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侵袭性念珠菌病(invasive candidiasis)是院内血液感染的第四大原因[1]。由于各类疾病导致的免疫力低下病人增多,光滑念珠菌(Candida glabrata)的感染率逐年递增,引起败血症的数量也随之增加。除白念珠菌外,光滑念珠菌已成为部分国家和地区侵袭性感染中第二常见的念珠菌种类[2]。光滑念珠菌是一种条件致病菌,它广泛存在于自然界,也在人体皮肤黏膜、消化道寄生。当人体免疫功能降低或皮肤黏膜环境发生改变时,光滑念珠菌即可大量繁殖,引起深部脏器感染。与其他念珠菌相比,光滑念珠菌对于抗真菌药物显著耐受[3],它可以在抗真菌治疗过程中迅速产生耐药性,最终导致治疗失败[4-5]。我国侵袭性真菌耐药监测网(CHIF-NET)2020年统计结果显示,临床常用抗真菌药物氟康唑和伏立康唑对光滑念珠菌的最低抑菌浓度(MIC90)分别32 μg/ml和1 μg/ml。目前治疗光滑念珠菌的药物主要包括广谱三唑类、棘白菌素类以及多烯类抗真菌药。本文对光滑念珠菌的耐药机制进行综述。
Research progress on drug resistance mechanism of Candida glabrata
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摘要: 随着念珠菌病患者中感染光滑念珠菌的比例逐年增加,光滑念珠菌已成为除白念珠菌、热带念珠菌外较为常见的致病念珠菌之一。抗光滑念珠菌的药物种类有限,随之而来的耐药问题日益严重,为临床治疗带来困难。本文综述了光滑念珠菌对唑类、棘白菌素类及多烯类药物的耐药机制。Abstract: With the increasing proportion of Candida glabrata in patients with candidiasis, C. glabrata has become one of the most common pathogenic Candida in clinical practice. There are limited types of antifungal drugs, and the consequent problem of drug resistance is severely increasing, which brings difficulties to clinical treatment. The resistance mechanisms of C. glabrata to azoles, echinocandins and polyenes were reviewed in this paper.
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Key words:
- Candida glabrata /
- azole /
- echinocandin /
- polyene /
- drug resistance
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[1] GRABOWSKI R, DUGAN E. Disseminated candidiasis in a patient with acute myelogenous leukemia[J]. Cutis,2003,71(6):466-468. [2] ARASTEHFAR A, LASS-FLÖRL C, GARCIA-RUBIO R, et al. The quiet and underappreciated rise of drug-resistant invasive fungal pathogens[J]. JoF,2020,6(3):138. doi: 10.3390/jof6030138 [3] HEALEY K R, PERLIN D S. Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata[J]. J Fungi (Basel),2018,4(3):105. doi: 10.3390/jof4030105 [4] GROSSET M, DESNOS-OLLIVIER M, GODET C, et al. Recurrent episodes of Candidemia due to Candida glabrata, Candida tropicalis and Candida albicans with acquired echinocandin resistance[J]. Med Mycol Case Rep,2016,14:20-23. doi: 10.1016/j.mmcr.2016.12.004 [5] WON E J, CHOI M J, KIM M N, et al. Fluconazole-resistant Candida glabrata bloodstream isolates, south Korea, 2008-2018[J]. Emerg Infect Dis,2021,27(3):779-788. doi: 10.3201/eid2703.203482 [6] HULL C M, PARKER J E, BADER O, et al. Facultative sterol uptake in an ergosterol-deficient clinical isolate of Candida glabrata harboring a missense mutation in ERG11 and exhibiting cross-resistance to azoles and amphotericin B[J]. Antimicrob Agents Chemother,2012,56(8):4223-4232. doi: 10.1128/AAC.06253-11 [7] TEO J Q M, LEE S J Y, TAN A L, et al. Molecular mechanisms of azole resistance in Candida bloodstream isolates[J]. BMC Infect Dis,2019,19(1):63. doi: 10.1186/s12879-019-3672-5 [8] PAIS P, CALIFÓRNIA R, GALOCHA M, et al. Candida glabrata transcription factor Rpn4 mediates fluconazole resistance through regulation of ergosterol biosynthesis and plasma membrane permeability[J]. Antimicrob Agents Chemother,2020,64(9):e00554-e00520. [9] VU B G, STAMNES M A, LI Y, et al. The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways[J]. PLoS Genet,2021,17(9):e1009582. doi: 10.1371/journal.pgen.1009582 [10] WANG Q Q, LI Y, CAI X, et al. Two sequential clinical isolates of Candida glabrata with multidrug-resistance to posaconazole and echinocandins[J]. Antibiotics (Basel),2021,10(10):1217. doi: 10.3390/antibiotics10101217 [11] LI Q Q, TSAI H F, MANDAL A, et al. Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress[J]. Mol Med Rep,2018,17(5):6585-6597. [12] WHALEY S G, ZHANG Q, CAUDLE K E, et al. Relative contribution of the ABC transporters Cdr1, Pdh1, and Snq2 to azole resistance in Candida glabrata[J]. Antimicrob Agents Chemother,2018,62(10):e01070-e01018. [13] YAO D T, CHEN J, CHEN W Q, et al. Mechanisms of azole resistance in clinical isolates of Candida glabrata from two hospitals in China[J]. Infect Drug Resist,2019,12:771-781. doi: 10.2147/IDR.S202058 [14] KHAKHINA S, SIMONICOVA L, MOYE-ROWLEY W S. Positive autoregulation and repression of transactivation are key regulatory features of the Candida glabrata Pdr1 transcription factor[J]. Mol Microbiol,2018,107(6):747-764. doi: 10.1111/mmi.13913 [15] HOU X, XIAO M, WANG H, et al. Profiling of PDR1 and MSH2 in Candida glabrata bloodstream isolates from a multicenter study in China[J]. Antimicrob Agents Chemother,2018,62(6):e00153-e00118. [16] HEALEY K R, ZHAO Y N, PEREZ W B, et al. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance[J]. Nat Commun,2016,7:11128. doi: 10.1038/ncomms11128 [17] BORDALLO-CARDONA M Á, AGNELLI C, GÓMEZ-NUÑEZ A, et al. MSH2 gene point mutations are not antifungal resistance markers in Candida glabrata[J]. Antimicrob Agents Chemother,2018,63(1):e01876-e01818. [18] AL-BAQSAMI Z F, AHMAD S, KHAN Z. Antifungal drug susceptibility, molecular basis of resistance to echinocandins and molecular epidemiology of fluconazole resistance among clinical Candida glabrata isolates in Kuwait[J]. Sci Rep,2020,10(1):6238. doi: 10.1038/s41598-020-63240-z [19] PHAM C D, IQBAL N, BOLDEN C B, et al. Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance[J]. Antimicrob Agents Chemother,2014,58(8):4690-4696. doi: 10.1128/AAC.03255-14 [20] BELENKY P, CAMACHO D, COLLINS J J. Fungicidal drugs induce a common oxidative-damage cellular death pathway[J]. Cell Rep,2013,3(2):350-358. doi: 10.1016/j.celrep.2012.12.021 [21] AHMAD S, JOSEPH L, PARKER J E, et al. ERG6 and ERG2 are major targets conferring reduced susceptibility to amphotericin B in clinical Candida glabrata isolates in Kuwait[J]. Antimicrob Agents Chemother,2019,63(2):e01900-e01918. [22] VANDEPUTTE P, TRONCHIN G, BERGÈS T, et al. Reduced susceptibility to polyenes associated with a missense mutation in the ERG6 gene in a clinical isolate of Candida glabrata with pseudohyphal growth[J]. Antimicrob Agents Chemother,2007,51(3):982-990. doi: 10.1128/AAC.01510-06 [23] VANDEPUTTE P, TRONCHIN G, LARCHER G, et al. A nonsense mutation in the ERG6 gene leads to reduced susceptibility to polyenes in a clinical isolate of Candida glabrata[J]. Antimicrob Agents Chemother,2008,52(10):3701-3709. doi: 10.1128/AAC.00423-08 [24] CANTURK Z. Evaluation of synergistic anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans[J]. J Food Drug Anal,2018,26(1):439-443. doi: 10.1016/j.jfda.2016.12.014 [25] SHARIFZADEH A, KHOSRAVI A R, SHOKRI H, et al. Synergistic anticandidal activity of menthol in combination with itraconazole and nystatin against clinical Candida glabrata and Candida krusei isolates[J]. Microb Pathog,2017,107:390-396. doi: 10.1016/j.micpath.2017.04.021 [26] SHARIFZADEH A, KHOSRAVI A R, SHOKRI H, et al. Potential effect of 2-isopropyl-5-methylphenol (thymol) alone and in combination with fluconazole against clinical isolates of Candida albicans, C. glabrata and C. krusei[J]. J De Mycol Médicale,2018,28(2):294-299. [27] HOOPER R W, ASHCRAFT D S, PANKEY G A. In vitro synergy with fluconazole plus doxycycline or tigecycline against clinical Candida glabrata isolates[J]. Med Mycol,2019,57(1):122-126. doi: 10.1093/mmy/myy008 [28] MORAES R C, CARVALHO A R, DALLA LANA A J, et al. In vitro synergism of a water insoluble fraction of Uncaria tomentosa combined with fluconazole and terbinafine against resistant non-Candida albicans isolates[J]. Pharm Biol,2017,55(1):406-415. doi: 10.1080/13880209.2016.1242631 [29] DAS P E, MAJDALAWIEH A F, ABU-YOUSEF I A, et al. Use of A hydroalcoholic extract of Moringa oleifera leaves for the green synthesis of bismuth nanoparticles and evaluation of their anti-microbial and antioxidant activities[J]. Materials (Basel),2020,13(4):876. doi: 10.3390/ma13040876 [30] LAZIĆ J, AJDAČIĆ V, VOJNOVIC S, et al. Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction[J]. Appl Microbiol Biotechnol,2018,102(4):1889-1901. doi: 10.1007/s00253-018-8749-3
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