmaceutical Sciences, Taishan Medical University, Taian, Shandong Province, China.
Respiration Medicine, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.
Int J Antimicrob Agents. 2017 Sep;50(3):399-405. doi: 10.1016/j.ijantimicag.2017.03.015. Epub 2017 Jun 30.
Candida albicans is the most commonly isolated Candida spp. in the clinic and its resistance to fluconazole (FLC) has been emerging rapidly. Combination therapy may be a potentially effective approach to combat drug resistance. In this study, the combination antifungal effects of dexamethasone (DXM) and FLC against resistant C. albicans in vitro were assayed using minimum inhibitory concentrations (MICs), sessile MICs and time-kill curves. The in vivo efficacy of this drug combination was evaluated using a Galleria mellonella model by determining survival rate, fungal burden and histological damage. In addition, the impact of DXM on efflux pump activity was investigated using a rhodamine 6G assay. Expression of CDR1, CDR2 and MDR1 was determined by real-time quantitative PCR, and extracellular phospholipase activity was detected by the egg yolk agar method to reveal the potential synergistic mechanism. The results showed that DXM potentiates the antifungal effect of FLC against resistant C. albicans strains both in vitro and in vivo, and the synergistic mechanism is related to inhibiting the efflux of drugs and reducing the virulence of C. albicans.
白色念珠菌是临床上最常分离到的念珠菌属，其对氟康唑（FLC）的耐药性迅速出现。联合治疗可能是一种对抗耐药性的潜在有效方法。在这项研究中，通过最小抑菌浓度（MIC）、固着 MIC 和时间杀伤曲线测定了地塞米松（DXM）和 FLC 联合抗耐药白色念珠菌的体外抗真菌作用。通过测定存活率、真菌负荷和组织学损伤，使用大蜡螟模型评估了这种药物组合的体内疗效。此外，还通过罗丹明 6G 测定法研究了 DXM 对流出泵活性的影响。通过实时定量 PCR 测定 CDR1、CDR2 和 MDR1 的表达，通过卵黄琼脂法检测细胞外磷脂酶活性，揭示潜在的协同作用机制。结果表明，DXM 增强了 FLC 对耐药白色念珠菌株的体外和体内抗真菌作用，协同作用机制与抑制药物外排和降低白色念珠菌毒力有关。
