Heterogeneous mechanisms of azole resistance in Candida albicans clinical isolates from an HIV-infected patient on continuous fluconazole therapy for oropharyngeal candidosis
Heterogeneous mechanisms of azole resistance in Candida albicans clinical isolates from an HIV-infected patient on continuous fluconazole therapy for oropharyngeal candidosis
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DOI：
10.1093/jac/49.3.515
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发表时间：
2002-03-01
影响因子：
5.2
通讯作者：
Patterson, TF
中科院分区：
文献类型：
--
作者：
Martínez, M;López-Ribot, JL;Patterson, TF
白念珠菌耐药的分子机制包括靶酶改变和药物外排增加，但具体治疗方案对耐药的影响尚不明确。对1例晚期艾滋病患者连续口服氟康唑(Flu)200 mg/d治疗口咽念珠菌病(OPC)进行纵向研究。在登记时、OPC期间和每季度进行口腔培养以进行监测。这名患者在43个月内因持续流感而5次出现症状复发。虽然随着时间的推移，白色念珠菌分离株的流感MIC增加，但所有OPC病例都成功地通过增加流感剂量进行了治疗。DNA分型技术表明，白念珠菌的一种持久性菌株产生了耐药性。在同一临床样本中，通过多个病例检测到敏感性降低的流感耐药株和同基因分离株。耐药的分子机制分析显示，在流感敏感性降低的分离株中，编码外排泵(但不包括ERG11)的MDR和CDR基因过度表达。此外，还检测到它们的羊毛甾醇去甲基酶中存在G464S氨基酸取代，影响其与流感的亲和力。然而，从相同样本中发现的其他同基因但对流感敏感的分离株没有包含突变，这表明口腔内酵母种群的微进化。在这位患者中，流感持续施加的抗真菌压力导致了多因素耐药性的产生。尽管它们起源于克隆，但不同的白色念珠菌亚群表现出不同的耐药机制，包括ERG11基因同时存在和不存在功能点突变。
Molecular mechanisms of azole resistance in Candida albicans include alterations in the target enzyme and increased efflux of drug, but the impact of specific treatment regimens on resistance has not been established. A patient with advanced AIDS was enrolled in a longitudinal study to receive continuous oral fluconazole (FLU) 200 mg/day for the treatment of oropharyngeal candidosis (OPC). Oral cultures were obtained at time of enrolment, during episodes of OPC and quarterly for surveillance. The patient had five symptomatic relapses on continuous FLU during 43 months. All OPC episodes were successfully treated with increasing doses of FLU although increased FLU MICs were detected for C. albicans isolates with progression of time. DNA-typing techniques demonstrated that resistance developed in a persistent strain of C. albicans. Both FLU-resistant and isogenic isolates with reduced susceptibility were detected in the same clinical samples through multiple episodes. Analysis of molecular mechanisms of resistance revealed overexpression of MDR and CDR genes encoding efflux pumps (but not ERG11) in isolates with decreased FLU susceptibility. In addition, the presence of the G464S amino acid substitution in their lanosterol demethylase, affecting its affinity for FLU, was also detected. However, other isogenic, but FLU-susceptible isolates recovered from the same samples did not harbour the mutation, indicating micro-evolution of yeast populations within the oral cavity. In this patient, the continuous antifungal pressure exerted by FLU resulted in development of resistance of multifactorial nature. Despite their clonal origin, different subpopulations of C. albicans demonstrated distinct resistance mechanisms, including concomitant presence and absence of functional point mutations in ERG11 genes.