舍曲林联合两性霉素B抗不同基因型隐球菌的效果

Anti-fungal effect of sertraline in combination with amphotericin B against different genotypes of Cryptococcus neoformans and Cryptococcus gattii

目的探究舍曲林(SERT)及其联合两性霉素B(Am B)抗不同基因型的隐球菌临床分离株的效果。方法通过多序列位点分型(MLST)的方法对63株脑脊液隐球菌临床分离株进行基因鉴定,并参照微量稀释法(M27-A3及M27-S4)对菌株进行体外单药[Am B、5-氟胞嘧啶(5-FC)、SERT]药敏实验及以分数抑菌浓度指数(FICI)为判定指标的联合药敏(Am B+SERT;Am B+5-FC)实验。结果 63株隐球菌中有59(93.6%)株为新型隐球菌,基因型均为VNI,其余4(6.4%)株为格特隐球菌,其中有3(4.8%)株为VGI,1(1.6%)株为VGⅡ。在Am B、5-FC、SERT的单药药敏实验中,敏感性降低的菌株均为VNI型,但各个基因型的药敏结果差异没有统计学意义(P>0.05)。在联合药敏实验中,Am B+SERT与Am B+5-FC有相似的协同作用比例(98.4%vs.92.1%),且前者的FICI更小(P<0.001)。结论舍曲林对不同基因型的隐球菌均具有较强的体外抗真菌活性,与Am B联合使用时能够发挥协同杀菌作用,推测舍曲林具有治疗隐球菌性脑膜炎的应用前景。

Objective This study evaluated sertraline（SERT）,alone and combined with amphotericin B（AmB）,correlating susceptibility to genotypes of clinical isolates of Cryptococcus neoformans and Cryptococcus gattii in vitro.Methods Multilocus sequence typing（MLST） was performed to genotype these cryptococcal isolates. Antifungal susceptibility was assessed for M27-A3 and S4 for AmB,5-flucytosine（5-FC）,and SERT. The lowest fractional inhibitory concentration index（FICI） was used to evaluate drug interaction of AmB ＋ SERT and AmB ＋ 5-FC, respectively. Results Among 63 strains of Cryptococcus,59（93.6%）were Cryptococcus neoformans,the genotypes were VNI,and the remaining4（6.4%）were Cryptococcus gattii,3（4.8%）were VGI,1（1.6%）was VGⅡ. In the single-drug susceptibility test of AmB,5-FC and SERT,the susceptible strains were all VNI-type,but there was no significant difference in drug susceptibility between different genotypes（P〈0.05）. AmB＋SERT had similar synergistic effects with AmB＋ 5-FC（98.4%vs.92.1%） in combined susceptibility testing,and the former had a smaller FICI（P〈0.001）. Conclusion Sertraline against different genotypes of Cryptococcus had strong antifungal activity in vitro,combined with AmB could play a synergistic bactericidal effect. This showed that sertraline had the potential for the treatment of cryptococcal meningitis.