Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect

被引:75
作者
Zhai, Bing [1 ]
Zhou, Henry [2 ]
Yang, Liangpeng [3 ]
Zhang, Jun [2 ]
Jung, Kathy [4 ]
Giam, Chou-Zen [3 ]
Xiang, Xin [2 ]
Lin, Xiaorong [1 ]
机构
[1] Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA
[2] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA
[3] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA
[4] NIAAA, Rockville, MD 20852 USA
基金
美国国家卫生研究院;
关键词
antifungal; combination therapy; antibiotic; fungal membrane; SUSCEPTIBILITY TESTING METHODS; VAR. GRUBII SEROTYPE; CRYPTOCOCCAL MENINGITIS; ANTIMICROBIAL PEPTIDE; SACCHAROMYCES-CEREVISIAE; INTRAVENOUS COLISTIN; ANTIFUNGAL AGENTS; DRUG-RESISTANCE; THERAPY; AIDS;
D O I
10.1093/jac/dkq046
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
The objective of this study was to identify existing clinical compounds that either possess a fungicidal activity alone or can act synergistically with fungistatic antifungals. We screened a clinical compound library for drugs that exhibited anti-Aspergillus activity. Among selected compounds, the cationic peptide antibiotic polymyxin B was chosen for further characterization because it can be used parenterally and topically. The fungicidal effect of polymyxin B and its synergistic interactions with azole antifungals were tested against a variety of fungal species. The toxicity of the drug combination of polymyxin B and fluconazole was compared with that of each drug alone in mammalian cell cultures. We found that polymyxin B possesses a broad-spectrum antifungal activity at relatively high concentrations. However, because of its synergistic interactions with azole antifungals, polymyxin B at much lower concentrations exerts a potent fungicidal effect against Cryptococcus neoformans, Candida albicans and non-albicans Candida species and moulds when combined with azoles. The combination of polymyxin B and fluconazole at concentrations within susceptible breakpoints is particularly potent against C. neoformans isolates, including fluconazole-resistant strains. The drug combination displayed no additional toxicity compared with polymyxin B alone when tested in cell culture. The combination of polymyxin B and fluconazole has the potential to be used in the clinic to treat systemic cryptococcosis. Our findings suggest that combining cationic peptide antibiotics with azole antifungals could provide a new direction for developing novel antifungal therapies.
引用
收藏
页码:931 / 938
页数:8
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