中国真菌学杂志 2023, Vol. 18 Issue (4): 370-376.
宋晓婷, 赵作涛, 王爱平
收稿日期:
2022-04-05
出版日期:
2023-08-28
发布日期:
2023-09-02
通讯作者:
王爱平,E-mail:wangap516@163.com
E-mail:wangap516@163.com
作者简介:
宋晓婷,女(汉族),博士研究生在读.E-mail:songxiaoting1996@163.com
基金资助:
Received:
2022-04-05
Online:
2023-08-28
Published:
2023-09-02
摘要: 该文就新型系统抗真菌药物(包括rezafungin、ibrexafungerp、fosmanogepix、olorofim、opelconazole和oteseconazole)的作用机制、药效学、药代动力学和临床研究进行综述。
中图分类号:
宋晓婷, 赵作涛, 王爱平. 新型系统性抗真菌药物研究进展[J]. 中国真菌学杂志, 2023, 18(4): 370-376.
[1] STEWART A G, PATERSON D L. How urgent is the need for new antifungals[J]. Expert Opin Pharmacother, 2021, 22(14):1857-1870. [2] ARASTEHFAR A, DE ALMEIDA JÚNIOR J N, PERLIN D S, et al. Multidrug-resistant Trichosporon species: Underestimated fungal pathogens posing imminent threats in clinical settings[J]. Crit Rev Microbiol, 2021, 47(6):679-698. [3] LAMOTH F, GLAMPEDAKIS E, BOILLAT-BLANCO N, et al. Incidence of invasive pulmonary aspergillosis among critically ill COVID-19 patients[J]. Clin Microbiol Infect, 2020, 26(12):1706-1708. [4] BARTOLETTI M, PASCALE R, CRICCA M, et al. Epidemiology of invasive pulmonary aspergillosis among intubated patients with COVID-19: A prospective study[J]. Clin Infect Dis, 2021, 73(11):e3606-e3614. [5] JAMES K D, LAUDEMAN C P, MALKAR N B, et al. Structure-activity relationships of a series of echinocandins and the discovery of CD101, a highly stable and soluble echinocandin with distinctive pharmacokinetic properties[J]. Antimicrob Agents Chemother, 2017, 61(2):e01541-01516. [6] PFALLER M A, MESSER S A, RHOMBERG P R, et al. Activity of a long-acting echinocandin, CD101, determined using CLSI and EUCAST reference methods, against Candida and Aspergillus spp., including echinocandin- and azole-resistant isolates[J]. J Antimicrob Chemother, 2016, 71(10):2868-2873. [7] WIEDERHOLD N P, LOCKE J B, DARUWALA P, et al. Rezafungin (CD101) demonstrates potent in vitro activity against Aspergillus, including azole-resistant Aspergillus fumigatus isolates and cryptic species[J]. J Antimicrob Chemother, 2018, 73(11):3063-3067. [8] MIESEL L, CUSHION MT, ASHBAUGH A, et al. Efficacy of rezafungin in prophylactic mouse models of invasive candidiasis, aspergillosis, and Pneumocystis pneumonia[J]. Antimicrob Agents Chemother, 2021, 65(3):e01992-20. [9] SANDISON T, ONG V, LEE J, et al. Safety and pharmacokinetics of CD101Ⅳ, a novel echinocandin, in healthy adults[J]. Antimicrob Agents Chemother, 2017, 61(2):e01627-01616. [10] ONG V, HOUGH G, SCHLOSSER M, et al. Preclinical evaluation of the stability, safety, and efficacy of CD101, a novel echinocandin[J]. Antimicrob Agents Chemother, 2016, 60(11):6872-6879. [11] THOMPSON G R, SORIANO A, SKOUTELIS A, et al. Rezafungin versus caspofungin in a phase 2, randomized, double-blind study for the treatment of candidemia and invasive candidiasis: The strive trial[J]. Clin Infect Dis,2021, 73(11):e3647-e3655. [12] JIMéNEZ-ORTIGOSA C, PEREZ W B, ANGULO D, et al. De novo acquisition of resistance to SCY-078 in Candida glabrata involves FKS mutations that both overlap and are distinct from those conferring echinocandin resistance[J]. Antimicrob Agents Chemother,2017, 61(9):e00833-17. [13] LAMOTH F, ALEXANDER B D. Antifungal activities of SCY-078(MK-3118) and standard antifungal agents against clinical non-Aspergillus mold isolates[J]. Antimicrob Agents Chemother,2015, 59(7):4308-4311. [14] DAVIS M R, DONNELLEY M A, THOMPSON G R. Ibrexafungerp: A novel oral glucan synthase inhibitor[J]. Med Mycol,2020, 58(5):579-592. [15] WRING S, BORROTO-ESODA K, SOLON E, et al.SCY-078, a novel fungicidal agent, demonstrates distribution to tissues associated with fungal infections during mass balance studies with intravenous and oral SCY-078 in albino and pigmented rats[J]. Antimicrob Agents Chemother,2019, 63(2):e02119-02118. [16] WRING S, MURPHY G, ATIEE G, et al. Clinical pharmacokinetics and drug-drug interaction potential for coadministered SCY-078, an oral fungicidal glucan synthase inhibitor, and tacrolimus[J]. Clin Pharmacol Drug Dev,2019, 8(1):60-69. [17] SPEC A, PULLMAN J, THOMPSON G R, et al. MSG-10: A phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis[J]. J Antimicrob Chemother,2019, 74(10):3056-3062. [18] ALEXANDER B D,Cornely O, PAPPAS P, et al. Effcacy and safety of oral ibrexafungerp in 41 patients with refractory fungal diseases, interim analysis of a phase 3 open-label study (FURI)[J]. Open Forum Infect Dis, 2020, 7(Suppl 1):S642. [19] HOENIGL M CO, KOEHLER P, PAPPAS P G, et al. Outcomes of oral ibrexafungerp in 33 patients with refractory fungal diseases, interim analysis of a phase 3 open-label study (FURI)[C]//31st ECCMID. Vienna:2021. [20] AZIE ND, ROSS C, BREEDT J, et al. Outcomes of oral ibrexafungerp in the treatment of ten patients with candida auris infections, from the cares study[C]//31st ECCMID. Vienna:2021. [21] HELOU S,ANGULO D. A multicenter, randomized, evaluator blinded, active-controlled study to evaluate the safety and efficacy of oral SCY-078vs. oral fuconazole in 96 subjects with moderate to severe vulvovaginal candidiasis[J]. Am J Obstet Gynecol,2017, 217(6):720-721. [22] SCHWEBKE J R, SOBEL R, GERSTEN J K, et al. Ibrexafungerp versus placebo for vulvovaginal candidiasis treatment: A phase 3, randomized, controlled superiority trial (vanish 303)[J]. Clin Infect Dis,2022, 74(11):1979-1985. [23] SOBEL R, NYIRJESY P, GHANNOUM M A, et al. Efficacy and safety of oral ibrexafungerp for the treatment of acute vulvovaginal candidiasis: A global phase 3, randomised, placebo-controlled superiority study (vanish 306)[J]. Bjog,2022, 129(3):412-420. [24] MURPHY G,DARPO B, MARBURY T. Lack of an effect of SCY-078 a novel antifungal agent on QTc interval in healthy subjects[C]//ASM Microbe. New Orleans:2017. [25] MIYAZAKI M, HORII T, HATA K, et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds[J]. Antimicrob Agents Chemother,2011, 55(10):4652-4658. [26] ZHAO Y, LEE M H, PADERU P, et al. Significantly improved pharmacokinetics enhances in vivo efficacy of APX001 against echinocandin- and multidrug-resistant Candida isolates in a mouse model of invasive candidiasis[J]. Antimicrob Agents Chemother,2018, 62(10):e00425-00418. [27] HAGER C L, LARKIN E L, LONG L, et al. In vitro and in vivo evaluation of the antifungal activity of APX001A/APX001 against Candida auris[J]. Antimicrob Agents Chemother,2018, 62(3):e02319-17. [28] ZHAO M, LEPAK A J, MARCHILLO K, et al. APX001 pharmacokinetic/pharmacodynamic target determination against aspergillus fumigatus in an in vivo model of invasive pulmonary aspergillosis[J]. Antimicrob Agents Chemother,2019, 63(4):e02372-02318. [29] VIRIYAKOSOL S, KAPOOR M, OKAMOTO S, et al.APX001 and other gwt1 inhibitor prodrugs are effective in experimental Coccidioides immitis pneumonia[J]. Antimicrob Agents Chemother,2019, 63(2):e01715-01718. [30] CASTANHEIRA M, DUNCANSON F P, DIEKEMA D J, et al. Activities of E1210 and comparator agents tested by CLSI and EUCAST broth microdilution methods against Fusarium and Scedosporium species identified using molecular methods[J]. Antimicrob Agents Chemother,2012, 56(1):352-357. [31] RIVERO-MENENDEZ O, CUENCA-ESTRELLA M, ALASTRUEY-IZQUIERDO A. In vitro activity of APX001A against rare moulds using eucast and CLSI methodologies[J]. J Antimicrob Chemother,2019, 74(5):1295-1299. [32] GEBREMARIAM T, ALKHAZRAJI S, ALQARIHI A, et al. Fosmanogepix (APX001) is effective in the treatment of pulmonary murine mucormycosis due to Rhizopus arrhizus[J]. Antimicrob Agents Chemother,2020, 64(6):e00178-00120. [33] ZHAO M, LEPAK A J, VANSCOY B, et al. In vivo pharmacokinetics and pharmacodynamics of APX001 against Candida spp. In a neutropenic disseminated candidiasis mouse model[J]. Antimicrob Agents Chemother,2018, 62(4):e02542-02517. [34] PFALLER M A, HUBAND M D, FLAMM R K, et al. In vitro activity of APX001A (manogepix) and comparator agents against 1,706 fungal isolates collected during an international surveillance program in 2017[J]. Antimicrob Agents Chemother,2019, 63(8):e00840-00819. [35] ARENDRUP M C, CHOWDHARY A, JØRGENSEN K M, et al. Manogepix (APX001A) in vitro activity against Candida auris: Head-to-head comparison of EUCAST and CLSI MICs[J]. Antimicrob Agents Chemother, 2020, 64(10):e00656-00620. [36] BERKOW E L, LOCKHART S R. Activity of novel antifungal compound APX001A against a large collection of Candida auris[J]. J Antimicrob Chemother,2018, 73(11):3060-3062. [37] ZHU Y, KILBURN S, KAPOOR M, et al. In vitro activity of manogepix against multidrug-resistant and panresistant Candida auris from the New York outbreak[J]. Antimicrob Agents Chemother,2020, 64(11):e01124-01120. [38] HODGES M R, OPLE E, SHAW K J, et al. Phase 1 study to assess safety, tolerability and pharmacokinetics of single and multiple oral doses of APX001 and to investigate the effect of food on APX001 bioavailability[J].Open Forum Infect Dis,2017, 4(Suppl_1):S534. [39] PAPPAS P, KULLBERG B J, VAZQUEZ J A, et al. Clinical safety and efficacy of novel antifungal, fosmanogepix, in the treatment of candidemia: Results from a phase 2 proof of concept trial [J].Open Forum Infect Dis, 2020, 7(Suppl 1): S203-S204. [40] BULPA P, RAHAV G, OREN I, et al.Clinical safety, efficacy, and pharmacokinetics of fosmanogepix, a novel first-in-class antifungal, in patients with renal insufficiency: subset analysis from a phase 2 candidemia trial [J].Open Forum Infect Dis, 2020, 7(Suppl 1): S605. [41] KULLBERG B B, PAPPAS L, VAZQUEZ P G, et al. Clinical efficacy and safety of the novel antifungal fosmanogepix in patients with candidaemia and/or invasive can- didiasis caused by Candida auris: results from a phase II proof of concept trial[C]//31st ECCMID. Vienna:2021. [42] OLIVER J D, SIBLEY G E M, BECKMANN N, et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase[J]. Proc Natl Acad Sci U S A,2016, 113(45):12809-12814. [43] WIEDERHOLD N P. Review of the novel investigational antifungal olorofim[J]. J Fungi (Basel),2020, 6(3):122. [44] ZHANG J, LIU H, XI L, et al. Antifungal susceptibility profiles of olorofim (formerly F901318) and currently available systemic antifungals against mold and yeast phases of Talaromyces marneffei[J]. Antimicrob Agents Chemother,2021, 65(6):e00256-00221. [45] LIM W, EADIE K, KONINGS M, et al. Madurella mycetomatis, the main causative agent of eumycetoma, is highly susceptible to olorofim[J]. J Antimicrob Chemother,2020, 75(4):936-941. [46] SINGH A, SINGH P, MEIS J F, et al. In vitro activity of the novel antifungal olorofim against dermatophytes and opportunistic moulds including Penicillium and Talaromyces species[J]. J Antimicrob Chemother, 2021, 76(5): 1229-1233. [47] SU H, ZHU M, TSUI C K, et al. Potency of olorofim (f901318) compared to contemporary antifungal agents against clinical Aspergillus fumigatus isolates, and review of azole resistance phenotype and genotype epidemiology in China[J]. Antimicrob Agents Chemother,2021, 65(5):e02546-02520. [48] BUIL J B, RIJS A, MEIS J F, et al. In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates[J]. J Antimicrob Chemother,2017, 72(9):2548-2552. [49] COLLEY T, ALANIO A, KELLY S L, et al. In vitro and in vivo antifungal profile of a novel and long-acting inhaled azole, PC945, on Aspergillus fumigatus infection[J]. Antimicrob Agents Chemother,2017, 61(5):e02280-02216. [50] RUDRAMURTHY S M, COLLEY T, ABDOLRASOULI A, et al. In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris[J]. J Antimicrob Chemother,2019, 74(10):2943-2949. [51] CASS L, MURRAY A, DAVIS A, et al. Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent[J]. Pharmacol Res Perspect,2021, 9(1):e00690. [52] KIMURA G, NAKAOKI T, COLLEY T, et al. In vivo biomarker analysis of the effects of intranasally dosed PC945, a novel antifungal triazole, on Aspergillus fumigatus infection in immunocompromised mice[J]. Antimicrob Agents Chemother,2017, 61(9):e00124-00117. [53] YATES C M, GARVEY E P, SHAVER S R, et al. Design and optimization of highly-selective, broad spectrum fungal CYP51 inhibitors[J]. Bioorg Med Chem Lett,2017, 27(15):3243-3248. [54] SCHELL W A, JONES A M, GARVEY E P, et al. Fungal cyp51 inhibitors VT-1161 and VT-1129 exhibit strong in vitro activity against Candida glabrata and C. krusei isolates clinically resistant to azole and echinocandin antifungal compounds[J]. Antimicrob Agents Chemother,2017, 61(3):e01817-01816. [55] NISHIMOTO A T, WIEDERHOLD N P, FLOWERS S A, et al. In vitro activities of the novel investigational tetrazoles VT-1161 and VT-1598 compared to the triazole antifungals against azole-resistant strains and clinical isolates of Candida albicans[J]. Antimicrob Agents Chemother,2019, 63(6):e00341-00319. [56] SHUBITZ L F, TRINH H T, GALGIANI J N, et al. Evaluation of VT-1161 for treatment of coccidioidomycosis in murine infection models[J]. Antimicrob Agents Chemother,2015, 59(12):7249-7254. [57] GEBREMARIAM T, ALKHAZRAJI S, LIN L, et al. Prophylactic treatment withVT-1161 protects immunosuppressed mice from Rhizopus arrhizus var. arrhizus infection[J]. Antimicrob Agents Chemother,2017, 61(9):e00390-00317. [58] BRAND S R, DEGENHARDT T P, PERSON K, et al. A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis[J]. Am J Obstet Gynecol,2018, 218(6):624. [59] ELEWSKI B, BRAND S, DEGENHARDT T, et al. A phaseⅡ, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of VT-1161 oral tablets in the treatment of patients with distal and lateral subungual onychomycosis of the toenail[J]. Br J Dermatol,2021, 184(2):270-280. |
[1] | 邓劲, 殷琳, 江海燕, 旷凌寒, 彭溪, 杨向贵, 倪苏娇, 张帮勤, 冯金芳, 王燕玲, 马瑜珊, 陈宗耀, 钟涵宇, 吴贤丽, 黎昆, 王玲, 高伟, 杨学强, 朱军, 陈喻, 张弦, 孙昌君, 罗军, 李玉梅, 李彦, 张兵, 谢宁, 王俊, 谢轶, 康梅. 2019—2021年四川省血流感染病原真菌分布特征及药敏分析[J]. 中国真菌学杂志, 2023, 18(3): 198-204,210. |
[2] | 赵旭初, 胡爱玲. 新型广谱唑类抗真菌药艾沙康唑的研究进展[J]. 中国真菌学杂志, 2023, 18(3): 265-269. |
[3] | 方婷婷, 何伊能, 王慧, 傅宏阳, 李园园, 曹毅, 陶茂灿. 浅部真菌病治疗中存在的问题及中医治疗对策[J]. 中国真菌学杂志, 2023, 18(1): 38-41. |
[4] | 吴雨娴, 张旺喆麒, 徐洋, 柴晓云. 基于抗真菌药物的近红外荧光探针研究进展[J]. 中国真菌学杂志, 2022, 17(5): 431-434. |
[5] | 杨之辉, 李若瑜. 浅部真菌感染中的抗真菌药物治疗进展[J]. 中国真菌学杂志, 2022, 17(4): 339-348. |
[6] | 高路, 吕权真, 甄诚, 阎澜, 姜远英. 化学基因组学在抗真菌药物研究中的应用[J]. 中国真菌学杂志, 2022, 17(3): 235-240. |
[7] | 肖湘. 泌尿系念珠菌感染的抗真菌药物合理选用[J]. 中国真菌学杂志, 2022, 17(3): 241-243,264. |
[8] | 唐人杰, 王瑞娜, 王智, 刘海燕, 刘旭, 李红磊, 刘佳存, 张大志, 阎澜. 某院校学员浅部真菌病调查分析[J]. 中国真菌学杂志, 2022, 17(2): 120-123. |
[9] | 王会伟, 姜伟伟, 徐媛, 李颖芳, 李航, 朱信霖, 陈天杨, 王启龙, 陈敏, 潘炜华, 廖万清. 中国大陆地区Fonsecaea临床分离株的体外抗真菌药物敏感性特征[J]. 中国真菌学杂志, 2022, 17(2): 132-136. |
[10] | 郁谨菡, 赵颖, 徐英春. 机会性致病真菌解脂耶氏酵母研究进展[J]. 中国真菌学杂志, 2022, 17(2): 168-172. |
[11] | 陈雪雯, 陈裕充, 温海. 部分新型外用唑类抗真菌药物治疗浅部真菌病的研究进展[J]. 中国真菌学杂志, 2022, 17(1): 55-58. |
[12] | 康烨, 王瑞娜, 阎澜. 抗真菌药物潜在靶点及化合物研究进展[J]. 中国真菌学杂志, 2021, 16(6): 414-419. |
[13] | 徐灵玲, 曾章锐, 丁银环, 杨葵. 川南地区侵袭性念珠菌感染流行病学及耐药性分析[J]. 中国真菌学杂志, 2021, 16(5): 319-325. |
[14] | 谭静文, 高志琴, 杨虹, 杨连娟. 国产泊沙康唑对生殖器来源念珠菌的体外药物敏感性研究[J]. 中国真菌学杂志, 2021, 16(5): 326-329,334. |
[15] | 张欠欠, 罗传玉, 陈嘉琪, 封小川. 白念珠菌感染现状及抗真菌药物研究进展[J]. 中国真菌学杂志, 2021, 16(5): 356-360. |
阅读次数 | ||||||
全文 |
|
|||||
摘要 |
|
|||||