An in vitro and in vivo study on the synergistic effect and mechanism of itraconazole or voriconazole alone and in combination with tetrandrine against Aspergillus fumigatus.
An in vitro and in vivo study on the synergistic effect and mechanism of itraconazole or voriconazole alone and in combination with tetrandrine against Aspergillus fumigatus.
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DOI：
10.1099/jmm.0.000120
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发表时间：
2015-09
影响因子：
3
通讯作者：
Shui-xiu Li;Yanjun Song;Ling-Ling Zhang-Ling;Jian-Ping Shi;Zheng-lai Ma;Hui Guo;Hui Dong;Yiming Li;Hong Zhang
中科院分区：
文献类型：
--
作者：
Shui-xiu Li;Yanjun Song;Ling-Ling Zhang-Ling;Jian-Ping Shi;Zheng-lai Ma;Hui Guo;Hui Dong;Yiming Li;Hong Zhang
本研究采用棋盘微量稀释法研究了伊曲康唑/伏立康唑(ITR/VRC)及其与粉防己碱(Tet)合用对23株临床分离的烟曲霉菌的体外抗真菌作用。采用小鼠全身感染烟曲霉菌后的时间-杀灭曲线，动态评价了ITR/VRC Tet对烟曲霉菌的体内抗真菌作用。治疗后，用罗丹明6G(R6G)的外排量测定外排泵的活性。当ITR与TET合用时，ITR MIC由0.125-32降至0.0625-2μg ml(-1)，TET MICs由256-512降至8-μg ml(-1)。当Vrc与Tet合用时，Vrc MIC由0.125-2降至0.03125-0.5μg ml(-1)，Tet MIC由256-512降至8-256μg ml(-1)。时间-杀灭曲线显示，与单独使用ITR/VRC相比，ITR/VRC与Tet联合处理后，烟曲霉菌的存活率降低。与单独使用ITR/VRC相比，ITR/VRC联合Tet显著延长了小鼠的存活时间，减轻了肾脏和脑组织的负担(P<；0.05)。此外，Tet还能抑制烟曲霉菌R6G的外流。因此，在体内外，Tet与ITR/VRC对烟曲霉菌有协同作用，其协同作用机制与抑制药物外排泵有关。
In this study, we investigated the in vitro antifungal effects of itraconazole/voriconazole (ITR/VRC) alone and in combination with tetrandrine (TET) against 23 clinical isolates of A. fumigatus using a chequerboard microdilution method. The dynamic antifungal effects of TET with ITR/VRC against A. fumigatus were assessed in vivo using time-kill curves following systemic infection of mice with A. fumigatus. After treatment, efflux pump activity was determined by the efflux of rhodamine 6G (R6G). When ITR was combined with TET, ITR MICs were reduced from 0.125-32 to 0.0625-2 μg ml(-1), and TET MICs were reduced from 256-512 to 8-64 μg ml(-1). When VRC was combined with TET, VRC MICs were reduced from 0.125-2 to 0.03125-0.5 μg ml(-1), and TET MICs were reduced from 256-512 to 8-256 μg ml(-1). Time-kill curves revealed that A. fumigatus viability was reduced after treatment with ITR/VRC combined with TET versus ITR/VRC alone. ITR/VRC combined with TET significantly prolonged mouse survival and reduced kidney and brain tissue burdens versus ITR/VRC alone (P < 0.05). Moreover, TET inhibited R6G efflux of A. fumigatus. Thus, in vitro and in vivo, TET acted synergistically with ITR/VRC against A. fumigatus, and the synergistic mechanism was related to inhibition of the drug efflux pump.