Nguyen M H, Barchiesi F, McGough D A, Yu V L, Rinaldi M G
Department of Medicine, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Antimicrob Agents Chemother. 1995 Aug;39(8):1691-5. doi: 10.1128/AAC.39.8.1691.
Amphotericin B and fluconazole are current acceptable therapies for cryptococcal meningitis; however, their effect remains suboptimal. The combination of fluconazole and flucytosine has yielded encouraging clinical results in human immunodeficiency virus patients with cryptococcal meningitis. To investigate the biological basis of this finding, we performed in vitro combination testing of fluconazole and flucytosine against 50 clinical strains of Cryptococcus neoformans var. neoformans. Synergy (fractional inhibitory concentration index of < 1.0) was observed in 62% of cases, while antagonism (fractional inhibitory concentration index of > 2.0) was not observed. For cases in which synergy was not achieved (autonomous or additive effects), the beneficial effect of the combination was still seen (i.e., there was still a decrease, although not as dramatic, in the MIC of one or both drugs when used in combination). The in vitro inhibitory action of flucytosine was greatly enhanced by the addition of fluconazole; the flucytosine MICs for Cryptococcus isolates were markedly decreased to concentrations which were severalfold lower than the achievable cerebrospinal fluid flucytosine concentration. On the other hand, the addition of flucytosine did not greatly enhance the in vitro activity of fluconazole if the initial fluconazole MIC for the isolate was > or = 8 micrograms/ml. Controlled clinical studies are warranted to further elucidate the potential utility of fluconazole-flucytosine combination therapy.
两性霉素B和氟康唑是目前治疗隐球菌性脑膜炎可接受的疗法；然而，它们的效果仍不尽人意。氟康唑和氟胞嘧啶联合用药在患有隐球菌性脑膜炎的人类免疫缺陷病毒患者中已取得了令人鼓舞的临床效果。为了探究这一发现的生物学基础，我们对氟康唑和氟胞嘧啶针对50株新型隐球菌新型变种的临床菌株进行了体外联合试验。62%的病例观察到协同作用（分数抑菌浓度指数<1.0），而未观察到拮抗作用（分数抑菌浓度指数>2.0）。对于未实现协同作用的病例（自主或相加作用），联合用药的有益效果仍然可见（即，联合使用时，一种或两种药物的最低抑菌浓度仍有下降，尽管降幅不那么显著）。加入氟康唑后，氟胞嘧啶的体外抑制作用大大增强；新型隐球菌分离株的氟胞嘧啶最低抑菌浓度显著降低至比可达到的脑脊液氟胞嘧啶浓度低几倍的浓度。另一方面，如果分离株的初始氟康唑最低抑菌浓度≥8微克/毫升，加入氟胞嘧啶并不会大大增强氟康唑的体外活性。有必要进行对照临床研究，以进一步阐明氟康唑-氟胞嘧啶联合疗法的潜在效用。
