Study on the effect of flunixin meglumine on the biofilm formation of Candida krusei and on the combination with azoles

Abstract

Abstract:

Objective This study was designed to evaluate the antifungal activity of flunixin meglumine (FM) against Candida krusei biofilm and the antifungal effects of azole combined with flunixin meglumine (FM) in vitro. Method Candida krusei clinically isolated from cows with fungal mastitis was used as a test strain. The antifungal activity of FM against Candida krusei was preliminarily investigated by measuring the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) by microdilution method. The effects of FM on the early 1-3h adhesion phase of Candida krusei biofilm formation and the mature biofilm after 24h were determined by XTT method and effects of cell surface hydrophobicity (CSH) were determined by Water-hydrocarbon two-phase. The static antifungal activity of FM combined with antifungal azoles against Candida krusei in vitro was detected by checkerboard method using the partial FICI as the detection index. Enzyme-labeled turbidimetry was used to plot the time-kill curves of different drugs after treatment. Results The MIC of FM single drug against Candida krusei was 0.625 mg/mL; FM could reduce cell surface hydrophobicity,FM had significant inhibitory effect on Candida krusei biofilm at different growth stages (early adhesion and maturation), and its inhibitory effect was time-and concentration-dependent. The FICI of FM combined with itraconazole against Candida krusei ranged from 0.5 to 1.5, showing synergistic/additive effects. The FICI index of FM combined with ketoconazole was ranged from 0.375 to 1.25, showing a synergistic/additive effect. In the time-kill curves, the combination of FM and azoles could enhance the inhibitory effect of azoles on Candida krusei and maintain a longer action time. Conclusion FM is an effective antifungal synergist and can promote the antifungal activity of itraconazole and ketoconazole.

Key words: Candida krusei, biofilm, combination therapy

CLC Number:

R379.4

MA Sheng-yan, ZHOU Xue-zhang. Study on the effect of flunixin meglumine on the biofilm formation of Candida krusei and on the combination with azoles[J]. Chinese Journal of Mycology, 2020, 15(1): 31-36.

References

[1] Zhou ZL, Lin CC, Chu WL, et al. The distribution and drug susceptibilities of clinical Candida species in TSARY 2014[J].Diagn Microbiol Infect Dis, 2016, 86(4):399-404.
[2] Vallabhaneni S, Cleveland AA, Farley MM, et al. Epidemiology and risk factors for echinocandin nonsusceptible Candida glabrata bloodstream infections:data from a large multisite population-based candidemia surveillance program, 2008-2014[J]. Open Forum Infect Dis, 2015, 2(4):ofv163.
[3] Silva S, Negri M, Henriques M, et al. Candida glabrata, Candida parapsilosis and Candida tropicalis:biology, epidemiology, pathogenicity and antifungal resistance[J].FEMS Microbiol Rev, 2012, 36(2):288-305.
[4] Falagas ME, Roussos N, Vardakas KZ. Relative frequency of albicans and the various non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world:a systematic review[J]. Int J Infect Dis, 2010, 14(11):e954-e966.
[5] Sanguinetti M, Posteraro B, Lass-Fl rl C. Antifungal drug resistance among Candida species:mechanisms and clinical impact[J]. Mycoses, 2015, 58(S2):2-13.
[6] Du J, Wang X, Luo H, et al. Epidemiological investigation of non-albicans Candida species recovered from mycotic mastitis of cows in Yinchuan, Ningxia of China[J]. BMC Vet Res, 2018, 14(1):251-260.
[7] 乔祖莎, 冯文莉. 克柔念珠菌对抗真菌药物耐药机制的研究进展[J]. 中国真菌学杂志, 2012, 7(1):55-58.
[8] Yang S, Liao Y, Cong L, et al. In vitro interactions between non-steroidal anti-inflammatory drugs and antifungal agents against planktonic and biofilm forms of Trichosporon asahii[J]. PLoS ONE, 2016, 11(6):e0157047.
[9] Begg LM, Hughes KJ, Kessell A, et al. Successful treatment of cryptococcal pneumonia in a pony mare[J].Aust Vet J, 2010, 82(11):686-692.
[10] Rodríguez-Tudela JL, Barchiesi F, Bille J, et al. Method for the determination of minimum inhibitory concentration (MIC) by broth dilution of fermentative yeasts[J].Clin Microbiol Infect, 2010, 9(8):i-viii.
[11] 王聪, 白丽. 真菌生物膜研究进展[J]. 中国病原生物学杂志, 2010,5(3):218-220.
[12] Alem MAS, L Julia D. Effects of aspirin and other nonsteroidal anti-inflammatory drugs on biofilms and planktonic cells of Candida albicans[J]. Antimicrob Agents Chemother, 2004, 48(1):41-47.
[13] Dalmont K, Biles CL, Konsure H, et al. Nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit the growth and reproduction of Chaetomium globosum and other fungi associated with water-damaged buildings[J]. Mycopathologia, 2017, 182:11-12.
[14] 单奇, 朱新平, 等. 氟尼辛葡甲胺在黄牛血浆、组织液和炎症渗出液中的药动学[J]. 中国兽医学报, 2018, 38(5):1003-1007.
[15] Chapinal N, Fitzpatrick CE, Leslie KE, et al. Short Communication:Automated assessment of the effect of flunixin meglumine on rumination in dairy cows with endotoxin-induced mastitis[J]. CAN J ANIM SCI, 2014, 94(1):21-25.
[16] Liu S, Hou Y, Chen X, et al. Combination of fluconazole with non-antifungal agents:A promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery[J]. Int J Antimicrob Agents, 2014, 43(5):395-402.
[17] Rantala MKL, Välimäki E, et al. Efficacy and pharmacokinetics of enrofloxacin and flunixin meglumine for treatment of cows with experimentally induced Escherichia coli mastitis[J]. J Vet Pharmacol Ther, 2010, 25(4):251-258.
[18] Sofia CDO, Miranda IM, Ana SD, et al. Ibuprofen potentiates the in vivo antifungal activity of fluconazole against Candida albicans murine infection[J]. Antimicrob Agents Chemother, 2015, 59(7):4289-4292.
[19] 李辉. 氟康唑与他克莫司联合抗非白色念珠菌的作用与机制研究[D].济南:山东大学, 2014.