Fluconazole and Echinocandin Resistance of Candida glabrata Correlates Better with Antifungal Drug Exposure Rather than with MSH2 Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance.
Fluconazole and Echinocandin Resistance of Candida glabrata Correlates Better with Antifungal Drug Exposure Rather than with MSH2 Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance.
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DOI：
10.3389/fmicb.2016.02038
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发表时间：
2016
影响因子：
5.2
通讯作者：
Alanio A
中科院分区：
文献类型：
--
作者：
Dellière S;Healey K;Gits-Muselli M;Carrara B;Barbaro A;Guigue N;Lecefel C;Touratier S;Desnos-Ollivier M;Perlin DS;Bretagne S;Alanio A
光滑念珠菌是人类的一种主要致病酵母菌，已知对三氮唑和棘球菌素类抗真菌药物迅速产生耐药性。最近，一种导致错配修复缺陷的突变基因(MSH2多态)被认为是导致光滑毛念珠菌临床分离株获得耐药性的原因。我们的目标是评估法国巴黎圣路易斯医院的一大群患者中的抗真菌耐药性的流行率，其中一些患者预先接触过抗真菌药物，并确定MSH2基因多态是否与氟康唑或棘球菌素耐药的增加有关。我们收集了147名患者的268株分离物，以及临床数据和既往的抗真菌暴露情况。检测氟康唑和米卡芬净的最低抑菌浓度(MICs)，进行短串联重复序列基因分型，并对msh2基因进行测序。根据欧洲药物敏感临界点委员会的数据，15.7%的菌株对氟康唑耐药(MIC&>32 mg/L)，0.7%的菌株对米卡芬净耐药(MIC&>0.03 mg/L)。44%的分离株出现MSH2非同义突变，17%的分离株对氟康唑耐药。而无MSH2突变的氟康唑耐药株占15%(P=0.65)。MSH2基因多态与短串联重复序列基因相关。棘球绦虫的耐药率很低，并与先前接触棘球绦虫有关。突变体型与氟康唑耐药增加无关，而是与罕见和特定的基因型别相对应。
Candida glabrata is a major pathogenic yeast in humans that is known to rapidly acquire resistance to triazole and echinocandin antifungal drugs. A mutator genotype (MSH2 polymorphism) inducing a mismatch repair defect has been recently proposed to be responsible for resistance acquisition in C. glabrata clinical isolates. Our objectives were to evaluate the prevalence of antifungal resistance in a large cohort of patients in Saint-Louis hospital, Paris, France, some of whom were pre-exposed to antifungal drugs, as well as to determine whether MSH2 polymorphisms are associated with an increased rate of fluconazole or echinocandin resistance. We collected 268 isolates from 147 patients along with clinical data and previous antifungal exposure. Fluconazole and micafungin minimal inhibition concentrations (MICs) were tested, short tandem repeat genotyping was performed, and the MSH2 gene was sequenced. According to the European Committee on Antimicrobial Susceptibility breakpoints, 15.7% of isolates were resistant to fluconazole (MIC > 32 mg/L) and 0.7% were resistant to micafungin (MIC > 0.03 mg/L). A non-synonymous mutation within MSH2 occurred in 44% of the isolates, and 17% were fluconazole resistant. In comparison, fluconazole resistant isolates with no MSH2 mutation represented 15% (P = 0.65). MSH2 polymorphisms were associated with the short tandem repeat genotype. The rate of echinocandin resistance is low and correlates with prior exposure to echinocandin. The mutator genotype was not associated with enrichment in fluconazole resistance but instead corresponded to rare and specific genotypes.